Determining Risk in Latent Tuberculosis
Determining Risk in Latent Tuberculosis
Background:

 - Tuberculosis (TB) is a leading cause of death worldwide. Those who are exposed to the TB
 bacteria but have not become sick are said to have latent TB. Many people with latent TB will
 not get sick from it, but some people will develop active TB and become sick. Much is known
 about how to treat and diagnose active TB, but little is known about the best way to treat
 latent TB. Researchers also want to know more about the risk that latent TB will develop into
 active TB, and whether it is possible to test for this risk.

 Objectives:

 - To test possible methods of determining a person s risk for developing active TB.

 Eligibility:

 - Individuals between 20 and 60 years of age who (1) have active TB, (2) were exposed to
 someone with active TB in the past 9 months, or (3) have not been exposed to TB.

 Design:

 -  Participants will be separated into groups based on their exposure to TB.

 -  Healthy participants who were not exposed to TB will answer questions about their
 medical history. They will also provide blood and urine samples.

 -  Participants who have active TB will have a physical exam and medical history. They will
 provide blood, urine, and sputum samples, and will have a chest x-ray. They will be
 treated with the standard of care for active TB. Some participants with active TB may
 have additional tests as part of this study.

 -  Participants who were exposed to TB and have latent TB will have a physical exam and
 medical history. They will provide blood, urine, and sputum samples, and will have a
 chest x-ray. They will be asked to return for five more clinic visits over the next 12
 months to repeat these tests. They may also have additional chest imaging studies
 depending on the study needs.

 -  Some of the exposed participants may have been exposed to drug-resistant TB. These
 participants will receive the drug isoniazid to take on a regular schedule to help
 prevent the latent TB from becoming active TB.
The efficacy of treating tuberculin skin test (TST) positive, or interferon gamma release
 assay (IGRA) positive, contacts of tuberculosis (TB) cases to prevent progression to disease
 is well established. However the length of treatment, and the toxicity associated with the
 currently used regimens, means that the risk may outweigh the benefit and treatment
 completion rates are poor. In addition, no proven regimens are available for contacts of
 multidrug resistant tuberculosis (MDR-TB) cases. Because as few as 2% of contacts develop
 active TB over 1 year and no surrogate markers are available, drug trials to assess novel
 treatments typically require thousands of subjects followed up for many years.
 (18F)-fluoro-2-deoxy-D-glucose positron emission tomography/computer tomography (FDG-PET/CT)
 may prove a useful surrogate for more targeted chemoprophylaxis as well as a means to rapidly
 evaluate novel prophylactic regimes in future studies.

 Up to 40% of immune-sensitized TB contacts with normal chest radiographs (CXR) have
 abnormalities on conventional chest CT. FDG-PET/CT not only will allow characterization of
 the metabolic activity of these lesions but is also likely to reveal significantly increased
 metabolic activity within regional lymph nodes that may otherwise be anatomically normal.
 Based on previous studies, we predict that up to 65% of contacts will have combined chest
 PET/CT abnormalities and that up to 50% of contacts who are treated, will have increased FDG
 uptake that will resolve with treatment. By contrast, PET screening studies demonstrate
 abnormal pulmonary FDG uptake occurs in 0.9% of healthy individuals.

 The development of biomarkers more predictive of disease progression is also highly
 desirable, but for similar reasons evaluating them is challenging. This novel approach of
 using FDG-PET/CT to benchmark the dynamic immunological, transcriptional, or metabolic
 changes that occur early in tuberculosis infection, we hope will accelerate biomarker
 discovery. In this study we propose to evaluate these predictions in order to lay the
 foundation for future studies.
-  INDEX CASES:

 INCLUSION CRITERIA:

 1. Either confirmed sputum smear positive and culture positive for M. tb within the last
 12 months OR sputum smear positive and genotypically confirmed M.tb with culture
 awaited

 2. Age greater than or equal to 20 years old

 20 Smear Positive Pulmonary TB Biomarker Index Case Controls:

 INCLUSION CRITERIA:

 1. Genotypically confirmed sputum smear positive pulmonary tuberculosis

 2. Culture awaited or confirmed Mtb

 3. Not commenced anti-tuberculous therapy

 4. Age greater than or equal to 20 years old

 EXCLUSION CRITERIA:

 1. Age >60 years old

 2. Known diagnosis of chronic inflammatory condition (e.g. Sarcoid, RA, connective tissue
 disorder) or on immunosuppressive medication

 WITHDRAWAL CRITERIA:

 1) Culture negative for M.tb

 QF-GIT Positive Contacts:

 INCLUSION CRITERIA:

 1. Contacts of index case

 2. QF-GIT positive

 3. Age greater than or equal to 20 years old

 4. Normal CXR

 EXCLUSION CRITERIA:

 1. Exposure to an index case who commenced treatment for a current episode of TB (one
 that was not successfully treated, per WHO definition) more than 15 months ago

 2. Previously diagnosed or treated TB

 3. Symptoms or signs of active TB

 4. Symptoms or signs of acute illness

 5. CXR suggestive of active tuberculosis or parenchymal abnormalities known or suspected
 to be caused by alternative pathology

 6. HIV positive or other significant immunocompromise

 7. Age >60

 8. Smoker >30 pack years

 9. Previously diagnosed malignancy

 10. Previously diagnosed chronic lung infection (e.g., non tuberculosis mycobacteria
 [NTM], Fungal, Paragonimus)

 11. Known diagnosis of chronic inflammatory condition associated with pulmonary pathology
 (e.g., Sarcoidosis, RA, Wegener s granulomatosis, bronchiectasis)

 12. Inhaled or systemic steroid use within previous 2 weeks (subject may return for
 enrollment 2 weeks after last dose) and need for ongoing steroid therapy

 13. Breast feeding, pregnant, or planning pregnancy

 14. Anticipated poor compliance