Uganda I AM OLD-DA Study (Inflammation, Aging, Microbes, Obstructive Lung Disease and Diffusion Abnormalities).
Study period: July 1, 2015-April 30, 2025.
The I AM OLD-DA Study is a multi-cohort study with clinical sites in Kampala, Uganda (and San Francisco, CA, USA) whose goal is to examine potential mechanisms for the development of obstructive lung disease and progression of airflow obstruction and diffusion abnormalities in a cohort of HIV-infected subjects recovered from opportunistic pneumonia.
The widespread use of antiretroviral therapy has changed HIV/AIDS from a near-universally fatal disease to a chronic medical condition with near-normal life expectancy in HIV-infected individuals responding to antiretroviral therapy. As a result, persons with HIV/AIDS develop medical conditions such as chronic obstructive pulmonary disease (COPD), typically seen in older individuals. COPD is an HIV-associated lung disease and a leading cause of morbidity and mortality, and its clinical significance is increasing as the HIV population ages worldwide. Despite this, our understanding of the mechanisms underlying HIV-associated COPD is limited, but both HIV-related and COPD- specific mechanisms are hypothesised. An improved account is critical for developing new therapies to treat or prevent this growing problem.
This study builds upon a novel, established multinational (Uganda and US) cohort of persons with HIV/AIDS who recovered from acute opportunistic pneumonia, including tuberculosis (TB). Our data show that different markers are associated with additional lung function abnormalities, suggesting that these abnormalities may be due to different underlying mechanisms. Interestingly, cytomegalovirus (CMV), which is a chronic viral infection common in HIV+ persons, has been associated with the three markers most strongly associated with one of the lung function abnormalities.
These data lead to the following specific aims:
Aims 1 and 2: To test the hypothesis that persistent abnormalities in selected markers of immune activation, inflammation, lung injury, and cellular ageing measured in the blood are associated with subsequent changes (declines) in lung function and that the specific markers associated with each lung function abnormality will be different. The longitudinal study design will strengthen the causal inferences from our earlier work. It will set the foundation for future trials of therapeutic interventions, including the potential for personalised medicine with potentially novel and/or different therapies for different biomarkers and/or lung function abnormalities.
Aim 3: In a cross-sectional subset of HIV-infected participants selected to undergo bronchoscopy and collect lung specimens, to test the hypothesis that abnormalities in the same markers but now measured in lung specimens are associated with abnormal lung function and test the hypothesis that asymptomatic CMV co-infection is also associated with lung function abnormalities and is mediated by these markers. This aim will determine whether CMV co-infection is involved in lung function abnormalities and potentially set the stage for trials of anti-CMV therapy in HIV-associated COPD.
To address these aims, we will conduct a longitudinal study of 400 HIV-infected subjects (200 in the US and 200 in Uganda) and collect and bank blood specimens simultaneously with lung function testing. We will also perform bronchoscopy in a subset of 80 subjects (40 in the US and 40 in Uganda) and collect and bank lung specimens and specimens to assess for CMV co-infection at the same time as lung function testing. The banked samples will allow efficient future testing of new and novel markers. Our long-term objective is to improve our mechanistic understanding of lung function abnormalities in persons with HIV. This would lead to a future study that tests new treatments for this critical and growing clinical problem.
Study site: China-Uganda Friendship Hospital-Naguru, Kampala
Collaborators: Infectious Diseases Research Collaboration, Makerere University College of Health Sciences, and the University of California San Francisco.
Principal Investigators: William Worodria
Study Sponsor: National Institutes of Health (NIH). National Heart, Lung, and Blood Institute (NHLBI)
Uganda I AM GOLD Study (Integrated Analysis of Microbial and Genomic Data in Obstructive Lung Disease).
Study period: September 15, 2019-July 31, 2024.
The I AM GOLD Study is a multi-cohort study with clinical sites in Kampala, Uganda (and San Francisco, CA, USA) whose goal is to examine potential microbial and host mechanisms for the development of obstructive lung disease and progression of airflow obstruction and diffusion abnormalities in a cohort of HIV-infected subjects recovered from opportunistic pneumonia. I AM GOLD enrols a subset of participants enrolled in I AM OLD-DA
Our central hypothesis is that enhanced Th17-driven inflammation and chronic Gammaproteobacteria-dominated airway microbiota interact to contribute to obstructive lung disease in HIV-infected individuals. In HIV-uninfected patients with COPD, we have found that a genomic signature of Th17-driven airway inflammation marks a subgroup with functional small airway disease thought to precede emphysema. Second, Th17-driven inflammation, a pathway classically thought to defend against bacteria, is enhanced in the airways of HIV-infected patients. Third, our group has shown that amongst Ugandan HIV-infected patients with pneumonia, a population at higher risk for lung function decline, subgroups are characterised by distinct lower airway microbial communities with differing immune responses. One subgroup had Pseudomonadaceae-dominated airway microbiota and inflammatory gene expression. Gammaproteobacteria, which includes Pseudomonas, are commonly found in COPD and, as with Th17 inflammation, are associated with emphysema. Thus, the Pseudomonadaceae-dominant pneumonia subgroup may be at higher risk for developing chronic disease in continued dysbiosis and low-level Th17-driven chronic inflammation.
These data lead to the following specific aims:
Aim 1: To identify the airway microbial communities and inflammatory gene expression markers during acute infection associated with subsequent incident COPD and lung function decline in persons with HIV/AIDS.
Aim 2: To identify the airway microbial communities and inflammatory gene expression markers during chronic stable disease enhanced in HIV-associated COPD compared to participants without COPD.
Aim 3: To perform integrative analyses of the airway microbiome, microbial and human transcriptome, metabolome and lung radiographic changes in HIV+COPD.
Study site: China-Uganda Friendship Hospital-Naguru, Kampala
Collaborators: Infectious Diseases Research Collaboration, Makerere University College of Health Sciences, and the University of California San Francisco
Principal Investigators: Laurence Huang, William Worodria, Susan Lynch, and Stephanie Christenson
Study Sponsor: National Institutes of Health (NIH). National Heart, Lung, and Blood Institute (NHLBI)
