Defining Small Airways Disease as a Therapeutic Target in Post-Acute Sequela of COVID-19 (PASC)
Abstract
FY21 PRMRP Focus Area: This project is directly responsive to the Topic Area of Respiratory Health, and addresses the Focus Area of encouragement: Research focused on acute and chronic lung injury/disorders due to viral infections, such as SARS-CoV-2. This project investigates novel mechanisms of shortness of breath and exercise limitation after SARS-CoV-2 infection. Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, has infected over 36 million people, and killed over 600,000 people in the United States as of August 2021. While treatments for acute COVID-19 infection have significantly improved since the disease was first identified in December 2019, a growing number of patients report ongoing symptoms that last for weeks or months after their infection resolves. These persistent symptoms have become known as post-acute sequelae of SARS-CoV-2 (PASC), or long COVID. Shortness of breath and limited exercise capacity are among the most common complaints in patients with long COVID, with many patients saying that these symptoms impact their quality of life and physical capabilities. With hundreds of thousands of military personnel, dependents, and contractors infected with SARS-CoV-2, long COVID is expected to be a major crisis for the military health system. The underlying cause of long COVID symptoms is unknown, and because of this lack of knowledge, treatment options are currently limited. Routine diagnostic tests, such as lung function testing (PFTs) and computed tomography (CT) imaging, often don’t show anything abnormal even in patients with severe symptoms of long COVID. Unfortunately, this makes effective treatment for long COVID impossible. There is an urgent need to develop better tools for diagnosis and to get a clearer understanding of the disease in order to treat patients effectively. We propose that many of the symptoms of long COVID are caused by inflammation and scarring of the small airways – a condition that would lead to shortness of breath and would be difficult to detect with standard diagnostic tests. The lungs contain airways, or pipes, that carry oxygen and other gases into and out of the lungs. The airways start at the trachea (or windpipe) and progressively branch into smaller airways as they move further into the lungs. Small airways are less than 2 mm in diameter. Small airways show signs of damage or abnormality in the early stages of many lung diseases, including after respiratory infections with viruses. Recent studies have shown that some patients with long COVID who have problems breathing have a feature called air-trapping on CT. This pattern on CT, which has also been reported after other respiratory viral infections, suggest that there may be inflammation (i.e., an active immune response) or fibrosis (i.e., thickening and scarring of the tissue) in the small airways of the lungs. However, CT has a limited ability to see damage in the small airways, so the number of affected patients may be much greater than the number with abnormal CT scans. It has been reported that up to 50%-60% of PASC patients do not show any abnormal imaging findings on CT. CT is also not able to differentiate between inflammation and fibrosis in the small airways, and the treatments for these diseases are very different. Thus, there is an urgent need for better diagnostic tools that can accurately identify changes in the small airways, and differentiate between inflammation and fibrosis, in order to prescribe effective treatments for long COVID patients. Rationale: Current standard-of-care diagnostic techniques are inadequate to identify the cause of persistent shortness of breath (dyspnea) in patients with long COVID. Our objective is to characterize the airways of patients using an innovative combination of advanced cardiopulmonary exercise testing (CPET), endobronchial optical coherence tomography (EB-OCT) imaging, single-cell RNA sequencing
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210712
Entities
People
- Charles Hardin
Organizations
- Massachusetts General Hospital
- United States Army