Everything you always wanted to know about TB…but were afraid to inhale? Kevin Schwartzman MD, MPH Respiratory Division, MUHC kevin.schwartzman@mcgill.ca RVH Internal Medicine Resident Core Teaching March 30, 2010

Learner Objectives--1 To describe basic concepts in tuberculosis epidemiology To recognize the spectrum of clinical and radiographic manifestations of active TB, in different patient populations To describe the essential pathophysiology of latent and active TB To identify and understand the rationale for evidence-based diagnostic strategies for active and latent TB

Learner Objectives--2 To describe standard treatment for active and latent TB To identify indications, contraindications, and potential complications of this treatment To identify key concepts in TB control, within and outside the hospital

Overview--1 Case presentations Epidemiology Pathophysiology and natural history Active TB: Diagnosis Treatment, including special considerations Infection control

Overview--2 Latent TB: Key concepts in TB control Diagnosis Tuberculin skin test, interferon-gamma release assays Treatment priorities Treatment regimens Special situations Key concepts in TB control

Jad Davenport, “Mural outside tuberculosis clinic, Dhaka” World Lung Foundation (http://worldlungfoundation.org)

Jad Davenport. “TB flourishes in crowded Dhaka shantytowns” World Lung Foundation (http://worldlungfoundation.org)

Pierre Virot, “A TB patient is examined by the doctor, Ghana” World Lung Foundation (http://worldlungfoundation.org)

www.nytimes.com On May 24, 2007, Andrew Speaker, a 31 year-old lawyer from Atlanta, landed at Trudeau Airport on a flight from Prague, with a diagnosis of extensively drug-resistant (XDR) tuberculosis. He drove a rented car across the US border, and was apprehended. He had smear-negative TB, later determined not to be XDR.

Case 1 35 y.o. Inuit female Referred to MGH after trauma Smoker, no other past history No respiratory or constitutional symptoms Previously exposed to brother with active TB Apparently did not receive treatment for latent infection

Next steps?

Case 1 Underwent bronchoscopy BAL cytology negative BAL smear-negative for AFB Discharged to the North with instructions for follow-up CXRs and clinical follow-up/other tests depending on results BAL ultimately culture-negative Apparently lost to follow-up until she developed left arm and shoulder pain in February 2010

Case 1 What would you recommend now?

Case 1 Bronchoscopy: some mucosal abnormalities seen on left side BAL AFB smear negative BUT necrotizing granulomatous inflammation and AFB seen on biopsy specimens Patient is staying at Northern Module What would you recommend now?

Case 2 32 y.o. male refugee claimant from Congo, arrived in Canada < 1 week previously Admitted to medical ward because of extensive herpes zoster in left V1 distribution, with probable bacterial superinfection Wife known HIV-positive, no respiratory issues Patient found to be HIV-positive with CD4 70 Complains of minor hemoptysis

Case 2 What investigations (if any) would you now arrange? Would you isolate this patient? What treatment (if any) would you recommend?

Case 3 50 year-old female respiratory therapist, Quebec-born, completely asymptomatic Smoker, treated for type 2 diabetes with oral hypoglycemic agent Referred for tuberculin skin test measuring 13 mm, done 1 week after assisting at bronchoscopy of patient whose BAL was 4+ smear-positive for AFB, and laryngeal lesions were seen What other information would you like?

Case 3 Received BCG vaccination in primary school, at about age 8 (~1968) Had tuberculin skin test results of 0 mm in 2005 and 2006, 2 mm in 2009. What do you think? What are the next steps?

