Safety and e1 TheHealth Care Quality of
David W. Bates
The safety and quality of care are two of the central dimensions of health care. It is increasingly clear that both could be much better, and in recent years it has become easier to measure both safety and quality. In addition, the public is—with good justification—demanding measurement and accountability, and increasingly payment for services will be based on performance in these areas. Thus, physicians must learn about these two domains, how they can be improved, and the relative strengths and limitations of our current ability to measure them. Safety and quality are closely related but do not completely overlap. The Institute of Medicine has suggested in a seminal series of reports that safety is the first part of quality, and that health care first must guarantee that it will deliver safe care, although quality is also pivotal. In the end, it is likely that more net clinical benefit may be derived from improving quality than safety, though both are important, and safety is in many ways more tangible to the public. Accordingly, the first section of this chapter will address issues relating to the safety of care, while the second will cover quality of care. SAFETY IN HEALTH CARE Safety Theory Safety theory clearly points out that individuals make errors all the time. Think of driving home from the hospital; you intend to stop and pick up a quart of milk on your way home, but you find yourself entering your driveway, without realizing how you got there. We all use low-level, semi-automatic behavior for many of our activities in daily life; this kind of error is called a “slip.” Slips occur often during care delivery; e.g., when someone intends to write an order but forgets because they have to complete another action first. “Mistakes,” by contrast, are errors of a higher level; they occur in new or non-stereotypic situations in which conscious decisions are being made. An example would be in dosing a medication with which the physician is not familiar. The strategies used to prevent slips and mistakes are often different. Another theory relating to errors is human factors theory, which describes how activities are carried out and offers a variety of insights into how to make them safer and more reliable. Systems theory suggests that most accidents occur as the result of a series of small failures, which happen to line up in an individual instance such that an accident can occur (Fig. e1-1). It also suggests that most individuals in an industry such as health care are trying to do the right thing (e.g., deliver safe care), and most accidents can be seen as the result of defects in the systems. Correspondingly, systems should be designed both to make errors less likely and to identify those that do occur, as some inevitably will. Factors That Increase the Likelihood of Errors A number of factors ubiquitous in health care systems can increase the likelihood of errors, including fatigue, stress, interruptions, complexity, and transitions. The effects of fatigue in other industries are clear, but its effects in health care have until recently been more controversial. For example, the accident rate in truck drivers increases dramatically if they work over a certain number of hours in a week, and especially with prolonged shifts. A recent study of house officers in the intensive care unit demonstrated that they were about one-third more likely to make errors when they were on a 24-h shift than when they were on a schedule that allowed them to sleep 8 h the previous night. The American College of Graduate Medical Education (ACGME) has moved to address this issue by putting in place the 80-h work week. While this is a step forward, it does not address the most important cause of fatigue-related errors, i.e., extended-duty shifts. High levels of stress and workload can also increase error rates. Thus, in extremely high-pressure situations, such as cardiac arrests, errors are more likely to occur. Strategies
e1
Hazards Some holes due to active failures
CHAPTER e1
The Safety and Quality of Health Care
Other holes due to latent conditions (resident "pathogens") Losses Succesive layers of defenses, barriers and safeguards
FIGURE e1-1 “Swiss cheese” diagram. Reason has argued that most accidents occur when a series of “latent failures” in a system are present, and that they happen to line up in a given instance, resulting in an accident. Examples of latent failures in the case of a fall might be that the unit was unusually busy that day, and that the floor happened to be wet. (Adapted from J Reason: Human error: Models and management. BMJ 320:768–770, 2000; with permission.) such as using protocols in these settings can be helpful, as can simply recognizing that the situation is stressful. Interruptions also increase the likelihood of error and are frequent in health care delivery. It is common to forget to complete an action when one is interrupted partway through it by a page, for example. Approaches that may be helpful in this area include minimizing the use of interruptions and setting up tools that help define the urgency of the interruption. In addition, complexity represents a key issue that contributes to errors. Providers are confronted by streams of data, such as laboratory tests and vital signs, many of which provide little useful information, but some of which are important and require action or suggest a specific diagnosis. Tools that emphasize specific abnormalities or combinations of abnormalities may be helpful in this area. Transitions between providers and settings are also frequent in health care, even more so with the advent of the 80-h work week, and generally represent vulnerabilities. Tools that provide structure in exchanging information, e.g., when transferring care between providers, may be helpful. The Frequency of Adverse Events in Health Care Most of the large studies focusing on the frequency and consequences of adverse events have been performed in the inpatient setting; some data are available for nursing homes, and much less information is available in the outpatient setting. The Harvard Medical Practice Study was one of the largest studies to address this issue, and was performed with hospitalized patients in New York. The primary outcome was the adverse event, which is an injury caused by medical management, rather than the patient’s underlying disease. In this study, an event either resulted in death or disability at discharge, or prolonged the length of stay by at least 2 days. Key findings were that the adverse event rate was 3.7%, and 58% of adverse events were considered preventable. Although there was some concern that New York is not representative of the rest of the country, the study was replicated later in Colorado and Utah, where the rates were essentially similar. Since then, other studies have been performed in a variety of developed nations using analogous methodologies, and the rates in most countries appear to be ~10%. In the Medical Practice Study, adverse drug events (ADEs) were the most frequent type, accounting for 19% of adverse events, followed by wound infections (14%) and technical complications (13%). Almost half of the adverse events were associated with a surgical procedure. Among the nonoperative events, 37% were ADEs, 15% were diagnostic mishaps, 14% were therapeutic mishaps, 13% were procedurerelated, and 5% were falls. ADEs have been studied more than any other category. Studies focusing specifically on ADEs have found that they appear to be much
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e2 more frequent than was suggested by the Medical Practice Study, although most other studies use more inclusive criteria. Detection approaches in the research setting include chart review and use of a computerized ADE monitor, which is a tool that explores the database and identifies signals that suggest an ADE may have occurred. Studies that use multiple approaches find more ADEs than any individual approach, suggesting that the true underlying rate in the population is higher than would be identified by any individual approach. About 6– 10% of patients admitted in U.S. hospitals suffer an ADE. Injuries caused by drugs are also frequent in the outpatient setting. One study found a rate of 21 ADEs per every 100 patients per year when patients were called to assess whether or not they had had a problem with one of their medications. The severity level was lower than in the inpatient setting, but approximately one-third of the ADEs were preventable. Another area that appears to be very risky is the period immediately after the patient is discharged from the hospital. One recent study of patients hospitalized on a medical service found an adverse event rate of 19%; about a third of these were preventable, and another third were ameliorable in that they could have been made less severe. ADEs were the single leading category. Prevention Strategies Most of the work on adverse event prevention strategies has targeted specific types of adverse events in the inpatient setting, with ADEs and nosocomial infections having received the most attention. For ADEs, several strategies have been found to reduce the medication error rate, although it has been harder to demonstrate that they reduce the ADE rate, and studies with adequate power to demonstrate a clinically meaningful reduction have not been published as yet. Computerized physician order entry (CPOE) linked with clinical decision support has been found to reduce the serious medication error rate—serious medication errors are those that harm someone or have the potential to do so. In one study, CPOE, even with limited decision support, decreased the serious medication error rate by 55%. CPOE can prevent medication errors by suggesting a default dose, ensuring that all orders are complete (e.g., include a dose, route, and frequency), and checking orders for allergies, drug-drug interactions, and drug-laboratory issues. In addition, clinical decision support can suggest the right dose for the patient, tailoring it to the patient’s level of renal function and age. In one study, without decision support patients with renal insufficiency received the appropriate dose only one-third of the time, while this fraction increased to approximately two-thirds with decision support, and patients with renal insufficiency were discharged from the hospital one-half day earlier. As of 2006, only about 15% of U.S. hospitals had implemented CPOE, but many more have plans to do so. Another technology that can improve medication safety is bar-coding linked with an electronic medication administration record. Barcoding can help ensure that the right patient gets the right medication at the right time. Electronic medication administration records can make it much easier to determine what medications a patient has received. Studies to assess the impact of bar-coding on medication safety are underway, and the early results are promising. Another technology that can be used to improve the safety of medication administration is “smart pumps.” These are pumps that can be instructed in which medication is being given, and at what dose; if the nurse tries to administer too high a dose, he or she will receive a warning. Non-technology-oriented interventions can also be highly effective. For example, having a pharmacist round with the team in the intensive care unit has been shown to decrease the ADE frequency substantially in that setting; this oversight is now a Joint Commission of Accreditation of Healthcare Organizations (JCAHO) requirement. The National Picture around Safety Several organizations, including the National Quality Forum (NQF) and the JCAHO, have made recommendations about how to improve safety. In particular, the NQF has released recommendations to the country’s hospitals about what
practices will most improve the safety of care, which all hospitals are expected to implement (Table e1-1). Many of these practices arise frequently in routine care. One example is “readback,” which is the practice of recording all verbal orders and immediately reading them back to the physician to verify the accuracy of what was heard. Another is to use only standard abbreviations and dose designations, since some abbreviations and dose designations are particularly prone to error; for example, 7U may be read as 70. Measurement of Safety Measuring the safety of care is quite difficult and expensive, since adverse events are fortunately rare. Most hospitals rely on spontaneous reporting to identify errors and adverse events, but this approach has a very low sensitivity, with only ~1 in 20 ADEs reported. There are promising research techniques that involve searching the electronic record for signals suggesting that an adverse event has occurred, which will likely be routine in the future but are not yet in wide use. Claims data have been used to identify the frequency of adverse events; this approach works much better for surgical care than for medical care and still requires additional validation. The net result is that except for a few specific types of events, such as falls and nosocomial infections, hospitals have little idea about the true frequency of safety issues. Nonetheless, all providers have the responsibility to report problems with safety as they are identified. All hospitals have spontaneous reporting systems, and if providers report events as they occur, these events can be used as lessons for subsequent improvement. Conclusions about Safety It is now abundantly clear that the safety of health care can be improved substantially; as more areas are studied closely, more problems are identified. Compared to the outpatient setting, much more is known about the epidemiology of safety in the inpatient setting, and a number of effective strategies for improving safety have been identified and are being used increasingly. Some effective strategies are also available in the outpatient setting. Transitions appear to be especially risky. The solutions to improving care will often involve leveraging information technology, but they will also involve many other domains, such as use of human factors techniques, team training, and building a culture of safety. QUALITY IN HEALTH CARE Quality of care has remained somewhat elusive, although the tools for measuring it have increasingly improved. Selecting health care and measuring its quality is a complex process. Quality Theory Donabedian has suggested that quality of care can be divided by type of measurement into structure, process, and outcome. Structure refers to whether or not a particular characteristic is present, e.g., whether a hospital has a catheterization laboratory or whether a clinic uses an electronic health record. Process refers to the way that care is delivered, and examples of process measures are whether a Pap smear was performed at the recommended interval or whether an aspirin was given to a patient with a suspected myocardial infarction. Outcomes refer to what actually happens, e.g., the mortality rate in myocardial infarction. It is important to note that good structure and process do not always result in good outcomes. For instance, a patient may present with a suspected myocardial infarction to an institution with a catheterization laboratory and receive recommended care, including aspirin, but still die because of their infarction. Quality theory also suggests that overall quality will be improved more in the aggregate by raising the level of performance of all providers rather than finding a few poor performers and punishing them. This view suggests that systems changes are especially likely to be helpful in improving quality, since large numbers of providers may be affected simultaneously. The theory of continuous quality improvement suggests that organizations should be evaluating the care they deliver on an on-going basis and continually making small changes to improve their individual processes. This approach can be very powerful if embraced over time.
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Introduction to Clinical Medicine
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TABLE e1-1 SAFE PRACTICES FOR BETTER HEALTH CARE a
1. Create a health care culture of safety. 2. For designated high-risk, elective surgical procedures or other specified care, patients should be clearly informed of the likely reduced risk of an adverse outcome at treatment facilities that have demonstrated superior outcomes and should be referred to such facilities in accordance with the patient’s stated preference. 3. Specify an explicit protocol to be used to ensure an adequate level of nursing based on the institution’s usual patient mix and the experience and training of its nursing staff. 4. All patients in general intensive care units (both adult and pediatric) should be managed by physicians having specific training and certification in critical care medicine (“critical care certified”). 5. Pharmacists should actively participate in the medication-use process, including, at a minimum, being available for consultation with prescribers on medication ordering, interpretation and review of medication orders, preparation of medications, dispensing of medications, and administration and monitoring of medications. 6. Verbal orders should be recorded whenever possible and immediately read back to the prescriber—i.e., a health care provider receiving a verbal order should read or repeat back the information that the prescriber conveys in order to verify the accuracy of what was heard. 7. Use only standardized abbreviations and dose designations. 8. Patient care summaries or other similar records should not be prepared from memory. 9. Ensure that care information, especially changes in orders and new diagnostic information, is transmitted in a timely and clearly understandable form to all of the patient’s current health care providers who need that information to provide care. 10. Ask each patient or legal surrogate to recount what he or she has been told during the informed consent discussion. 11. Ensure that written documentation of the patient’s preference for life-sustaining treatments is prominently displayed in his or her chart. 12. Implement a computerized prescriber order entry system. 13. Implement a standardized protocol to prevent the mislabeling of radiographs. 14. Implement standardized protocols to prevent the occurrence of wrong-site procedures or wrongpatient procedures. 15. Evaluate each patient undergoing elective surgery for risk of an acute ischemic cardiac event during surgery, and provide prophylactic treatment of high-risk patients with beta blockers. 16. Evaluate each patient upon admission, and regularly thereafter, for the risk of developing pressure ulcers. This evaluation should be repeated at regular intervals during care. Clinically appropriate preventive methods should be implemented consequent to the evaluation. 17. Evaluate each patient upon admission, and regularly thereafter, for the risk of developing deep vein thrombosis (DVT)/venous thromboembolism (VTE). Utilize clinically appropriate methods to prevent DVT/VTE. 18. Utilize dedicated anti-thrombotic (anti-coagulation) services that facilitate coordinated care management. 19. Upon admission, and regularly thereafter, evaluate each patient for the risk of aspiration. 20. Adhere to effective methods of preventing central venous catheter–associated bloodstream infections. 21. Evaluate each preoperative patient in light of his or her planned surgical procedure for the risk of surgical site infection, and implement appropriate antibiotic prophylaxis and other preventive measures based on that evaluation. 22. Utilize validated protocols to evaluate patients who are at risk for contrast media-induced renal failure, and utilize a clinically appropriate method for reducing risk of renal injury based on the patient’s kidney function evaluation. 23. Evaluate each patient upon admission, and regularly thereafter, for risk of malnutrition. Employ clinically appropriate strategies to prevent malnutrition. 24. Whenever a pneumatic tourniquet is used, evaluate the patient for the risk of an ischemic and/or thrombotic complication, and utilize appropriate prophylactic measures. 25. Decontaminate hands with either a hygienic hand rub or by washing with a disinfectant soap prior to and after direct contact with the patient or objects immediately around the patient. 26. Vaccinate health care workers against influenza to protect both them and patients from influenza. 27. Keep workspaces where medications are prepared clean, orderly, well lit, and free of clutter, distraction, and noise. 28. Standardize the methods for labeling, packaging, and storing medications. 29. Identify all “high alert” drugs (e.g., intravenous adrenergic agonists and antagonists, chemotherapy agents, anticoagulants and anti-thrombotics, concentrated parenteral electrolytes, general anesthetics, neuromuscular blockers, insulin and oral hypoglycemics, narcotics and opiates). 30. Dispense medications in unit-dose or, when appropriate, unit-of-use form, whenever possible.
processes, making this tool especially impor- e3 tant for improvement.
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Factors Relating to Quality Many factors can decrease the level of quality, including stress to providers, high or low levels of production pressure, and poor systems, to name but a few examples. Stress can adversely affect quality because it can lead providers to omit important steps, as can a high level of production pressure. Low levels of production pressure can also sometimes result in worse quality, as providers may be bored or have little experience with a specific problem. Poor systems can have a tremendous impact on quality, and even extremely dedicated providers typically cannot achieve high levels of performance if they are operating within a poor system. Data about the Current State of Quality A recent RAND study has provided the most complete picture of quality of care delivered in the United States to date. The results were sobering. The authors found that across a wide range of quality parameters, patients in the United States received only 55% of recommended care overall; there was little variation by subtype, with scores of 54% for preventive care, 54% for acute care, and 56% for care of chronic conditions, leading the authors to conclude that the chances of getting highquality care in the United States broadly were little better than those of winning a coin flip.
Strategies for Improving Quality and Performance A number of specific strategies can be used to improve quality at the individual level, including rationing, education, feedback, incentives, and penalties. Rationing has been effective in some specific areas, such as convincing physicians to prescribe within a formulary, but it generally has been resisted. Education is effective in the short run and is necessary for changing opinions, but its effect decays fairly rapidly with time. Feedback on performance can be given either at the group or individual level. Feedback is most effective if it is individualized and if it is given in close temporal proximity to the original events. Incentives can be effective, and many believe that this will be a key to improving quality, especially if pay-for-performance with sufficient incentives is broadly implemented (see below). Penalties produce provider resentment and are rarely used in health care. a These 30 practices are the recommendations from the National Quality Forum (NQF) for improving the safety of Another set of strategies for improving quality involves changing the systems of care. An exhealth care; the NQF believes these should be universally utilized in applicable care settings to reduce the risk of patient harm. The practices all have strong supporting evidence and are likely to have a significant benefit. ample would be introducing reminders about which specific actions need to be taken at a visit for a specific patient, which is a strategy that has A number of specific tools have been developed to help improve been demonstrated to improve performance in certain situations, e.g., in process performance. One of the most important of these tools is delivery of preventive services. Another approach that has been effective the Plan-Do-Check-Act cycle (Fig. e1-2). This approach can be is the development of “bundles” or groups of quality measures that can used to perform what is called rapid cycle improvement for a pro- be implemented together with a high degree of fidelity. A number of hoscess, e.g., the time for a patient with pneumonia to receive antibi- pitals have now implemented a bundle for ventilator-associated pneumootics after diagnosis. Often, specific statistical tools, such as control nia in the intensive care unit, which includes five measures, including, for charts, are used in conjunction to determine whether or not example, ensuring that the head of the bed is elevated. The hospitals have progress is being made. Most medical care comprises one or many found that they were able to substantially improve performance.
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Adopt or abandon strategies based on results
A
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Pl
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Identify potential improvement strategies
Ch
Measure effectiveness of strategies
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FIGURE e1-2 Plan-do-check-act (or PDCA) cycle. The PDCA cycle approach can be used to improve a specific process rapidly. First, planning is performed, and several potential improvement strategies are identified. Next, these strategies are trialed in small “tests of change.” “Checking” is measuring whether or not they appeared to make a difference, and “act” refers to acting on the results. Perhaps the most pressing need is to improve the quality of care for chronic diseases. The Chronic Care Model has been developed by Wagner and colleagues (Fig. e1-3); it suggests that a combination of strategies will be necessary, including self-management support, changes in delivery system design, decision support, and information systems, and that these must be delivered by a practice team composed of several providers, not just a physician. Recent evidence about the relative efficacy of strategies in reducing hemoglobin A1c (HbA1c) in outpatient diabetes care (Fig. e1-4) supports this general premise. It is especially notable that the outcome was HbA1c, as it has generally been much more difficult to improve outcome measures than process measures (such as whether a HbA1c was performed). In this meta-analysis, a variety of strategies were effective, but the most effective ones were the use of team changes and use of a case manager. When cost-effectiveness is considered in addition, it appears likely that an amalgam of strategies will be needed. However, the more expensive strategies, such as use of case managers, will likely be implemented widely only if pay-for-performance takes hold.
National State of Quality Measurement In the inpatient setting, quality measurement is now being performed by a very large proportion of hospitals for several conditions, including myocardial infarction, congestive heart failure, pneumonia, and surgical infection prevention; 20 measures are included in all. This is the result of the Hospital Quality Initiative, which represents a collaboration among many entities, including the Hospital Quality Alliance, the JCAHO, the NQF, and the Agency for Healthcare Research and Quality, among others. The data are housed at the Center for Medicare and Medicaid Services, which publicly releases performance on the measures on a website called Hospital Compare. These data are voluntarily reported and are available for a very high proportion of the nation’s hospitals; they were first released in April 2006. Early analyses demonstrate that there is substantial regional variation in quality and that there are important differences among hospitals. Analyses by the Joint Commission for very similar indicators demonstrate that performance on measures by hospitals did improve over time, and that, as might be hoped, lower performers improved more than higher performers. Analogous national data for ambulatory care are not yet available, but a group called the Ambulatory care Quality Alliance (AQA) has been formed and is developing an analogous set of measures. Public Reporting Overall, public reporting of quality data is becoming increasingly common. There are now commercial websites that have quality-related data for most regions of the country that can be accessed for a fee. Similarly, national data for hospitals are available. The evidence to date is that patients have not used such data very much, but that such data have had an important effect on provider and organization behavior. Instead, patients have relied on provider reputation to make choices. Part of the reason for this choice basis is that until very recently little information was available, and it was not necessarily represented in ways that were easy for patients to access. Many believe that as more information about quality becomes available, it will become increasingly central to patient choices about where to access care. Pay-for-Performance Currently, providers in the United States get paid exactly the same amount for a specific service regardless of what quality care is delivered. The theory of pay-for-performance suggests that if providers are paid more for higher-quality care, they will invest in strategies that enable them to deliver that care. The current key issues in the pay-for-performance debate relate to (1) how effective it is, (2) what levels of incentives are needed, and (3) what perverse consequences are produced. The evidence about effectiveness is fairly limited to date, although a number of studies are ongoing. With respect to levels, most performance incentives around quality have accounted for merely 1–2% of total payment in this country to date, but in the United Kingdom, 40% of general practitioners’ salaries have recently been placed at risk based on performance across a wide array of parameters. This has been associated with large improvements in reported quality performance, although it is still unclear as to what extent this represents better performance versus better reporting. The potential for perverse consequences exists with any incentive scheme. One problem is that if incentives are tied to outcomes, this introduces the incentive to transfer the sickest patients to other providers and systems. Another concern is that providers will pay too much attention to quality measures with incentives, and ignore the rest of the quality picture. The validity of these concerns remains to be determined. CONCLUSIONS The safety and quality of care in the United States could be improved substantially. A number of interventions are available today that have been demonstrated to improve the safety of care and should be used more widely; others are undergoing evaluation or will be evaluated. Quality could also be dramatically better, and the science of quality improvement is increasingly mature. Implementation of pay-forperformance should make it much easier for organizations to justify investments in improving these parameters, including health informa-
PART 1
Introduction to Clinical Medicine
Community
Resources and policies Selfmanagement Support
Health System
Organization of health care Delivery system design Decision support Clinical information systems
Informed, activated patient
Productive interactions
Prepared, proactive practice team
Improved Outcomes FIGURE e1-3 The chronic care model. The chronic care model, which focuses on improving care for chronic diseases, suggests that delivery of high-quality care demands a range of strategies that must closely involve and engage the patient, and, in addition, that team care is essential. (From Wagner et al: Eff Clin Pract 1:2, 1998.)
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Quality Improvement Strategy Team changes Case management Patient reminders Patient education Electronic patient registry Clinician education
No. of Trials 26 26 14 38 8 20 15 20 9 18 3 66 –1.0
Favors intervention
Favors control
Facilitated relay of clinical information Self-management Audit and feedback Clinician reminders Continuous quality improvement All interventions
much more robust; it would be particularly useful e5 if organizations had measures that they could use in routine operations to assess safety at reasonable cost. While the quality measures available are more robust than those for safety, they still cover a relatively small proportion of the entire domain of quality, and more need to be developed. The public and payers are now demanding better information about safety and quality, as well as better performance in these areas. The clear implication is that these domains will need to be addressed directly by providers.
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FURTHER READINGS
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BATES DW et al: Effect of computerized physician order entry and a team intervention on prevenDifference in postintervention HbA1c, % tion of serious medication errors. JAMA 280:1311, 1998 FIGURE e1-4 The efficacy of various strategies for improving diabetes care in outpatients. Shojania et al. performed a meta-analysis of evaluating the efficacy of strategies BRENNAN TA et al: Incidence of adverse events and negligence in hospitalized patients: Results for reducing hemoglobin A1c (HbA1c) in diabetic outpatients; they found that team from the Harvard Medical Practice Study I. N changes and case management had the largest impact on HbA1c, although there was a Engl J Med 324:370, 1991 trend toward improvement for many strategies. Interventions in which nurse or pharmacist case managers can make medication adjustments without awaiting physician autho- MCGLYNN EA et al: The quality of health care delivered to adults in the United States. N Engl J rization resulted in the largest reductions. (From Shojania et al: JAMA 296:427, 2006.) Med 348:2635, 2003 SHOJANIA KG et al: Effects of quality improvement tion technology; however, many will also require changing the strucstrategies for type 2 diabetes on glycemic control: A meta-regresture of care, e.g., moving to a more team-oriented approach, and sion analysis. JAMA 296:427, 2006 ensuring that the patients are more involved in their own care. The WAGNER EH et al: Improving chronic illness care: Translating evidence into action. Health Aff (Millwood) 20:64, 2001 measures of safety are still relatively immature and could be made
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e2 Economic Considerations in the Practice of Medicine
David Meltzer
The enormous and continuing growth of health care spending in the United States and many other countries over recent decades has focused attention on the causes, consequences, and possible responses to rising expenditures on health care. A variety of strategies to control costs have been developed that have made it increasingly important that physicians and other health care professionals understand a wide range of economic considerations in the practice of medicine. HEALTH CARE COSTS Between 1960 and 2005, health care spending in the United States increased from about $27 billion to $2.1 trillion. This growth in spending was about 2–3% higher per year than growth in the overall economy, causing health care spending to rise from 6% of gross domestic product to >16%. This increase in spending has produced enormous challenges for everyone who pays for health care. For government, these challenges include rising federal, state, and local government health care budgets, which have required increases in taxes. For firms and their workers, the biggest challenge is the high cost of insuring workers, which causes employers to drop (or reduce) health insurance coverage, to move jobs overseas, or to reduce wages. The rising cost of insurance coverage that is passed on to workers also increases rates of uninsurance, because some workers choose to forego insurance even when it is available or take jobs that do not offer insurance coverage. The increasing cost of medical care also raises the cost of any attempts through public policy to provide insurance coverage to the >45 million Americans who now lack health insurance. Increased outof-pocket costs for patients are also a common outgrowth of rising health care expenditures. Overall, about 15–20% of health care costs are now paid out of pocket by consumers. Because some persons consume no health care, the fraction of health care costs paid out of pocket by persons who actually use health care is even higher, ~35% of their total health care costs. The combination of rising costs and high rates of uninsurance, along with the knowledge that many other developed countries spend only about half as much on health care yet are able to provide universal coverage and have health outcomes that are as good as or better than those in the United States, has understandably created widespread concern that the U.S. health care system is neither as efficient nor as effective as it could be. This, in turn, has produced many efforts to understand the causes of increased costs and to improve the delivery and financing of health care in the United States. Causes of Rising Costs Many causes of the rise in health care costs have been suggested. An aging population is commonly cited but has actually contributed rather little to recent increases in per capita spending. One reason for this is that, unlike the large cohort of baby boomers who will reach old age in the coming years, the cohort of persons born during the Depression Era of the 1930s who have reached retirement age in recent years is relatively small, because birth rates were low during that depression. Another reason that aging has not contributed so greatly to increasing expenditures is that improving health during old age has tended to delay the onset of serious illness and high health care expenditures. Another commonly suggested cause of rising expenditures has been medical malpractice and resulting defensive medicine, but evidence suggests that this is not a large contributor to health care costs in the United States. Administrative costs have also have been suggested to play an important role and are probably at least 10–15% of total costs for private insurance. Despite the significant and rising number of persons who lack insurance in the United States, one possible cause of rising health care costs since 1960 for which there is strong evidence is the increasing in-
surance coverage of health care and resulting increases in demand for e7 health care. Some scholars date the growth in health insurance coverage to the beginning of World War II when an Internal Revenue Service ruling established that employer-provided health insurance would be exempt from personal income tax. Today, employer-sponsored health insurance provides insurance coverage for ~60% of Americans. The growth of Blue Cross and Blue Shield insurance plans dates from this period of the establishment of employer-sponsored health insurance, and these plans formed a model for private health insurance in the United States. This was followed in the 1960s by the creation of Medicare and then Medicaid and a series of subsequent expansion of these programs. Nevertheless, based on data from the effects of health insurance coverage on the demand for health care, experts have estimated that these increases in insurance coverage account for only about one-quarter of the increase in health care spending since 1960. Instead, most health economists now believe that the primary cause of increasing spending on health care is the development of new technologies that, on average, offer improvements in health that are of substantial value to patients. An illustrative example of this is the cost of treating an acute myocardial infarction, which grew at ~5% annually in real terms over the mid-1980s and -1990s. This occurred at the same time that the cost of the individual major treatments for acute myocardial infarction—medical management, fibrinolysis, percutaneous coronary intervention, and coronary bypass surgery—either fell or increased minimally. The change in the overall cost occurred because the more expensive treatment options (e.g., revascularization) were increasingly used over the less expensive ones (e.g., medical management). Most economists have concluded that similar increases in the use of new technologies explain most of the increase in health care spending over this period. Estimates of the value of these increases in spending in terms of health indicate that on average they have yielded benefits far in excess of their costs, suggesting that these changes are the result of expanding opportunities to produce increases in health that are valued well above the cost of producing them. However, a broad body of evidence also indicates that many new technologies are not worth their costs, and it has been suggested that the broad expansion of insurance coverage has increased the incentives to develop costly medical technologies, even when they are not worth their cost. These conclusions suggest that efforts to control the cost of health care must consider both immediate and longer-term effects and be acutely aware of the value of health that is produced. THE DEMAND FOR AND SUPPLY OF HEALTH CARE Demand and supply are the fundamental tools that economists use to analyze health care markets and the spending within them. The demand for health care derives ultimately from the desire of individuals to be healthy. Health economists think of health as a capital good (“health capital”) in the sense that it tends to be durable, so that health today contributes positively to health tomorrow. A logical consequence of this is that rational decisions about health involve thinking about benefits and costs both in the present and in the future. Although individuals cannot buy health, they can buy health care that they hope will improve their health. Because health care costs can be high and variable, health insurance is desirable to protect against the risk of catastrophic costs that could otherwise lead to bankruptcy and/or to limit access to health care. Insurance can produce incentives to consume more medical care than individuals would purchase if they faced the true cost of care, but such inefficiencies need to be balanced against the financial and health risks of lacking insurance. Contractual limits on what insurance will cover are a strategy to address this tendency for excessive consumption but are often sources of controversy and patient dissatisfaction. One reason for this is that health care spending tends to be highly concentrated, with ~5% of the population accounting for 50% of total spending. This concentration of spending makes it difficult to use cost-sharing to control health care without having these costs fall heavily on a small fraction of individuals. Because simple across-the-board cost-sharing can produce unacceptable financial risk, health care insurance is better constructed by
CHAPTER e2
Economic Considerations in the Practice of Medicine
Copyright © 2008 by McGraw-Hill Company. All rights reserved.
e8 designing a package of benefits that provides variable subsidies for access to different medical technologies that can improve health while leaving an acceptable level of financial risk and an affordable annual premium. These tradeoffs are increasingly being put in the hands of consumers as they choose among health plans. This has the advantage of allowing consumer choice but can also result in adverse selection in which people choose insurance plans based on their personal needs but, in so doing, undermine the ability of insurance to spread costs and risk among patient groups. An example of adverse selection would be if a low-cost plan were chosen only by healthy individuals, leaving sicker persons alone in the high-cost plan, which might then become unaffordable. These types of concerns greatly complicate the creation of successful insurance markets. Medicare and Medicaid Medicare provides health insurance for almost all Americans age 65 and older. Established in 1965, Medicare covers both hospital care (part A) and physician fees (part B). In 2006 Medicare also began offering a prescription drug benefit (part D). Insurance coverage within Medicare has some idiosyncrasies that, in part, reflect its origins in being modeled based on private health insurance in the 1960s. These include lifetime caps on benefits and copayment rates that are sometimes lower for low-use patients than for higher-use patients. Medicare beneficiaries who can afford them can purchase supplemental Medicare (Medigap) policies that can sometimes fill these gaps in coverage. Medicare also interfaces with the Medicaid program to address the needs of lower income older persons, as discussed below. The Part D program in Medicare addresses a long-standing need to provide older persons with better access to pharmaceuticals. This program has a complicated benefit structure, with varying copayment rates depending on an individual’s prescription drug expenditures within the year. There are also significant variations in the coverage provided by different plans, but online tools are available at www.medicare.gov to help patients and their families to make informed decisions. Medicare Advantage is a program developed by Medicare to provide managed care options for Medicare beneficiaries. Patients in these programs generally give up flexibility in the providers they can see without paying for visits themselves but benefit from lower copayments for covered services or coverage for certain benefits that traditional Medicare may not cover. Medicare also has a special program that provides health insurance coverage for persons with end-stage renal disease. Medicaid is an important source of insurance coverage for patients who lack private health insurance or Medicare and who cannot afford to purchase insurance on their own. Medicaid currently provides coverage to about 14% of the U.S. population. Like Medicare, Medicaid is managed by the Centers for Medicare and Medicaid services (CMS). However, unlike Medicare, Medicaid is a federal-state partnership with funding that is shared, and there is a great deal of variation across states as to who is eligible and what benefits are provided. In general, Medicaid tends to have lower copayments than other types of health insurance, which is important because of the limited income of the recipients of Medicaid. Older persons whose incomes and assets are low enough to qualify may be eligible for both Medicare and Medicaid (“dual-eligible”). One aspect of Medicaid coverage that is especially important for older persons and their families is that it pays for nursing home coverage for those whose income and assets are sufficiently low. For patients and their families for whom high health care costs and insurance coverage are major concerns, referral to a social worker, patient advocate, or another expert in health care costs is among the most valuable things a physician can do to help protect the family from unnecessary economic hardship. SUPPLY OF HEALTH CARE Physicians, nurses and other health professionals, hospitals, manufacturers of pharmaceuticals and devices, and researchers all provide key inputs into the health care system. Health Professionals The economics of medical practice are shaped by the high level of investment in tuition and time (foregone earnings)
that physicians must make during their training. Typically, longer training periods are associated with higher earnings. Nevertheless, some specialties with the longest training periods still offer exceptionally high returns on investment. In a competitive market with free entry, one might expect the returns on investment to equalize across specialties as high earnings encourage more entrants into a field and lowers average earnings. This tends not to happen because entry into medical specialties is often tightly controlled by a variety of accrediting agencies in collaboration with medical specialty societies. In addition, the large role of government as a payer in health care makes physician reimbursement a political issue in which lobbying and other strategies for specialty influence play a role. In the past, physicians usually owned their own practices, but this is increasingly less common in the United States as physicians more often work as part of large groups or for health plans. These models sometimes pay doctors fixed salaries, although incentives to see more patients are common. Incentives for physicians to provide services can lead to concerns about “demand inducement,” in which physicians provide more care than is desirable because of the financial returns they receive from providing that care, but the evidence for this being common is not compelling. Legal constraints exist to prevent physicians from gaining economically from referring patients for the services of other providers. Nurses and other health professionals also have complex labor market issues. Often the boundaries of practice between different forms of training (e.g., ophthalmologists and optometrists or nurse practitioners and physician assistants) are not clear, and so there can be intense competition between, as well as within, specialty areas. Hospitals These are complex organizations that require expensive capital investments, a large and complex staff, and close ties with physicians. Most hospitals are not-for-profit (NFP), meaning that any surplus left at the end of each year must be reinvested in the hospital or the health of the community it serves. This contrasts with a for-profit (FP) hospital, which can return profits to shareholders and is not required to provide benefits to its community in the same way as NFP hospitals are required to. NFP hospitals are exempt from many taxes, but there is active debate about whether NFP hospitals provide as much community benefit as would be expected based on the subsidies that they receive. Hospital management in NFP hospitals is supervised by a board of directors that typically includes community, staff, and physician participation. In contrast, FP hospitals are managed by a corporate structure. However, managers in both NFP and FP hospitals use similar tools to analyze and improve the cost and quality of care they provide. Increasingly, management tools such as process mapping, human factors analysis, and continuous quality improvement approaches (e.g., plan-do-study-act cycles) are becoming essential tools of a modern physician leader. The Pharmaceutical and Device Industries The pharmaceutical industry and its close cousin, the medical device industry, are among the most important aspects of the modern health care system and supply many of the products most responsible for improvements in public health, such as medications to treat hypertension, immunizations, and devices such as joint replacements and artificial lenses that allow the removal of cataracts. Concerns about the rising cost of pharmaceuticals, safety, direct-to-consumer advertising, and inappropriate marketing strategies have made the pharmaceutical industry and its regulators [e.g., the U.S. Food and Drug Administration (FDA)] the subject of a great deal of recent scrutiny. Another major concern is the rising costs of developing new drugs, which has recently been estimated to be in the vicinity of $1 billion per new chemical entity brought to market. The rising cost of prescription drugs and concern that prices charged in the United States are above those charged in other countries have led to calls for efforts to control drug pricing in the United States. Attempts to bring down the costs of prescription drugs both in the United States and internationally must balance their short-term effects on the cost of health care with longer-term effects on the incen-
PART 1
Introduction to Clinical Medicine
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
tives to produce innovative new drugs and effects on access to patients within and across countries with varying incomes and ability to pay. Innovation Medical innovation is also produced by academia and government, often in close collaboration. The National Institutes of Health (NIH) is the source of the vast majority of federal funding for health research, with the Centers for Disease Control and Prevention (CDC) a distant second and the Agency for Healthcare Research Quality (AHRQ) and a variety of other federal agencies further behind. NIH, CDC, and AHRQ support basic, translational, and clinical research as well as a wide range of programs to support the training and ongoing career development of researchers. There are also loan repayment programs to encourage entry into research careers. The federal government also supports academic medicine through extra payments to academic medical centers through Medicare. Teaching hospitals have traditionally made profits on their clinical care that have allowed them to subsidize their educational and research activities, but the increasingly competitive health care market place is making this progressively more difficult. Therefore, it is more important that research activities be supported by government, private foundations, philanthropy, or industry. Practice Variation Another major concern about health care spending is the large degree of variation in spending across small geographic areas around the United States. These variations in spending are due to variations in the rate at which expensive care is provided and yet do not appear to result in improved outcomes, suggesting that much of the excess utilization in high-cost areas is of little value. The causes of this excess utilization of services does not appear to result primarily from patient level factors or from differences in insurance coverage. Some have hypothesized that increased utilization of services results from increased capacity in some areas (“if you build it, they will come”). However, other experts have argued that variations in use across small areas may reflect differences in physician beliefs about appropriate practice patterns that are shaped by the influence of peers in their local area. COST-CONTROL STRATEGIES The rapid rise in health care costs over the past three decades has led to a variety of strategies to control costs. Some early programs focused on direct regulation of health care, such as the requirement that a “certificate of need” be issued by a local health authority before construction of a new medical facility can proceed. Other strategies have included direct regulation of payments through publicly established fee schedules for Medicare or Medicaid that often influence private payment rates. Sometimes fee schedules have been created with multiple policy goals. One example is the resource-based relative value scale (RBRVS), which was developed with the intent to realign incentives to encourage physicians to enter needed medical specialties (such as primary care) and be rewarded based on the effort and complexity of the work they do. Prospective Payment This is probably the most important cost-control strategy that has been adopted in the United States. Under a prospective payment system, a health care provider is provided a fixed amount of money to provide care for a patient over a specified episode of care. This contrasts with a retrospective reimbursement system, in which a provider is paid based on the amount of care they provide. The most important example of such a system has been the Medicare Prospective Payment system. This was established in 1983 and replaced the prior system, in which Medicare reimbursed hospitals based on the specific services they provided with a system that provided a fixed payment for a hospital stay for any given diagnosis, classified according to one of several hundred diagnosis-related groups, or DRGs. This provided strong incentives to decrease hospital length of stay and costs and had large effects on hospital cost growth for several years. It was also coupled with the creation of Professional Review Organizations (PROs) that, among other things, sought to ensure that hospitals were acting appropriately in admitting patients according to
the criteria for each DRG, and providing quality care within that diag- e9 nosis. This linkage of quality improvement and payment policy was an important move in the history of Medicare, from serving merely as a payer to acting as an increasingly active manager of care. Pay for Performance Today’s interest in pay for performance, in which providers receive higher reimbursement rates for care that meets specified quality indicators is an extension of this. Prospective payment is a key idea underlying the use of managed care organizations to control costs by providing a fixed payment for providing care for a patient over a given period of time. Because managed care organizations are responsible for all of the care of the patient over this time period, they may have more incentives and ability to provide integrated care. Health maintenance organizations (HMOs) and other managed care organizations may emphasize prevention as a key aspect of their strategy for managing care and controlling costs. However, the high rate at which individuals switch health care plans and the long period of time it takes for many preventive therapies (such as control of hypertension or diabetes) to exert their major benefits suggest that economic incentives for at least some forms of prevention are unlikely to be strong, even in HMOs. This is one motivation for the use of report cards for health plans, which often report on the rate at which various preventive care goals are met. As with prospective payment of hospitals, successful implementation of managed care requires the ability to adjust payments to reflect the underlying cost of care so that providers are not systematically penalized for caring for certain classes of patients. Likewise, development of tools to measure and reward the quality of care provided by managed care organization has arisen as a major priority for the field of health outcomes research. Competition This has been another important strategy used to attempt to control costs. Competitive bidding for contracts in which only the low-price bidders are able to provide services, often called selective contracting, is now common in medical care and provides a powerful strategy to encourage providers to lower their prices and, accordingly, costs. Competition does not always lower costs, however. For example, when hospital reimbursement was retrospective, competition between hospitals tended to increase costs as hospitals provided more and more services to attract patients and were well reimbursed for them. In the era of prospective payment, competition has the opposite effect of lowering costs because hospitals can no longer charge insurers for added costs and because, with a fixed reimbursement, hospitals can be more profitable only if they lower their costs. The combination of competition and prospective payment may be particularly powerful in reducing costs but can also create incentives to decrease the amount of care provided to the sickest patients within a given category, the costs of whose care may often exceed reimbursement. For this reason, it is especially important that quality-of-care measures not neglect the special needs of the sickest patients. Consumer-Driven Care Another cost-containment strategy that has recently received increasing attention is the idea of consumer-driven care, in which patients select an insurance plan tailored to their personal needs, but often with more limited coverage of certain services. Given the evidence on the effect of health insurance on the demand for medical care, consumer-driven health care will likely have only a modest effect on overall health care demand over the short run. Nevertheless, it is possible that there could be much larger effects over time if greater consumer sensitivity to cost leads to changes in the way new technologies are developed and their use diffuses. It is also possible—though still unproven—that the development of novel new insurance mechanisms, such as health savings accounts paired with high-deductible health insurance coverage for catastrophic care, could induce far more price sensitivity and cost control than was possible with traditional insurance arrangements. Cost-Effectiveness Analyses In making medical decisions, especially in making decisions when costs are a concern, cost-effectiveness analy-
CHAPTER e2
Economic Considerations in the Practice of Medicine
Copyright © 2008 by McGraw-Hill Company. All rights reserved.
e10 sis and other approaches to technology assessment are an important
source of evidence for decisions about when a medical technology is likely to be worthwhile. In cost-effectiveness analysis, the health benefits and costs of a medical intervention are compared to one or more other options by calculating a ratio of costs (C) to effectiveness (E), where the C/E ratio = change in health benefits/change in costs. Often benefits will be measured using a metric of quality-adjusted life years, or QALYs, which is a measure of life expectancy in which each year of life is weighted with a number between 0 (death) and 1 (perfect health) reflecting quality of life in that health state. In general, cost-effectiveness theory suggests that interventions that cost less than some threshold value per QALY (often $50,000/QALY or $100,000/QALY) would be considered cost-effective, though the appropriate threshold remains highly controversial. In countries (such as the United Kingdom) where cost-effectiveness analysis is used to inform coverage policy, it is most commonly used as part of a broader process of technology assessment that may incorporate other forms of evidence, including expert judgment and political concerns emanating from patient and providers, and from producers of new technologies. It is generally agreed that cost-effectiveness analysis take a societal perspective, accounting for all costs and benefits of a medical intervention regardless of to whom they accrue. There is also a strong case to be made for considering multiple perspectives in a cost-effectiveness analysis. For example, a costeffectiveness analysis done from the perspective of an HMO might find that intensive therapy for diabetes, for which most benefits are far in the future, is not cost-effective from a business perspective, even if it is cost-effective from a societal perspective. In such a case, knowing that the business case for this valuable intervention is not strong might help target attention to developing quality indicators to ensure that plans are making good efforts to encourage intensive therapy for the appropriate patients. Cost-effectiveness analysis can also sometimes be used to assess when it would be valuable to do more research on a technology in order to better characterize how it should be used. Evidence-Based Medicine and Physician Practice Patterns To the extent that variation in practice patterns is an important contributor to higher health care costs, it becomes important to control practice vari-
ations by improving alignment of practice patterns using evidence on the costs and benefits of care. The scientific literature provides important data for such evidence-based practice. Nevertheless, it is well established that there are large gaps between the time evidence becomes available and the time it is incorporated into practice. As a result, a great deal of effort has gone into approaches that may be used to change physician behavior and to create systems-level changes that can support the better use of evidence in clinical care. Health information systems provide a variety of tools, and their increasing use has already begun to show promise in addressing practice variations to improve meaningfully both the cost and effectiveness of care. Costs and the Clinician Economic concerns arise in clinical care on a daily basis. They range from patient–oriented concerns (such as outof-pocket costs or insurance purchase decisions) to system-oriented concerns (such as hospital or health plan management) to physicianoriented concerns (practice management and personal earnings). To be fully effective, physicians need to develop and maintain an understanding of these economic considerations in the practice of medicine and to reflect them in their professional behavior.
PART 1
Introduction to Clinical Medicine
FURTHER READINGS
BODENHEIMER T: High and rising health care costs. Part 3: The role of health care providers. Ann Intern Med 142(12):996, 2005 CUTLER DM, MCCLELLAN M: Is technological change in medicine worth it? Health Affairs 20(5):11, 2001 FISHER ES et al: The implications of regional variations in medicare spending. Part 1: The content, quality, and accessibility of care. Ann Intern Med 138(4):273, 2003 MELTZER D et al: Does competition under Medicare Prospective Payment selectively reduce expenditures on high-cost patients? RAND J Econ 33(3):447, 2002 MURPHY KM, TOPEL RH: Measuring the Gains from Medical Research: An Economic Approach. Chicago, University of Chicago Press, 2003 NEWHOUSE JP: Consumer-directed health plans and the RAND health insurance experiment. Health Affairs 23(6):107, 2004 Primer on cost-effectiveness analysis. Effect Clin Pract September/October, 253–255, 2000
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
Ethnic e3 Racial andCare Disparities in Health
Joseph R. Betancourt, David Blumenthal
Over the course of its history, the United States has experienced dramatic improvements in overall health and life expectancy due largely to initiatives in public health, health promotion, disease prevention, and chronic care management. Our ability to prevent, detect, and treat diseases in their early stages has allowed us to target and reduce morbidity and mortality. Despite interventions that have improved the overall health of the majority of Americans, racial and ethnic minorities (Blacks, Hispanics/Latinos, Native Americans/Alaska Natives, Asian/Pacific Islanders) have benefited less from these advances and suffer poorer health outcomes than whites from many major diseases (e.g., cardiovascular disease, cancer, diabetes) in the United States. Research has highlighted that minorities may receive lower quality of care than whites in the health care setting, even when confounders such as stage of presentation and comorbidities are controlled for and they have the same level of health insurance. These differences in quality are called racial and ethnic disparities in health care. This chapter will provide an overview of racial and ethnic disparities in health and health care, identify root causes, and provide key recommendations to address them at both the health system and clinical level. NATURE AND EXTENT OF RACIAL AND ETHNIC DISPARITIES IN HEALTH AND HEALTH CARE Minority Americans have poorer health outcomes (compared with whites) from preventable and treatable conditions such as cardiovascular disease, diabetes, asthma, cancer, and HIV/AIDS, among others (Fig. e3-1). Multiple factors contribute to these racial and ethnic disparities in health. First and foremost, there is little doubt that social determinants—such as lower levels of education, overall lower socioeconomic status, inadequate and unsafe housing, racism, and living in close proximity to environmental hazards—disproportionately impact minority populations and thus contribute to poorer health outcomes. For example, three of the five largest landfills in the country are found in African-American and Latino communities; these environmental hazards have contributed to some of the highest rates of pediatric asthma among these populations. Second, lack of access to care also takes a significant toll, as uninsured individuals are less likely to have a regular source of care, are more likely to report delaying seeking care, and are more likely to report that they have not received needed care—
Percent
80
2002 2003
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CHAPTER e3
60
40
Racial and Ethnic Disparities in Health Care
20
0
t To n No -H
al a nic W
hit
e ic an
Bl
k ac
As
ian
NA
/A
N sp Hi
an
ic
isp
n No
-H
isp
FIGURE e3-2 Recommended hospital care received by Medicare patients with pneumonia, by race/ethnicity, 2002–2003. Reference population is Medicare beneficiaries with pneumonia who are hospitalized. Composite is calculated by averaging the percentage of the population that received each of the five incorporated components of care. NA/AN, Native American or Alaska Native. (Adapted from Agency for Health Care Research and Quality: The 2005 National Health Care Disparities Report.) all resulting in avoidable hospitalizations, emergency hospital care, and adverse health outcomes. In addition to the existence of racial and ethnic disparities in health, there are racial/ethnic disparities in the quality of care for those with access to the health care system. For instance, disparities have been found in the treatment of pneumonia (Fig. e3-2) and congestive heart failure (African Americans receiving less optimal care than whites when hospitalized for these conditions) and referral to renal transplantation (African Americans with end-stage renal disease being referred less often to the transplant list than whites) (Fig. e3-3). Disparities have also been found in the utilization of cardiac diagnostic and therapeutic procedures (African Americans being referred less than whites for cardiac catheterization and bypass grafting), prescription of analgesia for pain control (African Americans and Latinos receiving less pain medication than whites for long bone fractures and cancer), and surgical treatment of lung cancer (African Americans re-
White Black Percentage of patients American Indian or Alaska Native Asian or Pacific Islander 200 150 100 50 0 Diseases of heart Cerebrovascular diseases Malignant neoplasms Diabetes mellitus Hispanic 100 80 60 40 20 0 Referred for evaluation
59.6 80.3 57.9 40.3 82.2 68.9
Black women White women Black men White men
67.9
40.6
Placed on waiting list or received transplant
FIGURE e3-1 Age-adjusted death rates for selected causes by race and Hispanic origin, 2000. (From Institute of Medicine: Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care. Washington, DC, National Academy Press, 2002.)
FIGURE e3-3 Referral for evaluation at a transplantation center or placement on a waiting list or receipt of a renal transplantation within 18 months after the start of dialysis among patients who wanted a transplant, according to race and sex. Reference population is 239 black women, 280 white women, 271 black men, and 271 white men. Racial differences were statistically significant among the women and the men (p6 mm. The more uncommon subtype, nodular melanoma, may not manifest all these features but present as a more symmetric, evenly pigmented or amelanotic lesion. Dysplastic (atypical) melanocytic nevi may occur as solitary or multiple lesions as well as in the setting of familial melanoma. They display some degree of asymmetry, border irregularity, and color variation. Ordinary nevi may be acquired or congenital and are quite common.
PART 2
Cardinal Manifestations and Presentation of Diseases
FIGURE e10-25 Keratoacanthoma is a low-grade squamous cell carcinoma that presents as an exophytic nodule with central keratinous debris.
FIGURE e10-26 Squamous cell carcinoma seen here as a hyperkeratotic crusted and somewhat eroded plaque on the lower lip. Sun-exposed skin such as the head, neck, hands, and arms are other typical sites of involvement.
FIGURE e10-28 Nevus. Nevi are benign proliferations of nevomelanocytes characterized by regularly shaped hyperpigmented macules or papules of a uniform color.
FIGURE e10-29 Dysplastic nevi are irregularly pigmented and shaped nevomelanocytic lesions which may be associated with familial melanoma.
FIGURE e10-27 Actinic keratoses consist of hyperkeratotic erythematous papules and patches on sun-exposed skin. They arise in middle-aged to older adults and have some potential for malignant transformation. (Courtesy of Robert Swerlick, MD; with permission.)
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
e67
CHAPTER e10 Atlas of Skin Manifestations of Internal Disease
FIGURE e10-30 Superficial spreading melanoma is the most common type of malignant melanoma and demonstrates color variegation (black, blue, brown, pink, and white) and irregular borders.
FIGURE e10-33 Acral lentiginous melanoma is more common in blacks, Asians, and Hispanics and occurs as an enlarging hyperpigmented macule or plaque on the palms or soles. Lateral pigment diffusion is present.
INFECTIOUS DISEASE AND THE SKIN
(Figs. e10-34 to e10-59) One of the roles of the skin is to function as a barrier from the outside world. In this capacity, exposure to infectious agents occurs, and bacterial, viral, fungal, and parasitic infections may result. In addition the skin may be secondarily involved and provide diagnostic clues to systemic infections such as meningococcemia, Rocky Mountain spotted fever, Lyme disease, and septic emboli. Most sexually transmitted bacterial and viral diseases exhibit cutaneous involvement, and examples include primary and secondary syphilis, chancroid, genital herpes simplex, and condyloma accuminatum.
FIGURE e10-31 Lentigo maligna melanoma occurs on sun-exposed skin as a large, hyperpigmented macule or plaque with irregular borders and variable pigmentation. (Courtesy of Alvin Solomon, MD; with permission.)
FIGURE e10-34 Erysipelas is a streptococcal infection of the superficial dermis and consists of well-demarcated, erythematous, edematous, warm plaques.
FIGURE e10-32 Nodular melanoma most commonly manifests itself as a rapidly growing, often ulcerated or crusted black nodule. (Courtesy of S. Wright Caughman, MD; with permission.) FIGURE e10-35 Spread of herpes zoster with chemotherapy. The patient reported external ear pain. A vesicular rash on the concha and antihelix suggested Ramsay Hunt syndrome.
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PART 2
Cardinal Manifestations and Presentation of Diseases
FIGURE e10-36 Varicella showing numerous lesions in various stages of evolution: vesicles on an erythematous base, umbilicated vesicles, and crusts. (Courtesy of Robert Hartman, MD; with permission.) FIGURE e10-37 Herpes zoster is seen in this HIV-infected patient as hemorrhagic vesicles and pustules on an erythematous base grouped in a dermatomal distribution. (Courtesy of Robert Swerlick, MD; with permission.) FIGURE e10-38 Impetigo contagiosa is a superficial streptococcal or Staphylococcus aureus infection consisting of honey-colored crusts and erythematous weeping erosions. Occasionally, bullous lesions may be seen. (Courtesy of Mary Spraker, MD; with permission.)
FIGURE e10-39 Tender vesicles and erosions in the mouth of a patient with hand-foot-and-mouth disease. (Courtesy of Stephen D. Gellis, MD; with permission.)
FIGURE e10-40 Lacy reticular rash of erythema infectiosum (fifth disease).
FIGURE e10-41 Molluscum contagiosum is a cutaneous poxvirus infection characterized by multiple umbilicated flesh-colored or hypopigmented papules. (Courtesy of Yale Resident’s Slide Collection; with permission.)
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
e69
CHAPTER e10 Atlas of Skin Manifestations of Internal Disease
FIGURE e10-42 Oral hairy leukoplakia often presents as white plaques on the lateral tongue and is associated with Epstein-Barr virus infection. (From K Wolff, RA Johnson, D Suurmond: Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatology, 5th ed. New York, McGraw-Hill, 2005. www.accessmedicine.com.)
FIGURE e10-45 Erythema chronicum migrans is the early cutaneous manifestation of Lyme disease and is characterized by erythematous annular patches, often with a central erythematous papule at the tick bite site. (Courtesy of Yale Resident’s Slide Collection; with permission.)
FIGURE e10-43 Fulminant meningococcemia with extensive angular purpuric patches. (Courtesy of Stephen D. Gellis, MD; with permission.) FIGURE e10-46 Primary syphilis with a firm, nontender chancre. (Courtesy of Gregory Cox, MD; with permission.)
FIGURE e10-44 Rocky Mountain spotted fever demonstrating pinpoint petechial lesions on the palm and volar aspect of the wrist. (Courtesy of Robert Swerlick, MD; with permission.)
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FIGURE e10-50 Tinea corporis is a superficial fungal infection, seen here as an erythematous annular scaly plaque with central clearing. FIGURE e10-47 Secondary syphilis commonly affects the palms and soles with scaling, firm, red-brown papules. (Courtesy of Alvin Solomon, MD; with permission.)
Cardinal Manifestations and Presentation of Diseases
FIGURE e10-51 Scabies showing typical scaling erythematous papules and few linear burrows.
FIGURE e10-48 Condylomata lata are moist, somewhat verrucous intertriginous plaques seen in secondary syphilis. (Courtesy of Yale Resident’s Slide Collection; with permission.)
FIGURE e10-52 Skin lesions caused by Chironex fleckeri sting. (Courtesy of V. Pranava Murthy, MD; with permission.)
FIGURE e10-49 Secondary syphilis demonstrating the papulosquamous truncal eruption.
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CHAPTER e10 Atlas of Skin Manifestations of Internal Disease
FIGURE e10-53 Chancroid with characteristic penile ulcers and associated left inguinal adenitis (bubo).
FIGURE e10-54 Condylomata acuminata are lesions induced by human papillomavirus and in this patient are seen as multiple verrucous papules coalescing into plaques. (Courtesy of S. Wright Caughman, MD; with permission.)
FIGURE e10-55 A patient with features of polar lepromatous leprosy; multiple nodular skin lesions, particularly of the forehead, and loss of eyebrows. (Courtesy of Robert Gelber, MD; with permission.)
FIGURE e10-56 Skin lesions of neutropenic patients. A. Papules related to Escherichia coli bacteremia in a neutropenic patient with acute lymphocytic leukemia. B. The same lesion the following day. C. Ecthyma gangrenosum in a neutropenic patient with Pseudomonas aeruginosa bacteremia. D. Papule in a neutropenic patient with Candida tropicalis fungemia.
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PART 2
FIGURE e10-57 Septic emboli with hemorrhage and infarction due to acute Staphylococcus aureus endocarditis. (Courtesy of L. Baden, MD; with permission.) FIGURE e10-58 Vegetations (arrows) due to viridans streptococcal endocarditis involving the mitral valve. (Courtesy of AW Kerchner, MD; with permission.)
Cardinal Manifestations and Presentation of Diseases
IMMUNOLOGICALLY MEDIATED SKIN DISEASE
(Figs. e10-60 to e10-71) Immunologically mediated skin disease may be largely localized to skin and mucous membranes and manifest with blisters and erosions such as pemphigus, pemphigoid, and dermatitis herpetiformis. In diseases such as systemic lupus erythematosus, dermatomyositis, and vasculitis, skin manifestations are often only one element of a widespread process.
FIGURE e10-59 Disseminated gonococcemia in the skin is seen as hemorrhagic papules and pustules with purpuric centers in an acral distribution. (Courtesy of Daniel M. Musher, MD; with permission.)
FIGURE e10-60 A. Systemic lupus erythematosus showing prominent, scaly, malar erythema. Involvement of other sun-exposed sites is also common. B. Acute lupus erythematosus on the upper chest demonstrating brightly erythematous and slightly edematous coalescence of papules and plaques. (B, Courtesy of Robert Swerlick, MD; with permission.)
