Tips and Tricks for Diagnosing and Treating Tuberculosis
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1 Tips and Tricks for Diagnosing and Treating Tuberculosis Bob Belknap M.D. Director, Denver Metro TB Program December 6,
2 Disclosures No conflicts of interest NAAT off label for non-pulmonary specimens
3 36 y/o male Fever & abdominal pain x months Born in Cuba PMHx: schizophrenia SocHx: homeless
4 36 y/o male 6 weeks
5 36 y/o male
6 36 y/o male Which test is the most sensitive for diagnosing TB in this patient? 1. Tuberculin skin test (TST) 2. Interferon-gamma release assay 3. AFB smear from a bronchoscopy 4. Nucleic acid amplification test on sputum
7 Be able to describe: Objectives: 1. the role of AFB smears, cultures and nucleic acid amplification tests 2. the performance of indirect tests for active TB (TST, IGRAs, ADA, and IFN-γ levels) 3. the management of some common problems with TB medications
8 Born in the Pacific Islands travel in the U.S. military 1 month of cough, fever, weight loss Refused admission 52 y/o male
9 Hospitalized 2 weeks later QuantiFERON negative Lung bx shows granulomas, AFB smear (-) 52 y/o male Presumed to have hypersensitivity pneumonitis or sarcoidosis
10 Clinically worse after 1 month on steroids Died shortly after readmission 52 y/o male What went wrong?
11 2017 New Guidelines Lewinsohn CID 2017: 64 (15 January)
12 7 Essential Lab Tests for Active TB TEST Time Required 1. Nucleic Acid Amplification for detection 1 d 2. Nucleic Acid Amplification for resistance 1-2 d 3. AFB smear microscopy 1 d 4. Culture (liquid and solid) 10-14d 3-4 wk 5. Identification by probe or HPLC 1d 6. First-line drug susceptibility 1-2 wk 7. Second-line drug susceptibility 3-4 wk Lewinsohn CID 2017: 64 (15 January)
13 Sensitivity of AFB Smears Respiratory specimens = 30-70% AJIC :58; IJTLD : 918 Lymphatic TB = 25% CID : Pleural / peritoneal fluid < 10% J Thorac Dis 2015;7(6): CSF < 20%, increased with large volume and serial taps British Medical Bulletin, 2015, 113:
14 Diagnosing Pulmonary TB AFB smears 3 specimens recommended by CDC and NTCA Sensitivity: 70% Specificity: > 90% AFB Cultures: Sensitivity: liquid 88-90% / solid 76% Specificity: > 99% Nucleic Acid Amplification Test (NAAT) recommended on the initial respiratory specimen Lewinsohn CID 2017: 64 (15 January)
15 GeneXpert for Pulmonary TB Xpert MTB/Rif for Culture confirmed TB in the US Smear AFB (+) 1 Xpert 2 Xpert 2 AFB Smears (n = 91) AFB (+) 68.1% 96.7% 100% AFB (-) 59.3% 71.4% 3 AFB Smears (n = 53) AFB (+) 60.4% 96.8% 100% AFB (-) 57.9% 70% Leutkemeyer CID 2016: 62 (1 May)
16 GeneXpert for Stopping Airborne Isolation 2 negative GeneXpert to stop isolation Well-collected sputa 5-10 ml (min 3 ml) Not a replacement for culture
17 GeneXpert Omni Small and Portable Durable Low Power Consumption Automatic Connectivity Integrated Battery
18 Near Future: Xpert - Ultra GeneXpert Imperfect sensitivity in smear (-) disease Detection of silent mutations affecting specificity GeneXpert Ultra Increased volume and optimized chemistry 10 sites /8 countries (Georgia, Belarus, Brazil, Kenya, Uganda, S Africa, India and China) Sensitivity Smear (-)/ Culture (+): Increased 17% HIV-infected patients +12% Rodwell CROI 2017 Oral Abstract