“I thought TB had disappeared” 2007: WHO estimated 9.3 million new cases, vs. 8.3 million cases in 2000 and 6 million cases in 1990 55% in Asia, 31% in Africa Overall global incidence 137 per 100,000 annually, down from peak 142 in 2004 1.3 million deaths in HIV-negative individuals, 450,000 deaths in HIV-positive individuals (~25% of all deaths in HIV-infected persons) 1/3 of world population believed to have latent TB infection http://www.who.int/tb/publications/global_report/2009/en/index.html

Major Determinants Basic elements of TB control e.g. diagnosis, consistent and appropriate treatment Health system infrastructure e.g. national control programs, public vs. private providers etc. General socioeconomic and health status, tobacco, alcohol HIV Drug resistance Obviously all these are interrelated

Bates et al, Arch Int Med 2007

HIV Strongest known risk factor for TB disease Increases risk of progression/reactivation of latent TB infection by 100-fold or more To date, impact on global epidemiology most evident in sub-Saharan Africa, but concern re unknown magnitude of HIV-TB coinfection notably in India

Drug Resistance In 2007, the estimated number of cases of multi-drug resistant TB was 511,000 3.1% of all new TB cases and 19% of retreatment cases were multi-drug resistant Defined as resistance to isoniazid AND rifampin, with or without resistance to other antibiotics A marker of treatment program quality Poor prognosis, treatment complexity and expense

WHO, Anti-Tuberculosis Drug Resistance in the World, 2008

WHO, Anti-Tuberculosis Drug Resistance in the World, 2008

TB in Canada Ellis et al, Public Health Agency of Canada

Drug Resistance in 2007 Of 1,188 Canadian cases with drug resistance data: 94 (8%) mono-resistance to first line drugs (82 INH), plus 6 INH/ethambutol 10 (0.8%) MDR-TB 1 (0.08%) XDR-TB

Montreal 123 reported active TB cases in 2007; maximum was 209 in 1994 Corresponding decrease in incidence from 11.6 to 6.4 per 100,000 Consistently ~80% of cases involve foreign-born persons DSP Montréal-Centre, Bureau de surveillance épidémiologique http://www.santepub-mtl.qc.ca/Mi/surveillance/mado/archives/90-2005/incidence90-2007.pdf

Pathophysiology Active Tuberculosis Airborne Droplets Case Finding (Passive or Active) Effective Drug Treatment Patient Behaviour (e.g. Cover Mouth) Airborne Droplets Respiratory Isolation Progression or Reactivation Ventilation and Air Filtration Ultraviolet Light BCG Vaccination Diagnosis and Treatment of Latent TB Inhalation by Others Antiretroviral Therapy for HIV Latent Infection

Long and Schwartzman, Transmission and Pathogenesis of TB, Chapter 3, Canadian Tuberculosis Standards 2007

Clinical Manifestations Pulmonary disease: 2/3 of cases in Canada Pleural TB and thoracic nodal disease ~ 10% Most common extrapulmonary site is peripheral lymph nodes (~12%) Patients often asymptomatic when they have less extensive disease (e.g. immigration screening) Most frequent symptom: cough, usually for weeks to months—in symptomatic patients, virtually always present (even if not the symptom that precipitated the visit)

Clinical Manifestations Other frequent symptoms: sputum, fever, malaise, loss of weight/appetite, night sweats, hemoptysis Symptoms generally not very specific, hence the importance of the clinical and epidemiologic context Timing of cough often used to estimate period of contagion Physical exam generally not helpful; may show cachexia, fever, sometimes adenopathy

Questions to Ask Place of birth, year of immigration (risk highest in years immediately after arrival) Known history of TB disease, latent TB, exposure Recent travel Visitors from abroad HIV issues Other past medical history

Chest Radiograph The key first step in investigation A normal chest X-ray usually excludes the diagnosis of pulmonary TB, except in some HIV-infected persons Reactivation disease: usually upper zone airspace disease (infiltrate; “fluffy” appearance), may have cavities Involvement of other areas of lung, or contralateral lung, suggests bronchogenic spread, and a higher bacterial load/potential for contagion Beware of judging active vs. inactive TB on a CXR

