AME 3.13.06 to 3.17.06: Screening and Treatment of Latent Tube rculosis Infection (Positive PPDs) Authors: Authors: Sara Luckhaupt, MD and Joel Tsevat, MD, MPH Competencies: Medical Knowledge, Patient Care Learning Objectives: After reading this information you should be able to: 1. Identify who should be tested and treated for latent tuberculosis infection (positive PPD) 2. List the recommended treatment regimens Key Points The goal of these PPD testing is to identify people at high risk for developing active TB who would benefit by treatment of latent TB infection. Age 35 is no longer a threshold for treatment for a positive PPD. Anergy testing is not recommended for routine use for people who are infected with HIV or are otherwise immunocompromised. 9 months of daily INH is the preferred regimen. Pyridoxine is recommended to be given with INH to groups of patients in which neuropathy is common and to pregnant women and patients with seizure disorders. Targeted Tuberculin Testing In April 2000, the CDC published guidelines for targeted tuberculin testing and treatment of latent TB infection.1 The goal of these recommendations is to identify people at high risk for developing active TB who would benefit by treatment of latent TB infection. According to the recommendations, a decision to test is a decision to treat (if positive), so the guidelines discourage tuberculin testing among groups that are at low risk of developing active TB. People at high risk for developing active TB who should be tested by PPD*: Those likely to have been recently infected with Mycobacterium tuberculosis o Close contacts of persons with infectious pulmonary TB o Immigrants from areas of the world with high rates of TB (e.g., SE Asia, Africa, Eastern Europe, Russia, and most parts of Latin America and the Caribbean) Certain epidemiologically defined groups: homeless persons, those with HIV infection, injection drug users, persons who live or work in institutional settings (hospitals, homeless shelters, correctional facilities, nursing homes, and residential homes for patients with AIDS)) Those with clinical conditions that are associated with an increased risk for progression from latent TB infection to active TB o HIV o Injection drug use o Silicosis o Radiographic findings consistent with prior TB o Underweight o Chronic renal failure/hemodialysis o Diabetes mellitus o Gastrectomy o Jejunoileal bypass o Solid organ transplantation o Carcinoma of the head or neck o Other neoplasms o Prolonged therapy with corticosteroids (>15 mg/day of prednisone or equivalent for 2-4 weeks) and other immunosuppressive agents *Persons whose PPDs convert from negative to positive within a period of 2 years (10 mm increase) and children, especially those younger than 4 years of age, who have a positive PPD have an increased risk of progression from latent TB infection to active TB, presumably due to recent infection. Notice that age 35 is no longer mentioned as a threshold for treatment, PPDs are not contraindicated for people who have been vaccinated with BCG, and anergy testing is not recommended for routine use in people who are infected with HIV or otherwise immunocompromised. Tube rculin Skin Testing Tuberculin skin testing is conducted by injecting 0.1 ml of 5 tuberculin units purified protein derivative (PPD) intradermally into the dorsal or volar surface of the forearm. Tests should be read 48-72 hours after administration, and the transverse diameter of the induration should be recorded in millimeters. In our clinic, tuberculin skin tests can be placed by an RN (any day except Thursday) and can be read at a follow-up nurse’s visit. Always make sure the patient can return within 48-72 hours for a reading before placing a PPD. Crite ria for PPD Positivity by Risk Group 5 mm of induration 10 mm of induration 15 mm of induration HIV+ Recent immigrants Persons with no Recent contacts of (5 yrs) from high risk factors for TB* active TB cases prevalence countries Fibrotic changes on Injection drug users CXR consistent Persons who live or with prior TB work in institutional Organ transplant settings recipients Mycobacteriology lab Other personnel immunosuppressed Persons with the patients clinical conditions listed above that increase risk Children younger than 4 yrs or infants, children, and *The guidelines do not adolescents exposed recommend testing these to adults at high risk people Pre-Treatment Evaluation Rule