1. Medical Update Webinar: Management of TB in the Elderly December 16, 2008 Reynard J. McDonald, M.D. Professor of Medicine Medical Director, Lattimore Clinic

2. Epidemiology - 1

3. Epidemiology - 2

4. Epidemiology - 3

5. Pathogenesis Primary TB infection is acquired by inhaling droplet nuclei containing viable M. tuberculosis These inhaled tubercle bacilli may evade destruction by host immune mechanisms and remain dormant as long as the host cell-mediated immunity remains intact

6. Pathogenesis - 2 In the elderly, reactivation is often caused by diseases common to the geriatric (≥ 65y) age group (eg: diabetes mellitus, malignancies, chronic renal failure), poor nutrition, and the use of immunosuppressants, especially corticosteroids

7. Pathogenesis - 3 The host immune response that occurs as a result of infection with M. tuberculosis is not fully understood A major component of the immune system affected by aging is a decline in the ability of aging T- lymphocytes to produce specific cytokines Macrophage function appears to remain intact Some infected older persons, given enough time, will eventually eliminate the viable AFB and revert to a negative tuberculin reaction status These older persons have no lasting immunity and are thus susceptible to reinfection

8. Pathogenesis - 4 In the geriatric population, tuberculosis disease occurs most frequently due to endogenous reactivation of dormant pulmonary foci resulting from earlier infection with M. tuberculosis (recrudescent disease) Factors including malnutrition, homelessness, imprisonment, substance abuse, and immune dysfunction caused by disease, drugs or aging can reactivate dormant bacilli

9. Diagnosis: Clinical Manifestations The clinical manifestations of tuberculosis differ depending on the site of involvement of the disease In >80% of cases of tuberculosis in the elderly, the lung is the site of involvement Symptoms are non-specific particularly in the elderly, indeed the patient may be asymptomatic, and a high index of suspicion is therefore required for early diagnosis and treatment

10. Diagnosis: Clinical Manifestations - 2 The most common symptom is cough The cough is usually nonproductive at its onset, but progressive, and may become productive of mucopurulent or blood-streaked sputum Other symptoms include fever, night sweats and weight loss

11. Diagnosis: Clinical Manifestations - 3 The presence of acute or chronic illnesses existing concurrently with tuberculosis may obscure the diagnosis by altering the presentation Tuberculosis in an elderly person with chronic obstructive pulmonary disease (COPD) or lung cancer may be misdiagnosed, delaying therapy or may be completely missed, only to be found at autopsy

12. Diagnosis: Radiological Features Primary TB can involve any lung segment but usually involves the middle or lower lobes as well as the mediastinal or hilar lymph nodes Infiltrates in the elderly may be interstitial, lobar, patchy or cavitary, and bilateral

13. Diagnosis: Radiological Features - 2 The usual sites of lung involvement for reactivated TB are the apical and posterior segments of the upper lobes and the superior segments of the lower lobes However, the lower lung fields and the anterior segment of the upper lobes may also be involved

14. Diagnosis: Primary TB in an Adult

15. Diagnosis: Post-Primary (Reactivation) TB (PA View)

16. Diagnosis: Post-Primary (Reactivation) TB (Lateral View)

17. Diagnosis: AFB Smear, Culture, and Nucleic Acid Amplification Test Elderly patients suspected of having pulmonary tuberculosis should have 10 cc of an early morning sputum specimen collected and submitted for smear and culture for acid-fast bacilli or PCR

18. Diagnosis: AFB Smear, Culture, and Nucleic Acid Amplification Test - 2 50 – 80% of patients with pulmonary tuberculosis will have sputum smears that are positive for AFB When smears are positive, the collection of three culture specimens on separate days is adequate

19. Diagnosis: AFB Smear, Culture, and Nucleic Acid Amplification Test - 3 Elderly patients are frequently unable to spontaneously produce sputum Under these circumstances, sputum induction by inhalation of a saline aerosol is successful in 30-60% of patients When lower-risk methods of collecting sputum are unsuccessful, fiber optic bronchoscopy (FOB) is a high-yield procedure that may be of benefit

20. Identifying Risk Factors Those who have been recently infected Those with clinical conditions that increase their risk of progressing from LTBI to TB disease Persons at high risk for developing TB disease fall into 2 categories:

21. Identifying Risk Factors: Increased Risk for Progression to TB Disease HIV-infected persons Those with a history of prior, untreated TB or fibrotic lesions on chest radiograph Persons more likely to progress from LTBI to TB disease include:

22. Identifying Risk Factors: Increased Risk for Progression to TB Disease - 2 Underweight or malnourished persons Injection drug users Those receiving TNF-α antagonists for treatment of rheumatoid arthritis or Crohn’s disease

23. Identifying Risk Factors: Increased Risk for Progression to TB Disease - 3 Persons with certain medical conditions such as: –Silicosis –Diabetes mellitus –Chronic renal failure or on hemodialysis –Solid organ transplantation (e.g., heart, kidney) –Carcinoma of head or neck –Gastrectomy or jejunoilial bypass

24. Diagnosis: Testing for M. tuberculosis Infection Mantoux tuberculin skin test (TST) Skin test that produces delayed-type hypersensitivity reaction in persons with M. tuberculosis infection QuantiFERON ® - Gold Blood test that measures and compares amount of interferon-gamma (IFN-  ) released by blood cells in response to antigens

25. Diagnosis: Mantoux Tuberculin Skin Test Preferred method of skin testing for M. tuberculosis infection TST is useful for: –Determining how many people in a group are infected (e.g., contact investigation) –Examining persons who have symptoms of TB Multiple puncture tests (e.g., Tine Test) are inaccurate and not recommended

