Research links rare, pathogenic variants with COVID-19 severity
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Researchers have found certain rare and pathogenic thrombotic microangiopathy-associated variants among patients with severe COVID-19, according to study results presented at the virtual ASH Annual Meeting and Exposition.
The findings suggest genetic susceptibility and define proof-of-concept for proper selection of patients who may benefit from complement inhibition, researchers noted.
“Our research was prompted by a scientific question that has arisen along with the COVID-19 pandemic: Why do some people infected with COVID-19 have few or no symptoms and others become gravely ill?” Eleni Gavriilaki, MD, PhD, researcher in the department of hematology at George Papanikolaou General Hospital in Thessaloniki, Greece, told Healio. “To answer this question, we invested in expertise gained by our laboratory in past years in complement-related diseases. Because severe COVID-19 disease shares common characteristics with thrombotic microangiopathy, we hypothesized that certain genetic mutations may influence the course of COVID-19 for some patients.”
Thrombotic microangiopathy is characterized by genetic susceptibility and presents with thrombocytopenia, anemia, elevated lactate dehydrogenase and organ damage, according to Gavriilaki.
For the prospective study, Gavriilaki and colleagues enrolled 60 consecutive adults hospitalized with COVID-19 in Greece between April and May whose diagnosis was confirmed by reverse-transcriptase polymerase chain reaction (RT-PCR). The researchers assessed COVID-19 severity by WHO criteria as moderate/severe and critical disease. Patients with moderate/severe disease (n = 40) were hospitalized in the COVID-19 general ward and patients with critical disease (n = 20) were hospitalized in ICUs.
The investigators gathered patient DNA from peripheral blood samples, and additional data on patient history and course were reported by the treating physicians who followed patients until discharge or death.
Eleven patients died of COVID-19.
Results of genetic analyses showed a median 62 (range, 51-89) variants, including those that were pathogenic, benign, likely benign and of unknown significance.
Seven patients each had one pathogenic or likely pathogenic variant in C3, CD46, DGKE and CFH. Twenty-eight patients carried a pathogenic variant of ADAMTS13 (rs2301612, missense).
Researchers additionally detected two missense risk factor variants that had been found in complement-related diseases, including rs2230199 in C3 (n = 13) and rs800292 in CFH (n = 26). Twenty-two patients had a combination of these variants, which was significantly associated with critical COVID-19 severity requiring intensive care (P = .037) as well as low lymphocyte counts (P = .021) and high neutrophil-to-lymphocyte ratio (P = .05).
Results of a multivariate model showed critical disease as an independent predictor of double heterozygocity in these variants, Gavriilaki added.
One patient with critical COVID-19 who survived after long-term ICU care had a rare germline missense variant in CFI (rs112534524), which was previously identified in complement-related diseases. Five patients who did not require ICU admission had a likely protective missense variant in CFB (rs641153).
“We are now working on algorithms for disease risk prediction, which for now suggests a protective variant in C3 is found in the majority of female patients [72.2%] who did not require ICU hospitalization,” Gavriilaki said. “This is compatible with the data we have on gender differences in patients with COVID-19.”
The results provide proof of concept for the potential benefits of complement inhibitors, especially for selected patients with complement-related genetic mutations, she added.
“If our results are verified, patients who harbor certain mutations could benefit from early and aggressive treatment with complement inhibitors,” Gavriilaki said. “We are in the process of verifying our results in larger validation cohorts. Using artificial intelligence models, we are also currently choosing which mutation or combination of mutations could be used as a simple molecular PCR assay to detect patients at risk for severe COVID-19.”
Perspective
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Iberia Romina Sosa, MD, PhD
Complement activation has been described in critically ill patients with COVID-19 infection. A role for complement inhibition in the pathogenesis of COVID-19 was suspected based on similarities in the clinical presentation and autopsy results of patients with COVID-19 and those clinically observed in thrombotic microangiopathy syndromes. The premise of this study was to investigate whether patients admitted with severe COVID-19 infection displayed defective complement regulation, specifically attributed to genetic susceptibility in complement proteins, which has been described in atypical hemolytic uremic syndrome (aHUS), a form of thrombotic microangiopathy.
The findings provide a new, welcomed perspective to our growing body of evidence describing the pathogenesis of complement activation in COVID-19 infection. However, there are a few caveats to be considered while building this story. The associations reported would be strengthened if the study included a mild disease group, with the assumption that if pathogenic variants contribute to susceptibility for COVID-19 infection severity, this group would have a low frequency of pathogenic variants. By the same token, the extent of protective missense variants or benign variants would be higher in the mild disease group. The inclusion of asymptomatic patients despite testing positive for COVID-19 also would add a new dimension to support the role of genetic susceptibility in COVID-19 infection.
A better understanding of genetic risks in the pathogenesis of COVID-19 infection would be expected to have important implications in our repertoire of therapeutic interventions. Currently, phase 2 and phase 3 studies targeting different components of the complement cascade have been initiated as the medical community expands its repertoire of therapies to mitigate the end-organ damage of virus infection.
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Gavriilaki E, et al. Abstract 376. Presented at: ASH Annual Meeting and Exposition (virtual meeting); Dec. 5-8, 2020.
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