out active TB by history, physical exam, CXR, and further studies as indicated (sputum samples if CXR suspicious or patient is HIV+ and there is a high index of suspicion) Baseline laboratory testing (i.e., liver enzymes) is not recommended unless the initial evaluation suggests an underlying liver disorder or risk factors for liver disease; liver enzymes are recommended for patients with HIV infection, for pregnant women, and for women in the immediate postpartum period Active hepatitis and end-stage liver disease are relative contraindications to the use of isoniazid or pyrazinamide for the treatment of latent TB infection Treatment Regimens Drug Duration Inte rval Adult Rating*/ Rating*/ Dose Evidence † Evidence † for HIV- for HIV+ Patients Patients Isoniazid 9 months Daily 300 mg A (II) A (II) (INH) 2/week 900 mg B (II) B (II) (DOT) Isoniazid 6 months Daily 300 mg B (I) C (I) 2/week 900 mg B (II) C (I) (DOT) Rifampin 4 months Daily 600 mg B (II) B (III) DOT= Directly observed therapy (for twice weekly dosing) *A=preferred; B=acceptable alternative; C=offer when A & B cannot be given; D=should generally not be offered † I=randomized clinical trial data; II=data from clinical trials that were not randomized or were conducted in other populations; III=expert opinion. As you can see, 9 months of daily INH is the preferred regimen. The effectiveness (relative risk reduction) of 12 months of INH has been shown to be as high as 90% among adherent HIV- patients and 83% among HIV+ patients, and additional studies of the effectiveness of various durations of INH therapy suggest that there is no increased protection in going from 9 months of therapy to 12 months of therapy, but that the 9- month regimen is more cost-effective. Idiosyncratic hepatitis (incidence of symptomatic hepatitis is 1-3/1000 persons treated; alcohol is a co-factor) is the most severe adverse reaction from INH, but peripheral neuropathy is also associated with INH administration due to interference with metabolism of pyridoxine (vitamin B6). Thus, pyridoxine therapy is recommended for groups of patients in which neuropathy is common (e.g., those with diabetes, uremia, alcoholism, malnutrition, and HIV infection), and for pregnant women and patients with seizure disorders. A 4- month course of rifampin is recommended as an alternative for patients presumed to be infected with INH-resistant TB (e.g., close contacts of patients with INH resistant TB). A 2- month course of rifampin and pyrazinamide is no longer recommended because of hepatotoxicity. No other regimens are currently recommended for the treatment of latent TB. Follow-up Patients being treated for latent TB infection should be scheduled for follow-up at least monthly Evaluation should include questioning about side effects and checking for signs of hepatitis Laboratory testing is indicated if baseline liver enzymes were abnormal, the patient has other risk factors for liver disease (i.e., HIV, pregnancy, <3 months post-partum, heavy alcohol use, pre-existing chronic liver disease, other hepatotoxic drugs), or the patient reports symptoms compatible with drug toxicity Some experts recommend that isoniazid should be withheld if transaminase levels exceed 3 times the upper limit of normal if the patient is symptomatic and 5 times the upper limit of normal if the patient is asymptomatic Completion of Treatment Completion of therapy is based on total number of doses administered not on duration of therapy alone. For the daily regimens: The 9- month regimen of isoniazid should consist of 270 doses, at minimum, administered within 12 months The 6- month regimen of isoniazid should consist of 180 doses, at minimum, administered within 9 months The 4- month regimen of rifampin should consist of 120 doses, at minimum, administered within 6 months When therapy is reinstituted after an interruption of more than 2 months, a medical examination to rule out active TB is indicated Advances on the Horizon(?) Peripheral blood T-cell based interferon assays are being developed and investigated.3 These assays may offer improved sensitivity and specificity over PPD testing, but prospective studies are still needed to evaluate the usefulness of these tests. References 1. Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR 2000;49 (No. RR-6):1-39. 2. Centers for Disease Control and Prevention. Update: adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection United States, 2003. MMWR 2003;52:735-739. 