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CHAPTER e10 Atlas of Skin Manifestations of Internal Disease
FIGURE e10-61 Discoid lupus erythematosus. Violaceous, hyperpigmented, atrophic plaques, often with evidence of follicular plugging, which may result in scarring, are characteristic of this cutaneous form of lupus. (Courtesy of Marilynne McKay, MD; with permission.)
FIGURE e10-64 Dermatomyositis often involves the hands as erythematous flat-topped papules over the knuckles (Gottron’s sign) and periungual telangiectasias.
FIGURE e10-65 Scleroderma showing acral sclerosis and focal digital ulcers.
FIGURE e10-62 Dermatomyositis. Periorbital violaceous erythema characterizes the classic heliotrope rash. (Courtesy of James Krell, MD; with permission.)
FIGURE e10-66 Erythema multiforme is characterized by multiple erythematous plaques with a target or iris morphology and usually represents a hypersensitivity reaction to drugs or infections (especially herpes simplex virus). (Courtesy of Yale Resident’s Slide Collection; with permission.)
FIGURE e10-63 Scleroderma characterized by typical expressionless, mask-like facies.
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FIGURE e10-67 Dermatitis herpetiformis manifested by pruritic, grouped vesicles in a typical location. The vesicles are often excoriated and may occur on knees, buttocks, and posterior scalp. FIGURE e10-69 Erythema nodosum is a panniculitis characterized by tender deep-seated nodules and plaques usually located on the lower extremities. (Courtesy of Robert Swerlick, MD; with permission.)
FIGURE e10-70 Vasculitis. Palpable purpuric papules on the lower legs are seen in this patient with cutaneous small vessel vasculitis. (Courtesy of Robert Swerlick, MD; with permission.)
FIGURE e10-68 A. Pemphigus vulgaris demonstrating flaccid bullae that are easily ruptured, resulting in multiple erosions and crusted plaques. B. Pemphigus vulgaris almost invariably involves the oral mucosa and may present with erosions involving the gingiva, buccal mucosa, palate, posterior pharynx, or the tongue. (B, Courtesy of Robert Swerlick, MD; with permission.)
FIGURE e10-71 Bullous pemphigoid with tense vesicles and bullae on an erythematous, urticarial base. (Courtesy of Yale Resident’s Slide Collection; with permission.)
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SKIN MANIFESTATIONS OF INTERNAL DISEASE
(Figs. e10-72 to e10-79) While many systemic diseases also have cutaneous manifestations, there are some well recognized dermatologic markers of internal disease, and some are demonstrated in this section. Many of these dermatologic markers may precede, accompany, or follow diagnosis of systemic disease. Acanthosis nigricans is a prototypical dermatologic process often occurring in association with underlying systemic abnormalities, most commonly obesity and insulin resistance. It may also be associated with other endocrine disorders and several rare genetic syndromes. Malignant acanthosis nigricans may occur in association with several malignancies, especially adenocarcinoma of the gastrointestinal tract, lung, and breast. Other markers of internal disease in this section include pretibial myxedema, which is associated with thyroid disease, and Sweet’s syndrome, which may be associated with hematologic malignancies, solid tumors, or inflammatory bowel disease. The skin is also involved in many systemic inflammatory diseases such as sarcoidosis, rheumatoid arthritis, and lupus erythematosus.
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FIGURE e10-75 Bilateral rheumatoid nodules of the upper extremities. (Courtesy of Robert Swerlick, MD; with permission.)
FIGURE e10-72 Acanthosis nigricans demonstrating typical hyperpigmented axillary plaques with a velvet-like, verrucous surface.
FIGURE e10-76 Neurofibromatosis demonstrating numerous fleshcolored cutaneous neurofibromas.
FIGURE e10-73 Pretibial myxedema manifesting as waxy, infiltrated plaques in a patient with Graves’ disease.
FIGURE e10-77 Coumarin necrosis showing cutaneous and subcutaneous necrosis of a breast. Other fatty areas such as buttocks and thighs are also common sites of involvement. (Courtesy of Kim Yancey, MD; with permission.)
FIGURE e10-74 Plaque of Sweet’s syndrome demonstrating an erythematous indurated plaque with a pseudo-vesicular border. (Courtesy of Robert Swerlick, MD, with permission.)
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FIGURE e10-78 A. Sarcoid. Infiltrated papules and plaques of variable color are seen in a typical paranasal and periorbital location. B. Sarcoid. Infiltrated, hyperpigmented, and slightly erythematous coalescent papules and plaques on the upper arm. (B, Courtesy of Robert Swerlick, MD; with permission.) FIGURE e10-79 Pyoderma gangrenosum on the posterior-lateral aspect of the lower leg demonstrating multiple purulent draining ulcers on an infiltrated erythematous plaque. (Courtesy of Robert Swerlick, MD; with permission.)
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e11
Atlas of Hematology and Analysis of Peripheral Blood Smears
Dan L. Longo
5. Polychromatophilia—the red cell cytoplasm has a bluish hue, re- e77 flecting the persistence of ribosomes still actively making hemoglobin in a young red cell Vital stains are necessary to see precipitated hemoglobin called Heinz bodies. Red cells can take on a variety of different shapes. All abnormally shaped red cells are poikilocytes. Small red cells without the central pallor are spherocytes; they can be seen in hereditary spherocytosis, hemolytic anemias of other causes, and clostridial sepsis. Dacrocytes are teardrop-shaped cells that can be seen in hemolytic anemias, severe iron deficiency, thalassemias, myelofibrosis, and myelodysplastic syndromes. Schistocytes are helmet-shaped cells that reflect microangiopathic hemolytic anemia or fragmentation on an artificial heart valve. Echinocytes are spiculated red cells with the spikes evenly spaced; they can represent an artifact of abnormal drying of the blood smear or reflect changes in stored blood. They can also be seen in renal failure and malnutrition and are often reversible. Acanthocytes are spiculated red cells with the spikes irregularly distributed. This process tends to be irreversible and reflects underlying renal disease, abetalipoproteinemia, or splenectomy. Elliptocytes are elliptical-shaped red cells that can reflect an inherited defect in the red cell membrane, but they are also seen in iron deficiency, myelodysplastic syndrome, megaloblastic anemia, and thalassemias. Stomatocytes are red cells in which the area of central pallor takes on the morphology of a slit instead of the usual round shape. Stomatocytes can indicate an inherited red cell membrane defect and can also be seen in alcoholism. Target cells have an area of central pallor that contains a dense center, or bull’s eye. These cells are seen classically in thalassemia, but they are also present in iron deficiency, cholestatic liver disease, and some hemoglobinopathies. They can also be generated artifactually by improper slide making. One last feature of the red cells to assess before moving to the white blood cells is the distribution of the red cells on the smear. In most individuals, the cells lie side by side in a single layer. Some patients have red cell clumping (called agglutination) in which the red cells pile upon one another; it is seen in certain paraproteinemias and autoimmune hemolytic anemias. Another abnormal distribution involves red cells lying in single cell rows on top of one another like stacks of coins. This is called rouleaux formation and reflects abnormal serum protein levels. Finally, one examines the white blood cells. Three types of granulocytes are usually present; neutrophils, eosinophils, and basophils, in decreasing frequency. Neutrophils are generally the most abundant white cell. They are round, 10–14 μm wide, and contain a lobulated nucleus with two to five lobes connected by a thin chromatin thread. Bands are immature neutrophils that have not yet completed nuclear condensation and have a U-shaped nucleus. Bands reflect a left shift in neutrophil maturation in an effort to make more cells more rapidly. Neutrophils can provide clues to a variety of conditions. Vacuolated neutrophils may be a sign of bacterial sepsis. The presence of 1- to 2μm blue cytoplasmic inclusions, called Dohle bodies, can reflect infections, burns, or other inflammatory states. If the neutrophil granules are larger than normal and stain a darker blue, “toxic granulations” are said to be present, and they also suggest a systemic inflammation. The presence of neutrophils with more than five nuclear lobes suggests megaloblastic anemia. Large misshapen granules may reflect the inherited Chédiak-Higashi syndrome. Eosinophils are slightly larger than neutrophils, have bilobed nuclei, and contain large red granules. Diseases of eosinophils are associated with too many of them rather than any morphologic or qualitative change. They normally total less than one-thirtieth the number of neutrophils. Basophils are even more rare than eosinophils in the blood. They have large dark-blue granules and may be increased as part of chronic myeloid leukemia, Lymphocytes can be present in several morphologic forms. Most common in healthy individuals are the small lymphocytes with a small dark nucleus and scarce cytoplasm. In the presence of viral infections, more of the lymphocytes are larger, about the size of neutrophils, with abundant cytoplasm and a less condensed nuclear chromatin. These
Some of the relevant findings in peripheral blood, enlarged lymph nodes, and bone marrow are illustrated here. Systematic histologic examination of the bone marrow and lymph node are beyond the scope of a general medicine textbook. However, every internist should know how to examine a peripheral blood smear. The examination of the peripheral blood smear is one of the most informative exercises a physician can perform. While advances in automated technology have made the examination of the peripheral blood smear by the physician seem less important, the technology is not a completely satisfactory replacement for blood smear interpretation by a trained medical professional who also knows the patient’s clinical history, family history, social history, and physical findings. It is useful to ask the laboratory to generate a Wright’s-stained peripheral blood smear and to examine it. The best place to examine blood cell morphology is the feathered edge of the blood smear where red cells lie in a single layer, side by side, just barely touching each other but not overlapping. My own approach is to look at the smallest cellular elements first, the platelets, and work my way up in size to red cells and then white cells. Using an oil immersion lens that magnifies the cells 100-fold, one first counts the platelets in five to six fields, averages the number per field, and multiplies by 20,000 to get a rough estimate of the platelet count. The platelets are usually 1–2 μm in diameter and have a blue granulated appearance. There is usually 1 platelet for every 20 or so red cells. Of course, the automated counter is much more accurate, but gross disparities between the automated and manual counts should be assessed. Large platelets may be a sign of rapid platelet turnover, as young platelets are often larger than old platelets; alternatively, certain rare inherited syndromes can produce large platelets. Platelet clumping visible on the smear can be associated with falsely low automated platelet counts. Similarly, neutrophil fragmentation can be a source of falsely elevated automated platelet counts. Next one examines the red blood cells. One can gauge their size by comparing the red cell to the nucleus of a small lymphocyte. Both are normally about 8 μm wide. Red cells that are smaller than the small lymphocyte nucleus may be microcytic; those larger than the small lymphocyte nucleus may be macrocytic. The automated mean corpuscular volume (MCV) can assist in making a classification. However, some patients may have both iron and vitamin B12 deficiency, which will produce an MCV in the normal range but wide variation in red cell size. When the red cells vary greatly in size, anisocytosis is said to be present. When the red cells vary greatly in shape, poikilocytosis is said to be present. After red cell size is assessed, one examines the hemoglobin content of the cells. They are either normal in color (normochromic) or they are pale in color (hypochromic). They are never “hyperchromic.” If more than the normal amount of hemoglobin is made, the cells get larger—they do not become darker. In addition to hemoglobin content, the red cells are examined for inclusions. Red cell inclusions are the following: 1. Basophilic stippling—diffuse fine or coarse blue dots in the red cell representing usually RNA residue—especially common in lead poisoning 2. Howell-Jolly bodies—dense blue circular inclusions that represent nuclear remnants—their presence implies defective splenic function 3. Nuclei—red cells may be released or pushed out of the marrow prematurely before nuclear extrusion—often implies a myelophthisic process 4. Parasites—red cell parasites include malaria and babesia (Chap. e18)
CHAPTER e11 Atlas of Hematology and Analysis of Peripheral Blood Smears
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e78 are called reactive lymphocytes. About 1% of the lymphocytes are larger
and contain blue granules in a light blue cytoplasm; these are called large granular lymphocytes. In chronic lymphoid leukemia, the small lymphocytes are increased in number, and many of them are ruptured in making the blood smear, leaving a smudge of nuclear material without a surrounding cytoplasm or cell membrane; these are called smudge cells and are rare in the absence of chronic lymphoid leukemia. Monocytes are the largest white blood cells, ranging from 15–22 μm in diameter. The nucleus can take on a variety of shapes but usually appears to be folded; the cytoplasm is gray. Abnormal cells may appear in the blood. Most often the abnormal cells originate from neoplasms of bone marrow–derived cells including lymphoid cells, myeloid cells, and occasionally red cells. More rarely, other types of tumors can get access to the blood stream, and rare epithelial malignant cells may be identified. The chances of seeing such abnormal cells is increased by examining blood smears made from buffy coats, the layer of cells that is visible on top of sedimenting red cells when blood is left in the test tube for an hour. Smears made from finger sticks may include rare endothelial cells. ACKNOWLEDGMENT Figures in this e-chapter were borrowed from Williams Hematology, 7th edition, M Lichtman et al (eds). New York, McGraw-Hill, 2005; Hematology in General Practice, 4th edition, RS Hillman, KA Ault, New York, McGraw-Hill, 2005.
PART 2
Cardinal Manifestations and Presentation of Diseases
FIGURE e11-3 Hypochromic microcytic anemia of iron deficiency. Small lymphocyte in field helps assess the red blood cell size.
FIGURE e11-4 Iron deficiency anemia next to normal red blood cells. Microcytes (right panel ) are smaller than normal red blood cells (cell diameter 100) and are somewhat oval in shape. Some morphologists call these cells “macroovalocytes.”
FIGURE e11-9 Rouleaux formation. Small lymphocyte in center of field. These red cells align themselves in stacks and are related to increased serum protein levels.
FIGURE e11-7 Hypersegmented neutrophils. Hypersegmented neutrophils (multilobed polymorphonuclear leukocytes) are larger than normal neutrophils with five or more segmented nuclear lobes. They are commonly seen with folic acid or vitamin B12 deficiency.
FIGURE e11-10 Red cell agglutination. Small lymphocyte and segmented neutrophil upper left center. Note irregular collections of aggregated red cells.
FIGURE e11-8 Spherocytosis. Note small hyperchromatic cells without the usual clear area in the center.
FIGURE e11-11 Fragmented red cells. Heart valve hemolysis.
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FIGURE e11-12 Sickle cells. Homozygous sickle cell disease. A nucleated red cell and neutrophil are also in the field.
FIGURE e11-15 Stomatocytosis. Red cells characterized by a wide transverse slit or stoma. This is often seen as an artifact in a dehydrated blood smear. These cells can be seen in hemolytic anemias and in conditions in which the red cell is overhydrated or dehydrated.
FIGURE e11-13 Target cells. Target cells are recognized by the bull’seye appearance of the cell. Small numbers of target cells are seen with liver disease and thalassemia. Larger numbers are typical of hemoglobin C disease. FIGURE e11-16 Acanthocytosis. Spiculated red cells are of two types: acanthocytes are contracted dense cells with irregular membrane projections that vary in length and width; echinocytes have small, uniform, and evenly spaced membrane projections. Acanthocytes are present in severe liver disease, in patients with abetalipoproteinemia, and in rare patients with McLeod blood group. Echinocytes are found in patients with severe uremia, in glycolytic red cell enzyme defects, and in microangiopathic hemolytic anemia.
FIGURE e11-14 Elliptocytosis. Small lymphocyte in center of field. Elliptical shape of red cells related to weakened membrane structure, usually due to mutations in spectrin.
FIGURE e11-17 Howell-Jolly bodies. Howell-Jolly bodies are tiny nuclear remnants that are normally removed by the spleen. They appear in the blood after splenectomy (defect in removal) and with maturation/dysplastic disorders (excess production).
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CHAPTER e11 Atlas of Hematology and Analysis of Peripheral Blood Smears
FIGURE e11-18 Teardrop cells and nucleated red blood cells characteristic of myelofibrosis. A teardrop-shaped red blood cell (left panel ) and a nucleated red blood cell (right panel ) as typically seen with myelofibrosis and extramedullary hematopoiesis.
FIGURE e11-21 Stippled red cell in lead poisoning. Mild hypochromia. Coarsely stippled red cell.
FIGURE e11-19 Myelofibrosis of the bone marrow. Total replacement of marrow precursors and fat cells by a dense infiltrate of reticulin fibers and collagen (H&E stain).
FIGURE e11-22 Heinz bodies. Blood mixed with hypotonic solution of crystal violet. The stained material is precipitates of denatured hemoglobin within cells.
FIGURE e11-23 Giant platelets. Giant platelets, together with a marked increase in the platelet count, are seen in myeloproliferative disorders, especially primary thrombocythemia. FIGURE e11-20 Reticulin stain of marrow myelofibrosis. Silver stain of a myelofibrotic marrow showing an increase in reticulin fibers (black-staining threads).
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FIGURE e11-24 Normal granulocytes. The normal granulocyte has a segmented nucleus with heavy, clumped chromatin; fine neutrophilic granules are dispersed throughout the cytoplasm.
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FIGURE e11-27 Normal basophil. The film was prepared from the buffy coat of the blood from a normal donor. L, lymphocyte; B, basophil.
FIGURE e11-28 Pelger-Hüet anomaly. In this benign disorder, the majority of granulocytes are bilobed. The nucleus frequently has a spectacle-like, or “pince-nez” configuration. FIGURE e11-25 Normal monocytes. The film was prepared from the buffy coat of the blood from a normal donor. L, lymphocyte; M monocyte; N, neutrophil.
FIGURE e11-29 Döhle body. Neutrophil band with Döhle body. The neutrophil with a sausage-shaped nucleus in the center of the field is a band form. Döhle bodies are discrete, blue-staining nongranular areas found in the periphery of the cytoplasm of the neutrophil in infections and other toxic states. They represent aggregates of rough endoplasmic reticulum.
FIGURE e11-26 Normal eosinophils. The film was prepared from the buffy coat of the blood from a normal donor. N, neutrophil; E, eosinophil.
FIGURE e11-30 Chédiak-Higashi disease. Note giant granules in neutrophil.
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CHAPTER e11 Atlas of Hematology and Analysis of Peripheral Blood Smears
FIGURE e11-31 Normal bone marrow. Low-power view of normal adult marrow (H&E stain), showing a mix of fat cells (clear areas) and hematopoietic cells. The percentage of the space that is hematopoietic cells is referred to as marrow cellularity. In adults, normal marrow cellularity is 35–40%. If demands for increased marrow production occur, cellularity may increase to meet the demand. As we age, the marrow cellularity decreases and the marrow fat increases. Patients >70 years may have a 20–30% marrow cellularity.
FIGURE e11-34 Lymphoma in the bone marrow. Nodular (follicular) lymphoma infiltrate in a marrow biopsy specimen. Note the characteristic paratrabecular location of the lymphoma cells.
FIGURE e11-32 Aplastic anemia bone marrow. Normal hematopoietic precursor cells are virtually absent, leaving behind fat cells, reticuloendothelial cells, and the underlying sinusoidal structure.
FIGURE e11-35 Erythroid hyperplasia of the marrow. Marrow aspirate specimen with a myeloid/erythroid ratio (M/E ratio) of 1:1–2, typical for a patient with a hemolytic anemia or recovering from blood loss.
FIGURE e11-33 Metastatic cancer in the bone marrow. Marrow biopsy specimen infiltrated with metastatic breast cancer and reactive fibrosis (H&E stain).
FIGURE e11-36 Myeloid hyperplasia of the marrow. Marrow aspirate specimen showing a myeloid/erythroid ratio of ≥3:1, suggesting either a loss of red blood cell precursors or an expansion of myeloid elements.
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FIGURE e11-37 Megaloblastic erythropoiesis. High-power view of megaloblastic red blood cell precursors from a patient with a macrocytic anemia. Maturation is delayed with late normoblasts showing a more immature appearing nucleus with a lattice-like pattern with normal cytoplasmic maturation.
FIGURE e11-40 Acute myeloid leukemia. Leukemic myeloblast with an Auer rod. Note two to four large, prominent nucleoli in each cell.
FIGURE e11-41 Acute promyelocytic leukemia. Note prominent cytoplasmic granules in the leukemia cells. FIGURE e11-38 Prussian blue staining of marrow iron stores. Iron stores can be graded on a scale of 0 to 4+. A: a marrow with excess iron stores (>4+); B: normal stores (2–3+); C: minimal stores (1+); and D: absent iron stores (0).
FIGURE e11-42 Acute erythroleukemia. Note giant dysmorphic erythroblasts, two are binucleate and one is multinucleate.
FIGURE e11-39 Ringed sideroblast. An orthochromatic normoblast with a collar of blue granules (mitochondria encrusted with iron) surrounding the nucleus.
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CHAPTER e11 Atlas of Hematology and Analysis of Peripheral Blood Smears
FIGURE e11-43 Acute lymphoblastic leukemia.
FIGURE e11-46 Chronic lymphoid leukemia in the peripheral blood.
FIGURE e11-44 Burkitt’s leukemia, acute lymphoblastic leukemia. FIGURE e11-47 Sézary’s syndrome. Lymphocytes with frequently convoluted nuclei (Sézary cells) in a patient with advanced mycosis fungoides.
FIGURE e11-48 Adult T cell leukemia. Peripheral blood smear showing leukemia cells with typical “flower-shaped” nucleus.
FIGURE e11-45 Chronic myeloid leukemia in the peripheral blood.
FIGURE e11-49 Follicular lymphoma in a lymph node. The normal nodal architecture is effaced by nodular expansions of tumor cells. Nodules vary in size and contain predominantly small lymphocytes with cleaved nuclei along with variable numbers of larger cells with vesicular chromatin and prominent nucleoli.
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FIGURE e11-50 Diffuse large B cell lymphoma in a lymph node. The neoplastic cells are heterogeneous but predominantly large cells with vesicular chromatin and prominent nucleoli.
FIGURE e11-53 Hodgkin’s disease. A Reed-Sternberg cell is present near the center of the field; a large cell with a bilobed nucleus and prominent nucleoli giving an “owl’s eyes” appearance. The majority of the cells are normal lymphocytes, neutrophils, and eosinophils that form a pleiomorphic cellular infiltrate.
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FIGURE e11-51 Burkitt’s lymphoma in a lymph node. Burkitt’s lymphoma with starry-sky appearance. The lighter areas are macrophages attempting to clear dead cells. FIGURE e11-52 Erythrophagocytosis accompanying aggressive lymphoma. The central macrophage is ingesting red cells, neutrophils, and platelets. (Courtesy of Dr. Kiyomi Tsukimori, Kyushu University, Fukuoka, Japan.)
FIGURE e11-54 Lacunar cell; Reed-Sternberg cell variant in nodular sclerosing Hodgkin’s disease. High-power view of single mononuclear lacunar cell with retracted cytoplasm in a patient with nodular sclerosing Hodgkin’s disease.
FIGURE e11-55 Normal plasma cell.
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CHAPTER e11 Atlas of Hematology and Analysis of Peripheral Blood Smears
FIGURE e11-56 Multiple myeloma. FIGURE e11-57 Color serum in hemoglobinemia. The distinctive red coloration of plasma (hemoglobinemia) in a spun blood sample in a patient with intravascular hemolysis.
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e12
Thymoma
Dan L. Longo
TABLE e12-1 MASAOKA STAGING SYSTEM FOR THYMOMAS Stage
I II IIA IIB III IIIA IIIB IV IVA IVB Pleural or pericardial dissemination Lymphatic or hematogenous metastases Macroscopic invasion into neighboring organs, pericardium, or pleura but not the great vessels Macroscopic invasion into neighboring organs that includes great vessels Microscopic invasion outside of the capsule Macroscopic invasion into surrounding fat or grossly adherent to pleura or pericardium
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Diagnostic Criteria
Macroscopically and microscopically completely encapsulated; no invasion through capsule
The thymus is derived from the third and fourth pharyngeal pouches and is located in the anterior mediastinum. The thymus is composed of epithelial and stromal cells derived from the pharyngeal pouch and lymphoid precursors derived from mesodermal cells. It is the site to which bone marrow precursors that are committed to differentiate into T cells migrate to complete their differentiation. Like many organs, it is organized into functional regions—in this case, the cortex and the medulla. The cortex of the thymus contains ~85% of the lymphoid cells and the medulla ~15%. It appears that the primitive bone marrow progenitors enter the thymus at the corticomedullary junction and migrate first through the cortex toward the periphery of the gland and then toward the medulla as they mature. Medullary thymocytes have a phenotype that cannot readily be distinguished from mature peripheral blood and lymph node T cells. Several things can go wrong with the thymus, but thymic abnormalities are very rare. If the thymus does not develop properly, serious deficiencies in T cell development ensue and severe immunodeficiency is seen (e.g., DiGeorge syndrome, Chap. 310). If a lymphoid cell within the thymus becomes neoplastic, the disease that develops is a lymphoma. The majority of lymphoid tumors that develop in the thymus are derived from the precursor T cells, and the tumor is a precursor T cell lymphoblastic lymphoma (Chap. 105). Rare B cells exist in the thymus, and when these become neoplastic, the tumor is a mediastinal (thymic) B cell lymphoma (Chap. 105). Germ cell tumors and carcinoid tumors may occasionally arise in the thymus. If the epithelial cells of the thymus become neoplastic, the tumor that develops is a thymoma. CLINICAL PRESENTATION AND DIFFERENTIAL DIAGNOSIS Thymoma is the most common cause of an anterior mediastinal mass in adults, accounting for ~40% of all mediastinal masses. The other major causes of anterior mediastinal mass are lymphomas, germ cell tumors, and substernal thyroid tumors. Carcinoid tumors, lipomas, and thymic cysts may also produce radiographic masses. Thymomas are most common in the fifth and sixth decades, are uncommon in children, and are distributed evenly between men and women. About 40–50% of patients are asymptomatic; masses are detected incidentally on routine chest radiographs. When symptomatic, patients may have cough, chest pain, dyspnea, fever, wheezing, fatigue, weight loss, night sweats, or anorexia. Occasionally, thymomas may obstruct the superior vena cava. About 40% of patients with thymoma have another systemic autoimmune illness related to the thymoma. About 30% of patients with thymoma have myasthenia gravis, 5–8% have pure red cell aplasia, and ~5% have hypogammaglobulinemia. Among patients with myasthenia gravis, ~10–15% have a thymoma. Thymoma more rarely may be associated with polymyositis, systemic lupus erythematosus, thyroiditis, Sjögren’s syndrome, ulcerative colitis, pernicious anemia, Addison’s disease, scleroderma, and panhypopituitarism. In one series, 70% of patients with thymoma were found to have another systemic illness (Souadjian et al, 1974). DIAGNOSIS AND STAGING Once a mediastinal mass is detected, a surgical procedure is required for definitive diagnosis. An initial mediastinoscopy or limited thoracotomy can be undertaken to get sufficient tissue to make an accurate diagnosis. Fine-needle aspiration is poor at distinguishing between lymphomas and thymomas but is more reliable in diagnosing germ cell tumors and metastatic carcinoma. Thymomas and lymphomas require sufficient tissue to examine the tumor architecture to assure an accurate diagnosis and obtain prognostic information. Once a diagnosis of thymoma is defined, subsequent staging generally occurs at surgery. However, chest CT scans can assess local invasiveness in some instances. MRI has a defined role in the staging of posterior mediastinal tumors, but it is not yet clear that it adds impor-
CHAPTER e12 Thymoma
Stage Distribution, %
I II III IV 65 25 5 5
5-Year Survival, %
95–100 70–100 50–70 11–50
10-Year Survival, %
86–100 5–100 47–60 0–11
Source: From A Masaoka et al: Cancer 48:2485, 1981.
tant information to the CT scan in anterior mediastinal tumors. Somatostatin receptor imaging with indium-labeled somatostatin analogues may be of value (Lin et al, 1999). If invasion is not distinguished by noninvasive testing, an effort to resect the entire tumor should be undertaken. If invasion is present, neoadjuvant chemotherapy may be warranted before surgery (see “Treatment,” below). Some 90% of thymomas are in the anterior mediastinum, but some may be in other mediastinal sites or even the neck, based on aberrant migration of the developing thymic enlage. The staging system for thymoma was developed by Masaoka and colleagues (Table e12-1). It is an anatomic system in which the stage is increased based on the degree of invasiveness. The 5-year survival of patients in the various stages is as follows: stage I, 96%; stage II, 86%; stage III, 69%; stage IV, 50%. The French Study Group on Thymic Tumors (GETT; Cowen et al, 1998) has proposed modifications to the Masaoka scheme based upon the degree of surgical removal because the extent of surgery has been noted to be a prognostic indicator. In their system, stage I tumors are divided into A and B based on whether the surgeon suspects adhesions to adjacent structures; stage III tumors are divided into A and B based upon whether disease was subtotally resected or only biopsied. The concurrence between the two systems is high. PATHOLOGY AND ETIOLOGY Thymomas are epithelial tumors and all of them have malignant potential. It is not worthwhile to try to divide them into benign and malignant forms; the key prognostic feature is whether they are noninvasive or invasive. About 65% of thymomas are encapsulated and noninvasive and about 35% are invasive. They may have a variable percentage of lymphocytes within the tumor, but genetic studies suggest that the lymphocytes are benign polyclonal cells. The epithelial component of the tumor may consist primarily of round or oval cells derived mainly from the cortex or spindle-shaped cells derived mainly from the medulla or combinations thereof (Table e12-2). Cytologic features are not reliable predictors of biological behavior. About 90% of A, AB, and B1 tumors are localized. A very small number of patients have aggressive histology features characteristic of carcinomas. Thymic carcinomas are invasive and carry a poor prognosis. The genetic lesions in thymomas are not well characterized. Some data suggest that Epstein-Barr virus may be associated with thymomas (Dimery et al, 1988). Some tumors overexpress the p21 ras gene product. However, molecular pathogenesis remains undefined. A thymoma susceptibility locus has been defined on rat chromosome 7, but the re-
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e90
TABLE e12-2 WHO HISTOLOGIC CLASSIFICATION OF THYMUS TUMORS a Type
A AB B1 B2 B3 C
Histologic Description
Medullary thymoma Mixed thymoma Predominantly cortical thymoma Cortical thymoma Well-differentiated thymic carcinoma Thymic carcinoma
Some thymic carcinomas express c-kit, and one patient whose c-kit locus was mutated responded dramatically to imatanib. Many thymomas express epidermal growth factor receptors, but the antibodies to the receptor and kinase inhibitors that block its action have not been systematically evaluated. Octreotide plus prednisone produces responses in about one-third of patients.
Type
A AB B1 B2 B3 C
Distribution, %
8 17 27 8 12 28
Prognosis (10-year disease-free survival), %
100 100 83 83 36 28
aWHO, World Health Organization.
lationship between this gene locus, termed Tsr1, and human thymoma has not yet been examined.
THYMOMA
Treatment is determined by the stage of disease. For patients with encapsulated tumors and stage I disease, complete resection is sufficient to cure 96% of patients. For patients with stage II disease, complete resection is usually followed by 30–60 Gy of postoperative radiation therapy to the site of the primary tumor. For patients with stage III and IV disease, the use of neoadjuvant chemotherapy followed by radical surgery, radiation therapy, and additional consolidation chemotherapy has been associated with excellent survival in a small group of patients so treated (Shin et al, 1998). Induction chemotherapy consisted of cyclophosphamide 500 mg/m2 on day 1; continuous-infusion doxorubicin, 20 mg/m2 per day on days 1–3 (total 60 mg/m2); cisplatin, 30 mg/m2 per day on days 1–3 (total 90 mg/ m2); and prednisone, 100 mg/d on days 1–5. Three cycles were given in 3to 4-week intervals. Of 12 patients treated with this regimen, 3 had complete responses, 8 had partial responses, and 1 had a minor response. These patients then underwent surgical resection; tumor was completely resected in nine and incompletely resected in two patients (one patient refused surgery and received radiation therapy only). After surgery, all patients received radiation therapy (50–60 Gy) and three additional courses of chemotherapy at 80% of the doses used for neoadjuvant therapy. At a median follow-up of 43 months, 10 of the 12 patients were free of disease, and the 2 patients who had local recurrence remain alive with disease. Survival at 7 years is 100%. This multimodality approach appears to be superior to the use of surgery followed by radiation therapy alone, which produces a 5-year survival of ≤50% in patients with advanced-stage disease.
INFLUENCE OF THYMECTOMY ON THE COURSE OF ACCOMPANYING DISEASES Patients with myasthenia gravis have a high incidence of thymic abnormalities (~80%) but overt thymoma is present in only ~10–15% of patients with myasthenia gravis. It is thought that the thymus plays a role in breaking self-tolerance and generating T cells that recognize the acetylcholine receptor as a foreign antigen. Although patients with thymoma and myasthenia gravis are less likely to have a remission in the myasthenia as a consequence of thymectomy than are patients with thymic abnormalities other than thymoma, the course of myasthenia gravis is not significantly different in patients with or without thymoma (Bril et al, 1998). Thymectomy produces at least some symptomatic improvement in ~65% of patients with myasthenia gravis. About 30–50% of patients with pure red cell aplasia have a thymoma. Thymectomy results in the resolution of pure red cell aplasia in ~30% of patients. About 10% of patients with hypogammaglobulinemia have a thymoma, but hypogammaglobulinemia rarely responds to thymectomy.
PART 6
Oncology and Hematology
FURTHER READINGS
BRIL V et al: The long-term clinical outcome of myasthenia gravis in patients with thymoma. Neurology 51:1198, 1998 [PMID: 9781560] COWEN D et al: Natural history and treatment of malignant thymoma. Oncology 12:1001, 1998 [PMID: 9684271] DIMERY IW et al: Association of Epstein-Barr virus with lymphoepithelioma of the thymus. Cancer 61:2475, 1998 [PMID: 2835144] GIACCONE G: Treatment of malignant thymoma. Curr Opin Oncol 17:140, 2005 [PMID: 15725919] LIN K et al: Somatostatin receptor scintigraphy and somatostatin therapy in the evaluation and treatment of malignant thymoma. Clin Nucl Med 24:24, 1999 [PMID: 9890489] PETRIE HT: Cell migration and the control of post-natal T-cell lymphopoiesis in the thymus. Nat Rev Immunol 3:859, 2003 [PMID: 14668802] SHIN DM et al: A multidisciplinary approach to therapy for unresectable malignant thymoma. Ann Intern Med 129:100, 1998 [PMID: 9669967] SOUADJIAN JV et al: The spectrum of diseases associated with thymoma. Arch Intern Med 134:374, 1974 [PMID: 4602050] WRIGHT CD: Management of thymomas. Crit Rev Oncol Hematol 64, 2007 [PMID: 17570676]
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Consequences e13 Late Its Treatment of Cancer and
Michael C. Perry, Dan L. Longo
Over 9 million Americans alive today have had cancer. Virtually all of these survivors will bear some mark of their diagnosis and its therapy, and many will experience long-term complications, including medical problems, psychosocial disturbances, sexual dysfunction, and inability to find employment or insurance. Problems may be related to the cancer itself (e.g., patients with primary cancers of the head and neck are at increased risk for subsequent lung cancer) or to the normal aging process (surviving one cancer does not necessarily alter the risk of other common tumors that increase in frequency with age). However, many of the problems affecting cured patients are related to the treatments. Individuals carefully followed for periods up to 30 years have taught us the spectrum of problems that can be CONSEQUENCES BY ORGAN SYSTEM encountered. Because of heterogeneity in treatment details and incom- CARDIOVASCULAR DYSFUNCTION pleteness of follow-up, some treatment-related problems went undetec- Most anthracyclines damage the heart muscle. A dose-dependent ted for many years. However, studies of long-term survivors of dropout of myocardial cells is seen on endomyocardial biopsy, and childhood cancers, acute leukemia, Hodgkin’s disease, lymphomas, tes- eventually ventricular failure ensues. About 5% of patients who receive ticular cancer, and localized solid tumors have identified the features of >550 mg/m2 of doxorubicin will develop congestive heart failure cancer treatment that are associated with later morbidity and mortality. (CHF). Coexisting cardiac disease, hypertension, advanced age, and We have been somewhat slow to act in changing those aspects of prima- concomitant therapy with thoracic radiation therapy may hasten the ry treatment that contribute to these late problems. This reticence is due onset of CHF. Anthracycline-induced CHF is not readily reversible; to the uncertainty associated with changing a treatment that is known to work before having a replacement that works as well. TABLE e13-1 LATE EFFECTS OF CANCER THERAPY Survivorship issues have been addressed by Surgical Procedure Effect the Institute of Medicine and the National Research Council, who have published a monoAmputation Functional loss Lymph node dissection Risk of lymphedema graph on this subject—From Cancer Patient to Ostomy Psychosocial impact Cancer Survivor: Lost in Transition. Their “SurSplenectomy Risk of sepsis vivorship Care Plan,” if uniformly carried out, Adhesions Risk of obstruction would inform clinicians who assume the care Bowel anastomoses Malabsorption syndromes of cancer survivors of their previous treatRadiation Therapy Effect ments; signs and symptoms of late effects; and, where established, guidelines for intervention. Organ An “End-of-Treatment Consultation Note” Bone Premature termination of growth, osteonecrosis would include the date, physician’s name, date Soft tissues Atrophy, fibrosis Brain Neuropsychiatric deficits, cognitive dysfunction of tissue diagnosis, diagnosis, stage, pathologic Thyroid Hypothyroidism, Graves’ disease, cancer findings, initial treatment plan, and treatment Salivary glands Dry mouth, caries, dysgeusia received. In addition, unusual or unexpected Eyes Cataracts toxicities would be noted and the expected Heart Pericarditis, myocarditis, coronary artery disease short- and long-term effects of treatment deLung Pulmonary fibrosis tailed. Suggestions for monitoring for late toxKidney Decreased function, hypertension Liver Decreased function icity should be given as well, including Intestine Malabsorption, stricture recommendations for surveillance for recurGonads Infertility, premature menopause rence and second malignancies, the physiAny Secondary neoplasia cian(s) responsible for monitoring, and any Chemotherapy Effect identified psychosocial issues or concerns. The first task in a newly diagnosed patient is Organ Drug always to eradicate the diagnosed malignancy. Bone Glucocorticoids Osteoporosis, avascular necrosis Late problems occurring in cured patients reBrain Methotrexate, ara-C, Neuropsychiatric deficits, cognitive decline? flect the success of such treatment. These probothers Peripheral nerves Vincristine, platinum, Neuropathy, hearing loss lems never develop in those who do not taxanes survive the cancer. Morbidity and mortality Eyes Glucocorticoids Cataracts from iatrogenic disease should be avoided, if Heart Anthracyclines, Cardiomyopathy possible; however, the risk of late complicatrastuzumab tions should not lead to the failure to apply poLung Bleomycin Pulmonary fibrosis tentially curative treatment. The challenge is to Methotrexate Pulmonary hypersensitivity Kidney Platinum, others Decreased function, hypomagnesemia preserve or augment the cure rate while deLiver Various Altered function creasing the risk of serious treatment-related Gonads Alkylating agents, Infertility, premature menopause illness. others The mechanisms of damage vary. Surgical Bone marrow Various Aplasia, myelodysplasia, secondary leukemia procedures can create abnormal physiology
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(such as blind loops leading to malabsorption) or interfere with nor- e91 mal organ function (splenectomy leading to impaired immune response). Radiation therapy can damage organ function directly (salivary gland toxicity leading to dry mouth and dental caries), act as a carcinogen (second solid tumors in radiation ports), or promote accelerated aging-associated changes (atherosclerosis). Cancer chemotherapy can produce damage to the bone marrow and immune system and induce a spectrum of organ dysfunctions. Therapy may produce subclinical damage that may only become recognized in the presence of a second inciting factor (such as the increased incidence of melanoma in patients with dysplastic nevus syndrome treated for Hodgkin’s disease with radiation therapy). Finally, cancer and its treatment are associated with psychosocial problems that can impair the survivor’s ability to adapt to life after cancer. Late effects by treatment modality are shown in Table e13-1. Drug toxicities and radiation therapy toxicities are discussed in Chap. 81.
CHAPTER e13 Late Consequences of Cancer and Its Treatment
e92 mortality is as high as 50%, thus, prevention is the best approach.
Mitoxantrone is a related drug that has less cardiac toxicity. Administration of doxorubicin by continuous intravenous infusion or encapsulated in liposomes appears to decrease the risk of heart damage. Dexrazoxane, an intracellular iron chelator, may protect the heart against anthracycline toxicity by preventing iron-dependent free-radical generation. Concern about antagonism of antitumor effects has restricted its use. Mediastinal radiation therapy that includes the heart can induce acute pericarditis, chronic constrictive pericarditis, myocardial fibrosis, valvular abnormalities, or accelerated premature coronary atherosclerosis. The incidence of acute pericarditis is 5–13%; patients may be asymptomatic or have dyspnea on exertion, fever, and chest pain. The onset is insidious, with a peak about 9 months after treatment. Pericardial effusion may be present. Chronic constrictive pericarditis can develop 5–10 years after treatment and usually presents with dyspnea on exertion. Myocardial fibrosis may present as unexplained CHF with diagnostic evaluation showing restrictive cardiomyopathy. Patients may have aortic insufficiency from valvular thickening or mitral regurgitation from papillary muscle dysfunction. Patients who receive mantle field radiation therapy have a threefold increased risk of fatal myocardial infarction. Similarly, radiation of the carotids is associated with premature atherosclerosis of the carotids and can produce central nervous system (CNS) embolic disease. At very high doses, such as those used before hematopoietic stem cell transplantation, cyclophosphamide can produce a hemorrhagic myocarditis. Trastuzumab (herceptin) has been associated with heart failure, particularly in patients also receiving anthracyclines. Compromised ejection fraction is noted in about 10% of patients; it is usually reversible with the cessation of therapy. PULMONARY DYSFUNCTION Pulmonary fibrosis from bleomycin is dose-related, with potential exacerbation by age, preexisting lung disease, thoracic radiation, high concentrations of inhaled oxygen, and the concomitant use of other chemotherapeutic agents. Several other chemotherapy agents and radiation therapy can cause pulmonary fibrosis, and several can cause pulmonary venoocclusive disease, especially following high-dose therapy such as that involved in hematopoietic stem cell transplantation. LIVER DYSFUNCTION Clinically significant long-term damage to the liver from standarddose chemotherapy is relatively infrequent and mostly confined to patients who have received chronic methotrexate for maintenance therapy of acute lymphoblastic leukemia. Radiation doses to the liver >1500 cGy can produce liver dysfunction. Although rarely seen with standard-dose chemotherapy, hepatic venoocclusive disease is more common with high-dose therapy, such as that given to prepare patients for autologous or allogeneic stem cell transplantation. Endothelial damage is probably the inciting event. RENAL/BLADDER DYSFUNCTION Reduced renal function may be produced by cisplatin; it is usually asymptomatic but may render the patient more susceptible to other renal insults. Cyclophosphamide cystitis may eventually lead to the development of bladder cancer. Ifosfamide produces cystitis and a proximal tubular defect, a Fanconi-like syndrome that is usually, but not always, reversible. ENDOCRINE DYSFUNCTION Long-term survivors of childhood cancer who received cranial irradiation are shorter, more likely to be obese, and have reductions in strength, exercise tolerance, and bone mineral density. The obesity may be related to alterations in leptin biology. Growth hormone deficiency is the most common hormone deficiency. Thyroid disease is common in patients who have received radiation therapy to the neck, such as patients with Hodgkin’s disease, with an incidence of up to 62% at 26 years post-therapy. Hypothyroidism
is the most common abnormality, followed by Graves’ disease, thyroiditis, and cancer. Such patients should have frequent measurement of thyroid-stimulating hormone (TSH) levels to detect hypothyroidism early and suppress the TSH drive, which may contribute to thyroid cancer. NERVOUS SYSTEM DYSFUNCTION Although many patients experience peripheral neuropathy during chemotherapy, only a few have chronic problems, perhaps because they have other coexisting diseases such as diabetes mellitus. High doses of cisplatin can produce severe sensorimotor neuropathy. Vincristine may produce permanent numbness and tingling in the fingers and toes. Neurocognitive sequelae from intrathecal chemotherapy, with or without radiation therapy, are recognized complications of the successful therapy of childhood acute lymphoblastic leukemia. Cognitive decline has been attributed to CNS radiation in the treatment of a variety of tumor types. In addition, cognitive decline (“chemo brain”) can follow the use of adjuvant chemotherapy in women being treated for breast cancer. Because the agents are given at modest doses and are not thought to cross the blood-brain barrier, the mechanism of the cognitive decline is not defined. The phenomenon has not yet been documented in adequately designed studies that take into account the normal age-associated decline in cognition. Many patients suffer intrusive thoughts about cancer recurrence for many years after successful treatment. Adjustment to normal expectations can be difficult. Cancer survivors may often have more problems holding a job, staying in a stable relationship, and coping with the usual stresses of daily life. Suicidal symptoms are reported by a significant minority of adult survivors of childhood cancer and represent treatable conditions requiring follow-up care. A dose-related hearing loss can occur with the use of cisplatin, usually with doses >400 mg/m2. This is irreversible, and patients should be screened with audiometric examinations periodically during such therapy. EYES Cataracts may be caused by chronic glucocorticoid use, radiation therapy to the head, and, rarely, by tamoxifen. SEXUAL AND REPRODUCTIVE DYSFUNCTION Reversible azoospermia can be caused by many chemotherapy agents. The gonads may also be permanently damaged by radiation therapy or by chemotherapeutic agents, particularly the alkylating agents. The extent of the damage depends upon the patient’s age and the total dose administered. As a woman nears menopause, smaller amounts of chemotherapy will produce ovarian failure. In men, chemotherapy may produce infertility, but hormone production is not usually affected. Women, however, commonly lose both fertility and hormone production. The premature induction of menopause in a young woman can have serious medical and psychological consequences. Hormone replacement therapy is controversial. Paroxetine and related drugs may be useful in controlling hot flashes. MUSCULOSKELETAL DYSFUNCTION Late consequences of radiation therapy on the musculoskeletal system occur mostly in children and are related to the radiation dose, volume of tissue irradiated, and the age of the child at the time of therapy. Damage to the microvasculature of the epiphyseal growth zone may result in leg length discrepancy, scoliosis, and short stature. RAYNAUD’S PHENOMENON Up to 40% of patients with testicular cancer treated with bleomycin may experience Raynaud’s phenomenon varying in severity from mild and transient to severe. The mechanism is unknown. ORAL COMPLICATIONS Radiation therapy can damage the salivary glands, producing dry mouth. Without saliva, dental caries develop, and many patients have
PART 6
Oncology and Hematology
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poor dentition. In rare patients, taste can be adversely affected and appetite can be suppressed.
SECOND MALIGNANCIES
Second malignancies are a major cause of death for those cured of cancer. Second malignancies can be grouped into three categories: those associated with the primary cancer, those caused by radiation therapy, and those caused by chemotherapy. Primary cancers increase the risk of secondary cancers in a number of settings. Patients with head and neck cancers are at increased risk of developing a lung or esophageal cancer, and vice versa, probably because of shared risk factors, especially tobacco abuse. Patients with breast cancer are at increased risk of a second breast cancer in the contralateral breast. Patients with Hodgkin’s disease are at increased risk of non-Hodgkin’s lymphoma. Patients with genetic syndromes, such as multiple endocrine neoplasia type 1 or Lynch syndrome, are at increased risk of second cancers of specific types. In none of these examples does it appear that treatment of the primary cancer is the cause of the secondary cancer, but a role for treatment is difficult to exclude. These predispositions should result in heightened surveillance in persons at risk. The risk of second cancer is often sufficiently high that cured cancer patients would make excellent candidates to assess chemoprevention strategies. Patients treated with radiation therapy have an increasing and apparently lifelong risk of developing second solid tumors, usually in or adjacent to the radiation field. The risk is modest in the first decade after treatment but reaches 1–2% per year in the second decade, such that populations followed for 25 years or more have a ≥25% chance of developing a second treatment-related tumor. Some organs differ in their susceptibility to radiation carcinogenesis with age; women receiving chest radiation therapy after age 30 have a small increased risk of breast cancer, but those 10 epithelial cells per low-power field and of multiple bacterial types suggests contamination with oral microflora. Despite the difficulty of discriminating between normal microflora and pathogens, Gram’s stain may prove useful for specimens from areas with a large resident microflora if a useful biologic marker (signal) is available. Gram’s staining of vaginal swab specimens can be used to detect epithelial cells covered with gram-positive bacteria in the absence of lactobacilli and the presence of gram-negative rods—a scenario regarded as a sign of bacterial vaginosis. Similarly, examination of stained stool specimens for leukocytes is useful as a screening procedure before testing for Clostridium difficile toxin or other enteric pathogens. The examination of CSF and joint, pleural, or peritoneal fluid with Gram’s stain is useful for determining whether bacteria and/or PMNs are present. The sensitivity is such that >104 bacteria per milliliter should be detected. Centrifugation is often performed before staining to concentrate specimens thought to contain low numbers of organisms. The pellet is examined after staining. This simple method is particularly useful for examination of CSF for bacteria and white blood cells or of sputum for acid-fast bacilli (AFB).
CHAPTER e14 Laboratory Diagnosis of Infectious Diseases
DETECTION METHODS
Reappraisal of the methods employed in the clinical microbiology laboratory has led to the development of strategies for detection of pathogenic agents through nonvisual biologic signal detection systems. Much of this methodology is based on the use of either electronic detection systems involving relatively inexpensive but sophisticated computers or nucleic acid probes directed at specific DNA or RNA targets. This chapter discusses both the methods that are currently available and those that are being developed. BIOLOGIC SIGNALS A biologic signal is a material that can be reproducibly differentiated from other substances present in the same physical environment. Key issues in the use of a biologic (or electronic) signal are distinguishing it from background noise and translating it into meaningful information. Examples of biologic signals applicable to clinical microbiology include structural components of bacteria, fungi, and viruses; specific antigens; metabolic end products; unique DNA or RNA base sequences; enzymes; toxins or other proteins; and surface polysaccharides. DETECTION SYSTEMS A detector is used to sense a signal and to discriminate between the signal and background noise. Detection systems range from the trained eyes of a technologist assessing morphologic variations to sensitive electronic instruments, such as gas-liquid chromatographs coupled to computer systems for signal analysis. The sensitivity with which signals can be detected varies widely. It is essential to use a detection system that discerns small amounts of signal even when biologic background noise is present—i.e., that is both sensitive and specific. Common detection systems include immunofluorescence; chemiluminescence for DNA/RNA probes; flame ionization detection of short- or long-chain fatty acids; and detection of substrate utilization or end-product formation as color changes, of enzyme activity as a change in light absorbance, of turbidity changes as a measure of growth, of cytopathic effects in cell lines, and of particle agglutination as a measure of antigen presence. AMPLIFICATION Amplification enhances the sensitivity with which weak signals can be detected. The most common microbiologic amplification technique is growth of a single bacterium into a discrete colony on an agar plate or into a suspension containing many identical organisms. The advantage of growth as an amplification method is that it requires only
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e98
or in viral cell cultures. The biologic signal in each case is the anGRx only Oxidase + Oxidase – Fastidious Anaerobic Curved tigen to be detected. Monoclonal or polyclonal antibodies couRod Pseudomonas Enterobacteriaceae Haemophilus Bacteroides Vibrio pled to a reporter (such as latex Aeromonas Others Legionella Prevotella Campylobacter Pasteurella Bordetella Fusobacterium particles or an enzyme) are used Others Brucella Others for detection of antibody-antiFrancisella gen binding reactions. Others Techniques such as direct agCoccus Neisseria Veillonella glutination of bacterial cells with Branhamella Acidaminococcus specific antibody are simple but Megasphaera relatively insensitive, while latex agglutination and EIAs are more Gram-Positive Organisms sensitive. Some cell-associated Branching Spores Acid-Fast Catalase + Catalase – antigens, such as capsular polysaccharides and lipopolysacRod Nocardia Clostridium Mycobacterium Corynebacterium Lactobacillus charides, can be detected by Actinomyces Bacillus Listeria Others agglutination of a suspension of Bifidobacterium Others bacterial cells when antibody is Coccus Streptococcus Staphylococcus added; this method is useful for Micrococcus typing of the somatic antigens of Others Shigella and Salmonella. In systems such as EIAs, which employ FIGURE e14-1 Interpretation of Gram’s stain. antibodies coupled to an enzyme, an antigen-antibody reacAcid-Fast Stain The acid-fast stain identifies organisms that retain tion results in the conversion of a colorless substrate to a colored carbol fuchsin dye after acid/organic solvent disruption (e.g., Myco- product. Because the coupling of an enzyme to the antibody can amplify bacterium spp.). Modifications of this procedure allow the differen- a weak biologic signal, the sensitivity of such assays is often high. In each tiation of Actinomyces from Nocardia or other weakly (or partially) instance, the basis for antigen detection is antigen-antibody binding, acid-fast organisms. The acid-fast stain is applied to sputum, other with the detection system changed to accommodate the biologic signal. fluids, and tissue samples when AFB (e.g., Mycobacterium spp.) are Most such assays provide information as to whether antigen is present suspected. The identification of the pink/red AFB against the blue but do not quantify the antigen. EIAs are also useful for detecting bactebackground of the counterstain requires a trained eye, since few AFB rial toxins—e.g., C. difficile toxins A and B in stool. may be detected in an entire smear, even when the specimen has been Rapid and simple tests for antigens of group A Streptococcus, influconcentrated by centrifugation. An alternative method is the au- enza virus, and respiratory syncytial virus can be used in the clinic setramine-rhodamine combination fluorescent dye technique. ting, without a specialized diagnostic laboratory. Such tests are usually reasonably specific but may have only modest sensitivity. Fluorochrome Stains Fluorochrome stains, such as acridine orange, are used to identify white blood cells, yeasts, and bacteria in body fluids. Other specialized stains, such as Dappe’s stain, may be used for the DETECTION OF PATHOGENIC AGENTS BY CULTURE detection of mycoplasmas in cell cultures. Capsular, flagellar, and SPECIMEN COLLECTION AND TRANSPORT spore stains are used for identification or demonstration of character- To culture bacterial, mycotic, or viral pathogens, an appropriate sample must be placed into the proper medium for growth (amplificaistic structures. tion). The success of efforts to identify a specific pathogen often Immunofluorescent Stains The direct immunofluorescent antibody depends on the collection and transport process coupled to a laboratotechnique uses antibody coupled to a fluorescing compound, such as ry-processing algorithm suitable for the specific sample/agent. In fluorescein, and directed at a specific antigenic target to visualize or- some instances, it is better for specimens to be plated at the time of ganisms or subcellular structures. When samples are examined under collection rather than first being transported to the laboratory (e.g., appropriate conditions, the fluorescing compound absorbs ultraviolet urethral swabs being cultured for Neisseria gonorrhoeae or sputum light and reemits light at a higher wavelength visible to the human eye. specimens for pneumococci). In general, the more rapidly a specimen In the indirect immunofluorescent antibody technique, an unlabeled is plated onto appropriate media, the better the chance for isolating (target) antibody binds a specific antigen. The specimen is then bacterial pathogens. Deep tissue or fluid (pus) samples are more likely stained with fluorescein-labeled polyclonal antibody directed at the to give useful culture results than are superficial swab specimens. Tatarget antibody. Because each unlabeled target antibody attached to ble e14-1 lists procedures for collection and transport of common the appropriate antigen has multiple sites for attachment of the second specimens. Because there are many pathogen-specific paradigms for antibody, the visual signal can be intensified (i.e., amplified). This these procedures, it is important to seek advice from the microbiology form of staining is called indirect because a two-antibody system is laboratory when in doubt about a particular situation. used to generate the signal for detection of the antigen. Both direct and indirect methods detect viral antigens (e.g., cytomegalovirus, her- ISOLATION OF BACTERIAL PATHOGENS pes simplex virus, and respiratory viruses) within cultured cells or Isolation of suspect pathogens from clinical material relies on the use clinical specimens as well as many difficult-to-grow bacterial agents of artificial media that support bacterial growth in vitro. Such media are composed of agar, which is not metabolized by bacteria; nutrients (e.g., Legionella pneumophila) directly in clinical specimens. to support the growth of the species of interest; and sometimes substances to inhibit the growth of other bacteria. Broth is employed for MACROSCOPIC ANTIGEN DETECTION Latex agglutination assays and EIAs are rapid and inexpensive methods growth (amplification) of organisms from specimens with few bactefor identifying organisms, extracellular toxins, and viral agents by means ria, such as peritoneal dialysis fluid, CSF, or samples in which anaerof protein and polysaccharide antigens. Such assays may be performed obes or other fastidious organisms may be present. The general use of directly on clinical samples or after growth of organisms on agar plates liquid medium for all specimens is not worthwhile.
Gram-Negative Organisms
PART 7
Infectious Diseases
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TABLE e14-1 INSTRUCTIONS FOR COLLECTION AND TRANSPORT OF SPECIMENS FOR CULTURE
Note: It is absolutely essential that the microbiology laboratory be informed of the site of origin of the sample to be cultured and of the infections that are suspected. This information determines the selection of culture media and the length of culture time.
e99
Type of Culture (Synonyms)
Blood Blood, routine (blood culture for aerobes, anaerobes, and yeasts) Blood for fungi/Mycobacterium spp.
Specimen
Whole blood
Minimum Volume
10 mL in each of 2 bottles for adults and children; 5 mL, if possible, in aerobic bottles for infants; less for neonates 10 mL in each of 2 bottles, as for routine blood cultures, or in Isolator tube requested from laboratory 10 mL
Container
See below.a
Other Considerations
See below.b
Whole blood
Same as for routine blood culture
Specify “hold for extended incubation,” since fungal agents may require ≥4 weeks to grow. Use mainly for isolation of fungi, Mycobacterium, or other fastidious aerobes and for elimination of antibiotics from cultured blood in which organisms are concentrated by centrifugation.
Blood, Isolator (lysis centrifugation)
Whole blood
Isolator tubes
CHAPTER e14 Laboratory Diagnosis of Infectious Diseases
Respiratory Tract Nose Throat
Swab from nares Swab of posterior pharynx, ulcerations, or areas of suspected purulence Fresh sputum (not saliva)
1 swab 1 swab
Sterile culturette or similar transport system containing holding medium Sterile culturette or similar swab specimen collection system containing holding medium Commercially available sputum collection system or similar sterile container with screw cap
Swabs made of calcium alginate may be used. See below.c
Sputum
2 mL
Bronchial aspirates
Transtracheal aspirate, bronchoscopy specimen, or bronchial aspirate Rectal swab or (preferably) fresh, randomly collected stool Fresh, randomly collected stool Fresh, randomly collected stool
1 mL of aspirate or brush in transport medium
Sterile aspirate or bronchoscopy tube, bronchoscopy brush in a separate sterile container
Cause for rejection: Care must be taken to ensure that the specimen is sputum and not saliva. Examination of Gram’s stain, with number of epithelial cells and PMNs noted, can be an important part of the evaluation process. Induced sputum specimens should not be rejected. Special precautions may be required, depending on diagnostic considerations (e.g., Pneumocystis).
Stool Stool for routine culture; stool for Salmonella, Shigella, and Campylobacter Stool for Yersinia, E. coli O157 Stool for Aeromonas and Plesiomonas Urogenital Tract Urine Urogenital secretions
1 g of stool or 2 rectal swabs 1g 1g
Plastic-coated cardboard cup or plastic cup with tight-fitting lid. Other leak-proof containers are also acceptable. Plastic-coated cardboard cup or plastic cup with tight-fitting lid Plastic-coated cardboard cup or plastic cup with tight-fitting lid
If Vibrio spp. are suspected, the laboratory must be notified, and appropriate collection/transport methods should be used. Limitations: Procedure requires enrichment techniques. Limitations: Stool should not be cultured for these organisms unless also cultured for other enteric pathogens. See below.d Vaginal swab samples for “routine culture” should be discouraged whenever possible unless a particular pathogen is suspected. For detection of multiple organisms (e.g., group B Streptococcus, Trichomonas, Chlamydia, or Candida spp.), 1 swab per test should be obtained. Do not refrigerate; transfer to laboratory as soon as possible. For some body fluids (e.g., peritoneal lavage samples), increased volumes are helpful for isolation of small numbers of bacteria. (continued)
Clean-voided urine specimen or urine collected by catheter Vaginal or urethral secretions, cervical swabs, uterine fluid, prostatic fluid, etc.
