Why Do Some People Get Severe COVID-19?

In a meta-analysis of over 24,000 patients with COVID-19 who spent time in the ICU, common genetic links point to evidence that may lead to an understanding of why some patients end up with severe respiratory virus and need acute hospital care.

“We found 49 common genetic associations with critical COVID-19 meeting our criteria for genome-wide significance in the absence of heterogeneity,” the study authors wrote.

There were over 2000 investigators involved in the study, which involved hospitalized COVID-19 patients requiring continuous cardiorespiratory monitoring or defined as having critical illness in the United Kingdom, during 2020-2022.

The study authors looked at the patients in this study and combined this information with data sets in patients treated around the world. In this study, 16 of the 49 common DNA sequences had not previously been reported.

The study was published in Nature.

The Unique Findings
The authors explain these DNA sequences may factor into both genes and proteins that involve the immune system. An accompanying article in Nature discussed the findings.

“Raging immune cells have long been implicated in causing some of the tissue damage seen in late-stage, severe cases of COVID-19. Baillie [Kenneth Baillie, study lead author] and his colleagues found genetic links to inflammatory responses and the activation of immune cells—processes that can damage the lungs and reduce their capacity to send oxygen to the body’s tissues.”

Baillie said in an interview these findings may point to the processes that lead to severe respiratory distress or sepsis. “These are likely to be processes that are active in other conditions,” Baillie, an intensive-care specialist at the University of Edinburgh, UK, said. “Everything that we’ve done in COVID will, I think, be relevant to other groups of patients that we haven’t identified yet.”

While the analysis confirmed previous studies on gene associations, it did reveal some novel evidence. “We identified 15 unique proteins linked to critical illness…Of the significant results, we found causal evidence implicating five new proteins in comparison to our previous [Generalized Summary-data-based Mendelian Randomisation] GSMR analysis,” the authors wrote. “Conditional analysis revealed two additional lead variants and statistical fine-mapping provided credible sets of putative causal variants for a majority of lead variants.”

Understanding the Genome Sequences Could Lead to Testing, Treatment
The study authors wrote the importance of genetic studies create the basis to understanding and aiding in the development of testing and therapeutics. “Our previous report of association between higher expression and critical illness, led directly to the inclusion of a new drug, baricitinib, in a large clinical trial; the result demonstrated a clear therapeutic benefit,” they wrote. “This therapeutic signal is consistent across multiple trials, providing the first proof-of-concept for drug target identification using genetics in critical illness and infectious disease.”

Limitations
The authors pointed out some of their limitations. “Our analysis is limited to common variants that are detectable on genotyping arrays and imputation panels. Although most lead variants are not directly causal, in some cases, they highlight molecular mechanisms that alter clinical outcomes in COVID-19, and may have direct therapeutic relevance.”