Key Issues in TB and HIV Co-Infection in the setting of HIV infection

1. Key Issues in TB and HIV Co-Infection in the setting of HIV infection Dr. Daniel Park University of California, San Diego ITECH

2. Clinical Presentation of TB in HIV Infection

3. Extra pulmonary TB 50-70% of TB cases in HIV infected patients are extra-pulmonary Common presentations of extra-pulmonary TB Meningitis Lymphadenitis Miliary Pleural effusion Empyema Pericardial Effusion Peritoneal Skeletal

4. Post-primary Pattern Consolidation in the upper lobes +/- cavitation. No adenopathy. Bronchogenic spread included. Primary Pattern Air space consolidation in the middle or lower lobes. Interstitial changes, including miliary pattern also considered to be primary. Adenopathy and pleural effusion may be present

5. Radiological Patterns in HIV + Retrospective study of 209 HIV + patients diagnosed with Cx + pulmonary TB 01/1987 – 12/2001 CT Scan performed in 42 patients Patients on HAART : 33/209 (16%) CD4 350 Patients not on HAART: 176/209 (84%) CD4 64 2 radiologist reviewed films – they were blinded to HAART therapy 2 radiologist reviewed films – they were blinded to HAART therapy

6. CXR CD4 < 200 CD4 > 200 (158) (51) Consolidation 90(57%) 44 (86%) Upper lobes Cavity 31(20%) 28 (55%) Pleural effusion 12(7%) 7 (14%) Adenopathy 18 (11%) 3 (6%) Miliary 88 (57%) 4 (8%)

7. Showing typical cavitary lesionsShowing typical cavitary lesions

9. Performance Characteristics of Diagnostic Tests for TB: Chest Radiography 4% (10/250) asymptomatic HIV infected patients with normal chest xrays and negative sputum smears were culture + for TB1 Prior to preventive therapy Yield very low unless symptomatic2,3 But has not been evaluated in setting immediately prior to HAART initiation 1.Swaninathan et al. Int J Tuberc Lung Dis 2004;8:896-8 2. Mosimaneotsile et al. Lancet 2003;362:1551-1552 3. Mohammed et al. Int J Tuberc Lung Dis 2004;8:792-7951.Swaninathan et al. Int J Tuberc Lung Dis 2004;8:896-8 2. Mosimaneotsile et al. Lancet 2003;362:1551-1552 3. Mohammed et al. Int J Tuberc Lung Dis 2004;8:792-795

10. Summary: CXR findings correlate with degree of immune suppression. CXR may appear atypical at higher degrees of immunosuppression. Primary TB infection is more common in advanced HIV patients. Extrapulmonary TB disease is more common in HIV patients.

11. Diagnosis TB is harder to diagnose in patients with HIV infection Increased prevalence of extrapulmonary TB Shed less tubercle bacilli, so less positive AFB sputum smears Do symptom screen.

12. Symptom Screen Cough > 3 weeks Fever Night sweats Fatigue Weakness Weight loss Poor appetite Chest wall pain Coughing up blood

13. South African National Guidelines for Diagnosis of Tuberculosis Sputum collection 2 expectorated for microscopy 1 expectorated for C&S (re-treatment cases only) Indications for culture Hx previous unsuccessful TB Rx Drug susceptibility necessary Smear + at 2 or 6 months 2 smears negative, no response to antibiotics, clinical suspicion TB Indications for CXR When sputum AFB + Suspected complications Haemoptysis Diagnose other lung diseases Only 1 of 2 sputum AFB smears + When sputum AFB – During & end of Rx If response not satisfactory TB suspect: persistent cough for more than 2 weeks (2004 guidelines) or 3 weeks (2000 guidelines)± sputum, SOB, chest pain, anorexia, weight loss, malaise, night sweats, fever. SPUTUM: 1st “spot specimen” obtained with supervision of HCW after bout of coughing and clearing of back of throat. 2nd early morning specimen self collected by patient following dayTB suspect: persistent cough for more than 2 weeks (2004 guidelines) or 3 weeks (2000 guidelines)± sputum, SOB, chest pain, anorexia, weight loss, malaise, night sweats, fever. SPUTUM: 1st “spot specimen” obtained with supervision of HCW after bout of coughing and clearing of back of throat. 2nd early morning specimen self collected by patient following day

