SARS-CoV-2 Variants in Patients with Immunosuppression

 

Lawrence Corey, M.D., 

Chris Beyrer, M.D., M.P.H., 

Myron S. Cohen, M.D., 

Nelson L. Michael, M.D., Ph.D., 

Trevor Bedford, Ph.D., 

and Morgane Rolland, Ph.D.

DOI: 10.1056/NEJMsb2104756

PDF: 

https://www.nejm.org/doi/pdf/10.1056/NEJMsb2104756?articleTools=true

Patients with immunosuppression are at risk for prolonged infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In several case reports, investigators have indicated that multimutational SARS-CoV-2 variants can arise during the course of such persistent cases of coronavirus disease 2019 (Covid-19).1-4 These highly mutated variants are indicative of a form of rapid, multistage evolutionary jumps (saltational evolution; see Glossary), which could preferentially occur in the milieu of partial immune control.2,3 The presence of a large number of mutations is also a hallmark of the variants of concern — including B.1.1.7 (alpha), B.1.351 (beta), P.1 (gamma), and B.1.617.2 (delta)5 — which suggests that viral evolution in immunocompromised patients may be an important factor in the emergence of such variants. Since a large number of persons globally are living with innate or acquired immunosuppression, the association between immunosuppression and the generation of highly transmissible or more pathogenic SARS-CoV-2 variants requires further delineation and mitigation strategies.

Rapid viral evolution has been described in immunosuppressed patients with persistent SARS-CoV-2 infection. Choi et al. described an immunosuppressed patient with antiphospholipid syndrome who was hospitalized in August 2020 and treated with anticoagulants, glucocorticoids, cyclophosphamide, intermittent rituximab, and eculizumab.2 During 152 days of persistent SARS-CoV-2 infection in this patient, the investigators identified 31 substitutions and three deletions in genome sequences. Twelve spike mutations were found, including seven in a segment of the receptor-binding domain consisting of 24 amino acids, some at sites linked to immune evasion (478, 484, and 493).6,7 The patient eventually died of severe Covid-19–related pneumonia. In another immunocompromised patient, Kemp and colleagues analyzed SARS-CoV-2 sequences at 23 time points over 101 days.4 Viral diversification was limited during the first 2 months but subsequently increased after the patient received an infusion of convalescent plasma on days 63 and 65, leading to rapid shifts in the frequency of the different variants. As such, sequences that were sampled on days 89, 93, and 102 showed distinct combinations of spike mutations. Truong et al. recently described the cases of three patients with B-cell acute lymphoblastic leukemia (including one with B-cell aplasia) after the receipt of chimeric antigen receptor (CAR) T cells. These patients were found to have multiple escape variants over the course of persistent Covid-19 infection.3 Some case reports have not identified highly divergent variants but have documented variants with mutations (e.g., V483A1-4 and E484K8) that alter antibody recognition.

https://www.nejm.org/doi/full/10.1056/NEJMsb2104756