0.5 mL 1 swab or 0.5 mL of fluid
Sterile, leak-proof container with screw cap or special urine transfer tube Vaginal and rectal swabs transported in Amies transport medium or similar holding medium for group B Streptococcus; direct inoculation preferred for Neisseria gonorrhoeae
Body Fluids, Aspirates, and Tissues Spinal fluid Cerebrospinal fluid (lumbar puncture) Body fluids Aseptically aspirated body fluids
1 mL for routine cultures; ≥5 mL for Mycobacterium 1 mL for routine cultures
Sterile tube with tight-fitting cap Sterile tube with tight-fitting cap. Specimen may be left in syringe used for collection if the syringe is capped before transport.
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e100
TABLE e14-1 INSTRUCTIONS FOR COLLECTION AND TRANSPORT OF SPECIMENS FOR CULTURE (CONTINUED) Type of Culture (Synonyms)
Biopsy and aspirated materials
Specimen
Tissue removed at surgery, bone, anticoagulated bone marrow, biopsy samples, or other specimens from normally sterile areas Purulent material or abscess contents obtained from wound or abscess without contamination by normal microflora
Minimum Volume
1 mL of fluid or a 1-g piece of tissue
Container
Sterile “culturette”-type swab or similar transport system containing holding medium. Sterile bottle or jar should be used for tissue specimens. Culturette swab or similar transport system or sterile tube with tight-fitting screw cap. For simultaneous anaerobic cultures, send specimen in anaerobic transport device or closed syringe. Sterile, leak-proof container with tight-fitting cap
Other Considerations
Accurate identification of specimen and source is critical. Enough tissue should be collected for both microbiologic and histopathologic evaluations. Collection: Abscess contents or other fluids should be collected in a syringe (rather than with a swab) when possible to provide an adequate sample volume and an anaerobic environment. Collection: Specimen should be transported to microbiology laboratory within 1 h of collection. Contamination with normal flora from skin, rectum, vaginal tract, or other body surfaces should be avoided. Detection of Mycobacterium spp. is improved by use of concentration techniques. Smears and cultures of pleural, peritoneal, and pericardial fluids often have low yields. Multiple cultures from the same patient are encouraged. Culturing in liquid media shortens the time to detection. —
Wounds
2 swabs or 0.5 mL of aspirated pus
Special Recommendations Fungi Specimen types listed above may be used. When urine or sputum is cultured for fungi, a first morning specimen is usually preferred. Mycobacterium Sputum, tissue, urine, (acid-fast bacilli) body fluids
1 mL or as specified above for individual listing of specimens. Large volumes may be useful for urinary fungi. 10 mL of fluid or small piece of tissue. Swabs should not be used.
Sterile container with tight-fitting cap
PART 7
Infectious Diseases
Legionella
Anaerobic organisms Virusesf
Pleural fluid, lung biopsy, bronchoalveolar lavage fluid, bronchial/ transbronchial biopsy. Rapid transport to laboratory is critical. Aspirated specimens from abscesses or body fluids Respiratory secretions, wash aspirates from respiratory tract, nasal swabs, blood samples (including buffy coats), vaginal and rectal swabs, swab specimens from suspicious skin lesions, stool samples (in some cases)
1 mL of fluid; any size tissue sample, although a 0.5-g sample should be obtained when possible. 1 mL of aspirated fluid, 1 g of tissue, or 2 swabs 1 mL of fluid, 1 swab, or 1 g of stool in each appropriate transport medium
—
An appropriate anaerobic transport device is required.e Fluid or stool samples in sterile containers or swab samples in viral culturette devices (kept on ice but not frozen) are generally suitable. Plasma samples and buffy coats in sterile collection tubes should be kept at 4−8°C. If specimens are to be shipped or kept for a long time, freezing at −80°C is usually adequate.
Specimens cultured for obligate anaerobes should be cultured for facultative bacteria as well. Fluid or tissue is preferred to swabs. Most samples for culture are transported in holding medium containing antibiotics to prevent bacterial overgrowth and viral inactivation. Many specimens should be kept cool but not frozen, provided they are transported promptly to the laboratory. Procedures and transport media vary with the agent to be cultured and the duration of transport.
aFor samples from adults, two bottles (smaller for pediatric samples) should be used: one with dextrose phosphate, tryptic soy, or another appropriate broth and the other with thioglycollate or another broth containing reducing agents appropriate for isolation of obligate anaerobes. For children, from whom only limited volumes of blood can be obtained, only an aerobic culture should be done unless there is specific concern about anaerobic sepsis (e.g., with abdominal infections). For special situations (e.g., suspected fungal infection, culture-negative endocarditis, or mycobacteremia), different blood collection systems may be used (Isolator systems; see table). bCollection: An appropriate disinfecting technique should be used on both the bottle septum and the patient. Do not allow air bubbles to get into anaerobic broth bottles. Special considerations: There is no more important clinical microbiology test than the detection of blood-borne pathogens. The rapid identification of bacterial and fungal agents is a major determinant of patients’ survival. Bacteria may be present in blood either continuously (as in endocarditis, overwhelming sepsis, and the early stages of salmonellosis and brucellosis) or intermittently (as in most other bacterial infections, in which bacteria are shed into the blood on a sporadic basis). Most blood culture systems employ two separate bottles containing broth medium: one that is vented in the laboratory for the growth of facultative and aerobic organisms and a second that is maintained under anaerobic conditions. In cases of suspected continuous bacteremia/fungemia, two or three samples should be drawn before the start of therapy, with additional sets obtained if fastidious organisms are thought to be involved. For intermittent bacteremia, two or three samples should be obtained at least 1 h apart during the first 24 h. cNormal microflora includes alpha-hemolytic streptococci, saprophytic Neisseria spp., diphtheroids, and Staphylococcus spp. Aerobic culture of the throat (“routine”) includes
screening for and identification of beta-hemolytic Streptococcus spp. and other potentially pathogenic organisms. Although considered components of the normal microflora, organisms such as Staphylococcus aureus, Haemophilus influenzae, and Streptococcus pneumoniae will be identified by most laboratories, if requested. When Neisseria gonorrhoeae or Corynebacterium diphtheriae is suspected, a special culture request is recommended. d(1) Clean-voided specimens, midvoid specimens, and Foley or indwelling catheter specimens that yield ≥50,000 organisms/mL and from which no more than three species are isolated should have organisms identified. Neither indwelling catheter tips nor urine from the bag of a catheterized patient should be cultured. (2) Straight-catheterized, bladder-tap, and similar urine specimens should undergo a complete workup (identification and susceptibility testing) for all potentially pathogenic organisms, regardless of colony count. (3) Certain clinical problems (e.g., acute dysuria in women) may warrant identification and susceptibility testing of isolates present at concentrations of 1 million burn injuries are brought to medical attention each year. While many burn injuries are minor and require little or no intervention, 50,000 persons are hospitalized for these injuries, and 20,000 have major burns involving at least 25% of the total body surface area. The majority of burn patients are men. Infants account for ~10% of all reported cases. Scalds, structural fires, and flammable liquids and gases are the major causes of burns, but electrical, chemical, and smoking-related sources are also important. Burns predispose to infection by damaging the protective barrier function of the skin, thus facilitating the entry of pathogenic microorganisms, and by inducing systemic immunosuppression. It is therefore not surprising that multiorgan failure and infectious complications are the major causes of morbidity and death in serious burn injury and that as many as 10,000 patients in the United States die of burn-related infections each year. PATHOPHYSIOLOGY Loss of the cutaneous barrier facilitates entry of the patient’s own flora and of organisms from the hospital environment into the burn wound. Initially, the wound is colonized with gram-positive bacteria from the surrounding tissue, but the number of bacteria grows rapidly beneath the burn eschar, reaching ~8.4 × 103 cfu/g on day 4 after the burn. The avascularity of the eschar, along with the impairment of local immune responses, favors further bacterial colonization and proliferation. By day 7, the wound is colonized with other microbes, including gram-positive bacteria, gram-negative bacteria, and yeasts derived from the gastrointestinal and upper respiratory flora. Invasive infection—localized and/or systemic—occurs when these bacteria penetrate viable tissue. In addition, a role for biofilms has been recognized in experimental animal models of burn-wound infection. (Biofilms are surface-associated communities of bacteria, often embedded in a matrix, that allow the microbes to persist and to resist the effects of host immunity and antimicrobial agents.) Streptococci and staphylococci were the predominant causes of burn-wound infection in the preantibiotic era and remain important pathogens at present. With the advent of antimicrobial agents, Pseudomonas aeruginosa became a major problem in burn-wound management. Less common anaerobic bacteria are typically found in infections of electrical burns or when open wound dressings are used. As antibiotics more effective against Pseudomonas have become available, fungi (particularly Candida albicans, Aspergillus spp., and the agents of mucormycosis) have emerged as increasingly important pathogens in burn-wound patients. Herpes simplex virus (HSV) infection has also been found in burn wounds, especially those on the face. The cascade of events that follow a severe burn injury and that lead to multiorgan system failure and death are thought to represent a two-
step process: The burn injury itself, with ensuing hypovolemia and tis- e107 sue hypoxia, is followed by invasive infection arising from large amounts of devitalized tissue. The frequency of infection parallels the extent and severity of the burn injury. Severe burn injuries cause a state of immunosuppression that affects innate and adaptive immune responses. The substantial impact of immunocompromise on infection is due to effects on both the cellular and the humoral arms of the immune system. For example, decreases in the number and activity of circulating helper T cells, increases in suppressor T cells, decreases in production and release of monocytes and macrophages, and diminution in levels of immunoglobulin follow major burns. Neutrophil and complement functions have also been shown to be impaired after burns. The increased levels of multiple cytokines detected in burn patients are compatible with the widely held belief that the inflammatory response becomes dysregulated in these individuals; bacterial cell products play a potent role in inducing proinflammatory mediators that contribute to this uncontrolled systemic inflammatory response. Increased permeability of the gut wall to bacteria and their components (e.g., endotoxin) also contributes to immune dysregulation and sepsis. Thus, the burn patient is predisposed to infection at remote sites (see below) as well as at the sites of burn injury. Another contributor to secondary immunosuppression after burn injuries is the endocrine system; increasing levels of vasopressin, aldosterone, cortisol, glucagon, growth hormone, catecholamines, and other hormones that directly affect lymphocyte proliferation, secretion of proinflammatory cytokines, natural killer cell activity, and suppressive T cells are seen. CLINICAL MANIFESTATIONS Since clinical indications of wound infection are difficult to interpret, wounds must be monitored carefully for changes that may reflect infection. A margin of erythema frequently surrounds the sites of burns and by itself is not usually indicative of infection. Signs of infection include the conversion of a partial-thickness to a full-thickness burn, color changes (e.g., the appearance of a dark brown or black discoloration of the wound), the new appearance of erythema or violaceous edema in normal tissue at the wound margins, the sudden separation of the eschar from subcutaneous tissues, and the degeneration of the wound with the appearance of a new eschar. Early surgical excision of devitalized tissue is now widely used, and burn-wound infections can be classified in relation to the excision site as (1) burn-wound impetigo (infection characterized by loss of epithelium from a previously reepithelialized surface, as seen in a partialthickness burn that is allowed to close by secondary intention, a grafted burn, or a healed skin donor site); (2) burn-related surgical wound infection (purulent infection of excised burn and donor sites that have not yet epithelialized, accompanied by positive cultures); (3) burnwound cellulitis (extension of infection to surrounding healthy tissue; Fig. e15-1); and (4) invasive infection in unexcised burn wounds (infection that is secondary to a partial- or full-thickness burn wound and is manifested by separation of the eschar or by violaceous, dark brown, or black discoloration of the eschar; Fig. e15-2). The appearance of a green discoloration of the wound or subcutaneous fat (Fig. e15-3) or the development of ecthyma gangrenosum at a remote site points to a diagnosis of invasive P. aeruginosa infection. Changes in body temperature, hypotension, tachycardia, altered mentation, neutropenia or neutrophilia, thrombocytopenia, and renal failure may result from invasive burn wounds and sepsis. However, because profound alterations in homeostasis occur as a consequence of burns per se and because inflammation without infection is a normal component of these injuries, the assessment of these changes is complicated. Alterations in body temperature, for example, are attributable to thermoregulatory dysfunction; tachycardia and hyperventilation accompany the metabolic changes induced by extensive burn injury and are not necessarily indicative of bacterial sepsis. Given the difficulty of evaluating burn wounds solely on the basis of clinical observation and laboratory data, wound biopsies are necessary for definitive diagnosis of infection. The timing of these biopsies can be guided by clinical changes, but in some centers burn wounds are rou-
CHAPTER e15 Infectious Complications of Burns and Bites
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e108
FIGURE e15-1 Cellulitis complicating a burn wound of the arm and demonstrating extension of the infection to adjacent healthy tissue. (Courtesy of Dr. Robert L. Sheridan, Massachusetts General Hospital, Boston; with permission.)
tinely biopsied at regular intervals. The biopsy specimen is examined for histologic evidence of bacterial invasion, and quantitative microbiologic cultures are performed. The presence of >105 viable bacteria per gram of tissue is highly suggestive of invasive infection and of a dramatically increased risk of sepsis. Histopathologic evidence of invasion of viable tissue by microorganisms is a more definitive indicator of infection. A blood culture positive for the same organism seen in large quantities in biopsied tissue is a reliable indicator of burn sepsis. Surface cultures may provide some indication of the microorganisms present in the hospital environment but are not indicative of the etiology of infection. This noninvasive technique might be of use in determining the flora present in excised burn areas or in areas where the skin is too thin for biopsy (e.g., over the ears, eyes, or digits). In addition to infection of the burn wound itself, a number of other infections due to the immunosuppression caused by extensive burns and the manipulations necessary for clinical care put burn patients at risk. Pneumonia, now the most common infectious complication among hospitalized burn patients, is most often nosocomially acquired via the respiratory route; among the risk factors associated with secondary pneumonia are inhalation injury, intubation, full-thickness chest wall burns, immobility, and uncontrolled wound sepsis with hematogenous spread. Septic pulmonary emboli may also occur. Suppurative thrombophlebitis may complicate the vascular catheterization necessary for fluid and nutritional support in burns. Endocarditis, urinary tract infection, bacterial chondritis (particularly in patients with burned ears), and intraabdominal infection also complicate serious burn injury.
PART 7
Infectious Diseases
BURN-WOUND INFECTIONS
The ultimate goal of burn-wound management is closure and healing of the wound. Early surgical excision of burned tissue, with extensive debridement of necrotic tissue and grafting of skin or skin substitutes, greatly decreases mortality rates associated with severe burns. In addition, the four widely used topical antimicrobial agents—silver sulfadiazine cream, mafenide acetate cream, silver nitrate cream, and nanocrystalline silver dressings—dramatically decrease the bacterial burden of burn wounds and reduce the incidence of burn-wound infection; these agents are routinely applied to partial- and full-thickness burns. The bactericidal properties of silver are related to its effect on respiratory enzymes on bacterial cell walls; its interaction with structural proteins causes keratinocyte and fibroblast toxicity that can delay wound healing if silver-based compounds are used indiscriminately. All four agents are broadly active against many bacteria and some fungi and are useful before bacterial colonization is established. Silver sulfadiazine is often used initially, but its value can be limited by bacterial resistance, poor wound penetration, or toxicity (leukopenia). Mafenide acetate has broader activity against gram-negative bacteria. The cream penetrates eschars and thus can prevent or treat infection beneath them; its use without dressings allows regular examination of the wound area. The foremost disadvantages of mafenide acetate are that it can inhibit carbonic anhydrase, resulting in metabolic acidosis, and that it elicits hypersensitivity reactions in up to 7% of patients. This agent is most often used when gram-negative bacteria invade the burn wound and when treatment with silver sulfadiazine fails. The activity of mafenide acetate against gram-positive bacteria is limited. Nanocrystalline silver dressings provide broader antimicrobial coverage than any other available topical preparation, exhibiting activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE), moderate ability to penetrate eschars, and limited toxicity. In addition, this approach provides controlled and prolonged release of nanocrystalline silver into the wound, limiting the number of dressing changes and therefore reducing the risk of nosocomial infections as well as the cost of treatment. Mupirocin, a topical antimicrobial agent used to eradicate nasal colonization with MRSA, is increasingly being used in burn units where MRSA is prevalent. The efficacy of mupirocin in reducing burn-wound bacterial counts and preventing systemic infections is comparable to that of silver sulfadiazine. In recent years, rates of fungal infection have increased in burn patients. When superficial fungal infection occurs, nystatin may be mixed with silver sulfadiazine or mafenide acetate as topical therapy. A small study found
FIGURE e15-2 A severe upper-extremity burn infected with Pseudomonas aeruginosa. The wound requires additional debridement. Note the dark brown to black discoloration of the eschar. (Courtesy of Dr. Robert L. Sheridan, Massachusetts General Hospital, Boston; with permission.)
FIGURE e15-3 A burn wound infected with Pseudomonas aeruginosa, with liquefaction of tissue. Note the green discoloration at the wound margins, which is suggestive of Pseudomonas infection. (Courtesy of Dr. Robert L. Sheridan, Massachusetts General Hospital, Boston; with permission.)
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that nystatin powder (6 million units/g) was effective for treatment of superficial and deep burn-wound infections caused by Aspergillus or Fusarium spp. In addition to these products, moisture-retention ointments with antimicrobial properties can promote rapid autolysis, debridement, and moist healing of partial-thickness wounds. When invasive wound infection is diagnosed, topical therapy should be changed to mafenide acetate. Subeschar clysis (the direct instillation of an antibiotic, often piperacillin, into wound tissues under the eschar) is a useful adjunct to surgical and systemic antimicrobial therapy. Systemic treatment with antibiotics active against the pathogens present in the wound should be instituted. In the absence of culture data, treatment should be broad in spectrum, covering organisms commonly encountered in that particular burn unit. Such coverage is usually achieved with an antibiotic active against gram-positive pathogens (e.g., oxacillin, 2 g IV every 4 h) and with a drug active against P. aeruginosa and other gram-negative rods (e.g., mezlocillin, 3 g IV every 4 h; and gentamicin, 5 mg/kg IV per day). In penicillin-allergic patients, vancomycin (1 g IV every 12 h) may be substituted for oxacillin (and is efficacious against MRSA), and ciprofloxacin (400 mg IV every 12 h) may be substituted for mezlocillin. Patients with burn wounds frequently have alterations in metabolism and renal clearance mechanisms that mandate the monitoring of serum antibiotic levels; the levels achieved with standard doses are often subtherapeutic. Treatment of infections caused by emerging resistant pathogens remains a challenge in the care of burn patients. MRSA, resistant enterococci, multidrug-resistant gram-negative rods, and Enterobacteriaceae producing extended-spectrum β-lactamases have been associated with burn-wound infections and identified in burn-unit outbreaks. Strict infection-control practices (including microbiologic surveillance in burn units) and appropriate antimicrobial therapy remain important measures in reducing rates of infection due to resistant organisms. In general, prophylactic systemic antibiotics have no role in the management of burn wounds and can in fact lead to colonization with resistant microorganisms. In some studies, antibiotic prophylaxis has been associated with increased secondary infections of the upper and lower respiratory tract and the urinary tract as well as with prolonged hospitalization. An exception involves cases requiring burn-wound manipulation. Since procedures such as debridement, excision, or grafting frequently result in bacteremia, prophylactic systemic antibiotics are administered at the time of wound manipulation; the specific agents used should be chosen on the basis of data obtained by wound culture or data on the hospital’s resident flora. The use of oral antibiotics for selective digestive decontamination (SDD) to decrease bacterial colonization and the risk of burn-wound infection is controversial and has not been widely adopted. In a randomized, doubleblind, placebo-controlled trial in patients with burns involving >20% of the total body surface area, SDD was associated with reduced mortality rates in the burn intensive care unit and in the hospital and also with a reduced incidence of pneumonia. The effects of SDD on the normal anaerobic bowel flora must be taken into consideration before this approach is used. All burn-injury patients should undergo tetanus booster immunization if they have completed primary immunization but have not received a booster dose in the past 5 years. Patients without prior immunization should receive tetanus immune globulin and undergo primary immunization.
of which become infected. Each year, 800,000 Americans seek medical e109 attention for dog bites; of those injured, 386,000 require treatment in an emergency department, with >1000 emergency department visits each day and about a dozen deaths per year. Most dog bites are provoked and are inflicted by the victim’s pet or by a dog known to the victim. These bites frequently occur during efforts to break up a dogfight. Children are more likely than adults to sustain canine bites, with the highest incidence of 6 bites per 1000 population among boys 5–9 years old. Victims are more often male than female, and bites most often involve an upper extremity. Among children 100 million; the annual incidence of dog and cat bites has been reported as 300 bites per 100,000 population. Other bite wounds are a consequence of encounters with animals in the wild or in occupational settings. While many of these wounds require minimal or no therapy, a significant number result in infection, which may be lifethreatening. The microbiology of bite-wound infections in general reflects the oropharyngeal flora of the biting animal, although organisms from the soil, the skin of the animal and victim, and the animal’s feces may also be involved. DOG BITES In the United States, dogs bite >4.7 million people each year and are responsible for 80% of all animal-bite wounds, an estimated 15–20%
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e110 OTHER ANIMAL BITES
Infections have been attributed to bites from many animal species. Often these bites are sustained as a consequence of occupational exposure (farmers, laboratory workers, veterinarians) or recreational exposure (hunters and trappers, wilderness campers, owners of exotic pets). Generally, the microflora of bite wounds reflects the oral flora of the biting animal. Most members of the cat family, including feral cats, harbor P. multocida. Bite wounds from aquatic animals such as alligators or piranhas may contain Aeromonas hydrophila. Venomous snakebites (Chap. 391) result in severe inflammatory responses and tissue necrosis—conditions that render these injuries prone to infection. The snake’s oral flora includes many species of aerobes and anaerobes, such as P. aeruginosa, Proteus spp., Staphylococcus epidermidis, Bacteroides fragilis, and Clostridium spp. Bites from nonhuman primates are highly susceptible to infection with pathogens similar to those isolated from human bites (see below). Bites from Old World monkeys (Macaca) may also result in the transmission of B virus (Herpesvirus simiae, cercopithecine herpesvirus), a cause of serious infection of the human central nervous system. Bites of seals, walruses, and polar bears may cause a chronic suppurative infection known as seal finger, which is probably due to one or more species of Mycoplasma colonizing these animals. Small rodents, including rats, mice, and gerbils, as well as animals that prey on rodents may transmit Streptobacillus moniliformis (a microaerophilic, pleomorphic gram-negative rod) or Spirillum minor (a spirochete), which cause a clinical illness known as rat-bite fever. The vast majority of cases in the United States are streptobacillary, whereas Spirillum infection occurs mainly in Asia. In the United States, the risk of rodent bites is usually greatest among laboratory workers or inhabitants of rodent-infested dwellings (particularly children). Rat-bite fever is distinguished from acute bitewound infection by its typical manifestation after the initial wound has healed. Streptobacillary disease follows an incubation period of 3– 10 days. Fever, chills, myalgias, headache, and severe migratory arthralgias are usually followed by a maculopapular rash, which characteristically involves the palms and soles and may become confluent or purpuric. Complications include endocarditis, myocarditis, meningitis, pneumonia, and abscesses in many organs. Haverhill fever is an S. moniliformis infection acquired from contaminated milk or drinking water and has similar manifestations. Streptobacillary rat-bite fever was frequently fatal in the preantibiotic era. The differential diagnosis includes Rocky Mountain spotted fever, Lyme disease, leptospirosis, and secondary syphilis. The diagnosis is made by direct observation of the causative organisms in tissue or blood, by culture of the organisms on enriched media, or by serologic testing with specific agglutinins. Spirillum infection (referred to in Japan as sodoku) causes pain and purple swelling at the site of the initial bite, with associated lymphangitis and regional lymphadenopathy, after an incubation period of 1–4 weeks. The systemic illness includes fever, chills, and headache. The original lesion may eventually progress to an eschar. The infection is diagnosed by direct visualization of the spirochetes in blood or tissue or by animal inoculation. Finally, NO-1 (CDC nonoxidizer group 1) is a recently identified bacterium associated with dog- and cat-bite wounds. Infections in which NO-1 has been isolated have tended to manifest locally (i.e., as abscess and cellulitis). These infections have occurred in healthy persons with no underlying illness and in some instances have progressed from localized to systemic illnesses. The phenotypic characteristics of NO-1 are similar to those of asaccharolytic Acinetobacter species; i.e., NO-1 is oxidase-, indole-, and urease-negative. To date, all strains identified have been shown to be susceptible to aminoglycosides, βlactam antibiotics, tetracyclines, quinolones, and sulfonamides. HUMAN BITES Human bites may be self-inflicted; may be sustained by medical personnel caring for patients; or may take place during fights, domestic abuse, or sexual activity. Human-bite wounds become infected more frequently (~10–15% of the time) than do bites inflicted by other animals. These infections reflect the diverse oral microflora of humans, which includes
multiple species of aerobic and anaerobic bacteria. Common aerobic isolates include viridans streptococci, Staphylococcus aureus, E. corrodens (which is particularly common in clenched-fist injury; see below), and Haemophilus influenzae. Anaerobic species, including Fusobacterium nucleatum and Prevotella, Porphyromonas, and Peptostreptococcus spp., are isolated from 50% of human-bite wound infections; many of these isolates produce β-lactamases. The oral flora of hospitalized and debilitated patients often includes Enterobacteriaceae in addition to the usual organisms. Hepatitis B, hepatitis C, HSV infection, syphilis, tuberculosis, actinomycosis, and tetanus have been reported to be transmitted by human bites; it is biologically possible to transmit HIV through human bites, although this event is quite unlikely. Human bites are categorized as “occlusional” injuries, which are inflicted by actual biting, and “clenched-fist” injuries, which are sustained when the fist of one individual strikes the teeth of another, causing traumatic laceration of the hand. For several reasons, clenched-fist injuries, which are more common than occlusional injuries, result in particularly serious infections. The deep spaces of the hand, including the bones, joints, and tendons, are frequently inoculated with organisms in the course of such injuries. The clenched position of the fist during injury, followed by extension of the hand, may further promote the introduction of bacteria as contaminated tendons retract beneath the skin’s surface. Moreover, medical attention is often sought only after frank infection develops.
PART 7
Infectious Diseases
APPROACH TO THE PATIENT: Animal or Human Bites
A careful history should be elicited, including the type of biting animal, the type of attack (provoked or unprovoked), and the amount of time elapsed since injury. Local and regional authorities should be contacted to determine whether an individual species could be rabid and/or to locate and observe the biting animal when rabies prophylaxis may be indicated (Chap. 188). Suspicious human-bite wounds should provoke careful questioning regarding domestic or child abuse. Details on antibiotic allergies, immunosuppression, splenectomy, liver disease, mastectomy, and immunization history should be obtained. The wound should be inspected carefully for evidence of infection, including redness, exudate, and foul odor. The type of wound (puncture, laceration, or scratch); the depth of penetration; and the possible involvement of joints, tendons, nerves, and bones should be assessed. It is often useful to include a diagram or photograph of the wound in the medical record. In addition, a general physical examination should be conducted and should include an assessment of vital signs as well as an evaluation for evidence of lymphangitis, lymphadenopathy, dermatologic lesions, and functional limitations. Injuries to the hand warrant consultation with a hand surgeon for the assessment of tendon, nerve, and muscular damage. Radiographs should be obtained when the bone may have been penetrated or a tooth fragment may be present. Culture and Gram’s staining of all infected wounds are essential; anaerobic cultures should be undertaken if abscesses, devitalized tissue, or foul-smelling exudate is present. A small-tipped swab may be used to culture deep punctures or small lacerations. It is also reasonable to culture samples from uninfected wounds due to bites inflicted by animals other than dogs and cats, since the microorganisms causing disease are less predictable in these cases. The white blood cell count should be determined and blood cultured if systemic infection is suspected.
BITE-WOUND INFECTIONS
WOUND MANAGEMENT Wound closure is controversial in bite injuries. Many authorities prefer not to attempt primary closure of wounds that are or may become infected, preferring to irrigate these wounds copiously, debride devitalized tissue, remove foreign bodies, and approximate the wound edges. Delayed primary closure may be undertaken after the risk of infection is over. Small uninfected wounds may be allowed to close by sec-
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TABLE e15-1 MANAGEMENT OF WOUND INFECTIONS FOLLOWING ANIMAL AND HUMAN BITES Prophylaxis Advised for Early Uninfected Wounds
Sometimesb
e111
Biting Species
Dog
Commonly Isolated Pathogens
Staphylococcus aureus, Pasteurella multocida, anaerobes, Capnocytophaga canimorsus P. multocida, S. aureus, anaerobes
Preferred Antibiotic(s)a
Amoxicillin/clavulanate (250–500 mg PO tid) or ampicillin/ sulbactam (1.5–3.0 g IV q6h) Amoxicillin/clavulanate or ampicillin/ sulbactam, as above Amoxicillin/clavulanate or ampicillin/ sulbactam, as above Ampicillin/sulbactam as above or imipenem (500 mg q6h) As for human bite
Alternative in Penicillin-Allergic Patient
Clindamycin (150–300 mg PO qid) plus either TMP-SMX (1 DS tablet PO bid) or ciprofloxacin (500 mg PO bid) Clindamycin plus TMP-SMX as above or a fluoroquinolone
Other Considerations
Consider rabies prophylaxis.
Cat
Usually
Consider rabies prophylaxis. Carefully evaluate for joint/ bone penetration.
Human, occlusional Human, clenchedfist Monkey
Viridans streptococci, S. aureus, Haemophilus influenzae, anaerobes As for occlusional plus Eikenella corrodens
Erythromycin (500 mg PO qid) or a fluoroquinolone Cefoxitinc
Always
Always
Examine for tendon, nerve, or joint involvement. For macaque monkeys, consider B virus prophylaxis with acyclovir. Antivenin for venomous snake bite
As for human bite
As for human bite
Always
CHAPTER e15 Infectious Complications of Burns and Bites
Snake
Rodent
Pseudomonas aeruginosa, Proteus spp., Bacteroides fragilis, Clostridium spp. Streptobacillus moniliformis, Leptospira spp., P. multocida
Ampicillin/sulbactam as above Penicillin VK (500 mg PO qid)
Clindamycin plus TMP-SMX as above or a fluoroquinolone Doxycycline (100 mg PO bid)
Sometimes, especially with venomous snakes Sometimes
aAntibiotic choices should be based on culture data when available. These are suggestions for empirical therapy and need to be tailored to individual circumstances and local conditions. IV regimens should be used for hospitalized patients. A single IV dose of antibiotics may be given to patients who will be discharged after initial management. bProphylactic antibiotics are suggested for severe or extensive wounds, facial wounds,
and crush injuries; when bone or joint may be involved; and when comorbidity is present (see text). cMay be hazardous in patients with immediate-type hypersensitivity reaction to penicillin. Note: TMP-SMX, trimethoprim-sulfamethoxazole; DS, double-strength.
ondary intention. Puncture wounds due to cat bites should be left unsutured because of the high rate at which they become infected. Facial wounds are usually sutured after thorough cleaning and irrigation because of the importance of a good cosmetic result in this area and because anatomic factors such as an excellent blood supply and the absence of dependent edema lessen the risk of infection.
Established Infection Antibiotics should be administered in all established bite-wound infections and should be chosen in light of the most likely potential pathogens, as indicated by the biting species and by Gram’s stain and culture results (Table e15-1). For dog and cat bites, antibiotics should be effective against S. aureus, Pasteurella spp., C. canimorsus, streptococci, and oral anaerobes. For human bites, agents with activity against S. aureus, H. influenzae, and β-lactamasepositive oral anaerobes should be used. The combination of an extendedspectrum penicillin with a β-lactamase inhibitor (amoxicillin/clavulanic acid, ticarcillin/clavulanic acid, ampicillin/sulbactam) appears to offer the most reliable coverage for these pathogens. Second-generation cephalosporins (cefuroxime, cefoxitin) also offer substantial coverage. The choice of antibiotics for penicillin-allergic patients (particularly those in whom immediate-type hypersensitivity makes the use of cephalosporins hazardous) is more difficult and is based primarily on in vitro sensitivity since data on clinical efficacy are inadequate. The combination of an antibiotic active against gram-positive cocci and anaerobes (such as clindamycin) with trimethoprim-sulfamethoxazole or a fluoroquinolone, which is active against many of the other potential pathogens, would appear reasonable. In vitro data suggest that azithromycin alone provides coverage against most commonly isolated bite-wound pathogens. Antibiotics are generally given for 10–14 days, but the response to therapy must be carefully monitored. Failure to respond should prompt a consideration of diagnostic alternatives and surgical evaluation for possible drainage or debridement. Complications such as osteomyelitis or septic arthritis mandate a longer duration of therapy. Management of C. canimorsus sepsis requires a 2-week course of IV penicillin G (2 million units IV every 4 h) and supportive measures. Alternative
ANTIBIOTIC THERAPY
agents for the treatment of C. canimorsus infection include cephalosporins and fluoroquinolones. Serious infection with P. multocida (e.g., pneumonia, sepsis, or meningitis) should also be treated with IV penicillin G. Alternative agents include second- or third-generation cephalosporins or ciprofloxacin. Bites by venomous snakes (Chap. 391) may not require antibiotic treatment. Because it is often difficult to distinguish signs of infection from tissue damage caused by the envenomation, many authorities continue to recommend treatment directed against the snake’s oral flora—i.e., the administration of broadly active agents such as ceftriaxone (1–2 g IV every 12–24 h) or ampicillin/sulbactam (1.5–3.0 g IV every 6 h). Seal finger appears to respond to doxycycline (100 mg twice daily for an interval guided by the response to therapy).
Presumptive or Prophylactic Therapy The use of antibiotics in patients presenting early after bite injury (within 8 h) is controversial. Although symptomatic infection frequently will not yet have manifested at this point, many early wounds will harbor pathogens, and many will become infected. Studies of antibiotic prophylaxis for wound infections are limited and have often included only small numbers of cases in which various types of wounds have been managed according to various protocols. A meta-analysis of eight randomized trials of prophylactic antibiotics in patients with dog-bite wounds demonstrated a reduction in the rate of infection by 50% with prophylaxis. However, in the absence of sound clinical trials, many clinicians base the decision to treat bite wounds with empirical antibiotics on the species of the biting animal; the location, severity, and extent of the bite wound; and the existence of comorbid conditions in the host. All human- and monkey-bite wounds should be treated presumptively because of the high rate of infection. Most cat-bite wounds, particularly those involving the hand, should be treated. Other factors favoring treatment for bite wounds include severe injury, as in crush wounds; potential bone or joint involvement; involvement of the hands or genital region; host immunocompromise, including that due to liver disease or splenectomy; and prior mastectomy on the side of an involved upper extremity. When prophylactic antibiotics are administered, they are usually given for 3–5 days.
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e112 Rabies and Tetanus Prophylaxis Rabies prophylaxis, consisting of
both passive administration of rabies immune globulin (with as much of the dose as possible infiltrated into and around the wound) and active immunization with rabies vaccine, should be given in consultation with local and regional public health authorities for many wild-animal (and some domestic-animal) bites and scratches as well as for certain nonbite exposures (Chap. 188). Rabies is endemic in a variety of animals, including dogs and cats in many areas of the world. Many local health authorities require the reporting of all animal bites. A tetanus booster immunization should be given if the patient has undergone primary immunization but has not received a booster dose in the past 5 years. Patients who have not previously completed primary immunization should be immunized and should also receive tetanus immune globulin. Elevation of the site of injury is an important adjunct to antimicrobial therapy. Immobilization of the infected area, especially the hand, is also beneficial.
FURTHER READINGS
BAKER AS et al: Isolation of Mycoplasma species from a patient with seal finger. Clin Infect Dis 27:1168, 1998 CENTERS FOR DISEASE CONTROL AND PREVENTION: Nonfatal dog bite– related injuries treated in hospital emergency departments— United States, 2001. MMWR 52:605, 2003 CUMMINGS P: Antibiotics to prevent infection in patients with dog bite wounds: A meta-analysis of randomized trials. Ann Emerg Med 23:535, 1994 DE LA CAL M et al: Survival benefit in critically ill burned patients receiving selective decontamination of the digestive tract: A randomized, placebo-controlled, double-blind trial. Ann Surg 241:424, 2005 FALLOUJI MA: Traumatic love bites. Br J Surg 77:100, 1990 FLEISHER GR: The management of bite wounds. N Engl J Med 340:138, 1999 GOLDSTEIN EJ: Bite wounds and infection. Clin Infect Dis 14:633, 1992
HOLMES GP et al: Guidelines for the prevention and treatment of Bvirus infections in exposed persons. The B Virus Working Group. Clin Infect Dis 20:421, 1995 KAYE ET: Topical antibacterial agents. Infect Dis Clin North Am 14:321, 2000 KULLBERG BJ et al: Purpura fulminans and symmetrical peripheral gangrene caused by Capnocytophaga canimorsus (formerly DF-2) septicemia—a complication of dog bite. Medicine (Baltimore) 70:287, 1991 MCMANUS WF et al: Subeschar antibiotic infusion in the treatment of burn wound infection. J Trauma 20:1021, 1980 PRUITT BJ et al: The changing epidemiology of infection in burn patients. World J Surg 16:57, 1992 SHERIDAN RL et al: Cutaneous herpetic infections complicating burns. Burns 26:621, 2000 STEER JA et al: Quantitative microbiology in the management of burn patients. I. Correlation between quantitative and qualitative burn wound biopsy culture and surface alginate swab culture. Burns 22:173, 1996 ——— et al: Quantitative microbiology in the management of burn patients. II. Relationship between bacterial counts obtained by burn wound biopsy culture and surface alginate swab culture, with clinical outcome following burn surgery and change of dressings. Burns 22:177, 1996 TALAN DA et al: Bacteriological analysis of infected dog and cat bites. N Engl J Med 340:85, 1999 TAN JS: Human zoonotic infections transmitted by dogs and cats. Arch Intern Med 157:1933, 1977 WEBER DJ et al: Infections resulting from animal bites. Infect Dis Clin North Am 5:663, 1991 WEISS HB et al: Incidence of dog bite injuries treated in emergency departments. JAMA 279:51, 1998 YOUN YK et al: The role of mediators in the response to thermal injury. World J Surg 16:30, 1992 YURT RW: Burns, in Principles and Practice of Infectious Diseases, 5th ed, G Mandell et al (eds). New York, Churchill Livingstone, 2000, pp 3198–3206
PART 7
Infectious Diseases
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e16
Laboratory Diagnosis of Parasitic Infections
Sharon L. Reed, Charles E. Davis
The cornerstone for the diagnosis of parasitic infections is a thorough history of the patient’s illness. Epidemiologic aspects of the illness are especially important because the risks of acquiring many parasites are closely related to occupation, recreation, or travel to areas of high endemicity. Without a basic knowledge of the epidemiology and life cycles of the major parasites, it is difficult to approach the diagnosis of parasitic infections systematically. Accordingly, the medical classification of important human parasites in this chapter emphasizes their geographic distribution, their transmission, and the anatomic location and stages of their life cycle in humans. The text and tables are intendTABLE e16-1 FLATWORM INFECTIONS Life-Cycle Hosts Parasite
Tapeworms (Cestodes) Intestinal tapeworms Taenia saginata (beef tapeworm) Hymenolepis nana (dwarf tapeworm) Diphyllobothrium latum (fish tapeworm) T. soliumb (pork tapeworm) Somatic tapeworms Echinococcus granulosus (hydatid disease) E. multilocularis (hydatid disease) T. soliumb (pork tapeworm) Flukes (Trematodes) Intestinal flukes Fasciolopsis buski Heterophyes heterophyes Metagonimus yokogawai Liver flukes Clonorchis sinensis Fasciola hepatica Lung flukes Paragonimus spp. Blood flukes Schistosoma mansoni S. haematobium S. japonicum
bT.
ed to serve as a guide to the correct diagnostic procedures for the ma- e113 jor parasitic infections and to direct the reader to other chapters that contain more comprehensive information about each infection. Tables e16-1, e16-2, and e16-3 summarize the geographic distributions, the anatomic locations, and the methods employed for the diagnosis of flatworm, roundworm, and protozoal infections, respectively. In addition to selecting the correct diagnostic procedures, physicians must counsel their patients to ensure that specimens are collected properly and arrive at the laboratory promptly. For example, the diagnosis of bancroftian filariasis is unlikely to be confirmed by the laboratory unless blood is drawn near midnight, when the nocturnal microfilariae are active. Laboratory personnel and surgical pathologists should be notified in advance when a parasitic infection is suspected. Continuing interaction with the laboratory staff and the surgical pathologists increases the likelihood that parasites in body fluids or biopsy specimens will be examined carefully by the most capable individuals.
Diagnosis
CHAPTER e16 Laboratory Diagnosis of Parasitic Infections
Geographic Distribution
Intermediate (Transmission)
Definitive
Parasite Stage
Body Fluid or Tissue
Serologic Tests
Other
Worldwide Worldwide Worldwide Worldwide
Beef Grain beetles Copepods–fishc Swine
Humans Humans, micea Humans, other mammals Humans
Ova, segments Ova Ova, segments Ova, segments Hydatid Hydatid Cysticercus
Feces Feces Feces Feces
— — — WB
Motile segments — Megaloblastic anemia in 1% Especially Mexico, Central and South America, Africa Chest radiography, CT, MRI May resemble cholangiocellular carcinoma CT, MRI, radiography
Sheep-raising and hunting areas Subarctic areas Worldwide
Sheep, camels, humans, others Rodents, humans Swine, humans
Dogs Foxes, dogs, cats Humans
Lung, liver Liver Muscles, CNS
WB, EIA — WB
China, India Far East, India Far East, Balkans, North Africa China, Southeast Asia Sheep-raising areas Orient, Africa, South America
Snails–water chestnuts Snails–fish Snails–fish Snails–fish Snails–watercress Snails–crabs/ crayfish
Humans Humans Humans Humans Humans, sheep Humans, other mammals Humans Humans Humans
Ova Ova Ova Ova Ova Adults, ova Ova, adults Ova, adults Ova, adults
Feces Feces Feces Feces, bile Feces,d bile Lung, sputum, feces Feces Urine Feces
— — — — EIA WB, EIA EIA, WB WB WB
— — — Recurrent bacterial cholangitis Cirrhosis, portal hypertension Chest radiography, CT, MRI Rectal snips, liver biopsy Liver, urine, or bladder biopsy Liver biopsy
Africa, Central and Snails South America, West Indies Snails Africa Far East Snails
aLarvae also can mature in intestinal villi of humans and mice.
solium can cause either intestinal infections or cysticercosis. Its ova are identical to those of T. saginata; scolices and segments of the two species differ. cWhen there are two intermediate hosts, the first is separated from the second by a dash. Definitive hosts are infected by the second intermediate host.
dOva seldom reach the fecal stream during acute disease. Note: WB, western blot; CNS, central nervous system; EIA, enzyme immunoassay. Serologic tests listed in Tables e16-1, e16-2, and e16-3 are available commercially or from the Centers for Disease Control and Prevention, Atlanta, GA.
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e114
TABLE e16-2 ROUNDWORM INFECTIONS Life-Cycle Hosts Parasite
Intestinal Roundworms Enterobius vermicularis (pinworm) Trichuris trichiura (whipworm) Ascaris lumbricoides (roundworm of humans) Ancylostoma duodenale (Old World hookworm) Necator americanus (New World hookworm) Strongyloides stercoralis (strongyloidiasis) Capillaria philippinensis Temperate and tropical zones Temperate and tropical zones Temperate and tropical zones Eurasia, Africa, Pacific U.S., Africa, worldwide Moist tropics and subtropics Southeast Asia, Taiwan, Egypt Fecal-oral Soil, fecal-oral Soil, fecal-oral Soil→skin Soil→skin Soil→skin Raw fish Humans Humans Humans Humans Humans Humans Birds Ova Ova Ova Ova/larvae Ova/larvae Larvae Ova, larvae, adults Perianal skin Feces Feces Feces Feces Feces, sputum, duodenal fluid Feces — — — — — EIA — “Cellophane tape” test Rectal prolapse Sx of pulmonary migration Sx of pulmonary migration, anemia Sx of pulmonary migration, anemia Dissemination in immunodeficiency Malabsorption/autoinfection, biopsy
Diagnosis Parasite Stage Body Fluid or Tissue Serologic Tests Other
Geographic Distribution
Intermediate (Transmission)
Definitive
PART 7
Infectious Diseases
Tissue Roundworms Trichinella spiralis (trichinellosis) Wuchereria bancrofti (filariasis) Brugia malayi (filariasis) Loa loa (African eye worm) Onchocerca volvulus (river blindness) Dracunculus medinensis (guinea worm) Angiostrongylus cantonensis Worldwide Coastal areas in tropics and subtropics Asia, Indian subcontinent West and Central Africa Africa, Mexico, Central and South America Africa Southeast Asia, Pacific, Caribbean Swine/humans Mosquitoes Mosquitoes Mango flies (Chrysops) Blackflies Cyclops Snails/slugs, shrimp/fish Swine/ humans Humans Humans Humans Humans Humans Rats Larvae Microfilariae Microfilariae Microfilariae Adults/larvae Adults/larvae Larvae Muscle Blood, lymph nodes Blood Blood Skin/eye Skin CSF (rarely found) EIA EIA, RAPID EIA, RAPID — — — — Muscle biopsy Nocturnal periodicitya Nocturnal May be visible in eye, diurnal Examine nodules or skin snips May be visible in lesion Eosinophilic meningitis
Larva Migrans Syndromes Ancylostoma braziliense (creeping eruption) Toxocara canis and cati (visceral larva migrans) Tropical and temperate zones Tropical and temperate zones Soil→skin Soil, fecal-oral Dogs/cats, humans Dogs/cats, humans Larvae Larvae Skin Viscera, CNS, eye — EIAb Dog and cat hookworm Also caused by roundworms of other species
aBlood should be drawn at midnight, except for infection acquired in the South Pacific. bThe presence of hemagglutinins is a useful clue.
RAPID, rapid immunographic assay [available at the National Institutes of Health (301496-5398)].
Note: Sx, signs/symptoms; EIA, enzyme immunoassay; CNS, central nervous system;
INTESTINAL PARASITES Most helminths and protozoa exit the body in the fecal stream. The patient should be instructed to collect feces in a clean waxed or cardboard container and to record the time of collection on the container. Contamination with water (which could contain free-living protozoa) or with urine (which can damage trophozoites) should be avoided. Fecal samples should be collected before ingestion of barium or other contrast agents for radiologic procedures and before treatment with antidiarrheal agents and antacids, because these substances change the consistency of the feces and interfere with microscopic detection of parasites. Because of the cyclic shedding of most parasites in the feces, a minimum of three samples collected on alternate days should be examined. Examination of a single sample can be up to 50% less sensitive. When delays in transport to the laboratory are unavoidable, fecal samples should be kept in polyvinyl alcohol or another fixative to preserve protozoal trophozoites. New collection kits with instructions for the patient to transfer portions of the sample directly into fixative and bacterial carrier medium may enhance the recovery of trophozoites.
Refrigeration will also preserve trophozoites for a few hours and protozoal cysts and helminthic ova for several days. Analysis of fecal samples entails both macroscopic and microscopic examination. Watery or loose stools are more likely to contain protozoal trophozoites, but protozoal cysts and all stages of helminths may be found in formed feces. If adult worms or tapeworm segments are observed, they should be transported promptly to the laboratory or washed and preserved in fixative for later examination. The only tapeworm with motile segments is Taenia saginata, the beef tapeworm, which patients sometimes bring to the physician. Motility is an important distinguishing characteristic, because the ova of T. saginata are morphologically indistinguishable from those of Taenia solium, the cause of cysticercosis. Microscopic examination of feces is not complete until direct wet mounts have been evaluated and concentration techniques as well as permanent stains have been applied. Before accepting a report of negativity for ova and parasites as final, the physician should insist that the laboratory undertake each of these procedures. Some intestinal parasites are more readily detected in material other than feces. For ex-
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TABLE e16-3 PROTOZOAL INFECTIONS Life-Cycle Hosts Parasite
Intestinal Protozoans Entamoeba histolytica (amebiasis) Giardia lamblia (giardiasis) Isospora belli Cryptosporidium Cyclospora cayetanensis Microsporidium (Enterocytozoon bieneusi, Encephalitozoon spp.) (microsporidiosis) Free-Living Amebas Naegleria Acanthamoeba Worldwide Worldwide Warm water Soil, water Humans Humans Troph, cyst Troph, cyst CNS, nares CNS, skin, cornea DFA DFA Biopsy, nasal swab, culture Biopsy, scrapings, culture Worldwide, especially tropics Worldwide Worldwide Worldwide Worldwide? Worldwide? Fecal-oral Fecal-oral Fecal-oral Fecal-oral Fecal-oral ? Humans Humans Humans Humans, other animals Humans, other animals? Animals, humans Troph, cyst Troph, cyst Oocyst Oocyst Oocyst Spore Feces, liver Feces Feces Feces Feces Feces EIA, antigen detection Antigen detection — Antigen detection — — Ultrasound, liver CT, PCR String test, DFA, PCR Acid-fasta Acid-fast,a DFA, biopsy, PCR Acid-fast,a modified safranin, autofluorescence, biopsy, PCR Modified trichrome, acid-fast,a biopsy, PCR
e115
Diagnosis Parasite Stage Body Fluid or Tissue Serologic Tests Other Intermediate (Transmission)
Geographic Distribution
Definitive
CHAPTER e16 Laboratory Diagnosis of Parasitic Infections
Blood and Tissue Protozoans Plasmodium spp. (malaria) Babesia microti (babesiosis) Trypanosoma rhodesiense (African sleeping sickness) T. gambiense (African sleeping sickness) T. cruzi (Chagas’ disease) Leishmania tropica, etc. L. braziliensis (mucocutaneous) L. donovani (kala-azar) Toxoplasma gondii (toxoplasmosis) Subtropics and tropics U.S., especially New England Sub-Saharan East Africa Sub-Saharan West Africa Mexico→ South America Widespread in tropics and subtropics Mexico→ South America Widespread in tropics and subtropics Worldwide Mosquitoes Ticks Tsetse flies Tsetse flies Reduviid bugs (triatomes) Sandflies (Phlebotomus) Sandflies (Lutzomyia) Sandflies (Phlebotomus) Humans, other mammals Humans Rodents, humans Humans, herbivores Humans, swine Humans, dogs, wild animals Humans, dogs, rodents Humans, dogs, rodents Humans, dogs, wild animals Cats Asexual Asexual Tryp Tryp Amastigote, tryp Amastigote Amastigote Amastigote Cyst, troph Blood Blood Blood, CSF Blood, CSF Multiple organs/ blood Skin Skin, mucous membranes RE system CNS, eye, muscles, other Limited use IIF IIFb Card agglutination, IIFb, c IIF, EIA IFA, EIAd IFAb, EIA IFAb, EIA EIA, IIF PCR Animal spp. in asplenia, PCR Also chancre, lymph nodes Also chancre, lymph nodes Reactivation in immunosuppression Biopsy, scrapings, culture Biopsy, scrapings, culture Biopsy, culture, PCR PCR
aAcid-fastness is best demonstrated by auramine fluorescence or modified acid-fast stain. bContact the CDC at 770-488-7760. cCard agglutination is provided to endemic countries by the World Health Organization. dLimited specificity; most sensitive for L. donovani.
Note: troph, trophozoite; tryp, trypomastigote form; IIF, indirect immunofluorescence; RE, reticuloendothelial; PCR, polymerase chain reaction; EIA, enzyme immunoassay; CNS, central nervous system; IFA, indirect fluorescent antibody; CSF, cerebrospinal fluid; DFA, direct fluorescent antibody.
ample, examination of duodenal contents is sometimes necessary to detect Giardia lamblia, Cryptosporidium, and Strongyloides larvae. Use of the “cellophane-tape” technique to detect pinworm ova on the perianal skin sometimes also reveals ova of T. saginata deposited perianally when the motile segments disintegrate (Table e16-4). Two routine solutions are used to make wet mounts for the identification of the various life stages of helminths and protozoa: physiologic saline for trophozoites, cysts, ova, and larvae and dilute iodine solution for protozoal cysts and ova. Iodine solution must never be used to examine specimens for trophozoites because it kills the parasites and thus eliminates their characteristic motility. The two most common concentration procedures for detecting small numbers of cysts and ova are formalin-ether sedimentation and
zinc sulfate flotation. The formalin-ether technique is preferable, because all parasites sediment but not all float. Slides permanently stained for trophozoites should be prepared before concentration. Additional slides stained for cysts and ova may be made from the concentrate. In many instances, especially in the differentiation of Entamoeba histolytica from other amebas, identification of parasites from wet mounts or concentrates must be considered tentative. Permanently stained smears allow study of the cellular detail necessary for definitive identification. The iron-hematoxylin stain is excellent for critical work, but trichrome staining, which can be completed in 1 h, is a satisfactory alternative that also reveals parasites in specimens preserved in polyvinyl alcohol fixative. Modified acid-fast staining and fluorescent auramine microscopy are useful adjuncts for detection and identifica-
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e116 TABLE e16-4 ALTERNATIVE PROCEDURES FOR LABORATORY DIAGNOSIS OF PARASITES FOUND IN FECES a
tients with Chagas’ disease present in the chronic phase, when Trypanosoma cruzi Parasites and Fecal Stages Alternative Diagnostic Procedures is no longer microscopically detectable Tapeworms (Cestodes) in blood smears. Wet mounts are sometimes more sensitive than stained smears Taenia saginata ova and segments Perianal “cellophane tape” test for ova for the detection of microfilariae and AfT. solium ova and segments Serology; brain biopsy for neurocysticercosis rican trypanosomes because these active Flukes (Trematodes) parasites cause noticeable movement of the erythrocytes in the microscopic field. Clonorchis (Opisthorchis) sinensis ova Examination of bile for ova and adults in cholangitis Nuclepore filtration of blood facilitates Fasciola hepatica ova Examination of bile for ova and adults in cholangitis the detection of microfilariae. The intraParagonimus spp. ova Serology; sputum; biopsy of lung or brain for larvae Schistosoma ova Serology for all; rectal snips (especially for S. mansoni), urine (S. cellular amastigote forms of Leishmania haematobium), liver biopsy and liver ultrasound spp. and T. cruzi can sometimes be visualized in stained smears of peripheral Roundworms blood, but aspirates of the bone marrow, Enterobius vermicularis ova and adults Perianal “cellophane tape” test for ova and adults liver, and spleen are the best sources for Trichuris trichiura ova None microscopic detection and culture of Ascaris lumbricoides ova and adults Examination of sputum for larvae in lung disease Leishmania in kala-azar and of T. cruzi in Hookworm ova and occasional larvae Examination of sputum for larvae in lung disease chronic Chagas’ disease. The diagnosis Strongyloides larvae Duodenal aspirate or jejunal biopsy; serology; sputum or lung of malaria and the critical distinction biopsy for filariform larvae in disseminated disease among the various Plasmodium species Protozoans are made by microscopic examination of Entamoeba histolytica trophozoites and cysts Serology; liver biopsy for trophozoites stained thick and thin blood films Giardia lamblia trophozoites and cysts Duodenal aspirate or jejunal biopsyb (Chap. 203). Isospora belli oocysts Duodenal aspirate or jejunal biopsyb Although most tissue parasites stain b Cryptosporidium oocysts Duodenal aspirate or jejunal biopsy with the traditional hematoxylin and b Microsporidium spores Duodenal aspirate or jejunal biopsy eosin, surgical biopsy specimens should aStains and concentration techniques are discussed in the text. also be stained with appropriate special bCommercial string test is satisfactory; Isospora and Cryptosporidium are acid-fast. stains. The surgical pathologist who is accustomed to applying silver stains for tion of several intestinal protozoa, including Cryptosporidium and Cy- Pneumocystis to induced sputum and transbronchial biopsies may clospora (Table e16-3). need to be reminded to examine wet mounts and iron-hematoxylin– stained preparations of pulmonary specimens for helminthic ova and BLOOD AND TISSUE PARASITES E. histolytica. The clinician should also be able to advise the surgeon Invasion of tissue by protozoa and helminths renders the choice of diag- and pathologist about optimal techniques for the identification of parnostic techniques more difficult. For example, physicians must under- asites in specimens obtained by certain specialized minor procedures stand that aspiration of an amebic liver abscess rarely reveals E. histolytica (Table e16-6). For example, the excision of skin snips for the diagnosis because the trophozoites are located primarily in the abscess wall. They of onchocerciasis, the collection of rectal snips for the diagnosis of must remember that the urine sediment offers the best opportunity to schistosomiasis, and punch biopsy of skin lesions for the identification detect Schistosoma haematobium in the young Ethiopian immigrant or the AmerTABLE e16-5 IDENTIFICATION OF PARASITES IN BLOOD AND OTHER BODY FLUIDS ican traveler who returns from Africa with hematuria. Tables e16-1, e16-2, and Body Fluid, Parasite Enrichment/Stain Culture Technique e16-3, which offer a quick guide to the Blood geographic distribution and anatomic locations of the major tissue parasites, Plasmodium spp. Thick and thin smears/Giemsa or Wright’s Not useful for diagnosis should help the physician to select the apBuffy coat/Giemsa Media available from CDC Leishmania spp. propriate body fluid or biopsy site for miAfrican trypanosomesa Mouse or rat inoculationb Buffy coat, anion column/wet mount and Giemsa croscopic examination. Tables e16-5 and As above and xenodiagnosis Trypanosoma cruzic As for African species e16-6 provide additional information Fibroblast cell lines Toxoplasma gondii Buffy coat/Giemsa about the identification of parasites in Microfilariaed None Nuclepore filtration/wet mount and Giemsa samples from specific anatomic locations. Urine The laboratory procedures for detection of parasites in other body fluids are simiNone Schistosoma haematobium Centrifugation/wet mount lar to those used in the examination of feMicrofilariae (in chyluria) As for blood None ces. The physician should insist on wet Spinal Fluid mounts, concentration techniques, and permanent stains for all body fluids. The Centrifugation, anion column/wet mount As for blood African trypanosomes trichrome or iron-hematoxylin stain is and Giemsa Nonnutrient agar overlaid with Naegleria fowleri Centrifugation/wet mount and Giemsa satisfactory for all tissue helminths in Escherichia coli or trichrome body fluids other than blood, but microfilarial worms and blood protozoa are aTrypanosoma rhodesiense and T. gambiense. bInject mice intraperitoneally with 0.2 mL of whole heparinized blood (0.5 mL for rats). After 5 days, tail blood should be more easily visualized when stained with Giemsa or Wright’s stain. checked daily for trypanosomes as described above. Call the CDC (770-488-7775) for information on diagnosis and treatment. cDetectable in blood by conventional techniques only during acute disease. Xenodiagnosis is successful in ∼50% of patients The most common parasites detected with chronic Chagas’ disease. in Giemsa-stained blood smears are the dDay (1000–1400 h) and night (2200–0200 h) blood should be drawn to maximize the chance of detecting Wuchereria (nocplasmodia, microfilariae, and African turnal except for Pacific strains), Brugia (nocturnal), and Loa loa (diurnal). trypanosomes (Table e16-5). Most paCopyright © 2008 The McGraw-Hill Companies. All rights reserved.
