What the Primary Physician Topics for Discussion Should Know about - - PDF document

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What the Primary Physician Should Know about Tuberculosis

Henry F. Chambers, M.D Professor of Medicine, UCSF

Topics for Discussion

• Epidemiology
• Common disease presentations
• Diagnosis of active TB
• Screening for latent TB infection

Global Impact of TB – 2017-18

• World population 7,700,000,000
• Number infected with TB: 2,500,000,000
• Incident cases of active TB: 10,000,000

(~140 per 100,000)

– US rate 2.8/100,000 in 2017

• 500,000 new MDR cases per year
• #1 cause of death (1.7 M) worldwide from

infectious disease (#2 AIDS, #3 malaria)

TB Case Rates,* United States, 2017

*Cases per 100,000

DC, District of Columbia; NYC, New York City (excluded from New York state)

≤2.8 (2017 national average) >2.8

DC NYC

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TB Cases and Rates Among U.S.-Born versus Non-U.S.–Born Persons, United States, 1993– 2017

• No. of cases

5 10 15 20 25 30 35 40 5,000 10,000 15,000 20,000 25,000 30,000 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015 2017 U.S.-born Cases Non-U.S.–born Cases U.S.-born Rate Non-U.S.–born Rate

Year Cases per 100,000

Demographic Groups with Higher Rates of TB

• Foreign-born other than Western Europe
• Incarcerated persons
• Homeless, marginally housed
• HIV positive

Active Tuberculosis

• Pulmonary tuberculosis: 85% of all cases
• The infectious form of the disease
• Clinical suspicion based on

– Signs, symptoms, setting – Chest x-ray

Case Presentation

• 63 y/o inmate transferred from jail for r/o TB
• No fever, cough, weight loss
• 12 mm + PPD, HIV negative
• Prior work-up

– 2/2007: AFB smear/culture neg x3 – 4/2011: AFB smear/culture neg x3 – 8/2011: AFB smear/culture neg x3 – 3/2016: AFB smear/culture neg x1 – 9/2016: AFB smear/culture neg x4

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CXR: LUL nodular infiltrate, slight volume loss, maybe slightly worse since prior film

What is your estimate of the likelihood of active TB in this case?

• 1. 75% or higher
• 2. 50-75%
• 3. 25-50%
• 4. 5-25%
• 5. < 5%

Work-Up

• CXR: LUL nodular infiltrate, slight

volume loss, maybe slightly worse since prior film?

• Sputum examination

– Routine: OF on culture and Gram-stain – AFB x2 and BAL x1: no AFB – GenProbe Amplified MTD test: negative

What is your revised estimate of the likelihood of active TB in this case?

• 1. 75% or higher
• 2. 50-75%
• 3. 25-50%
• 4. 5-25%
• 5. < 5%

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Diagnosis of TB

Performance of Diagnostic Tests for Pulmonary TB

Sensitivity Specificity AFB smear 60% 99% NAAT* 85% 99% Culture 90% 99% PPD (or QTF) 60% 10%

*NAAT = Nucleic Acid Amplification Test

Xpert MTB/RIF Test Performance – Pulmonary TB

Sensitivity Specificity Smear pos. TB 95-98% 99% Smear neg. TB* 70-90% Rifampin “R” 98-99% 99-100%

* Lower value for single specimen, higher for 3 specimens

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Organism Burden in TB

Cavitary TB Pulmonary infiltrate Lymphadenopathy 106 - 107 cfu/g 104 - 105 cfu/g 102 - 104 cfu/g

When to Use NAAT for TB Diagnosis in Addition to Culture

Suspected pulmonary tuberculosis Suspected tuberculous lymphadenitis Suspected tuberculous meningitis Children (nasophyngeal aspirate)

Detection Thresholds of Tests for TB Diagnosis

Positive smear Positive NAAT Positive culture 104 - 105 cfu/ml 101 - 102 cfu/ml 101 cfu/ml

Performance of NAAT for Diagnosis of Pulmonary TB

Pre-test probability PPV NPV 90% 100% 43% 75% 98% 69% 50% 96% 87% 25% 91% 95% 5% 57% 99%

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Clinical Course

• Patient was discharged back to jail
• Treatment for tuberculosis withheld

pending results of work-up

• 16 days after discharge, one sputum

culture and the BAL specimen were reported positive for Mtb!