Gary Hampton, “Paula Fujiwara of the IUATLD talks to the mother of a TB patient…” World Lung Foundation (http://worldlungfoundation.org)

Ms CL

Chest X-Ray Primary disease (usually children, or persons with advanced HIV infection): lower zone disease, often dense consolidation, with or without cavitation May mimic bacterial pneumonia May be associated with intrathoracic adenopathy Miliary disease (rare)

Ms GL

Diagnosis of Active TB For pulmonary disease, diagnosis hinges on growth of mycobacteria from respiratory secretions, i.e. sputum (spontaneous or induced), and/or bronchoalveolar lavage

Diagnosis Culture of a single induced sputum has similar sensitivity to BAL culture for the diagnosis of pulmonary TB 3 induced sputa may have better sensitivity than BAL

Diagnosis For other sites, biopsy (showing necrotizing granulomas, and ideally acid-fast bacteria) and/or culture according to the site Very low yield of fluid smear and culture for serosal disease (pleural, pericardial, peritoneal) Biopsies needed, with histology and culture

Diagnosis For pulmonary TB, typically 50-60% smear-positive, though this will vary with clinical context Lower with HIV, or persons diagnosed with screening (e.g. immigration, contacts) Higher with more advanced symptoms, more extensive radiographic abnormalities

Nucleic Acid Amplification (PCR) Limited use in diagnosis of smear-negative pulmonary TB, or extrapulmonary disease Sensitivity typically reported to be ~60% for smear-negative pulmonary disease Lower for extrapulmonary disease A negative result cannot be used to exclude the diagnosis Occasionally ordered under very specific circumstances e.g. contact investigation that will start sooner if PCR positive

Menzies and Khan, Diagnosis of Tuberculosis Infection and Disease, Chapter 4, Canadian Tuberculosis Standards, 2007

Nucleic Acid Amplification Now used as standard method to confirm that an isolate is M. tuberculosis AFB smear-positive specimens Cultures growing mycobacteria Final confirmation is performed at the provincial reference laboratory

Reporting Once identified in the laboratory, reporting of active TB to public health authorities is mandatory by law “Double reporting” by laboratory and treating physician Treating physician must report cases treated on the basis of clinical diagnosis alone Treatment of contagious tuberculosis is also required by law, and can be imposed

Tuberculin Skin Testing Is NOT an appropriate diagnostic test for active TB A positive test may indicate TB infection, but cannot distinguish active from latent TB Pre-test probability of latent TB infection may be 50% or higher, depending on the patient’s origin

Tuberculin Skin Testing Well-known false negative rate of ≥ 10% in active TB A negative TST does not exclude the diagnosis False negatives also seen with HIV, other immune suppression e.g. in rheumatologic disease, transplant Anergy screens poorly reliable in this context Similar considerations apply to interferon-gamma release assays

Initiating Treatment Empiric treatment for active TB may sometimes be started without culture confirmation This depends on the perceived likelihood of active TB, the potential consequences of waiting for confirmation, and the potential risks of treatment

Initiating Treatment Treatment for latent TB should NEVER be started if active disease is a possibility If cultures have been sent, await results before treating for latent TB (if appropriate) However, it IS acceptable to initiate treatment for active TB, then modify if cultures are negative 4-month modified regimen for “culture-negative” TB Also beware of treating pneumonia with a fluoroquinolone, if TB is a possibility

Treatment Intensive phase: first 2 months Daily isoniazid, rifampin, pyrazinamide, and ethambutol Continuation phase: usually 4 additional months Daily or intermittent isoniazid and rifampin If intermittent, must be directly observed PZA stopped after 2 month intensive phase Ethambutol discontinued once drug susceptibility confirmed

Treatment Isoniazid: 5 mg/kg, to 300 mg max plus pyridoxine 25 mg daily Rifampin: 10 mg/kg, to 600 mg max Ethambutol: 15 mg/kg, to 1600 mg max Pyrazinamide: 20 mg/kg, to 2000 mg max

