Clinical trial NCT05027958: Characterization of Tissue-Specific Immune Responses to Bronchoscopic Instillation of Mycobacterial Antigens Into the Human Lung
Official title: Characterization of Tissue-Specific Immune Responses to Bronchoscopic Instillation of Mycobacterial Antigens Into the Human Lung
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Healthy
Latent Tuberculosis Infection (LTBI)
Keywords: Tuberculin Purified Protein Derivative
PPD
antigen-specific immune cells in airways
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2021-08-31
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: Background:

Tuberculosis (TB) is a lung disease. It is caused by inhaling a type of airborne bacterium. Tuberculin Purified Protein Derivative (PPD) is used to test for TB exposure. It is usually injected under a person s skin. In this study, it will be applied in the lung.

Objective:

To learn how the cells within the lung react (immune response) when exposed to PPD.

Eligibility:

Adults ages 18-64 who (1) have been exposed to TB but do not have active disease or symptoms or (2) have never been exposed to TB.

Design:

Participants will be screened with a medical history, physical exam, and blood tests. They will have a TB skin test. They will also have an electrocardiogram to examine heart rhythm. For this, sticky patches will be placed on their chest.

Some screening tests will be repeated at study visits.

Participants will have 3 FDG PET-CT scans. They will lie in a machine that creates pictures of the inside of their body. They will get a radioactive substance injected into their arm called 18FDG. It helps make the pictures.

Participants will have 3 bronchoscopies. Their mouth and nasal airways will be numbed. They will get drugs to relax. A tube will be inserted through their nose or mouth into a lung. Fluid will be delivered into the lung and suctioned back out to collect cells. They will get PPD during the first bronchoscopy.

Participation will last for about 30 days. Participants will visit the clinic up to 8 times. They will go home after each procedure. No hospital stays are needed....

Detailed description: Study Description: We propose a pilot study in which we employ directed bronchoscopic instillation of Mycobacterium tuberculosis (Mtb)-Tuberculin Purified Protein Derivative (PPD) to evaluate local airway immune response in adults with or without latent tuberculosis infection (LTBI).

Primary Objective: The primary objective of this study is to understand the pulmonary immune response to mycobacterial antigens by determining the persistence of antigen-specific immune cells in the airways versus circulation after local bronchoscopic instillation of Tuberculin Purified Protein Derivative (PPD) into the lungs of adults with or without LTBI.

Secondary Objective: The secondary objective is to characterize the location and persistence of immune cell activity in the pulmonary parenchyma and thoracic lymph nodes with positron emission tomography combined with chest computed tomography (PET-CT) after bronchoscopic Tuberculin Purified Protein Derivative (PPD) instillation in adults with or without LTBI.

Exploratory Objectives: (a) An exploratory objective will be to perform phenotypic and functional analysis of immune cell populations in the airways vs circulation following bronchoscopic instillation of Tuberculin Purified Protein Derivative (PPD) into the lungs of individuals with or without LTBI. (b) An additional exploratory objective will be to characterize the production of soluble mediators (including but not limited to: cytokines, lipid mediators, and defensins) in BAL fluid vs blood within the same context.

Endpoints:

Primary Endpoint: The primary endpoint will be the enumeration of Mtb antigen-specific CD4+ and CD8+ T cell populations in the airway and peripheral blood at early and late time points after bronchoscopic Tuberculin Purified Protein Derivative (PPD) instillation.

Secondary Endpoint: The secondary endpoint will be the quantification of \[18F\]fluoro-D-glucose (FDG) uptake in adjacent pulmonary parenchyma and draining thoracic lymph nodes via PET-CT at early and late time points after PPD instillation.

Exploratory Endpoints: (a) An exploratory endpoint will be the quantification of frequencies of cell surface molecules, intracellular cytokines and transcription factors among immune cell populations in the airways vs circulation following bronchoscopic instillation of Tuberculin Purified Protein Derivative (PPD) into the lungs of individuals with or without LTBI. (b) An exploratory endpoint will involve the identification and quantification of soluble mediators in the airway and peripheral blood after PPD instillation in the lungs within the same context.

