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Tuberculosis Tools:
A Clinical Update
CAPA Conference 2014
JoAnn Deasy, PA-C. MPH, DFAAPA
Adjunct Faculty Touro PA Program
Learning Objectives
• Outline the pathogenesis of active pulmonary and extra-pulmonary tuberculosis and latent TB
• Differentiate between latent and active TB
• Outline the diagnostic work-up for patients with symptoms and signs of tuberculosis and for patients with a positive PPD or interferon-gamma release assay
• List the therapeutic regimens for active TB and latent TB
Article in Sacramento Bee
July 2, 2014
• February 2014 a high school student diagnosed with active tuberculosis
• Subsequently 4 more students diagnosed with active TB (2 in lymph nodes) and 4 family and friends diagnosed with active TB
• 450 students and staff tested for TB and 116 tested positive
– Most of these = latent TB with 30 still
pending further testing to rule out active TB
• If any concerns, contact your PCP
Tuberculosis (TB)
• Causative agent: Mycobacterium tuberculosis
• One-third of world is latently infected
– 11 million in US latently infected
• In 90%, infection remains latent
– Infection spread limited by immune system
•
Pathogenesis of TB
• M. tuberculosis = aerobic bacillus
– Neither gram positive or gram negative
– Acid fast bacilli
• Transmitted by inhalation (rarely ingestion)
• Cytokine and cellular activation
• Immune system tries to limit spread of infection
– Granuloma formation around bacilli
– Intracellular killing of bacilli
•
Possible Outcomes of Infection
with M. tuberculosis bacilli
• Active TB disease usually in first 2 years
after infection
• Latent infection (chronic infection)
– Can develop active disease many years
after infection (re-activation) usually when
immune system wanes
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75% Pulmonary Disease
25% Extrapulmonary
Latent TB Infection (LTBI) vs
TB Disease (Active TB)
LTBI TB Disease
Infected with M. tuberculosis
alive but not active
Infected with M. tuberculosis
alive and active
Usually positive PPD or
TB blood test
Usually positive PPD or
TB blood test
No symptoms or signs Usually symptoms such as
cough, fever, others
Not contagious Contagious
No infiltrate on CXR Usually infiltrate on CXR or
Other abnormality
TB Disease (Active TB) 9,9445 cases of TB disease in 2012 in US
World Wide
World Health Organization.
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Reported TB cases (CDC)
United States, 1982-2010
TB Cases: United States 2010
Number of TB Cases in US-born
vs. Foreign-born Person
United States 2012-2014
Risk of Developing Active TB
• Persons at high risk for developing TB disease fall into 2 categories – Those who have been recently infected
• Within past 2 years
– Those with clinical conditions that increase their risk of progressing from LTBI to TB disease
Symptoms
• Cough - over weeks (>2-3 wks) to months
–Non-productive or productive
• Hemoptysis (blood streaked sputum)
• Chest pain
• Fatigue
• Anorexia
• Weight loss
• Fever with night sweats
• Dyspnea - extensive disease or pl effusions
Physical Examination
• Few physical findings in pulmonary TB
disease unless extensive disease
–Extensive: tubercular apical disease percussion
to dullness along clavicles or wheezes in apices
–Extensive: may show wasting and use of
accessory muscles
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Radiologic Studies
• CXR : suspicious but does not confirm TB
– Multinodular infiltration
• superior segments of lower lobes
• apical segment of upper lobes
– Cavitation
– Hilar adenopathy
– Old (healed) TB
– Nodules (granulomas) calcified or not calcified
– Views
• posterior-anterior (PA) and lateral
• lordotic views
• CT scan of chest
45 yo man with cough and fever
for 3-4 weeks
Bacteriologic Evaluation
• AFB smear and culture X3 – 3 separate days or at least 8 hrs apart with one early morning
– Induction of sputum
• AFB sputum smears X3 – 5000-10000 bacilli/ml
• AFB cultures x3 – as few as 10 bacilli/ml – Solid media = 3-8 weeks
– Liquid culture systems = 7-14 days
– DNA probes of culture growth (2-4 hours)
• Nucleic amplification tests (PCR) on sputum
• Drug susceptibility on isolate • Follow-up cultures : monthly until convert to negative
AFB Smear
AFB (shown in red) are tubercle bacilli
Treatment of Active Disease
(HIV negative adults)
• Adult patients = 4 drug regimen - Start: – Isoniazid (INH)
– Rifampin
– Pyrazinamide (PZA)
– Ethambutol • Obtain baseline CBC, liver enzymes, uric acid, bilirubin, creatinine
• If organism is susceptible to all meds, stop ethambutol
• PZA should be administered for 2 months
• INH and rifampin given for 6 months
• Most patients=noninfectious within 2 weeks after starting chemotherapy
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Directly Observed Therapy
(DOT)
• To optimize patient drug compliance and
tolerability, directly observed therapy through
the county or state health department is
