What the Primary Physician Should Know about Tuberculosis Henry F. - - PDF document

What the Primary Physician Should Know about Tuberculosis

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

Disclosures of Financial Relationships with Relevant Commercial Interests

• None

Topics for Discussion

• Epidemiology
• Diagnosis of active TB
• Latent TB infection

Definitions

• Multi-drug resistant TB (MDR-TB):

Resistance to both INH and rifampin

• Extensively drug-resistant TB (XDR-TB):

Resistance to INH + rifampin + any fluoroquinolone + at least one injectable second line anti-TB agents

Global Impact of TB – 2018

• 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 2018

• ~500,000 new rifampin-resistant cases per year

– 3.4% of new cases, 18% of previously treated cases – 78% MDR (~6% of these are XDR) – India (27% of total), China (14%), Russian federation (9%)

• Mortality

– 1.2 million deaths in HIV-neg – 250,000 deaths in HIV-pos (1/3 of all HIV-related deaths)

2019 WHO Global Tuberculosis Report

Countries with Highest TB Incidence – 2018

2019 WHO Global Tuberculosis Report

US Trends in TB – 2018

• 9,025 cases (0.7% decrease from 2017)
• US rate 2.8/100,000 (1.3% decrease from 2017)
• 515 deaths from TB in 2017 (565 in 2016)
• 70% of US cases occurred in non-US-born people
• 13,000,000 latent TB infections (LTBI)
• Drug resistance

– 9.4% of cases with INH resistance – 98 MDR cases (1.5%) – 1 XDR case

https://www.cdc.gov/tb/publications/factsheets/statistics/tbtrends.htm

Race/ Ethnicity % US cases Incidence per 100,000 Native American 1.2 4.3 Asian 35.3 17.0 Black or African American 19.9 4.4 Native Hawaiian, Pacific Islander 1.3 20.0 Hispanic, Latino 29 4.4 White 11.9 0.5

50% of US Cases

US Trends in TB – 2018

https://www.cdc.gov/tb/publications/factsheets/statistics/tbtrends.htm

Demographic Groups with Higher Rates of TB

• Foreign-born other than Western Europe
• Incarcerated persons
• Homeless, marginally housed
• HIV positive
• Children < age 5 with positive TB test

Active Tuberculosis

• Pulmonary tuberculosis: ~80% of all cases
• The infectious form of the disease
• Clinical suspicion based on

– Signs, symptoms, setting – Chest x-ray

Diagnosis of TB 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

– 2/2012: AFB smear/culture neg x3 – 4/2014: AFB smear/culture neg x3 – 8/2015: AFB smear/culture neg x3 – 3/2017: AFB smear/culture neg x1 – 9/2018: AFB smear/culture neg x4

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%

Performance of Diagnostic Tests for Pulmonary TB

Sensitivity Specificity AFB smear 60% 99% NAAT* 85% 99% Culture 90% 99% PPD (or QTF) 60-70% 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

Organism Burden in TB

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

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%

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

Case Presentation

• 45 yo M from India with 2 weeks of fever and non-

productive cough

• Chest x-ray: right pleural effusion, otherwise negative
• HIV-negative, TST = 20 mm
• Pleural fluid

– 1200 cells/mm3, 65% lymphs – Glucose 90 mg%, Protein 3.5 g/dL, LDH 540 IU/L – Gram-strain, AFB smear negative, cultures pending – Nucleic acid amplification test negative – Pleural adenosine deaminase 9.2 U/L (normal < 9.4)

Which of the following is the best approach

• 1. Treat for latent TB infection with INH or Rifampin
• 2. Perform quantiferon test and if positive, treat for

latent TB infection with INH or Rifampin

• 3. Start 4-drug therapy for active TB
• 4. Perform pleural biopsy, start 4-drug therapy for

active TB

• 5. Perform pleural biopsy, start 4-drug therapy for

active TB if cultures are positive

Active TB Cases by Site

20 40 60 80 100 120 Percent

All Cases

Pulmonary Extrapulmonary

Extrapulmonary

Lymphatic Pleural Bone/jt Peritoneal GU CNS Other

Work-up of Suspected Extrapulmonary TB

• Tuberculin test (negative does not it rule out)
• Check HIV serology (also true for any TB)
• Chest x-ray to r/o pulmonary TB
• Get tissue for histopathology, culture (and