PART 7
Infectious Diseases
TABLE e16-6 MINOR PROCEDURES FOR DIAGNOSIS OF PARASITIC INFECTIONS Parasite(s) and Stage
Onchocerca volvulus and Mansonella streptocerca microfilariae
Procedure
Skin snips: Lift skin with a needle and excise ∼1 mg to a depth of 0.5 mm from several sites. Weigh each sample, place it in 0.5 mL of saline for 4 h, and examine wet mounts and Giemsa stains of the saline either directly or after filtration. Count microfilariae.a Biopsies of subcutaneous nodules: Stain routine histopathologic sections and impression smears with Giemsa. Muscle biopsies: Excise ~1.0 g of deltoid or gastrocnemius muscle and squash between two glass slides for direct microscopic examination. Rectal snips: From four areas of mucosa, take 2-mg snips, tease onto a glass slide, and flatten with a second slide before examining directly at 10×. Preparations may be fixed in alcohol or stained. Aspirate of chancre or lymph node:b Aspirate center with 18-gauge needle, place a drop on a slide, and examine for motile forms. An otherwise insufficient volume of material may be stained with Giemsa. Corneal scrapings: Obtain sample from ophthalmologist for immediate Giemsa staining and culture on nutrient agar overlaid with Escherichia coli. Swabs, aspirates, or punch biopsies of skin lesions: Obtain specimen from margin of lesion for Giemsa staining of impression smears, and section and culture on special media from CDC.
Loa loa adults and O. volvulus adults and microfilariae Trichinella spiralis larvae (and perhaps Taenia solium cysticerci) Schistosoma ova of all species, but especially S. mansoni Trypanosoma gambiense and T. rhodesiense trypomastigotes Acanthamoeba spp. trophozoites or cysts Cutaneous and mucocutaneous Leishmania spp.
Like the hypochromic, microcytic e117 anemia of heavy hookworm infections, other nonspecific laboratory abnormalities may suggest parasitic infection in patients with appropriate geographic and/ or environmental exposures. Biochemical evidence of cirrhosis or an abnormal urine sediment in an African immigrant certainly raises the possibility of schistosomiasis, and anemia and thrombocytopenia in a febrile traveler or immigrant are among the hallmarks of malaria. CT and MRI also contribute to the diagnosis of infections with many tissue parasites and have become invaluable adjuncts in the diagnosis of neurocysticercosis and cerebral toxoplasmosis.
ANTIBODY AND ANTIGEN DETECTION Useful antibody assays for many of the important tissue parasites are available; aCounts of >100/mg are associated with significant risk of complications. most of those listed in Table e16-8 can bLymph node aspiration is contraindicated in some infections and should be used judiciously. be obtained from the Centers for Disease Control and Prevention (CDC) in and culture of cutaneous and mucocutaneous species of Leishmania Atlanta. The results of serologic tests not listed in the tables should be are simple procedures, but the diagnosis can be missed if the speci- interpreted with caution. mens are improperly obtained or processed. TABLE e16-8 SEROLOGIC AND MOLECULAR TESTS FOR NONSPECIFIC TESTS PARASITIC INFECTIONS a Eosinophilia (>500/μL) is a common accompaniment of infections with Parasite, Infection Antibody Antigen or DNA/RNA most of the tissue helminths; absolute numbers of eosinophils may be high in trichinellosis and the migratory phases of filariasis (Table e16-7). Tapeworms Intestinal helminths provoke eosinophilia only during pulmonary miEchinococcosis WB, EIA gration of the larval stages. Eosinophilia is not a manifestation of protoCysticercosis WB zoal infections, with the possible exceptions of those due to Isospora and Flukes Dientamoeba fragilis.
Paragonimiasis Schistosomiasis Fascioliasis Roundworms Strongyloidiasis Trichinellosis Toxocariasis Filariasis Protozoans Uniformly high in acute stage May be high in acute stage Variable 50% of infected travelers 25% of infected travelers Up to 6000/μL in acute infection Amebiasis Giardiasis Cryptosporidiosis Malaria (all species) Babesiosis Chagas’ disease Leishmaniasis Toxoplasmosis Microsporidiosis Cyclosporiasis Acanthamoebiasis Naegleriasis Balmuthiasis EIA IIFd IIF IIF, EIA IIF, EIA IIF, EIA (IgM)e EIA,b RAPID,b PCR EIA,b RAPID,b DFA, PCR EIA,b DFA, RAPID,b PCR PCR PCR PCR PCRb PCRb PCR PCR DFA, PCR DFA, PCR DFA EIA EIA EIA EIAc WB, EIAb EIA, WB EIAb
CHAPTER e16 Laboratory Diagnosis of Parasitic Infections
TABLE e16-7 PARASITES FREQUENTLY ASSOCIATED WITH Parasite
Tapeworms (Cestodes) Echinococcus granulosus Taenia solium Flukes (Trematodes) Paragonimus spp. Fasciola hepatica Clonorchis (Opisthorchis) sinensis Schistosoma mansoni S. haematobium S. japonicum Roundworms Ascaris lumbricoides Hookworm species Strongyloides stercoralis Trichinella spiralis Filarial speciesb Toxocara spp. Ancylostoma braziliense Gnathostoma spinigerum Angiostrongylus cantonensis A. costaricensis
EOSINOPHILIA a
Comment
When hydatid cyst leaks During muscle encystation and in CSF with neurocysticercosis
RAPIDc
During larval migration During larval migration Profound during migration and early years of infection Up to 7000/μL Varies but can reach 5000–8000/μL >3000/μL With extensive cutaneous eruption In visceral larva migrans and eosinophilic meningitis In eosinophilic meningitis During larval migration in mesenteric vessels
aUnless otherwise noted, all tests are available at the CDC. bResearch or commercial laboratories only. cAvailable at the NIH (301-496-5398) and commercially. dOf limited use for management of acute disease. eDetermination of infection within the last 3 months may require additional tests by a research laboratory. Note: EIA, enzyme immunoassay; WB, western blot; IIF, indirect immunofluorescence; DFA, direct fluorescent antibody; PCR, polymerase chain reaction; RAPID, rapid immunographic assay. Most antigen and antibody parasite detection kits are available commercially. Most PCRs listed are now available at the CDC and in commercial or research laboratories. Contact Dr. Alexandre da Silva at the CDC (770-488-4072).
a Virtually every helminth has been associated with eosinophilia. This table includes both common and uncommon parasites that frequently elicit eosinophilia during infection. bWuchereria bancrofti, Brugia spp., Loa loa, and Onchocerca volvulus.
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e118
The value of antibody assays is limited by several factors. For example, the preparation of thick and thin blood smears remains the procedure of choice for the diagnosis of malaria in individual patients because diagnostic titers to plasmodia develop slowly and do not differentiate species—a critical step in patient management. Filarial antigens cross-react with those from other nematodes; as in assays for antibody to most parasites, the presence of antibody in the filarial assay fails to distinguish between past and current infection. Despite these specific limitations, the restricted geographic distribution of many tropical parasites increases the diagnostic usefulness of both the presence and the absence of antibody in travelers from industrialized countries. In contrast, a large proportion of the world’s population has been exposed to Toxoplasma gondii, and the presence of IgG antibody to T. gondii does not constitute proof of active disease. Fewer antibody assays are available for the diagnosis of infection with intestinal parasites. E. histolytica is the major exception. Sensitive, specific serologic tests are invaluable in the diagnosis of amebiasis. Commercial kits for the detection of antigen by enzyme-linked immunosorbent assay or of whole organisms by fluorescent antibody assay are now available for several protozoan parasites (Table e16-8). MOLECULAR TECHNIQUES DNA hybridization with probes that are repeated many times in the genome of a specific parasite and amplification of a specific DNA fragment by the polymerase chain reaction (PCR) have now been established as useful techniques for the diagnosis of several protozoan infections (Table e16-8). Although PCR is very sensitive, it is an adjunct to conventional techniques for parasite detection and should be requested only when microscopic and immunodiagnostic procedures fail to establish the probable diagnosis. For example, only multiple negative blood smears or the failure to identify the infecting species justifies PCR for the diagnosis or proper management of malaria. In addition to PCR of anticoagulated blood, the CDC (contact Dr. Alexandre da Silva, 770-488-4072, for details) and several commercial lab-
oratories now perform PCRs for detection of certain specific parasites in stool samples, biopsy specimens, and bronchoalveolar lavage fluid (Table e16-8). Although PCRs are now used primarily for the detection of protozoans, active research efforts are likely to establish their feasibility for the detection of several helminths.
FURTHER READINGS
FLECK SL, MOODY AH: Diagnostic Techniques in Medical Parasitology. London, Wright, 1988 FREEDMAN DO et al: Spectrum of disease and relation to place of exposure among ill returned travelers. N Engl J Med 354:119, 2006 GARCIA LS: Laboratory identification of the microsporidia. J Clin Microbiol 40:1892, 2002 ——— et al: Algorithms for detection and identification of parasites, in Manual of Clinical Microbiology, 9th ed, vol 2, PR Murray et al (eds). Washington, DC, ASM Press, 2007, pp 2020–2039 HERWALDT BL: Cyclospora cayetanensis: A review, focusing on the outbreaks of cyclosporiasis in the 1990s. Clin Infect Dis 31:1040, 2000 SEYBOLT LM et al: Diagnostic evaluation of newly arrived asymptomatic refugees with eosinophilia. Clin Infect Dis 42:363, 2006 TANYUKSEL M et al: Laboratory diagnosis of amebiasis. Clin Microbiol Rev 16:713, 2003 WALKER M et al: Parasitic central nervous system infections in immunocompromised hosts: Malaria, microsporidiosis, leishmaniasis, and African trypanosomiasis. Clin Infect Dis 42:115, 2006 WILSON M et al: Toxoplasma, in Manual of Clinical Microbiology, 9th ed, vol 2, PR Murray et al (eds). Washington, DC, ASM Press, 2007, pp 2070–2081 ——— et al: Molecular immunological approaches to the diagnosis of parasitic infection, in Manual of Molecular and Clinical Laboratory Immunology, 7th ed, B Detrick et al (eds). Washington, DC, ASM Press, 2006, pp 557–568
PART 7
Infectious Diseases
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
e17
Pharmacology of Agents Used to Treat Parasitic Infections
Thomas A. Moore
Amphotericin B See Table 201-1 and Chap. 191. Antimonials* Despite associated adverse reactions and the need for prolonged parenteral treatment, the pentavalent antimonial compounds (designated Sbv) have remained the first-line therapy for all forms of leishmaniasis throughout the world, primarily because they are affordable, are effective, and have survived the test of time. Although they have been used for almost 100 years, their mechanism of action against Leishmania spp. has only recently come to light. Pentavalent antimonials are active only after bioreduction to the trivalent Sb(III) form. This form inhibits trypanothione reductase, a critical enzyme involved in the oxidative stress management of Leishmania spp. The fact that Leishmania spp. use trypanothione rather than glutathione (which is used by mammalian cells) may explain the parasite-specific activity of antimonials. The drugs are taken up by the reticuloendothelial system, and their activity against Leishmania spp. may be enhanced by this localization. Sodium stibogluconate is the only pentavalent antimonial available in the United States; meglumine antimonate is principally used in francophone countries. Resistance is a major problem in some areas. Although low-level unresponsiveness to Sbv was identified in India in the 1970s, incremental increases in both the recommended daily dosage (to 20 mg/kg) and the duration of treatment (to 28 days) satisfactorily compensated for the growing resistance until around 1990. There has since been a steady erosion in the capacity of Sbv to induce long-term cure in patients with kala-azar who live in eastern India. Foremost among the many factors that have probably contributed to this failure is the provision of suboptimal treatment for years, which led to the development of drug resistance among parasites. Co-infection with HIV impairs the treatment response. Sodium stibogluconate is available in aqueous solution and is administered parenterally. Antimony appears to have two elimination phases. When administered IV, the mean half-life of the first phase is 40 years. Like chloroquine (the other major 4-aminoquinoline), amodiaquine is now of limited use because of the spread of resistance. Amodiaquine interferes with hemozoin formation through complexation with heme. Although rapidly absorbed, amodiaquine behaves as a prodrug after oral administration, with the principal plasma metabolite monodesethylamodiaquine as the predominant antimalarial agent. Amodiaquine and its metabolites are all excreted in urine, but there are no recommendations concerning dosage adjustment in patients with impaired renal function. Severe adverse events can occur, albeit rarely (1 case in 2000 treatment courses), with amodiaquine administration. Agranulocytosis and hepatotoxicity can develop with repeated use; therefore, this drug should not be used for prophylaxis.
CHAPTER e17 Pharmacology of Agents Used to Treat Parasitic Infections
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e120 veloped for the treatment of acute uncomplicated falciparum malaria
in areas where Plasmodium falciparum is resistant to chloroquine and antifolates. Atovaquone Atovaquone is a hydroxynaphthoquinone that exerts broad-spectrum antiprotozoal activity via selective inhibition of parasite mitochondrial electron transport. This agent exhibits potent activity against toxoplasmosis and babesiosis when used with pyrimethamine and azithromycin, respectively. Atovaquone possesses a novel mode of action against Plasmodium spp., inhibiting the electron transport system at the level of the cytochrome bc1 complex. The drug is active against both the erythrocytic and the exoerythrocytic stages of Plasmodium spp.; however, because it does not eradicate hypnozoites from the liver, patients with Plasmodium vivax or Plasmodium ovale infections must be given radical prophylaxis. Malarone is a fixed-dose combination of atovaquone and proguanil used for malaria prophylaxis as well as for the treatment of acute, uncomplicated P. falciparum malaria. Malarone has been shown to be effective in regions with multidrug-resistant P. falciparum. Resistance to atovaquone has yet to be reported. The bioavailability of atovaquone varies considerably. Absorption after a single oral dose is slow, increases two- to threefold with a fatty meal, and is dose-limited above 750 mg. The elimination half-life is increased in patients with moderate hepatic impairment. Because of the potential for drug accumulation, the use of atovaquone is contraindicated in persons with severe renal impairment (creatinine clearance rate 80% of the drug dose; therefore, the dosage should be reduced in patients with renal failure. Fumagillin Fumagillin is a water-insoluble antibiotic that is derived from the fungus Aspergillus fumigatus and is active against microsporidia. This drug is effective when used topically to treat ocular infections due to Encephalitozoon spp. When given systemically, fumagillin was effective but caused thrombocytopenia in all recipients in the second week of treatment; this side effect was readily reversed when administration of the drug was stopped. The mechanisms by which fumagillin inhibits microsporidial replication are poorly understood, although the drug may inhibit methionine aminopeptidase 2 by irreversibly blocking the active site. Furazolidone This nitrofuran derivative is an effective alternative agent for the treatment of giardiasis and also exhibits activity against Isospora belli. Since it is the only agent active against Giardia that is available in liquid form, it is often used to treat young children. Furazolidone undergoes reductive activation in Giardia lamblia trophozoites—an event that, unlike the reductive activation of metronidazole, involves an NADH oxidase. The killing effect correlates with the toxicity of reduced products, which damage important cellular compo-
nents, including DNA. Although furazolidone had been thought to be e121 largely unabsorbed when administered orally, the occurrence of systemic adverse reactions indicates that this is not the case. More than 65% of the drug dose can be recovered from the urine as colored metabolites. Omeprazole reduces the oral bioavailability of furazolidone. Furazolidone is a monoamine oxidase (MAO) inhibitor; thus caution should be used in its concomitant administration with other drugs (especially indirectly acting sympathomimetic amines) and in the consumption of food and drink containing tyramine during treatment. However, hypertensive crises have not been reported in patients receiving furazolidone, and it has been suggested that—since furazolidone inhibits MAO gradually over several days—the risks are small if treatment is limited to a 5-day course. Because hemolytic anemia can occur in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency and glutathione instability, furazolidone treatment is contraindicated in mothers who are breast-feeding and in neonates. Halofantrine This 9-phenanthrenemethanol is one of three classes of arylaminoalcohols first identified as potential antimalarial agents by the World War II Malaria Chemotherapy Program. Its activity is believed to be similar to that of chloroquine, although it is an oral alternative for the treatment of malaria due to chloroquine-resistant P. falciparum. Although the mechanism of action is poorly understood, halofantrine is thought to share mechanism(s) with the 4-aminoquinolines, forming a complex with ferriprotoporphyrin IX and interfering with the degradation of hemoglobin. Halofantrine exhibits erratic bioavailability, but its absorption is significantly enhanced when it is taken with a fatty meal. The elimination half-life of halofantrine is 1–2 days; it is excreted mainly in feces. Halofantrine is metabolized into N-debutyl-halofantrine by the cytochrome P450 enzyme CYP3A4. Grapefruit juice should be avoided during treatment because it increases both halofantrine’s bioavailability and halofantrine-induced QT interval prolongation by inhibiting CYP3A4 at the enterocyte level. Iodoquinol Iodoquinol (diiodohydroxyquin), a hydroxyquinoline, is an effective luminal agent for the treatment of amebiasis, balantidiasis, and infection with Dientamoeba fragilis. Its mechanism of action is unknown. It is poorly absorbed. Because the drug contains 64% organically bound iodine, it should be used with caution in patients with thyroid disease. Iodine dermatitis occurs occasionally during iodoquinol treatment. Protein-bound serum iodine levels may be increased during treatment and can interfere with certain tests of thyroid function. These effects may persist for as long as 6 months after discontinuation of therapy. Iodoquinol is contraindicated in patients with liver disease. Most serious are the reactions related to prolonged high-dose therapy (optic neuritis, peripheral neuropathy), which should not occur if the recommended dosage regimens are followed. Ivermectin Ivermectin (22,23-dihydroavermectin) is a derivative of the macrocyclic lactone avermectin produced by the soil-dwelling actinomycete Streptomyces avermitilis. Ivermectin is active at low doses against a wide range of helminths and ectoparasites. It is the drug of choice for the treatment of onchocerciasis, strongyloidiasis, cutaneous larva migrans, and scabies. Ivermectin is highly active against microfilariae of the lymphatic filariases but has no macrofilaricidal activity. When ivermectin is used in combination with other agents such as DEC or albendazole for treatment of lymphatic filariasis, synergistic activity is seen. While active against the intestinal helminths Ascaris lumbricoides and Enterobius vermicularis, ivermectin is only variably effective in trichuriasis and is ineffective against hookworms. Widespread use of ivermectin for treatment of intestinal nematode infections in sheep and goats has led to the emergence of drug resistance in veterinary practice; this development may portend problems in human medical use. Recent data suggest that ivermectin acts by opening the neuromuscular membrane-associated, glutamate-dependent chloride channels. The influx of chloride ions results in hyperpolarization and muscle pa-
CHAPTER e17 Pharmacology of Agents Used to Treat Parasitic Infections
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e122 ralysis—particularly of the nematode pharynx, with consequent
blockage of the oral ingestion of nutrients. Because these chloride channels are present only in invertebrates, the paralysis is seen only in the parasite. Ivermectin is available only as an oral formulation. The drug is highly protein bound; it is almost completely excreted in feces. The effect of food on bioavailability is unknown. Ivermectin is distributed widely throughout the body; animal studies indicate that it accumulates at the highest concentration in adipose tissue and liver, with little accumulation in the brain. Few data exist to guide therapy in hosts with conditions that may influence drug pharmacokinetics. Ivermectin is generally administered as a single dose of 150–200 μg/ kg. In the absence of parasitic infection, the adverse effects of ivermectin in therapeutic doses are minimal. Adverse effects in patients with filarial infections include fever, myalgia, malaise, lightheadedness, and (occasionally) postural hypotension. The severity of such side effects is related to the intensity of parasite infection, with more symptoms in individuals with a heavy parasite burden. In onchocerciasis, skin edema, pruritus, and mild eye irritation may also occur. The adverse effects are generally self-limiting and only occasionally require symptom-based treatment with antipyretics or antihistamines. More severe complications of ivermectin therapy for onchocerciasis include encephalopathy in patients heavily infected with Loa loa. This reaction has led to the suspension of ivermectin distribution for this indication in regions where the two filarial infections are coendemic. Levamisole Levamisole is the levo-isomer of tetramisole and is used to treat ascariasis and hookworm infection. Levamisole appears to act by binding to a distinctive ion channel that forms a nicotinic acetylcholine receptor on nematode muscle. This event causes sustained depolarization of the muscle membrane and results in paralysis of the worm. Levamisole is rapidly absorbed from the GI tract and is extensively metabolized in the liver; the metabolites are excreted in the urine. The use of this drug is contraindicated in patients with preexisting blood disorders (e.g., agranulocytosis) or Sjögren’s syndrome. When used for the treatment of helminthic infections, levamisole is well tolerated, with side effects usually limited to GI disturbances. Lumefantrine Lumefantrine (benflumetol), a fluorene (benzindene) derivative synthesized in the 1970s by the Chinese Academy of Military Medical Sciences (Beijing), has marked blood schizontocidal activity against a wide range of plasmodia. This agent conforms structurally and in mode of action to the arylaminoalcohol group of antimalarial drugs, including quinine, mefloquine, and halofantrine. Lumefantrine exerts its antimalarial effect as a consequence of its interaction with heme, a degradation product of hemoglobin metabolism. Although its antimalarial activity is slower than that of the artemisinin-based drugs, the recrudescence rate with the recommended lumefantrine regimen is lower. The pharmacokinetic properties of lumefantrine are reminiscent of those of halofantrine, with variable oral bioavailability, considerable augmentation of oral bioavailability by concomitant fat intake, and a terminal elimination half-life of ~4–5 days in patients with malaria. Artemether and lumefantrine have synergistic activity, and clinical studies in China on several hundred patients show the combination to be safe and well tolerated. The combined formulation of artemether and lumefantrine has been developed for the treatment of falciparum malaria in areas where P. falciparum is resistant to chloroquine and antifolates. Mebendazole This benzimidazole is a broad-spectrum antiparasitic agent widely used to treat intestinal helminthiases. Its mechanism of action is similar to that of albendazole; however, it is a more potent inhibitor of parasite malic dehydrogenase and exhibits a more specific and selective effect against intestinal nematodes than the other benzimidazoles. Mebendazole is available only in oral form but is poorly absorbed from the GI tract; only 5–10% of a standard dose is measurable in
plasma. The proportion absorbed from the GI tract is extensively metabolized in the liver. Metabolites appear in the urine and bile; impaired liver or biliary function results in higher plasma mebendazole levels in treated patients. No dose reduction is warranted in patients with renal function impairment. Because mebendazole is poorly absorbed, its incidence of side effects is low. Transient abdominal pain and diarrhea sometimes occur, usually in persons with massive parasite burdens. Mefloquine Mefloquine is the preferred drug for prophylaxis of chloroquine-resistant malaria; high doses can be used for treatment. Despite the development of drug-resistant strains of P. falciparum in parts of Africa and Southeast Asia, mefloquine is an effective drug throughout most of the world. Cross-resistance of mefloquine with halofantrine and with quinine has been documented in limited areas. Like quinine and chloroquine, this quinoline is active only against the asexual erythrocytic stages of malarial parasites. Unlike quinine, however, mefloquine has a relatively poor affinity for DNA and, as a result, does not inhibit the synthesis of parasitic nucleic acids and proteins. Although both mefloquine and chloroquine inhibit hemozoin formation and heme degradation, mefloquine differs in that it forms a complex with heme that may be toxic to the parasite. Mefloquine HCl is poorly water soluble and intensely irritating when given parenterally; thus it is available only in tablet form. Its absorption is adversely affected by vomiting and diarrhea but is significantly enhanced when the drug is administered with or after food. About 98% of the drug binds to protein. Mefloquine is excreted mainly in the bile and feces; therefore, no dose adjustment is needed in persons with renal insufficiency. The drug and its main metabolite are not appreciably removed by hemodialysis. No special chemoprophylactic dosage adjustments are indicated for the achievement of plasma concentrations in dialysis patients that are similar to those in healthy persons. Pharmacokinetic differences have been detected among various ethnic populations. In practice, however, these distinctions are of minor importance compared with host immune status and parasite sensitivity. In patients with impaired liver function, the elimination of mefloquine may be prolonged, leading to higher plasma levels. Mefloquine should be used with caution by individuals participating in activities requiring alertness and fine-motor coordination. If the drug is to be administered for a prolonged period, periodic evaluations are recommended, including liver function tests and ophthalmic examinations. Sleep abnormalities (insomnia, abnormal dreams) have occasionally been reported. Psychosis and seizures occur rarely; mefloquine should not be prescribed to patients with neuropsychiatric conditions, including depression, generalized anxiety disorder, psychosis, schizophrenia, and seizure disorder. If acute anxiety, depression, restlessness, or confusion develops during prophylaxis, these psychiatric symptoms may be considered prodromal to a more serious event, and the drug should be discontinued. Concomitant use of quinine, quinidine, or drugs producing β-adrenergic blockade may cause significant electrocardiographic abnormalities or cardiac arrest. Halofantrine must not be given simultaneously with or 65 years of age, persons with the most advanced disease, breast-feeding women, HIV-infected patients, and individuals with significant renal or hepatic insufficiency. Niclosamide Niclosamide is active against a wide variety of adult tapeworms but not against tissue cestodes. It is also a molluscacide and is used in snail-control programs. The drug uncouples oxidative phosphorylation in parasite mitochondria, thereby blocking the uptake of glucose by the intestinal tapeworm and resulting in the parasite’s death. Niclosamide rapidly causes spastic paralysis of intestinal cestodes in vitro. Its use is limited by its side effects, the necessarily long duration of therapy, the recommended use of purgatives, and— most important—limited availability (i.e., on a named-patient basis from the manufacturer). Niclosamide is poorly absorbed. Tablets are given on an empty stomach in the morning after a liquid meal the night before, and this dose is followed by another 1 h later. For treatment of hymenolepiasis, the drug is administered for 7 days. A second course is often prescribed. The scolex and proximal segments of the tapeworms are killed on contact with niclosamide and may be digested in the gut. However, disintegration of the adult tapeworm results in the release of viable ova, which theoretically can result in autoinfection. Although fears of the development of cysticercosis in patients with Taenia solium infections have proved unfounded, it is still recommended that a brisk purgative be given 2 h after the first dose. Nifurtimox* This nitrofuran compound is a cheap and effective oral agent for the treatment of acute Chagas’ disease. Trypanosomes lack catalase and have very low levels of peroxidase; as a result, they are very vulnerable to by-products of oxygen reduction. When nifurtimox is reduced in the trypanosome, a nitro anion radical is formed and undergoes autooxidation, resulting in the generation of the superoxide anion O2–, hydrogen peroxide (H2O2), hydroperoxyl radical (HO2), and other highly reactive and cytotoxic molecules. Despite the abundance of catalases, peroxidases, and superoxide dismutases that neutralize these destructive radicals in mammalian cells, nifurtimox has a poor therapeutic index. Prolonged use is required, but the course may have to be interrupted because of drug toxicity, which develops in 40– 70% of recipients. Nifurtimox is well absorbed and undergoes rapid and extensive biotransformation; 99.9%). Therefore, caution should be used when administering this agent concurrently with other highly plasma protein–bound drugs with narrow therapeutic indices, as competition for binding sites may occur. Oxamniquine This tetrahydroquinoline derivative is an effective alternative agent for the treatment of Schistosoma mansoni, although susceptibility to this drug exhibits regional variation. Oxamniquine exhibits anticholinergic properties, but its primary mode of action seems to rely on ATP-dependent enzymatic drug activation generating an intermediate that alkylates essential macromolecules, including DNA. In treated adult schistosomes, oxamniquine produces marked tegumental alterations that are similar to those seen with praziquantel but that develop less rapidly, becoming evident 4–8 days after treatment. Oxamniquine is administered orally as a single dose and is well absorbed. Food retards absorption and reduces bioavailability. About 70% of an administered dose is excreted in urine as a mixture of pharmacologically inactive metabolites. Patients should be warned that their urine might have an intense orange-red color. Side effects are uncommon and usually mild, although hallucinations and seizures have been reported. Paromomycin (Aminosidine) First isolated in 1956, this aminoglycoside is an effective oral agent for the treatment of infections due to intestinal protozoa. Parenteral paromomycin appears to be effective against visceral leishmaniasis in India. Paromomycin inhibits protozoan protein synthesis by binding to the 30S ribosomal RNA in the aminoacyl-tRNA site, causing misreading of mRNA codons. Paromomycin is less active against G. lamblia than standard agents; however, like other aminoglycosides, paromomycin is poorly absorbed from the intestinal lumen, and the high levels of drug in the gut compensate for this relatively weak activity. If absorbed or administered systemically, paromomycin can cause ototoxicity and nephrotoxicity. However, systemic absorption is very limited, and toxicity should not be a concern in persons with normal kidneys. Topical formulations are not generally available. Pentamidine Isethionate This diamidine is an effective alternative agent for some forms of leishmaniasis and trypanosomiasis. It is available for parenteral and aerosolized administration. While its mechanism of action remains undefined, it is known to exert a wide range of effects, including interaction with trypanosomal kinetoplast DNA; interference with polyamine synthesis by a decrease in the activity of ornithine decarboxylase; and inhibition of RNA polymerase, ribosomal function, and the synthesis of nucleic acids and proteins. Pentamidine isethionate is well absorbed, is highly tissue bound, and is excreted slowly over several weeks, with an elimination half-life of 12 days. No steady-state plasma concentration is attained in persons given daily injections; the result is extensive accumulation of pentamidine in tissues, primarily the liver, kidney, adrenal, and spleen. Pentamidine does not penetrate well into the CNS. Pulmonary concentrations of pentamidine are increased when the drug is delivered in aerosolized form. Piperazine The antihelminthic activity of piperazine is confined to ascariasis and enterobiasis. Piperazine acts as an agonist at extrasynaptic γ-aminobutyric acid (GABA) receptors, causing an influx of chloride ions in the nematode somatic musculature. The ultimate effect is flaccid paralysis of the muscle fibers, leading to the expulsion of live but mostly paralyzed worms. Patients should be warned, as this occurrence can be unsettling. Praziquantel This heterocyclic pyrazinoisoquinoline derivative is highly active against a broad spectrum of trematodes and cestodes. It
is the mainstay of treatment for schistosomiasis and is a critical part of community-based control programs. All of the effects of praziquantel can be attributed either directly or indirectly to an alteration of intracellular calcium concentrations. Although the exact mechanism of action remains unclear, the major mechanism is disruption of the parasite tegument, causing tetanic contractures with loss of adherence to host tissues and, ultimately, disintegration or expulsion. Praziquantel induces changes in the antigenicity of the parasite by causing the exposure of concealed antigens. Praziquantel also produces alterations in schistosomal glucose metabolism, including decreases in glucose uptake, lactate release, glycogen content, and ATP levels. Praziquantel exerts its parasitic effects directly and does not need to be metabolized to be effective. It is well absorbed but undergoes extensive first-pass hepatic clearance. Levels of the drug are increased when it is taken with food, particularly carbohydrates, or with cimetidine. Serum levels are reduced by glucocorticoids, chloroquine, carbamazepine, and phenytoin. Praziquantel is completely metabolized in humans, with 80% of the dose recovered as metabolites in urine within 4 days. It is not known to what extent praziquantel crosses the placenta. Patients with schistosomiasis who have heavy parasite burdens may develop abdominal discomfort, nausea, headache, dizziness, and drowsiness. Symptoms begin 30 min after ingestion, may require spasmolytics for relief, and usually disappear spontaneously after a few hours. Primaquine Phosphate Primaquine, an 8-aminoquinoline, has a broad spectrum of activity against all stages of plasmodial development in humans but has been used most effectively for eradication of the hepatic stage of these parasites. Despite its toxicity, it remains the drug of choice for radical cure of P. vivax infections. Primaquine must be metabolized by the host to be effective. It is, in fact, rapidly metabolized; only a small fraction of the dose of the parent drug is excreted unchanged. Although the parasiticidal activity of the three oxidative metabolites remains unclear, they are believed to affect both pyrimidine synthesis and the mitochondrial electron transport chain. The metabolites appear to have significantly less antimalarial activity than primaquine; however, their hemolytic activity is greater than that of the parent drug. Primaquine causes marked hypotension after parenteral administration and therefore is given only by the oral route. It is rapidly and almost completely absorbed from the GI tract. Patients should be tested for G6PD deficiency before they receive primaquine. The drug may induce the oxidation of hemoglobin into methemoglobin, irrespective of the G6PD status of the patient. Primaquine is otherwise well tolerated. Proguanil (Chloroguanide) Proguanil inhibits plasmodial dihydrofolate reductase and is used with atovaquone for oral treatment of uncomplicated malaria or with chloroquine for malaria prophylaxis in parts of Africa without widespread chloroquine-resistant P. falciparum. Proguanil exerts its effect primarily by means of the metabolite cycloguanil, whose inhibition of dihydrofolate reductase in the parasite disrupts deoxythymidylate synthesis, thus interfering with a key pathway involved in the biosynthesis of pyrimidines required for nucleic acid replication. There are no clinical data indicating that folate supplementation diminishes drug efficacy; women of childbearing age for whom atovaquone/proguanil is prescribed should continue taking folate supplements to prevent neural-tube birth defects. Proguanil is extensively absorbed regardless of food intake. The drug is 75% protein-bound. The main routes of elimination are hepatic biotransformation and renal excretion; 40–60% of the proguanil dose is excreted by the kidneys. Drug levels are increased and elimination is impaired in patients with hepatic insufficiency. Pyrantel Pamoate Pyrantel is a tetrahydropyrimidine formulated as pamoate. This safe, well-tolerated, inexpensive drug is used to treat a variety of intestinal nematode infections but is ineffective in trichuriasis. Pyrantel pamoate is usually effective in a single dose. Like levami-
PART 7
Infectious Diseases
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
sole, the drug has as its target the nicotinic acetylcholine receptor on the surface of nematode somatic muscle. Pyrantel depolarizes the neuromuscular junction of the nematode, resulting in its irreversible paralysis and allowing the natural expulsion of the worm. Pyrantel pamoate is poorly absorbed from the intestine; >85% of the dose is passed unaltered in feces. The absorbed portion is metabolized and excreted in urine. Piperazine, which produces hyperpolarization of muscle cells in intestinal helminths, is antagonistic to pyrantel pamoate and should not be used concomitantly. Pyrantel pamoate has minimal toxicity at the oral doses used to treat intestinal helminthic infection. It is not recommended for pregnant women or for children 50%. Therefore, serum levels of theophylline should be monitored closely in this situation.
CHAPTER e17 Pharmacology of Agents Used to Treat Parasitic Infections
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
e126 Tinidazole This nitroimidazole is effective for the treatment of amebiasis, giardiasis, and trichomoniasis. Like metronidazole, tinidazole must undergo reductive activation by the parasite’s metabolic system before it can act on protozoal targets. Tinidazole inhibits the synthesis of new DNA in the parasite and causes degradation of existing DNA. The reduced free-radical derivatives alkylate DNA, with consequent cytotoxic damage to the parasite. This damage appears to be produced by short-lived reduction intermediates, resulting in helix destabilization and strain breakage of DNA. The mechanism of action and side effects of tinidazole are similar to those of metronidazole, but adverse events appear to be less frequent and severe with tinidazole. In addition, the significantly longer half-life of tinidazole (>12 h) offers potential cure with a single dose. Triclabendazole While most benzimidazoles have broad-spectrum antihelminthic activity, they exhibit minimal or no activity against F. hepatica. In contrast, the antihelminthic activity of triclabendazole is highly specific for Fasciola spp. and Paragonimus spp., with little activity against nematodes, cestodes, and other trematodes. Triclabendazole is effective against all stages of Fasciola spp. The active sulfoxide metabolite of triclabendazole binds to fluke tubulin by assuming a unique nonplanar configuration and disrupts microtubule-based processes. Resistance to triclabendazole in veterinary use has been reported in Australia and Europe; however, no resistance has been documented in humans. Triclabendazole is rapidly absorbed after oral ingestion; administration with food enhances its absorption and shortens the elimination half-life of the active metabolite. Both the sulfoxide and the sulfone
metabolites are highly protein bound (>99%). Treatment with triclabendazole is typically given in one or two doses. No clinical data are available regarding dose adjustment in renal or hepatic insufficiency; however, given the short course of therapy and extensive hepatic metabolism of triclabendazole, dose adjustment is unlikely to be necessary. No information exists on drug interactions. Trimethoprim-Sulfamethoxazole See Table 201-1 and Chap. 127.
FURTHER READINGS
ABRAMOWICZ M (ed): Drugs for parasitic infections. Med Lett Drugs Ther 46:1, 2004 MOORE TA, MCCARTHY JS: Benzimidazoles (albendazole, mebendazole, thiabendazole, triclabendazole), in Antimicrobial Therapy and Vaccines, 2d ed, VL Yu et al (eds). Pittsburgh, ESun Technologies, 2005, pp 1021–1036 SHAPIRO TA, GOLDBERG DE: Drugs used in the chemotherapy of protozoal infections: Malaria, in Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 11th ed, L Brunton et al (eds). New York, McGraw-Hill, 2005, pp 1021–1048 WARD SA et al: Antimalarial drugs and pregnancy: Safety, pharmacokinetics, and pharmacovigilance. Lancet Infect Dis 7:136, 2007 WINSTANLEY P, WARD S: Malaria chemotherapy. Adv Parasitol 61:47, 2006 WORLD HEALTH ORGANIZATION: Model Prescribing Information: Drugs Used in Parasitic Diseases, 2d ed. Geneva, WHO, 1995
PART 7
Infectious Diseases
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
e18
Atlas of Blood Smears of Malaria and Babesiosis
Nicholas J. White, Joel G. Breman
Four species of blood protozoan parasites cause human malaria: the potentially lethal and often drug-resistant Plasmodium falciparum; the relapsing parasites P. vivax and P. ovale; and P. malariae, which can persist at low densities for years. Occasional infections in individuals who have been in tropical forests may be caused by monkey parasites—notably, P. knowlesi. The malaria parasites are readily seen under the microscope (×1000 magnification) in thick and thin blood smears stained with
supravital dyes (e.g., Giemsa’s, Field’s, Wright’s, Leishman’s). The e127 morphologic characteristics of the parasites are summarized in Table e18-1. In the thick film, lysis of red blood cells by water leaves the stained white cells and parasites, allowing detection of densities as low as 50 parasites/μL. This degree of sensitivity is up to 100 times greater than that of the thin film, in which the red cells are fixed and the malaria parasites are seen inside the cells. The thin film is better for speciation and provides useful prognostic information in severe falciparum malaria. Several findings are associated with increased mortality risk: high parasite counts, more mature parasites (>20% containing visible malaria pigment), and phagocytosed malaria pigment in >5% of neutrophils. Babesia microti appears as a small ring form resembling P. falciparum. Unlike Plasmodium, Babesia does not cause the production of pigment in parasites, nor are schizonts or gametocytes formed.
TABLE e18-1 MORPHOLOGIC CHARACTERISTICS OF HUMAN MALARIA PARASITES P. falciparum
Asexual parasites Usually only fine blue ring forms (some resembling stereo headsets) are seen. Parasitemia level may exceed 2%. Rare in peripheral blood; 8–32 merozoites, dark brown-black pigment Banana-shaped; male: light blue; female: darker blue; a few scattered blue-black pigment granules in cytoplasm RBCs are normal in size. As the parasite matures, the RBC cytoplasm becomes pale, the cells become crenated, and a few small red dots may appear over the cytoplasm (Maurer’s clefts).
P. vivax
Irregular, large, fairly thick rings become highly pleomorphic as the parasite grows. Parasitemia level is low. Common; 12–18 merozoites, orange-brown pigment Round or oval; male: round, pale blue; female: oval, dark blue; triangular nucleus, a few orange pigment granules RBCs are enlarged. Pale red Schüffner’s dots increase in number as the parasite matures.
P. ovale
Regular, dense ring enlarges to compact, blue, mature trophozoite (rectangular or band-form). Parasitemia level is low. 8–14 merozoites, brown or black pigment Large, round, dense, and blue (like P. malariae), but prominent James’s dots; brown pigment RBCs become oval with tufted ends. Red James’s dots are prominent.
P. malariae
Dense, thick rings mature to dense, round trophozoites. Parasitemia level is low. 8–10 merozoites, dark brown or black pigment Large, oval; male: pale blue; female: dense blue; large black pigment granules RBCs are normal in size and shape. No red dots are seen.
CHAPTER e18 Atlas of Blood Smears of Malaria and Babesiosis
Schizonts Gametocytes RBC changes
Note: RBC, red blood cell.
FIGURE e18-1 Thin blood films of Plasmodium falciparum. A. Young trophozoites. B. Old trophozoites. C. Pigment in polymorphonuclear cells and trophozoites. D. Mature schizonts. E. Female gametocytes. F. Male gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2d ed, with the permission of the World Health Organization.)
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
e128
PART 7
FIGURE e18-2 Thin blood films of Plasmodium vivax. A. Young trophozoites. B. Old trophozoites. C. Mature schizonts. D. Female gametocytes. E. Male gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2d ed, with the permission of the World Health Organization.)
Infectious Diseases
FIGURE e18-3 Thin blood films of Plasmodium ovale. A. Old trophozoites. B. Mature schizonts. C. Male gametocytes. D. Female gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2d ed, with the permission of the World Health Organization.)
FIGURE e18-4 Thin blood films of Plasmodium malariae. A. Old trophozoites. B. Mature schizonts. C. Male gametocytes. D. Female gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2d ed, with the permission of the World Health Organization.)
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
e129
FIGURE e18-5 Thick blood films of Plasmodium falciparum. A. Trophozoites. B. Gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2d ed, with the permission of the World Health Organization.)
CHAPTER e18 Atlas of Blood Smears of Malaria and Babesiosis
FIGURE e18-6 Thick blood films of Plasmodium vivax. A. Trophozoites. B. Schizonts. C. Gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2d ed, with the permission of the World Health Organization.)
FIGURE e18-7 Thick blood films of Plasmodium ovale. A. Trophozoites. B. Schizonts. C. Gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2d ed, with the permission of the World Health Organization.)
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
e130
FIGURE e18-8 Thick blood films of Plasmodium malariae. A. Trophozoites. B. Schizonts. C. Gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2d ed, with the permission of the World Health Organization.)
FURTHER READINGS
WARHURST C, WILLIAMS JE: Laboratory procedures for diagnosis of malaria, in Abdalla SH, Pasvol G (series eds): Malaria: A Hematological Perspective. G Pasvol, SL Hoffman (eds): Tropical Medicine: Science and Practice, vol 4. London, Imperial College Press, 2004
PART 7
FIGURE e18-9 Thin blood film showing trophozoites of Babesia. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2d ed, with the permission of the World Health Organization.)
Infectious Diseases
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
e19
Atlas of Electrocardiography
Ary L. Goldberger
e131
CHAPTER e19 Atlas of Electrocardiography
The electrocardiograms (ECGs) in this Atlas supplement those illustrated in Chap. 221. The interpretations emphasize findings of specific teaching value. All of the figures are from ECG Wave-Maven, Copyright 2003, Beth Israel Deaconess Medical Center, http://ecg.bidmc.harvard.edu. The abbreviations used in this chapter are as follows: AF—atrial fibrillation HCM—hypertrophic cardiomyopathy LVH—left ventricular hypertrophy MI—myocardial infarction NSR—normal sinus rhythm RBBB—right bundle branch block RV—right ventricular RVH—right ventricular hypertrophy MYOCARDIAL ISCHEMIA AND INFARCTION
I aVR V1 V4
II
aVL
V2
V5
III
aVF
V3
V6
II
FIGURE e19-1 Anterior wall ischemia (deep T-wave inversions and ST-segment depressions in I, aVL, V3–V6) in a patient with LVH (increased voltage in V2–V5).
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e132
I
aVR
V1
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FIGURE e19-2 Acute anterolateral wall ischemia with ST elevations in V4–V6. Probable old inferior MI with Q waves in leads II, III and aVF.
I aVR V1 V4
II
aVL
V2
V5
III
aVF
V3
V6
II
FIGURE e19-3 Acute lateral ischemia with ST elevations in I and aVL with probable reciprocal ST depressions inferiorly (II, III, and aVF). Ischemic ST depressions also in V3 and V4. Left atrial abnormality.
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
I
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V1
V4
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CHAPTER e19 Atlas of Electrocardiography
II
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V2
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III
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V3
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II
FIGURE e19-4 Sinus tachycardia. Marked ischemic ST-segment elevations in inferior limb leads (II, III, aVF) and laterally (V6) suggestive of
I aVR
acute inferolateral MI, and prominent ST-segment depressions with upright T waves in V1–V4 consistent with acute posterior MI.
V1 V4
II
aVL
V2
V5
III
aVF
V3
V6
II
FIGURE e19-5 Acute MI with marked ST elevations in I, aVL, V1–V6 and small pathologic Q waves in V3–V6. Marked reciprocal ST-segment depressions in III and aVF.
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e134
I
aVR
V1
V4
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Disorders of the Cardiovascular System
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V2
V5
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aVF
V3
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FIGURE e19-6 Acute anterior wall MI with ST elevations and Q waves in V1–V4 and aVL and reciprocal inferior ST depressions.
I aVR V1 V4
II
aVL
V2
V5
III
aVF
V3
V6
II
FIGURE e19-7 NSR with premature atrial complexes. RBBB; pathologic Q waves and ST elevation due to acute anterior/septal MI in V1–V3.
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I
aVR
V1
V4
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CHAPTER e19 Atlas of Electrocardiography
II
aVL
V2
V5
III
aVF
V3
V6
II
FIGURE e19-8 Acute anteroseptal MI (Q waves and ST elevations in V1–V4) with RBBB (see I, V1).
I aVR V1 V4
II
aVL
V2
V5
III
aVF
V3
V6
II
FIGURE e19-9 Extensive old MI involving inferior-posterior-lateral wall (Q waves in leads II, III, aVF, tall R waves in V1,V2, and Q waves in V5, V6). T-wave abnormalities in leads I and aVL, V5, and V6.
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e136
I
aVR
V1
V4
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II
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V2
V5
III
aVF
V3
V6
II
FIGURE e19-10 NSR with PR prolongation (“1st degree AV block”), left atrial abnormality, LVH, and RBBB. Pathologic Q waves in V1–V5 and
I aVR
aVL with ST elevations (a chronic finding in this patient). Findings compatible with old anterolateral MI and LV aneurysm.
V1 V4
II
aVL
V2
V5
III
aVF
V3
V6
II
FIGURE e19-11 Old inferior-posterior MI. Wide (0.04 s) Q waves in the inferior leads (II, III, aVF); broad R wave in V1 (a Q wave equivalent).
Absence of right-axis deviation and the presence of upright T waves in V1–V2 are also against RVH.
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I
aVR
V1
V4
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CHAPTER e19 Atlas of Electrocardiography
II
aVL
V2
V5
III
aVF
V3
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II
FIGURE e19-12 NSR with RBBB (broad terminal R wave in V1) and left anterior hemiblock, pathologic anterior Q waves in V1–V3 with slow R wave progression. Patient had severe multivessel coronary artery
disease with echocardiogram showing septal dyskinesis and apical akinesis.
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e138 PERICARDITIS
I aVR V1 V4
PART 9
II aVL V2 V5
Disorders of the Cardiovascular System
III
aVF
V3
V6
II
FIGURE e19-13 Acute pericarditis with diffuse ST elevations in I, II, III, aVF, V3–V6, without T-wave inversions. Also PR-segment elevation in aVR and PR depression in the inferolateral leads.
I aVR V1 V4
II
aVL
V2
V5
III
aVF
V3
V6
II
FIGURE e19-14 Sinus tachycardia; diffuse ST elevations (I, II, aVL, aVF, V2–V6) with associated PR deviations (elevated PR in aVR; depressed in
V4–V6); borderline low voltage. Q-wave and T-wave inversions in II, III, and aVF. Diagnosis is acute pericarditis with inferior Q wave MI.
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VALVULAR HEART DISEASE AND HYPERTROPHIC CARDIOMYOPATHY
I aVR V1 V4
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II
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V2
V5
III
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V3
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II
FIGURE e19-15 NSR, left atrial abnormality (see l, II, V1), right-axis deviation and RVH (Rr' in V1) in a patient with mitral stenosis.
I aVR V1 V4
II
aVL
V2
V5
III
aVF
V3
V6
II
FIGURE e19-16 NSR, left atrial abnormality, and LVH by voltage criteria with borderline right-axis deviation in a patient with mixed mitral stenosis (left atrial abnormality and right-axis deviation) and mitral
regurgitation (LVH). Prominent precordial T-wave inversions and QT prolongation also present.
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e140
I aVR V1 V4
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II
aVL
V2
V5
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aVF
V3
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FIGURE e19-17 Coarse AF, tall R in V2 with vertical QRS axis (positive R in aVF) indicating RVH. Tall R in V4 may be due to concomitant LVH. Patient had severe mitral stenosis with moderate mitral regurgitation.
I aVR V1 V4
II
aVL
V2
V5
III
aVF
V3
V6
II
FIGURE e19-18 NSR; first-degree A-V block (P-R prolongation); LVH (tall R in aVL); RBBB (Rr') and left anterior fascicular block in a patient with HCM. Deep Q waves in I and aVL consistent with septal hypertrophy.
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e141
CHAPTER e19 Atlas of Electrocardiography
I
aVR
V1
V4
II
aVL
V2
V5
III
aVF
V3
V6
II
FIGURE e19-19 LVH with deep T-wave inversions in limb leads and precordial leads. Striking T-wave inversions in mid-precordial leads suggest apical HCM.
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
e142 PULMONARY EMBOLISM AND CHRONIC PULMONARY HYPERTENSION
I aVR V1 V4
PART 9
II aVL V2 V5
Disorders of the Cardiovascular System
III
aVF
V3
V6
II
FIGURE e19-20 Sinus tachycardia with S1Q3T3 pattern (T-wave inversion in III), incomplete RBBB, and right precordial T-wave inversions
I aVR
consistent with acute RV overload in a patient with pulmonary emboli.
V1 V4
II
aVL
V2
V5
III
aVF
V3
V6
II
FIGURE e19-21 Sinus tachycardia, right-axis deviation, RVH with tall R in V1 and deep S in V6 and inverted T waves in II, III, aVF, and V1–V5 in a patient with atrial septal defect and severe pulmonary hypertension.
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
I
aVR
V1
V4
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CHAPTER e19 Atlas of Electrocardiography
II
aVL
V2
V5
III
aVF
V3
V6
II
FIGURE e19-22 Signs of right atrial/RV overload in a patient with chronic obstructive lung disease: (1) peaked P waves in II; (2) QR in
I aVR
V1 with narrow QRS; (3) delayed precordial transition, with terminal S waves in V5/V6; (4) superior axis deviation with an S1-S2-S3 pattern.
V1 V4
II
aVL
V2
V5
III
aVF
V3
V6
II
FIGURE e19-23 (1) Low voltage; (2) incomplete RBBB (rsr' in V1–V3); (3) borderline peaked P waves in lead II with vertical P-wave axis (probable right atrial overload); (4) slow R-wave progression in V1–
V3; (5) prominent S waves in V6; and (6) atrial premature beats. This combination is seen typically in severe chronic obstructive lung disease.
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e144 ELECTROLYTE DISORDERS
I aVR V1 V4
PART 9
II aVL V2 V5
Disorders of the Cardiovascular System
III
aVF
V3
V6
II
FIGURE e19-24 Prominent U waves (II, III, V4–V6) with Q-TU prolongation in a patient with severe hypokalemia.
I
aVR
V1
V4
II
aVL
V2
V5
III
aVF
V3
V6
II
FIGURE e19-25 Abbreviated ST segment such that the T wave looks like it takes off directly from QRS in some leads (I, V4, aVL, and V5) in a patient with hypercalcemia. High take-off of ST segment in V2/V3.
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
I
aVR
V1
V4
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CHAPTER e19 Atlas of Electrocardiography
II
aVL
V2
V5
III
aVF
V3
V6
II
FIGURE e19-26 NSR with LVH, left atrial abnormality, and tall peaked T waves in the precordial leads with inferolateral ST depressions (II, III, aVF, and V6); left anterior fascicular block and borderline prolonged QT
interval in a patient with renal failure, hypertension, and hyperkalemia; prolonged QT is secondary to associated hypocalcemia.
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e146 MISCELLANEOUS
I aVR V1 V4
PART 9
II aVL V2 V5
Disorders of the Cardiovascular System
III
aVF
V3
V6
II
FIGURE e19-27 Normal ECG in an 11-year-old male. T-wave inversions in V1–V2. Vertical QRS axis (+90°) and early precordial transition between V2 and V3 are normal findings in children.
I aVR V1 V4
II
aVL
V2
V5
III
aVF
V3
V6
II
FIGURE e19-28 Left atrial abnormality and LVH in a patient with long-standing hypertension.
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
I
aVR
V1
V4
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CHAPTER e19 Atlas of Electrocardiography
II
aVL
V2
V5
III
aVF
V3
V6
II
FIGURE e19-29 Normal variant ST-segment elevations in a healthy 21year-old male (commonly referred to as early repolarization pattern). ST elevations exhibit upward concavity and are most apparent in V3 and
I aVR
V4. Precordial QRS voltages are prominent, but within normal limits for a young adult. No evidence of left atrial abnormality or ST depression/ T wave inversions to go along with LVH.
V1 V4
II
aVL
V2
V5
III
aVF
V3
V6
II
FIGURE e19-30 NSR with first-degree AV block (PR interval = 0.24 s), and complete left bundle branch block.
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e148
I
aVR
V1
V4
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Disorders of the Cardiovascular System
I II III II
II
aVL
V2
V5
III
aVF
V3
V6
II
FIGURE e19-31 Dextrocardia with: (1) inverted P waves in I and aVL; (2) negative QRS complex and T wave in I; and (3) progressively decreasing voltage across the precordium.
aVR V1 V4
aVL
V2
V5
aVF
V3
V6
FIGURE e19-32 Sinus tachycardia; intraventricular conduction delay with a rightward QRS axis. QT interval is prolonged for the rate. The triad of sinus tachycardia, a wide QRS complex, and a long QT suggest
tricyclic antidepressant overdose. Terminal S wave (rS) in I, and terminal R wave (qR) in aVR are also seen in this condition.
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e149
e20
Atlas of Noninvasive Cardiac Imaging
Rick Nishimura, Raymond J. Gibbons, James F. Glockner, A. Jamil Tajik
Noninvasive cardiac imaging is essential to the diagnosis and management of patients with known or suspected cardiovascular disease. Chapter 222 describes the principles and clinical applications of these important techniques. This atlas supplements Chap. 222. It provides “real time” image clips, as they are viewed in clinical practice, as well as additional static images.
VIDEO e20-1 Real-time echocardiographic images of a patient with a normal heart. A. (Play video) Parasternal long axis view. B. (Play video) Parasternal short axis view. C. (Play video) Apical four-chamber view. There is symmetric contraction of the ventricles, evidenced by a decrease in cavity size and an increase in wall thickness during systole. Echocardiographic imaging is performed from multiple acoustic windows with different transducer rotations so that the entire heart and great vessels can be displayed in various planes. Most information from a study is obtained from a visual analysis of the two-dimensional images, although objective measurements of cardiac dimensions can be made (see Fig. e20-1).
CHAPTER e20 Atlas of Noninvasive Cardiac Imaging
FIGURE e20-1 Still frame images of an echocardiogram in diastole (left) and systole (right). Apical four-chamber view (top) and apical two-chamber view (bottom) comprise two orthogonal views. This illustrates the quantitative assessment of ejection fraction. The endocardial area is outlined and is used for calculation of ejection fraction. With quantitative two-dimensional echocardiography, endocardial outlines of the left ventricle (LV) cavity are traced in systole and diastole and the LV cavity areas are then fitted to computer models of the LV to obtain systolic and diastolic volumes. The presence or absence of regional wall motion abnormalities can be assessed by examining endocardial motion as well as wall thickening. VIDEO e20-2 Real-time echocardiographic images of a patient with a severe decrease in left ventricular systolic function. The estimated ejection fraction is 20%. A. (Play video) Parasternal long axis view. B. (Play video) Parasternal short axis view. VIDEO e20-3 Real-time echocardiographic images of a patient with hypertrophic cardiomyopathy, demonstrating an increase in wall thickness during systole. A. (Play video) Parasternal long axis view. B. (Play video) Parasternal short axis view. VIDEO e20-4 Real-time echocardiographic images of a patient with mitral stenosis. There is diastolic doming and restricted leaflet opening secondary to fusion of the commissures. A. (Play video) Parasternal long axis. B. (Play video) Parasternal short axis.
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e150
PART 9
Disorders of the Cardiovascular System
FIGURE e20-2 Continuous wave Doppler (DOPP) echocardiographic tracings across the mitral valve in a patient with mitral stenosis with simultaneous pressures in the left atrium (LA) and left ventricle (LV). The velocity of flow is high in early diastole, followed by a prolonged deceleration of transmitral mitral flow velocity, and a reacceleration during atrial systole (A). There is a mean gradient of 10 mmHg derived from the Doppler tracing, which corresponds to the simultaneous transmitral gradient of 11 mmHg derived from cardiac catheterization. These are consistent with the diagnosis of moderate mitral stenosis. LA, left atrial pressure; LV, left ventricular pressure; a, atrial contraction wave. (From RA Nishimura et al: J Am Coll Cardiol 24:152, 1994.) FIGURE e20-3 Continuous-wave Doppler echocardiogram across the mitral valve of a patient with mitral stenosis. In the resting state (left) there is a mean gradient of 8 mmHg. During exercise (right), the mean gradient rises to 29 mmHg, indicating hemodynamically significant mitral stenosis. VIDEO e20-5 Real-time images with color-flow Doppler imaging of a patient with mitral regurgitation due to ruptured chordae tendinae. A. (Play video) Gray scale image showing a thickened redundant posterior leaflet with loss of coaptation. B. (Play video) Color-flow imaging showing the regurgitation as a high-velocity turbulence (mosaic pattern) regurgitating into the left atrium during systole. C. (Play video) Color-flow imaging of a patient with a normal mitral valve showing no regurgitation into the left atrium. VIDEO e20-6 (Play video) Real-time transesophageal echocardiographic images of a patient with severe mitral regurgitation due to a flail posterior leaflet. The posterior mitral valve leaflet is completely unsupported and moves into the left atrium during systole. VIDEO e20-7 Real-time echocardiographic images from the parasternal long axis view of a patient with mitral valve prolapse. Both leaflets prolapse into the left atrium during systole. A. (Play video) Black and white images demonstrating leaflet morphology and motion. B. (Play video) Color-flow imaging demonstrating a late systolic blue-colored jet of mitral regurgitation. Annular dilatation, prolapse, flail leaflets, vegetation, and rheumatic involvement can all be diagnosed and the LV response to volume overload assessed by two-dimensional echocardiography.
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VIDEO e20-8 (Play video) Real-time two-dimensional echocardiographic images of a patient with a vegetation on the mitral valve. There is a mobile echo density attached directly to the mitral valve apparatus.
VIDEO e20-9 (Play video) Real-time two-dimensional parasternal e151 long axis echocardiographic images from a patient with aortic stenosis. The aortic valve is calcified with restricted opening.
CHAPTER e20 Atlas of Noninvasive Cardiac Imaging
FIGURE e20-4 Continuous-wave Doppler tracings across the aortic valve in a patient with aortic stenosis. There is an increase in velocity to 3 m/s, with a mean transvalvular gradient calculated to be 24 mmHg. This corresponds to the simultaneous catheterization gradient of 24 mmHg between left ventricle (LV) and aorta (Ao).
