1. Pulmonary TB Steve Burdette, MD, FIDSA Professor of Medicine Wright State University Boonshoft School of Medicine

2. M. tuberculosis Complex M. tuberculosis M. bovis M. ulcerans M. microti M. africanum

3. Pathophysiology Humans only known reservoir Transmission - airborne droplet nuclei Exposure - sharing airspace with a patient who produces droplet nuclei Droplet nuclei inhaled, deposited within terminal airspaces of the lung Bacteria ingested by macrophages

25. Tuberculin Skin Test (TST) Mantoux test preferred – 5 tuberculin units of purified protein derivative (ppd) injected intradermally – Response = induration at 48 to 72 hrs – Erythema irrelevant to the interpretation Testing of low risk individuals discouraged

26. Interferon-gamma Release Assays Results comparable to TST Higher sensitivity for active TB Higher specificity (no cross reactivity to BCG) Single visit Higher cost Based on proteins present in M. tuberculosis – Absent from most Non-tuberculous mycobacteria – Present in M. kansasii, M. marinum, and M. szulgai)

28. Latent TB Infection (LTBI) LTBI - immune system keeps tubercle bacilli under control LTBI characteristics – Usually positive TST or IGRA – Not infectious – No symptoms – Normal chest x-ray – Sputum smears and cultures are negative Not a “case” of TB

29. LTBI Progressing to TB Disease Risk of developing TB disease is highest in the first 2 years after infection People with LTBI can be treated to prevent development of TB disease Detecting LTBI early and providing treatment helps prevent new cases of TB disease

30. Children younger than 5 years of age Weakened immune systems – Infection with HIV – Diabetes mellitus – Organ transplant – Silicosis – Severe kidney disease – Certain types of cancer – Certain intestinal conditions – Prolonged therapy with corticosteroids and other immunosuppressive therapy, such as prednisone and tumor necrosis factor-alpha [TNF-α] antagonists Chest x-ray findings suggestive of previous TB Low body weight Cigarette smokers and persons who abuse drugs and/or alcohol Recent TB infection (within past 2 years) Conditions that Increase Risk of Progressing to TB Disease

31. What are Symptoms of TB Disease? Cough lasting 3 or more weeks Coughing up sputum or blood Fever Chills Night sweats Weight loss Appetite loss Fatigue Malaise Chest pain

32. LTBI vs. TB Disease LTBITB Disease (in the lungs) Inactive tubercle bacilli in the body Active tubercle bacilli in the body TST or IGRA usually positive Chest x-ray usually normalChest x-ray usually abnormal Sputum smears and cultures negative Sputum smears and cultures usually positive No symptomsSymptoms such as cough, fever, weight loss Not infectiousOften infectious before treatment Not a case of TBA case of TB

33. Treatment of Latent Tuberculosis Formerly “preventive treatment” Regimens – INH daily or 2x/wk† for 9 mos – INH daily or 2x/wk† for 6 mos* – Rifampin daily for 4 mos Not acceptable for children, pts with HIV, or pts with fibrotic lesions on CXR † Given only as DOT

35. CXR “Consistent with Prior TB”

36. Solitary Nodule

38. PK

39. Miliary TB Credit: David Park, University of Washington Francis J Curry National TB Center Workshop

40. Diagnosis

41. Sputum collected for smear and culture Early morning 3 consecutive days – In hospital, q 8 hours – 2 sputum adequate If there is no adequate sputum – Morning gastric aspirate – Fiberoptic bronchoscopy

42. Kinyoun Stain

44. Culture Solid or liquid media Liquefaction-decontamination – N-acetyl-L-cysteine – Sodium hydroxide Detection in 9-16 days (liquid media) Colonies lack pigment (solid media) Cording (liquid media) Nucleic acid hybridization

45. Nucleic Acid Assays Smear positive sputum – Gen-Probe MTB (rRNA hybridization) – Amplicor M. tb test (DNA PCR) Smear pos or neg sputum – Enhanced MTB Other tissues – Gastric, LN, Skin, CSF – Not pleural fluid

46. Treatment

47. Clinical Infectious Diseases 2006; 42:1755

48. TB Drugs First LineSecond Line Isoniazid (INH) Quinolones Rifamycins:Linezolid - Rifampin (RIF) Para-aminosalicylic acid (PAS) - RifabutinCycloserine - RifapentineEthionamide Pyrazinamide (PZA) Clofazimine Ethambutol (EMB) Injectables Streptomycin - Aminoglycosides - Capreomycin

49. Standard Therapy Non-Cavitary Disease* RIF/INH/PZA/EMB until susceptibilities confirmed RIF/INH/PZA for 8 weeks RIF/INH for 18 weeks (BIW or TIW) Six months total Directly observed therapy (DOT) * Culture negative at 2 months

50. Treatment of Culture-Negative TB Abnl CXR + positive TST/IGRA –Start standard treatment –Attempt to collect appropriate specimen –No specimen or culture negative Clinical improvement (radiograph) –Clinical diagnosis of TB –Complete 2 more months of INH/RIF Radiograph stable after 2 months –Completed therapy for LTBI –Discontinue treatment

51. Treatment Monitoring (Cultures) Serial sputum smears every 2 weeks to assess early response Monthly sputum for AFB smear and culture (until 2 consecutive cultures negative) Repeat drug-susceptibility tests if culture-positive after 3 months of treatment

52. Drug Resistance (Management when a medication is stopped for a side effect is the same as dealing with resistance)

56. Multi-drug Resistant Tuberculosis MDR-TB By definition, resistant to INH & RIF No uniform protocol DOT mandatory Use 4-5 susceptible drugs including – Quinolone – Aminoglycoside

57. Extensively Drug Resistant TB XDR-TB Resistant to INH and Rifampin Resistant to fluoroquinolones Resistant to at least one injectable – Aminoglycosides – Capreomycin Many resistant to all second line agents

58. Prognosis Mortality 3% (50% untreated) Relapse rate 0-20% – Assuming DOT – Susceptible isolates – Usually within 2 years of completion Recurrent TB (> 100 days) probably reinfection rather than endogenous reactivation