everything you always wanted to know about tb…but were afraid to inhale? kevin schwartzman md, mph...
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Everything you always wanted to know about TB…but were afraid to inhale?
Kevin Schwartzman MD, MPHRespiratory Division, MUHC
RVH Internal Medicine Resident Core TeachingMarch 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: 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.comOn 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
Active Tuberculosis
Airborne Droplets
Inhalation by Others
Latent Infection
Case Finding (Passive or Active)
Effective Drug Treatment
Patient Behaviour (e.g. Cover Mouth)
Respiratory Isolation
Ventilation and Air Filtration
Ultraviolet Light
Progression or Reactivation
Antiretroviral Therapy for HIV
BCG Vaccination
Diagnosis and Treatment of Latent TB
Pathophysiology
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. 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
~0.1%/year
Menzies and Khan, Chapter 4, Canadian Tuberculosis Standards, 2007
Particularly if ≥ 15 mg prednisone daily
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 cohorthepatic events / total
(rate per 100 persons)
Untreated (LTBI) cohorthepatic events1 / total (rate per 100 persons)
Risk differenceLTBI Treated - Untreated
(95% CI)
AllLTBI
Treated
LTBI Treated without
co-morbidity2
All Untreated
Untreatedwithout
co-morbidity2
AllPatients
Patientswithout co-morbidity2
≤355/4523 (0.1) 5/3765 (0.1)
1/9046 (0.0)
0/7530 (0.0) 0.1 (0.0-0.2) 0.1 (0.0-0.2)
36-508/2533 (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)
51-6510/1232 (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)
Smith et al, CMAJ (Submitted), 2010: Risk of hepatic toxicity requiring hospitalization
~95% INH, 5%rifampin
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 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)