FIGURE e20-5 Continuous-wave Doppler echocardiogram across the aortic valve in a patient with low output–low gradient aortic stenosis and a reduced ejection fraction. Left. At baseline, there is a mean left ventricular (LV)-aortic (Ao) gradient of 24 mmHg (by Doppler) with a calculated aortic valve area (AVA) of 0.5 cm2. This presents a diagnostic dilemma as the reduced aortic valve area may be due to either critical aortic stenosis and secondary LV dysfunction or a low-output state, in which there is not enough force to open fully a mildly stenotic aortic valve. Right. During dobutamine infusion, there is an increase in the transvalvular pressure gradient to 55 mmHg, with normalization of the stroke volume. This indicates the presence of severe aortic stenosis. VIDEO e20-10 Real-time echocardiographic images showing a close-up view of the atrial septum in a patient with a large secundum atrial septal defect. A. (Play video) Gray scale image showing a questionable “drop-out” in the atrial septum. B. (Play video) Color-flow imaging confirms flow across the atrial septum. VIDEO e20-11 (Play video) Real-time transesophageal echocardiographic images of a patient with a left atrial myxoma. There is a large echo-dense mass in the left atrium that is attached to the atrial septum. The mass moves across the mitral valve in diastole. Although an echocardiographic examination cannot provide pathologic confirmation of the etiology of a mass, in many instances the diagnosis can be suspected from the appearance, mobility, attachments, and concomitant abnormalities.
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e152 VIDEO e20-12 (Play video) Real-time two-dimensional echocardiographic images of a patient with a pericardial effusion. The effusion is shown as black echo-free space surrounding the heart.
PART 9
Disorders of the Cardiovascular System
FIGURE e20-6 Pulsed-wave Doppler echocardiogram of transmitral flow recorded simultaneously with pulmonary artery wedge pressure (PAWP) and left ventricular (LV) pressure in a patient with constrictive pericarditis. There is a dissociation of intrathoracic and intracardiac pressures so that the PAWP has a larger inspiratory (INSP) fall than the LV pressure, causing a decrease in the driving force across the mitral valve. This results in a fall in the transmitral flow velocity. The opposite occurs during expiration (EXP). VIDEO e20-13 (Play video) Real-time two-dimensional echocardiographic images from the parasternal long axis view of a patient with a large aneurysm of the ascending aorta. FIGURE e20-8 High-fidelity left ventricular pressure (LV) curve superimposed on a mitral inflow velocity curve obtained by Doppler echocardiography in a patient with stage I diastolic dysfunction. There is a decrease in the early diastolic filling and an increase with filling at atrial contraction, resulting in a low E:A ratio and prolonged deceleration time (DT). The LV diastolic pressure is normal at 12 mmHg. FIGURE e20-7 Pulsed-wave Doppler tracings of the mitral valve inflow velocities superimposed on left atrial (LA) and left ventricular (LV) pressures. The initial (early diastolic) velocity of mitral inflow (E) correlates with the driving pressure across the mitral valve. The deceleration time (DT) indicates the relative change in LA and LV pressures as blood begins to fill the LV. This increases LV pressure, which rises to meet the LA pressure. The A velocity on the mitral flow velocity curve is a reacceleration of flow due to atrial contraction. Normally, the E velocity exceeds the A velocity. In this patient, they are equal, suggestive of mild diastolic dysfunction (see Fig. e20-8). FIGURE e20-9 High-fidelity left ventricular (LV) and right ventricular (RV) pressure tracings superimposed on a Doppler mitral inflow velocity tracing in a patient with stage III diastolic dysfunction. There is a restriction to filling, in which there is a high early diastolic velocity [rapid filling wave (RFW)] and low velocity of atrial contraction resulting in a high E:A ratio with a short (150 ms) deceleration time (DT). Both ventricular diastolic pressures (*) are elevated.
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VIDEO e20-14 Real-time two-dimensional stress echocardiogram in a normal subject. The studies at rest are shown on the left and the studies during peak exercise are on the right. A. (Play video) Parasternal long axis (top) and short axis (bottom) views. B. (Play video) Apical four-chamber (top) and two-chamber (bottom) views. At rest, there is contraction of all segments of the myocardium. During exercise, there are increases in contractility and in the thickening of all segments of the myocardium.
VIDEO e20-15 Real-time two-dimensional stress echocardiogram of e153 a patient with coronary artery disease. The studies at rest are shown on the left and the studies during peak exercise are on the right. A. (Play video) Parasternal long axis (top) and short axis (bottom) views. B. (Play video) Apical four-chamber (top) and two-chamber views (bottom). The images during peak exercise show regional wall motion abnormalities in the anteroapical distribution indicative of myocardial ischemia.
CHAPTER e20 Atlas of Noninvasive Cardiac Imaging
FIGURE e20-10 Strain rate images from a patient with severe left ventricular dysfunction illustrating dyssynchronous contraction. Strain rate is a measure of regional deformation (or contraction). Strain rates can be used to examine the degree of dyssynchronous contraction of the ventricle, which may help in determining patients who would benefit from biventricular pacing. Shown are the different strain rates over time of the basal septum (yellow line), mid septum (blue line), and apical septum (red line).
FIGURE e20-11 Still frame images demonstrating regional wall motion abnormalities during an exercise echocardiogram in a patient with known coronary artery disease. Left. The systolic frames in the resting state show symmetric contraction of all segments of the myocardium. The upper frame is from the apical four-chamber view and the lower frame is from the apical twochamber view. Right. The systolic frames immediately after exercise show regional wall motion abnormalities in the anterior and apical segments (arrows). LV, left ventricle; RV, right ventricle (From JK Oh et al: The Echo Manual, 2d ed. Philadelphia, Lippincott Williams & Wilkins, 1999, with permission.)
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e154
TABLE e20-1
Thallium
RELATIVE ADVANTAGES OF THALLIUM 201 AND TECHNETIUM 99M
PART 9
FIGURE e20-12 Anterior planar thallium images following stress, showing increased lung uptake on the left (count intensity in lung >50% of that in myocardium) and normal lung uptake on the right (count intensity in lung 13 Hz); the alpha rhythm is attenuated when the eyes are opened (Fig. e31-1). During drowsiness, the alpha rhythm is also at- showing certain abnormalities that are strongly supportive of a diagtenuated; with light sleep, slower activity in the theta (4–7 Hz) and nosis of epilepsy. Such epileptiform activity consists of bursts of abnormal discharges containing spikes or sharp waves. The presence of delta (1.5–2.0 g/L (150–200 mg/dL)]. Prior to removing the LP needle, the stylet is reinserted to avoid the possibility of entrapment of a nerve root in the dura as the needle is being withdrawn; entrapment could result in a dural CSF leak, causing headache. Some practitioners question the safety of this maneuver, with its potential risk of causing a needle-stick injury to the examiner. Injury is unlikely, however, given the flexibility of the small-diameter stylet, which tends to bend, rather than penetrate, on contact. Following LP, the patient is customarily positioned in a comfortable, recumbent position for 1 h before rising, although recent data suggests that assuming a recumbent position may be unnecessary as it does not appear to affect the development of headache (see below). POST-LP HEADACHE The principal complication of LP is headache, occurring in 10–30% of patients. Younger age and female gender are associated with an increased risk of post-LP headache. Headache usually begins within 48 h but may be delayed for up to 12 days. Head pain is dramatically positional; it begins when the patient sits or stands upright; there is relief upon reclining or with abdominal compression. The longer the patient is upright, the longer the latency before head pain subsides. The pain is usually a dull ache but may be throbbing; its location is occipitofrontal. Nausea and stiff neck often accompany headache, and occasionally, patients report blurred vision, photophobia, tinnitus, and vertigo. Symptoms usually resolve over a few days but may on occasion persist for weeks to months. Post-LP headache is caused by a drop in CSF pressure related to persistent leakage of CSF at the site where the needle entered the subarachnoid space. Loss of CSF volume decreases the brain’s supportive cushion, so that when a patient is upright there is probably dilation and tension placed on the brain’s anchoring structures, the pain-sensitive dural sinuses, resulting in pain. Although intracranial hypotension is the usual explanation for severe LP headache, the syndrome can occur in patients with normal CSF pressure. Post-LP headache usually resolves without specific treatment, and care is largely supportive with oral analgesics [acetaminophen, nonsteroidal anti-inflammatory drugs, opioids (Chap. 12)] and antiemetics.
TABLE e32-1 REDUCING THE INCIDENCE OF POST-LP HEADACHE
Effective Strategies Use of small-diameter needle (22-gauge or smaller) Use of atraumatic needle (Sprotte and others) Replacement of stylet prior to removal of needle Insertion of needle with bevel oriented in a cephalad to caudad direction (when using standard needle) Ineffective Strategies Bed rest (up to 4 h) following LP Supplemental fluids Minimizing the volume of spinal fluid removed Immediate mobilization following LP
Patients may obtain relief by lying in a comfortable position. For some patients beverages with caffeine can provide temporary pain relief. For patients with persistent pain, treatment with IV caffeine (500 mg in 500 mL saline administered over 2 h) may be effective; atrial fibrillation is an uncommon side effect. For patients who do not respond to caffeine, an epidural blood patch accomplished by injection of 15 mL of autologous whole blood is usually effective. This procedure is usually performed by a pain specialist or anesthesiologist. The mechanism for these treatment effects is not straightforward. The blood patch has an immediate effect, making it unlikely that sealing off a dural hole with blood clot is its sole mechanism of action. Strategies to decrease the incidence of post-LP headache are listed in Table e32-1. Use of a smaller caliber needle is associated with a lower risk: in one study, the risk of headache following use of a 20- or 22-gauge standard (Quinke) needle was 20–40%, compared to 5–12% when a 24- to 27gauge needle was used. The smallest gauge needles usually require the use of an introducer needle and are associated with a slower CSF flow rate. Use of an “atraumatic” (Sprotte, “pencil point,” or “non-cutting”) needle also reduces the incidence of moderate to severe headache compared with standard LP (Quinke, or “traumatic”) needles (Fig. e32-2). However, because atraumatic needles are more difficult to use, more attempts may be required to perform the LP, particularly in overweight patients. It may also be necessary to use an introducer with the atraumatic needle, which does not have the customary cutting, beveled tip. There is a low risk of needle damage, e.g., breakage, with the Sprotte atraumatic needle. Another strategy to decrease the incidence of headache is to replace the stylet before removing the LP needle. Studies comparing mobilization immediately following LP with bed rest for up to 4 h show no significant differences in the incidence of headache, suggesting that the customary practice of remaining in a recumbent position post-LP may be unnecessary. NORMAL VALUES (See Table e32-2) In uninfected CSF, the normal white blood cell count is fewer than five mononuclear cells (lymphocytes and monocytes) per μL. Polymorphonuclear leukocytes (PMNs) are not found in normal unconcentrated CSF; however, rare PMNs can be found in centrifuged or concentrated CSF specimens such as those utilized for cytologic examination.
PART 16
Neurologic Disorders
FIGURE e32-2 Comparison of the standard (“traumatic” or Quinke) LP needle with the “atraumatic” (Sprotte). The “atraumatic” needle has its opening on the top surface of the needle, a design intended to reduce the chance of cutting dural fibers that, by protruding through the dura, could be responsible for subsequent CSF fluid leak and post-LP headache. (From Thomas et al.)
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TABLE e32-2 CEREBROSPINAL FLUID a Constituent
Glucose Lactate Total protein Lumbar Cisternal Ventricular Albumin IgG IgG indexb Oligoclonal bands (OGB) Ammonia CSF pressure CSF volume (adult) Red blood cells Leukocytes Total Differential Lymphocytes Monocytes Neutrophils
SI Units
2.22–3.89 mmol/L 1–2 mmol/L 0.15–0.5 g/L 0.15–0.25 g/L 0.06–0.15 g/L 0.066–0.442 g/L 0.009–0.057 g/L 0.29–0.59 325 mOsm/kg. Hyperosmolality is usually due to hypernatremia, hyperglycemia, azotemia, or the addition of extrinsic osmoles such as mannitol, which is commonly used in critically ill neurologic patients. Hyperosmolality itself can lead to a generalized encephalopathy that is nonspecific and without focal findings; however, an underlying lesion such as a mass can become symptomatic under the metabolic stress of a hyperosmolar state, producing focal signs. Some patients with hyperosmolality from severe hyperglycemia can present, for unclear reasons, with generalized seizures or unilateral movement disorders, which usually respond to lowering of the serum glucose. The treatment of all forms of hyperosmolality involves calculation of apparent water losses and slow replacement so that the serum sodium declines no faster than 2 mmol/L (2 meq/L) per hour. Hypernatremia leads to the loss of intracellular water, leading to cell shrinkage. In the cells of the brain, solutes such as glutamine and urea are generated under these conditions in order to minimize this shrinkage. Despite this corrective mechanism, when hypernatremia is severe [serum sodium > 160 mmol/L (>160 meq/L)] or occurs rapidly, cellular metabolic processes fail and encephalopathy will result. There are many etiologies of hypernatremia including, most commonly, renal and extrarenal losses of water. Causes of neurologic relevance include central diabetes insipidus, where hyperosmolality is accompanied by submaximal urinary concentration due to inadequate release of antidiuretic hormone (ADH) from the posterior pituitary, resulting often from pituitary injury in the setting of surgery, hemorrhage, infiltrative processes, or cerebral herniation.
HYPONATREMIA e273 Hyponatremia is commonly defined as a serum sodium 5.5 mmol/L (>5.5 meq/L) and can neurologically present as muscle weakness with or without paresthesias. Hyperkalemia becomes life threatening when it produces electrocardiographic abnormalities such as peaked T waves or a widened QRS complex. In these cases, prompt treatment is essential and consists of strategies that protect the heart against arrhythmias (calcium gluconate administration), promote potassium redistribution into cells (with glucose, insulin, and β2-agonist medications), and increase potassium removal (through sodium polystyrene sulfonate, loop diuretics, or hemodialysis). CALCIUM DISTURBANCES Hypercalcemia usually occurs in the setting of either hyperparathyroidism or systemic malignancy. Neurologic manifestations include encephalopathy as well as muscle weakness due to reduced neuromuscular excitability. Seizures can occur but are more common in states of low calcium.
CHAPTER e33 Special Issues in Inpatient Neurologic Consultation
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e274
A
Radial nerve
Sensory distribution of the radial nerve Lateral cutaneous nerve of arm Posterior cutaneous nerve of arm Posterior cutaneous nerve of forearm Superficial branch
B
Ulnar nerve
C
Peroneal nerve Sensory distribution of the peroneal nerve
Lateral cutaneous nerve of calf Sensory distribution of the ulnar nerve Superficial peroneal nerve
Deep peroneal nerve
D
Sensory distribution of the femoral nerve Anterior femoral cutaneus nerve Medial femoral cutaneus nerve
E
Lateral femoral cutaneus nerve
Saphenous nerve
PART 16
Neurologic Disorders
FIGURE e33-3 Sensory distribution of peripheral nerves commonly affected by entrapment neuropathies. A. Radial nerve. Hypocalcemia in adults often follows surgical treatment of the thyroid or parathyroid. Seizures and altered mental status dominate the neurologic picture and usually resolve with calcium repletion. Tetany is due to spontaneous, repetitive action potentials in peripheral nerves and remains the classic sign of symptomatic hypocalcemia. MAGNESIUM DISTURBANCES Disorders of magnesium are difficult to correlate with serum levels because a very small amount of total-body magnesium is located in the extracellular space. Hypomagnesemia presents neurologically with seizures, tremor, and myoclonus. When intractable seizures occur in the setting of hypomagnesemia, only administration of magnesium will lead to resolution. High levels of magnesium, in contrast, lead to CNS depression. Hypermagnesemia usually only occurs in the setting of renal failure and can lead to confusion and muscular paralysis when severe.
B. Ulnar nerve. C. Peroneal nerve. D. Femoral nerve. E. Lateral femoral cutaneous nerve. clinical examination and then confirmed with electrodiagnostic studies in the subacute period, if necessary. Treatment consists mainly of avoidance of repetitive trauma but may also include surgical approaches to relieve pressure on the nerve. Radial Neuropathy Radial nerve injury classically presents with weakness of extension of the wrist and fingers (“wrist drop”) with or without more proximal weakness of extensor muscles of the upper extremity, depending on the site of injury. Sensory loss is in the distribution of the radial nerve, which includes the dorsum of the hand (Fig. e33-3A). Compression at the level of the axilla, e.g., resulting from use of crutches, includes weakness of the triceps, brachioradialis, and supinator muscles in addition to wrist drop. A more common site of compression occurs in the spiral groove of the upper arm in the setting of a humerus fracture or from sleeping with the arm draped over a bench or chair (“Saturday night palsy”). Sparing of the triceps is the rule when the nerve is injured in this location. Because extensors of the upper extremity are injured preferentially in radial nerve injury, these lesions may be mistaken for the pyramidal distribution of weakness that accompanies upper motor neuron lesions from brain or spinal cord processes. Ulnar Neuropathy Compression of the ulnar nerve is the second most common entrapment neuropathy after carpal tunnel syndrome. The most frequent site of compression is at the elbow where the nerve passes superficially in the ulnar groove. Symptoms usually begin with tingling in the ulnar distribution, including the fourth and fifth digits of the hand (Fig. e33-3B). Sensory symptoms may be worsened by elbow flexion due to increased pressure on the nerve, hence the tendency of patients to complain of increasing paresthesias at night when the arm is flexed at the elbow during sleep. Motor dysfunction can be dis-
CONSULTATIONS REGARDING PERIPHERAL NERVOUS SYSTEM DYSFUNCTION
ENTRAPMENT NEUROPATHIES Polyneuropathy is a common cause of outpatient neurologic consultation (Chap. 379). In the inpatient setting, however, mononeuropathies are more frequent, especially the entrapment neuropathies that complicate many surgical procedures and medical conditions. Median neuropathy at the wrist (carpal tunnel syndrome) is the most frequent entrapment neuropathy by far, but it is rarely a cause for inpatient consultation. Mechanisms for perioperative mononeuropathy include traction, compression, and ischemia of the nerve. Imaging with MR neurography may allow these causes to be distinguished definitively. In all cases of mononeuropathy, the diagnosis can be made through the
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abling and involves most of the intrinsic hand muscles, limiting dexterity and strength of grasp and pinch. Etiologies of ulnar entrapment include trauma to the nerve (hitting the “funny bone”), malpositioning during anesthesia for surgical procedures, and chronic arthritis of the elbow. When a perioperative ulnar nerve injury is considered, stretch injury or trauma to the lower trunk of the brachial plexus should be entertained as well since its symptoms can mimic those of an ulnar neuropathy. If the clinical examination is equivocal, electrodiagnostic studies can definitively distinguish between plexus and ulnar nerve lesions a few weeks after the injury. Conservative methods of treatment are often the first step, but a variety of surgical approaches may be effective, including anterior ulnar nerve transposition and release of the flexor carpi ulnaris aponeurosis. Peroneal Neuropathy The peroneal nerve winds around the head of the fibula in the leg below the lateral aspect of the knee, and its superficial location at this site makes it vulnerable to trauma. Patients present with weakness of foot dorsiflexion (“foot drop”) as well as with weakness in eversion but not inversion at the ankle. Sparing of inversion, which is a function of muscles innervated by the tibial nerve, helps to distinguish peroneal neuropathies from L5 radiculopathies. Sensory loss involves the lateral aspect of the leg as well as the dorsum of the foot (Fig. e33-3C). Fractures of the fibular head may be responsible for peroneal neuropathies, but in the perioperative setting poorly applied braces exerting pressure on the nerve while the patient is unconscious are more often responsible. Tight-fitting stockings or casts of the upper leg can also cause a peroneal neuropathy, and thin individuals and those with recent weight loss are at increased risk. Proximal Femoral Neuropathy Lesions of the proximal femoral nerve are relatively uncommon but may present dramatically with weakness of hip flexion, quadriceps atrophy, weakness of knee extension (often manifesting with leg-buckling falls), and an absent patellar reflex. Adduction of the thigh is spared as these muscles are supplied by the obturator nerve, thereby distinguishing a femoral neuropathy from a more proximal lumbosacral plexus lesion. The sensory loss found is in the distribution of the femoral nerve sensory branches on the anterior part of the thigh (Fig. e33-3D). Compressive lesions from retroperitoneal hematomas or masses are common, and a CT of the pelvis should be obtained in all cases of femoral neuropathy to exclude these conditions. Bleeding into the pelvis resulting in hematoma can occur spontaneously, following trauma, or after intrapelvic surgeries such as renal transplantation. In intoxicated or comatose patients, stretch injuries to the femoral nerve are seen following prolonged, extreme hip flexion or extension. Rarely, attempts at femoral vein or arterial puncture can be complicated by injury to this nerve.
Lateral Femoral Cutaneous Nerve The symptoms of lateral femoral e275 cutaneous nerve entrapment, commonly known as “meralgia paresthetica,” include sensory loss, pain, and dysesthesia in part of the area supplied by the nerve (Fig. e33-3E). There is no motor component to the nerve, and therefore weakness is not a part of this syndrome. Symptoms often are worsened by standing or walking. Compression of the nerve occurs where it enters the leg near the inguinal ligament, usually in the setting of tight-fitting belts, pants, corsets, or recent weight gain, including that of pregnancy. The differential diagnosis of these symptoms includes hip problems such as trochanteric bursitis. OBSTETRIC NEUROPATHIES Pregnancy and delivery place women at special risk for a variety of nerve injuries. Radiculopathy due to a herniated lumbar disc is not common during pregnancy, but compressive injuries of the lumbosacral plexus do occur secondary to either the fetal head passing through the pelvis or the use of forceps during delivery. These plexus injuries are more frequent with cephalopelvic disproportion and often present with a painless unilateral foot drop which must be distinguished from a peroneal neuropathy caused by pressure on the nerve while in lithotomy position during delivery. Other compressive mononeuropathies of pregnancy include meralgia paresthetica, carpal tunnel syndrome, femoral neuropathy when the thigh is abducted severely in an effort to facilitate delivery of the fetal shoulder, and obturator neuropathy during lithotomy positioning. The latter presents with medial thigh pain that may be accompanied by weakness of thigh adduction. There is also a clear association between pregnancy and an increased frequency of idiopathic facial palsy (Bell’s palsy).
CHAPTER e33 Special Issues in Inpatient Neurologic Consultation
FURTHER READINGS
JENSEN BO et al: Cognitive outcomes in elderly high-risk patients after off-pump versus conventional coronary artery bypass grafting: A randomized trial. Circulation 113:2784, 2006 JILLAPALLI D, SHEFNER JM: Electrodiagnosis in common mononeuropathies and plexopathies. Semin Neurol 25:196, 2005 KARNAD DR, GUNTUPALLI KK: Neurologic disorders in pregnancy. Crit Care Med 33:S362, 2005 KUMAR S et al: Central pontine myelinolysis, an update. Neurol Res 28:360, 2006 LAMY C et al: Neuroimaging in posterior reversible encephalopathy syndrome. J Neuroimaging 14:89, 2004 VAN DIJK D et al: Cognitive and cardiac outcomes 5 years after offpump vs. on-pump coronary artery bypass graft surgery. JAMA 297;701, 2007
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e34 Heavy Metal Poisoning
Howard Hu
Metals pose a significant threat to health through occupational as well as environmental exposures. One indication of their importance relative to other potential hazards is their ranking by the U.S. Agency for Toxic Substances and Disease Registry, which lists all hazards present in toxic waste sites according to their prevalence and the severity of their toxicity. The first, second, third, and sixth hazards on the list are heavy metals: lead, mercury, arsenic, and cadmium, respectively. Specific information pertaining to each of these metals, including sources and metabolism, toxic effects produced, diagnosis, and the appropriate treatment for poisoning, is summarized in Table e34-1. Metals are inhaled primarily as dusts and fumes (the latter defined as tiny particles generated by combustion). Metal poisoning can also result from exposure to vapors (e.g., mercury vapor in creating dental amalgams). When metals are ingested in contaminated food or drink or by hand-to-mouth activity (implicated especially in children), their gastrointestinal absorption varies greatly with the specific chemical form of the metal and the nutritional status of the host. Once a metal is absorbed, blood is the main medium for its transport, with the precise kinetics dependent on diffusibility, protein binding, rates of biotransformation, availability of intracellular ligands, and other factors. Some organs (e.g., bone, liver, and kidney) sequester metals in relatively high concentrations for years. Most metals are excreted through renal clearance and gastrointestinal excretion; some proportion is also excreted through salivation, perspiration, exhalation, lactation, skin exfoliation, and loss of hair and nails. The intrinsic stability of metals facilitates tracing and measurement in biologic material, although the clinical significance of the levels measured is not always clear. Some metals, such as copper and selenium, are essential to normal metabolic function as trace elements (Chap. 71) but are toxic at high TABLE e34-1 HEAVY METALS Main Sources Metabolism Toxicity
levels of exposure. Others, such as lead and mercury, are xenobiotic e277 and theoretically are capable of exerting toxic effects at any level of exposure. Indeed, much research is currently focused on the contribution of low-level xenobiotic metal exposure to chronic diseases and to subtle changes in health that may have significant public health consequences. Genetic factors also may modify the impact of metals on health and thereby account, at least in part, for individual susceptibility to metal effects. The most important component of treatment for metal toxicity is the termination of exposure. Chelating agents are used to bind metals into stable cyclic compounds with relatively low toxicity and to enhance their excretion. The principal chelating agents are dimercaprol (British Anti-Lewisite, BAL), edetate (EDTA), succimer (DMSA, dimercaptosuccinic acid), and penicillamine; their specific use depends on the metal involved and the clinical circumstances. Activated charcoal does not bind metals and thus is of limited usefulness in cases of acute metal ingestion. In addition to the information provided in Table e34-1, several other aspects of exposure, toxicity, or management are worthy of discussion with respect to the four most hazardous toxicants (arsenic, cadmium, lead, and mercury). Arsenic exposure from natural contamination of shallow tube wells inserted for drinking water is a huge environmental problem for millions of residents in parts of Bangladesh and Western India. Contamination was formerly considered only a problem with deep wells; however, the geology of this region allows most residents only a few alternatives for potable drinking water. Serious cadmium poisoning from the contamination of food and water by mining effluents in Japan contributed to the 1946 outbreak of “itai-itai” (“ouch-ouch”) disease, so named because of cadmium-induced bone toxicity that led to painful bone fractures. Modest exposures from environmental contamination near a smelter in Belgium were recently associated with a lower bone density, a higher incidence of fractures, and a faster decline in height in both men and women, ef-
CHAPTER e34 Heavy Metal Poisoning
Diagnosis
Arsenic
Treatment
Smelting and microelectronics industries; wood preservatives, pesticides, herbicides, fungicides; contaminant of deep-water wells; folk remedies; and coal; incineration of these products
Organic arsenic (arsenobentaine, arsenocholine) is ingested in seafood and fish, but is nontoxic; inorganic arsenic is readily absorbed (lung and GI); sequesters in liver, spleen, kidneys, lungs, and GI tract; residues persist in skin, hair, and nails; biomethylation results in detoxification, but this process saturates.
Acute arsenic poisoning results in necrosis of intestinal mucosa with hemorrhagic gastroenteritis, fluid loss, hypotension, delayed cardiomyopathy, acute tubular necrosis, and hemolysis. Chronic arsenic exposure causes diabetes, vasospasm, peripheral vascular insufficiency and gangrene, peripheral neuropathy, and cancer of skin, lung, liver (angiosarcoma), bladder, kidney. Lethal dose: 120–200 mg (adults); 2 mg/kg (children). Cadmium
Nausea, vomiting, diarrhea, abdominal pain, delirium, coma, seizures; garlicky odor on breath; hyperkeratosis, hyperpigmentation, exfoliative dermatitis, and Mees’ lines (transverse white striae of the fingernails); sensory and motor polyneuritis, distal weakness. Radiopaque sign on abdominal x-ray; ECG–QRS broadening, QT prolongation, ST depression, T-wave flattening; 24-h urinary arsenic >67 μmol/d or 50 μg/d; (no seafood × 24 h); if recent exposure, serum arsenic >0.9 μmol/L (7 μg/dL). High arsenic in hair or nails.
If acute ingestion, ipecac to induce vomiting, gastric lavage, activated charcoal with a cathartic. Supportive care in ICU. Dimercaprol 3–5 mg/kg IM q4h × 2 days; q6h × 1 day, then q12h × 10 days; alternative: oral succimer.
Metal-plating, pigment, smelting, battery, and plastics industries; tobacco; incineration of these products; ingestion of food that concentrates cadmium (grains, cereals).
Absorbed through ingestion or inhalation; bound by metallothionein, filtered at the glomerulus, but reabsorbed by proximal tubules (thus, poorly excreted). Biologic 1/2 life: 10–30 y. Binds cellular sulfhydryl groups, competes with zinc, calcium for binding sites. Concentrates in liver and kidneys.
Acute cadmium inhalation causes pneumonitis after 4–24 h; acute ingestion causes gastroenteritis. Chronic exposure causes anosmia, yellowing of teeth, emphysema, minor LFT elevations, microcytic hypochromic anemia unresponsive to iron therapy, proteinuria, increased urinary β2- microglobulin, calciuria, leading to chronic renal failure, osteomalacia, and fractures.
With inhalation: pleuritic chest pain, dyspnea, cyanosis, fever, tachycardia, nausea, noncardiogenic pulmonary edema. With ingestion: nausea, vomiting, cramps, diarrhea. Bone pain, fractures with osteomalacia. If recent exposure, serum cadmium >500 nmol/L (5 μg/dL). Urinary cadmium >100 nmol/L (10 μg/g creatinine) and/or urinary β2-microglobulin >750 μg/g creatinine (but urinary β2microglobulin also increased in other renal diseases such as pyelonephritis).
There is no effective treatment for cadmium poisoning (chelation not useful; dimercaprol can exacerbate nephrotoxicity). Avoidance of further exposure, supportive therapy, vitamin D for osteomalacia.
(continued)
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e278
TABLE e34-1 HEAVY METALS (CONTINUED) Main Sources Metabolism Toxicity
Lead Manufacturing of auto batteries, lead crystal, ceramics, fishing weights, etc.; demolition or sanding of leadpainted houses, bridges; stained glass making, plumbing, soldering; environmental exposure to paint chips, house dust (in home built 20 years. Excreted mostly in urine, but also appears in other fluids including breast milk. Interferes with mitochondrial oxidative phosphorylation, ATPases, calcium-dependent messengers; enhances oxidation and cell apoptosis. Acute exposure with blood lead levels (BPb) of > 60–80 μg/dL can cause impaired neurotransmission and neuronal cell death (with central and peripheral nervous system effects); impaired hematopoiesis and renal tubular dysfunction. At higher levels of exposure (e.g., BPb > 80–120 μg/dL), acute encephalopathy with convulsions, coma, and death may occur. Subclinical exposures in children (BPb 25–60 μg/dL) are associated with anemia; mental retardation; and deficits in language, motor function, balance, hearing, behavior, and school performance. Impairment of IQ appears to occur at even lower levels of exposure with no measurable threshold above the limit of detection in most assays of 1 μg/dL. In adults, chronic subclinical exposures (BPb > 40 μg/dL) are associated with an increased risk of anemia, demyelinating peripheral neuropathy (mainly motor), impairments of reaction time, hypertension, ECG conduction delays, interstitial nephritis and chronic renal failure, diminished sperm counts, spontaneous abortions. Mercury Metallic, mercurous, and mercuric mercury (Hg°, Hg+, Hg2+) exposures occur in some chemical, metal-processing, electrical-equipment, automotive industries; they are also in thermometers, dental amalgams, batteries. Mercury is dispersed by waste incineration. Environmental bacteria convert inorganic to organic mercury, which then bioconcentrates up the aquatic food chain to contaminate tuna, swordfish, and other pelagic fish. Elemental mercury (Hg°) is not well absorbed; however, it will volatilize into highly absorbable vapor. Inorganic mercury is absorbed through the gut and skin. Organic mercury is well absorbed through inhalation and ingestion. Elemental and organic mercury cross the blood-brain barrier and placenta. Mercury is excreted in urine and feces and has a 1/2 life in blood of ∼60 days; however, deposits will remain in the kidney and brain for years. Exposure to mercury stimulates the kidney to produce metallothionein, which provides some detoxification benefit. Mercury binds sulfhydryl groups and interferes with a wide variety of critical enzymatic processes. Acute inhalation of Hg° vapor causes pneumonitis and noncardiogenic pulmonary edema leading to death, CNS symptoms, and polyneuropathy. Chronic high exposure causes CNS toxicity (mercurial erethism; see diagnosis); lower exposures impair renal function, motor speed, memory, coordination. Acute ingestion of inorganic mercury causes gastroenteritis, the nephritic syndrome, or acute renal failure, hypertension, tachycardia, and cardiovascular collapse, with death at a dose of 10–42 mg/kg. Ingestion of organic mercury causes gastroenteritis, arrhythmias, and lesions in the basal ganglia, gray matter, and cerebellum at doses >1.7 mg/kg. High exposure during pregnancy causes derangement of fetal neuronal migration resulting in severe mental retardation. Mild exposures during pregnancy (from fish consumption) are associated with declines in neurobehavioral performance in offspring. Dimethylmercury, a compound only found in research labs, is “supertoxic”—a few drops of exposure via skin absorption or inhaled vapor can cause severe cerebellar degeneration and death. Chronic exposure to metallic mercury vapor produces a characteristic intention tremor and mercurial erethism: excitability, memory loss, insomnia, timidity, and delirium (“mad as a hatter”). On neurobehavioral tests: decreased motor speed, visual scanning, verbal and visual memory, visuomotor coordination. Children exposed to mercury in any form may develop acrodynia (“pink disease”): flushing, itching, swelling, tachycardia, hypertension, excessive salivation or perspiration, irritability, weakness, morbilliform rashes, desquamation of palms and soles. Toxicity from elemental or inorganic mercury exposure begins when blood levels >180 nmol/L (3.6 μg/ dL) and urine levels >0.7 μmol/L (15 μg/dL). Exposures that ended years ago may result in a >20-μg increase in 24-h urine after a 2-g dose of succimer. Organic mercury exposure is best measured by levels in blood (if recent) or hair (if chronic); CNS toxicity in children may derive from fetal exposures associated with maternal hair Hg > 30 nmol/g (6 μg/g). Treat acute ingestion of mercuric salts with induced emesis or gastric lavage and polythiol resins (to bind mercury in the GI tract). Chelate with dimercaprol (up to 24 mg/kg per day IM in divided doses), DMSA (succimer), or penicillamine, with 5-day courses separated by several days of rest. If renal failure occurs, treat with peritoneal dialysis, hemodialysis, or extracorporeal regional complexing hemodialysis and succimer. Chronic inorganic mercury poisoning is best treated with N-acetyl penicillamine. Abdominal pain, irritability, lethargy, anorexia, anemia, Fanconi’s syndrome, pyuria, azotemia in children with blood lead level (BPb) >80 μg/ dL; may also see epiphyseal plate “lead lines” on long bone x-rays. Convulsions, coma at BPb > 120 μg/dL. Noticeable neurodevelopmental delays at BPb of 40–80 μg/dL; may also see symptoms associated with higher BPb levels. In the U.S., screening of all children when they begin to crawl (∼6 months) is recommended by the CDC; source identification and intervention is begun if the BPb > 10 μg/ dL. In adults, acute exposure causes similar symptoms as in children as well as headaches, arthralgias, myalgias, depression, impaired short-term memory, loss of libido. Physical exam may reveal a “lead line” at the gingiva-tooth border, pallor, wrist drop, and cognitive dysfunction (e.g., declines on the mini-mental status exam); lab tests may reveal a normocytic, normochromic anemia, basophilic stippling, an elevated blood protoporphyrin level (free erythrocyte or zinc), and motor delays on nerve conduction. In the U.S., OSHA requires regular testing of lead-exposed workers with removal if BPb > 40 μg/dL. Identification and correction of exposure sources is critical. In some U.S. states, screening and reporting to local health boards of children with BPb > 10 μg/dL and workers with BPb > 40 μg/dL is required. In the highly exposed individual with symptoms, chelation is recommended with oral DMSA (succimer); if acutely toxic, hospitalization and IV or IM chelation with edentate calcium disodium (CaEDTA) may be required, with the addition of dimercaprol to prevent worsening of encephalopathy. It is uncertain whether children with asymptomatic lead exposure (e.g., BPb 20–40 μg/ dL) benefit from chelation. Correction of dietary deficiencies in iron, calcium, magnesium, and zinc will lower lead absorption and may also improve toxicity. Vitamin C is a weak but natural chelating agent.
Diagnosis
Treatment
PART 17
Poisoning, Drug Overdose, and Envenomation
Note: GI, gastrointestinal; ECG, electrocardiogram; ICU, intensive care unit; LFT, liver function tests; RBC, red blood cell; IQ, intelligence quotient; CDC, Centers for Disease
Control and Prevention; OSHA, Occupational Safety and Health Administration; CNS, central nervous system.
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
fects that may be related to cadmium’s calciuric effect on the kidney. Such research is creating concern that cadmium exposure may be contributing significantly to morbidity and mortality from osteoporosis in the general population. Advances in our understanding of lead toxicity have recently benefited by the development of K-x-ray fluorescence (KXRF) instruments for making safe in vivo measurements of lead levels in bone (which, in turn, reflect cumulative exposure over many years, as opposed to blood lead levels, which mostly reflect recent exposure). High bone lead levels measured by KXRF have been linked to increased risk of hypertension in both men and women from an urban population. In addition, high maternal bone lead levels were found to predict lower birth weight, head circumference, birth length, and neurodevelopmental performance in offspring by age 2. The toxicity of low-level organic mercury exposure (as manifested by neurobehavioral performance) is of increasing concern based on studies of the offspring of mothers who ingested mercury-contaminated fish. However, current evidence has not supported the recent contention that ethyl mercury, used as a preservative in multiuse vaccines administered in early childhood, has played a significant role in causing neurodevelopmental problems such as autism. A few additional metals deserve brief mention but are not covered in Table e34-1 because of the relative rarity of their being clinically encountered, or the uncertainty regarding their potential toxicities. Aluminum contributes to the encephalopathy in patients with severe renal disease who are undergoing dialysis (Chap. 347). High levels of aluminum are found in the neurofibrillary tangles in the cerebral cortex and hippocampus of patients with Alzheimer’s disease, as well as in the drinking water and soil of areas with an unusually high incidence of Alzheimer’s. The experimental and epidemiologic evidence for the aluminum–Alzheimer’s disease link is so far relatively weak, however, and it cannot be concluded that aluminum is a causal agent or a contributing factor in neurodegenerative disease. Hexavalent chromium is corrosive and sensitizing. Workers in the chromate and chrome pigment production industries have consistently had a greater risk of lung cancer. The introduction of cobalt chloride as a fortifier in beer led to outbreaks of fatal cardiomyopathy among heavy consumers. Occupational exposure (e.g., of miners, dry-battery manufacturers, and arc welders) to manganese can cause a Parkinsonian syndrome within 1–2 years, including gait disorders; postural instability; a masked, expres-
sionless face; tremor; and psychiatric symptoms. With the introduc- e279 tion of methylcyclopentadienyl manganese tricarbonyl (MMT) as a gasoline additive, there is concern for the toxic potential of environmental manganese exposure. Nickel exposure induces an allergic response, and inhalation of nickel compounds with low aqueous solubility (e.g., nickel subsulfide and nickel oxide) in occupational settings is associated with an increased risk of lung cancer. Overexposure to selenium may cause local irritation of the respiratory system and eyes, gastrointestinal irritation, liver inflammation, loss of hair, depigmentation, and peripheral nerve damage. Workers exposed to certain organic forms of tin (particularly trimethyl and triethyl derivatives) have developed psychomotor disturbances, including tremor, convulsions, hallucinations, and psychotic behavior. Thallium, which is a component of some insecticides, metal alloys, and fireworks, is absorbed through the skin as well as by ingestion and inhalation. Severe poisoning follows a single ingested dose of >1 g or >8 mg/kg. Nausea and vomiting, abdominal pain, and hematemesis precede confusion, psychosis, organic brain syndrome, and coma. Thallium is radiopaque. Induced emesis or gastric lavage is indicated within 4–6 h of acute ingestion; Prussian blue prevents absorption and is given orally at 250 mg/kg in divided doses. Unlike other types of metal poisoning, thallium poisoning may be less severe when activated charcoal is used to interrupt its enterohepatic circulation. Other measures include forced diuresis, treatment with potassium chloride (which promotes renal excretion of thallium), and peritoneal dialysis.
CHAPTER e34 Heavy Metal Poisoning
FURTHER READINGS
BRODKIN E et al: Lead and mercury exposures: Interpretation and action. CMAJ 176(1):59, 2007 CENTENO JA et al: Pathology related to chronic arsenic exposure. Environ Health Perspect 110(Suppl 5):883, 2002 JÄRUP L: Hazards of heavy metal contamination. Br Med Bull 68:167, 2003 MISRA UK: Thallium poisoning: Emphasis on early diagnosis and response to haemodialysis. Postgrad Med J 79:103, 2003 PARK S, JOHNSON MA: Awareness of fish advisories and mercury exposure in women of childbearing age. Nutr Rev 64:250, 2006 SAPER RB et al: Heavy metal content of ayurvedic herbal medicine products. JAMA 292: 2868, 2004
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e35
Poisoning and Drug Overdosage
Christopher H. Linden, Michael J. Burns, Mark B. Mycyk
Poisoning refers to the development of dose-related adverse effects following exposure to chemicals, drugs, or other xenobiotics. To paraphrase Paracelsus, the dose makes the poison. In excessive amounts, substances that are usually innocuous, such as oxygen and water, can cause poisoning. Conversely, in small doses, substances commonly regarded as poisons, such as arsenic and cyanide, can be consumed without ill effect. There is, however, substantial individual variability in the response to, and disposition of, a given dose. Some of this variability is genetic, and some is acquired on the basis of enzyme induction or inhibition, or because of tolerance. Poisoning may be local (e.g., skin, eyes, or lungs) or systemic depending on the chemical and physical properties of the poison, its mechanism of action, and the route of exposure. The severity and reversibility of poisoning also depend on the functional reserve of the individual or target organ, which is influenced by age and preexisting disease. EPIDEMIOLOGY About 5 million poison exposures occur in the United States each year. Most are acute, accidental (unintentional), involve a single agent, occur in the home, result in minor or no toxicity, and involve children under 6 years of age. Pharmaceuticals are involved in 47% of exposures and 84% of serious or fatal poisonings. Unintentional exposures can result from the improper use of chemicals at work or play; product mislabeling; label misreading; mistaken identification of unlabeled chemicals; uninformed self-medication; and dosing errors by nurses, parents, pharmacists, physicians, and the elderly. Excluding the recreational use of ethanol, attempted suicide (deliberate self-harm) is the most common reason for intentional exposure. Unintended poisonings may result from the recreational use of prescribed and over-thecounter drugs for psychotropic or euphoric effects (abuse) or excessive self-dosing (misuse). About 25% of exposures require health professional evaluation, and 5% of all exposures require hospitalization. Poisonings account for 5– 10% of all ambulance transports, emergency department visits, and intensive care unit admissions. Up to 30% of psychiatric admissions are prompted by attempted suicide via overdosage. Overall, the mortality rate is low: 0.4% of all exposures. It is much higher (1–2%) in hospitalized patients with intentional (suicidal) overdose, who account for the majority of serious poisonings. Acetaminophen is the pharmaceutical agent most often implicated in fatal poisoning. Overall, carbon monoxide is the leading cause of death from poisoning, but this is not reflected in hospital or poison center statistics because patients with such poisoning are typically dead when discovered and are referred directly to medical examiners. DIAGNOSIS Although poisoning can mimic other illnesses, the correct diagnosis can usually be established by the history, physical examination, routine and toxicologic laboratory evaluations, and characteristic clinical course. The history should include the time, route, duration, and circumstances (location, surrounding events, and intent) of exposure; the name and amount of each drug, chemical, or ingredient involved; the time of onset, nature, and severity of symptoms; the time and type of first aid measures provided; and the medical and psychiatric history. In many cases the victim is confused, comatose, unaware of an exposure, or unable or unwilling to admit to one. Suspicious circumstances include unexplained illness in a previously healthy person; a history of psychiatric problems (particularly depression); recent changes in health, economic status, or social relationships; and onset of illness while working with chemicals or after ingesting food, drink
(especially ethanol), or medications. Patients who become ill soon af- e281 ter arriving from a foreign country or being arrested for criminal activity should be suspected of “body packing” or “body stuffing” (ingesting or concealing illicit drugs in a body cavity). Relevant history may be available from family, friends, paramedics, police, pharmacists, physicians, and employers, who should be questioned regarding the patient’s habits, hobbies, behavior changes, available medications, and antecedent events. A search of clothes, belongings, and place of discovery may reveal a suicide note or a container of drugs or chemicals. The imprint code on pills and the label on chemical products may be used to identify the ingredients and potential toxicity of a suspected poison by consulting a reference text, a computerized database, the manufacturer, or a regional poison information center. Occupational exposures require review of available MSDS (Material Safety Data Sheets) from the worksite. The physical examination should focus initially on the vital signs, cardiopulmonary system, and neurologic status. The neurologic examination should include documentation of neuromuscular abnormalities such as dyskinesia, dystonia, fasciculations, myoclonus, rigidity, tremors. The patient should also be examined for evidence of trauma and underlying illnesses. Focal neurologic findings are uncommon in poisoning, and their presence should prompt evaluation for a structural central nervous system (CNS) lesion. Examination of the eyes (for nystagmus, pupil size and reactivity), abdomen (for bowel activity and bladder size), and skin (for burns, bullae, color, warmth, moisture, pressure sores, and puncture marks) may reveal findings of diagnostic value. When the history is unclear, all orifices should be examined for the presence of chemical burns and drug packets. The odor of breath or vomitus and the color of nails, skin, or urine may provide diagnostic clues. The diagnosis of poisoning in cases of unknown etiology primarily relies on pattern recognition. The first step is to assess the pulse, blood pressure, respiratory rate, temperature, and neurologic status and characterize the overall physiologic state as stimulated, depressed, discordant, or normal (Table e35-1). Obtaining a complete set of vital signs and reassessing them frequently are critical. Measuring core temperature is especially important, even in difficult or combative patients, since temperature elevation is the most reliable prognosticator of poor outcome in poisoning. The next step is to consider the underlying causes of the observed physiologic state and attempt to identify a pathophysiologic pattern or toxic syndrome (toxidrome) based on further analysis of the vital signs, neurologic status, and other physical findings. Assessing the severity of physiologic derangements (Table e35-2) is useful in this regard and also for assessing the clinical course and response to treatment. The final step is to attempt to identify the particular agent involved by looking for unique or relatively poisonspecific physical or ancillary test abnormalities. This approach is summarized below. Increased pulse, blood pressure, respiratory rate, temperature, and neuromuscular activity characterize the stimulant toxidromes: sympathetic, antimuscarinic (anticholinergic), hallucinogen poisoning and drug withdrawal (Table e35-1). Other features are noted in Table e35-2. Mydriasis, a characteristic feature of all stimulant toxidromes, is most marked in antimuscarinic (anticholinergic) poisoning since pupillary reactivity relies on muscarinic control; in sympathetic poisoning (e.g., cocaine), pupils are also enlarged but some reactivity to light is observed. The anticholinergic (antimuscarinic) toxidrome is also distinguished by the presence of hot, dry, flushed skin; decreased bowel sounds; and urinary retention (Table e35-1). Other stimulant toxidromes increase sympathetic activity and cause diaphoresis, pallor, and increased bowel activity with varying degrees of nausea, vomiting, abnormal distress, and occasionally diarrhea. The absolute and relative degree of vital sign changes and neuromuscular hyperactivity can help distinguish among stimulant toxidromes. Since sympathetics stimulate the peripheral nervous system more directly than do hallucinogens or drug withdrawal, markedly increased vital signs and organ ischemia suggest sympathetic poisoning. Findings helpful in suggesting the particular drug or class causing physiologic stimulation include reflex
CHAPTER e35 Poisoning and Drug Overdosage
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e282
TABLE e35-1 DIFFERENTIAL DIAGNOSIS OF POISONING BASED ON PHYSIOLOGIC STATE Stimulated
Sympathetics Sympathomimetics Ergot alkaloids Methylxanthines Monoamine oxidase inhibitors Thyroid hormones Anticholinergics Antihistamines Antiparkinsonian agents Antipsychotics Antispasmodics Belladonna alkaloids Cyclic antidepressants Muscle relaxants Mushrooms and plants Hallucinogens Cannabinoids (marijuana) LSD and analogues Mescaline and analogues Mushrooms Phencyclidine and analogues Withdrawal syndromes Barbiturates Benzodiazepines Ethanol Opioids Sedative-hypnotics Sympatholytics
Depressed
Sympatholytics α1-Adrenergic antagonists α2-Adrenergic agonists ACE inhibitors Angiotensin receptor blockers Antipsychotics β-adrenergic blockers Calcium channel blockers Cardiac glycosides Cyclic antidepressants Cholinergics Acetylcholinesterase inhibitors Muscarinic agonists Nicotinic agonists Opioids Analgesics GI antispasmodics Heroin Sedative-hypnotics Alcohols Anticonvulsants Barbiturates Benzodiazepines GABA precursors Muscle relaxants Other agents GHB Products
Discordant
Asphyxiants Cytochrome oxidase inhibitors Inert gases Irritant gases Methemoglobin inducers Oxidative phosphorylation inhibitors AGMA inducers Alcohol (ketoacidosis) Ethylene glycol Iron Methanol Salicylate Toluene CNS syndromes Extrapyramidal reactions Hydrocarbon inhalation Isoniazid Lithium Neuroleptic malignant syndrome Serotonin syndrome Strychnine Membrane-active agents Amantidine Antiarrhythmics Antihistamines Antipsychotics Carbamazepine Cyclic antidepressants Local anesthetics Opioids (some) Orphenadrine Quinoline antimalarials
Normal
Nontoxic exposure Psychogenic illness Toxic time-bombs Slow absorption Anticholinergics Carbamazepine Concretion formers Dilantin Kapseals Drug packets Enteric-coated pills Lomotil Opioids Salicylates Sustained-release pills Slow distribution Cardiac glycosides Lithium Metals Salicylate Toxic metabolite Acetaminophen Carbon tetrachloride Cyanogenic glycosides Ethylene glycol Methanol Methemoglobin inducers Mushroom toxins Organophosphate insecticides Paraquat Metabolism disruptors Antineoplastic agents Antiviral agents Colchicine Hypoglycemic agents Immunosuppressive agents MAO inhibitors Metals Salicylate Warfarins
PART 17
Poisoning, Drug Overdose, and Envenomation
Note: ACE, angiotensin-converting enzyme; AGMA, anion-gap metabolic alkalosis; GHB, γ-hydroxybutyric; GI, gastrointestinal; CNS, central nervous system; LSD, lysergic acid di-
ethylamide; GABA, γ-aminobutyric acid; MAO; monoamine oxidase; GHB, γ-hydroxybutyric.
bradycardia from selective α-adrenergic stimulants (e.g., decongestants), hypotension from selective β-adrenergic stimulants (e.g., asthma therapeutics), limb ischemia from ergot alkaloids, nystagmus from phencyclidine and ketamine (the only physiologic stimulants that cause this finding), and delayed cardiac conduction from high doses of cocaine and some anticholinergic agents (e.g., antihistamines, cyclic antidepressants, and antipsychotics). Seizures suggest a sympathetic etiology, an anticholinergic agent with membrane-active properties (e.g., cyclic antidepressants, orphenadrine, phenothiazines), or a withdrawal syndrome. Other manifestations of grade 4 physiologic stimulation (Table e35-2) are likely only in sympathetic poisoning. Close attention to core temperature is critical in these patients. Decreased pulse, blood pressure, respiratory rate, temperature, and neuromuscular activity are indicative of physiologic depression caused by “functional” sympatholytics (agents that decrease cardiac function and vascular tone as well as symthathetic activity), cholinergic (muscarinic and nicotinic) agents, opioids, and sedative-hypnotic γ-aminobutyric acid (GABA)-ergic] agents (Tables e35-1 and e35-2). Miosis is also common and most pronounced in opioid and cholinergic poisoning. The latter is distinguished from other depressant toxidromes by the presence of muscarinic and nicotinic signs and symptoms (Table e35-1). Pronounced cardiovascular depression in the absence of significant CNS depression suggests a direct or peripherally acting sympatholytic. In contrast, in opioid and sedative-hypnotic poisoning, vital sign changes are secondary to depression of CNS cardiovascular and respiratory centers (or consequent hypoxemia) and significant abnormalities in these parameters do not occur until there is a marked
decrease in the level of consciousness (grade 3 or 4 physiologic depression, Table e35-2). Other clues that suggest the cause of physiologic depression include cardiac arrhythmias and conduction disturbances (due to antiarrhythmics, β-adrenergic antagonists, calcium-channel blockers, digitalis glycosides, propoxyphene, and cyclic antidepressants), mydriasis [due to tricyclic antidepressants, some antiarrhythmics, meperidine, and diphenoxylate-atropine (Lomotil)], nystagmus (due to sedative-hypnotics), and seizures (due to cholinergic agents, propoxyphene, cyclic antidepressants). Discordant or mixed vital sign and neuromuscular abnormalities are characteristic of poisoning by asphyxiants, CNS syndromes, membrane-active agents, and anion-gap metabolic acidosis (AGMA) inducers (Table e35-1). In these conditions, manifestations of physiologic stimulation and physiologic depression occur together or at different times during the clinical course. For example, membrane-active agents can cause simultaneous coma, seizures, hypotension, and tachyarrhythmias. Alternatively, vital signs may be normal but the patient has altered mental status or is obviously sick or clearly symptomatic. Early, pronounced vital sign and mental status changes suggest asphyxiant or membrane-active agent poisoning; the lack of such abnormalities suggests an AGMA inducer, and marked neuromuscular dysfunction without significant vital sign abnormalities suggests a CNS syndrome. As noted below, AGMA inducer poisoning can be distinguished from other causes of AGMA by the serum lactate concentration. A normal physiologic status and physical examination may be due to a nontoxic exposure, psychogenic illness, or poisoning by “toxic time-bombs,” agents that are slowly absorbed, slowly distributed to
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TABLE e35-2 SEVERITY OF PHYSIOLOGIC STIMULATION AND DEPRESSION IN POISONING AND DRUG WITHDRAWAL
Physiologic Stimulation Grade 1 Grade 2 Grade 3 Grade 4 Anxious, irritable, tremulous; vital signs normal; diaphoresis, flushing or pallor, mydriasis, and hyperreflexia may be present Agitated; may have confusion or hallucinations but is able to converse and follow commands; vital signs mildly to moderately increased Delirious; unintelligible speech, uncontrollable motor hyperactivity; moderately to markedly increased vital signs; tachyarrhythmias possible Coma, seizures, cardiovascular collapse
Physiologic Depression Grade 1 Grade 2 Grade 3 Grade 4 Awake, lethargic, or sleeping but arousable by voice or tactile stimulation; able to converse and follow commands; may be confused Responds to pain but not voice; can vocalize but not converse; spontaneous motor activity present; brainstem reflexes intact Unresponsive to pain; spontaneous motor activity absent; brainstem reflexes depressed; motor tone, respirations, and temperature decreased Unresponsive to pain; flaccid paralysis; brainstem reflexes and respirations absent; cardiovascular vital signs decreased
their sites of action, require metabolic activation, or disrupt metabolic processes (Table e35-1). Because so many medications are now reformulated in a once-a-day form for patient convenience and adherance, “toxic time-bombs” are increasingly common. Diagnosing a nontoxic exposure requires that the identity of the exposure agent be known or that a toxic time-bomb exposure has been excluded and that the time since exposure exceeds the longest known or predicted interval between exposure and peak toxicity. Psychogenic illness (fear of being poisoned, mass hysteria) may also occur after a nontoxic exposure and should be considered when symptoms are inconsistent with the exposure history. Anxiety reactions resulting from a nontoxic exposure can cause mild physiologic stimulation (Table e35-2) and be indistinguishable from toxicologic causes (Table e35-1) without ancillary testing or a suitable periAnion Gap od of observation. Laboratory assessment may be helpful in the differential diagnosis (Fig. e35-1). An increased AGMA is charIncreased with metabolic acidosis Normal Decreased acteristic of advanced methanol, ethylene glycol, and salicylate intoxication but can occur with other agents Lactate level (Table e35-1) and in any poisoning that results in hepatic, renal, or respiratory failure; seizures; or shock. The serum lactate concentration is low (less than the anion gap) in the former and high (nearly equal to the anion High Low Ketosis Iron Bromide Iodine gap) in the latter. An abnormally low anion gap can be Lithium due to elevated blood levels of bromide, calcium, iodine, Nitrate Absent Toluene lithium, magnesium, or nitrate. An increased osmolal Present gap—a difference between the serum osmolality (measured by freezing point depression) and that calculated from the serum sodium, glucose, and blood urea nitroAsphyxiants Propylene Formaldehyde Alcoholic Ethylene Ethanol Calcium gen of >10 mmol/L—suggests the presence of a low-moketoacidosis glycol Biguanides glycol Kidney failure Magnesium lecular-weight solute such as acetone, an alcohol (benzyl, Acetone Liver failure Paraldehyde Methanol ethanol, isopropanol, methanol), a glycol (diethylene, Isopropanol Seizures Phosphates Valproic Severe Salicylates ethylene, propylene), ether (ethyl, glycol), or an “unmeaacid agitation Sulfur/sulfate sured” cation (calcium, magnesium) or sugar (glycerol, Shock mannitol, sorbitol). Ketosis suggests acetone, isopropyl alcohol, or salicylate poisoning. Hypoglycemia may be due to poisoning with β-adrenergic blockers, ethanol, Normal Increased insulin, oral hypoglycemic agents, quinine, and salicylates, whereas hyperglycemia can occur in poisoning with acetone, β-adrenergic agonists, caffeine, calcium channel Osmolal Gap blockers, iron, theophylline, or N-3-pyridylmethyl-N′-pnitrophenylurea (PNU, Vacor). Hypokalemia can be FIGURE e35-1 Differential diagnosis of poisoning based on the results of routine caused by barium, β-adrenergic agonists, caffeine, di- laboratory tests.