Extrapulmonary TB

20 40 60 80 100 120 All cases Expul Percent Extrapulmonar y Pulmonary Other Bone/jt Miliar y GU Pleural Lymphatic

Sites of TB Infection

7 Differential Dx of Cervical Adenitis

• Tuberculosis
• Non-tuberculous mycobacterial infection
• Kikuchi-Fujimoto’s syndrome (histiocytic

necrotizing lymphadenitis)

• Staph or strep infection
• Cat scratch
• Lymphoma, other malignancy
• Other: syphilis, HIV, tularemia, listeria, plague

Tuberculous Adenitis

• Clinically presentation not distinctive
• Constitutional symptoms not usually present
• Seen in children, young adults > adults
• PPD + in 75-80%
• Chest x-ray abnormality (15-20%) favors MTB

Work-up of Suspected TB Adenitis

• Tuberculin test
• Check HIV serology
• Chest x-ray to r/o pulmonary
• Get tissue for histopathology, culture, and

NAAT

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Diagnosis of TB Adenitis

• Tissue is the issue

– to exclude other etiologies – for sensitivity testing

• FNA

– Characteristic granulomas in 80% – Culture + in 40-70% – Smear + < 50%

• Biopsy: partial vs. total excision

Performance of NAAT for Extrapulmonary TB

Sensitivity Specificity Lymphadenitis 90% 92% Meningitis 53% 100% Pleural 30% 100% Peritoneal 32% 100%

Tedesse, et al. Clin Microbiol Infect 2018 Dec 21. Cochrane Data base Syst Rev. 2018 Aug 27;8:CD012768

When to Use NAAT for TB Diagnosis in Addition to Culture

Suspected pulmonary tuberculosis Suspected tuberculous lymphadenitis Suspected tuberculous meningitis Children (nasophyngeal aspirate)

Treatment of TB Cervical Adenitis

• Responsive to medical therapy alone
• If excisional surgery performed,

medical therapy still must be given

• Paradoxical “worsening” can occur;

needle aspiration effective management

• Sinus track formation, non-healing

wounds may benefit from surgery

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Similar Scenario for TB Pleuritis

• Unilateral, benign, lymphocytic effusion
• Primary infection, newly + PPD
• Fluid usually smear and culture

negative (NAAT insensitive)

• Pleural biopsy culture positive ~60%,

with granulomas ~80%

• Treat as for adenitis or pulmonary TB

Principles of Therapy

• Start 4 drugs (RIPE) for suspected active TB
• Never use a single drug for treating active TB:

resistance can emerge (1 mutant in 104 to 106)

• Never add a single drug to a failing regimen
• Consult and expert and/or local health

department

• Francis Curry National TB Center:

http://www.nationaltbcenter.edu/

Screening for Latent TB Infection (LTBI) Case Presentation

• LV is a 58 y/o female from Ukraine

referred for treatment of hypertension and diabetes

• She is otherwise well
• She gives a history of BCG vaccination

as a teen

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What is the best course of action?

• 1. The patient should be screened for LTBI with a

tuberculin test

• 2. The patient should not be screened for LTBI

because she is not a candidate for INH prophylaxis due to her age

• 3. The patient should not be screened because with

prior BCG vaccination the tuberculin test will be false positive

• 4. The patient should be screened for LTBI by chest

x-ray

Who Should Be Screened?

• Persons likely to have TB infection
• Persons with increased risk of progression
• Not the general population

Increased Risk of Infection

• Recent contacts of an active TB case

– About 30% are infected

• Foreign-born persons from high TB

prevalence areas

– Asia, Mexico, Middle East, Central and South America, Africa, Eastern Europe

• Medically underserved, low-income, racial

and ethnic minorities

• Others: HCW, residents of congregate living

settings

Increased Risk of Progression

• Children < 5 years old
• Recent infection (contacts and converters)
• HIV+
• Prior TB
• Various medical conditions:

– Diabetes, hematologic/reticuloendotheial diseases, intestinal or gastric bypass, renal dialysis – Malabsorption syndromes, malnutrition, silicosis, alcoholism, smokers – Immunosuppression, anti-TNF agents – > 15 mg prednisone QD for > 3 wks

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Risk of Progression

Risk Factor Increase in risk (+TST) AIDS/Advanced HIV 9.9 Anti-TNF agent 7.9 Old TB, untreated 5.2 Diabetes 3.1 Smoker 2.7 Underweight 1.6

Flowchart: Evaluation and Treatment of LTBI

TB Risk?

