WinthropREVFeb27BDF.pdf

8/18/2019 WinthropREVFeb27BDF.pdf

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Tuberculosis in Twenty Minutes

Kevin L. Winthrop, MD, MPH

Assistant Professor

Divisions of Infectious Diseases, PublicHealth, and Preventive Medicine

Oregon Health & Science University

Portland, OR


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• M. tuberculosis complex

– M. tuberculosis, M. bovis, M. africanum

• One-third of world is infected

• In 90%, infection remains latent

– Infection spread limited by immune system

• 10% develop disease

– Immunosuppression increases risk of progression todisease

Tuberculosis (TB)


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TB Pathogenesis

• Transmitted by inhalation or ingestion of M. tuberculosis bacilli

– Bacilli replication

– Brief hematogenous dissemination

• Cytokine and cellular activation

• Immune system attempts to limit spread of infection

– Granuloma formation around bacilli

– Intracellular killing of bacilli


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Reported TB cases

United States, 1982–2010*

Centers for Disease Control. July 2011.*Updated as of July 21, 2011.


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TB Case Rates, United States, 2010*

*Updated as of July 21, 2011. Centers for Disease Control. July 2011.


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Trends in TB Cases in Foreign-born

Persons, United States, 1987–2010*

Percentage

*Updated as of July 21, 2011. Centers for Disease Control. July 2011.


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a priori probability

World Health Organization.


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Pulmonary

72.5%

Extrapulmonary

20.1%

Both7.4%

Pleural 18.3%

Lymphatic

42.5%

Bone/joint 10.2%

Genitourinary

5.9%

Meningeal 6.0%

Peritoneal

4.6%

Other 12.3%

Clinical Presentation Site of DiseaseReported TB Cases by Form of Disease United States, 2001


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• Isoniazid (INH)

• Rifampin (RIF)

• Pyrazinamide

(PZA)

• Ethambutol (EMB)

• Rifabutin

• Rifapentine

First-Line Drugs Second-Line Drugs Antituberculosis Therapy• Streptomycin

• Cycloserine

• p-Aminosalicylic acid

• Ethionamide

• Amikacin or kanamycin

• Capreomycin

•

Levofloxacin• Moxifloxacin

• Gatifloxacin


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Primary MDR TB,

United States, 1993 -2010*

*Updated as of July 21, 2011Note: Based on initial isolates from persons with no prior history of TB.MDR TB: resistance to at least INH and rifampin .


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Bennett, et al. Am J Respir Crit Care Med. 2008; 177:348–55.


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Winthrop. Intl J Rheum. 2010;8(2):43-52.

Risk Factors for Prior Tuberculosis

Exposure• Known prior exposure to active tuberculosis case

• Birth or extended residence in a country where tuberculosis is

prevalent

• Latin America, Asia, the Caribbean, Eastern Europe, Africa, Russia

• History of living or working with congregate settings where TB is more

common

• Jail or prison, homeless shelters, health care centers that treat TB

patients

• History suggestive of prior LTBI diagnosis including the following:

• Prior positive screening tests (TST, IGRA)

• Chest radiographic findings (ie, fibronodular opacities) associated with

prior TB

LTBI: latent tuberculosis infection; IGRA: interferon-ү-release assay; TST:tuberculin skin test.


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Measuring T Cell Responses to TB

release (IFN-gamma)

T cell

Presenting cell

Cell recruitment

&

Activation

Swelling at

Injection Site

Inject Tuberculin

PPD


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LTBI Diagnosis• Tuberculin Skin Test – 10mm is positive result for most

• If already immunocompromised (e.g., HIV, chronic

steroid usage, anti-TNF drugs) – 5 mm cut-point to define TST positive result

– If TST negative, consider epidemiologic risk factors

and radiologic findings


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Problems with TST…

• Return visit necessary

• Poor inter-reader reliability

– 9 mm (negative) vs. 10mm (positive)?