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uretics, theophylline, or toluene; hyperkalemia suggests poisoning e283 with an α-adrenergic agonist, a β-adrenergic blocker, cardiac glycosides, or fluoride. Hypocalcemia may be seen in ethylene glycol, fluoride, and oxalate poisoning. The electrocardiogram (ECG) can sometimes be useful for rapid diagnostic purposes. Bradycardia and atrioventricular block may occur in patients poisoned by α-adrenergic agonists, antiarrhythmic agents, beta blockers, calcium channel blockers, cholinergic agents (carbamate and organophosphate insecticides), cardiac glycosides, lithium, magnesium, or tricyclic antidepressants. QRS- and QT-interval prolongation may be caused by hyperkalemia and by membrane-active drugs (Table e35-1). Ventricular tachyarrhythmias may be seen in poisoning with cardiac glycosides, fluorides, membrane-active drugs, methylxanthines, sympathomimetics, and agents that cause hyperkalemia or potentiate the effects of endogenous catecholamines (e.g., chloral hydrate, aliphatic and halogenated hydrocarbons). Radiologic studies may also be useful. Pulmonary edema (adult respiratory distress syndrome, or ARDS) can be caused by poisoning with carbon monoxide, cyanide, an opioid, paraquat, phencyclidine, a sedative-hypnotic, or salicylate; by inhalation of irritant gases, fumes, or vapors (acids and alkali, ammonia, aldehydes, chlorine, hydrogen sulfide, isocyanates, metal oxides, mercury, phosgene, polymers); or by prolonged anoxia, hyperthermia, or shock. Aspiration pneumonia is common in patients with coma, seizures, and petroleum distillate ingestion. The presence of radiopaque densities on abdominal x-rays suggests the ingestion of calcium salts, chloral hydrate, chlorinated hydrocarbons, heavy metals, illicit drug packets, iodinated compounds, potassium salts, psychotherapeutic agents, lithium, phenothiazines, enteric-coated tablets, or salicylates. Toxicologic analysis of urine and blood (and occasionally of gastric contents and chemical samples) can sometimes confirm or rule out suspected poisoning. Interpretation of laboratory data requires knowledge of the tests used for screening and confirmation (thin-layer, gas-liquid, or high-performance liquid chromatography; colorimetric and fluorometric assays; enzyme-multiplied, fluorescence polarization, and radio-
CHAPTER e35 Poisoning and Drug Overdosage
e284 immunoassays; gas chromatography; mass spectrometry), their sensitivity (limit of detection) and specificity, the preferred biologic specimen for analysis, and the optimal time of specimen sampling. Personal communication with the laboratory is essential. A negative result may mean the substance is not detectable by the test used or that its concentration is too low for detection at the time of sampling. In the latter case, repeating the test at a later time may yield a positive result. Although rapid qualitative screening tests for a limited number of drugs of abuse are available, comprehensive screening tests require 2–6 h for completion. Thus, immediate management must often be based on the history, physical examination, and routine bedside ancillary tests (e.g., ECG). In addition, when the patient is asymptomatic, or when the clinical picture is consistent with the reported history, qualitative screening is neither clinically useful nor cost-effective. It is of greatest value in patients with severe or unexplained toxicity such as coma, seizures, cardiovascular instability, metabolic or respiratory acidosis, and non-sinus cardiac rhythms. Quantitative analysis is useful for poisoning with acetaminophen (Chap. 299), acetone, alcohols (including ethylene glycol and methanol), antiarrhythmics, anticonvulsants, barbiturates, digoxin, heavy metals, lithium, salicylate, and theophylline, as well as for carboxyhemoglobin and methemoglobin. Results can often be available within an hour. The response to antidotes may be useful for diagnostic purposes. Resolution of altered mental status and abnormal vital signs within minutes of IV administration of dextrose, naloxone, or flumazenil is virtually diagnostic of hypoglycemia, narcotic poisoning, and benzodiazepine intoxication, respectively. The prompt reversal of dystonic (extrapyramidal) signs and symptoms following an IV dose of benztropine or diphenhydramine confirms a drug etiology. Although complete reversal of both central and peripheral manifestations of anticholinergic poisoning by physostigmine is diagnostic of this condition, physostigmine may cause some arousal in patients with CNS depression of any etiology.
TABLE e35-3 FUNDAMENTALS OF POISONING MANAGEMENT
Supportive Care Airway protection Oxygenation/ventilation Treatment of arrhythmias Hemodynamic support Treatment of seizures Correction of temperature abnormalities Correction of metabolic derangements Prevention of secondary complications
Prevention of Further Poison Absorption Gastrointestinal decontamination Syrup of ipecac–induced emesis Gastric lavage Activated charcoal Whole-bowel irrigation Catharsis Dilution Endoscopic/surgical removal Decontamination of other sites Eye decontamination Skin decontamination Body cavity evacuation
PART 17
Poisoning, Drug Overdose, and Envenomation
Enhancement of Poison Elimination Multiple-dose activated charcoal Diuresis Alteration of urinary pH Chelation Extracorporeal removal Peritoneal dialysis Hemodialysis Hemoperfusion Hemofiltration Plasmapheresis Exchange transfusion Hyperbaric oxygenation
Administration of Antidotes Neutralization by antibodies Neutralization by chemical binding Prevention of Reexposure Adult education Child-proofing Notification of regulatory agencies Psychiatric referral Metabolic antagonism Physiologic antagonism
POISONING AND DRUG OVERDOSE
GENERAL PRINCIPLES Treatment goals include support of vital
signs, prevention of further poison absorption, enhancement of poison elimination, administration of specific antidotes, and prevention of reexposure (Table e35-3). Specific treatment depends on the identity of the poison, the route and amount of exposure, the time of presentation relative to the time of exposure, and the severity of poisoning. Knowledge of the offending agents’ pharmacokinetics and pharmacodynamics is essential. During the pretoxic phase, prior to the onset of poisoning, decontamination is the highest priority, and treatment is based solely on the history. The maximum potential toxicity based on the greatest possible exposure should be assumed. Since decontamination is more effective when accomplished soon after exposure, the initial history and physical examination should be focused and brief. It is also advisable to establish IV access and initiate cardiac monitoring, particularly in patients with potentially serious ingestions or unclear histories. When an accurate history is not obtainable and a poison causing delayed toxicity or irreversible damage is suspected, blood and urine should be sent for toxicologic screening and, if indicated, for quantitative analysis. During absorption and distribution, blood levels may be greater than those in tissue and may not correlate with toxicity. However, high blood levels of agents whose metabolites are more toxic than the parent compound (acetaminophen, ethylene glycol, or methanol) may indicate the need for additional interventions (antidotes, dialysis). Most patients who remain or become asymptomatic 4–6 h after ingestion will not develop subsequent toxicity and can be discharged safely. Longer observation will likely be necessary for patients who have ingested toxic time-bombs, agents that are slowly absorbed, slowly distributed to their sites of action, require metabolic activation, or disrupt metabolic processes (Table e35-1). During the toxic phase, the time between the onset of poisoning and the peak effects, management is based primarily on clinical and laboratory findings. Effects after an overdose usually begin sooner, peak later, and last longer than they do after a therapeutic dose. A drug’s published pharmacokinetic profile in standard references like the Physician’s Desk Reference (PDR) is usually different from its toxicokinetic profile in over-
dose. Resuscitation and stabilization are the first priority. Symptomatic patients should have an IV line, oxygen saturation determination, cardiac monitoring, and continuous observation. Baseline laboratory, ECG, and xray evaluation may also be appropriate. Intravenous glucose (unless the serum level is documented to be normal), naloxone, and thiamine should be considered in patients with altered mental status, particularly those with coma or seizures. Decontamination should also be considered, but it is less likely to be effective during this phase than during the pretoxic one. Measures that enhance poison elimination may shorten the duration of toxicity and lessen its severity. However, they are not without risk, which must be weighed against the potential benefit. Diagnostic certainty (usually via laboratory confirmation) is generally a prerequisite. Intestinal (or “gut”) dialysis with repetitive doses of activated charcoal is usually safe and can enhance the elimination of selected poisons. Urinary alkalinization and chelation therapy enhance the elimination of a relatively small number of poisons, and their use is associated with potential complications. Extracorporeal elimination methods are effective for many poisons, but their expense and risk make their use reasonable only in patients who would otherwise have an unfavorable outcome. During the resolution phase of poisoning, supportive care and monitoring should continue until clinical, laboratory, and ECG abnormalities have resolved. Since chemicals are eliminated sooner from the blood than from tissues, blood levels are usually lower than tissue levels during this phase and again may not correlate with toxicity. This is particularly true when extracorporeal elimination procedures are used. Redistribution from tissues may cause a rebound increase in the blood level after termination of these procedures. When a metabolite is responsible for toxic effects, continued treatment might be necessary in the absence of clinical toxicity or abnormal laboratory studies.
SUPPORTIVE CARE The goal of supportive therapy is to maintain
physiologic homeostasis until detoxification is accomplished and to prevent and treat secondary complications such as aspiration, bedsores, cerebral and pulmonary edema, pneumonia, rhabdomyolysis, renal failure, sepsis, thromboembolic disease, coagulopathy, and generalized organ dysfunction due to hypoxia or shock.
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Admission to an intensive care unit is indicated for the following: patients with severe poisoning (coma, respiratory depression, hypotension, cardiac conduction abnormalities, cardiac arrhythmias, hypothermia or hyperthermia, seizures); those needing close monitoring, antidotes, or enhanced elimination therapy; those showing progressive clinical deterioration; and those with significant underlying medical problems. Patients with mild to moderate toxicity can be managed on a general medical service, intermediate care unit, or emergency department observation area, depending on the anticipated duration and level of monitoring needed (intermittent clinical observation versus continuous clinical, cardiac, and respiratory monitoring). Patients who have attempted suicide require continuous observation and measures to prevent self-injury until they are no longer suicidal.
longed QT intervals. Magnesium and anti-digoxin antibodies should be e285 considered in patients with severe cardiac glycoside poisoning. Invasive (esophageal or intracardiac) ECG recording may be necessary to determine the origin (ventricular or supraventricular) of wide-complex tachycardias (Chap. 226). If the patient is hemodynamically stable, however, it is reasonable to simply observe them rather than to administer another potentially proarrhythmic agent. Arrhythmias may be resistant to drug therapy until underlying acid-base, electrolyte, oxygenation, and temperature derangements are corrected.
Respiratory Care Endotracheal intubation for protection against the
aspiration of gastrointestinal contents is of paramount importance in patients with CNS depression or seizures as this complication can increase morbidity and mortality. Mechanical ventilation may be necessary for patients with respiratory depression or hypoxia and to facilitate therapeutic sedation or paralysis in order to prevent or treat hyperthermia, acidosis, and rhabdomyolysis associated with neuromuscular hyperactivity. Since clinical assessment of respiratory function can be inaccurate, the need for oxygenation and ventilation is best determined by continuous pulse oximetry or arterial blood-gas analysis. The gag reflex is not a reliable indicator of the need for intubation. A patient with CNS depression may maintain airway patency while being stimulated but not if left alone. Those who cannot respond to voice or who are unable to sit and drink fluids without assistance are best managed by prophylactic intubation. Drug-induced pulmonary edema is usually noncardiac rather than cardiac in origin, although profound CNS depression and cardiac conduction abnormalities suggest the latter. Measurement of pulmonary artery pressure may be necessary to establish the cause and direct appropriate therapy. Extracorporeal measures (membrane oxygenation, venoarterial perfusion, cardiopulmonary bypass) and partial liquid (perfluorocarbon) ventilation may be appropriate for severe but reversible respiratory failure.
Cardiovascular Therapy Maintenance of normal tissue perfusion is
critical for complete recovery to occur once the offending agent has been eliminated. If hypotension is unresponsive to volume expansion, treatment with norepinephrine, epinephrine, or high-dose dopamine may be necessary. Intraaortic balloon pump counterpulsation and venoarterial or cardiopulmonary perfusion techniques should be considered for severe but reversible cardiac failure. Bradyarrhythmias associated with hypotension generally should be treated as described in Chap. 225. Glucagon, calcium, and high-dose insulin with dextrose may be effective in both beta blocker and calcium channel blocker poisoning. Antibody therapy may be indicated for cardiac glycoside poisoning. Supraventricular tachycardia associated with hypertension and CNS excitation is almost always due to agents that cause generalized physiologic excitation (Table e35-1). Most cases are mild or moderate in severity and require only observation or nonspecific sedation with a benzodiazepine. In severe cases or those associated with hemodynamic instability, chest pain, or ECG evidence of ischemia, specific therapy is indicated. When the etiology is sympathetic hyperactivity, treatment with a benzodiazepine should be prioritized. Further treatment with a combined alpha and beta blocker (labetalol), a calcium channel blocker (verapamil or diltiazem), or a combination of a beta blocker and a vasodilator (esmolol and nitroprusside) may be considered for cases refractory to high doses of benzodiazepines. Treatment with an α-adrenergic antagonist (phentolamine) alone may sometimes be appropriate. If the cause is anticholinergic poisoning, physostigmine is the treatment of choice. Supraventricular tachycardia without hypertension is generally secondary to vasodilation or hypovolemia and responds to fluid administration. For ventricular tachyarrhythmias due to tricyclic antidepressants and probably other membrane-active agents (Table e35-1), sodium bicarbonate is indicated, whereas class IA, IC, and III antiarrhythmic agents are contraindicated because of similar electrophysiologic effects. Although lidocaine and phenytoin are historically safe for ventricular tachyarrhythmias of any etiology, sodium bicarbonate should be considered first for any ventricular arrhythmia suspected to have a toxicologic etiology. Beta blockers can be hazardous if the arrhythmia is due to sympathetic hyperactivity. Magnesium sulfate and overdrive pacing (by isoproterenol or a pacemaker) may be useful in patients with torsades des pointes and pro-
Central Nervous System Therapies Neuromuscular hyperactivity and seizures can lead to hyperthermia, lactic acidosis, and rhabdomyolysis, with their attendant complications, and should be treated aggressively. Seizures caused by excessive stimulation of catecholamine receptors (sympathomimetic or hallucinogen poisoning and drug withdrawal) or decreased activity of GABA (isoniazid poisoning) or glycine (strychnine poisoning) receptors are best treated with agents that enhance GABA activity, such as benzodiazepine or barbiturates. Since benzodiazepines and barbiturates act by slightly different mechanisms (the former increases the frequency and the latter increases the duration of chloride channel opening in response to GABA), therapy with both may be effective when neither is effective alone. Seizures caused by isoniazid, which inhibits the synthesis of GABA at several steps by interfering with the cofactor pyridoxine (vitamin B6), may require high doses of supplemental pyridoxine. Seizures resulting from membrane destabilization (beta blocker or cyclic antidepressant poisoning) require GABA enhancers (benzodiazepines first, barbiturates second). Phenytoin is contraindicated in toxicologic seizures: animal and human data demonstrate worse outcomes after phenytoin loading, especially in theophylline overdose. For poisons with central dopaminergic effects (phencyclidine) manifested by psychotic behavior, a dopamine receptor antagonist, such as haloperidol, may be useful. In anticholinergic and cyanide poisoning, specific antidotal therapy may be necessary. The treatment of seizures secondary to cerebral ischemia or edema or to metabolic abnormalities should include correction of the underlying cause. Neuromuscular paralysis is indicated in refractory cases. Electroencephalographic monitoring and continuing treatment of seizures are necessary to prevent permanent neurologic damage. Serotonergic receptor overstimulation in serotonin syndrome may be treated with cyproheptadine. Other Measures Temperature extremes, metabolic abnormalities, hepatic and renal dysfunction, and secondary complications should be treated by standard therapies.
CHAPTER e35 Poisoning and Drug Overdosage
PREVENTION OF POISON ABSORPTION Gastrointestinal Decontamination Whether or not to perform gastrointestinal decontamination, and which procedure to use, depends on the time since ingestion; the existing and predicted toxicity of the ingestant; the availability, efficacy, and contraindications of the procedure; and the nature, severity, and risk of complications. The efficacy of activated charcoal, gastric lavage, and syrup of ipecac decreases with time, and there are insufficient data to support or exclude a beneficial effect when they are used >1 h after ingestion. The average time from ingestion to presentation for treatment is >1 h for children and >3 h for adults. Most patients will recover from poisoning uneventfully with good supportive care alone, but complications of gastrointestinal decontamination, particularly aspiration, can prolong this process. Hence, gastrointestinal decontamination should be performed selectively, not routinely, in the management of overdose patients. It is clearly unnecessary when predicted toxicity is minimal or the time of expected maximal toxicity has passed without significant effect. Activated charcoal has comparable or greater efficacy, fewer contraindications and complications, and is less aversive and invasive than ipecac or gastric lavage; thus it is the preferred method of gastrointestinal decontamination in most situations. Activated charcoal suspension (in water) is given orally via a cup, straw, or small-bore nasogastric tube. The recommended dose is 1 g/kg body weight. Palatability may be increased by adding a sweetener (sorbitol) or a flavoring agent (cherry, chocolate, or cola syrup) to the suspension. Charcoal adsorbs ingested poisons within the gut lumen, allowing the charcoal-toxin complex to be evacuated with stool. In vitro, charcoal adsorbs ≥90% of most substances when given in an amount equal to 10 times the weight of the substance. Charged (ionized) chemicals such as mineral acids, alkalis, and highly dissociated salts of cyanide, fluoride, iron, lithium, and other inorganic compounds are not well
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e286 adsorbed by charcoal. In animal and human volunteer studies, charcoal
decreases the absorption of ingestants by an average of 73% when given within 5 min of ingestant administration, 51% when given at 30 min, and 36% at 60 min. Side effects of charcoal include nausea, vomiting, and diarrhea or constipation. Charcoal may also prevent the absorption of orally administered therapeutic agents. Complications include mechanical obstruction of the airway, aspiration, vomiting, and bowel obstruction and infarction caused by inspissated charcoal. Charcoal is not recommended for patients who have ingested corrosives because it obscures endoscopy. Gastric lavage is performed by sequentially administering and aspirating ~5 mL fluid per kilogram of body weight through a no. 40 French orogastric tube (no. 28 French tube for children). Except for infants, where normal saline is recommended, tap water is acceptable. The patient should be placed in Trendelenburg and left lateral decubitus positions to prevent aspiration (even if an endotracheal tube is in place). Lavage decreases ingestant absorption by an average of 52% if performed within 5 min of ingestion administration, 26% if performed at 30 min, and 16% if performed at 60 min. Its efficacy is similar to that of ipecac. Significant amounts of ingested drug are recovered in ~10% of patients. Aspiration is a common complication (occurring in up to 10% of patients), especially when lavage is perfomed improperly. Serious complications (esophageal and gastric perforation, tube misplacement in the trachea) occur in ~1% of patients. For this reason, the physician should personally insert the lavage tube and confirm its placement, and the patient must be cooperative or adequately restrained (with pharmacologic sedation if necessary) during the procedure. Gastric lavage is contraindicated in corrosive or petroleum distillate ingestions because of the respective risks of gastroesophageal perforation and aspiration pneumonitis. It is also contraindicated in those with a compromised unprotected airway and those at risk for hemorrhage or perforation due to esophageal or gastric pathology or recent surgery. Finally, gastric lavage is absolutely contraindicated in combative patients or those who refuse, as most published complications involve patient resistance to the procedure. Syrup of ipecac, once the most commonly used decontamination procedure, has no role in the hospital setting. Even the American Academy of Pediatrics (AAP), traditionally the strongest proponent of ipecac, issued a policy statement in 2003 recommending that ipecac should no longer be used in poisoning treatment. Some argue it can still be considered for the home management of patients with unintentional ingestions, reliable histories, and mild predicted toxicity when transport to a hospital site is prolonged. Ipecac irritates the stomach and stimulates the central chemoreceptor trigger zone. Vomiting usually occurs about 20 min after administration. Nausea and vomiting from ipecac may prevent use of other, more effective decontamination procedures. Chronic ipecac use (by patients with anorexia nervosa or bulimia) may cause electrolyte and fluid abnormalities, cardiac toxicity, and myopathy. Except for aspiration, serious complications (e.g., gastric or esophageal tears and perforations) are rare. Ipecac is contraindicated in patients with recent gastrointestinal surgery, CNS depression, or seizures, and in those who have ingested corrosives or rapidly acting CNS poisons (camphor, cyanide, tricyclic antidepressants, propoxyphene, strychnine). Whole-bowel irrigation is performed by administering a bowel-cleansing solution containing electrolytes and polyethylene glycol (Golytely, Colyte) orally or by gastric tube at a rate of 2.0 L/h (0.5 L/h in children) until rectal effluent is clear. The patient must be in a sitting position. Although data are limited, whole-bowel irrigation appears to be as effective as other decontamination procedures. It is most appropriate for those who have ingested foreign bodies, packets of illicit drugs, slow-release or enteric-coated medications, and agents that are poorly adsorbed by charcoal (e.g., heavy metals). It is contraindicated in patients with bowel obstruction, ileus, hemodynamic instability, and compromised unprotected airways. Cathartics are salts (disodium phosphate, magnesium citrate and sulfate, sodium sulfate) or saccharides (mannitol, sorbitol) that promote the rectal evacuation of gastrointestinal contents. The most effective cathartic is sorbitol in a dose of 1–2 g/kg of body weight. Alone, cathartics do not prevent ingestant absorption and should not be used as a method of gut decontamination. Their primary use is to prevent constipation following a single dose of charcoal. Abdominal cramps, nausea, and occasional vomiting are side effects. Complications of repeated dosing include hypermagnesemia (from magnesium salts) and excessive diarrhea. Cathartics are contraindicated in patients who have ingested corrosives and in those with preexisting diarrhea. Magnesium-containing cathartics should not be used in patients with renal failure.
Dilution (i.e., drinking 5 mL/kg of body weight of water or another clear liquid) is recommended only after the ingestion of corrosives (acids, alkali). It may increase the dissolution rate (and hence absorption) of capsules, tablets, and other solid ingestants and should not be used in these circumstances. Endoscopic or surgical removal of poisons may be useful in rare situations, such as ingestion of a potentially toxic foreign body that fails to transit the gastrointestinal tract, a potentially lethal amount of a heavy metal (arsenic, iron, mercury, thallium), or agents that have coalesced into gastric concretions or bezoars (barbiturates, glutethimide, heavy metals, lithium, meprobamate, salicylates, sustained-release preparations). Patients who become toxic from cocaine due to its leakage from ingested drug packets require immediate surgical intervention.
Decontamination of Other Sites Immediate, copious flushing with water, saline, or another available clear, drinkable liquid is the initial treatment for topical exposures (exceptions include alkali metals, calcium oxide, phosphorus). Saline is preferred for eye irrigation. A triple wash (water, soap, water) may be best for dermal decontamination. Inhalational exposures should be treated initially with fresh air or oxygen. The removal of liquids from body cavities such as the vagina or rectum is best accomplished by irrigation. Solids (drug packets, pills) should be removed manually, preferably under direct visualization. ENHANCEMENT OF POISON ELIMINATION Although the elimination of most poisons can be accelerated by therapeutic interventions, the pharmacokinetic efficacy (removal of drug at a rate greater than that accomplished by intrinsic elimination) and clinical benefit (shortened duration of toxicity or improved outcome) of such interventions are often more theoretical than proven. Hence, the decision to use such measures should be based on the actual or predicted toxicity and the potential efficacy, cost, and risks of therapy. Multiple-Dose Activated Charcoal Repetitive oral dosing with charcoal can enhance the elimination of previously absorbed substances by binding them within the gut as they are excreted in the bile, secreted by gastrointestinal cells, or passively diffuse into the gut lumen (reverse absorption or enterocapillary exsorption). Doses of 0.5–1 g/kg body weight every 2–4 h, adjusted downward to avoid regurgitation in patients with decreased gastrointestinal motility, are generally recommended. Pharmacokinetic efficacy approaches that of hemodialysis for some agents (e.g., phenobarbital, theophylline). Multiple-dose therapy should be considered only for selected agents (theophylline, phenobarbital, carbamazepine, dapsone, quinine) and is not effective in accelerating elimination of chlorpropamide, tobramycin, or agents that adsorb poorly to charcoal. Complications include intestinal obstruction, pseudoobstruction, and nonocclusive intestinal infarction in patients with decreased gut motility. Sorbitol and other cathartics are absolutely contraindicated when administering multiple doses of activated charcoal because of electrolyte and fluid shifts.
PART 17
Poisoning, Drug Overdose, and Envenomation
Urinary Alkalinization Ion trapping via alteration of urine pH may prevent the renal reabsorption of poisons that undergo excretion by glomerular filtration and active tubular secretion. Since membranes are more permeable to nonionized molecules than to their ionized counterparts, acidic (low-pKa) poisons are ionized and trapped in alkaline urine, whereas basic ones become ionized and trapped in acid urine. Urinary alkalinization (producing a urine pH ≥7.5 and a urine output of 3–6 mL/kg body weight per hour by adding sodium bicarbonate to an IV solution) enhances the excretion of chlorphenoxyacetic acid herbicides, chlorpropamide, diflunisal, fluoride, methotrexate, phenobarbital, sulfonamides, and salicylates. Contraindications include congestive heart failure, renal failure, and cerebral edema. Acid-base, fluid, and electrolyte parameters should be monitored carefully. While making theoretical sense for some overdoses (amphetamines), acid diuresis is never indicated and is potentially harmful.
Extracorporeal Removal Peritoneal dialysis, hemodialysis, charcoal or resin hemoperfusion, hemofiltration, plasmapheresis, and exchange transfusion are capable of removing any toxin from the bloodstream. Agents most amenable to enhanced elimination by dialysis have low molecular mass (5.5 meq/L; in acute poisoning only). Temporizing measures include atropine, dopamine, epinephrine, phenytoin, and external cardiac pacing for bradydysrhythmias and magnesium, lidocaine, phenytoin, and bretylium for ventricular tachydysrhythmias. Internal cardiac pacing and cardioversion can increase ventricular irritability and should be reserved for refractory cases. Hypertonic sodium bicarbonate (or hypertonic saline) and lidocaine for ventricular tachydysrhythmias associated with QRS prolongation. Use of phenytoin is controversial. Avoid class IA, IC, and III antiarrhythmics.
CHAPTER e35 Poisoning and Drug Overdosage
Cyclic antidepressants
Amitriptyline, doxepin, imipramine
Inhibition of α-adrenergic dopaminergic, GABA-ergic, histaminergic, muscarinic, and serotonergic receptors; inhibition of sodium channels (see membraneactive agents); inhibition of norepinephrine and serotonin reuptake. Inhibition of acetylcholinesterase leading to increased synaptic acetylcholine at muscarinic and nicotinic cholinergic receptor sites
Physiologic depression (Table e35-2), seizures, tachycardia, cardiac conduction delays (increased PR, QRS, JT, and QT intervals; terminal QRS right axis deviation) with aberrancy and ventricular tachydysrhythmias. Anticholinergic toxidrome (see above). Physiologic depression (Table e35-2). Muscarinic signs and symptoms: seizures, excessive secretions (lacrimation, salivation, bronchorrhea and wheezing, diaphoresis), and increased bowel and bladder activity with nausea, vomiting, diarrhea, abdominal cramps, and incontinence of feces and urine. Nicotinic signs and symptoms: hypertension, tachycardia, muscle cramps, fasciculations, weakness, and paralysis. Death is usually due to respiratory failure. Cholinesterase activity in plasma and red cells 15–20%, headache, lactic acidosis (at methemoglobin fractions > 45%), normal PO2 and calculated oxygen saturation but decreased oxygen saturation and increased methehemoglobin fraction by co-oximetry (oxygen saturation by pulse oximetry may be falsely increased or decreased but is less than normal and less than the calculated value). Initial ethanol-like intoxication, nausea, vomiting, increased osmolar gap, calcium oxylate crystalluria. Delayed AGMA, back pain, renal failure. Coma, seizures, hypotension, ARDS in severe cases. High-dose oxygen. Inhaled amyl nitrite and IV sodium nitrite and sodium thiosulfate (Lilly cyanide antidote kit) for coma, metabolic acidosis, and cardiovascular dysfunction in cyanide poisoning. Amyl and sodium nitrite (without thiosulfate) for similar toxicity in hydrogen sulfide poisoning. Hyperbaric oxygen for moderate to severe carbon monoxide poisoning and for cyanide or hydrogen sulfide poisoning unresponsive to other measures.
Methemoglobin inducers
Aniline derivatives, dapsone, local anesthetics, nitrates, nitrites, nitrogen oxides, nitro- and nitrosohydrocarbons, phenazopyridine, primaquine-type antimalarials, sulfonamides.
Oxidation of hemoglobin iron from ferrous (Fe2+) to ferric (Fe3+) state prevents oxygen binding, transport, and tissue uptake (methemoglobinemia shifts oxygen dissociation curve to the left). Oxidation of hemoglobin protein causes hemoglobin precipitation and hemolytic anemia (manifest as Heinz bodies and “bite cells” on peripheral blood smear).
High-dose oxygen. Intravenous methylene blue for methemoglobin fraction > 30%, symptomatic hypoxia, or ischemia (contraindicated in G6PD deficiency). Exchange transfusion and hyperbaric oxygen for severe or refractory cases.
AGMA inducers
Ethylene glycol
Ethylene glycol causes CNS depression and increased serum osmolality. Metabolites (primarily glycolic acid) cause AGMA, CNS depression, and renal failure. Precipitation of oxalic acid metabolite as calcium salt in tissues and urine results in hypocalcemia, tissue edema, and crystalluria.
Gastric aspiration for recent ingestions. Sodium bicarbonate to correct acidemia. Thiamine, folinic acid, magnesium, and high-dose pyridoxine to facilitate metabolism. Ethanol or fomepizole for AGMA, crystalluria or renal dysfunction, ethylene glycol level > 3 mmol/L (20 mg/dL), and for ethanol-like intoxication or increased osmolal gap if level not readily obtainable. Hemodialysis for persistent AGMA, lack of clinical improvement, and renal dysfunction. Hemodialysis also useful for enhancing ethylene glycol elimination and shortening duration of treatment when ethylene glycol level > 8 mmol/L (50 mg/dL). (continued)
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TABLE e35-4 PATHOPHYSIOLOGIC FEATURES AND TREATMENT OF SPECIFIC TOXIC SYNDROMES AND POISONINGS (CONTINUED) Physiologic Condition, Causes
AGMA inducers
e291
Examples
Iron
Mechanism of Action
Hydration of ferric (Fe3+) ion generates H+. Non-transferrin-bound iron catalyzes formation of free radicals that cause mitochondrial injury, lipid peroxidation, increased capillary permeability, vasodilation, and organ toxicity. Methanol causes ethanollike CNS depression and increased serum osmolality. Formic acid metabolite causes AGMA and retinal toxicity.
Clinical Features
Initial nausea, vomiting, abdominal pain, diarrhea. AGMA, cardiovascular and CNS depression, hepatitis, coagulopathy, and seizures in severe cases. Radiopaque iron tablets may be seen on abdominal x-ray. Initial ethanol-like intoxication, nausea, vomiting, increased osmolar gap. Delayed AGMA, visual (clouding, spots, blindness) and retinal (edema, hyperemia) abnormalities. Coma, seizures, cardiovascular depression in severe cases. Possible pancreatitis.
Specific Treatments
Whole-bowel irrigation for large ingestions. Endoscopy and gastrostomy if clinical toxicity and large number of tablets still visible on x-ray. IV hydration. Sodium bicarbonate for acidemia. IV deferoxamine for systemic toxicity, iron level > 90 μmol/L (500 μg/dL). Gastric aspiration for recent ingestions. Sodium bicarbonate to correct acidemia. High-dose folinic acid or folate to facilitate metabolism. Ethanol or fomepizole for AGMA, visual symptoms, methanol level > 6 mmol/L (20 mg/dL), and for ethanol-like intoxication or increased osmolal gap if level not readily obtainable. Hemodialysis for persistent AGMA, lack of clinical improvement, and renal dysfunction. Hemodialysis also useful for enhancing methanol elimination and shortening duration of treatment when methanol level > 15 mmol/L (50 mg/dL). IV hydration and supplemental glucose. Sodium bicarbonate to correct acidemia. Alkaline diuresis for systemic toxicity. Hemodialysis for coma, cerebral edema, seizures, pulmonary edema, renal failure, progressive acid-base disturbances or clinical toxicity, salicylate level > 7 mmol/L (100 mg/dL) following acute overdose.
CHAPTER e35 Poisoning and Drug Overdosage
Methanol
Salicylate
Increased sensitivity of CNS respiratory center to changes in PO2 and PCO2 stimulates respiration. Uncoupling of oxidative phosphorylation, inhibition of Kreb’s cycle enzymes, and stimulation of carbohydrate and lipid metabolism generate unmeasured endogenous anions and cause AGMA. Decreased CNS dopaminergic activity with relative excess of cholinergic activity. Interference with activation and supply of pyridoxal-5phosphate, a cofactor for glutamic acid decarboxylase, which converts glutamic acid to GABA, results in decreased levels of this inhibitory CNS neurotransmitter; complexation with and depletion of pyridoxine itself; inhibition of nicotine-adenine dinucleotide dependent lactate and hydroxybutyrate dehydrogenases resulting in substrate accumulation.
Initial nausea, vomiting, hyperventilation, alkalemia, alkaluria. Subsequent alkalemia with both respiratory alkalosis and AGMA, and paradoxical aciduria. Late acidemia with CNS and respiratory depression. Cerebral and pulmonary edema in severe cases. Hypoglycemia, hypocalcemia, hypokalemia, and seizures can occur. Akathisia, dystonia, parkinsonism Nausea, vomiting, agitation, confusion; coma, respiratory depression, seizures, lactic and ketoacidosis in severe cases.
CNS syndromes Extrapyramidal reactions Isoniazid
Antipsychotics (see above), some cyclic antidepressants and antihistamines.
Oral or parenteral anticholinergic agent such as benztropine or diphenhydramine. High-dose intravenous pyridoxine (vitamin B6 ) for agitation, confusion, coma, and seizures. Diazepam or barbiturates for seizures.
(continued)
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e292
TABLE e35-4 PATHOPHYSIOLOGIC FEATURES AND TREATMENT OF SPECIFIC TOXIC SYNDROMES AND POISONINGS (CONTINUED) Physiologic Condition, Causes
Lithium
Examples
Mechanism of Action
Interference with cell membrane ion transport, adenylate cyclase and Na+, K+-ATPase activity, and neurotransmitter release.
Clinical Features
Nausea, vomiting, diarrhea, ataxia, choreoathetosis, encephalopathy, hyperreflexia, myoclonus, nystagmus, nephrogenic diabetes insipidus, falsely elevated serum chloride with low anion gap, tachycardia. Coma, seizures, arrhythmias, hyperthermia, and prolonged or permanent encephalopathy and movement disorders in severe cases. Delayed onset after acute overdose, particularly with delayed-release formations. Toxicity occurs at lower drug levels in chronic poisoning than in acute poisoning. Altered mental status (agitation, confusion, mutism, coma, seizures), neuromuscular hyperactivity (hyperreflexia, myoclonus, rigidity, tremors), and autonomic dysfunction (abdominal pain, diarrhea, diaphoresis, fever, flushing, labile hypertension, mydriasis, tearing, salivation, tachycardia). Complications include hyperthermia, lactic acidosis, rhabdomyolysis, and multisystem organ failure. QRS and JT prolongation (or both) with hypotension, ventricular tachyarrhythmias, CNS depression, seizures. Anticholinergic effects with amantidine, antihistamines, carbamazepine, disopyramide, antipsychotics, and cyclic antidepressants (see above). Opioid effects with meperidine and propoxyphene (see Chap. 388). Cinchonism (hearing loss, tinnitus, nausea, vomiting, vertigo, ataxia, headache, flushing, diaphoresis) and blindness with quinoline antimalarials.
Specific Treatments
Whole-bowel irrigation for large ingestions. Consider endoscopic removal if high and rising drug level with progressive clinical toxicity. IV hydration. Hemodialysis for coma, seizures, severe, progressive, or persistent encephalopathy or neuromuscular dysfunction, peak lithium level > 8 meq/L (mmol/L) following acute overdose.
PART 17
Poisoning, Drug Overdose, and Envenomation
Serotonin syndrome Amphetamines, cocaine, dextromethorphan, meperidine, MAO inhibitors, selective serotonin (5HT) reuptake inhibitors, tricyclic antidepressants, tramadol, triptans, tryptophan. Promotion of serotonin release, inhibition of serotonin reuptake, or direct stimulation of CNS and peripheral serotonin receptors (primarily 5HT-1a and 5HT-2), alone or in combination. Membrane-active agents Amantidine, antiarrhythmics (class I and III agents; some β blockers), antipsychotics (see above), antihistamines (particularly diphenhydramine), carbamazepine, local anesthetics (including cocaine), opioids (meperidine, propoxyphene), orphenadrine, quinoline antimalarials (chloroquine, hydroxychloroquine, quinine), cyclic antidepressants (see above). Blockade of fast sodium membrane channels prolongs phase 0 (depolarization) of the cardiac action potential, which prolongs the QRS duration and promotes reentrant (monomorphic) ventricular tachycardia. Class Ia, Ic, and III antiarrhythmics also block potassium channels during phases 2 and 3 (repolarization) of the action potential, prolonging the JT interval and promoting early afterdepolarizations and polymorphic (torsades des pointes) ventricular tachycardia. Similar effects on neuronal membrane channels cause CNS dysfunction. Some agents also block α-adrenergic and cholinergic receptors or have opioid effects (see above and Chap. 388).
Note: AGMA, anion-gap metabolic acidosis; ARDS, adult respiratory distress syndrome; CNS, central nervous system; GABA, γ-aminobutyric acid; G6PD, glucose-6-phosphate
Serotonin receptor antagonist such as cyproheptadine or chlorpromazine.
Hypertonic sodium bicarbonate (or hypertonic saline) for cardiac conduction delays and monomorphic ventricular tachycardia. Lidocaine for monomorphic ventricular tachycardia (except when due to class Ib antiarrhythmics). Magnesium, isoproterenol, and overdrive pacing for polymorphic ventricular tachycardia. Physostigmine for anticholinergic effects (see above). Naloxone for opioid effects (see Chap. 388). Extracorporeal removal for some agents (see text).
dehydrogenase; MAO, monoamine oxidase; SIADH, syndrome of inappropriate antidiuretic hormone.
PREVENTION OF REEXPOSURE Poisoning is a preventable illness.
Unfortunately, some adults and children are poison-prone, and recurrences are common. Unintentional polypharmacy poisoning has become especially common among adults with developmental delays and among the growing population of geriatric patients who are prescribed a large number of medi-
cations. Adults with unintentional exposures should be instructed regarding the safe use of medications and chemicals (according to labeling instructions). Confused patients may need assistance with the administration of their medications. Errors in dosing by health care providers may require educational efforts. Patients should be advised to avoid circumstances that result
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in chemical exposure or poisoning. Appropriate agencies and health departments should be notified in cases of environmental or workplace exposure. The best approach with young children and patients with intentional overdose (deliberate self-harm or suicide) is to limit their access to poisons. In households where children live or visit, alcoholic beverages, medications, household products (automotive, cleaning, fuel, pet-care, toiletry products), nonedible plants, and vitamins should be kept out of reach or in locked or child-proof cabinets. Depressed or psychotic patients should receive psychiatric assessment, disposition, and follow-up. They should be given prescriptions for a limited supply of drugs and with a limited number of refills and be monitored for compliance and response to therapy.
HENDERSON A et al: Experience with 732 acute overdose patients admit- e293 ted to an intensive care unit over 6 years. Med J Aust 158:28, 1993 OLSON KR et al: Physical assessment and differential diagnosis of the poisoned patient. Med Toxicol 2:52, 1987 RUMACK BH (eds): Poisindex Information System (updated quarterly). Denver, Micromedex SULLIVAN JB, KRIEGER GR: Clinical Environmental Health and Toxic Exposures 2d ed. Philadelphia, Lippincott Williams & Wilkins, 2001 ZACCARA G et al: Clinical features, pathogenesis, and management of drug-induced seizures. Drug Safety 5:109, 1990 SPECIFIC POISONINGS AND TREATMENTS
CHAPTER e35 Poisoning and Drug Overdosage
SPECIFIC TOXIC SYNDROMES AND POISONINGS Table e35-4 summarizes the pathophysiology, clinical features, and treatment of toxidromes and poisonings that are common, produce life-threatening toxicity, or require unique therapeutic interventions. In all cases, treatment should include attending to the general principles discussed above, particularly supportive care. Details regarding specific therapies can be found in the references cited here and at harrisonsonline.com. Poisonings not covered in this chapter are discussed in the referenced texts. Alcohol, cocaine, hallucinogen, and opioid poisoning and alcohol and opioid withdrawal are discussed in Chaps. 387 to 390; acetaminophen poisoning is discussed in Chap. 299; the neuroleptic malignant syndrome is discussed in Chap. 366; and heavy metal poisoning is discussed in Chap. e34.
Antiarrhythmics KOLECKI PF, CURRY SC: Poisoning by sodium channel blocking agents. Crit Care Clin 13:829, 1997 STRATMAN HG, KENNEDY HL: Torsades de pointes associated with drugs and toxins: Recognition and management. Am Heart J 113:1470, 1987 Anticholinergics BURNS MJ et al: A comparison of physostigmine and benzodiazepines for the treatment of anticholinergic poisoning. Ann Emerg Med 35:374, 2000 CLARK RF, VANCE MV: Massive diphenhydramine poisoning resulting in wide-complex tachycardia: Successful treatment with sodium bicarbonate. Ann Emerg Med 21:318, 1992 DAUNDERER M: Physostigmine salicylate as an antidote. Int J Clin Pharmacol Ther Toxicol 18:523, 1980 KLEIN-SCHWARTZ W, ODERDA GM: Jimsonweed intoxication in adolescents and young adults. Am J Dis Child 138:737, 1984 Anticonvulsants DUPUIS R et al: Acute valproic acid overdose. Drug Safety 5:65, 1990 EARNEST M et al: Complications of intravenous phenytoin for acute treatment of seizures. JAMA 249:762, 1983 MURPHY JM et al: Phenytoin intoxication. South Med J 84:1199, 1991 SEYMOUR JF: Carbamazepine overdose. Drug Safety 8:81, 1993 TANK JE, PALMER BF: Simultaneous in series hemodialysis and hemoperfusion in the management of valproic acid overdose. Am J Kidney Dis 22:431, 1993 Antidotes BAILEY B: Are there teratogenic risks associated with antidotes used in the acute management of poisoned pregnant women? Birth Defect Res A Clin Mol Teratol 67(2):133, 2003 DART RC et al: Combined evidence-based literature analysis and consensus guidelines for stocking emergency antidotes in the United States. Ann Emerg Med 36(2):126, 2000 MYCYK MB et al: Compliance with poison center fomepizole recommendations is suboptimal in cases of toxic alcohol poisoning. Am J Ther 13(6):485, 2006 RIES NL et al: New developments in antidotes. Med Clin North Am 89(6):1379, 2005 Antipsychotics BURNS M: The pharmacology and toxicology of atypical antipsychotic agents. J Toxicol Clin Toxicol 39(1):1, 2001 BARRY D et al: Phenothiazine poisoning: A review of 48 cases. Calif Med 118:1, 1983 LE BLAYE I et al: Acute overdosage with thioridazine: A review of the available clinical experience. Vet Hum Toxicol 35:147, 1993 LEE A: Treatment of drug-induced dystonic reactions. J Am Coll Emerg Phys 8:453, 1979 WILT JL et al: Torsades de pointes associated with the use of intravenous haloperidol. Ann Intern Med 119:391, 1993 Barbiturates MATTHEW H: Barbiturates. Clin Toxicol 8(5):495, 1975
FURTHER READINGS
AMERICAN ACADEMY OF CLINICAL TOXICOLOGY/EUROPEAN ASSOCIATION OF POISONS CENTERS AND CLINICAL TOXICOLOGISTS: Position Statements on Gastrointestinal Decontamination: Introduction; Ipecac syrup; Gastric lavage; Single-dose activated charcoal; Cathartics; Whole bowel irrigation. Clin Toxicol 35:695, 699, 711, 721, 743, 753, 1997 BOSSE GM, MATYUNAS NJ: Delayed toxidromes. J Emerg Med 17:679, 1999 BRUNTON L et al (eds): Goodman and Gilman’s The Pharmacologic Basis of Therapeutics, 11th ed. New York, McGraw-Hill, 2005 KLAASSEN CD (ed): Casarett and Doull’s Toxicology: The Basic Science of Poisons, 6th ed. New York, McGraw-Hill, 2001 LAI MW et al: 2005 Annual Report of the American Association of Poison Control Centers National Poisoning and Exposure Database. Clin Toxicol 44(6-7):803, 2006 SZTAJNKRYCER MD et al: Development and implementation of an emergency department observation unit protocol for deliberate drug ingestion in adults—preliminary results. Clin Toxicol (Phila) 45(5):499, 2007
BIBLIOGRAPHY
REFERENCE TEXTS AND GENERAL PRINCIPLES BASELT RC: Disposition of Toxic Drugs and Chemicals in Man, 7th ed. Foster City, CA, Chemical Toxicity Institute, 2004 BRETT AS et al: Predicting the clinical course of intentional drug overdose: Implications for utilization of the intensive care unit. Arch Intern Med 147:133, 1987 BURGESS JL et al: Emergency department hazardous materials protocol for contaminated patients. Ann Emerg Med 34:205, 1999 DART RC et al (eds): Ellenhorn’s Medical Toxicology 3d ed. New York: Lippincott Williams & Wilkins, 2003 FORD MD et al (eds): Clinical Toxicology. Philadelphia, Saunders, 2001 GOLDFRANK LR et al (eds): Goldfrank’s Toxicologic Emergencies, 8th ed. New York, McGraw-Hill, 2007 GREENBERG MI et al (eds): Occupational, Industrial, and Environmental Toxicology. St. Louis, Mosby, 2003 HADDAD LM et al (eds): Clinical Management of Poisoning and Drug Overdose, 3d ed. Philadelphia, Saunders, 1998 HARBISON RD (ed): Hamilton and Hardy’s Industrial Toxicology, 5th ed. St. Louis, Mosby, 1998
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e294 MCCARRON MM et al: Short-acting barbiturate overdosage: Correlation of intoxication score with serum barbiturate concentration. JAMA 248:55, 1982 REED CE et al: Acute barbiturate intoxication: A study of 300 cases based on a physiologic classification of severity of the intoxication. Ann Intern Med 37:290, 1952 Benzodiazepines GOLDFRANK LR: Flumazenil: a pharmacologic antidote with limited medical toxicology utility, or…an antidote in search of an overdose. Acad Emerg Med 36(2):126, 2000 HOJER J et al: Diagnostic utility of flumazenil in coma with suspected poisoning: A double-blind, randomized controlled study. BMJ 301:1308, 1990 SPIVEY WH: Flumazenil and seizures: Analysis of 43 cases. Clin Ther 14:292, 1992 THE FLUMAZENIL IN BENZODIAZEPINE INTOXICATION STUDY GROUP (Bayer MJ et al): Treatment of benzodiazepine overdose with flumazenil. Clin Ther 14:978, 1992 Beta Blockers CRITCHLEY JA, UNGAR A: The management of acute poisoning due to betaadrenoreceptor antagonists. Med Tox Adverse Drug Exp 4:32, 1989 HEATH A: α-Adrenoreceptor blocker toxicity: Clinical features and therapy. Am J Emerg Med 2:518, 1984 KERNS W et al: β-blocker and calcium channel blocker toxicity. Emerg Med Clin North Am 12:365, 1994 WEINSTEIN RS: Recognition and management of poisoning with betaadrenergic blocking agents. Ann Emerg Med 13:1123, 1984 Calcium Channel Blockers HOWARTH DM et al: Calcium channel blocking drug overdose: An Australian series. Hum Exp Toxicol 13:161, 1996 KERNS W et al: β-blocker and calcium channel blocker toxicity. Emerg Med Clin North Am 12:365, 1994 PEARIGEN PD, BENOWITZ NL: Poisoning due to calcium antagonists. Drug Safety 6:408, 1991 YUAN TH et al: Insulin-glucose as adjunctive therapy for severe calcium channel antagonist poisoning. J Toxicol Clin Toxicol 37(4):463, 1999 Carbon Monoxide ERNST A, ZIBRAK JD: Carbon monoxide poisoning. N Engl J Med 339:1603, 1998 SCHEINKESTEL CD et al: Hyperbaric or normobaric oxygen for acute carbon monoxide poisoning: A randomised controlled clinical trial. Med J Aust 170:203, 1999 THOM SR et al: Delayed neurological sequelae following carbon monoxide poisoning. Ann Emerg Med 25:474, 1995 WEAVER LK et al: Hyperbaric oxygen for acute carbon monoxide poisoning. N Engl J Med 347(14):1057, 2002 Cardiac Glycosides ANTMAN EM et al: Treatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments. Circulation 81:1744, 1990 SMITH TW et al: Digitalis glycosides: Mechanisms and manifestations of toxicity. Prog Cardiovasc Disc 26:413, 1984 (part I); 26:495, 1984 (part II); 27:26, 1984 (part III) UJHELYI MR et al: Influence of digoxin immune Fab therapy and renal function on the disposition of total and free digoxin. Ann Intern Med 119:273, 1993 Cyanide DART RC: Hydroxocobalamin for acute cyanide poisoning: New data from preclinical and clinical studies; new results from the prehospital emergency setting. Clin Toxicol 44(S):1, 2006
GRAHAM DL et al: Acute cyanide poisoning complicated by lactic acidosis and pulmonary edema. Arch Intern Med 137:1051, 1977 HALL AH, RUMACK BH: Clinical toxicology of cyanide. Ann Emerg Med 15:1067, 1986 YEN D et al: The clinical experience of acute cyanide poisoning. Am J Emerg Med 13:524, 1995 Cyclic Antidepressants BOEHNERT MT, LOVEJOY FH JR: Value of the QRS duration versus serum drug level in predicting seizures and ventricular arrhythmias after an acute overdose of tricyclic antidepressants. N Engl J Med 313(8):474, 1985 BORYS DJ et al: Acute fluoxetine overdose: A report of 234 cases. Am J Emerg Med 10:115, 1992 LIEBELT EL et al: ECG lead aVR versus QRS in predicting seizures and arrhythmias in acute tricyclic antidepressant toxicity. Ann Emerg Med 26:195, 1995 PIMENTEL L, TROMMER L: Cyclic antidepressant overdoses: A review. Emerg Med Clin North Am 12:533, 1994 Decontamination AMERICAN ACADEMY OF CLINICAL TOXICOLOGY AND THE EUROPEAN ASSOCIATION OF POISON CENTRES AND CLINICAL TOXICOLOGISTS: Position statement: Whole bowel irrigation. J Toxicol Clin Toxicol 35(7):753, 1997 AMERICAN ACADEMY OF PEDIATRICS COMMITTEE ON INJURY, VIOLENCE, AND POISON PREVENTION: Poison treatment in the home. Pediatrics 112(5):1182, 2003 BOND GR: The role of activated charcoal and gastric emptying in gastric decontamination: A state-of-the-art review. Ann Emerg Med 39(3):273, 2002 KULIG KW et al: Management of acutely poisoned patients without gastric emptying. Ann Emerg Med 14(6):562, 1985 Enhanced Elimination AMERICAN ACADEMY OF CLINICAL TOXICOLOGY AND THE EUROPEAN ASSOCIATION OF POISON CENTRES AND CLINICAL TOXICOLOGISTS: Position statement: multi-dose activated charcoal in the treatment of acute poisoning. J Toxicol Clin Toxicol 37(6):381, 1999 GARRETTSON LK, GELLER RJ: Acid and alkaline diuresis: When are they of value in the treatment of poisoning? Drug Safety 5:220, 1990 PROUDFOOT AT: Position paper on urinary alkalinization. J Toxicol Clin Toxicol 42(1):1, 2004 SHANNON MW: Comparative efficacy of hemodialysis and hemoperfusion in severe theophylline intoxication. Acad Emerg Med 4(7):674, 1997 SMITH SW et al: Whole-bowel irrigation as a treatment for acute lithium overdose. Ann Emerg Med 20:536, 1991 Ethylene Glycol BRENT J et al: Fomepizole for the treatment of ethylene glycol poisoning. N Engl J Med 340:832, 1999 GABOW PA et al: Organic acids in ethylene glycol intoxication. Ann Intern Med 105:16, 1986 JACOBSEN D, MCMARTIN KE: Methanol and ethylene glycol poisonings: Mechanism of toxicity, clinical course, diagnosis and treatment. Med Toxicol 1:309, 1986 MYCYK MB et al: A visual schematic for clarifying the temporal relationship between the anion and osmol gaps in toxic alcohol poisoning. Am J Emerg Med 21(4):333, 2003 Industrial Exposures BOSSE GM: Nebulized sodium bicarbonate in the treatment of chlorine gas inhalation. J Toxicol Clin Toxicol 32(3):233, 1994 HOIDAL CR et al: Hydrogen sulfide poisoning from toxic inhalations of roofing fumes. Ann Emerg Med 15:826, 1986
PART 17
Poisoning, Drug Overdose, and Envenomation
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KAO WF et al: Ingestion of low concentration hydrofluoric acid: An insidious and potentially fatal poisoning. Ann Emerg Med 34(1):35, 1999 Iron MILLS KC, CURRY SC: Acute iron poisoning. Emerg Med Clin North Am 12:397, 1994 Isoniazid HOLDINESS MR: Neurological manifestations and toxicities of antituberculosis drugs—a review. Med Toxicol 2:33, 1987 ORLOWSKI JP et al: Treatment of potentially lethal dose isoniazid ingestion. Ann Emerg Med 17:73, 1988 Laboratory Evaluation BELSON MG et al: The utility of toxicologic analysis in children with suspected ingestions. Pediatr Emerg Care 15(6):383, 1999 BOYER EW et al: Which drug tests in medical emergencies? Clin Chem 49(3):353, 2003 WARNER EA: Should informed consent be required for laboratory testing for drugs of abuse in medical settings? Am J Med 115(1):54, 2003 Lithium BAILEY B, MCGUIGAN ML: Comparison of patients hemodialyzed for lithium poisoning and those for whom dialysis was recommended by PCC but not done: What lesson can we learn? Clin Nephrol 54(5):388, 2000 GROLEAU G: Lithium toxicity. Emerg Med Clin North Am 12:511, 1994 MAO Inhibitors LIPPMAN SB, NASH K: Monoamine oxidase inhibitor update: Potential adverse food and drug interactions. Drug Safety 5:195, 1990 Methanol BURNS MJ et al: Treatment of methanol poisoning with intravenous 4methylpyrazole. Ann Emerg Med 30:829, 1997 JACOBSEN D, MCMARTIN KE: Methanol and ethylene glycol poisoning: Mechanism of toxicity, clinical course, diagnosis and treatment. Med Toxicol 1:309, 1986 MYCYK MB et al: A visual schematic for clarifying the temporal relationship between the anion and osmol gaps in toxic alcohol poisoning. Am J Emerg Med 21(4):333, 2003 SWARTZ RD et al: Epidemic methanol poisoning: Clinical and biochemical analysis of a recent episode. Medicine 60:373, 1981 Methemoglobinemia CURRY S: Methemoglobinemia. Ann Emerg Med 11:214, 1982 HALL AH et al: Drug- and chemical-induced methaemoglobinaemia. Med Toxicol 1:253, 1986 Muscle Relaxants and Sedative-Hypnotics GARNIER R: Acute zolpidem poisoning: Analysis of 344 cases. Clin Toxicol 32:391, 1994 LINDEN CH et al: Cyclobenzaprine overdose. Clin Toxicol 20:281, 1983 MASON PE, KERNS WP 2ND: Gamma hydroxybutyric acid (GHB) intoxication. Acad Emerg Med 9(7):730, 2002 PERRY HE et al: Baclofen overdose: Drug experimentation in a group of adolescents. Pediatrics 101(6):1045, 1998 SING K et al: Chloral hydrate toxicity from oral and intravenous administration. Clin Toxicol 34:101, 1996 Organophosphate and Carbamate Insecticides BARDIN PG et al: Organophosphate and carbamate poisoning. Arch Intern Med 154:1433, 1994
BRYANT SM et al: Pretreating rats with parenteral ophthalmic anti- e295 muscarinic agents decreases mortality from lethal organophosphate poisoning. Acad Emerg Med 14(4):370, 2007 HOLSTEGE CP et al: Chemical warfare: Nerve agent poisoning. Crit Care Clin 13:923, 1997 MARRS TC: Organophosphate poisoning. Pharmacol Ther 58:51, 1993 SIVILOTTI ML et al: Multiple centrally acting antidotes protect against severe organophosphate toxicity. Acad Emerg Med 13(4):359, 2006 Pharmacogenomics ENSOM MH et al: Pharmacogenetics: The therapeutic drug monitoring of the future? Clin Pharmacokinet 40(11):783, 2001 GASCHE Y et al: Codeine intoxication associated with ultra-rapid CYP2D6 metabolism. N Engl J Med 351(27):2827, 2004 Salicylates BRENNER BE, SIMON RR: Management of salicylate intoxication. Drugs 24:335, 1987 TEMPLE AR: Acute and chronic effects of aspirin toxicity and their treatment. Arch Intern Med 141:364, 1981 YIP L et al: Concepts and controversies in salicylate toxicity. Emerg Med Clin North Am 12:351, 1994 Serotonin Syndrome BOYER EW: The serotonin syndrome. N Engl J Med 352(11):1112, 2005 BROWN TM et al: Pathophysiology and management of the serotonin syndrome. Ann Pharmacother 30:527, 1996 GRAUDINS A et al: Treatment of the serotonin syndrome with cyproheptadine. J Emerg Med 16:615, 1998 Substance Abuse BOYER EW et al: The internet and psychoactive substance use among innovative drug users. Pediatrics 115(2):302, 2005 MCCABE SE et al: Medical and non-medical use of prescription drugs among secondary school students. J Adolesc Health 40(1):76, 2007 TETER CJ et al: Illicit use of specific prescription stimulants among college students. Pharmacotherapy 26(1):1501, 2006 TRAUB SJ et al: Body-packing—the internal concealment of drugs. N Engl J Med 349(26):2519, 2003 Sympathomimetics AARON CK: Sympathomimetics. Emerg Med Clin North Am 8:513, 1990 CATRAVS JD, WATERS IW: Acute cocaine intoxication in the conscious dog: Studies on the mechanism of lethality. J Pharmacol Exp Ther 217(2):350, 1981 PENTEL P: Toxicity of over-the-counter stimulants. JAMA 252:1898, 1984 ROTH D et al: Acute rhabdomyolysis associated with cocaine intoxication. N Engl J Med 319(11):673, 1988 WIJETUNGA M et al: Acute coronary syndrome and crystal methamphetamine use: A case series. Hawaii Med J 63(1):8, 2004 Theophylline PALOUCEK FP, RODVOLD KA: Evaluation of theophylline overdoses and toxicities. Ann Emerg Med 17(2):135, 1988 PARK GD et al: Use of hemoperfusion for treatment of theophylline intoxication. Am J Med 74:961, 1983 Withdrawal DYER JE et al: Gamma hydroxybutyrate withdrawal syndrome. Ann Emerg Med 37(2):147, 2001. KOSTEN TR, O’CONNOR PG: Management of drug and alcohol withdrawal. N Engl J Med 348(18):1786, 2003
CHAPTER e35 Poisoning and Drug Overdosage
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e36 Pulmonary Biomarkers in COPD
Peter J. Barnes
INTRODUCTION There has been increasing interest in using pulmonary biomarkers to understand and monitor the inflammation in the respiratory tracts of patients with chronic obstructive pulmonary disease (COPD). COPD involves a specific pattern of inflammation in the respiratory tract and lung parenchyma, with increased production of multiple inflammatory mediators.1 A biomarker refers to the measurement of any molecule or material (cells, tissue) that reflects the disease process. In COPD, several types of biomarker have been measured that are related to disease pathobiology and the inflammatory and destructive process in the lung. Here, biomarkers in bronchial biopsies, sputum, bronchoalveolar lavage (BAL), and exhaled breath are considered. Unfortunately, few of these biomarkers have been validated, and there is little information about their reproducibility and the relationship to disease severity or progression.2 A meta-analysis of biomarker measurements in 150,000 patients with COPD revealed the poor sensitivity of current biomarkers to define clinical status and quantify the effect of treatment. Only sputum neutrophils, interleukin (IL) 8, serum tumor necrosis factor (TNF) α, and C-reactive protein (CRP) showed any trend towards separating different stages of COPD.3 More research in this area is now needed with repeated measurements in carefully phenotyped patients. With the development of many new drugs that target inflammation in COPD, there is a pressing need to identify reliable biomarkers that may indicate whether an anti-inflammatory therapy is likely to have clinical benefit. A major barrier is the lack of any “gold standard” antiinflammatory therapy that is effective in COPD, as are inhaled glucocorticoids in asthma, as a yardstick to compare potential therapies. Many inflammatory cells, mediators, and enzymes are involved in the complex pathobiology of COPD, and, as a result, there are many possible biomarkers to study with a high degree of redundancy.1 Pulmonary inflammation in COPD appears to increase with disease progression and increases during exacerbations. It is likely that some biomarkers will prove to be much more useful than others in terms of reproducibility of measurement, ease of assay, relationship to disease severity, and predictability for assessing therapeutic efficacy. Some biomarkers are more easily measurable and reliable than others and are more easily applied in clinical studies, especially in multicenter studies involving large numbers of patients. New assays may have greater sensitivity and assay reproducibility; in addition, many novel biomarkers may be identified by genomic and proteomic analyses of COPD samples in the future.