3. Blumberg HM, Leonard MK Jr., Jasmer RM. Update on the treatment of tuberculosis and latent tuberculosis infection. JAMA 2005;293:2776-2784. Questions 1. A 68-year-old man with hypertension and chronic renal insufficiency tells you that his wife has recently been diagnosed with tuberculosis, and asks you whether he needs to be tested. a. Should you order a PPD? b. What is the cut-off point for reading this patient’s PPD as positive? c. What kind of evaluation would this patient need to have before starting treatment for latent TB infection? 2. For which of the following patients is treatment of latent TB infection recommended? a. A health care worker with a PPD of 12 mm who had a negative PPD 2 years ago b. An infant, born to an HIV+ mother, with a PPD of 10 mm c. A 70-year-old HIV- man with steroid-dependent COPD (20 mg prednisone/day for 2 months) with a PPD of 8 mm d. A 25-year-old female teacher with no significant past medical history, with a pre-employment PPD of 14 mm 3. Which of the following patients has most likely completed a recommended adequate course of therapy for latent TB infection? a. An HIV+ man who took 180 doses of isoniazid in a 9- month period b. An HIV- woman who took 180 doses of isoniazid in a 6- month period c. An HIV- man who completed a 2- month regimen of rifampin and pyrazinamide 4. Which drug regimen is appropriate for a 50-year-old diabetic male with a positive PPD? a. 9 months of daily INH b. 4 months of daily rifampin c. 2 months of rifampin and pyrazinamide d. 9 months of daily INH and pyridoxine 5. Which of the following patients has a PPD that qualifies as positive? a. A 40-year-old asthmatic who recently finished a 5-day course of prednisone and who has 8 mm of induration b. An injection-drug user with 6 mm of induration c. A recent immigrant from Somalia with 12 mm of induration d. An HIV+ male with 3 mm of induration 6. For which of the following patients should you consider placing a PPD test? a. A 68-year-old woman who is beginning hemodialysis and moving into a nursing home b. A receptionist at a dentist’s office c. A recent immigrant from Vietnam with a history of BCG vaccination d. A patient with chronic silicosis who is having increased shortness of breath Ans wers 1. Answers and Discussion: This patient should be tested due to his close contact with his wife with TB. The fact that he has renal insufficiency may also increase his risk of developing active TB. His PPD would be considered positive at 5 mm induration. Pre-treatment evaluation should include history and physical for symptoms or signs of active TB or liver disease and a CXR to look for active TB. Baseline laboratory testing is probably not necessary unless there is suspicion for pre-existing liver dysfunction. 2. Answer: a, b, c Discussion: The CDC recommends treatment for the first three patients due to their combination of risk factors and PPD results. They do not recommend routine testing of teachers without risk factors, although this is commonly required for employment. You do not need to consider treating Patient D unless her PPD results in 15 mm induration, because otherwise it is likely a false positive result and her risk of developing active TB is low. 3. Answer: b Discussion: The first patient has only completed the equivalent of a 6- month regimen, which has a C rating for HIV+ persons, so he should continue treatment to complete 270 doses within 12 months. The second patient has completed a 6- month regimen, which is rated B for HIV- persons. The third patient has completed a regimen that followed the 2000 guidelines but is no longer recommended due to risk of liver injury. 4. Answer: d Discussion: It is important that a patient with diabetes receives pyridoxine along with INH to prevent onset or worsening of peripheral neuropathy. 5. Answer: c Discussion: Patient A is not at increased risk for developing TB because s/he has not been on steroids long enough to be immunosuppressed. The appropriate PPD cut-off for Patients B and C is 10mm, and the appropriate cut-off for Patient D is 5 mm. 6. Answer: a, c, d Discussion: Hemodialysis, residence in a nursing home, recent immigration from SE Asia, and silicosis all increase the chance of recent infection and/or the risk of progression from latent to active TB. Previous vaccination with BCG is not a contraindication to PPD testing.
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