SARS-CoV-2 viral dynamics in immunocompromised patients

Abstract

To the Editor, While the median duration of SARS-CoV-2 viral RNA detection in nasopharyngeal swabs collected from immunocompetent subjects is approximately 18 days,1Zheng S Fan J Yu F et al.Viral load dynamics and disease severity in patients infected with SARS-CoV-2 in Zhejiang province, China, January-March 2020: retrospective cohort study.BMJ. 2020; : m1443Crossref PubMed Scopus (946) Google Scholar data for immunocompromised patients are not yet available. Here, we prospectively monitored the dynamic change in SARS-CoV-2 RNA viral loads in serial nasopharyngeal swab, saliva, and respiratory specimens collected from kidney transplant recipients (KTR) hospitalized with a confirmed diagnosis of COVID-19. Nasopharyngeal samples were collected by trained nurses following the CDC recommendations. Sample collection was performed using a single type of collection tube (UTM Viral Transport; COPAN Diagnostics, Murrieta, CA). Serial dilutions of in vitro transcribed RNA (quantity: 1011 copies) derived from the BetaCoV_Wuhan_WIV04_2019 strain (EPI_ISL_402124) were used. An in-house reverse transcriptase polymerase chain reaction (RT-PCR)–based assay targeting two different regions of the RNA-dependent RNA polymerase (RdRp) gene was used for the detection of SARS-CoV-2 in accordance with the WHO technical guidance.2Protocol: real-time RT-PCR assays for the detection of SARS-CoV-2 Institut Pasteur, Paris. https://www.who.int/docs/default-source/coronaviruse/real-time-rt-pcr-assays-for-the-detection-of-sars-cov-2-institut-pasteur-paris.pdf?sfvrsn=3662fcb6_2. Accessed June 1, 2020.Google Scholar A total of 168 swab samples (median number of specimens per patient: 4; interquartile range: 3–5) were obtained from 31 men and 11 women over a period that spanned from the onset of symptoms up to 60 days afterward, with the exception of patients who died before. Two cases—in whom the diagnosis was made based on chest CT findings—had persistently negative RT-PCR results throughout the entire study period. Table 1 summarizes the general characteristics of the study patients and their clinical course.TABLE 1General characteristics, immunosuppressive treatment, COVID-19 symptoms, and clinical course in the 42 study patientsCharacteristicsValueMen, n (%)31 (73.8)Age (years), median (interquartile range)63.3 (55.8–67.9)BMI (kg/m2), median (interquartile range)27 (23.2–33.7)Cardiovascular disease, n (%)16 (38)Respiratory disease, n (%)15 (35.7)Diabetes, n (%)19 (45.2)Hypertension, n (%)35 (83.3)Use of RAAS inhibitors, n (%)15 (35.7)Delay since transplantation (years), median (interquartile range)5.3 (2–13.6)Maintenance immunosuppression, n (%)Tacrolimus23 (54.7)Ciclosporin13 (30.9)MMF/MPA35 (83.3)mTOR inhibitors6 (14.3)Azathioprine1 (2.4)Steroids24 (57.1)Clinical symptoms at hospitalization, n (%)Dyspnea16 (38)Cough26 (61.9)Fever37 (88)Myalgia23 (54.7)Headache9 (21.4)Diarrhea26 (61.9)Anosmia/ageusia7 (16.7)Evolution, n (%)O2 requirement22 (52.3)Need for ICU transfer14 (33.3)Need for RRT4 (9.5)Death7 (16.7)Abbreviations: BMI, body mass index; ICU, intensive care unit, RRT: renal replacement therapy; MMF, mycophenolate mofetil; MPA, mycophenolic acid; RAAS, renin–angiotensin–aldosterone system. Open table in a new tab Abbreviations: BMI, body mass index; ICU, intensive care unit, RRT: renal replacement therapy; MMF, mycophenolate mofetil; MPA, mycophenolic acid; RAAS, renin–angiotensin–aldosterone system. The median viral load at diagnosis was 5.12 (interquartile range: 3.8–6.5) log10 copies per reaction, followed by a gradual decline over the subsequent weeks. The temporal profile of viral loads for each patient is presented in Figure 1A, whereas their general