TABLE e36-1 MORPHOLOGIC CHANGES IN BRONCHIAL BIOPSIES OF PATIENTS WITH COPD AND ASTHMA COPD
Reticular basement membrane thickness Inflammatory cell infiltrate Within normal range Macrophages CD8+ T lymphocytes Eosinophils and neutrophils during exacerbations Neutrophils in severe disease IFN-γ, CXCL10, IL-9, CXCR3
e297
Asthma
Increased Eosinophils, mast cells CD4+ T lymphocytes Eosinophils and neutrophils during exacerbations Neutrophils in severe disease IL-4, IL-5, IL-9, IL-13, CCR4
Cytokines, chemokines, and receptors
Abbreviations: IFN, interferon; IL, interleukin; CXCL, CXC chemokine ligand; CCR, CC chemokine receptor.
BRONCHIAL BIOPSIES
Although the inflammation in COPD involves predominantly lung parenchyma and small airways, bronchial biopsies appear to reflect at least some of the cellular abnormalities described in peripheral lung tissue. Bronchial biopsies are useful for documenting the structural changes, cellular patterns, and expression of inflammatory proteins in patients with COPD.4 In stable COPD, there is increased infiltration of macrophages and activated T lymphocytes, particularly of CD8+ T lymphocytes, which express interferon (IFN) γ, CXCL10 (IP-10), and IL-9, and the pattern of inflammation differs substantially from that described in asthma (Table e36-1). Moreover, these lymphocytes express chemokine receptors associated with a type 1 response, such as CXCR3, in contrast to lymphocytes in asthma, which express chemokine receptors typical of a type 2 response (chemokine receptor CCR4). There is also a reduction in T cells expressing CCR5 in COPD. While a prominent neutrophilia is present in the airway lumen of stable patients with COPD, it is not observed at the tissue level, except in patients with severe airflow limitation. During exacerbations of the disease, an increased recruitment of eosinophils and neutrophils has
been described, which is associated with upregulation of specific chemoattractants, such as CCL5 (RANTES) and CXCL5 (ENA-78). Bronchial biopsies may give some insights into disease pathogenesis. For example, there is increased activation of the transcription factor nuclear factor-κB (NF-κB) in bronchial epithelial cells of COPD patients, which increases with disease severity.5 There is also a reduction in histone deacetylase (HDAC) activity and HDAC2 expression in bronchial biopsies of COPD patients compared to normal smokers and nonsmokers, and this change is correlated with a reduction in NFκB activity and increased expression of inflammatory genes.6 These changes in bronchial biopsies reflect the changes in NF-κB and HDAC found in lung parenchyma. Several studies have assessed the potential anti-inflammatory effects of treatments in bronchial biopsies of patients with COPD. These studies usually involve either a baseline biopsy and then a second biopsy after a defined period of treatment, or a single biopsy at the end of active treatment with a biopsy in a parallel group of patients taking placebo therapy. Overall, inhaled glucocorticoids seem to have little effect on the airway inflammation typical of COPD, although they are able to reduce mast cells, an effect associated with a reduction in the frequency of exacerbations. Greater anti-inflammatory effects have been obtained after treatment with either a phosphodiesterase (PDE) 4 inhibitor or with the combination of a glucocorticoid and a longacting β2-agonist, but these changes have not been related to functional or clinical improvements. However, further studies are required to establish whether the airway inflammation in COPD can be successfully suppressed (as with glucocorticoids in asthma) and whether this would result in significant clinical improvement. The main advantage of endobronchial biopsies is that they directly sample airway tissue, maintaining the spatial relationships of structural components that may be important for functional changes. Unlike sputum and BAL, bronchial biopsies provide an assessment of structural components of the airway wall, such as epithelium, basement membrane, vessels, connective tissue, and, on occasion, smooth muscle and submucosal glands. This means that biomarkers of structural modification, apoptosis or uncontrolled proliferation, can be measured. Moreover, the different inflammatory cell subtypes can be identified by immunohistochemistry in their microenvironment, thus allowing investigation of interactions between inflammatory and resident cells. Finally, individual structural components can be dissected from the biopsies and studied in isolation using techniques recently developed, such as laser microdissection. Problems There are, however, several limitations to analysis of bronchial biopsies to assess outcome in COPD. Since this is an invasive procedure, it may be difficult to recruit patients, especially in studies investigating treatment effects that require two biopsies (pre- and posttreatment). The biopsy of proximal airways may not closely reflect all the pathologic changes present in peripheral airways and lung parenchyma, the primary sites responsible for airflow limitation in COPD. Moreover, it may not be possible to apply this procedure to pa-
CHAPTER e36 Pulmonary Biomarkers in COPD
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e298 tients with more severe disease, complicated by cardiac comorbid conditions and often associated with significant oxygen desaturation and hypercapnia. There is also a relatively high variability in baseline measurements of inflammatory cells, which necessitates multiple biopsies. Finally, since studies evaluating the effect of treatment should be designed to provide a power of at least 80%, a large number of patients for each treatment group is usually required.
BRONCHOALVEOLAR LAVAGE
BAL has the advantage, unlike bronchial biopsies, of sampling inflammation in the lung periphery. BAL can generally be safely performed, provided careful assessment is performed and guidelines are followed. In general, fluid recovery is greater in patients with less extensive emphysema as assessed by diffusion capacity.7 BAL may be performed in the same patients as bronchial biopsy, thus providing additional and complementary information. Cellular Composition The cellular composition in individuals with COPD is predominantly (>80%) alveolar macrophages, with some neutrophils and T lymphocytes, and some patients having increased numbers of eosinophils. The percentages of macrophages and neutrophils are usually higher than in healthy nonsmokers and healthy smokers. Studies investigating individuals with COPD, healthy smokers, and exsmokers show that smoking is generally associated with increased numbers of neutrophils. Numbers of lymphocytes are generally higher in ex-smokers than in smokers, with or without COPD. Moreover, some studies have shown that patients with COPD have higher eosinophil percentages than healthy smokers. Alveolar macrophages, which may be separated by adhesion and cultured in vitro for functional studies, from COPD patients behave abnormally in tissue culture, with increased expression of inflammatory proteins, such as TNF-α, IL-8, and matrix metalloproteinase (MMP) 9. Alveolar macrophages also show a reduction in expression and activity of HDAC2, which modulates the expression of inflammatory genes, with progressive reduction with disease severity. The reduction in HDAC2 is associated with increased activation of the NF-κB. It may be possible in the future to study the effects of treatment in patients on cellular behavior in vitro. Mediators and Proteases Several inflammatory mediators can be measured in BAL fluid. Levels of eosinophil cationic protein (ECP), myeloperoxidase (MPO), and IL-8 are increased in COPD patients and in healthy smokers, compared to healthy nonsmokers, suggesting that smoking induces the changes, rather than COPD itself. Studies investigating other mediators have not been replicated and are not discussed here. Proteases and antiproteases are also detectable in BAL fluid: there is an increase in total elastase activity and a decrease in antielastase activity in COPD patients compared to normal smokers, confirming the imbalance between proteases and antiproteases. Effect of Smoking and Disease Severity In one study, ex-smokers with COPD had lower mast cell numbers in BAL than ex-smokers without COPD. No other studies have compared smokers and ex-smokers with COPD. Only one study has investigated the association between the severity of COPD and BAL inflammation, and showed that healthy smoking men with a near normal FEV1 show signs of inflammation in the lower airways that are related to a decrease in lung diffusion (DLCO) and to emphysematous lesions on high-resolution CT. This inflammation seems to be the result of macrophage and neutrophil activation, as assessed by mediators measured in BAL. In contrast, in a healthy population, the number of inflammatory cells did not correlate with lung function decline over a 4-year follow-up; however, higher levels of neutrophil elastase-α1 protease inhibitor complexes in BAL fluid have been significantly associated with accelerated decline in FEV1. This also suggests that the number or percentage of cells is not a prerequisite for development or progression of emphysema, but that the activation state of these cells with accompanying mediator release may be important.
Effects of Therapy There are few published studies of the effects of treatments on cellular and mediator components of BAL. Three studies, one open label and two double-blind, assessed the effect of different types of inhaled glucocorticoids, for various periods of treatment on inflammatory cell counts and mediators in BAL.2 Although the numbers of patients involved were small, precluding firm conclusions, these studies suggest that there may be a reduction in percentages of neutrophils and lymphocytes with inhaled glucocorticoid treatment; however, longterm studies in larger populations are needed. Some studies have investigated the effects of smoking cessation on BAL composition, showing inconsistent decreases in cell numbers, particularly macrophages. Problems BAL is an invasive procedure and may cause more discomfort to the patients than bronchial biopsy; it may also cause transient fever. The recovery of fluid is often reduced in COPD patients, resulting in samples that are inadequate for analysis. Quantification of biomarkers in supernatant is a problem as there is no satisfactory marker to account for the dilutional effect of the saline lavage. This is one of the factors that may contribute to the variability in measurements and the necessity for relatively large numbers of patients.
SPUTUM
Many COPD patients produce suitable sputum spontaneously, but spontaneously produced sputum may contain a high proportion of dead cells, which potentially give misleading cell counts and mediator measurements. For this reason, induced sputum has usually been the procedure of choice.8 It should be recognized that “sputum” obtained after inhaling nebulized hypertonic saline may have a different composition than mucus and may be more similar to proximal airway washings. The procedure is tolerated by patients with FEV1 >30% predicted; however, airflow obstruction is often observed and cannot be prevented by premedication with β2-agonists. Cells There is an abnormal pattern of inflammatory cells in COPD patients, with an increase in the number of total inflammatory cells and in the percentage of neutrophils, and, in some patients, eosinophils (the latter predicting a greater likelihood of response to glucocorticoids). CD8+ T cells are increased in the induced sputum of COPD patients. An increased number of eosinophils may indicate concomitant asthma and appears to predict the patients who show a larger bronchodilator response and improvement with glucocorticoids. There is little information about the reproducibility of differential cell counts in induced sputum of COPD patients, but there appears to be a reasonably good reproducibility of cells and mediators in long-term repeatability studies.9 Neutrophils have been studied most extensively and are increased in number in COPD patients compared to those in matched smokers with normal lung function. Several studies have reported the effects of drugs on sputum neutrophils. Most studies have shown no change in inflammatory cells with inhaled or oral glucocorticoids. A significant reduction in neutrophils with low-dose oral theophylline has been reported. Mediators Many mediators have been reported to be increased in the sputum supernatant of COPD patients, and most show a greater increase in COPD than in smokers without COPD, with a further increase during exacerbations; few have been related to disease severity or progression.2 Sputum IL-8 has been studied most extensively, is increased in COPD patients compared to smokers, is related to disease severity (FEV1 % predicted), and may be further increased with exacerbations. Sputum concentrations are unaffected by glucocorticoids but are reduced by theophylline. Increased concentrations of TNF-α and soluble TNF receptors are found in sputum of COPD patients compared to that in normal smokers. Higher concentrations of inflammatory cytokines, including TNF-α, IL-8, and IL-6, are reported in patients with more severe compared to less severe COPD. Leptin is detectable in the induced sputum of COPD patients and is correlated with other inflammatory markers, including TNF-α and CRP.
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Increased concentrations of proteases have been reported in the sputum of patients with COPD, including neutrophil elastase, MMP8, MMP-9, and MMP-12. MMP-9 is increased more in COPD patients with CT evidence of emphysema than in patients of similar respiratory functional severity without evidence of emphysema.10 Sputum markers of structural changes in the airways have been difficult to identify. Hyaluronan, a component of extracellular matrix, is found in higher concentration in the sputum of COPD patients than in the sputum of smokers without COPD and nonsmokers, especially in patients with the lowest FEV1 values; this suggests increased degradation of extracellular matrix in COPD. No differences in the concentrations of the tachykinins substance P and neurokinin A were found in COPD patients compared with smokers without COPD and nonsmokers, although there was a reduction in tachykinins noted during exacerbations of COPD in one study. Problems Although induced sputum samples are relatively easy to obtain in COPD patients and give a lot of information about inflammatory cells and mediators, there are several problems that need to be addressed. Induced sputum samples predominantly derive from large airways and may not reflect the peripheral inflammation that may be important for clinical outcomes in COPD. Sputum induction with hypertonic saline promotes neutrophilic inflammation that persists for 24 h and, thus, repeated sampling within this period is not possible. Solubilization of sputum with dithiothreitol (DTT), which disrupts sulfhydryl bonds, may alter proteins so that they are not recognized by antibodies; this is a particular problem with several cytokines and chemokines. Furthermore, proteases in sputum, particularly in COPD, may degrade certain protein mediators. Recent studies using dialysis to remove DTT and protease inhibitors show that it is possible to increase markedly the concentrations of several cytokines in induced sputum of COPD patients. More work is needed on long-term reproducibility in COPD patients, studying the effect and duration of exacerbations and correlating individual biomarkers with disease severity and progression.
Carbon Monoxide Although it is easy to measure carbon monoxide e299 (CO) in the breath this has not turned out to be as useful a measurement as FENO. Exhaled CO is elevated in patients with COPD, but it is also elevated in normal smokers owing to the high CO content in cigarette smoke; however, exhaled CO is elevated to a greater extent in COPD patients than in matched smokers without COPD, and it remains elevated in sustained ex-smokers. Importantly, the signal is low and the measurement is also confounded by highly variable environmental CO levels and the effects of passive smoking. Hydrocarbons Volatile hydrocarbons, such as ethane and pentane, have been detected in exhaled breath and are biomarkers of lipid peroxidation as a result of oxidative stress. Concentrations of ethane are elevated in patients with COPD and correlate with disease severity. Measurement of ethane by gas chromatography–mass spectrometry offline is difficult and thus unlikely to be useful in clinical trials; smaller and more sensitive detectors for hydrocarbons are now in development.
EXHALED BREATH CONDENSATE
Many mediators have now been detected in exhaled breath condensate (EBC), which has the advantage that it is easy to perform and completely noninvasive.11 Several factors affect the measurement, and recommendations have recently been formulated by an ERS/ATS task force. A limitation of the technique is the variability of the measurement and the low concentrations of mediators (often close to the limits of detection). Oxidative/Nitrative Stress Hydrogen peroxide (H2O2) is increased in EBC of COPD patients, is further increased during exacerbations, and is related to disease severity. Exhaled H2O2 is reported to be reproducible in repeated measurements over 3 days. 8-Isoprostane is a stable marker of oxidative stress and is also increased in EBC of COPD patients. The isoprostanes represent a family of isomers that are derived from the nonoxidative metabolism of arachidonic acid and are stable biomarkers of oxidative stress.13 Concentrations of 8-isoprostane are greater in COPD patients than in smokers without COPD, are related to disease severity, and are further increased during exacerbations. Certain aldehydes resulting from lipid peroxidation are also increased in COPD patients, but only malondialdehyde is increased in COPD patients compared to smokers without COPD. Increased nitrative stress in COPD is indicated by increased concentrations of nitrite and S-nitrosothiols in EBC. Mediators Inflammation is associated with tissue acidification, and there is a decrease in pH in EBC of COPD patients. There is considerable variability in exhaled pH in COPD patients, which is greater than in normal subjects, and the lower pH has been ascribed to increased acidity of salivary contaminants. There is an increase in the concentration of leukotriene (LT) B4 in COPD patients, which is further increased during exacerbations. Increased prostaglandin E2 and IL-6 have also been reported in COPD patients. It is not yet clear how most of these biomarkers relate to disease severity. Most proteins, including cytokines and enzymes, cannot reliably be measured in EBC. A recent study reported increases in the concentrations of proinflammatory cytokines, including IL-1β, IL-6, and TNF-α, during exacerbations of COPD, but reproducibility was not reported. Chemokines cannot be reliably measured in EBC. Problems There is a relative high variability in repeated measurements of EBC biomarkers, and this may relate (1) to the extensive variable dilution that occurs from water vapor during condensation, and (2) the low concentrations that may be near to the detection limits of the assays used. Further work is needed to optimize these measurements and to determine the causes of variability. Correction for the variable dilution is one approach. Assays are usually performed using enzyme-linked immunosorbent assay, and these assays have been validated using gas chromatography–mass spectrometry for some mediators.
CHAPTER e36 Pulmonary Biomarkers in COPD
EXHALED GASES
Measuring biomarkers in the breath is a very attractive approach to monitoring inflammation in COPD as it is noninvasive and makes repeated sampling possible.11 However, there are important issues about reproducibility and sensitivity that need to be addressed before this approach can be recommended as a routine outcome measurement. Nitric Oxide Exhaled nitric oxide (FENO) has been extensively investigated in asthma and shown to correlate with airway inflammation and to be reduced by glucocorticoid therapy. The measurement is highly reproducible in normal and asthmatic subjects if careful attention is paid to technique. In COPD, however, conventionally measured FENO is less useful as the levels are usually normal or only slightly elevated, except during exacerbations; this is likely to be due to the increase in oxidative stress, resulting in formation of peroxynitrite and nitrate so that NO is removed from the gaseous phase. This observation also explains why FENO is reduced in normal smokers. An increase in FENO in COPD patients is correlated with increased numbers of eosinophils, an increased bronchodilator response, and steroid responsiveness, and thus may be useful in detecting associated asthma. Recently, the measurement of FENO has been extended by making measurements of exhaled NO at different flows, so that it is possible to partition airwayderived NO, which is flow-independent, from peripheral NO derived from endothelium via the alveoli and probably from small airways. Using this technique it is possible to show that while airway NO is low or normal in COPD, there is an increase in peripheral NO that is related to disease severity.12 This may reflect the increase in inducible NO synthase in the lung periphery of patients with COPD. Peripheral NO may prove to be a useful noninvasive biomarker of COPD inflammation, but further studies on reproducibility, relationship to disease severity, and the effects of treatment are now needed.
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e300 USE OF BIOMARKERS TO ASSESS RESPONSE TO THERAPY
Many drugs are now in development as potential anti-inflammatory therapies for COPD. Because no effective anti-inflammatory treatments for COPD currently exist, it is not certain how much and how rapidly clinical parameters will change in patients. This uncertainty makes it important to develop reliable biomarkers to quantify inflammation in COPD patients and to validate these against some other measure of disease activity and progression. For assessment of anti-inflammatory treatments, it is important to identify biomarkers that indicate the efficacy of the drug on components of the inflammatory process before proceeding to large and prolonged clinical trials. Biomarkers can facilitate drug development in a number of ways, such as providing evidence that a drug can reach its target and modify that target in some positive way, identifying criteria for dose selection for phase 2 and phase 3 studies, providing “go/no-go” decisions at early stages of the drug development process, identifying populations that are more likely to benefit from a drug, and predicting safety problems. There are several types of drugs that can be developed for COPD based on whether the drug is intended to improve airflow obstruction, provide symptom relief, modify or prevent exacerbations, alter disease progression, or modify lung structure. The efficacy endpoints that are currently used in phase 3 studies to support registration of a drug for COPD are based on measures that translate to direct benefit of some aspects of the disease that is clinically meaningful to patients, such as improvement of symptoms, functional capacity, or survival. Examples of such endpoints include pulmonary function tests; test of exercise capacity, e.g., treadmill or cycle ergometry; activity scales, e.g., Medical Research Council dyspnea score, Borg scale, Mahler baseline dyspnea index (BDI)/transitional dyspnea index (TDI); health-related quality-of-life (QOL) instruments, e.g., St. George’s respiratory questionnaire (SGRQ), chronic respiratory disease questionnaire (CRQ); scores based on patient- or physician-reported symptom severity; and death. With the possible exception of a drug that is intended to improve airflow obstruction, whose efficacy can be relatively easily assessed by measuring FEV1 in short-term studies, drugs of other types will likely require prolonged studies, often extending to many years. These studies become rather risky expensive endeavors, and this further underscores the need of development of biomarkers. The biomarkers described elsewhere in this chapter are not sufficiently validated to date for use as evidence of efficacy in phase 3 studies or for supporting specific labeling claims. Nevertheless, these biomarkers are reflective of the disease and have potential use for regulatory purposes. Carefully selected biomarkers, with or without a patient-centered clinically meaningful endpoint, can be used in early phase studies, such as proof-of-action or proof-of-concept studies, based on which a rational decision can be made on further development of the drug. Biomarkers can also be used in either early phase studies or phase 3 studies to support the drug’s putative mode of action. In addition, use of the biomarkers in phase 3 studies in conjunction with clinically meaningful endpoints may help validate the use of the biomarker, or even help elevate a biomarker to a surrogate endpoint status.
biomarkers. The technique probably samples more proximal airways and thus may not reflect the inflammatory process in the lung periphery. Exhaled biomarkers are noninvasive and may be repeated but are technique-dependent and have a relatively high variability. For all of these biomarkers, there is a relative lack of information about how they relate to disease severity, how reproducible they are, and how they may be affected by concurrent therapies. In addition, there is little information at present about how they relate to other outcome measurements in COPD, such as rate of decline in FEV1, exacerbation frequency, and mortality. There is a need for comparison of all pulmonary biomarkers in COPD patients with those in smokers without airflow limitation but matched for smoke exposure (pack-years) and also with those in age-matched nonsmoking control subjects. The effect of smoking itself is rarely documented, and ex-smokers may have a different profile of biomarkers than active smokers. Patients with mixed asthma and COPD and patients who have COPD without smoking also need to be characterized. COPD involves small airway inflammation and fibrosis as well as alveolar destruction. It is not yet clear whether pulmonary biomarkers will be able to discriminate these two pathophysiologic processes. The recent demonstration by CT scan that MMP-9 is some ninefold higher in COPD patients with emphysema than in those without indicates that sputum biomarkers may be useful in the future in discriminating parenchymal disease from small-airway involvement.10 How other biomarkers relate to the phenotype of COPD deserves further investigation. Clinical Perspective Although many pulmonary biomarkers have been described in COPD patients, their clinical relevance is far from certain. None of the approaches described in this chapter are in routine use for the diagnosis of COPD, for predicting disease progression, or for predicting response to therapy. However, progress is now being made in asthma, where monitoring sputum eosinophils and FENO appears to improve control of asthma and at the same time reduce steroid requirements. Similar studies have not been done in COPD patients, as these patients do not respond well to glucocorticoids. However, measurement of sputum eosinophils and FENO may be very useful in clinical practice in identifying the patients with COPD who have concomitant asthma and who may respond better to bronchodilators and inhaled glucocorticoids. When more effective anti-inflammatory treatments become available for COPD patients, it is possible that inflammatory cells in sputum may be used to monitor the response to treatment, which may be difficult using physiologic parameters that are likely to improve only very slowly. What is of critical importance is to ensure that there are carefully matched control groups (smokers and nonsmokers) and that the COPD patients are phenotypes in as much detail as possible, ideally with detailed lung function assessments (including lung volumes and gas transfer), exercise performance, measurement of free fat mass, and high-resolution CT scanning. Which Biomarker? The choice of which pulmonary biomarker is measured will depend on the research question posed or the clinical problem that is being addressed. Bronchial biopsies and BAL provide important information about cellular composition but cannot be repeated, whereas induced sputum and exhaled markers are repeatable. The biomarkers selected for measurement will depend on the nature of the study. For example, assessment of an anti-inflammatory drug will require the measurement of inflammatory cells and specific inflammatory mediators, whereas assessment of an antioxidant may require measurements of oxidative stress and an antiprotease will require measurement of protease activity. Prediction of steroid responsiveness may be given by increased FENO and sputum eosinophils. In the future it is possible that patterns of pulmonary biomarkers may predict exacerbations, as they do in asthma, and may reflect different mechanisms of exacerbations, discriminating between bacterial, viral, and noninfective mechanisms. This is an active research area, and further studies addressing several of the issues raised in this chapter are already in progress. Correlation of
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OVERVIEW
Many biomarkers of inflammation and oxidative/nitrative stress have now been measured in the airways of patients with COPD using a variety of techniques of differing invasiveness. Bronchial biopsies provide valuable information about inflammatory cells and mediators, as well as the spatial relationships between the inflammatory process in the airway wall. However, they may not reflect all pathologic changes in the periphery of the lung that appear to be more important in COPD, and its invasiveness precludes repeated measurements. BAL may provide more information about peripheral inflammation, but there are problems of quantification of mediators because of variable dilution and the same problems as with biopsies in reproducibility. Induced sputum is a valuable procedure giving information about cells, mediators, and markers of oxidative/nitrative stress, but standardization of the technique is important to reduce the high variability in the
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pulmonary biomarkers with other outcome measures is essential for the future assessment of the inflammatory destructive process and for measuring the effects of the new anti-inflammatory drugs that are now in development for the treatment of COP, as well as for understanding how disease mechanisms relate to clinical outcomes.
REFERENCES
1. Barnes PJ et al: Chronic obstructive pulmonary disease: Molecular and cellular mechanisms. Eur Respir J 22:672, 2003 2. Barnes PJ et al: Pulmonary biomarkers in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 174:6, 2006 3. Franciosi LG et al: Markers of disease severity in chronic obstructive pulmonary disease. Pulm Pharmacol Ther 19:189, 2006 4. Jeffery PK et al: Methods for the assessment of endobronchial biopsies in clinical research. Application to studies of pathogenesis and the effects of treatment. Am J Respir Crit Care Med 168:S1, 2003 5. Di Stefano A et al: Increased expression of NF-κB in bronchial biopsies from smokers and patients with COPD. Eur Resp J 20:556, 2002
6. Ito K et al: Decreased histone deacetylase activity in chronic ob- e301 structive pulmonary disease. N Engl J Med 352:1967, 2005 7. Lofdahl JM et al: Bronchoalveolar lavage in COPD: Fluid recovery correlates with the degree of emphysema. Eur Respir J 25:275, 2005 8. Tsoumakidou M et al: Induced sputum in the investigation of airway inflammation of COPD. Respir Med 97:863, 2003 9. Beeh KM et al: Long-term repeatability of induced sputum cells and inflammatory markers in stable, moderately severe COPD. Chest 123:778, 2003 10. Boschetto P et al: Association between markers of emphysema and more severe chronic obstructive pulmonary disease. Thorax 61:1037, 2006 11. Kharitonov SA, Barnes PJ: Exhaled biomarkers. Chest 130:1541, 2006 12. Brindicci C et al: Exhaled nitric oxide from lung periphery is increased in COPD. Eur Respir J 26:52, 2005 13. Montuschi P et al: Isoprostanes: Markers and mediators of oxidative stress. FASEB J 18:1791, 2004 14. Celli BR, Barnes PJ: Exacerbations of chronic obstructive pulmonary disease. Eur Resp J 29:1224, 2007
CHAPTER e36 Pulmonary Biomarkers in COPD
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e37 Chagas’ Disease: Advances in Diagnosis and Management
Andrei C. Sposito, Jose A. F. Ramires
INTRODUCTION Chagasic cardiomyopathy is the major complication resulting from infection by Trypanosoma cruzi, occurring in up to 30% of individuals who have a positive specific serology. The T. cruzi infection is related to the close proximity between humans and triatomines carrying T. cruzi and extends from the Southern United States11 and Mexico to the south of Argentina. According to the World Health Organization Technical Report, among individuals living in Latin American countries, 5–6 million are infected and 25 million are at risk of contracting the infection (Chap. 206). It usually takes 10–20 years for the infection to manifest the disease in a broad range of clinical presentations including heart failure, cardiac arrhythmias, thromboembolism, and sudden death. Once established, the signs of heart failure result in life expectancy being reduced to ≤5 years. Therefore, strategies to identify the disease in the early phase and characterize predictive signs and potential therapeutic targets have been intensely pursued. In this chapter, we discuss the results from recent, novel research on the diagnosis and management of Chagas’ disease.
ANATOMIC DIAGNOSIS
Myocardial Fibrosis and Inflammation T. cruzi can be easily detected in muscle cells and interstitial histiocytes of individuals in the acute phase of Chagas’ disease. However, such a finding is rare in the chronic phase of the disease. Hence, the main finding in the hearts of patients with chronic Chagas’ disease is the presence of inflammatory infiltrates. Chagas’ myocarditis lesions are spread out over both ventricles and in a large spectrum of severity, transforming myofibers into fibrous tissue and featuring the changes in heart structure and function. Accordingly, myocardial fibrosis caused by Chagas’ disease is a strong marker of clinical impairment and ventricular dysfunction. The histopathologic evaluation of myocardial fibrosis and inflammation can be obtained through a percutaneous and transvenous endomyocardial biopsy of the right ventricle. This diagnostic procedure has been proved to be a powerful tool for both the prediction of clinical outcome and estimation of the severity of myocardial damage in Chagas’ disease and in other primary and secondary cardiac diseases. In patients with Chagas’ disease who undergo heart transplantation, endomyocardial biopsy is considered the “gold standard” technique in the differentiation between allograft rejection and reactivation of the disease. In such patients, however, the use of endomyocardial biopsy has been limited by the mild, albeit significant, intrinsic risk of the procedure and the lack of evidence-based parameters that may guide clinical decisions. Consequently, noninvasive methods have been developed to explore potential clinical benefits from assessing the degree of myocardial inflammation and fibrosis in patients with Chagas’ disease. In our group, the histopathologic findings of myocardial inflammation via endomyocardial biopsy were compared with two noninvasive techniques, gallium-67 myocardial uptake scintigraphy and MRI. Despite both noninvasive techniques detecting Chagas’ myocarditis, MRI was more accurate due to the higher spatial resolution. Myocardial delayed enhancement by MRI has been proved to be efficient in detecting myocardial fibrosis in ischemic and nonischemic myocardial disease. In Chagas’ disease, delayed enhanced MRI can detect even traces of myocardial fibrosis in individuals in the indeterminate phase, that is, the period before presentation of cardiac electrical or mechanical abnormalities.3 Such refined accuracy would potentially be helpful for characterization and treatment of arrhythmogenic foci in patients with Chagas’ disease. Moreover, the severity of myocardial fibrosis detected by MRI is proportional to the severity of myocardial dysfunction and clinical symptoms. In patients in the chronic phase of the disease, myocardial fibrosis is found particularly at the apex and inferolateral regions of the left ventricle. Ischemia, inflammation, mechanical factors, and parasympathetic nerve cell destruction are considered among potential underlying mechanisms for these lesions. In these affected regions, ventricular wall aneurysms would develop in a later stage of Chagas’ cardiomyopathy, constituting a classic sign of the disease. Figure e37-1 shows the typical apex lesion with severe myocardial fibrosis in a heart examined at autopsy. Myocardial Perfusion Myocardial ischemia has been frequently reported in patients with Chagas’ disease and normal coronary angiograms. In fact, these patients have chest pain associated with electrocardiographic signs of ischemia simulating obstructive coronary artery disease. From a pathophysiologic standpoint, vascular dysautonomia due to denervation and inflammatory damage of the microcirculation is considered the leading cause of myocardial ischemia in these patients. Figure e37-2 shows myocardial denervation and ischemia by scintigraphic imaging; the denervation demonstrated by the reduced cardiac uptake of 123I-metaiodobenzylguanidine (MIBG) is concordant with the perfusion deficit, but is much larger, suggesting that denervation is the initiating event. In angiographic studies, endothelium-dependent and -independent impairment in coronary vasodilation have been observed in patients with Chagas’ disease.4 With scintigraphic perfusion imaging using thallium-201, transient and permanent myocardial perfusion abnormalities have been described in patients with the disease (Chaps. 222
e303
CHAPTER e37 Chagas’ Disease: Advances in Diagnosis and Management
LABORATORY DIAGNOSIS
Parasitemia During the acute phase of the disease, parasites can easily be found by microscopic observation of fresh blood. Morphologic characteristics of the parasite and differentiation from T. rangeli can also be determined by staining the blood smears. When parasitemia is low, procedures for parasite concentration or indirect methods (xenodiagnosis and hemoculture) can be used instead. Parasite concentration could be obtained either by microhematocrit or by the Strout method. In the microhematocrit, blood is centrifuged and the buffy coat examined by microscopy to visualize trypomastigote movements. In the Strout method, blood cells are first eliminated by precipitation and centrifugation. The supernatant is then submitted to a second centrifugation and the precipitate is examined as fresh blood. The xenodiagnostic method consists of feeding uninfected triatominae with blood from the patient under examination and then investigating the intestinal contents of the insects some days later to search for metacyclic trypomastigotes. Artificial xenodiagnosis is preferred to avoid inconveniences from direct contact between the triatomines and patients’ skin. Recently, amplification of T. cruzi DNA target sequences by polymerase chain reaction (PCR) has become a preferred method for the detection of parasites in blood and tissues. Such PCR techniques are especially helpful for the follow-up of chemotherapy for T. cruzi. However, despite being more sensitive than xenodiagnosis and hemoculture, this sensitivity is equally dependent on the magnitude of the parasitemia. Immunodiagnosis Infected individuals soon develop antibodies, initially IgM and later IgG, against several epitopes of T. cruzi allowing the indirect diagnosis of Chagas’ disease. Conventional immunodiagnostic tests are available worldwide and are based on three main techniques: hemagglutination, immunofluorescence, and ELISA. Nonconventional tests using recombinant chimeric proteins, synthetic peptides, or purified antigens have been developed to increase specificity and reduce cross-reactivity with other infections and with autoimmune diseases. In general, conventional tests have elevated sensitivity, and a positive result in two conventional tests is sufficient to diagnose the infection. In parallel with PCR for detecting T. cruzi parasitemia, conventional serologic tests could also be used for the follow-up of patients undergoing chemotherapy.
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e304
FIGURE e37-3 Echocardiographic analysis of mitral inflow by pulse-wave Doppler showing diastolic function in a patient with Chagas’ disease. Normally, the early flow velocity (E) is higher than the late flow velocity (A), which is related to atrial contraction. In this case, there is an inverted E/A relation, indicating the impairment of left ventricular relaxation. FIGURE e37-1 Photo of a heart from a patient with chronic chagasic cardiac disease, exhibiting a typical lesion at the left ventricle. and e20). These studies demonstrate an elevated topographic correlation between perfusion and wall motion abnormalities. Even though prospective cohorts demonstrating a temporal association between perfusion defects and the development of wall motion dysfunction are lacking, it is plausible to consider that such perfusion defects would represent an early sign of Chagas’ cardiomyopathy. In addition, these radionuclide studies also indicate that the perfusion defects are predominantly in the apex and inferolateral regions, which are those most affected by the inflammatory damage and the autonomic denervation. From a clinical perspective, caution must be taken to interpret the presence of perfusion defects detected by either scintigraphy or MRI as an indication of epicardial coronary disease in patients with Chagas’ disease. Actually, both the endothelium-dependent and -independent vasodilatory responses of coronary resistance vessels are also affected in patients with idiopathic dilated cardiomyopathy and angiographically normal coronary arteries. These patients have impairment of the vasodilator responses to both metabolic and pharmacologic stimuli and an increased sensitivity to vasoconstrictors. Such evidence indicates that the segmental microvascular dysfunction observed in patients with Chagas’ disease is unlikely to be pathogen-dependent but rather an early sign of ventricular wall disease. Whether such perfusion disturbances also contribute to the detriment of ventricular wall motion is presently unknown. Myocardial Wall Motion In the acute phase of the disease, pericardial effusion and occasionally myocardial wall motion abnormalities have been described. By definition, in the indeterminate phase, chronically infected individuals remain a parasite reservoir without being affected by the disease and consequently have a normal life expectancy. Hence, the appearance of an abnormality of the ventricular wall reflects progression of the disease and must be considered, accordingly, as the onset of the chronic phase of Chagas’ disease. In the chronic phase, thinning, aneurysm formation, and wall motion dysfunction are the most frequent findings detected on echocardiography. In keeping with necropsy, scintigraphic, and MRI studies, these echocardiographic findings are mostly observed in the apex and inferobasal regions of the left ventricle. The segmental thinning of the ventricular wall, particularly at the apex, promotes remodeling of the left ventricle, which may increase mechanical tension and contribute to aneurysm formation in this area. Nevertheless, abnormalities of other left ventricular segments can also be found. As the disease progresses, the affected segments of the ventricular wall become hypokinetic, akinetic, or even dyskinetic. Frequently, diastolic dysfunction occurs in an early phase of the disease, as shown in Fig. e37-3. The thinning of the apex becomes an aneurysm, and the global systolic function of the left and right ventricles deteriorates. Initially, the systolic dysfunction may be apparent only under pharmacologic stress by dobutamine or phenylephrine, characterizing the reduction of systolic reserve. Echocardiography or MRI can accurately detect these characteristics. The right ventricle is first and predominantly affected in the majority of patients with Chagas’ disease. This may occur even in the absence of any detectable abnormality in the left ventricle. Accordingly, in these patients, the development of heart failure is typically manifested with a predominance of systemic over pulmonary congestion. Because echocardiography has a low accuracy for detecting right ventricular dysfunction, radionuclide angiography or MRI is preferred for evaluation of this chamber.
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CHAGAS’ DISEASE
FIGURE e37-2 Myocardial denervation and ischemia detected by scintigraphic imaging. Above. The denervation is demonstrated by the reduced cardiac uptake of 123l-metaiodobenzylguanidine (MIBG) (arrows). Below. A permanent perfusion deficit with smaller size as compared with the denervation is demonstrated by scintigraphic perfusion with 99mTc-sestamibi (MIBI). ETIOLOGIC TREATMENT Nitrofurans and nitroimidazole derivatives (nifurtimox and benznidazole respectively) have been the cornerstones of trypanosomicidal treatment in recent decades. These compounds seem to exert their trypanosomicidal action by the generation of superoxide radicals causing oxidative stress and cell death in susceptible parasites. From the clinical point of view, the activity of treatment with both compounds is evident in terms of parasite load reduction and serologic conversion to negative in the acute phase of Chagas’ disease and in congenital
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infection. In the indeterminate phase, new promising findings have been reported particularly in children and young adults, showing long-lasting disappearance of specific antibodies in 58–98% of treated individuals together with a 10–20% rate reduction of side effects. In general, treatment with nitroimidazole derivatives, especially benznidazole, has been shown to be effective more frequently in reducing parasitemia and specific antibody titers in individuals in the indeterminate phase. Whether this treatment will prevent the development of cardiac or digestive complications of the disease is still unclear. Large randomized controlled trials are required to define this issue. The effect of trypanosomicidal therapies on parasite load or disease progression in patients in the chronic symptomatic phase of Chagas’ disease is even less clear. The disappearance of specific antibodies is uncommon in the chronic phase and may take up to 10–20 years. Parasite DNA is present in several tissues and may induce immune response and perhaps disease progression. Hence, the ideal therapeutic schema or duration for such chronic patients is unknown. In addition, several adverse reactions, such as peripheral neuropathy and skin disorders, have been reported in a large proportion of patients treated with both nifurtimox and benznidazole. Thus, there is insufficient evidence to demonstrate the clinical benefit for trypanosomicidal treatment in patients in the chronic phase of Chagas’ disease. Novel potential targets for trypanosomicidal treatment have been investigated to reduce side effects and increase treatment efficacy. Sterol biosynthesis inhibitors, protein prenylation inhibitors, protease inhibitors, and phospholipid analogues are among potential chemotherapeutic agents for this purpose. Although some of these compounds have already demonstrated potent inhibitory activity in vitro against T. cruzi, clinical benefits have not been proved thus far.
eurysmatic zone or in focal areas of fibrosis in the inferolateral region of the e305 left ventricle. Surgical treatment consists of conventional aneurysmectomy associated with endocardial or myocardial resection and/or isolation of critical sites of reentry by endocardiectomy or cryoablation guided by electrophysiologic mapping. Alternatively, interpapillary endomyocardial cryoablation without electrophysiologic mapping has been attempted in patients with sustained ventricular tachycardia and akinesia or dyskinesia of the inferolateral region of the left ventricle, with efficacy in nearly 60%. Because the mortality of the procedure is high, surgical ablation should be considered only when systolic dysfunction is not severe, the overall surgical risk is low, and when other surgical procedures, such as aneurysmectomy, are not indicated. Nonsurgical simultaneous epicardial and endocardial catheter ablation has been introduced recently as an alternative approach in the treatment of patients with Chagas’ disease and recurrent ventricular tachycardia.10 Because critical sites of reentry may be endocardial, intramural, or epicardial, this combined approach provides a higher efficacy for treating recurrent ventricular tachycardia. For patients with severe systolic dysfunction, however, the insertion of an ICD is the treatment of choice, particularly in those with left ventricular ejection fractions 55 years. Even the addition of a (Table e38-1). Even if folic acid were omitted from the formulation, statin to aspirin does not significantly improve cost-effectiveness in the authors estimate that 86% of ischemic heart disease events could primary prevention models, unless absolute risks are high. still be averted. Similarly, absence of aspirin reduces the advantage of the TABLE e38-1 EFFECT OF POLYPILL ON RISK OF ISCHEMIC HEART DISEASE (IHD) AND STROKE, AS polypill by only 5 percentage points to ESTIMATED BY WALD AND LAW, AFTER 2 YEARS OF TREATMENT AT THE AGE 55–64 YEARS 83%. These benefits accrued with a low incidence of projected side effects. It % Reduction in Risk (95% CI) Reduction in was estimated that only 15% of patients Risk Factor Risk Factor Agent IHD Event Stroke would be expected to have adverse efa b fects due to the formulation, mostly as61 (51–71) 17 (9–25) LDL cholesterol Statin 1.8 mmol/L (70 mg/ dL) reduction cribable to aspirin. If all people >55 Blood pressure Three classes of drugs 11 mmHg diastolic 46 (39–53) 63 (55–70) years used the pill, it was estimated that at half standard dose one in three people would benefit diSerum homocysteine Folic acid (0.8 mg/d) 3 μmol/L 16 (11–20) 24 (15–33) rectly, gaining an additional 12–20 years Platelet function Aspirin (75 mg/d) Not quantified 32 (23–40) 16 (7–25) of life-years without a coronary heart Combined effect All 88 (84–91) 80 (71–87) disease event or stroke. aLDL, Low-density lipoprotein. Gaziano et al. further quantified bAtorvastatin, 10 mg/d, or simvastatin or lovastatin, 40 mg/d taken in the evening or 80 mg/d taken in the morning. these assertions in a subsequent study Source: Adapted from Wald and Law. that examined cost-effectiveness of comCopyright © 2008 The McGraw-Hill Companies. All rights reserved.
bination pharmacotherapy in reducing CVD in low-income and middle-income countries. Using a Markov model to assess cost-effectiveness, the authors used a combination of four drugs—aspirin, a calcium channel blocker, an ACE inhibitor, and a statin—for primary prevention. For secondary prevention, the authors substituted a beta blocker for the calcium channel blocker while retaining the other three constituents. For primary prevention, the authors included patients with a 10-year absolute risk of CVD of between 5% and 35%. This strategy thus required an additional hospital visit to assess CVD risk factors such as blood pressure, diabetes, serum cholesterol, and smoking status. The authors estimated that a nearly 50–60% reduction in CVD-related events could be expected if all patients with a 10-year absolute risk >5% were treated. This would lead to at least a 2-year increase in life expectancy in those above the age of 35 years. Using the secondary prevention strategy, the authors predicted a 10–15% reduction in lifetime risk of death due to CVD. Using this model, the authors reported that the incremental cost-effectiveness of the primary prevention strategy was US$746–890 per quality-adjusted life year (QALY) for patients with a 10-year absolute CVD risk >25%, across six developing regions, as defined by the World Bank. The cost was higher in patients with lower levels of absolute 10-year cardiovascular risk, as more patients needed to be treated to achieve a similar reduction in CVD events, leading to higher expenditure and lower cost-effectiveness. However, incremental cost-effectiveness was still favorable for all primary prevention strategies, except for the strategy of treating all patients >55 years. For secondary prevention, incremental cost-effectiveness of the polypill was most favorable, at US$306–388 per QALY gained.
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The projected benefits of these combinations of drugs have been assumed using mathematical multiplication of relative risks. For some drugs, the authors have included the best-case scenario figures for risk reduction. For example, Wald and Law assumed a relative risk reduction of 61% of CVD events with the use of statins. However, data from many large randomized trials of statins have estimated the relative risk reduction to be at a more conservative level of 35%. These assumptions therefore need to be verified by an actual clinical trial. This is especially important in the case of primary prevention. In secondary prevention trials, the sequential evaluation of cardioprotective drugs has seen each new drug being tested for incremental benefit when added to previously tested drugs and only then becoming standard therapy. Thus the value of combination therapy of multiple drugs (given separately and not as a single pill) is well proven. However, multiple drugs have not been used in such an incremental manner in primary prevention trials. It is essential that trial evidence, using major event-related endpoints, be generated for such multidrug combinations when used for primary prevention. In the case of secondary prevention, evidence on bioavailability, pharmacokinetics, and intermediate variables (risk factor levels) may suffice. Even in secondary prevention, some questions remain: Are beta blockers useful for secondary prevention of stroke? Are diuretics needed for secondary prevention of CAD? The actual incidence of adverse events or other side effects associated with the use of the polypill is also unknown. Beta blockers, ACE inhibitors, calcium channel blockers, statins, and aspirin are all known to produce side effects requiring discontinuation of therapy. Although Wald and Law estimated that 15% of patients would be expected to discontinue therapy due to side effects, the actual incidence may be higher. Polypills would need to be available in different formulations to avoid anticipated side effects due to one or more components in susceptible persons. The dilemma of primary prevention becomes more obvious when an attempt is made to treat all patients alike, regardless of their absolute risk with one fixed combination of drugs. On the one hand, many asymptomatic persons with low absolute risk of events would be treated with little or no expected benefit; however, they would be exposed to the adverse effects of combination multidrug therapy. On the other hand, there would be high-risk patients who would be undertreated and might not reach the desired therapeutic goals. Without appropriate risk profiling, the latter patients would be diligently taking drugs but not accruing the maximum benefits. Although the population risk would still be lowered by such an approach, the individual at risk would not derive optimum benefit in spite of drug therapy. Whether the polypill will necessarily improve compliance is not known. Although a low daily pill count does improve compliance, it is also affected by many other social and behavioral factors that are not necessarily overcome with the convenience associated with a polypill. Patient motivation and counselling, educational status, health education campaigns, and economic considerations are among the many factors that impact adherence positively and are unaffected by combination pharmacotherapy. Patients with overt clinical heart disease are more receptive to information regarding personal health behavior and its modification and are also more compliant with drug therapy. Longterm adherence to advice about behavior and drugs is lower when it is used for primary prevention in “real-world” settings. This can have a significant negative impact on the projected benefits. An important assumption made by Wald and Law in targeting multiple risk factors simultaneously is that there are no clear demarcations between “normal” and “abnormal” levels of risk factors. They proposed, after appraising data from many observational and randomized trials, that there is a continuum of risk, with no specific risk factor thresholds that need to be targeted. It was recommended that interventions to modify risk factors should be guided by a person’s level of absolute cardiovascular risk rather than the level of individual risk factors. Thus, patients with what is currently considered borderline elevation of multiple risk factors would derive benefit from interventions designed to modify those risk factors. However, data from the Framingham study suggest that 90% of CVD events occur in individuals with at least one preexisting major cardiovascular risk factor. Clus-
tering of these risk factors is frequently observed in individuals and e309 contributes to high level of absolute risk of CVD. Therefore, it is important to screen the population for these risk factors and then treat individuals at a high absolute risk with the combination pharmacotherapy, rather than treat the entire population >55 years with a blanket therapy. The ideal approach would be to assess an individual’s global (absolute) cardiovascular risk, based on available algorithms for different populations, to maximize the benefits of the polypill and thus make it cost-effective, as shown in the study by Gaziano. Another concern with use of a widespread pharmacologic intervention at the population level is the likely sense of complacency among both users and health care providers. Critics have expressed a fear that emphasis on healthy diet, physical activity, smoking cessation, and other lifestyle changes, which are essential elements in the management of these chronic diseases, may not be treated with the seriousness that they deserve. The polypill will not reduce the number of individuals acquiring a high-risk status in any population—it can only avert their future risk, if detected and treated. On the other hand, population-wide changes in diet, physical activity, and tobacco use are likely to reduce the number of individuals who enter this high-risk zone. Many other factors such as physician attitudes, cost-effectiveness, and long-term affordability have to be addressed before the promise of the polypill can be realized. These concerns would be best addressed by clinical trials that examine the benefits in the setting of both primary and secondary prevention.
CHAPTER e38 The Polypill
IMPACT ON DEVELOPING COUNTRIES
CAD is an emerging epidemic in low- and middle-income countries. By 2020, >80% of all CVD-related deaths worldwide are expected to occur in the developing world. Moreover, even as age-adjusted cardiovascular disease rates are declining in the developed world, rates of CVD are rising rapidly in these low- and middle-income countries. The same risk factors responsible for CAD in the western population are operative in these countries, as shown by the INTERHEART study. In the absence of well-resourced CVD prevention programs and limited public awareness of risk factors, the polypill appears attractive for such populations, especially for secondary prevention and highrisk primary preventions. It overcomes the problems of inadvertent drug omission by under-informed physician and provides the opportunity to include generic drugs such as lovastatin or simvastatin, enalapril, and propranolol to lower the cost of pharmacotherapy. The presence of a strong pharmaceutical industry in countries such as India offers the opportunity to lower the costs of drug production significantly, making the therapy more affordable and applicable. A World Health Organization report on chronic diseases suggests that a polypill could be made available for a little over US$1 per patient per month, using these generic products. Moreover, with the expected low side-effect profile of these pills, it may be possible to shift identification and treatment of high-risk individuals to non-physician health workers in these resource-poor countries, thereby lowering the cost and widening the access for effective risk reduction. However, the developing countries would need to place even greater emphasis on policies and educational interventions that protect their populations from the risk of CVD, while judiciously applying interventions such as the polypill.
CONCLUSIONS
The concept of a polypill to reduce the burden of CVD is attractive and seems to have great potential, especially in secondary and highrisk primary prevention. However, its role is presently speculative and needs to be assessed in randomized trials. It should not distract clinicians from the importance of managing risk factor levels; rather, it should enable persons at high risk of CVD to access affordable and easy-to-consume therapy for reducing that risk. It is also important that the polypill should not lull the patient and the physician into a false sense of security—continued emphasis on targeting modifiable risk behaviors such as smoking, sedentary lifestyle, and unhealthy diet
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e310 would continue to yield equal dividends. They would also be applicable to the wider population, with greater safety.
FURTHER READINGS
COMBINATION PHARMACOTHERAPY AND PUBLIC HEALTH RESEARCH WORKING GROUP: Combination pharmacotherapy for cardiovascular disease. Ann Intern Med 143:593, 2005 CONSTANTINO G et al: Prevention of cardiovascular disease with a polypill. Lancet 369:185, 2007 GAZIANO TA et al: Cardiovascular disease prevention with a multidrug regimen in the developing world: A cost-effectiveness analysis. Lancet 368:679, 2006
REDDY KS: The preventive polypill—much promise, insufficient evidence. N Engl J Med 356:212, 2007 SLEIGHT P et al: Benefits, challenges, and registerability of the polypill. Eur Heart J 27:1651, 2006 VASAN RS et al: Relative importance of borderline and elevated levels of coronary heart disease risk factors. Ann Intern Med 142:393, 2005 WALD NJ, LAW MR: A strategy to reduce cardiovascular disease by more than 80%. BMJ 326:1419, 2003 YUSUF S et al, on behalf of the INTERHEART Study Investigators: Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): Casecontrol study. Lancet 364:937, 2004
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Mitochondrial e39 Heritable TraitsDNA and and Diseases
Karl Skorecki, Hanna Mandel
Mitochondria are cytoplasmic organelles whose major function is to generate ATP by the process of oxidative phosphorylation under aerobic conditions. This process is mediated by the respiratory electron transport chain (ETC) multiprotein enzyme complexes I–V, and the two electron carriers, coenzyme Q (CoQ) and cytochrome-c. Other cellular processes to which mitochondria make a major contribution include apoptosis (programmed cell death), as well as additional celltype specific functions (Table e39-1). The efficiency of the mitochondrial ETC in ATP production is a major determinant of overall body energy balance and thermogenesis. In addition, mitochondria serve as the predominant source for the generation of reactive oxygen species (ROS), whose rate of production also relates to the coupling of ATP production to oxygen consumption. Given the centrality of oxidative phosphorylation to the normal activities of almost all cells, it is not surprising that mitochondrial dysfunction can affect almost any organ system (Fig. e39-1). Thus, physicians in many specialties might encounter patients with mitochondrial diseases and should be aware of their existence and characteristics. The integrated activity of several hundred proteins is required for normal mitochondrial biogenesis, function, and integrity. Most of these are encoded by nuclear genes and thus follow the rules and patterns of nuclear genomic inheritance (see Part 3, Genetics and Disease). These nuclear-encoded proteins are synthesized in the cell cytoplasm and imported to their location of activity in mitochondria through a complex biochemical process. In addition, the mitochondria themselves have their own genome consisting of numerous copies (polyploidy) per mitochondrion of a circular, double-strand mitochondrial DNA (mtDNA) molecule consisting of a 16,569-nucleotide sequence. This mtDNA sequence contains a total of 37 genes, of which 13 encode mitochondrial protein components of the ETC (Fig. e39-2). The remaining 22 tRNAand 2 rRNA-encoding genes are dedicated to Skeletal muscle Weakness the process of translation of the 13 mtDNA-enFatigue coded proteins. This dual genetic control of miMyopathy tochondrial function can result in fascinating Neuropathy patterns of inheritance, which may be challenging to unravel. The current chapter focuses on diseases and heritable traits related to the mtDNA component of the dual genetic control of mitochondrial function. The reader is reBrain ferred elsewhere for consideration of mitochonSeizures drial disease originating from mutations in the Myoclonus nuclear genome. The latter include (1) nuclear Ataxia genomic mutations that disrupt the integrity of Stroke Dementia the mitochondrial genome itself (mtDNA deleMigraine tion and depletion states), (2) disorders due to mutations in nuclear genes encoding structural components or assembly factors of the oxidative Nuclear DNA phosphorylation complexes, and (3) mitochondrial disorders due to mutations in nuclear genes encoding proteins indirectly related to oxidative phosphorylation.
TABLE e39-1 FUNCTIONS OF MITOCHONDRIA
All cells and tissues Oxidative phosphorylation Apoptosis (programmed cell death) Tissue- or cell-specific Cholesterol metabolism Amino and organic acid metabolism Fatty acid beta oxidation Sex steroid synthesis Heme synthesis Hepatic ammonia detoxification Neurotransmitter metabolism
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mechanisms of mtDNA differ from the corresponding mechanisms in the nuclear genome, whose nucleosomal packaging and structure is more complex. In terms of mtDNA replication, at least two major models have been proposed, which differ principally in whether the two strands of the mtDNA double helix replicate simultaneously or consecutively. Since each mitochondrion contains many copies of mtDNA, and because the number of mitochondrion per cell can vary during the lifetime of a cell through the processes of fission, fusion, and mitochondrial biogenesis, mtDNA copy number per mitochondrion and per cell can also vary within the lifetime of a cell, and it is not directly coordinated with the cell cycle. Thus, it is not surprising that vast differences in mtDNA copy number are observed between different cell types and tissues and during the lifetime of a cell. Another important feature of the mtDNA replication process is a greatly reduced stringency of proofreading and replication error correction, leading to a much greater degree of sequence variation compared to the nuclear genome. Some of these sequence variants are silent polymorphisms that do not
CHAPTER e39 Mitochondrial DNA and Heritable Traits and Diseases
Heart Conduction disorder Wolff-Parkinson-White syndrome Cardiomyopathy
Eye Optic neuropathy Ophthalmoplegia Retinopathy
Liver Hepatopathy
ATP
Nuclear DNA
Subunits
Oxidative phosphorylation
Kidney Fanconi's syndrome Glomerulopathy
Mitochondrial DNA
Pancreas Diabetes mellitus
Blood Pearson's syndrome Inner ear Sensorineural hearing loss
MITOCHONDRIAL DNA (mtDNA) STRUCTURE AND FUNCTION
As a result of its circular structure and extranuclear location, the replication and transcription
Colon Pseudo-obstruction
FIGURE e39-1 Dual genetic control and multiple organ system manifestations of mitochondrial disease. (Reproduced with permission from DR Johns: Mitochondrial DNA and disease. N Engl J Med 333:638, 1995.)
