Because they are molecularly susceptible to SARS-CoV-2, patients with chronic lung diseases appear to be primed for worse outcomes after infection, through the dysregulation of genes related to viral replication and the innate immune response in epithelial cells, and basal differences in inflammatory cell gene expression programs, according to a new study. The authors cautioned that patients with idiopathic pulmonary fibrosis are most at risk, but the greater danger also affects those with chronic obstructive pulmonary disease and interstitial lung disease.
An aircrew walks in from the flightl ine during a sandstorm at Sather Air Base, Iraq in 2006. Exposures such as that increase risk of chronic lung diseases, which, in turn, can make COVID-19 more severe. Source: U.S. Air Force photo by Staff Sgt. William Bennett
TEMPE, AZ — Airborne environmental exposures during military service —including Agent Orange, burn pits, sandstorms or fumes from aircraft exhaust put veterans at an increased risk of chronic lung conditions such as chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD) and especially idiopathic pulmonary fibrosis (IPF).
(High use of tobacco products, which have been documented in current and former servicemembers, just further exacerbate the diagnoses.)
These conditions, which have grown in prevalence and incidence among veterans over the past decade, have presented a particular concern during the pandemic, as patients with chronic lung disease have been shown to have increased risk of severe disease and significantly higher COVID-19 mortality rate.
A recent study, which details the genetic changes caused by chronic lung disease in the molecular makeup of a variety of cells, including the epithelial cells that line the lung and airways, helps explain why chronic lung disease puts people at increased for poor COVID-19 outcomes, and potentially offers new insight into reducing that risk.1
The international study was led by researchers at Translational Genomics Research Institute (TGen) Tempe, AZ, who wanted to put the knowledge they had gained on the genetics of one form of chronic lung disease—ILD —to improve the understanding of how COVID-19 affect people with that and other lung diseases.
“As scientists and physicians, we wanted to contribute to the urgent need to understand more about the COVID-19 pandemic and the virus that caused it, SARS-CoV-2,” said Linh T. Bui, PhD, a postdoctoral research fellow at TGen and lead author of the study, which was published in Nature Communications. “While we were not virologists, our labs have been studying the genetic composition of ILD and have considerably deep knowledge of the genetic and molecular mechanisms that regulate lung homeostasis and disease, and how these programs changed in disease.”
For their work in ILD, the group had collected a large single-cell RNA sequencing (scRNA-seq) data set derived from tissues that came from patients with chronic lung disease and others with healthy lungs, said Bui. “We quickly realized that we had the unique opportunity to gain an understanding of why patients with chronic lung disease are doing poorly with SARS-CoV-2 infection and severity.”
To increase the scope and power of their study, the researchers pulled together a group of researchers with similar datasets. The result of this collaboration was an integrated scRNA-seq dataset consisting of transcriptomes of 611,398 single cells from healthy (78 samples) and CLD lungs, including obstructive pulmonary disease (COPD, 31 samples), idiopathic pulmonary fibrosis (IPF, 82 samples) and other non-IPF interstitial lung diseases (19 samples).
Second, the researchers mined into the literature to gain some understanding of the known pathways involved in SARS-CoV-2 viral entry, infection and host responses. “We then focused our study on the expression of genes in these pathways in disease lungs versus healthy control lungs and whether changes in gene expression led to the alterations of these pathways that result in a more severe response to SARS-CoV-2 infection,” Bui said.
In the cells of CDL patients, the researchers observed broad changes and dysregulation in the gene expression profile related to viral infection and host response, suggesting that CLD patients may respond completely differently to viral infection, including SARS-CoV2, compared to individuals without lung disease.
Specifically, they identified in patients with CLD a preexisting dysregulation of genes involved in viral infection and the immune response in the disease epithelial cells, especially AT2 cells, compared to healthy cells.
“A severe inflammatory condition called acute respiratory distress syndrome, or ARDs, can be triggered in a viral infection,” said Bui. In ARDS, damage to alveolar cells—both AT2 and type 1 (AT1)—will lead to the alveolus being filled with fluid and inflammatory cells; thus, preventing gas exchange, she said. Many of the patients with COVID-19 who were hospitalized in an ICU or died developed ARDS in response to their infection.
Other key findings of the study included the following:
- The viral entry score, which is a composite of all genes associated with SARS-CoV-2 entry into the cells, is increased in the lungs of patients with CLD.
- Patients with CLD have a higher proportion of CD4, CD8 and NK cells than controls.
- The expression of cytotoxicity and exhaustion genes in the T-cell populations is increased and there are alterations in the expression level of genes involved in the viral response pathways (interferon, antigen presentation) in disease compared to healthy cells.
In short, “patients with chronic lung disease may be molecularly susceptible to SARS-CoV-2 and primed for worse outcomes after infection, through the dysregulation of genes related to viral replication and the innate immune response in epithelial cells, and basal differences in inflammatory cell gene expression programs,” Bui said.
The findings have the potential to affect decisions concerning the treatment plan and medication being administered to patients when they are hospitalized due to COVID-19 infection, said Bui. For example, serum interleukin-6 elevation was previously found to associate with COVID-19 severity and mortality, and the use of tocilizumab, an IL-6 antibody, has been used in COVID-19 treatment to treat COVID-19 induced cytokine storm, she said. “In our study, we found that IL-6 associated tocilizumab responsive genes are expressed higher in the IPF and other-ILD samples, but not COPD samples; thus, suggesting that different COVID-19 treatment approaches should be considered when it comes to patient’s comorbidities.”
- Bui LT, Winters NI, Chung MI, Joseph C, Gutierrez AJ, et. al. Human Cell Atlas, Lung Biological Network. Chronic lung diseases are associated with gene expression programs favoring SARS-CoV-2 entry and severity. Nat Commun. 2021 Jul 14;12(1):4314. doi: 10.1038/s41467-021-24467-0. PMID: 34262047; PMCID: PMC8280215.