乌鸦传媒

People with cardiovascular disease and clonal hematopoiesis of indeterminate potential (CHIP) appeared to be primed for the excessive inflammatory response typical of COVID-19, a small study found.

People with the most common acquired mutations in CHIP -- DNMT3A or TET2 sequence variations -- had mutated white blood cells with significantly increased expression of inflammatory genes, including:

• Interleukin 1β
• The interleukin 6 (IL-6) receptor
• The NLRP3 inflammasome complex
• CD163, a cellular receptor capable of mediating infection, macrophage activation syndrome, and other genes involved in cytokine response syndrome (CRS)

The most significantly upregulated genes encoded for leukocyte-activation and interleukin-signaling pathways in monocytes, according to Andreas Zeiher, MD, of Goethe University in Frankfurt, Germany, and colleagues. Their manuscript appeared in .

"Taken together, the apparent sensitization ... may provide a putative explanation for the increased morbidity and mortality of COVID-19 in elderly patients and patients with cardiovascular disease," the authors suggested.

CHIP, an age-associated condition of expanded somatic blood cell clones (due to acquired leukemic sequence variations) without other hematological abnormalities, has been associated with excess cardiovascular risk, including coronary artery disease, chronic heart failure, and severe calcified aortic valve stenosis.

The implications from the new study are that people with DNMT3A or TET2 CHIP-driver sequence variations may be identified as high-risk for adverse outcomes of COVID-19, and that patients infected with SARS-CoV-2 could be tested for these variations to personalize IL-6-targeted treatment strategies to mitigate CRS, the investigators suggested.

However, this hypothesis linking CHIP and COVID-19 is based on the controversial idea that exuberant inflammation is a major contributing factor to poor outcomes in COVID-19, according to Siddhartha Jaiswal, MD, PhD, of Stanford School of Medicine, California, who was not involved in the study.

"The Regeneron-sponsored trial in severe COVID-19 was negative, whereas the trial of dexamethasone was positive. I suspect there will be several studies examining the link between CHIP, dysregulated inflammation, and COVID-19 coming out in the next several months," Jaiswal told 乌鸦传媒.

Zeiher's group performed single-cell RNA sequencing to find activation of the inflammatory cascade from the transcriptome of circulating peripheral monocytes. Blood samples were drawn from eight patients with severe degenerative aortic valve stenosis, six with chronic post-infarction heart failure, and three age-matched healthy controls.

All patients were recruited prior to the outbreak of COVID-19 in Europe. Patients with evidence for acute inflammatory or hematological disease were excluded.

Participants averaged 75.7 years of age. The cohort included six women. Mean CHIP-driver gene variant allele frequency was 4.2% for DNMT3A and 14.3% for TET2 for each person.

"Although single-cell sequencing is an extremely powerful method to decipher the transcriptional signatures of individual cells in an unbiased manner, its very high costs prohibit large-scale studies using this technique. Therefore, the present study is limited by its small sample size and should be regarded as hypothesis generating," Zeiher's group acknowledged.

Nevertheless, the findings are "entirely consistent with prior data in mice and people," according to Jaiswal.

Comment