• False negatives/sensitivity (anergy)

• False-positives/specificity

– NTM infection

– Prior Bacille-calmette Guerin (BCG) vaccination

• Poor positive-predictive value in low prevalence

populations (like US)


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Interferon-gamma Release Assays

(IGRAs)

• T-Spot.TB

• QuantiFERON-TB Gold


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Species Specificity of ESAT-6 and CFP-10Environmental

strains

Antigens

ESAT

CFP

M abcessus - - M avium - - M branderi - - M celatum - - M chelonae - -

M fortuitum - - M gordonii - - M intracellulare - - M kansasii + + M malmoense - - M marinum + + M oenavense - -

M scrofulaceum - - M smegmatis - - M szulgai + + M terrae - - M vaccae - - M xenopi - -

Tuberculosis

complex

Antigens

ESAT

CFP

M tuberculosis + +

M africanum + +

M bovis + +

BCG substrain

gothenburg - -

moreau - -

tice - -

tokyo - -

danish - -

glaxo - -

montreal - -

pasteur - -

Andersen, et al. Lancet. 2000;356(9235):1099-104.


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The ChallengeHow do you evaluate a new diagnostic testwithout a Gold Standard?

=


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IGRAs Performance Compared to TST

Performance TST IGRA

Est. sensitivity 75-90% 85-95%

Est. specificity 80-90% 95-100%

Correlates with exposure Depends Yes

Results change with Rx ?? Yes

Diel, et al. CHEST. 2010;137(4):952-58.


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New CDC Guidelines• IGRAs preferred for: – Unlikely to return for TST reading

– BCG vaccinated

• TST preferred:

– Kids under 5

Little specific guidance: Immunocompromised

settings, use of quantitative values for QFT-IT

MMWR. 2010;59(RR5).


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Immunosuppression• Increased risk of progression of latent TB infection(LTBI) to active disease

• Medical conditions

–

Renal disease, cancer, rheumatoid arthritis (RA),transplant recipients, diabetes, HIV, others

• Immunosuppressive therapies

– Corticosteroids, tumor necrosis factor antagonists

(anti-TNF), anti-T cell therapies, others


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IGRA Role in Screening

Immunosuppressed• Role of IGRA and how to use

– Replacement of TST?

– Supplement to TST?

• Last 5 years

– Large number of head to head studies

– Rheumatic diseases, HIV, transplant, others


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LTBI Treatment• Begin treatment before starting anti-TNF therapy – 9 months isoniazid (INH) preferred in U.S.

– 4 months rifampin is alternative

• Start INH one month prior to anti-TNF initiation

– 83% reduction in infliximab-associated cases Spain

(Carmona et al. Arthritis Rheum 2005)

– Ensure INH compliance and tolerance

• Liver function testing

– Many patients on methotrexate


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3 IR Therapy

Sterling, et al. N Eng J Med. 2011;365:2155-66.

Number of Subjects with TB and Event Rates

Population and Study

Group

No. of

SubjectSubjects with TB

Modified intention-to-treat

analysis no.

no. per pt.

pop

cumulative

rate

Isoniazid only 3745 15 0.16 0.43

Combination therapy 3986 7 0.07 0.19

Combination therapy consisted of 3 months of directly observed once-weekly therapy with

rifapentine (900 mg) plus isoniazid (900 mg). Isoniazid-therapy consisted of 9 mos. Of selfadministered daily isoniazid (300 mg). Data are shown for period up to 33 mos. after study

enrollment.


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Participate in more Tuberculosis in the 21st

Century webcasts:

• 100 Years of TB Testing – Dr. John J. Cush

• Tuberculosis in Twenty Minutes – Dr. Kevin L. Winthrop

• Detection of Latent TB infection in the Immunosuppressed Patient

– Defining the Utility of IGRA in a Vulnerable Population – Dr.

Arthur Kavanaugh

• Tuberculosis and Biologics: Relating Mechanisms of Action to

Immunopathogenesis of Granulomatous Infections – Dr. Xavier

Mariette

• Panel Discussion – Dr. Leonard Calabrese, Moderator

www.ccfcme.org

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