Literature Review ID Homepage: Community-Acquired Bacterial Meningitis in Adults Community-Acquired Bacterial Meningitis in Adults [van de Beek D, de Gans J, Tunkel AR, et al. N Engl J Med 2006;354:44 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstr act&list_uids=16394301&query_hl=27&itool=pubmed_docsum]: The authors provide a “Review Article” on current concepts of the management of pyogenic meningitis in adults. Presentation: Only 44% of patients present with the classic triad of fever, stiff neck and altered mental status; nearly all have at least two of the four classic symptoms: headache, fever, stiff neck and altered mental status defined as a score of less than 14 on the Glasgow Coma Scale. Diagnostic Evaluation: “Lumbar puncture is mandatory …” although the procedure can be hazardous. Indications for cranial imaging (CT or MRI) should be done before LP with the following conditions: new-onset seizures, immunocompromised patient, signs of a space-occupying lesion or moderate-severe impairment of consciousness [Hasbun R, Abrahams J, Jekel J, et al. N Eng J Med 2001;345:1727 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstr act&list_uids=11742046&query_hl=29&itool=pubmed_docsum]. These indications apply to about 45% of patients [van de Beek D, de Gans J, Spanjaard L, et al. N Engl J Med 2004;351:1849 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstr act&list_uids=15509818&query_hl=27&itool=pubmed_docsum]. In addition to herniation, the LP may be harmful with a coagulopathy that may lead to a spinal subdural or epidural hematoma. Delays in treating pyogenic meningitis of over 4-6 hours are associated with increase in complications or death [Proulx N, Frechette D, Toye B, et al. QJM 2005;98:1091 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstr act&list_uids=15760921&query_hl=32&itool=pubmed_docsum]. Thus, if imaging is performed prior to LP, antibiotic therapy should be initiated first. The expected findings on CSF analysis are summarized in the following table: CSF Findings Analysis Expected Result WBC 100-10,000/mm3 PMNs 80-95% Glucose <40% serum levels Protein > 50 mg/dL Gram stain positive 60-90% specificity 97% PCR for bacteria “Promising” Bacteriology: The following table summarizes the anticipated pathogens and suggested antibiotic treatment: Treatment of Pyogenic Meningitis Risk Factor Common Pathogen Antibiotic Treatment Age 16-50 years N. meningitis Vancomycin + ceftriaxone S. pneumoniae or cefotaxime > 50 years Above plus L. monocytogenes Vancomycin + (ceftriaxone Gram + neg bacilli or cefotaxime) + ampicillin Alcoholism or immune S. pneumoniae As above suppression L. monocytogenes H. influenza Adjunctive Dexamethasone: The indications are a CSF that is cloudy, has a WBC over 1,000/mm3 or has bacteria on Gram stain. Support for this is from studies showing a reduction in mortality from 15% to 7% [de Gans J, van de Beek D N Engl J Med 2002;347:1549 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstr act&list_uids=12432041&query_hl=34&itool=pubmed_docsum]. The authors also recommend the administration of adjunctive dexamethasone in patients with suspected meningitis. The dose is 10 mg, it should be initiated before or with the first dose of antibiotics and it should be continued for four days at a dose of 10 mg every six hours. This treatment should be stopped if the diagnosis of pyogenic meningitis is not established. The authors recommend continuation of dexamethasone for four days regardless of the microbial pathogen or clinical severity, although efficacy is best established for pneumococcal meningitis [Tunkel AR, Hartman BJ, Kaplan SL,et al. Clin Infect Dis 2004;39:1267 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstr act&list_uids=15494903&query_hl=36&itool=pubmed_docsum]. Clinical efficacy has been analyzed and meta-analysis by clinical trials which showed a mortality relative risk of 0.9 and a risk of neurologic sequelae of 0.5 [van de Beek D, de Gans J, McIntyre P,et al. Lancet Infect Dis 2004;4:139 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstr act&list_uids=14998499&query_hl=27&itool=pubmed_docsum ]. Intensive Care Management: The following table summarizes recommendations for management in the intensive care unit: ICU Management High risk of brain herniation: Monitor intracranial pressure and: Osmotic diuretics (mannitol 25%) or hypertonic saline (3%) to keep intracranial pressure <15 mm3 + perfusion > 60 mm Hg Initiate repeated LP’s, lumbar drain or ventriculoscopy EEG monitoring with history of seizures Airway: Intubate or non-invasive ventilatory support Circulatory support Septic shock: Low dose steroids if corticotrophin test is positive Inotropic agents (dopamine or milrinone) to keep BP > 70-100 Crystalloids or 5% albumin to maintain fluid balance Consider Swan-Ganz catheter GI care: N-G tube + prophylaxis with PPI Other: SC heparin, maintain normoglycemic, antipyretic agents for temperature > 40° C Repeat LP: If no improvement within 48 hours Outcome: Patients who have a decline in consciousness or fail to improve within 48 hours of appropriate antibiotic therapy should have imaging and a repeat LP. The most