19 61 y/o female s/p pneumonectomy for granulomatous disease 2 years prior Presented with cough for 1 month, fever and SOB DX: pneumonia and bronchopleural fistula
20 61 y/o female (-) TST and QFT HD#10 sputum AFB (-) HD#12 BAL AFB (+) Treating physicians believe this is a non-tb mycobacteria (NTM) OK for discharge
21 Induced sputa vs Bronchoscopy All BAL (+) patients were diagnosed by induced sputa (BAL missed 2) No difference in yield between sputa collected over 3 days vs. 1 day BAL should be limited to patients where other diagnoses are likely or can t induce sputum CID 2007; 44: 1415, IJTLD : 918
22 Tuberculin Skin Test (TST) and Interferon-gamma Release Assays (IGRAs) Meta-analysis Data presented for the commercially available assays (QFT-GIT and T-SPOT) Results: % (95% CI) TST 70 (67-72) QFT-GIT 84 (81-87) T-SPOT 88 (85-90) Diel, Chest April (4):
23 QFT-plus for Active TB Italy 88% (Eur Resp J 2016) Japan 91% (Sci Rep Jul 29) 98.9% (J Infect Chemother Nov 3) Zambia 83% (Int J Tuberc Lung Dis Jun 1)
24 60 y/o with cryptogenic cirrhosis Jan UGIB May Sepsis
25 60 y/o with cryptogenic cirrhosis Pleural fluid RBC 48,000 WBC 1,800 (73% L) Prot 2.2 LDH 279 (serum 422) May Sepsis Procalcitonin < 0.05
26 60 y/o with cryptogenic cirrhosis June July
27 60 y/o with cryptogenic cirrhosis Pleural fluid ph 7.35 Gluc 138 RBC 46,000 WBC 1,749 (78% L) Prot 2.5 LDH 215 (serum 421) ADA 2.1 Sputum 1+ AFB; GeneXpert (+) TB and Rifampin resistant
28 ADA and Free IFN-γ Levels Suspected TB Meningitis (1490 suspected / 92 diagnosed) Sens Spec ADA (> 2 U/L) Ekermans BMC ID 2017, 17:104 Meta-analysis Pleural TB (n=1626) Sens Spec ADA IFN-γ Suspected Pericardial TB (151 suspected / 74 definite /50 probable) Sens Spec ADA (> 35IU/L) IFN-γ (> 44 pg/ml) GeneXpert Pandie BMC Med 2014, 12:101 Zhou Scientific Reports 2015
29 ADA and Free IFN-γ Levels Guidelines recommend measuring ADA and IFN-γ levels in fluid when pleural, meningeal, peritoneal, and pericardial TB is suspected Rationale: if sensitivity is > 70% and specificity > 80% then it may be beneficial BUT Lewinsohn CID 2017: 64 (15 January) 1. Generally send-out tests with turn-around times in days 2. Don t replace the need to get tissue cultures for AFB So I think they have a very limited the role in the U.S.
30 GeneXpert for Extrapulmonary TB WHO - Xpert the preferred initial test for XPTB CDC/ATS/IDSA recommend NAAT testing on XPTB specimens (off label use) Denkinger Eur Resp J 2014 Sensitivity vs Composite Reference GeneXpert Culture Lymph 83 [71-91] 81 [72-88 CSF 81 [59-92] 63 [48-76] Pleural 46 [26-68] 21 [9-34]
31 29 y/o male with ascites Presents with 2 weeks of fever, chills, nausea and vomiting Originally from Somalia h/o (+) TST and Rx with INH x 9 months
32 29 y/o male with ascites Peritoneal fluid WBCs 5,904 (71% L) RBCs 4,738; Alb 2.6, LD 195, Prot 5.3 CT with omental thickening Should we get a NAAT on peritoneal fluid?