Toxicity Liver: pyrazinamide > isoniazid > rifampin Asymptomatic transaminase rises are much more common than overt hepatitis Skin rashes: same Neuropathy: isoniazid Hematologic: rifampin Hypersensitivity, flu-like: rifampin Optic neuropathy: ethambutol [Orange discolouration: rifampin]

From Yee et al, Am J Respir Crit Care Med 2003 From Yee et al, Am J Respir Crit Care Med 2003. Bars show isoniazid, rifampin and PZA in that order, except for visual disturbance with ethambutol. Standard definition of hepatitis was used, i.e. transaminases ≥ 3 x upper limit of normal with symptoms, or ≥ 5 x upper limit without symptoms

Special Considerations Drug interactions Rifampin: potent P450 inducer Warfarin, antiretrovirals, cyclosporin, tacrolimus, oral contraceptives, anti-seizure medications, etc. Isoniazid: increases phenytoin levels Hepatic disease: close supervision May consider avoiding PZA, substituting moxifloxacin Active TB patients are usually seen at least monthly after discharge

Special Considerations Renal dysfunction Dose adjustment for ethambutol Pyrazinamide is dialyzed Both given 3 times weekly for dialysis patients Pregnancy INH, rifampin, ethambutol safe Safety of pyrazinamide undocumented, so usually avoided No quinolones

Special Considerations HIV Timing of antiretroviral therapy in patients with new diagnosis of HIV concomitant with TB Immune reconstitution Drug-drug interactions Drug absorption Length of treatment

Length of Treatment Usually 6 months Extended to 9 months if culture-positive at 2 months Also extended for bone or joint disease, CNS disease (12 months)

Other Considerations Adjunctive corticosteroids TB meningitis Pericardial TB Therapeutic drug monitoring Clinical response slower than expected Concern about absorption or interactions Direct observation Drug resistance

Infection Control Most important: institution of appropriate isolation, diagnostics and treatment Use of negative pressure room Use of N95 masks Patients can use surgical masks when outside their rooms

Infection Control Smear-positive patients usually hospitalized until repeatedly smear-negative Occasional exceptions for patients who live alone and will remain at home Smear-negative patients may be treated as outpatients, depending on the home situation and prospects for adherence Admission of patients with young children Admission of patients from congregate settings

Long and Schwartzman, Transmission and Pathogenesis of TB, Chapter 3, Canadian Tuberculosis Standards 2007

Contact Investigation An important element of TB control in industrialized countries “Concentric circle” approach for patients with pulmonary disease, beginning with household contacts More extensive investigation for patients with smear-positive or laryngeal disease Also extended if there is evidence of significant transmission, e.g. secondary active cases or excessive latent infection in contacts

Contact Investigation One of the most cost-effective TB prevention strategies Contacts diagnosed with latent TB infection are a high priority for treatment Active TB MUST be excluded

Approach to Latent Tuberculosis Testing should reflect priorities for treatment: targeted testing “A decision to test is a decision to treat” Treatment priorities reflect risk of active TB if left untreated, balanced against toxicity risk

Menzies and Khan, Chapter 4, Canadian Tuberculosis Standards, 2007 Particularly if ≥ 15 mg prednisone daily ~0.1%/year Menzies and Khan, Chapter 4, Canadian Tuberculosis Standards, 2007

Hoeppner, Ward and Elwood, Chapter 6, Canadian Tuberculosis Standards 2007

TST Interpretation Definition of a “positive” result depends on the clinical context, e.g. contacts vs. baseline health care worker screens Conversion: ≥ 10 mm increase, when first result was < 5 mm 6 or 10 mm increase may be used, when first result 5-9 mm (6 mm more sensitive, 10 mm more specific)