NAAT)

Diagnosis of Extrapulmonary TB

• Tissue is the issue

– to exclude other etiologies – for sensitivity testing

• FNA (lymph node) or biopsy

Characteristic granulomas in 80%

– Culture + in 40-70% – Smear + < 50%

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 2019; 25:1000-1005 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)

Principles of Therapy

• Start 4 drugs (RIPE) for suspected active TB

– INH 300 mg once daily – Rifampin 600 mg once daily – Pyrazinamide 25 mg/kg once daiky – Ethambutol 15-25 mg/kg once daily

• 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: https://www.currytbcenter.ucsf.edu/

Treatment of Extrapulmonary TB

• Same as for pulmonary TB although 9-12 months for

CNS, bone, joint

• Responsive to medical therapy alone
• Paradoxical “worsening” can occur

Latent TB Infection (LTBI)

Case Presentation

• Lev P is a 58 y/o male from Ukraine referred for

treatment of hypertension and diabetes

• He is overweight, otherwise well
• He gives a history of BCG vaccination as a teen

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 (new CDC guidance*), residents of congregate

living settings

*MMWR / May 17, 2019 / Vol. 68 / No. 19/ page 439

Increased Risk of Progression

• Children < 5 years old
• Recent infection (contacts and converters)

– Recent = within 2 years of documented prior negative – Conversion: a positive TST of ≥10 mm and an increase of at least 6 mm in induration compared with the last TST

• 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

Risk of Progression

Risk Factor Increase in risk (+TST) AIDS/Advanced HIV 9.9 Anti-TNF agent, others Mabs 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

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 of skin test 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)

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 occur 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

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

LTBI Treatment Guidelines

• Decision to test is decision to treat
• No 35 year-old cut-off
• Preferred regimens, no pregnancy, no HIV (better tolerated, higher

completion rates)*:

– Rifampin 600 mg x 4 months (better compliance, similar tox) (120 doses within 6 months, re-initiate if break > 2 months) – Rifapentine weight based dosing + INH 900 mg once weekly for 12 weeks* (11 doses within 16 weeks, re-initiate if break > 2 months)

• 9 months of INH 300 mg (preferred over 6 months) (270 doses within 12

months, re-initiate if break > 3 months) in pregnant patient

• 25-50 mg per day of pyridoxine daily for INH regimens
• Rifapentine/INH in selected HIV+ patients; rifabutin can sub for rifampin

*MMWR/June 29, 2018/Vol. 67/No. 25/Page 723

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

Monitoring LTBI Treatment

• Baseline lab monitoring (AST. ALT, Billirubin) not routinely indicated
• Baseline monitoring indicated for any of the following

– Known liver disease, risks for chronic liver disease – History of liver disease (e.g., hepatitis B or C, alcoholic hepatitis, or cirrhosis), – Regular use of alcohol – HIV infection – Pregnancy or the immediate postpartum period (i.e., within 3 months of delivery)

• After baseline testing, routine periodic retesting is recommended for persons

who had abnormal initial results and other persons at risk for hepatic disease

• Laboratory testing is recommended for patients who have symptoms

suggestive of hepatitis

• Withhold therapy for 3x ULN AST/ALT with symptoms, 5x without

What is the best course of action for Lev?

• 1. The patient should be offered IGRA testing for LTBI (and HIV testing)
• 2. If the IGRA is positive, a CXR should be obtained to r/o active

disease

• 3. If the CXR is negative for active TB the patient should be offered
• Rifampin for 4 months or
• Rifapentine/INH for 12 weeks
• 4. Assess need for monitoring and review meds.

Thanks!