16. WHO TB Diagnosis Algorithm

18. Sputum Microscopy

19. Sputum AFB Smear Several quantitative studies have shown that there must be 5,000 to 10,000 bacilli per milliliter of specimen to allow the detection of bacteria in stained smears. In contrast, 10 to 100 organisms are needed for a positive culture. Concentration procedures in which a liquefied specimen is centrifuged and the sediment is used for staining increases the sensitivity of the test; thus, smears of concentrated material are preferred. Am J Respir Crit Care Med Vol 161. pp 1376–1395, 2000 Am J Respir Crit Care Med Vol 161. pp 1376–1395, 2000

20. Performance Characteristics of Diagnostic Tests for TB Sensitivity of expectorated sputum1 for PTB 55% (1 sputum) 70% ( 2 sputa) 70% (3 sputa) Auramine staining increases yield by 18%2 Finch & Beaty. Chest 1997;111:1174-1179. Data for 20 HIV + patients with TB Lipsky et al. Rev Infect Dis 1984;6:214-22 Bell et al. J Infect 2003;47:317-21 Hartung et al S Afr Med J 2002;92:455-8Finch & Beaty. Chest 1997;111:1174-1179. Data for 20 HIV + patients with TB Lipsky et al. Rev Infect Dis 1984;6:214-22 Bell et al. J Infect 2003;47:317-21 Hartung et al S Afr Med J 2002;92:455-8

21. Performance Characteristics of Diagnostic Tests for TB Sputum induction in patients with negative smears or unable to expectorate has positive yield varying from 13.2%3 – 29%4 Sputum concentration by centrifugation and NaOCl liquefaction increases sensitivity from 54.2% - 67.5% to (conventional direct microscopy) to 63.1%5 -87.1%6 Finch & Beaty. Chest 1997;111:1174-1179. Data for 20 HIV + patients with TB Lipsky et al. Rev Infect Dis 1984;6:214-22 Bell et al. J Infect 2003;47:317-21 Hartung et al S Afr Med J 2002;92:455-8 Bruchfeld et al. Trans R Soc Trop Med & Hyg 2000;94:677-680 Apers et al. Int J Tberc Lung Dis 2003;7:376-81Finch & Beaty. Chest 1997;111:1174-1179. Data for 20 HIV + patients with TB Lipsky et al. Rev Infect Dis 1984;6:214-22 Bell et al. J Infect 2003;47:317-21 Hartung et al S Afr Med J 2002;92:455-8 Bruchfeld et al. Trans R Soc Trop Med & Hyg 2000;94:677-680 Apers et al. Int J Tberc Lung Dis 2003;7:376-81

22. Are sputum smears graded as scanty false-positive? Abuja, Nigeria, sputum smears from 1068 patients One specimen was cultured. 824 (26%) smears were positive, 137 (4%) scanty and 2243 negative. One hundred and thirty (95%) scanty and 809 (98%) positive smears were culture-positive. <5% scanty results, <1% of the patients treated for TB, are false-positive. Of 1068 cultures, 680 (64%) were positive. Of 1068 cultures, 680 (64%) were positive.

23. Smear Negative TB Disproportionate increase in rates of smear-negative pulmonary and extrapulmonary tuberculosis in HIV-prevalent and resource-constrained settings Higher mortality in HIV-infected, especially smear negative Over twice the risk of death in Malawi study with 7 years of follow-up data (Kang’ombe CT, et al. Int J Tuberc Lung Dis 2004;8:829-36.) Smear negative status leads to delayed diagnosis and may contribute mortality. Cultures frequently not available HIV prevalent= HIV >1% in pregnant women or among Tb patients>5% Expert panel recognized the need for timely diagnosis and flexibity when it comes to HIV, especially those who are severely ill.HIV prevalent= HIV >1% in pregnant women or among Tb patients>5% Expert panel recognized the need for timely diagnosis and flexibity when it comes to HIV, especially those who are severely ill.

24. Smear Negative TB Infectivity of smear-negative tuberculosis 22% relative transmission rate compared to smear positive Siddiqi K, et al. Lancet Infect Dis 2003;3:288-296.