Tuberculin Test + symptom review Negative Positive Chest x-ray Normal Abnormal STOP

No Yes

Treatment not indicated R/o active TB Candidate for Rx

• f LTBI

Diagnosis of LTBI

TB Skin Test (TST) Interferon-gamma Release Assay (IGRA)

Reading the TST

• Measure reaction in 48

to 72 hours

• Measure induration, not

erythema

• Record reaction in

millimeters, not as “negative” or “positive”

• Positive reactions can

be read for up to 7 days

• Negative reactions can

be read accurately for

• nly 72 hours

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TST Positivity

• 5 mm + PPD

– HIV, immunocompromised, contacts, abnl CXR

• 10 mm + PPD

– Those at increased risk of infection: IVDU, health care workers, foreign born, children < 4 yo, high-risk medical conditions

• 15 mm +PPD

– Persons not at risk (why did you do the test?)

TST/IGRA Conversion

• Signifies new infection
• > 10 mm increase within 2-year period
• Conversions may represent boosted

reactions in some individuals

• IGRA result: prior negative, new

positive (no boosting)

LTBI Testing

• TST should NOT be performed on someone

with a documented history of a positive test

• TST should be applied, read, and interpreted

by a trained health professional

• RULE OUT active TB before treating for LTBI

Interferon-Gamma Release Assays (IGRA)

• Indirect test for M. tuberculosis infection

using whole blood

• Tests for generation of interferon-gamma

by cell-mediated immunity (not antibody)

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FDA Approved Interferon Gamma Release Assays (IGRA)

• Quantiferon-TB Gold and Gold-Plus

(Cellestis, Ltd)

– Uses ESAT-6 and CFP-10 as antigens

• T-Spot-TB (Oxford Immunotec)

– Uses ESAT-6 and CFP-10

IGRA Advantages

• Requires a single patient visit to draw a

blood sample

• Results within 24 hours
• No boosting
• Is not subject to reader bias that can
• ccur with TST
• Is not affected by prior BCG

IGRAS: Species Specificity of ESAT- 6 and CFP-10

Mycobacterial species ESAT-6 CFP-10

• M. tuberculosis

+ +

• M. africanum

+ +

• M. bovis

+ + BCG strains

• M. avium-intracellulare
• M. abscessus
• M. smegmatis
• M. kansasii

+ +

• M. marinum

+ +

• M. szulgai

+ +

Performance of IGRA vs TST

Performance characteristics TST IGRA

Sensitivity 75-91% 80-95% Specificity 80-90% 95-100% Correlates with exposure Often no Yes Results change with Rx ?? Sometimes

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When Should You Use IGRA?

• IGRA generally preferred to TST in those > 5

years of age in whom testing for LTBI is indicated

• Can be used in all circumstances in which the

TST is currently used, including

– contact investigations – evaluation of recent immigrants who have had BCG vaccination – TB screening of health care workers – others undergoing serial evaluation for M. tuberculosis

• Limited data for children < 5 years old and

immunocompromised (IGRA acceptable)

ATS/IDSA/CDC. Clin Infect Dis 2017;64(2):e1–e33

Current LTBI Treatment Guidelines

• Decision to test is decision to treat
• No 35 year-old cut-off
• 9 months of INH 300 mg preferred over 6

months

• 4 months Rifampin 600 mg (better

adherence, better tolerated)*

• Baseline lab monitoring not routinely

indicated

*Menzies, et al. NEJM 379(5):440-453

Rifapentine (Rfp) + INH for Rx of LTBI

Regimen TB rate Compliance AE* (hepatitis)

INH 300 mg qd x 9 mo 15/3745 69% 3.7% (0.4%) Rfp 900 mg + INH 900 mg qwk x 3 mo§ 7/3986 82% 4.9% (2.7%)

NEJM 365:2155, 2011

* Treatment ending

§ DOT or self-administered

What is the best course of action?

• 1. The patient should be offered a tuberculin test to

screen for LTBI

• 2. The patient should not be screened for LTBI

because she is not a candidate for INH prophylaxis due to her age

• 3. The patient should not be screened with

tuberculin test because with prior BCG vaccination the test will be false positive

• 4. The patient should be screened for LTBI by chest

x-ray

• 1. The patient should be offered a tuberculin test to

screen for LTBI

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Thanks!