Alternative complement pathway upregulated in severe, critical COVID-19

In patients with severe coronavirus disease 2019 (COVID-19), the leptin and alternative complement pathways are hyperactivated, which in turn might lead to greater inflammation, a new study has found.

Whole blood samples were drawn from 32 COVID-19 patients (median age 55.6 years, 75 percent men), of whom 10 had severe disease and 11 were critical. To assess the role of the complement system in promoting inflammation in COVID-19, expression levels of 28 complement genes were measured at the transcriptomic and protein levels. A parallel group of 13 healthy controls (median age 59.2 years, 77 percent men) was also included in the analysis.

The researchers found 19 differentially expressed genes that could be clustered into two groups according to disease severity. In particular, the first group, expressed at higher levels in moderate disease, included genes in the classical complement pathway such as the C1QA, C1QB, and C5 genes.

Meanwhile, the second group of genes was highly expressed in patients with severe and critical COVID-19 and contained genes belonging to alternative complement (C3 and CFP genes, which encodes for the protein properdin) and lectin (MBL2 and C4 genes) pathways.

Protein analysis found that despite heightened RNA expression in severe COVID-19, properdin protein levels decreased with increasing disease severity, “suggesting the deposition of properdin to complement activating surface and the triggering of the alternative pathway,” the researchers said.

Receiver operating characteristic curve analysis further identified properdin as a strong predictor of the need for mechanical ventilation, with an area under the curve of 0.82 (p=0.002) at a threshold of 25.5 µg/mL.

“Specific targeting of the alternative pathway rather than the classical pathway may prove useful to control disease severity without hampering essential antiviral responses,” the researchers said.