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Effects of a major deletion in the SARS-CoV-2 genome on the severity of infection and the inflammatory response: an observational cohort study

Our take —

This study provides evidence from Singapore that a SARS-CoV-2 variant (involving a 382-nucleotide deletion in the ORF8 protein) was associated with a less severe clinical presentation, and found that differences in concentrations of immunological markers may mediate this relationship. Although this variant is now apparently extinct, the deletion is in a region coding for the ORF8 protein, which has previously been associated with the immune response to SARS-CoV-2 infection. The paper presents compelling evidence for further investigation of the role of the ORF8 protein in SARS-CoV-2 pathogenesis.

Study design

Cross-sectional

Study population and setting

This study includes data from 131 patients with PCR-confirmed SARS-CoV-2 infection collected between January 22 and March 21, 2020 in Singapore. Authors were interested in understanding the relationship between a 382-nucleotide deletion in open reading frame (ORF) 8 of the SARS-CoV-2 genome and clinical presentation of the disease. Eligible patients were enrolled in an ongoing prospective cohort study of COVID-19 (PROTECT) conducted at seven public hospitals in Singapore, and therefore had detailed clinical data available from electronic medical records. All patients, regardless of disease severity, were isolated in hospital until two consecutive negative PCR test results. Plasma concentrations of 45 immune mediators were measured with a multiplex assay in a subset of 97 individuals with available plasma.

Summary of Main Findings

The authors found that 92 of the 131 (70%) patients were infected with wild-type virus only (no deletion), 29 (22%) had virus with the 382-nucleotide deletion, and 10 (8%) had co-infection with these two virus types. In four individuals with co-infections for which serial samples were available, the variant virus (with the deletion) replaced the wild-type virus starting in the second week of infection. Patients with the variant virus had better clinical outcomes: none with only the 382-nucleotide deletion developed hypoxia needing supplemental oxygen, required ICU admission, or required mechanical ventilation (3 of the 10 with mixed variant and wild-type virus developed each outcome). By contrast, among those with wild-type virus, 28% developed hypoxia needing supplemental oxygen, 14% required ICU admission, and 10% required mechanical ventilation. The difference in the proportion developing hypoxia was statistically significant after adjusting for age, sex, and comorbidities. Patients with the deletion variants also had lower concentrations of growth factors associated with lung injury, and higher levels of T-cell activation.

Study Strengths

The detailed clinical data available as part of this study allowed the authors to investigate several different markers of clinical presentation that could be correlated with the deletion mutation, including hypoxia and multiple immune markers. Additionally, serial sampling of four individuals allowed the authors to better understand the relationship of this variant to the wild-type virus over time.

Limitations

Only 29 patients had the deletion variant, increasing the possibility that clinical differences were due to chance and limiting the authors’ ability to assess possible confounding variables. Plasma samples were not available for all study participants, and were collected at variable times with respect to the course of illness. Many patients were part of transmission clusters, which could amplify bias from unmeasured confounding.

Value added

This study adds to evidence that the ORF8 protein may be important in determining COVID-19 disease severity.

This review was posted on: 20 November 2020