common cause of a decline in consciousness is development of meningoencephalitis leading to cerebral edema and increased intracranial pressure. For patients whose course is complicated by focal cerebral abnormalities, the most common causes are stroke, seizures or a combination of both. The frequency of these and other complications are summarized in the following table: Complications Complications Frequency Systemic Cardiorespiratory failure 29% Hyponatremia (inappropriate ADH) 26% DIC 8% Decreased consciousness increases Meningoencephalitis 15-20% Seizures 10-15% Neurologic sequelae Cerebrovascular complications 15-20% Arterial infarction/vasculitis 10-15% Hearing loss 14-20% With regard to microbial pathogen, the following table summarizes mortality rates and frequency of neurologic sequelae for pneumococcal and meningococcal meningitis: Outcome Fatality Neuro sequelae Microbial pathogen S. pneumoniae 19-37% 30%* N. meningitis 3-13% 3-7% * Primarily cognitive impairment [van de Beek D, Schmand B, de Gans J, et al. J Infect Dis 2002;186:1047 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstr act&list_uids=12232850&query_hl=27&itool=pubmed_docsum] Homepage: Worldwide distribution of HPV types of cytologically normal women in the IARC HPV prevalence surveys. Worldwide distribution of human papillomavirus types of cytologically normal women in the International Agency for Research on Cancer HPV prevalence surveys: a pooled analysis [Clifford GM, Gallus S, Herrero R, et al. Lancet 2005;366:991 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstr act&list_uids=16168781&query_hl=40&itool=pubmed_docsum ]: The report is from the International Agency for Research on Cancer (IARC) HPV prevalence surveys with a goal to compare HPV-type distribution in representative samples of women from 13 areas and 11 countries including sub-Saharan Africa, Asia, South America and Europe. The results are based on observations in 15,613 women age 15-74 who did not have cytologic abnormalities. The most common HPV type was 16 followed in rank order by 42, 58, 31, 18, 56, 81, 35, 33 and 45. There were a total of 1,429 positive specimens including 1250 with high risk types and 675 with low risk types. There were substantial regional differences between HPV prevalence and prevalence of specific types, such as HPV 16. These data are shown on the following table: Country/Area Age standardized prevalence Any HPV HPV 16 in HPV positive cases Nigeria 25.6% 12.3% Asia 8.7% 18.4% S. America 14.3% 21.4% Europe 5.2% 25.5% All areas 10.5% 19.7% The authors conclude that the distribution of HPV types in different populations need to be taken into account when developing tests for screening for HPV and for predicting the effect of vaccines on the incidence of infection. Comment: These data are obviously important in the context of the newly licensed HPV vaccine. Homepage: Routine Hospital Use of a Whole Blood Interferon-γ Assay for the Diagnosis of TB Infection Routine Hospital Use of a New Commercial Whole Blood Interferon-γ Assay for the Diagnosis of Tuberculosis Infection [Ferrara G, Losi M, Meacci M, et al. Am J Respir Crit Care Med 2005;172:631 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstr act&list_uids=15961696&query_hl=42&itool=pubmed_DocSum]: The report is from Italy with the analysis of results using the Quanti-FERON-TB-Gold (QFT-Gold) a IFN- gamma assay for detection of M. tuberculosis which appears to show higher specificity than the tuberculin skin test (TST). The test was performed according to physician request. Results were correlated with clinical observations and results of TST. Of the 318 patients, 65 (20%) were receiving immunosuppressive treatment. Of the 318, 68 (21%) had an indeterminate QFT-Gold result. This group had a significantly higher rate of indeterminate results with an odds ratio of 3.35. The authors conclude that immunosuppressive therapy and possibly other immunosuppressive conditions limit the performance of this test, particularly in the most vulnerable population. Comment: IFN gamma assays for detection of M. tuberculosis including the QFT-Gold assay which has been approved by the FDA. The definition of an indeterminate test is the lack of a response to the positive mitogen control. As noted in the accompanying editorial by Pai and Lewinsohn [Am J Respir Crit Care Med 2004;172:519 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstr act&list_uids=16120714&query_hl=45&itool=pubmed_DocSum] this low mitogen response may reflect anergy or inability to mount a T-cell response. This is viewed as potentially useful information in the sense that it indicates the possibility of anergy and a false-negative result, thus avoiding the confusion between anergy and a true negative test. Homepage: Reinfection and Mixed Infection Cause Changing TB Drug-Resistance Patterns Reinfection and Mixed Infection Cause Changing Mycobacterium tuberculosis Drug- Resistance Patterns [van Rie A, Victor TC, Richardson M, et al. Am J Respir Crit Care Med 2005;172:636 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstr act&list_uids=15947286&query_hl=47&itool=pubmed_docsum ]: The study was done in