Relationship of Fungal Translocation, Inflammation, and Pulmonary Function in HIV
Trial Snapshot
- Phase
- Not Applicable
- Status
- Active, not recruiting
- Sponsor
- University of Pittsburgh
- Enrollment
- 102
- Locations
- 1
- Primary Endpoint
- Assess intestinal and lung permeability with the lactulose/mannitol differential sugar absorption test
Study Overview
Brief Summary
The investigator will study the origin of fungal translocation in HIV, its relationship to the mycobiome, and its relationship to lung function and inflammation. Supported by the preliminary data and published studies, this project is based on the premise that circulating BDG derived from microbial translocation stimulates inflammation and worsens lung function in PWH.
Chronic obstructive pulmonary disease (COPD) is a significant public health problem with few therapies that modify disease trajectory. COPD is a leading cause of mortality in the United States associated with increased morbidity and healthcare costs. Long-acting bronchodilators and inhaled corticosteroids are mainstays of therapy that control symptoms and reduce acute exacerbation frequency, but do not have a significant impact on mortality or lung function trajectory. The National Heart, Lung, and Blood Institute's COPD National Action Plan focuses on the critical need for research to characterize COPD risk factors and disease mechanisms in order to improve the understanding of causes and progression of disease. The ultimate goal is to provide precision therapy to appropriate patient subgroups to preserve health or arrest disease progression.
Microbial organisms in the gut may have a profound effect on lung disease. The role of the gut-lung axis, defined as the cross-talk between gut microbiota and the lungs, in the pathogenesis of chronic respiratory diseases is emerging as an area of interest. Perturbations of gut microbiota characterized by low microbial diversity and changes in microbiota abundance are linked to childhood asthma risk, airflow obstruction in adult asthma, and severe lung dysfunction in cystic fibrosis. Studies in animals show that both a high fiber diet that modulates gut microbiota and an abundance of beneficial bacterial strains attenuate inflammation, emphysema, and COPD development in response to cigarette smoke exposure in murine models. In humans, recent investigations show differences in the gut microbial communities between COPD patients and healthy individuals as well as shifts in the gut microbiome with acute exacerbations of COPD.
Detailed Description
Baseline, 18 month and 36 month visits will all be the same.
URINE COLLECTION/INGESTION OF HYPOTONIC SOLUTION:
Assessment of gut epithelial barrier integrity: Gut epithelial barrier integrity will be measured by the lactulose/mannitol differential sugar absorption test. The test will be performed at the CTRC the morning of the baseline visit. After an overnight fast, participants will be asked to ingest a solution of 5 grams of lactulose and 2 grams of mannitol in 100 mL of tap water. All urine passed in the subsequent five hours will be collected. Total urine volume will be measured and then a 100 mL volume will be stored at -80 degrees Celsius for later measurement of sugar absorption.
BLOOD:
The investigator will obtain approximately 90 ml (6 tablespoons) blood samples for measurement of BDG and proteins. Blood will be processed for serum, plasma, and PBMCs. Small amount will be used for hemoglobin and carboxyhemoglobin to accurately interpret PFT data.
Study Design
- Study Type
- Observational
- Observational Model
- Cohort
- Time Perspective
- Prospective
Eligibility Criteria
- Ages
- 18 Years to 80 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Age 18 to 80
- •HIV positive
- •Virally-suppressed on ART for at least 6 months
- •subjects enrolled in Dr. Morris's HLRC Studies STUDY20020151, STUDY19080258, STUDY19060243, STUDY19070181, STUDY19070181, STUDY19050326 OR subjects being seen at the HIV/PACT clinics.
Exclusion Criteria
- •Contraindication to pulmonary function testing (i.e., abdominal or cataract surgery within 3 months, recent myocardial infarction, etc.).
- •individuals with clinical or radiographic evidence of another significant pulmonary diagnosis (e.g. interstitial lung disease, active asthma)
- •inflammatory bowel disease
- •pregnancy
- •use of antibiotics in the prior 2 weeks
- •immunomodulators in the prior 6 months
- •unable to perform any study procedures.
Outcomes
Primary Outcomes
Assess intestinal and lung permeability with the lactulose/mannitol differential sugar absorption test
Time Frame: urine collection over 6 hours after ingestion of sugar solution at baseline
measure of BDG levels with the Fungitell assay44 in urine collected after 5 grams of lactulose and 2 grams of mannitol have been ingested
Assess intestinal and lung permeability with the lactulose/mannitol differential sugar absorption test
Time Frame: urine collection over 6 hours after ingestion of sugar solution at 18 months
measure of BDG levels with the Fungitell assay44 in urine collected after 5 grams of lactulose and 2 grams of mannitol have been ingested
BDG levels will be assayed in undiluted plasma samples
Time Frame: Blood will be collected at baseline after ingestion of 5 grams of lactulose and 2 grams of mannitol.
Using the Fungitell Assay (Associates of Cape Cod, East Falmouth, MA)62,63 according to manufacturer's instructions, modified to utilize a lower standard curve, 7.8 -250 pg/mL. The Fungitell Assay is a chromogenic kinetic test that was approved by the Food and Drug Administration in 2003 for the clinical measurement of BDG with \>80 pg/mL is considered a positive test.
BDG levels will be assayed in undiluted plasma samples
Time Frame: Blood will be collected at 18 months after ingestion of 5 grams of lactulose and 2 grams of mannitol.
Using the Fungitell Assay (Associates of Cape Cod, East Falmouth, MA)62,63 according to manufacturer's instructions, modified to utilize a lower standard curve, 7.8 -250 pg/mL. The Fungitell Assay is a chromogenic kinetic test that was approved by the Food and Drug Administration in 2003 for the clinical measurement of BDG with \>80 pg/mL is considered a positive test.
BDG levels will be assayed in undiluted plasma samples
Time Frame: Blood will be collected at 36 months after ingestion of 5 grams of lactulose and 2 grams of mannitol.
Using the Fungitell Assay (Associates of Cape Cod, East Falmouth, MA)62,63 according to manufacturer's instructions, modified to utilize a lower standard curve, 7.8 -250 pg/mL. The Fungitell Assay is a chromogenic kinetic test that was approved by the Food and Drug Administration in 2003 for the clinical measurement of BDG with \>80 pg/mL is considered a positive test.
Assess intestinal and lung permeability with the lactulose/mannitol differential sugar absorption test
Time Frame: urine collection over 6 hours after ingestion of sugar solution at 36 months
measure of BDG levels with the Fungitell assay44 in urine collected after 5 grams of lactulose and 2 grams of mannitol have been ingested
Secondary Outcomes
- Determine if higher circulating BDG levels predict disease progression and systemic immune cell activation in HIV COPD(baseline)
- Determine if higher circulating BDG levels predict disease progression and systemic immune cell activation in HIV COPD(at 18 months)
- Determine if higher circulating BDG levels predict disease progression and systemic immune cell activation in HIV COPD(at 36 months)
Investigators
Ioannis Konstantinidis
Assistant Professor
University of Pittsburgh