dynamics are summarized in Figure 1B. At day 30, 15 patients (43%) were considered to have a viral load >3 log10 copies per reaction, the threshold above which there may be a SARS-CoV-2 transmission risk.3Arons MM Hatfield KM Reddy SC et al.Presymptomatic SARS-CoV-2 Infections and Transmission in a Skilled Nursing Facility.N Engl J Med. 2020; 382 (https://doi.org/10.1056/NEJMoa2008457): 2081-2090Crossref PubMed Scopus (1358) Google Scholar Thirteen patients had low but detectable viral loads and only eight patients (23%) achieved complete viral clearance. At day 45, 66% of the study patients had negative swabs; however, 12 cases still had detectable viral loads in their specimens. Notably, five patients had still viral loads >3 log10 copies per reaction after day 30 (Figure 1B). The maximum duration of a viral load >3 log10 copies per reaction was not lower than 43 days (possibly until 54 days; Figure 1A). At the time of last follow-up (D60), six of 35 patients (17%) had low but still detectable SARS-CoV-2 loads. The present study demonstrates that most KTR harbor high viral loads within the first 15 days from the onset of symptoms. These results are in line with those obtained in the general population4To K-W Tsang O-Y Leung W-S et al.Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study.Lancet Infect Dis. 2020; 20: 565-574Abstract Full Text Full Text PDF PubMed Scopus (2095) Google Scholar and suggest a high risk of transmissibility. Moreover, we show that almost half of our patients still had sustained viral loads at day 30—with only 23% achieving complete viral clearance at this time point. Finally, immunocompromised KTR may have SARS-CoV-2–positive nasopharyngeal swabs as long as 60 days after the onset of symptoms—a remarkably longer period than that described for the immunocompetent population (20–25 days).4To K-W Tsang O-Y Leung W-S et al.Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study.Lancet Infect Dis. 2020; 20: 565-574Abstract Full Text Full Text PDF PubMed Scopus (2095) Google Scholar,5Wölfel R Corman VM Guggemos W et al.Virological assessment of hospitalized patients with COVID-2019.Nature. 2020; 581: 465-469Crossref PubMed Scopus (4156) Google Scholar It should be kept in mind that the detection of viral RNA does not necessarily equate to the presence of a live, infectious virus. Currently, the more widely accepted viral load threshold for virus isolation (and—consequently—the risk of contagion) is approximately 1000000 copies/mL.5Wölfel R Corman VM Guggemos W et al.Virological assessment of hospitalized patients with COVID-2019.Nature. 2020; 581: 465-469Crossref PubMed Scopus (4156) Google Scholar,6L’Huillier AG Torriani G Pigny F Kaiser L Eckerle I. Culture-competent SARS-CoV-2 in nasopharynx of symptomatic neonates, children, and adolescents.Emerg Infect Dis. 2020; 26 (https://doi.org/10.3201/eid2610.202403): 2494-2497Crossref PubMed Scopus (87) Google Scholar While viral loads were low in the majority of cases, transplant recipients should be considered a vulnerable population7Akalin E Azzi Y Bartash R et al.Covid-19 and kidney transplantation.N Engl J Med. 2020; 382 (https://doi.org/10.1056/NEJMc2011117): 2475-2477Crossref PubMed Scopus (551) Google Scholar,8Caillard S, Anglicheau D, Matignon M, et al. An initial report from the French SOT COVID Registry suggests high mortality due to Covid-19 in recipients of kidney transplants [published online ahead of print, 2020 Aug 24]. Kidney Int. 2020;S0085–2538(20)30961–3. https://doi.org/10.1016/j.kint.2020.08.005Google Scholar characterized by a prolonged viral shedding. In this scenario, transmission-based precautions should be enforced longer in KTR than in healthy persons.

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