Reasons Seen for COPD Patients’ Susceptibility to Severe COVID-19
The infection rate of SARS-CoV-2, the virus that causes COVID-19, is 24 times higher in lab-grown airway cells from people with chronic obstructive pulmonary disease (COPD) than in those from healthy people, a study shows.
This increased susceptibility to infection, which makes severe outcomes more likely, was associated with higher enzyme levels the virus uses to enter cells, as well as higher pro-inflammatory molecule levels and lower levels of anti-viral proteins.
“Collectively, these findings have allowed us to understand the mechanisms of increased COVID-19 susceptibility in COPD patients,” Phil Hansbro, PhD, the study’s senior author, said in a press release. Hansbro is a professor of microbiology at the University of Newcastle and the director of the Centenary UTS Centre for Inflammation, both in Australia,
“We believe that new [therapies] targeting relevant enzymes and pro-inflammatory responses in SARS-CoV-2 infection could have excellent therapeutic potential in reducing the severity of COVID-19 in patients with COPD,” Hansbro added.
The study, “Increased SARS-CoV-2 Infection, Protease and Inflammatory Responses in COPD Primary Bronchial Epithelial Cells Defined with Single Cell RNA-Sequencing,” was published in the American Journal of Respiratory and Critical Care Medicine.
Associated mainly with long-term exposure to irritants such as cigarette smoke, COPD is marked by excessive airway inflammation, lung tissue remodeling, and the progressive destruction of alveoli — the tiny lung air sacs responsible for gas exchange.
Increasing evidence shows COPD patients are more susceptible to severe COVID-19, but the underlying mechanisms of this susceptibility remain largely unclear.
One potential factor is the increased production of ACE2 — the cell surface receptor to which SARS-CoV-2 binds to enter cells — in airway cells following cigarette smoke exposure. Also, COPD patients’ lungs have higher-than-normal levels of proteases, a family of enzymes that include, among others, those used by SARS-CoV-2 to enter cells.
To learn more about what contributes to COPD patients’ increased susceptibility to SARS-CoV-2 infection, Hansbro’s research team, along with colleagues in Australia, analyzed the viral load and gene activity profiles of lab-grown airway cells — called primary bronchial epithelial cells (pBECs) — from four adults with COPD and three healthy adults using a high-resolution technique called single cell RNA-sequencing.
Patients included two women and two men (age range, 67–85 years), while healthy controls comprised two women and one man (age range, 55–75 years). No participant had a history of respiratory tract infection within the past month, or a lung cancer diagnosis.
Results showed that seven days after cells were exposed to SARS-CoV-2, “there was a 24-fold increase of viral load in the COPD patient airway cells compared to the cells taken from healthy individuals,” Matt Johansen, PhD, the study’s first author from the Centenary UTS Centre for Inflammation, said.
Gene activity profiles between infected and bystander cells in both groups were generally similar, highlighting that “there are commonly utilized pathways in SARS-CoV-2 [infection], which are independent of pre-existing disease status,” the researchers wrote.
However, compared with controls, airway cells from COPD patients showed significantly increased levels of the transmembrane protease serine 2 (TMPRSS2), cathepsin B (CTSB), and cathepsin L (CTSL), three proteases known to promote SARS-CoV-2’s entry into cells.
In turn, the levels of several serpins — proteins known to suppress the activity of proteases — were significantly reduced in COPD cells relative to healthy controls, regardless of infection.
These results “highlight a protease imbalance in COPD pBECs, which may be critical for increased SARS-CoV-2 infectivity and severe disease,” the researchers wrote.
“Simply put, easier and increased cell infection makes it far more likely that individuals with COPD will have more severe disease outcomes,” Johansen said.
The team also found the levels of pro-inflammatory molecules linked to COPD’s sudden disease-worsening episodes and severe COVID-19 were significantly increased in both infected and non-infected airway cells from people with COPD.
“COPD is an inflammatory disease with patients having increased inflammation … compared to healthy people,” and “it’s highly likely that SARS-CoV-2 exacerbates this existing high inflammation level which leads to even poorer outcomes,” Johansen said.
Also, key antiviral responses involving proteins called interferons were largely blunted in airway cells from COPD patients compared with those from controls, which may be “a key driver for increased susceptibility to elevated inflammatory responses and viral [infection],” the research team wrote.
ACE2 was found to be significantly increased upon infection in both COPD and control cells, but there were no significant differences between groups, suggesting that ACE2 may not be a contributing factor for increased infection susceptibility in COPD.
In addition, therapeutic interventions suppressing either TMPRSS2, CTSB, inflammation, or all three at the same time, significantly reduced SARS-CoV-2 load and pro-inflammatory molecules in COPD patient cells, in particular.
This is the “first study to show biological evidence that COPD pBECs are substantially more permissive to SARSCoV-2 infection compared to healthy pBECs,” the researchers wrote.
The findings also highlighted that this increased susceptibility is due to protease imbalances, greater inflammatory responses, and reduced interferon responses, potentially outlining “biological mechanisms responsible for exacerbations and severe COVID-19 in COPD,” the research team wrote.
More studies are needed to analyze the relevance of these candidates, as well as the therapeutic potential of targeting protease imbalance, excessive inflammation, or deficient interferon responses in COPD patients with COVID-19.
Hansbro said these results are critical as hundreds of millions of people are affected by COPD globally and COVID-19 will likely be around for years to come.