Intractable Coronavirus Disease 2019 (COVID-19) and Prolonged Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Replication in a Chimeric Antigen Receptor-Modified T-Cell Therapy Recipient: A Case Study

Abstract

A CAR-T-cell recipient developed severe COVID-19, intractable RNAemia, and viral replication lasting >2 months. Pre-mortem endotracheal aspirate contained 2x10 10 SARS-CoV-2 RNA copies/mL and infectious virus. Deep sequencing revealed multiple sequence variants consistent with intra-host virus evolution. SARS-CoV-2 humoral and cell-mediated immunity were minimal. Prolonged transmission from immunosuppressed patients is possible.

The emerging plasticity of SARS-CoV-2

“…SARS-CoV-2 variants from two of these patients had up to fivefold reduction in neutralization sensitivity to CP (3,7). Although these are case studies in immunocompromised individuals, they raise concern because the deletions of amino acids 69 to 70 (D69-70), D141-144, or D242-248 in S1 were observed in four out of the five infections (3,(5)(6)(7); the N501T (Asn 501 Thr) or N501Y (Asn 501 Tyr) mutations were seen in two out of the five (5,6); and the E484K (Glu 484 Lys) and Q493K (Gln 493 Lys) mutations in the RBD of one infection also arose in antibodyresistant viruses after in vitro selection. These reports preceded the detection of three major circulating variants-B.1.1.7, B.1.351, and P.1-which all contain at least eight single, nonsynonymous nucleotide changes, including E484K, N501Y, and/or K417N (Lys 417 Asn) in the ACE2 interface of the RBD (shown in the illustration).…”

“…Studies evaluating the linkage of these mutations in individual SARS-CoV-2 genomes using single-genome amplification and sequencing, as has been used to characterize genetic diversity of HIV-1 and other viruses, are needed to accurately assess the infectivity and phenotype of individual variants. A case report of intrahost SARS-CoV-2 evolution showed that SARS-CoV-2 can evolve multiple distinct lineages within the same individual (6).…”

“…Extensive intrahost evolution of SARS-CoV-2 has been reported in at least five individuals with protracted infection because of immune impairment from therapy for hematologic malignancies or autoimmunity (3)(4)(5)(6)(7). They had active SARS-CoV-2 infection for an average of 115 days before clearing the infection or succumbing to COVID-19.…”

SARS-CoV-2 Persistent Viral Shedding in the Context of Hydroxychloroquine-Azithromycin Treatment

“…Previous case reports and a small series of patients experienced prolonged shedding with SARS-CoV-2 ( Table 4 ) [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ], mostly involving immunocompromised individuals, including patients diagnosed with hematological malignancies in most cases.…”

SARS-CoV-2 Portrayed Against HIV: Contrary Viral Strategies in Similar Disguise

“…Differences in variant distribution between upper and lower respiratory tract have been observed; however, the number of minority variants per patient usually remains <30% based on only a few variants (Table 1) [40,[272][273][274][275][276][277][278][279]. A higher intrapatient evolution of SARS-CoV-2 yielding several tens of variants appears to be associated with prolonged replication, as frequently found in more severe cases, older individuals, and particularly immunocompromised patients [40,193,[246][247][248][249][250]280,281]. Nonetheless, in most SARS-CoV-2 infections, there is one dominant variant throughout the course of the disease and upon onward transmission [279].…”