Cape Town, South Africa where the incidence of new culture-positive tuberculosis is 313/100,000 per year. The study included serial mycobacterial cultures of sputum from patients with MDR TB and genotypic analysis was done by IS6110 DNA fingerprinting on serial sputum cultures. Using a strain-specific PCR, it was noted that up to 20% of patients simultaneously secreted two different mycobacterial strains in their sputum [Warren RM, Victor TC, Streicher EM, et al. Am J Respir Crit Care Med 2004;169:610 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstr act&list_uids=14701710&query_hl=49&itool=pubmed_DocSum]. This was previously reported by the authors and represented a surprise in the sense that tuberculosis has always been considered a disease caused by a single strain. Further, the incidence of reinfection disease after successful treatment was about 2%/year [Verver S, Warren RM, Beyers N, et al. Am J Respir Crit Care Med 2005;171:1430 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstr act&list_uids=15831840&query_hl=51&itool=pubmed_docsum]. This observation suggested that these cases which had been attributed to re-infection, could represent relapse by a concurrently present strain. In the present report, DNA fingerprinting of serial sputum cultures from 48 patients with MDR TB showed 10 were due to reinfection and one was a mixed infection, but analysis of strain-specific PCR in nine of the eleven showed mixed infection in five and re-infection in three. Analysis of the clinical data suggested that the first line therapy possibly selected for a resistant subpopulation; by contrast, poor adherence resulted in relapse with drug-susceptible MTB. Conclusion: The authors conclude that some cases of recurrent TB now called reinfection may actually represent relapse. Treatment combined with adherence dictate which strain from a mixed population will dominate. Homepage: Advancement of global health: key messages from the Disease Control Priorities Project Advancement of global health: key messages from the Disease Control Priorities Project [Laxminarayan R, Mills AJ, Breman JG, et al. Lancet 2006;367:1193 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstr act&list_uids=16616562&query_hl=53&itool=pubmed_docsum ]: The Disease Control Priorities Project is a joint effort of the Fogarty International Center, NIH, WHO, World Bank and Gates Foundation which was launched in 2001 to identify policy changes and interventions to deal with health problems in developing countries. The following is a selected summary of their conclusions for interventions in a multitude of different health problems expressed as cost effective according to disability-adjusted life years averted. Disease/Intervention DALY* Tuberculosis DOTS $5-35 BCG vaccinations-peds $40-170 INH prophylaxis without HIV infection $4,000-$25,000 MDRTB management $70-450 HIV/AIDS Prevention-counseling high risk groups $1-74 Voluntary testing & counseling $14-261 Condom promotion & distribution $19-205 Blood & needle safety $4-51 Treatment of STDs $16-105 Treatment of HIV $350-500 Vaccine preventable diseases DPT, polio & measles $13-24 Rotavirus immunization $1402-8357 Cholera immunization $1658-8274 Diarrheal disease Oral rehydration $132 Breast-feeding promotion $527-2001 Water sanitation $1118-14901 Malaria Insecticide treated bednets $5-17 Insecticide spraying $13-24 *DALY= Disability-adjusted life-years The authors conclude with a tabulation of what they consider to be four important challenges that face the world in the 21st century. 1. High levels of non-communicable conditions in developing countries (such as heart disease, cancer, traffic accidents and smoking); 2. The HIV pandemic; 3. The possibility of an influenza pandemic similar to that of 1918; and 4. The persistence of population subgroups with high levels of preventable disease (such as malaria, tuberculosis, diarrhea and pneumonia). They urge wider use of interventions that have already proven cost-effective and more attention to some of the non-communicable diseases noted above. They also urge more research to identify those prevention and treatment programs that are likely to be most effective. Homepage: Prophylactic human papillomavirus vaccines Prophylactic human papillomavirus vaccines Lowy DR, Schiller JT J Clin Invest 2006;116:1167 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstr act&list_uids=16670757&query_hl=59&itool=pubmed_docsum ]: This is a report from the National Cancer Institute of the NIH dealing with the exciting development of vaccines for human papillomavirus (HPV). These vaccines are being developed by Merck and Glaxo. Both target HPV16 and HPV18 which account for about 70% of cases of cervical cancer; the Merck vaccine also targets HPV6 and HPV11 which account for about 90% of external genital warts. The following summarizes background information relevant to this issue: Cervical cancer: 10% of cancers in women Developing countries account for 80% of cases due to lack of cancer screening programs – e.g. Pap smear Oncogenic HPV types: total is 15, HPV16 accounts for 50%; HPV18 accounts for 20% Prevalence of HPV infection: 20-40% of