Tuberculosis in Twenty Minutes

Kevin L. Winthrop, MD, MPH

Assistant Professor
Divisions of Infectious Diseases, Public
Health, and Preventive Medicine
Oregon Health & Science University
Portland, OR

Tuberculosis (TB)
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 to
disease

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

Reported TB cases
United States, 19822010*

*Updated as of July 21, 2011.

Centers for Disease Control. July 2011.

TB Case Rates, United States, 2010*

*Updated as of July 21, 2011.

Centers for Disease Control. July 2011.

Trends in TB Cases in Foreign-born

Persons, United States, 19872010*
Percentage

*Updated as of July 21, 2011.

Centers for Disease Control. July 2011.

a priori probability

World Health Organization.

Clinical Presentation Site of Disease

Reported TB Cases by Form of Disease United States, 2001
Both
Extrapulmonary
7.4%
20.1%
Pleural
18.3%
Pulmonary
72.5%

Lymphatic
42.5%
Other
12.3%
Bone/joint
10.2%

Peritoneal
Genitourinary Meningeal 4.6%
6.0%
5.9%

Antituberculosis
Therapy
Second-Line Drugs
First-Line Drugs
Isoniazid (INH)
Rifampin (RIF)
Pyrazinamide
(PZA)

Ethambutol (EMB)
Rifabutin
Rifapentine

Streptomycin
Cycloserine
p-Aminosalicylic acid
Ethionamide
Amikacin or kanamycin
Capreomycin
Levofloxacin
Moxifloxacin
Gatifloxacin

Primary MDR TB,

United States, 1993 -2010*

*Updated as of July 21, 2011

Note: Based on initial isolates from persons with no prior history of TB.
MDR TB: resistance to at least INH and rifampin .

Bennett, et al. Am J Respir Crit Care Med. 2008; 177:34855.

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--release assay; TST:
tuberculin skin test.

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

Measuring T Cell Responses to TB

Inject Tuberculin
PPD

Presenting cell
T cell

release (IFN-gamma)

Cell recruitment
&
Activation

Swelling at
Injection Site

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

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)

Interferon-gamma Release Assays

(IGRAs)
T-Spot.TB
QuantiFERON-TB Gold

Species Specificity of ESAT-6 and CFP-10

Tuberculosis
complex

M tuberculosis
M africanum
M bovis
BCG substrain
gothenburg
moreau
tice
tokyo
danish
glaxo
montreal
pasteur

Antigens
ESAT

CFP

+
+
+

+
+
+

Environmental
strains
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

Antigens
ESAT

CFP

+
+
+
-

+
+
+
-

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

The
Challenge
How do you evaluate a new diagnostic test
without a Gold Standard?

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.

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).

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

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

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

3 IR Therapy
Number of Subjects with TB and Event Rates
Population and Study
Group

No. of
Subject

Modified intention-to-treat
analysis

Subjects with TB

no.

no. per pt.

pop

cumulative
rate

Isoniazid only

3745

15

0.16

0.43

Combination therapy

3986

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 self
administered daily isoniazid (300 mg). Data are shown for period up to 33 mos. after study
enrollment.

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

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