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Immune complement and coagulation dysfunction in adverse outcomes of SARS-CoV-2 infection

Our take —

With data from a retrospective cohort study, transcriptional profiling of nasopharyngeal swabs, and candidate-driven genetic association study, these results add to the growing body of research that suggests the complement system and coagulation function influence severity of COVID-19. Given these results, additional research should investigate whether people with pre-existing hyperactive complement or coagulation disorders are more susceptible to the virus, and whether complement/coagulation-targeting therapies are effective.

Study design

Case Series, Retrospective Cohort

Study population and setting

This was a three-part study: 1) a retrospective clinical analysis to evaluate whether history of macular degeneration or coagulation disorders were associated with intubation or death among 6,393 individuals diagnosed with SARS-CoV-2 infection from a single medical center in New York City from February 1 to April 25, 2020; 2) a transcriptomic analysis of 650 SARS-CoV-2 infected patients and controls from a second medical center in New York City to identify differentially regulated genes and pathways; and 3) a candidate-driven genetic association analysis of two releases of UK Biobank data (April 2020 and May 2020) to identify variants associated with hospitalization for SARS-CoV-2. Data for the retrospective clinical study were collected from contemporary (current encounter) and historical (collected before September 24, 2019) data in electronic health records. Macular degeneration was used as a proxy for complement activation disorders. History of coagulatory disorders was defined as any previous thrombocytopenia, thrombosis, or hemorrhage.

Summary of Main Findings

Among 6,393 SARS-CoV-2 patients (median age: 57 years, 50% female) in the retrospective cohort, 88 had a history of macular degeneration, 4 had a complement deficiency disorder, and 1,179 had a coagulation-related disorder. Overall, 484 patients were intubated and 618 died. In Cox models adjusting for age and sex, macular degeration and coagulation disorders were associated with severe COVID-19 outcomes (intubation and death). Whole genome RNA sequencing comparing SARS-CoV-2 infected individuals to controls indicated that, in addition to previously reported biomarkers of poor clinical outcome (type 1 interferons and dysregulation of IL-6 dependent inflammatory responses), activation of complement and coagulation-related gene sets were associated with SARS-CoV-2 infection. Finally, UK biobank data from April 2020 identified 11 variants associated with severe clinical outcomes following SARS-CoV-2 infection, 6 of these associations were replicated in data from May 2020. Several of the variants are linked to complement and coagulatory functions.

Study Strengths

This study leveraged multiple data sources to explore a range of clinical and genetic associations between complement- and coagulation-related factors and SARS-CoV-2 infection and outcome.

Limitations

The retrospective clinical study did not adjust a number of possible confounders, such as other comorbidities, socio-economic status, and access to care, that are related to complement/coagulation disorders and COVID-19, so residual confounding is likely. False positive results are a general concern in genetic association studies, and the discordance between the April 2020 and May 2020 UK Biobank data casts uncertainty on the findings. The three analyses were performed on three different study populations, attenuating inference across analyses.

Value added

This was a thorough and multi-level study of the relationship between coagulation and complement-related factors and severe SARS-CoV-2 outcomes.

This review was posted on: 13 October 2020