sexually active 20 year old; lifetime risk 75% Most important risk for high grade dysplasia: infection with HPV16 or HPV18 that persists > 6 months The interval between infection and malignant progression take > 10 years The following table summarizes four clinical trials with these new vaccines: Koutsky Harper Villa Mao Source** 1 2 3 4 HPV type 16 16, 18 6, 11, 16, 18 16 Sponsor MSD GSK MSD MSD Trial site US US, Canada, Brazil US, Europe, Brazil US Age (years) 16-23 15-25 16-23 16-23 Number 1533 721 468 1,505 Schedule (mo) 0,2,6 0,1,6 0,2,6 0,2,6 Follow-up (year) 1.5 1.5 2.5 3.5 Persistent infection* 42/0 7/0 36/4 111/7 CINI* 9/0 6/0 3/0 24/0 *Values for controls/vaccine recipients ** 1) Koutsky LA, et al N Engl J Med 2002;347:1645 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstr act&list_uids=12444178&query_hl=61&itool=pubmed_DocSum ; 2) Harper DM, et al. Lancet 2004;364:1757 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstr act&list_uids=15541448&query_hl=63&itool=pubmed_docsum ; 3) Villa LL, et al. Lancet Oncol 2005;6:271 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstr act&list_uids=15863374&query_hl=65&itool=pubmed_docsum ; 4) Mao C, et al. Obstet Gynec 2006;107:18 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstr act&list_uids=16394035&query_hl=67&itool=pubmed_DocSum In terms of impact, the short term outcome in industrialized countries such as the US would be an anticipated reduction in the number of CIN2 cases by about 1/3 to 1/2 for vaccinated women compared to those without the vaccine. This would reduce medical and psychological morbidity in the short run and reduce the incidence of cervical cancer in the long run. For the developing countries which account for 80% of cervical cancers, the potential is to save several hundred thousand cancers annually, but there would be a substantial lag before this benefit would be realized and the authors consider that vaccination in low-resource settings would be considered cost-effective only if the expense of the vaccine was modest. Homepage: Strategies for mitigating an influenza pandemic Strategies for mitigating an influenza pandemic [Ferguson NM, Cummings DA, Fraser C, et al. Nature. 2006 Apr 26; Epub ahead of print]: This is a follow-up report by experts in epidemic modeling to deal with global public health priorities in the event of pandemic influenza. Here the authors examine four issues as follows: Internal or border travel restrictions: This and other analyses are based on data for the US and Great Britain. The results show that border control to restrict passage by 90%, 99% or 99.9% might delay the peak of a US pandemic by 1.5, 3 or 6 weeks, respectively. Their analysis also showed the eliminating travel in and out of the affected areas would delay the spread by up to two weeks. Closing airports for domestic airports had minimal impact. Treatment of Cases: The analysis showed that this would be effective only if there was very rapid treatment, meaning “same day treatment” of 90% of cases. This would reduce the attack rate from 34% to 29% and peak attack rate from 1.9% to 1.6% assuming an antiviral stockpile sufficient for 25% of the population. The urge for early therapy was based on the fact that transmission is at a peak soon after symptoms develop. They also note that effectiveness of antiviral treatment is based on the assumption that there would not be resistant strains with efficient transmissibility similar to that of wild- type virus. They point out that such strains have not been reported to date. Social Distancing: Isolation such as school closings during the peak of the epidemic could reduce the peak attack rate by up to 40%, but this has little impact on the overall attack rate. However, case isolation or household quarantine could have substantial impact. Antiviral prophylaxis to household contacts would reduce the cumulative attack rates, but this would require a stockpile of antivirals sufficient to treat 46-57% of the population which was considered unlikely. Vaccine: Evaluations were based on the assumption that single dose would give 70% protection. Vaccination at a rate of 1% of the population/day would need to begin two months before the pandemic outbreak to have a substantial impact. A delay of four months from the start of the pandemic would mean that the vaccine was available when the pandemic was over. The authors conclude by noting the limitation of their data which would be quite different if the modeling was based on the 1968 or 1957 pandemic rather than the 1918 pandemic. Comment: It should be noted that this is the team that provided one of the initial strategies that received substantial attention including adoption of many of the recommendations by WHO [Ferguson NM, Cummings DA, Cauchemez S, et al. Nature 2005;437:209 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstr act&list_uids=16079797&query_hl=69&itool=pubmed_docsum ]. This report seems rather depressing in terms of strategies that are likely to be effective, it is the quick fix that we have all wanted. Nevertheless, it is somewhat reassuring that the avian influenza spread has slowed in both people and poultry.