Download Everything you always wanted to know about TB…but were afraid to

Everything you always
wanted to know about
TB…but were afraid to
inhale?
Kevin Schwartzman MD, MPH
Respiratory Division, MUHC
[email protected]
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
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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.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 drugresistant (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
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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
infection
did not receive treatment for latent
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
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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,


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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,
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
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,

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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 multidrug 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/incidence902007.pdf
Pathophysiology
Active Tuberculosis
Case Finding (Passive or Active)
Effective Drug Treatment
Patient Behaviour (e.g. Cover Mouth)
Airborne Droplets
Respiratory Isolation
Progression or
Reactivation
BCG Vaccination
Diagnosis and
Treatment of Latent TB
Ventilation and Air Filtration
Ultraviolet Light
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
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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 HIVinfected 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 acidfast 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 interferongamma 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
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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 smearnegative
 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
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
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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 interferongamma 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
LTBI therapy cohort
hepatic events / total
(rate per 100 persons)
Age
Group
Untreated (LTBI) cohort
hepatic events1 / total
(rate per 100 persons)
Risk difference
LTBI Treated - Untreated
(95% CI)
~95% INH, 5%rifampin
All
Untreated
Untreated
without
comorbidity2
All
Patients
Patients
without comorbidity2
5/3765 (0.1)
1/9046 (0.0)
0/7530 (0.0)
0.1 (0.0-0.2)
0.1 (0.0-0.2)
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)
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)
≤35
36-50
51-65
All
LTBI Treated
LTBI Treated
without
comorbidity2
5/4523 (0.1)
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



Importance of microbiologic diagnosis;
biopsy/histology for extrapulmonary disease
Standard treatment regimens
Suitable respiratory isolation
 Latent TB



Uses and limitations of tuberculin skin test, interferongamma release assays
Importance of TARGETED testing and treatment
Appropriate use of isoniazid or rifampin
van den Hombergh, Ethiopian girls in Assosa Mooi (World Lung
THANK YOU! WHO/TBP/Jan
Foundation)