TST Interpretation True converters are a high treatment priority Note that sensitization requires 3 to 8 weeks to be detectable by TST If less than 3 weeks, will have false-negative results, and positive results will not reflect recent exposure After 8 weeks, time needed for conversion has elapsed True negatives at that point Rationale for a single test ≥ 2 months after contact, if possible

TST Interpretation False positives: BCG vaccination Not if administered in infancy May have up to 25%-40% persistent positive results if administered after infancy Boosting: lower-level immunity, particularly associated with BCG Denotes an apparent conversion referable to such immunity Elicited by obtaining 2 tests a week apart Non-tuberculous mycobacteria Not an issue for Canadian-born, but sensitization occurs in southern US and many other countries

TST Interpretation False negatives HIV, other immune suppression as noted Active TB itself Severe malnutrition Certain viral illnesses and vaccines (MMR, varicella)

Serial Tuberculin Skin Testing Situations in which screening for latent TB infection will be undertaken repeatedly Notably health care workers Relevance of baseline two-step testing, to dispense with boosting issue The two-step test need only be performed at baseline Single-step testing thereafter

Interferon-Gamma Release Assays Newer tests use blood samples Detect interferon-gamma release by T cells after stimulation by M. tuberculosis antigens Two commercially available platforms: Quantiferon, T-Spot.TB Avoid false-positive results by using antigens absent from BCG and most non-tuberculous mycobacteria (e.g. M. avium) ESAT-6, CFP-10

Interferon-Gamma Release Assays Pooled sensitivity (based on patients with active TB): 70-90%, vs. 70-80% for TST depending on cutoff used Pooled specificity 93-99%, vs. 59% or 97% for TST (with/without BCG vaccination—based on low risk group for latent TB infection) Menzies, Pai and Comstock Ann Intern Med 2007 Pai, Zwerling and Menzies Ann Intern Med 2008 Note the absence of a gold standard for latent TB infection

Stephan et al, AIDS 2008 Study of 286 HIV-positive persons in Germany, median CD4 408 12.8% TST ≥ 5 mm, vs. 25.2% positive on T-SPOT.TB and 20% on QuantiFERON

Interferon-Gamma Release Assays US guidelines suggest these can replace TST in all contexts Canadian guidelines suggest these be used in specific situations To confirm latent TB after a positive TST, in persons where there is a low risk of latent TB infection and reasonable suspicion of a false-positive TST Not usually appropriate for contact investigation May be considered for immunosuppressed persons with negative TSTs, when false-negative TST results are of particular concern

Interferon-Gamma Release Assays Limited data on future risk of active TB, after positive interferon-gamma test Well established for TST No clear data or guidelines as to correct interpretation of serial interferon-gamma results There is test-retest variability just as for TST Threshold for “true” increase in interferon-gamma release has not been established

Treatment of Latent TB Standard of care: Isoniazid daily x 9 months Based on randomized, placebo-controlled trial in Eastern Europe by IUAT Evaluated 6 and 12 month treatment courses 69% protective efficacy at 6 months, 93% protective efficacy at 12 months, if > 80% adherent ~75% effective after 12 months, accounting for adherence

Treatment of Latent TB Subsequent analysis of data from Alaskan Inuit (Comstock) showed plateau in effect after 9 months Note ~50% completion in most cohorts outside the clinical trial setting This is the major limitation to effectiveness of treatment for LTBI on an individual level, and as a TB control strategy

Alternatives Isoniazid daily x 6 months Intermittent isoniazid (2-3 x weekly)—very uncommon Rifampin daily x 4 months Efficacy not established, though indirect evidence suggests it will likely be at least equivalent to 9 months of INH Better completion and side effect profile than 9 INH in recent RCT run from the MCI CIHR-funded efficacy trial (4RIF vs. 9INH) now underway

Hepatoxicity Risk increases with age Extremely rare below age 20, increases markedly over 50 and especially 65 years of age