33 Diagnosing Extrapulmonary TB AFB Smear (%) AFB Culture (%) Pleural fluid Histology (%) Pleural tissue Genitourinary Urine Endometrial CSF Peritoneal fluid < Pericardial fluid Lewinsohn CID 2017: 64 (15 January)
34 29 y/o male with ascites Peritoneal biopsy poorly-formed epithelioid granulomas and chronic inflammation with rare possible AFB Side note ADA 4.5 (norm 0-7.3)
35 Summary 1. the role of AFB smears, cultures and nucleic acid amplification tests AFB smears are not sensitive or specific NAAT testing is recommended in the guidelines fast, accurate, and underutilized AFB culture remains the gold standard Tissue is better than fluid
36 Summary - Diagnostics 2. the performance of indirect tests for active TB TST, IGRAs, and ADA are not sensitive or specific May have a role as adjuncts when there is diagnostic uncertainty but should not replace biopsies and cultures IFN-γ levels from fluid may be better than ADA but are not yet available
37
38 Tuberculosis Treatment Empirical TB treatment Clinical reasons at risk for life-threatening TB, including ones often never confirmed (e.g. < 50% of TB meningitis is culture positive) Public health reasons return to work/school while cultures are pending, children at home, staying in a congregate setting (nursing home or homeless shelter)
39 23 y/o with lymphadenopathy smear (-), NAAT (+) Started on INH, rifampin, PZA, EMB At 1 month, complaint of losing his hair What is the likely cause? 1. INH 2. Rifampin 3. PZA 4. EMB
40 Isoniazid (INH) More common Fatigue GI anorexia, nausea, vomiting Hepatitis Maculopapular rash Peripheral neuropathy Sleep hygiene Tip Anti-nausea (ondansetron), anti-anxiety (hydroxyzine) Stop if ALT/AST 3x ULN (>120) with symptoms or > 5x ULN (>200) Treat with topical lotions +/- steroid and anti-histamines Mostly prevented with B6; can be problematic with DM and/or EtOH
41 Isoniazid (INH) Less common Alopecia Optic neuritis Seizure Vasculitis Anemia Thrombocytopenia Tip Temporary can often continue treatment and reassure Typically think EMB or linezolid Unlikely the sole source, look for other causes (CNS tuberculoma) Stop INH +/- steroids Stop Stop
42 79 y/o male CC: Cough x 5 months with 20lb wt loss CXR: Large L apical cavity: Sputum: 4+ smear (+) Started on IRZE after 10 days c/o a rash
43 79 yr old male Platelets 756 LFTs normal
44 79 yr old male Biopsy - Leukocytoclastic vasculitis Potential causes TB, INH or Rif Treated successfully with Rif, PZA, and EMB
45 Rifampin (Rif) More common Drug-drug interactions Discoloration of body fluids GI anorexia, nausea, vomiting Maculopapular rash Tip Many are relatively minor (ex. HTN); Important to always review Educate patients to prevent panic see INH see INH
46 Rifampin (Rif) Less common Hepatitis Hemolytic anemia Management Less than PZA or INH; more often associated with bilirubin Stop Rifampin Thrombocytopenia Stop Rifampin Acute renal failure Stop Rifampin
47 60 y/o with cryptogenic cirrhosis and rifampin resistant TB
48 Pyrazinamide (PZA) More common GI anorexia, nausea, vomiting Hepatitis Tip Both are more common with PZA and worse with increasing age Maculopapular rash Arthralgias /myalgias Gout flare see INH Acetaminophen or NSAIDS Anti-inflammatory
49 60 y/o with cryptogenic cirrhosis Rif-resistant TB Levofloxacin Linezolid EMB Amikacin (TIW) Imipenem
50 Fluoroquinolones Clearance Prolonged QT - Arrhythmia Tendinitis Tip Moxifloxacin (liver) Levofloxacin (Kidney but not removed by hemodialysis) Moxifloxacin > Levofloxacin Achilles, shoulder, other large joints Hepatotoxicity Maybe Moxifloxacin > Levofloxacin
51 Fluoroquinolones GI anorexia, nausea, vomiting CNS headache, dizziness, fatigue Tip sometimes improved by switching moxi to levo or levo to moxi Usually can treat symptoms and continue
52 21 y/o from Micronesia Active TB diagnosed post-partum 1 month reports a mild rash on arm At 2 months it s worse
53
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