Training Protocol on the Natural History of Tuberculosis

Mycobacterium tuberculosis is a slow-growing bacterium that establishes latent infection in
millions of persons worldwide, but only leads to disease in 10% or less of these individuals.
It typically causes pneumonia, however dissemination to almost any other organ is possible.
Drug resistance of the organism, co-infection with HIV, and paradoxical reactions upon
treatment are all factors that may complicate treatment.

Host defense against mycobacterial infections is important. Specific defects within the
innate immune system lead to Mendelian susceptibility to mycobacterial infections. Human
immunodeficiency virus (HIV) infected individuals and persons treated with anti-tumor
necrosis factor antibodies are highly susceptible to tuberculosis infection. Genetic
influence on susceptibility to TB disease is complex and does not seem to be confined to a
single gene or pathway.

Advancement in molecular techniques has expanded our understanding of the pathogenesis and
epidemiology of M. tuberculosis. Identification of gene mutations that confer antibiotic
resistance are being exploited as alternatives to conventional drug susceptibility testing.

The natural history of all forms of TB disease (including co-infection with HIV and other
infections) will be followed, and M. tuberculosis isolates and blood from 100 infected
patients will be obtained in order to study organism virulence and host immune function and
genetic/epigenetic factors. While it is recognized that the number of tuberculosis cases that
occur in the Washington, DC area and nationally is low, it is imperative that a mechanism is
in place to evaluate and treat these patients at the NIH Clinical Center. This protocol will
allow NIH infectious diseases trainees to manage challenging cases of tuberculosis.

- INCLUSION CRITERIA:

For All Patients

Patients may be included in this study who:

- Have a type of TB disease which, in the opinion of the Principal Investigator (PI),
will assist in meeting the Primary Objective of this study (i.e., Develop experience
in the standard of care of tuberculosis patients ).

- Are aged 2 years or older.

- Have a primary care physician, infectious diseases physician, pulmonologist, or
tuberculosis specialist outside of the NIH who can provide care of his or her TB
infection outside the NIH, provide directly observed therapy (DOT) if necessary, and
monitor for side effects and toxicity of TB medications.

- Are willing to consent to storage of specimens for future research.

- Subjects enrolled will be able to provide informed consent for themselves, or if they
lack the capacity to provide informed consent, the study team will comply with MAS
M87.4, if the Principal Investigator believes there is the prospect of direct benefit
for the patient.

For Patients with Latent TB

In addition to the above described inclusion criteria for all patients, patients may be
included in the Latent TB part of this protocol who:

- Have documented evidence of a positive PPD skin test or Interferon Gamma Release Assays
(IGRA) test meeting American Thoracic Society (ATS)/CDC guidelines for latent TB (Appendix
B); conversion can have occurred at any time.

For Patients with Active TB

In addition to the above described inclusion criteria for all patients, patients may be
included in the Active TB part of this protocol who:

- Have active tuberculosis of any drug susceptibility pattern and any site of infection
as determined by smear, culture, or biopsy.

- Have appropriately documented clinically suspicious active tuberculosis without
definitive microbiology confirmation.

EXCLUSION CRITERIA:

Patients will be excluded from this study who:

- Are incarcerated.

- Have been ordered by a court to take TB medications.

- Are unwilling or unable to comply with prescribed therapy.

- Subjects that lack the capacity to provide informed consent autonomously are excluded;
unless there is an appropriate legal guardian, Durable Power of Attorney (DPA) or
surrogate who is willing to provide consent. A Bioethics consult will make this
determination, based on an assessment of the patient and potential surrogate, in
accordance with policy MAS M87-4.