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Tuberculosis Tools:

A Clinical Update

CAPA Conference 2014

JoAnn Deasy, PA-C. MPH, DFAAPA

jadeasy@sbcglobal.net

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

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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