25. Smear Negative PTB

27. Antibiotics Trial Primary role should not be as a diagnostic aid Treat concomitant bacterial infection Common both with and without tuberculosis Non-response increases the likelihood of TB but a response to antibiotics should not exclude TB Antibiotic choice should cover typical causes of community acquired pneumonia but should NOT INCLUDE FLUOROQUINOLONE

28. Antibiotics trial Validation of antibiotic algorithm Patients TB suspects respiratory symptoms>3 weeks, abnormal CXR consistent with TB OR acute pneumonia and failed outpatient antibiotics Patients with Negative AFB smears treated with amoxicillin x 5 days and erythromycin x 5 days if not improved. 120 patients evaluated PPV 95%PPV 95%

29. Antibiotics trial “Non-response increases the likelihood of TB” PPV 73% “Response to antibiotics should not exclude TB” NPV 61% Sensitivity 55%, Specificity 77% Must maintain high clinical vigilance; patients advised to come back if symptoms return; must have good followupMust maintain high clinical vigilance; patients advised to come back if symptoms return; must have good followup

30. Etiology of pneumonia Prospective study to evaluate etiology of AFB sputum smear negative pneumonia in HIV-infected patients BAL in 71% and 75% in Senegal and CAR

31. Cases from the Field A man dies of unrecognized pulmonary KS while being repeatedly treated for tuberculosis A child dies of an undiagnosed abdominal malignancy after being diagnosed with extrapulmonary TB on the basis of abdominal ultrasound and treated for > 12 months for TB with no improvement A women is diagnosed with extrapulmonary TB based on abnormal liver chemistries with normal chest xray, no cough, no fever, no lymphadenopathy? she actually had lactic acidosis from stavudine therapy

32. Isoniazid Preventive Therapy

33. Isoniazid Preventive Therapy

35. Immune Reconstitution Inflammatory Syndrome (IRIS) Paradoxical reaction: temporary exacerbation of symptoms, signs, or radiographic manifestations of TB after beginning TB treatment, may include High fever Increase in size of lymph nodes New lymphadenopathy Worsened CNS lesions Worsened pulmonary infiltrates Increasing pleural effusions Occurs in HIV-uninfected patients, but more common in HIV-infected patients, especially those on ART

36. Type 1 IRIS

37. Type 2 IRIS

38. Time of onset of IRIS IRIS associated with Mycobacterium tuberculosis occurs within 2 months of starting antiretroviral therapy, usually within the first 2-3 weeks (French et al, AIDS 2004, 18:1615–1627) But a recent case series suggested a broader range on time of onset (Shelburne et al. AIDS 2005, 19:399–406)

42. Figure 1. Case 1. (a) Chest radiograph shows right paratracheal adenopathy and a reticulonodular infiltrate. The patient was diagnosed as having HIV and M. tuberculosis and commenced on anti-tuberculosis therapy and HAART. (b) Chest radiograph 2 months later, when the patient presented with stridor, shows massive right paratracheal adenopathy displacing and compressing the trachea, minor right hilar adenopathy and a nodular infiltrate in the mid-zone. Computed tomography (CT) (c) shows a 6×7 cm nodal mass in the right paratracheal region causing displacement and marked compression of the trachea. The low-density centre and rim enhancement of the nodal mass is typical of tuberculous infection.Figure 1. Case 1. (a) Chest radiograph shows right paratracheal adenopathy and a reticulonodular infiltrate. The patient was diagnosed as having HIV and M. tuberculosis and commenced on anti-tuberculosis therapy and HAART. (b) Chest radiograph 2 months later, when the patient presented with stridor, shows massive right paratracheal adenopathy displacing and compressing the trachea, minor right hilar adenopathy and a nodular infiltrate in the mid-zone. Computed tomography (CT) (c) shows a 6×7 cm nodal mass in the right paratracheal region causing displacement and marked compression of the trachea. The low-density centre and rim enhancement of the nodal mass is typical of tuberculous infection.

43. May be difficult to distinguish IRIS from worsening of TB, treatment failure, new infection, adverse drug reaction, etc Evaluate thoroughly for other causes Can be prolonged and severe

44. Management of IRIS Management Mild-moderate reactions: Symptomatic treatment, NSAIDs Continue TB therapy and ART Severe reactions (eg, high fever, airway compromise from enlarging lymph nodes, enlarging serosal fluid collections, sepsis syndrome): Not studied; consider prednisone or methylprednisolone(1 mg/kg daily, with taper after 1-2 weeks) Continue TB therapy Continue ART if possible (unless IRIS is life threatening)

45. Summary TB and HIV coinfection is common and associated with higher mortality rates TB in the setting of HIV may often have atypical presentations, especially with lower CD4 counts Smear Negative TB is common and clinician should not be hesitant to make the diagnosis. IRIS is a common complication occurring after initiation of ARV treatment in pts undergoing treament for TB.

46. Thanks to Dr. Mathews, Shimbakuro, Dr. Campbell who provided some of the slides used in this presentation.