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e312
A
16S Leu (UUR) 12S Phe Val
D-loop region
Pro Thr
Cyt b
ND1
IIe Gln Met
Glu
ND6
ND2
Trp Ala Asn Cys Tyf
ND5
Leu (CUN) Ser (AGY) His
COXI
Ser (UCN) Asp Arg Lys Gly
ND4 ND4L
COXII
ND3 A8 A6 COXIII
ATPase 6 NARP MILS FBSN H+ ATP
A8 A6
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B
ND1, ND2, ND3, ND4 ND4L, ND5, ND6 LHON MELAS LHON and dystonia Sporadic myopathy H+ Matrix Succinate
ND1 ND2 ND3 ND6 ND4L ND5 ND4
COXI, COXII, Cyt b COX III Sporadic myopathy Encephalomyopathy Sporadic anemia Septo-optic dysplasia Sporadic myopathy Encephalomyopathy Cardiomyopathy ALS-like syndrome H+ H+ Fumarate
Cyt b
O2
COXI COXII COXIII Cyt c
H2O ADP
Inner mitochondrial membrane Intermembrane space
e−
e−
CoQ
e−
Complex I NDUFS1, NDUFS2 NDUFS4, NDUFS7 NDUFS8, NDUFV1 Leigh’s syndrome Leukodystrophy No. of mtDNAencoded subunits No. of nDNAencoded subunits 7 -39
Complex II SDHA, SDHB SDHC, SDHD Leigh’s syndrome Paraganglioma Pheochromocytoma 0 4
Complex III BCS1L Leigh’s syndrome GRACILE syndrome 1 10
Complex IV Complex V COX10, COX15 SCO1, SCO2, SURF1 Leigh’s syndrome Hepatopathy Cardioencephalomyopathy Leukodystrophy and tubulopathy 3 10 2 14
FIGURE e39-2 Mitochondrial DNA (mtDNA) and the mitochondrial respiratory chain. A. The map of the human mitochondrial genome. The protein-coding genes—seven subunits of complex I (ND), three subunits of cytochrome-c oxidase (COX), the cytochrome-b subunit of complex III (Cyt b), and two subunits of adenosine triphosphate (ATP) synthase (A6 and A8)—are shown in red. The protein-synthesis genes—the 12S and 16S ribosomal RNAs and the 22 transfer RNAs (three-letter amino acid symbols)—are shown in blue. The D-loop region controls the initiation of replication and transcription of mtDNA. B. The subunits of the respiratory chain encoded by nuclear DNA (nDNA) are shown in blue and the subunits encoded by mtDNA are shown in red. As electrons (e–) flow along the electron-transport chain, protons (H+) are pumped from the matrix to the intermembrane space through complexes I, III, and IV and then back into the matrix have the potential for a phenotypic or pathogenic effect, whereas others may be considered pathogenic mutations. With respect to transcription, initiation can occur on both strands and proceeds through the production of an intronless polycistronic precursor RNA that is then processed to produce the 13 individual mRNA and 24 individual tRNA and rRNA products. The 37 mtDNA genes comprise fully 93% of the 16,569 nucleotides of the mtDNA in what is known as the coding region. The control region consists of ~1.1
through complex V, to produce ATP. Coenzyme Q (CoQ) and cytochrome-c (Cyt c) are electron-transfer carriers. Genes responsible for the indicated respiratory-chain disorders are also shown. ATPase 6 denotes ATP synthase 6; BCS1L, cytochrome b–c complex assembly protein (complex III); NDUF, NADH dehydrogenase–ubiquinone oxidoreductase; SCO, synthesis of cytochrome oxidase; SDHA, SDHB, SDHC, and SDHD, succinate dehydrogenase subunits; SURF1, surfeit gene 1; FBSN, familial bilateral striatal necrosis; LHON, Leber hereditary optic neuropathy; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; MILS, maternally inherited Leigh’s syndrome; NARP, neuropathy, ataxia, and retinitis pigmentosa; GRACILE, growth retardation, aminoaciduria, lactic acidosis, and early death; and ALS, amyotrophic lateral sclerosis. (Reproduced with permission from DiMauro and Schon.) kilobases (kb) of noncoding DNA, thought to have a major role in replication and transcription initiation. The mutation rate is considerably higher in the control region, which contains a displacement, or D, loop, in turn containing two adjacent hypervariable regions (HVR-I and HVR-II) that give rise to large interindividual variability within the human population. Indeed mtDNA sequence variants at both the coding and control regions are more highly partitioned across geographically defined populations than sequence variants in other parts of the ge-
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nome, and combinations of these sequence variants define phylogeographic mtDNA haplogroups and haplotypes. A major active research question is whether or not differences in these haplotypes are of medical significance in terms of disease predisposition. The foregoing structural and functional features of mtDNA lead to the expectation that phenotypic inheritance and disease patterns for disorders related to mtDNA sequence variation and mutation should be quite different from the more familiar inheritance and disease patterns attributed to variation and mutation of nuclear DNA. Intensive research during the past two decades has confirmed that this is, indeed, the case. MATERNAL INHERITANCE AND LACK OF RECOMBINATION The nuclear genome is characterized by homologous pairs of chromosomes of biparental origin. With the exception of the nonrecombining region of the Y chromosome in males, these homologous pairs undergo meiotic recombination during gametogenesis, which, together with mutation, serves as the source of universal genetic diversity. In contrast, mtDNA molecules do not undergo recombination, such that mutational events represent the only source of mtDNA genetic diversification. Moreover, with very rare exceptions, it is only the maternal DNA that is transmitted to the offspring. The fertilized oocyte degrades mtDNA carried from the sperm in a complex process involving the ubiquitin proteasome system. Thus, while mothers transmit their mtDNA to both their sons and daughters, only the daughters are able to transmit the inherited mtDNA to future generations. Accordingly, mtDNA sequence variation and associated phenotypic traits and diseases are inherited exclusively along maternal lines. As will be noted below, because of the complex relationship between mtDNA mutations and disease expression, sometimes this maternal inheritance is difficult to recognize at the clinical or pedigree level. However, evidence of paternal transmission can almost certainly rule out an mtDNA genetic origin of phenotypic variation or disease; conversely, a disease affecting both sexes without evidence of paternal transmission strongly suggests a heritable mtDNA disorder (Fig. e39-3). One interesting consequence of uniparental inheritance and lack of recombination is the utility of mtDNA marker and sequence analysis in tracing matrilineal ancestry in phylogenetic research. MULTIPLE COPY NUMBER (POLYPLOIDY), MITOTIC SEGREGATION, AND HIGH MUTATION RATE Each aerobic cell in the body has multiple mitochondria, often numbering many hundreds or more in cells with extensive energy production requirements. Furthermore, the number of copies of mtDNA within each mitochondrion varies from several to hundreds; this is true of both somatic as well as germ cells, including oocytes in females. In the case of somatic cells, this means that the impact of each individual, newly acquired somatic mutation is likely to be very small in terms of total cellular or organ system function; however, because of the manyfold higher mutation rate during mtDNA replication, numerous different mutations may accumulate with the aging of the organism. It has been proposed that the total cumulative burden of acquired somatic mtDNA mutations with age may result in an overall perturbation of mitochondrial function, contributing to age-related reduction in the efficiency of oxidative phosphorylation and increased production of damaging ROS. According to this formulation, the high somatic mtDNA mutation rate and the global effect on mitochondrial function counterbalance the reduced impact of the multiple copy number of each individual mtDNA mutation. The potential contribution of such acquired somatic mtDNA mutations to aging and to common age-related disturbances, such as metabolic syndrome and diabetes, cancer, neurodegenerative, and cardiovascular disease, will be considered in greater detail below. It is evident that just as in the case of acquired somatic mutations in the nuclear genome, so, too, the somatic mutations in mtDNA are not carried forward to the next generation. Therefore, in terms of heritable traits and disease, it is impor-
e313 I II
III
FIGURE e39-3 Maternal inheritance of mtDNA disorders and heritable traits. Affected women (filled circles) transmit the trait to their children. Affected men (filled square) do not transmit the trait to any of their offspring. tant to focus on the consequence of mtDNA polyploidy within the germ cells of the female reproductive system. The multiple mtDNA copy number within the maternal germ cells result in the phenomenon of heteroplasmy of inherited mtDNA mutations. Heteroplasmy for a given mtDNA sequence variant or mutation arises as a result of the coexistence within the oocyte of mtDNA molecules bearing both versions of the sequence variant (Fig. e39-4). In the case of pathogenic mutations, this means coexistence within the oocyte of both the wildtype and mutant versions. For each oocyte, the percentage of mtDNA molecules bearing each version of the polymorphic sequence variant or mutation depends on stochastic events related to partitioning of mtDNA molecules during the process of oogenesis itself. Thus, oocytes differ from each other in the degree of heteroplasmy for that sequence variant or mutation. In turn, the heteroplasmic state is carried forward to the zygote and then, to varying degrees, depending on mitotic segregation of mtDNA molecules, during organ system development and maintenance. Mitotic segregation refers to the unequal distribution of wild-type and mutant versions of the mtDNA molecules during all cell divisions that occur during prenatal development and subsequently throughout the lifetime of an individual. The particular mtDNA sequence variant may be entirely silent in terms of phenotype or disease predisposition
Oocyte maturation and mtDNA amplification Mutant mitochondrion Normal mitochondrion Nucleus
CHAPTER e39 Mitochondrial DNA and Heritable Traits and Diseases
Fertilization
High level of mutation (affected offspring)
Intermediate level of mutation (mildly affected offspring)
Primordial germ cell containing mutant mtDNA Primary oocytes Mature oocytes
Low level of mutation (unaffected offspring)
FIGURE e39-4 Heteroplasmy and the mitochondrial genetic bottleneck. During the production of primary oocytes, a selected number of mitochondrial DNA (mtDNA) molecules are transferred into each oocyte. Oocyte maturation is associated with the rapid replication of this mtDNA population. This restriction-amplification event can lead to a random shift of mtDNA mutational load between generations and is responsible for the variable levels of mutated mtDNA observed in affected offspring from mothers with pathogenic mtDNA mutations. Mitochondria that contain mutated mtDNA are shown in red, and those with normal mtDNA are shown in green. (Reproduced with permission from Taylor and Turnbull.)
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e314 and only detectable upon mtDNA sequencing. By contrast, the mtDNA
sequence variant may affect one or more aspects of mitochondrial function in a manner that gives rise to a phenotypic effect or predisposes to a disease. The phenotypic effect or disease impact of a given mtDNA sequence variant will be a function not only of its inherent disruptive effect (pathogenicity) on the mtDNA-encoded gene (coding region mutations) or integrity of the mtDNA molecule (control region mutations), but also of its distribution among the multiple copies of mtDNA in the various mitochondria, cells, and tissues of the affected individual. This leads to the notion of a “threshold” effect, wherein the actual expression of disease depends upon the relative percentage of mitochondria whose function is disrupted by mtDNA mutations. Consequently, there is tremendous heterogeneity in disease penetrance and severity, as well as complexity of organ system involvement among the offspring of women with pathogenic heteroplasmic mutations. This heterogeneity arises from differences in the degree of heteroplasmy among oocytes and with subsequent mitotic segregation of the pathogenic mutation during tissue and organ development, and throughout the lifetime of the individual. This may create difficulty in recognizing a maternal pattern of inheritance and making the diagnosis of an mtDNA genetic cause of disease. During the course of human evolution, certain heteroplasmic mtDNA sequence variants may drift to a state of homoplasmy, wherein all of the mtDNA molecules in the organism contain the new sequence variant. This arises due to a “bottleneck” effect followed by genetic drift during the very process of oogenesis itself (Fig. e39-4). In other words, during certain stages of oogenesis, the mtDNA copy number becomes substantially reduced, such that the particular mtDNA species bearing the novel or derived sequence variant may become the increasingly predominant, and eventually exclusive, version of the mtDNA for that particular nucleotide site. The offspring of a woman bearing an mtDNA sequence variant or mutation that has become homoplasmic will also be homoplasmic for that variant, and the female offspring will transmit it forward in subsequent generations; this process establishes a new mtDNA haplotype in the human population. Considerations of reproductive fitness limit the evolutionary or population emergence of homoplasmic mutations that are lethal or cause severe disease in infancy or childhood. Thus, with a number of notable exceptions (e.g., mtDNA mutations causing Leber hereditary optic neuropathy; see below), most homoplasmic mutations were considered to be neutral markers of human evolution—useful and interesting in the population genetics analysis of shared maternal ancestry but with little significance in human phenotypic variation or disease predisposition. However, recent research and clinical attention have focused on the potential for certain of these homoplasmic mtDNA sequence variants to contribute to the evolutionary adaptation of populations to their climatic environment or to predispose to heritable late postreproductive and age-associated disease predisposition.
genome also complicates our ability to ascertain the extent of contribution of heritable mtDNA mutations to human illness. Finally, assessment of the impact of the accumulation of acquired somatic mtDNA mutations on late-onset common disease predisposition, or on diseases arising from exposure to metabolic stress, also needs to be considered in order to appreciate the full impact of mtDNA in human health and disease. OVERVIEW OF CLINICAL AND PATHOLOGIC FEATURES OF HUMAN mtDNA DISEASE Given the vital roles of mitochondria in all nucleated cells, it is not surprising that mtDNA mutations can affect numerous tissues with pleiotropic effects. More than 200 different disease-causing mtDNA mutations have been described to date, all affecting ETC function. Figure e39-5 provides an mtDNA map of some of the better characterized disorders. A number of clues can increase the index of suspicion for mtDNA mutation as an etiology of a heritable trait or disease, including (1) familial clustering with absence of paternal transmission; (2) adherence to one of the classic syndromes (see below) or paradigmatic combinations of disease phenotypes involving several organ systems that normally do not fit together within a single nuclear genomic mutation category; (3) a complex of laboratory and pathologic abnormalities that reflect disruption in cellular energetics (e.g., lactic acidosis and neurodegenerative and myodegenerative symptoms with the finding of ragged red fibers, reflecting the accumulation of abnormal mitochondria under the muscle sarcolemmal membrane); or (4) a mosaic pattern reflecting a heteroplasmic state. Heteroplasmy can sometimes be elegantly demonstrated at the tissue level using histochemical staining for enzymes in the oxidative phosphorylation pathway, with a mosaic pattern indicating heterogeneity of the genotype for the coding region for the mtDNA-encoded enzyme. Complex II, CoQ, and cytochrome-c are exclusively encoded by nuclear DNA. In contrast, complexes I, III, IV, and V contain at least some subunits encoded by mtDNA. Just 3 of the 13 subunits of the ETC complex IV enzyme, cytochrome-c oxidase, are encoded by mtDNA, and, therefore, this enzyme has the lowest threshold for dysfunction when a threshold of mutated mtDNA is reached. Histochemical staining for cytochrome-c oxidase activity in tissues of patients affected with heteroplasmic inherited mtDNA mutations (or with the somatic accumulation of mtDNA mutations, see below) can show a mosaic pattern of reduced histochemical staining in comparison with histochemical staining for the complex II enzyme, succinate dehydrogenase (Fig. e39-6). Heteroplasmy can also be detected at the genetic level through direct mtDNA genotyping under special conditions. It is not always possible to detect heteroplasmy readily in genomic samples extracted from whole blood. Only when a substantial proportion of mtDNA molecules carry the mutant genotype within a sampled tissue does heteroplasmy become detectable by more conventional sequencing or genotyping approaches. Clinically, the most striking overall characteristic of mitochondrial genetic disease is the phenotypic heterogeneity associated with mtDNA mutations. This extends to intrafamilial phenotypic heterogeneity for the same mtDNA pathogenic mutation and, conversely, to the overlap of phenotypic disease manifestations with distinct mutations. Thus, while fairly consistent and well-defined “classic” syndromes have been attributed to specific mutations, frequently “nonclassic” combinations of disease phenotypes ranging from isolated myopathy to extensive multisystem disease are often encountered, rendering genotype-phenotype correlation challenging. In both classic and nonclassic mtDNA disorders, there is often a clustering of some combination of abnormalities affecting the neurologic system (including optic nerve atrophy, pigment retinopathy, sensorineural hearing loss), cardiac and skeletal muscle (including extraocular muscles), and endocrine and metabolic systems (including diabetes mellitus). Additional organ systems that may be affected include the hematopoietic, renal, hepatic, and gastrointestinal systems, though these are more frequently involved in infants and children. Disease-causing mtDNA coding region mutations can affect either one of the 13 protein encoding genes, or one of the 24 protein synthetic
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MITOCHONDRIAL DNA DISEASE
The true prevalence of mtDNA disease is difficult to estimate because of the phenotypic heterogeneity that occurs as a function of heteroplasmy, the challenge of detecting and assessing heteroplasmy in different affected tissues, and the other unique features of mtDNA function and inheritance described above. Very rough estimates suggest that heteroplasmic germ-line pathogenic mtDNA mutations may affect up to approximately 1 in 5000 individuals. The true overall impact of mtDNA mutation in human health and disease is certainly much greater, if the potential contribution of homoplasmic mtDNA sequence variation to common complex diseases appearing in the postreproductive age is also considered. Only when the ability to distinguish a completely neutral sequence variant from a true phenotypemodifying or pathogenic mutation is achieved, and when an accurate assessment of heteroplasmy can be determined with fidelity, will the true extent and contribution of mtDNA sequence variation to human traits and health be determined. In addition, the combination of interactions of mtDNA sequence variation with mutations in the nuclear
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Parkinsonism, aminoglycoside-induced deafness LS, MELAS, multisystem disease Cardiomyopathy PEO, LHON, MELAS, myopathy, cardiomyopathy, diabetes and deafness Myopathy, LHON cardiomyopathy, PEO Myopathy, MELAS Myopathy, lymphoma Cardiomyopathy LHON LS, ataxia, chorea, myopathy PEO Myopathy, PEO ECM Myoglobinuria, motor neuron disease, sideroblastic anemia PPK, deafness, MERRF-MELAS PEO I Q M ND2 W A N C Y COXI S1 D ND4L ND3 R G ND4 L1 ND1 ND6 MELAS myoglobinuria Myopathy, PEO Cardiomyopathy ECM ECM, LHON, myopathy, PT Cyt b E cardiomyopathy, MELAS and parkinsonism Cardiomyopathy ECM LHON, MELAS, diabetes, LHON and dystonia ND5 LS, MELAS Cardiomyopathy, ECM PEO, myopathy, sideroblastic anemia Diabetes and deafness LHON, myopathy, LHON and dystonia
e315
16S
V
12s F
L2 S2 H
CHAPTER e39 Mitochondrial DNA and Heritable Traits and Diseases
COXII A8 K A6 COXIII
Cardiomyopathy myoclonus
LHON
Myopathy, multisystem disease, NARP, MILS, FBSN encephalomyopathy LS, ECM, Cardiomyopathy, myoglobinuria PEO, MERRF, MELAS, deafness
Progressive myoclonus, epilepsy, and optic atrophy Cardiomyopathy, SIDS, ECM
FIGURE e39-5 Mutations in the human mitochondrial genome known to cause disease. Disorders that are frequently or prominently associated with mutations in a particular gene are shown in boldface. Diseases due to mutations that impair mitochondrial protein synthesis are shown in blue. Diseases due to mutations in protein-coding genes are shown in red. ECM denotes encephalomyopathy; FBSN, familial bilateral striatal necrosis; LHON, Leber hereditary optic neuropgenes. Clinical manifestations do not readily distinguish these two categories, though lactic acidosis and muscle pathologic findings tend to be more prominent in the latter. In all cases, either defective ATP production due to disturbances in the ETC or enhanced generation of reactive oxygen species has been invoked as the mediating biochemical mechanism between mtDNA mutation and disease manifestation. mtDNA DISEASE PRESENTATIONS The clinical presentation of adult patients with mtDNA disease can be divided into three categories: (1) clinical features suggestive of mitochondrial disease (Table e39-2), but not a well-defined classic syndrome; (2) classic mtDNA syndromes; and (3) clinical presentation confined to one organ system (e.g., isolated sensorineural deafness, cardiomyopathy, or diabetes mellitus). Table e39-3 provides a summary of eight illustrative classic mtDNA syndromes or disorders that affect adult patients and highlights some of the most interesting features of mtDNA disease in terms of molecular pathogenesis, inheritance, and clinical presentation. The first five of these syndromes result from heritable point mutations in either protein encoding or protein synthetic mtDNA genes; the other three result from rearrangements or deletions that usually do not involve the germ line. Leber hereditary optic neuropathy (LHON) is a common cause of maternally inherited visual failure. LHON typically presents during young adulthood with subacute painless loss of vision in one eye, with symptoms developing in the other eye 6–12 weeks after the initial onset. In some instances, cerebellar ataxia, peripheral neuropathy, and cardiac conduction defects are observed. In >95% of cases, LHON is due to one of three homoplasmic point mutations of mtDNA that af-
athy; LS, Leigh’s syndrome; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; MERRF, myoclonic epilepsy with ragged red fibers; MILS, maternally inherited Leigh’s syndrome; NARP, neuropathy, ataxia, and retinitis pigmentosa; PEO, progressive external ophthalmoplegia; PPK, palmoplantar keratoderma; and SIDS, sudden infant death syndrome. (Reproduced with permission from DiMauro and Schon.) fect genes encoding different subunits of complex I of the mitochondrial ETC; however, not all individuals who inherit a primary LHON mtDNA mutation develop optic neuropathy, indicating that additional environmental (e.g., tobacco exposure) or genetic factors are important in the etiology of the disorder. Both the nuclear as well as mitochondrial genomic background modify disease penetrance. Thus, for example, LHON has a greater penetrance and severity in men than in women, pointing to an epistatic interaction with the nuclear genome. Moreover, disease susceptibility for a given mutation is modulated by mtDNA haplotype background, with certain haplotypes being protective. Of interest, patients with this syndrome are often homoplasmic for the disease-causing mutation. The somewhat later onset in young adulthood and modifying effect of genetic background may have enabled homoplasmic pathogenic mutations to have escaped evolutionary censoring. Mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) is probably the most common mtDNA disease, consisting of a progressive encephalomyopathy characterized by repeated stroke-like events involving mainly posterior cerebral areas. Of note, brain lesions do not respect the distribution of vascular territories. Recurrent migraine-like headache and vomiting, exercise intolerance, seizures, short stature, and lactic acidosis are other frequent clinical features. The most commonly described pathogenic point mutations are A3243G and T3271C in the gene encoding the leucine tRNA. Myoclonic epilepsy with ragged red fibers (MERRF) is a multisystem disorder characterized by myoclonus, seizures, ataxia, and myopathy with ragged red fibers. Hearing loss, exercise intolerance, neuropathy, and short stature are often present. Almost all MERRF patients have
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e316
FIGURE e39-6 Cytochrome-c oxidase deficiency in mitochondrial DNA–associated disease. Transverse tissue sections that are reacted for both cytochrome-c oxidase (COX) and succinate dehydrogenase (SDH) activities sequentially, with COX-positive cells shown in brown and COX-deficient cells shown in blue. A. Skeletal muscle from a patient with a heteroplasmic mitochondrial tRNA point mutation. The section shows a typical “mosaic” pattern of COX activity, with many muscle fibers harboring levels of mutated mtDNA that are above the crucial threshold to produce a functional enzyme complex. B. Cardiac tissue (left ventricle) from a patient with a homoplasmic tRNA mutation that causes hypertrophic cardiomyopathy, whichdemonstrates an absence of COX in most cells. C. A section of cerebellum from a patient with mtDNA rearrangement that highlights the presence of COX-deficient neurons. D, E. Tissues that show COX deficiency due to clonal expansion of somatic mtDNA mutations within single cells—a phenomenon that is seen in both postmitotic cells (D; extraocular muscles) and rapidly dividing cells (E; colonic crypt) in aging humans. (Reproduced with permission from Taylor and Turnbull.) mutation in the mtDNA tRNAlys gene and the A8344G mutation in the mtDNA gene encoding the lysine amino acid tRNA is responsible for 80–90% of MERRF cases. Neurogenic weakness, ataxia, and retinitis pigmentosa (NARP) is characterized by moderate diffuse cerebral and cerebellar atrophy and symmetric lesions of the basal ganglia on MRI. A heteroplasmic T8993G mutation in the gene ATPase 6 subunit gene has been identified as causative. Ragged red fibers are not observed in muscle biopsy. When >95% of mtDNA molecules are mutant, a more severe clinical, neuroradiologic and neuropathologic picture (Leigh’s syndrome) emerges. Point mutations in the mtDNA gene encoding the 12S rRNA result in heritable nonsyndromic hearing loss. One such mutation causes heritable ototoxic susceptibility to aminoglycoside antibiotics, which opens a pathway for a simple pharmacogenetic test in the appropriate clinical settings. Kearns-Sayre syndrome (KSS), sporadic progressive external ophthalmoplegia (PEO), and Pearson syndrome are three disease phenotypes caused by large-scale mtDNA rearrangements including partial deletions or partial duplication. The majority of single large-scale re-
arrangements of mtDNA are thought to result from clonal amplification of a single sporadic mutational event, occurring in the maternal oocyte or during early embryonic development. Since germ line involvement is rare, most cases are sporadic rather than inherited. KSS is characterized by the triad of onset before age 20, chronic progressive external ophthalmoplegia, and pigmentary retinopathy. Cerebellar syndrome, heart block, increased cerebrospinal fluid protein content, diabetes, and short stature are also part of the syndrome. Single deletions/duplication can also result in milder phenotypes such as PEO, characterized by late-onset progressive external ophthalmoplegia, proximal myopathy, and exercise intolerance. In both KSS and PEO, diabetes mellitus and hearing loss are frequent accompaniments. Pearson syndrome is also characterized by diabetes mellitus from pancreatic insufficiency, together with pancytopenia and lactic acidosis, caused by the largescale sporadic deletion of several mtDNA genes.
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TABLE e39-2 COMMON FEATURES OF mtDNA-ASSOCIATED DISEASES IN ADULTS
Neurologic: stroke, epilepsy, migraine headache, peripheral neuropathy, cranial neuropathy (optic atrophy, sensorineural deafness, dysphagia, dysphasia) Skeletal myopathy: ophthalmoplegia, exercise intolerance, myalgia Cardiac: conduction block, cardiomyopathy Respiratory: hypoventilation, aspiration pneumonitis Endocrine: diabetes mellitus, premature ovarian failure, hypothyroidism, hypoparathyroidism Ophthalmologic: cataracts, pigment retinopathy, neurologic and myopathic (optic atrophy, ophthalmoplegia)
THE INVESTIGATION OF SUSPECTED mtDNA DISEASE The clinical presentations of classic syndromes, groupings of disease manifestations in multiple organ systems, or unexplained isolated presentations of one of the disease features of a classic mtDNA syndrome should prompt a systematic clinical investigation as outlined in Fig. e39-7. Despite the centrality of disruptive oxidative phosphorylation, an elevated blood lactate level is neither specific nor sensitive because there are many causes of blood lactic acidosis, and many patients with mtDNA defects presenting in adulthood have normal blood lactate. A raised cerebrospinal fluid lactate is a more specific test for mitochondrial disease if there is central neurologic involvement. The serum creatine kinase may be elevated but is often normal, even in the presence of a proximal myopathy. Urine organic and amino acids may also be abnormal. Every patient with seizures or cognitive decline should have an electroencephalogram. A brain CT scan may show calcified basal ganglia or bilateral hypodense regions with cortical atrophy. MRI is indicated in patients with brain stem signs or stroke-like episodes. For some mitochondrial diseases, it is possible to obtain an accurate diagnosis with a simple molecular genetic screen. For examples, 95% of patients with LHON harbor one of three mtDNA point mutations (A11778G, A3460G, and T14484C). These patients have very high levels of mutated mtDNA in peripheral blood cells, and it is, therefore, appropriate to send a blood sample for molecular genetic analysis by polymerase chain reaction (PCR) or restriction fragment length polymorphism. The same is true for most MERRF patients who harbor a point mutation in the lysine tRNA gene at position 8344. In contrast, patients with the A3243G MELAS mutation often have low levels of mutated mtDNA in blood. If clinical suspicion is strong enough to warrant peripheral blood testing, then patients with a negative result should be investigated further by performing a skeletal muscle biopsy. Muscle biopsy histochemical analysis is the cornerstone for investigation of patients with suspected mitochondrial disease. Histochemical analysis may show subsarcolemmal accumulation of mitochondria with the appearance of ragged red fibers. Electron microscopy might show abnormal mitochondria with paracrystalline inclusions. Muscle histochemistry may show cytochrome-c oxidase (COX)–deficient fi-
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TABLE e39-3 MITOCHONDRIAL DISEASES DUE TO mtDNA POINT MUTATIONS AND LARGE-SCALE REARRANGEMENTS Disease
Leber hereditary optic neuropathy (LHON) NARP, Leigh’s disease MELAS MERRF Deafness Chronic progressive external ophthalmoplegia (PEO) Pearson syndrome Kearn-Sayre syndrome (KSS)
Note: CSF, cerebrospinal fluid.
e317
Inheritance
Maternal Maternal Maternal Maternal Maternal Maternal Mostly sporadic, somatic mutations Sporadic, somatic mutations Sporadic, somatic mutations
Phenotype
Loss of central vision leading to blindness in young adult life Neuropathy, ataxia, retinitis pigmentosa, developmental delay, mental retardation, lactic acidemia Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; may manifest only as diabetes Myoclonic epilepsy, ragged red f ibers in muscle, ataxia, increased CSF protein, sensorineural deafness, dementia Progressive sensorineural deafness, often induced by aminoglycoside antibiotics. Nonsyndromic sensorineural deafness Late-onset bilateral ptosis and ophthalmoplegia, proximal muscle weakness, and exercise intolerance Pancreatic insufficiency, pancytopenia, lactic acidosis External ophthalmoplegia, heart-block, retinal pigmentation, ataxia
Most Frequent mtDNA Mutations
G1778A, T14484C, G3460A Point mutation in ATPase subunit 6 gene Point mutation in tRNAleu Point mutation in tRNAlys A1555G mutation in 12S rRNA A7445G mutation in 12S rRNA Single deletions or duplications Large deletion The 5-kb “common deletion”
Homoplasmy or Heteroplasmy
Homoplasmic (usually) Heteroplasmic Heteroplasmic Heteroplasmic Homoplasmic Homoplasmic Heteroplasmic Heteroplasmic Heteroplasmic
CHAPTER e39 Mitochondrial DNA and Heritable Traits and Diseases
bers, which indicate mitochondrial dysfunction (Fig. e39-6). Respiratory chain complex assays may also show a deficiency. Either of these two abnormalities confirm that a patient has mitochondrial disease, and this should lead to in-depth molecular genetic analysis.
IMPACT OF HOMOPLASMIC SEQUENCE VARIATION ON HERITABLE TRAITS AND DISEASE
The relationship among the degree of heteroplasmy, tissue distribution of the mutant mtDNA, and disease phenotype simplifies inference of a clear causative relationship between heteroplasmic mutation and disease. With the exception of certain mutations (e.g., those causing most cases of LHON), drift to homoplasmy of such mutations would be precluded normally by the severity of impaired oxidative phosphorylation and the consequent reduction in reproductive fitness. Therefore, it has been previously thought that sequence variants that have reached homoplasmy should be neutral in terms of human evolution and useful only for tracing human evolution, demography, and migration; however, recent studies have suggested that some homoplasmic mtDNA sequence variants may affect heritable traits or health through one or more mechanisms. The first such mechanism relates to locally adaptive evolutionary forces. As noted above, homoplasmic mtDNA sequence variants that partition population groups are designated as defining maternal “haplogroups.” Striking discontinuities have been observed in mtDNA haplogroup distribution among climatic zones across the globe. For example, of the extensive mtDNA sequence diversity in Africa, only a limited number of haplogroups and their derivative lineages successfully colonized all of Eurasia and then the Americas. Furthermore, it was shown that ancient missense mutations that define these haplogroups alter amino acids that are as highly conserved in evolution as are those known to result from pathogenic mutations. Retention of mutations altering such highly conserved amino acids, over many tens of thousands of years, suggests that they must be adaptive since they could not have been maintained if they were pathogenic and destructive to reproductive fitness. This phenomenon has been attributed to adaptive differences in the efficiency of oxidative phosphorylation and consequent thermogenesis, according to differences in prevailing climates in different global geographic regions during much of human evolution. A potential health implication of this finding is the possibility that these same mutations might result in deleterious effects on energy metabolism and caloric balance in the current era of human transglobal migration or climate control.
A much broader extrapolation of the foregoing mechanism states that many homoplasmic mtDNA mutations affect human health in the postreproductive age only and therefore escaped evolutionary censoring altogether. In the modern era of increased median life span, such mutations are thought to account for a considerable burden of age-associated common complex disease. Mean life expectancy has risen from ~47 years to ~77 years during the past century alone; thereCLINICAL AND LABORATORY INVESTIGATION OF SUSPECTED MTDNA DISORDER
Clinical investigations Blood: creatine kinase, liver functions, glucose, lactate Urine: organic and amino acids CSF: glucose, protein, lactate Cardiac x-ray, ECG, ECHO EEG, EMG, nerve conduction Brain CT/MRI
Specific point mutation syndrome: e.g., MELAS, MERRF, and LHON
Yes
PCR/RFLP analysis of blood for known mutations No
Histochemistry
Muscle biopsy
Study of respiratorychain complexes activities
Molecular genetic analysis rearrangements PCR/RFLP for common point mutation mtDNA automated sequencing
FIGURE e39-7 Clinical and laboratory investigation of suspected mtDNA disorder. CSF, cerebrospinal fluid; ECG, electrocardiogram; EEG, electroencephalogram; EMG, electromyogram; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and stoke-like episodes; MERFF, myoclonic epilepsy with ragged red fibers; LHON, Leber hereditary optic neuropathy; PCR, polymerase chain reaction; RFLP, restriction fragment length polymorphism.
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e318 fore, late-onset effects of a subset of homoplasmic mtDNA mutations
may contribute significantly to the burden of human illness only in the current era when a relatively higher percentage of the population is surviving beyond reproductive age. Many homoplasmic mtDNA variants have been and will continue to be identified by whole mtDNA sequencing in various global populations. The challenge is to identify the subsets that modify mtDNA function and contribute to late-onset, common complex disease. Indeed, given the finding that global populations are more differentiated at the level of mtDNA than they are at the level of the nuclear genome, it also attractive to postulate that population differences in the predisposition to certain late-onset common complex metabolic diseases may be attributed in part to populationbased mtDNA sequence variation. The diseases that have been of particular interest are those that affect the very organ systems familiar from the known classic mtDNA syndromes described above. METABOLIC SYNDROME AND TYPE 2 DIABETES MELLITUS (T2DM) Insulin release by pancreatic beta cells is modulated in response to ATP metabolism, and insulin action is perturbed by metabolites of mitochondrial fatty acid oxidation. This has led investigators to consider mtDNA itself as a potential genomic locus for susceptibility to T2DM. A rather clear-cut case is that of a mutation in mtDNA nucleotide 3243 encoding the mitochondrial tRNA for the amino acid leucine. Even a low level of heteroplasmy for a particular point mutation in the mtDNA tRNA gene encoding the leucine tRNA is thought to contribute to the pathogenesis of up to 1% of all cases of T2DM. This and other findings at the biochemical and population genetics levels have motivated the search for more definitive evidence of the role of homoplasmic variants in the predisposition to metabolic syndrome and T2DM. Such evidence has been obtained with the finding of significant segregation of a homoplasmic mtDNA tRNA mutation (T→ C transition in the nucleotide immediately 5′ to the isoleucine tRNA anticodon) with metabolic syndrome phenotypes in a large Caucasian kindred. Since the metabolic syndrome is so common, and can result from numerous different genetic susceptibility loci and environmental causes, and since its pathogenesis involves a large number of recently identified genetic susceptibility loci coupled with environmental factors— additional features in this particular reported kindred—researchers were able to tease out affected from unaffected individuals for purposes of the association study. The affected individuals had signs of hypomagnesemia, hypertension, and hypercholesterolemia. This finding highlights the problem of underdiagnosing homoplasmic mtDNA sequence variants as pathogenic causes of common symptoms and syndromes. This particular mutation in a tRNA-encoding mtDNA gene also highlights the expected difference in the phenotypic impact of mutations in genomic regions encoding tRNAs in the mitochondrial versus the nuclear genome. In the case of the mitochondrial genome, mutations affecting mtDNA-encoded tRNAs perturb the translation of only up to 13 protein products and may be compatible with life. In contrast, severe loss of function of nuclear genome–encoded tRNA might be expected to perturb the function of a much greater array of nuclear-encoded proteins. It is also of interest to contrast the anticipated effects of point mutations in one of the 13 protein-coding genes of mtDNA with those of the 24 genes encoding tRNAs and rRNAs. Whereas the former would disrupt the function of a single protein product, the latter group would perturb translation of up to all 13 of the mtDNA-encoded proteins. Under these circumstances, a tolerable loss of function of all 13 proteins might be compatible with life, although it would be expected to cause a pleiotropic multiorgan heritable syndrome, as was indeed observed for the mtDNA isoleucine tRNA mutation causing an extended metabolic syndrome phenotype. At the population level, the finding of an apparent excess of maternal inheritance in T2DM suggests the potential involvement of mtDNA. A common variant mtDNA sequence variant (T16189C) has been related to both low birth weight, impaired glucose tolerance, and metabolic syndrome in specific populations. However, rigorous population-based association studies using case-control designs have not yet provided definitive evidence for a re-
lationship between mtDNA haplogroups and susceptibility to T2DM or its complications. NEURODEGENERATIVE DISEASE The prominence of neurologic injury in classic mtDNA diseases, together with the presumed role of reactive oxygen species in neuronal injury and late age of onset of neurodegenerative diseases, have led investigators to consider the possibility that homoplasmic variants in mtDNA sequence that define population haplogroups might also modify the susceptibility to neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease. Thus, for example, particular configurations of mtDNA sequence polymorphisms that define population haplogroups designated in phylogenetics by the labels J, T, U, and K have been reported to be potentially protective against Parkinson’s disease in different populations. In the case of Alzheimer’s disease, some studies have shown haplogroup J to increase risk, with haplogroup D decreasing risk. Mutations located in the mtDNA control region do not produce defective polypeptide products but affect both the light and heavy strand promoters, as well as the heavy strand origin of replication, and thus may modulate mtDNA replication and transcription. Mitochondrial DNA control region sequence variants (e.g., T414G) have been identified in Alzheimer’s disease brains in association with a significant reduction in mtDNA copy number and reduction in specific transcripts. A number of studies have focused on the interaction of mtDNA haplogroup–designating mutations with the well-established Alzheimer’s disease risk alleles at the nuclear APOE4 locus. From these studies it was postulated that ETC-uncoupling mutations that minimize ROS production are those that confer protection against neuronal injury, but definitive proof of this postulate awaits further studies. OTHER DISEASES AND NONDISEASE HERITABLE TRAITS Consideration of the potential contribution of mtDNA mutations to numerous heritable traits and common complex diseases requires consideration of the common variant–common phenotype model (including disease phenotype) versus the rare variant–common phenotype model, which are also applicable to the nuclear genome. According to the common variant–common phenotype model, DNA sequence variants inherited identically by descent and present in large numbers of individuals within one or more populations, may predispose to common phenotypes. In the rare variant–common phenotype model, different mutations within one or more genetic loci involved in a particular molecular pathway may predispose to a common phenotype or disease. In this regard, the entire mtDNA can be considered as a single genomic locus. Genome-wide association studies have been utilized to try to map common variants responsible for common diseases, using case-control or multiplex family approaches. These approaches have been applied to common variants in mtDNA sequence as well, as noted above for metabolic syndrome and neurodegenerative disease. Additional examples include the variable length of an mtDNA control region polycytosine stretch (16189 variant) as a contributing genomic influence in the onset of age-related cardiomyopathy with T2DM. An association of mtDNA haplogroup T, and a polymorphism at position 13368 with hypertrophic cardiomyopathy has been reported in a European population, and a number of studies have suggested an association between mtDNA mutations and mitochondrial dysfunction in heart failure predisposition. In the case of age-related cancers as well, the association of a number of heritable homoplasmic mtDNA mutations with certain cancers has been reported, including prostate, kidney, and breast cancer. The association of mtDNA haplogroups with at least two nondisease heritable traits has also been studied. These are life expectancy and exercise endurance. Several mtDNA control region mutations, including the C150T mutation that shifts the heavy chain origin of replication, have been reported to accumulate with age in specific tissues, including lymphocytes of centenarians and their twins. The relationship between the C150T mutation and longevity has been replicated in Italian, Finnish, and Japanese populations—suggesting a common ancient origin.
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The alternative of evolutionary convergence of this mutation for longevity seems less likely, as trait does not confer reproductive advantage. The association of haplogroup J and its sub-haplogroups with longevity has been demonstrated in north Italian, north Irish, and Finnish sample sets. At least in the Italian study, this association was shown to be population specific, since it was not reproduced in sample sets of southern Italian communities. Furthermore, in the case of the north Italian communities, an additional interaction of the mtDNA haplogroup designated as J2 with several different mutations adjacent to replication origins, including the aforementioned C150T, has been noted. The functional importance of one or more of the mutations designated as haplogroup J is further strengthened by the finding of the interesting interaction with the mtDNA mutations causing LHON, as noted previously. Reduced disease predilection suggests that one or more of the ancient sequence variants designated as haplogroup J appear to attenuate predisposition to degenerative disease, in the face of other risk factors. It has been proposed that the mtDNA haplogroups associated with exceptional longevity favor a relatively uncoupled state of the ETC, with reduced efficiency of production of ATP and ROS and increased thermogenesis. While this has not been demonstrated biochemically, the notion is strengthened by the finding of a relative paucity of these mtDNA haplogroups among successful endurance athletes, for whom maximum efficiency of oxidative phosphorylation confers an athletic competitive advantage. It should be noted that not all studies have replicated associations of mtDNA haplogroups with longevity, athletic performance, or other heritable phenotypes. Most of these studies are limited by small sample sizes and the possibility of population stratification or ethnic ancestry bias. Since mtDNA haplogroups are so prominently partitioned along phylogeographic lines, it is difficult to rule out the possibility that a haplogroup for which an association has been found is simply a marker for differences in populations with a societal or environmental difference or with different allele frequencies at other genomic loci, which are actually causally related to the heritable trait or disease of interest. The difficulty in generating cellular or animal models to test the functional influence of homoplasmic sequence variants (as a result of mtDNA polyploidy) further compounds the challenge. The most likely formulation is that different mtDNA haplogroup–defining homoplasmic mutations serve to provide different “risk backgrounds” for common age-related diseases whose major molecular pathogenesis emanates from a combination of mutations in the nuclear genome, together with environmental influences. Progress in minimizing potentially misleading associations in mtDNA heritable trait and disease studies should include ensuring adequate sample size taken from a large sample recruitment base, together with the use of carefully matched controls, and analysis that takes into account the interaction with other genomic loci and environmental factors.
accumulation of mtDNA deletions has been observed, including dele- e319 tions involved in known heritable mtDNA disorders, as well as others. The accumulation of functional mtDNA deletions in a given tissue is expected to be associated with mitochondrial dysfunction, as reflected in an age-associated patchy and reduced cytochrome-c oxidase activity upon histochemical staining, especially in skeletal and cardiac muscle and brain. A particularly well studied and potentially important example is the accumulation of mtDNA deletions and cytochrome-c oxidase deficiency observed in neurons of the substantia nigra in Parkinson’s disease patients. The progressive accumulation of ROS has been proposed as the key factor connecting mtDNA mutations with aging and age-related disease pathogenesis (Fig. e39-8). As noted above, ROS are a byproduct of oxidative phosphorylation and are removed by detoxifying antioxidants into less harmful moieties; however, exaggerated production of ROS or impaired removal results in their accumulation. One of the main targets for ROS-mediated injury is DNA, and mtDNA is particularly vulnerable because of its lack of protective histones and less efficient injury repair systems compared with nuclear DNA. In turn, accumulation of mtDNA mutations results in inefficient oxidative phosphorylation, with the potential for excessive production of ROS, generating a “vicious cycle” of cumulative mtDNA damage. Indeed, measurement of the oxidative stress biomarker 8-hydroxy-2-deoxyguanosine has been used to measure age-dependent increases in mtDNA oxidative damage at a rate exceeding that of nuclear DNA. It should be noted that mtDNA mutation can potentially occur in postmitotic cells as well, since mtDNA replication is not synchronized with the cell cycle. Two other proposed links between mtDNA mutation and aging, besides ROS-mediated tissue injury, are the perturbations in efficiency of oxidative phosphorylation with disturbed cellular aerobic function and perturbations in apoptotic pathways, whose execution steps involve mitochondrial activity. Genetic intervention studies in animal models have sought to clarify the potential causative relationship between acquired somatic mtDNA mutation and the aging phenotype, and the role of ROS in particular.
Damaged mitochondrial proteins
CHAPTER e39 Mitochondrial DNA and Heritable Traits and Diseases
Mutant mitochondrial proteins
Error-prone DNA Pol-γ
Decreased DNA repair
O2
− O2
X
DNA mutations
X
H2O
H2O2 OH
IMPACT OF ACQUIRED SOMATIC mtDNA MUTATION ON HUMAN HEALTH AND DISEASE
Studies on aging humans and animals have shown a potentially important correlation of age with the accumulation of heterogeneous mtDNA mutations, especially in those organ systems that undergo the most prominent age-related degenerative tissue phenotype. Sequencing of PCR-amplified single mtDNA molecules has demonstrated an average of two to three point mutations per molecule in elderly subjects when compared with younger ones. Point mutations observed include those responsible for known heritable heteroplasmic mtDNA disorders, such as the A3344G and A3243G mutations responsible for the MERRF and MELAS syndromes, respectively. However, the cumulative burden of these acquired somatic point mutations with age was observed to remain well below the threshold expected for phenotypic expression (350 lymphocytes/mm3. J Infect Dis 192:950, 2005 HUNT PW, DEEKS SG: Immune-based therapy for HIV infection: Are acute and chronic HIV infection different diseases? J Infect Dis. 194:1632, 2006 IDE M et al: Long-term remission in HIV-negative patients with multicentric Castleman’s disease using rituximab. Eur J Haematol 76:119, 2006
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34 OBERLIN E et al: The CXC chemokine receptor SDF-1 is the ligand for
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184 Enteroviruses and Reoviruses
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36 CENTERS FOR DISEASE CONTROL AND PREVENTION: Prolonged poliovirus excretion in an immunodeficient person with vaccine-associated paralytic poliomyelitis. MMWR 46:641, 1997 CHEN RT et al: Seroprevalence of antibody against poliovirus in innercity preschool children: Implications for vaccination policy in the United States. JAMA 275:1639, 1996 HENDERSON DA: Countering the posteradication threat of smallpox and polio. Clin Infect Dis 34:79, 2002 HO M et al: An epidemic of enterovirus 71 infection in Taiwan. N Engl J Med 341:929, 1999 HUANG C-C et al: Neurologic complications in children with enterovirus 71 infection. N Engl J Med 341:936, 1999 IKEDA RM et al: Pleurodynia among football players at a high school. JAMA 270:2205, 1993 KEW O et al: Outbreak of poliomyelitis in Hispaniola associated with circulating type 1 vaccine-derived poliovirus. Science 296:356, 2002 LIN T-Y et al: The 1998 enterovirus 71 outbreak in Taiwan: Pathogenesis and management. Clin Infect Dis 34(Suppl 2):S52, 2002 MCKINNEY R et al: Chronic enteroviral meningoencephalitis in agammaglobulinemic patients. Rev Infect Dis 9:334, 1987 RAMERS C et al: Impact of a diagnostic cerebrospinal fluid enterovirus polymerase chain reaction test on patient management. JAMA 283:2680, 2000 ROTBART HA (ed): Human Enterovirus Infections. Washington, DC, ASM Press, 1995 ROTBART HA et al: Treatment of potentially life-threatening enterovirus infections with pleconaril. Clin Infect Dis 32:28, 2001 STRICKLER HD et al: Contamination of poliovirus vaccines with simian virus 40 (1955–1963) and subsequent cancer rates. JAMA 279:292, 1998 SUTTER RW et al: Trial of a supplemental dose of four poliovirus vaccines. N Engl J Med 343:767, 2000 TECHNICAL CONSULTATIVE GROUP TO THE WORLD HEALTH ORGANIZATION ON THE GLOBAL ERADICATION OF POLIOMYELITIS: Endgame issues for the global polio eradication initiative. Clin Infect Dis 34:72, 2002
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187 Mumps
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185 Measles (Rubeola)
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189 Infections Caused by Arthropodand Rodent-Borne Viruses
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186 Rubella (German Measles)
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50 TALIANI G et al: Pegylated interferon alfa-2b plus ribavirin in the retreatment of interferon-ribavirin nonresponder patients. Gastroenterology 130:1098, 2006 THIMME R et al: Hepatitis B or hepatitis C and human immunodeficiency virus infection. J Hepatol 42:S37, 2005 VON WAGNER M et al: Peginterferon-α-2a (40KD) and ribavirin for 16 or 24 weeks in patients with genotype 2 or 3 chronic hepatitis C. Gastroenterology 129:522, 2005 WONG W, TERRAULT N: Update on chronic hepatitis C. Clin Gastroenterol Hepatol 3:507, 2005 YOSHIDA H et al: Interferon therapy prolonged life expectancy among chronic hepatitis C patients. Gastroenterology 123:483, 2002
305 Diseases of the Gallbladder and Bile Ducts
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304 Liver Transplantation
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307 Acute and Chronic Pancreatitis
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311 Allergies, Anaphylaxis, and Systemic Mastocytosis
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312 Autoimmunity and Autoimmune Diseases
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314 Rheumatoid Arthritis
ASKLING J, FORED CM, BRANDT L, BAECKLUND E, BERTILSSON L, FELTELIUS N, COSTER L, GEBOREK P, JACOBSSON LT, LINDBLAD S, LYSHOLM J, RANTAPAA-DAHLQVIST S, SAXNE T, KLARESKOG L: Risks of solid cancers in patients with rheumatoid arthritis and after treatment with tumour necrosis factor antagonists. Ann Rheum Dis 64(10):1421, 2005 Epub 2005 Apr 13. AUGER I, SEBBAG M, VINCENT C, BALANDRAUD N, GUIS S, NOGUEIRA L, SVENSSON B, CANTAGREL A, SERRE G, ROUDIER J: Influence of HLA-DR genes on the production of rheumatoid arthritis-specific autoantibodies to citrullinated fibrinogen. Arthritis Rheum 2005 52(11):3424, 2005 BAECKLUND E, SUNDSTROM C, EKBOM A, CATRINA AI, BIBERFELD P, FELTELIUS N, KLARESKOG L: Lymphoma subtypes in patients with rheumatoid arthritis: Increased proportion of diffuse large B cell lymphoma. Arthritis Rheum 48(6):1543, 2003 BAECKLUND E, ILIADOU A, ASKLING J, EKBOM A, BACKLIN C, GRANATH F, CATRINA AI, ROSENQUIST R, FELTELIUS N, SUNDSTROM C, KLARESKOG L: Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis. Arthritis Rheum 54(3):692, 2006 BEGOVICH AB, CARLTON VE, HONIGBERG LA, SCHRODI SJ, CHOKKALINGAM AP, ALEXANDER HC, ARDLIE KG, HUANG Q, SMITH AM, SPOERKE JM, CONN MT, CHANG M, CHANG SY, SAIKI RK, CATANESE JJ, LEONG DU, GARCIA VE, MCALLISTER LB, JEFFERY DA, LEE AT, BATLIWALLA F, REMMERS E, CRISWELL LA, SELDIN MF, KASTNER DL, AMOS CI, SNINSKY JJ, GREGERSEN PK: A missense singlenucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet 75(2):330, 2004 Epub 2004 Jun 18. BERGLIN E, PADYUKOV L, SUNDIN U, HALLMANS G, STENLUND H, VAN VENROOIJ WJ, KLARESKOG L, DAHLQVIST SR: A combination of autoantibodies to cyclic citrullinated peptide (CCP) and HLA-DRB1 locus antigens is strongly associated with future onset of rheumatoid arthritis. Arthritis Res Ther 6(4):R303, 2004 Epub 2004 May 11. BORCHERS AT, KEEN CL, CHEEMA GS, GERSHWIN ME: The use of methotrexate in rheumatoid arthritis. Semin Arthritis Rheum 34(1):465, 2004 BROWN SL, GREENE MH, GERSHON SK, EDWARDS ET, BRAUN MM: Tumor necrosis factor antagonist therapy and lymphoma development: Twenty-six cases reported to the Food and Drug Administration. Arthritis Rheum 46(12):3151, 2002 BUCH MH, BINGHAM SJ, SETO Y, MCGONAGLE D, BEJARANO V, WHITE J, EMERY P: Lack of response to anakinra in rheumatoid arthritis following failure of tumor necrosis factor alpha blockade. Arthritis Rheum 50(3):725, 2004 BUKHARI M, LUNT M, HARRISON BJ, SCOTT DG, SYMMONS DP, SILMAN AJ: Rheumatoid factor is the major predictor of increasing severity of radiographic erosions in rheumatoid arthritis: results from the Norfolk Arthritis Register Study, a large inception cohort. Arthritis Rheum 46(4):906, 2002 CARREIRA PE, GONZALEZ-CRESPO MR, CIRUELO E, PABLOS JL, SANTIAGO B, GOMEZ-CAMARA A, GOMEZ-REINO JJ: Polymorphism of the interleukin-1 receptor antagonist gene: A factor in susceptibility to rheumatoid arthritis in a Spanish population. Arthritis Rheum 52(10):3015, 2005 CHOY EH, ISENBERG DA, GARROOD T, FARROW S, IOANNOU Y, BIRD H, CHEUNG N, WILLIAMS B, HAZLEMAN B, PRICE R, YOSHIZAKI K, NISHIMOTO N, KISHIMOTO T, PANAYI GS: Therapeutic benefit of blocking interleukin-6 activity with an anti-interleukin-6 receptor monoclonal antibody in rheumatoid arthritis: A randomized, double-blind, placebo-controlled, dose-escalation trial. Arthritis Rheum 46(12):3143, 2002 COHEN G, COURVOISIER N, COHEN JD, ZALTNI S, SANY J, COMBE B: The efficiency of switching from infliximab to etanercept and viceversa in patients with rheumatoid arthritis. Clin Exp Rheumatol 23(6):795, 2005
COMBE B, DOUGADOS M, GOUPILLE P, CANTAGREL A, ELIAOU JF, SIBILIA J, MEYER O, SANY J, DAURES JP, DUBOIS A: Prognostic factors for radiographic damage in early rheumatoid arthritis: A multiparameter prospective study. Arthritis Rheum 44(8):1736, 2001 CONAGHAN PG, O’CONNOR P, MCGONAGLE D, ASTIN P, WAKEFIELD RJ, GIBBON WW, QUINN M, KARIM Z, GREEN MJ, PROUDMAN S, ISAACS J, EMERY P: Elucidation of the relationship between synovitis and bone damage: A randomized magnetic resonance imaging study of individual joints in patients with early rheumatoid arthritis. Arthritis Rheum 48(1):64, 2003 CRISWELL LA, GREGERSEN PK: Current understanding of the genetic aetiology of rheumatoid arthritis and likely future developments. Rheumatology 44(Suppl. 4):iv13, 2005 DEL RINCON I, WILLIAMS K, STERN MP, FREEMAN GL, O’LEARY DH, ESCALANTE A: Association between carotid atherosclerosis and markers of inflammation in rheumatoid arthritis patients and healthy subjects. Arthritis Rheum 48(7):1833, 2003 DE RYCKE L, PEENE I, HOFFMAN IE, KRUITHOF E, UNION A, MEHEUS L, LEBEER K, WYNS B, VINCENT C, MIELANTS H, BOULLART L, SERRE G, VEYS EM, DE KEYSER F: Rheumatoid factor and anticitrullinated protein antibodies in rheumatoid arthritis: Diagnostic value, associations with radiological progression rate, and extra-articular manifestations. Ann Rheum Dis 63(12):1587, 2004 DIEUDE P, GARNIER S, MICHOU L, PETIT-TEIXEIRA E, GLIKMANS E, PIERLOT C, LASBLEIZ S, BARDIN T, PRUM B, CORNELIS F; EUROPEAN CONSORTIUM ON RHEUMATOID ARTHRITIS FAMILIES: Rheumatoid arthritis seropositive for the rheumatoid factor is linked to the protein tyrosine phosphatase nonreceptor 22-620W allele. Arthritis Res Ther 7(6):R1200, 2005 Epub 2005 Aug 25. DORAN MF, POND GR, CROWSON CS, O’FALLON WM, GABRIEL SE: Trends in incidence and mortality in rheumatoid arthritis in Rochester, Minnesota, over a forty-year period. Arthritis Rheum 46(3):625, 2002 DROSSAERS-BAKKER KW, ZWINDERMAN AH, VLIELAND TP, VAN ZEBEN D, VOS K, BREEDVELD FC, HAZES JM: Long-term outcome in rheumatoid arthritis: A simple algorithm of baseline parameters can predict radiographic damage, disability, and disease course at 12-year followup. Arthritis Rheum 47(4):383, 2002 DU MONTCEL ST, MICHOU L, PETIT-TEIXEIRA E, OSORIO J, LEMAIRE I, LASBLEIZ S, PIERLOT C, QUILLET P, BARDIN T, PRUM B, CORNELIS F, CLERGET-DARPOUX F: New classification of HLA-DRB1 alleles supports the shared epitope hypothesis of rheumatoid arthritis susceptibility. Arthritis Rheum 52(11):3659, 2005. Erratum in: Arthritis Rheum 52(11):3659, 2005. EDWARDS JC et al: Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 350(25):2572, 2004 ENZER I, DUNN G, JACOBSSON L, BENNETT PH, KNOWLER WC, SILMAN A: An epidemiologic study of trends in prevalence of rheumatoid factor seropositivity in Pima Indians: Evidence of a decline due to both secular and birth-cohort influences. Arthritis Rheum 46(7):1729, 2002 FLEISCHMANN R, BAUMGARTNER SW, WEISMAN MH, LIU T, WHITE B, PELOSO P: Long term safety of etanercept in elderly subjects with rheumatic diseases. Ann Rheum Dis65(3):379, 2006 Epub 2005 Sep 8. GABRIEL SE, CROWSON CS, KREMERS HM, DORAN MF, TURESSON C, O’FALLON WM, MATTESON EL: Survival in rheumatoid arthritis: A population-based analysis of trends over 40 years. Arthritis Rheum 48(1):54, 2003 GEBOREK P, BLADSTROM A, TURESSON C, GULFE A, PETERSSON IF, SAXNE T, OLSSON H, JACOBSSON LT: Tumour necrosis factor blockers do not increase overall tumour risk in patients with rheumatoid arthritis, but may be associated with an increased risk of lymphomas. Ann Rheum Dis 64(5):699, 2005 Epub 2005 Feb 4. GENOVESE MC, BATHON JM, MARTIN RW, FLEISCHMANN RM, TESSER JR, SCHIFF MH, KEYSTONE EC, WASKO MC, MORELAND LW, WEAVER AL, MARKENSON J, CANNON GW, SPENCER-GREEN G, FINCK BK: Etanercept versus methotrexate in patients with early rheumatoid arthritis: Two-year radiographic and clinical outcomes. Arthritis Rheum 46(6):1443, 2002
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54 LARD LR, VAN GAALEN FA, SCHONKEREN JJ, PIETERMAN EJ, STOEKEN
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319 The Vasculitis Syndromes
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58 SIEPER J et al: No benefit of long-term ciprofloxacin treatment in patients with reactive arthritis and undifferentiated oligoarthritis: A three-month, multicenter, double-blind, randomized, placebocontrolled study. Arthritis Rheum 42:1386, 1999 SILVEIRA LH et al: Candida arthritis. Rheum Dis Clin North Am 19:427, 1993 SPANGEHL MJ et al: Prospective analysis of preoperative and intraoperative investigations for the diagnosis of infection at the sites of two hundred and two revision total hip arthroplasties. J Bone Joint Surg Am 81:672, 1999 TATTEVIN P et al: Prosthetic joint infection: When can prosthesis salvage be considered? Clin Infect Dis 29:292, 1999 THOMAS MG et al: Adhesion of Staphylococcus aureus to collagen is not a major virulence determinant for septic arthritis, osteomyelitis, or endocarditis. J Infect Dis 179:291, 1999 TOBIN EH: Prosthetic joint infections: Controversies and clues. Lancet 353:770, 1999 TSUKAYAMA DT et al: Infection after total hip arthroplasty. A study of the treatment of one hundred and six infections. J Bone Joint Surg Am 78:512, 1996 TUNNEY MM et al: Improved detection of infection in hip replacements. A currently underestimated problem. J Bone Joint Surg Br 80:568, 1998 VAN DER HEIJDEN IM et al: Detection of bacterial DNA in serial synovial samples obtained during antibiotic treatment from patients with septic arthritis. Arthritis Rheum 42:2198, 1999 VAN ELSACKER-NIELE AM, KROES AC: Human parvovirus B19: Relevance in internal medicine. Neth J Med 54:221, 1999 VASSILOPOULOS D et al: Musculoskeletal infections in patients with human immunodeficiency virus infection. Medicine 76:284, 1997 VON ESSEN R: Culture of joint specimens in bacterial arthritis. Impact of blood culture bottle utilization. Scand J Rheumatol 26:293, 1997 WAHL MJ: Myths of dental-induced prosthetic joint infections. Clin Infect Dis 20:1420, 1995 WALDMAN BJ et al: Total knee arthroplasty infections associated with dental procedures. Clin Orthop 343:164, 1997 WISE CM et al: Gonococcal arthritis in an era of increasing penicillin resistance. Presentations and outcomes in 41 recent cases (1985– 1991). Arch Intern Med 154:2690, 1994 WUORELA M, GRANFORS K: Infectious agents as triggers of reactive arthritis. Am J Med Sci 316:264, 1998 WYSENBEEK AJ et al: Treatment of staphylococcal septic arthritis in rabbits by systemic antibiotics and intra-articular corticosteroids. Ann Rheum Dis 57:687, 1998 YTTERBERG SR: Viral arthritis. Curr Opin Rheumatol 11:275, 1999 ZABRISKIE JB et al: The arthritogenic properties of microbial antigens. Their implications in disease states. Rheum Dis Clin North Am 24:211, 1998 ZAVASKY DM, SANDE MA: Reconsideration of rifampin: A unique drug for a unique infection. JAMA 279:1575, 1998 ZIMMERLI W et al: Role of rifampin for treatment of orthopedic implant– related staphylococcal infections: A randomized controlled trial. Foreign-Body Infection (FBI) Study Group. JAMA 279:1537, 1998
330 Arthritis Associated with Systemic Disease and Other Arthritides
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