The angiotensin converting enzyme 2 (ACE2) receptor, which enables entry of SARS-CoV-2 into lung epithelial cells, appears to mediate the severity of COVID-19 in patients with chronic obstructive pulmonary disease (COPD), according to a research letter published in the Annals of the American Thoracic Society.

The authors sought to identify molecular interactions between COVID-19 and lung cells in 70 patients with COPD. Potential effects of smoking exposure and/or use of inhaled corticosteroids on expression of ACE2 were examined. Linear regression analysis was used to identify genes associated with forced expiratory volume in 1 second (FEV1).

There was a negative correlation between the level of ACE2 expression and FEV1 in the 70 former smokers with COPD. Neither ICS use (P =.687) or cumulative smoking exposure (P =.999) in these patients significantly affected ACE2 expression.

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The researchers attempted to validate these observations in a Lung Tissue Research Consortium (LTRC) cohort. They also evaluated how many of the reported SARS-CoV-2 host protein-protein interaction (PPI) genes were differentially expressed in regard to COPD or airflow limitation severity.

In the LTRC, the investigators found 18 SARS-CoV-2 host PPI genes differentially expressed in COPD compared with nonsmoker control individuals. These genes included ACE2, AP2A2, ATP1B1, CIT, DCAF7, ERMP1, FAM98A, GDF15, GNB1, IDE, LOX, NPTX1, PUSL1, SIRT5, TAPT1, TMED5, TMPRSS2, USP54, and WFS1.

A total of 1249 genes were significantly associated with FEV1 in the patients with COPD, and 31 genes belonged to the SARS-CoV-2 PPI network. In the LTRC cohort, there was a significant association between a total of 2993 genes and FEV1, and 34 genes belonged to the SARS-CoV-2 PPI network. In addition, ACE2, FAM98A, MFGE8, and HMOX1 were found to be differentially expressed in the patients with COPD vs the LTRC cohort.

A limitation of this study is the lack of data on circulating ferritin levels in the patients with COPD, which could have served as a marker of the patients’ COVID-19 severity. In spite of this limitation, the investigators wrote their findings “contribute to a better understanding of the molecular relationships between COVID-19 and COPD.”


Agusti A, Sibila O, Casas-Recasens S, et al. Molecular interactions of SARS-CoV-2 in lung tissue of patients with chronic obstructive pulmonary disease. Ann Am Thorac Soc. Published online May 5, 2021. doi:10.1513/AnnalsATS.202006-619RL