Age Group LTBI therapy cohort hepatic events / total (rate per 100 persons) Untreated (LTBI) cohort hepatic events1 / total Risk difference LTBI Treated - Untreated (95% CI) All LTBI Treated LTBI Treated without co-morbidity2 All Untreated Untreated without Patients without co-morbidity2 ≤35 5/4523 (0.1) 5/3765 (0.1) 1/9046 (0.0) 0/7530 (0.0) 0.1 (0.0-0.2) 36-50 8/2533 (0.3) 4/1898 (0.2) 7/5066 (0.1) 5/3796 (0.1) 0.2 (-0.1-0.4) 0.1 (-0.2-0.3) 51-65 10/1232 (0.8) 2/668 (0.3) 4/2464 (0.2) 1/1336 (0.1) 0.6 (0.1-1.2) 0.2 (-0.2-0.7) >65 22/857 (2.6) 4/205 (2.0) 3/1714 (0.2) 0/410 (0.0) 2.4 (1.3-3.5) 2.0 (0.1-3.8) Total 45/9145 (0.5) 15/6536 (0.2) 15/18290 (0.1) 6/13072 (0.1) 0.4 (0.3-0.6) 0.2 (0.1-0.3) ~95% INH, 5%rifampin Smith et al, CMAJ (Submitted), 2010: Risk of hepatic toxicity requiring hospitalization

Monitoring Importance of clinical monitoring, ideally monthly Patients must have an action plan in the event of new symptoms (stop medication, whom to call, etc.) Routine monthly LFT monitoring not recommended as part of guidelines

Monitoring However at MCI our practice has been to obtain baseline LFTs, and repeat after 1-2 months on treatment Regular LFTs if liver disease, alcohol abuse, age > 35, or within 3 months postpartum

Special Considerations Liver disease or alcohol abuse Weigh risks vs. benefits e.g. pre-transplant, HIV, close contact vs. incidental finding Severity of liver disease Close supervision and monitoring Can discuss with liver specialist Pregnancy Treatment generally withheld until end of pregnancy and breastfeeding Exceptions for HIV, close contacts, other important immunosuppression

Special Considerations Drug interactions as previously outlined INH preferred if on antiretroviral treatment Contacts of drug-resistant index case Rifampin if INH-resistant Moxifloxacin if multi-drug resistant (defined as INH and rifampin) Note absence of trial data to support this practice

Key Concepts in TB Control Priority is diagnosis and treatment of the most infectious patients WHO “DOTS” strategy focuses on diagnosis using sputum smear microscopy Appropriate and complete drug treatment, most often with direct supervision Monitoring and documentation of treatment outcomes Major limitations include HIV, drug resistance

Key Concepts in TB Control Adjuncts to improve diagnostic yield Enhanced microscopy Availability of mycobacterial cultures in some settings Linkage of TB and HIV control activities Rethinking empiric TB retreatment strategies to deal with resistance Better MDR coverage Increasing the availability of drug susceptibility testing

Key Concepts in TB Control In middle- and high-income countries, contact investigation with treatment of latent infection among contacts at risk In the US and Canada, targeted testing and treatment for latent TB infection Immigration-related screening activities Detection and treatment of active TB at time of immigration Detection and potential treatment of “high-risk” inactive TB

Summary TB remains a major global health problem Although incidence has decreased in Canada (and Montreal), we will continue to see it Foreign-born, Aboriginals, homeless, immunosuppressed Essential to keep the diagnosis of TB in mind, and pursue it using the right tools, in the appropriate clinical, radiographic, and epidemiologic context

Summary Active TB Latent TB Importance of microbiologic diagnosis; biopsy/histology for extrapulmonary disease Standard treatment regimens Suitable respiratory isolation Latent TB Uses and limitations of tuberculin skin test, interferon-gamma release assays Importance of TARGETED testing and treatment Appropriate use of isoniazid or rifampin

THANK YOU! WHO/TBP/Jan van den Hombergh, Ethiopian girls in Assosa Mooi (World Lung Foundation)