Detection of replication-competent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the most reliable indicator of infectiousness.1 Although the duration of live-virus shedding is well characterized in immunologic patients with coronovirus disease 19 (Kovid-19), little is known about how long-term immunologic patients are infectious. Consequently, the Guidelines on Transmission-Based Precautions for Immune-based Patients for Disease Control and Prevention (CDC) are based on limited data.2
Panel A shows patient enrollment, respiratory specimen collection (all nasopharyngeal specimens except a sputum specimen), and trial design. The bar indicates the serial collection of samples. RT-qPCR demonstrates quantitative reverse-transcriptase polymerase chain reaction. Panel B shows the genetic morphological profile of SARS-CoV-2 sequenced relative to the Wuhan-Hu-1 reference genome in 13 patients who had at least one cultured isolate (plus sign), more than one longitudinal sample, or both. The genes shown were derived from the original respiratory samples. The mean (mean SD) read depth was 2481 rea 1558 per base. The assembled genomic regions are indicated by colored shaded regions according to the patient, and gaps in coverage are indicated by white regions. Complete genome sequences from 4 patients who did not have a similar culture or follow-up samples are not included. Recticase domains (ORF1ab 1 and 2, ORF3a, ORF6, ORF7a, and ORF8) and the S, M, and N regions of the reference genome are shown on the x axis. UTR denotes uncontrolled area.
In the present study, we used cell cultures to detect viable viruses in chronically collected respiratory samples (nasopharyngeal and sputum samples) obtained from 20 immunodepromised patients who had Kovid-19 (Figure 1a). These patients included 18 recipients of hematopoietic stem cell transplant or 2 patients with chimeric antigen receptor (CAR) T-cell therapy and lymphoma. Covid-19 was diagnosed between March 10 and April 20, 2020, using a modified CDC nucleic acid amplification test. Live viruses were isolated in Vero cells, and genetic variants were identified by whole-genome sequencing of nasopharyngeal and cultured samples (see Supplementary Methods). Supplementary Addendum, With the full text of this paper available at NEJM.org). Patients’ demographic characteristics, medical history and the clinical course of Kovid-19 were separated from the medical record (Table S1 in 1). Supplementary Addendum).
15 out of 20 patients were receiving active treatment or chemotherapy. Eleven had Kovid-19. A total of 78 samples were collected from 20 patients; 57 samples were obtained over the time period shown in Figure S1. Viral RNA was detected up to 78 days after the onset of symptoms (intercellular range, 24 to 64 days). Viable virus was detected in 10 14 nasopharyngeal samples (71%) available from the first day of laboratory testing. Follow-up samples (patients MSK-3, MSK-4, MSK-6, MSK-8, and MSK-9) obtained from 5 patients initially amplified the virus in culture for 8, 17, 25, 26 and 61 days . symptoms of (Figure 1). 3 patients with viable virus for more than 20 days had received allogeneic hematopoietic stem-cell transplantation (2 patients) or CAR T-cell therapy (1 patient) within the last 6 months and became seronegative for antibodies to viral nucleoproteins. are; Of these 2 patients, Kovid-19 was severely affected and received investigational treatment.
Whole genome sequencing revealed viral reads in all samples and over 95% complete SARS-CoV- for 17 patients and 37 of 57 nasopharyngeal samples obtained from all 18 cultured samples (accession number, EPI_ISL_583426 to EPI_ISL_5834808080). 2 genome) has been received. [55 complete genomes]). Serial sample genomes were obtained for 11 patients up to 63 days after the onset of symptoms. Each patient was infected with a different virus, and there was no major change in consensus sequences of the original serial samples or cultured isolates (Figure 1b); These findings were accompanied by persistent infection.
Patients with intensive immunosuppression after hematopoietic stem-cell transplantation or after receiving cellular therapy may shed viable SARS-CoV-2 for at least 2 months. Current guidelines for Kovid-19 isolation precautions may need to be revised for immunocompromised patients.
Teresa Idillo, Ph.D.
Ana s. Gonzalez-Reche, Ph.D.
Sadaf Aslam, B.A.
Adriana van de Guche, MS
Zainab Khan, B.S.
Ajay Obla, Ph.D.
Jayita Dutta, MBA
Haram van Bakel, Ph.D.
Judith Eberg, MD
Adolfo Garcia-Sastre, Ph.D.
Aiken School of Medicine at Mount Sinai, New York, NY
Gunjan Shah, MD
Tobias Hohl, MD, PhD.
Genova Fapanicolaou, MD
Miguel-Angel Perales, MD
Kent Sepkowitz, MD
N. Esther Babadi, Ph.D.
Mini Kamboj, MD
Memorial Sloan Catering Cancer Center, New York, NY
Supported by an award (P01 CA23766) and a National Institute of Health (NIH) –National Cancer Institute Cancer Center Grant-in-aid (P30 CA008748) from the NIH, a grant from the Jack and Dorothy Byron Foundation (to Dr. Hohl, Babadi, and Kamboj). National Institute of Allergy and Infectious Diseases (HHSN272201400008C) Awarded to the Center for Research on Influenza Pathogenesis – (Center of Excellence for Influenza Research and Surveillance), donation from philanthropic charity JPB Foundation, A research grant (2020-215611) Open philanthropy project from Mount Sinai philanthropy, philanthropic donation (to Dr. Garcia-Sastre), awards from NI Office of Research Infrastructure Programs (S10OD018522 and S10OD026880), and one Robin Chambers Nestine Postdoctoral Fellowship Award.(To Dr. Gonzalez-Reche).
Disclosure forms The full text of this paper is available at NEJM.org provided by the authors.
The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.
The paper was published on December 1, 2020 on NEJM.org.
DRS. Babadi and Kamboj contributed equally to this paper.
1. Aaron MM, Hatfield KM, Reddy S.C., and others. Preceptomatic SARS-CoV-2 infection and transmission in a skilled nursing facility. N angle j med 2020; 382:2081–2090.
2. Center for Disease Control and Prevention. Dissection of transmission-based precautions and dispositions of patients with COVID-19 in health care settings (interim guidance). August 10, 2020 (https://www.cdc.gov/coronavirus/2019-ncov/hcp/disposition-hospitalized-patients.html).
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