Eligibility criteria: * INCLUSION CRITERIA:

Adults 18-64 years old will be recruited for the two groups (non-LTBI controls vs confirmed LTBI). The lower limit of this age range is based on the need for invasive bronchoscopic procedures and exposure to radiation, both of which carry more risk at younger ages. In addition, most adults present with post-primary or reactivation TB that most often occurs radiographically in the upper lobes of the lungs, often with cavitation. Conversely, children and rare adults with primary TB have non-cavitary disease in the lower lobes. The higher limit of this age range is based on the known property of immune senescence, i.e., the waning of the strength of immune responses with advancing age.

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

* Ability of subject to understand and the willingness to sign a written informed consent document.
* Stated willingness to comply with all study procedures and availability for the duration of the study
* Male or female, aged 18 - 64 years of age
* No significant active medical problems. This would include but not limited to any cardiac disorder (e.g. arrhythmia, valvular disease), pulmonary disease (e.g. asthma requiring chronic medications, chronic bronchitis, emphysema, obstructive sleep apnea), kidney disease (e.g. nephritis, nephrosis), rheumatologic disorder (e.g. inflammatory arthritis), endocrine disorder (e.g. diabetes, thyroid disease), liver disease (e.g. hepatitis), gastrointestinal disorder (e.g. inflammatory bowel disease) or infectious disease (e.g. active tuberculosis).
* For females of reproductive potential: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation
* For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner and agreement to use such a method during study participation

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from participation in this study:

* Pregnancy as assessed by urinary or plasma HCG or breastfeeding
* History of clinically significant respiratory dysfunction 3 months prior to participating

  * Evidence of new pulmonary infection
  * History of any chronic lung infections or chronic lung disease
  * History of pulmonary hypertension
  * Need for supplemental oxygen administration at rest
* Current use or inability to suspend use of anticoagulant therapy including platelet inhibitors (e.g. clopidogrel) within 7 days of study bronchoscopy or systemic anticoagulants (e.g. warfarin, enoxaparin, or DOAC) within 14 days of study bronchoscopy
* Any symptoms consistent with infection including fever, chills, night sweats, or unexplained weight loss
* A history of a necrotic reaction to a tuberculin skin test, including during screening
* A history of human immunodeficiency virus (HIV) infection
* A history of coughing up blood in the last 3 months
* Cigarette smoking, vaping or recreational drug use within the past 6 months (self-reported)
* If there is any discrepancy in tuberculin skin test and Interferon Gamma Release Assay test results (i.e. PPD+ but IGRA- or PPD- but IGRA+)
* Refusal or inability to undergo bronchoscopy, or a history of poor tolerance of a bronchoscopy
* If undergoing PET-CT imaging during this study places a participant over his/her annual radiation dose limit. Radiation exposure within the previous 12 months of \>= 2.3 rem
* BMI \> 40
* Diabetes
* Known life-threatening allergic reaction to Tuberculin, Lidocaine, Midazolam, Fentanyl or medications of similar classes
* Presence of any immunosuppressive diseases, including cancers with the exception of non-melanomatous skin cancer.
* Use of any systemic immunosuppressive medications, including corticosteroids (e.g., prednisone) or biological agents in the last 6 months prior to enrollment
* Any medical, psychiatric, social condition, occupational reason or other responsibility, in the judgement of the investigator, that is a contraindication to protocol participation or impairs a participant s ability to give informed consent
* Positive for COVID-19. (with-in 6 months prior to enrollment self-reported and or via PCR)

Primary outcomes:
measure: pulmonary immune response to mycobacterial antigens
timeFrame: 30 days
Secondary outcomes:
measure: location and longevity of immune cell activity in the pulmonary parenchyma and thoracic lymph nodes
timeFrame: 30 days
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
Study officials:
affiliation: National Heart, Lung, and Blood Institute (NHLBI)
name: Kevin P Fennelly, M.D.
role: PRINCIPAL_INVESTIGATOR
References: