Training Protocol on the Natural History of Tuberculosis

Mycobacterium tuberculosis (MTB) 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. HIV infected individuals and persons treated with anti-tumor necrosis factor antibodies are highly susceptible to tuberculosis (TB) 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 MTB. 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 MTB 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 TB 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 also allow NIH infectious diseases trainees to manage challenging cases of TB.

• INCLUSION CRITERIA:

FOR ALL PATIENTS

Patients may be included in this study who:

• Have or are suspected to have TB infection.
• Are aged 2 years or older.
• Have a primary care physician, infectious diseases physician, pulmonologist, or TB 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.
• Able to provide informed consent for themselves or, if they lack the capacity to provide informed consent, have an appropriate Legally Authorized Representative (LAR; the study team will comply with NIH Human Research Protection Program [HRPP] Policy 403).

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 purified protein derivative (PPD) skin test or Interferon-gamma Release Assays (IGRA) test meeting American Thoracic Society (ATS)/CDC guidelines for latent TB; 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 TB of any drug susceptibility pattern and any site of infection as determined by smear, culture, or biopsy.
• Have appropriately documented clinically suspicious active TB 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.
• Are pregnant.

EXCLUSION OF SPECIFIC POPULATIONS

Children: Children under the age of 2 are not eligible to enroll. The addition of the very young will not provide enough additional insights to justify the risk to this specific population.

Pregnant women: Pregnant women are not eligible for participation in this protocol because the study objectives can be achieved without the enrollment of this population. Enrolled participants who become pregnant during the study will be withdrawn.