strongly recommended
Patient Education and
Follow-up
• Inform re: natural history of the disease
• Importance of adherence to med regimen
• Side effects of medications – hepatitis
– rifampin may cause urine to become orange and stain contact lenses
• Follow-up cultures monthly until 2 neg
• CXR after treatment for baseline for further comparison
Latent Tuberculosis
(Class II TB)
Targeted Testing
Decision to test = Decision to treat
• Test patients at risk for active TB
–Patients with medical conditions that increase risk
of active TB
–Patients in whom active TB is more prevalent
• health care workers
• nursing home residents / institutionalized
• recent arrival from high prevalence country (5 years)
–Contact with person with TB
–Old fibrotic lesion on CXR
Risk Factors for Developing Active
TB from Latent Infection
• High risk – single test for latent TB regardless of age
– Persons with major immunocompromising
conditions
– CXR shows fibronodular changes typical of healed
TB
• Moderate risk - ≤ 65 single test for latent TB
– Diabetes mellitus
– Corticosteroid therapy
• Slightly increased risk - ≤ 50 single test for latent TB
• Underweight, smoker, small granulomas on CXR
Diagnosis of LTBI
• Tuberculin skin test (TST, PPD)
• M. tuberculosis antigen-specific interferon-
gamma release assay (IGRA)
• If either TST or IGRA positive → CXR
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Tuberculin Skin Test (TST)
• Intradermal injection of
• 0.1ml of 5 TU of PPD
• At 48-72 hrs report diameter of induration (not erythema)
• Positive at 3-7 weeks after infection
• False positives and false negatives do occur
Reading the Tuberculin Skin Test
• Read reaction 48-72 hours
after injection
• Measure only induration
• Record reaction in millimeters
Problems with TST
• Return visit necessary
• Poor inter-reader reliability –9 mm vs 10 mm ?
• False positive and false negatives
• Poor positive predictive value in low prevalence populations
Factors that May Affect the
Skin Test Reaction
Type of Reaction Possible Cause
False-positive Nontuberculous mycobacteria
BCG vaccination
Anergy
False-negative Recent TB infection
Very young age (< 6 months old)
Live-virus vaccination
Overwhelming TB disease
LTBI Diagnosis with TST
• 5 mm = positive –HIV positive, close contact to person with active
TB, CXR consistent with old/healed TB, organ
transplant or other immunosuppressed
• 10 mm = positive for most
–Foreign born, IVDU, residents of high risk
settings or employees, listed co-morbidities
• 15 mm = positive –No known risk factors for TB
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Boosting (Booster Phenomenon)
• Some persons with LTBI may have negative
TST when tested years after infection
• Initial skin test may stimulate (boost) ability to
react to tuberculin
• Positive reactions to subsequent tests may be
misinterpreted as a new infection
Two-Step Testing
Use two-step testing for initial skin testing of adults who will be retested periodically • If first test positive, consider the person infected • If first test negative, give second test 1-3 weeks
later • If second test positive, consider person infected • If second test negative, consider person
uninfected
M. tuberculosis antigen-specific
interferon-gamma release assay
(IGRAs)
• Whole blood test for diagnosing LTBI
– QuantiFERON-TB GOLD and T-SPOT.TB
• Detect interferon-gamma release from previously
sensitized memory T-cells via in vitro simulation by M.
tuberculosis specific proteins
• No false positives due to BCG
• Cannot distinguish latent infection from active disease
• Immunocompromise conditions can give false negatives
Interpretation of IGRA Results
• Laboratories provide both qualitative and quantitative
results
– Qualitative: positive, negative and indeterminate (borderline)
– Quantitative
Selecting a Test to Detect TB Infection
New CDC Guidelines (2010)
• IGRAs preferred for:
– Unlikely to return for TST reading
– BCG vaccinated
• TST preferred:
– Children under 5 years
• Little specific guidance for immunocompromised patients
Positive TST or IGRA
What Next
• Chest x-ray
– All with positive TST or IGRA
– To differentiate between LTBI and TB disease
• Sputum AFB smear and culture
– Perform if positive TST or IGRA and abnormal
CXR or negative CXR and respiratory symptoms
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Treatment of LTBI in Adults
(HIV negative)
Drugs Duration Interval
Isoniazid 9 months Daily or 2x week
Isoniazid 6 months Daily or 2x week
Isoniazid 3 months Once weekly
+ rifapentin
Rifampin 4 months Daily
Add pyridoxine (VitB6) for prevention of neuropathy in patients at
risk
Tuberculosis Screening Flowchart.
Jasmer RM et al. N Engl J Med 2002;347:1860-1866.
Take Home Points
• Prevent TB by assessing risk factors
• If risk present, perform TST or IGRA
• If TST or IGRA is positive, rule out active disease
• If active disease is ruled out, initiate treatment for
LTBI
– If treatment is initiated, ensure completion