Training Protocol on the Natural History of Tuberculosis

Natural History of Tuberculosis

Background:

- Tuberculosis (TB) is an infectious disease that affects numerous people worldwide. Researchers are interested in actively recruiting individuals with TB for research and treatment studies.

Objectives:

- To collect blood and other samples to study the natural history of tuberculosis.

Eligibility:

- Individuals 2 years of age and older who have either active or latent tuberculosis.

Design:

• Latent TB patients: Participants will have a single study visit with a physical examination and medical history, and will provide blood samples for testing.
• Active TB patients: Participants will have an initial visit with a physical examination and medical history, and will provide blood samples for testing. Participants will also provide sputum samples if required, and may have an optional skin punch biopsy to collect a sample of skin tissue for study.
• Treatment for active TB will be provided as part of this protocol.
• Active TB participants may be asked to return for study visits every 1-2 months while receiving treatment....

Study Overview

• Status: Recruiting
• Conditions: Mycobacterium Infections; Latent Tuberculosis; Tuberculosis; Tuberculosis, Multidrug-Resistant; Extensively Drug-Resistant Tuberculosis

Detailed Description

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.

• Study Type: Observational
• Enrollment (Estimated): 150

Contacts and Locations

• Study Contact: Name: Steven M Holland, M.D.; Phone Number: (301) 402-7684; Email: sholland@mail.nih.gov
• Study Contact Backup: Name: Carla D Williams, R.N.; Phone Number: (301) 443-9460; Email: carla.williams@nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center
      • Contact: Carla Williams, B.S.N.; Phone Number: 301-443-9460; Email: williamscd@mail.nih.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients will be referred by their physicians for study participation. In many cases, participants will be referred by physicians at their local health department tuberculosis clinics (where they often receive DOT for TB treatment). Family members may be recruited through requests made by the index case that family members contact study personnel for participation. A patient can be referred at any time point while he or she is receiving active treatment for tuberculosis. Male and female patients will be accepted without preference. Patients age 2 and older are eligible; however, severe infections may require highly specialized pediatric teams and institutions. Some referrals of pediatric cases will not be able to be handled appropriately at the NIH and may be deemed ineligible for admission, as determined by the Principal Investigator (PI). NIH employees and members of their immediate families may participate in this protocol.

Description

• 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.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Active TB; subjects with active TB as determined by smear, culture, or biopsy or have appropriately documented clinically suspicious active TB without definitive microbiology confirmation
Latent TB; subjects with 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Increase in the number of TB patients being actively followed at the NIH CC to provide information on TB patients with DS and drug-resistant disease for hypothesis generation and hands-on experience in the management of TB	increased number of TB patients being actively followed at the NIH CC	ongoing

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determination of subsets of lymphoid populations during various points in the treatment of TB	subsets of lymphoid populations during various points in treatment of TB	ongoing
Description of whole genome sequences and their possible relationship to TB infection	possible relationship of whole genome sequences to TB infection	ongoing
Collection of MTB specimens for studies of the organism and its pathogenesis	collection of MTB specimens	ongoing

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Principal Investigator: Steven M Holland, M.D., National Institute of Allergy and Infectious Diseases (NIAID)

Publications and helpful links

General Publications

• Rosenzweig SD, Holland SM. Defects in the interferon-gamma and interleukin-12 pathways. Immunol Rev. 2005 Feb;203:38-47. doi: 10.1111/j.0105-2896.2005.00227.x.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): June 30, 2011

Study Registration Dates

• First Submitted: September 29, 2010
• First Submitted That Met QC Criteria: September 29, 2010
• First Posted (Estimated): September 30, 2010

Study Record Updates

• Last Update Posted (Estimated): April 18, 2024
• Last Update Submitted That Met QC Criteria: April 17, 2024
• Last Verified: April 9, 2024

More Information

Terms related to this study

• Keywords: Natural History; Tuberculosis; TB; Latent Tuberculosis; Mycobacterium Tuberculosis; Active Tuberculosis; MDR TB
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Latent Infection; Mycobacterium Infections; Tuberculosis; Latent Tuberculosis; Tuberculosis, Multidrug-Resistant; Extensively Drug-Resistant Tuberculosis
• Other Study ID Numbers: 100195; 10-I-0195

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No