26. Diagnosis: Administering the TST Inject 0.1 ml of 5 TU PPD tuberculin solution intradermally on volar surface of lower arm using a 27-gauge needle Produce a wheal 6 to 10 mm in diameter

27. Diagnosis: Reading the TST Measure reaction in 48 to 72 hours Measure induration, not erythema Record reaction in millimeters, not “negative” or “positive” Ensure trained health care professional measures and interprets the TST

28. Diagnosis: TST Interpretation 5-mm induration is interpreted as positive in: HIV-infected persons Close contacts to an infectious TB case Persons with chest radiographs consistent with prior untreated TB

29. Diagnosis: TST Interpretation - 2 5-mm induration is interpreted as positive in: Organ transplant recipients Other immunosuppressed patients (e.g., those taking the equivalent of >15 mg/d of prednisone for 1 month or those taking TNF-α antagonists)

30. Diagnosis: TST Interpretation - 3 10-mm induration is interpreted as positive in: Recent immigrants Injection drug users Residents or employees of congregate settings Mycobacteriology laboratory personnel Persons with clinical conditions that place them at high risk

31. Diagnosis: TST Interpretation - 4 Persons with no known risk factors for TB* *Although skin testing programs should be conducted only among high-risk groups, certain individuals may require TST for employment or school attendance. Diagnosis and treatment of LTBI should always be tied to risk assessment. 15-mm induration is interpreted as positive in: ____________________________________________________

32. Diagnosis: TST Boosting Some people with LTBI may have a negative skin test reaction when tested years after infection because of a waning response An initial skin test may stimulate (boost) the ability to react to tuberculin Positive reactions to subsequent tests may be misinterpreted as new infections rather than “boosted” reactions

33. Diagnosis: Two-Step Testing A strategy to determine the difference between boosted reactions and reactions due to recent infection –If first TST is positive, consider the person infected –If first TST is negative, give second TST 1–3 weeks later –If second TST is positive, consider the person infected –If second TST is negative, consider the person uninfected at baseline

34. Diagnosis: Two-Step Testing -2 Use two-step tests for initial baseline skin testing of adults who will be retested periodically (e.g., health care workers)

35. Diagnosis: QuantiFERON ® -Gold Test Whole-blood test used to detect M. tuberculosis infection Approved by the U.S. Food and Drug Administration (FDA) Entails mixing blood samples with antigens from M. tuberculosis, M. avium complex, and controls and incubating for 16 to 24 hours

36. Diagnosis: QuantiFERON ® -Gold Test - 2 Cells that recognize the antigen release interferon-  Amount of interferon released in response to tuberculin is compared to amount released in response to other antigens 5 5 MMWR January 31,2003; 52 (RR-02): 15-18 and CDC Fact Sheet Document # 250103, March 2003 _____________________________________________

37. Prevention and Treatment: Isoniazid Regimens 9-month regimen of isoniazid (INH) is the preferred regimen 6-month regimen is less effective but may be used if unable to complete 9 months May be given daily or intermittently (twice weekly) –Use directly observed therapy (DOT) for intermittent regimen

38. Prevention and Treatment: Isoniazid Regimens - 2 INH daily for 9 months (270 doses within 12 months) INH twice/week for 9 months (76 doses within 12 months) INH daily for 6 months (180 doses within 9 months) INH twice/week for 6 months (52 doses within 9 months)

39. Prevention and Treatment: Rifampin Regimens Rifampin (RIF) given daily for 4 months is an acceptable alternative when treatment with INH is not feasible (120 doses within 6 mos.) In situations where RIF cannot be used (e.g., HIV-infected persons receiving protease inhibitors), rifabutin may be substituted

40. Prevention and Treatment: Clinical Monitoring Rash Anorexia, nausea, vomiting, or abdominal pain in right upper quadrant Fatigue or weakness Dark urine Persistent numbness in hands or feet Instruct patient to report signs or symptoms of adverse drug reactions

41. Prevention and Treatment: Clinical Monitoring - 2 Incidence of hepatitis in persons taking INH is lower than previously thought (0.1 to 0.15%) Hepatitis risk increases with age –Uncommon in persons < 20 years old –Nearly 2% in persons 50 to 64 years old Risk increased with underlying liver disease or heavy alcohol consumption

42. Prevention and Treatment: Laboratory Monitoring Asymptomatic elevation of hepatic enzymes seen in 10%-20% of people taking INH –Levels usually return to normal after completion of treatment Some experts recommend withholding INH if transaminase level exceeds 3 times the upper limit of normal if patient has symptoms of hepatotoxicity, and 5 times the upper limit of normal if patient is asymptomatic 7 7 MMWR June 9, 2000; 49(No. RR-6): 39

43. Prevention and Treatment: Treatment of Tuberculosis

44. Clinically Significant Drug-Drug Interactions Involving the Rifamycins Drug ClassDrugs whose concentration are substantially decreased by rifamycins (references)

45. Clinically Significant Drug-Drug Interactions Involving the Rifamycins - 2 Drug ClassDrugs whose concentration are substantially decreased by rifamycins (references)

46. QUESTIONS & DISCUSSION

47. Case Report March 25 – PA CXR March 25 – Lateral CXR

48. Case Report March 29 – PA CXR

49. Case Report April 6 – PA CXR

50. Case Report April 13 – RAO CXR

51. Case Report April 21 – AP CXR

52. Case Report Autopsy – Rt. lung

53. Case Report Lung bx – Alveoli filled with proteinatious material

54. Case Report Lung bx - Granuloma

55. Case Report ZN Stain – AFB+