SARS-CoV-2 Shedding in Dialysis Patients With COVID-19

Abstract

The impact of COVID-19 on patients with end-stage kidney disease (ESKD) on dialysis is substantial. Dialysis patients are especially vulnerable to COVID-19 because of their significant comorbidities, impaired immune function, and frequent face-to-face interactions as part of their life-sustaining therapy. Consistent with this premise, dialysis units are prone to COVID-19 outbreaks, and ESKD patients with COVID-19 experience higher morbidity and mortality compared to the general population, with a reported case fatality rate of 20% to 30%.1De Meester J. De Bacquer D. Naesens M. et al.Incidence, characteristics, and outcome of COVID-19 in adults on kidney replacement therapy: a regionwide registry study.J Am Soc Nephrol. 2021; 32: 385-396Crossref PubMed Scopus (72) Google Scholar In response to this risk, multiple guidelines and protocols have been developed by individual groups and nephrology societies to limit SARS-CoV-2 transmission and COVID-19 outbreaks in dialysis units.2Dudreuilh C. Kumar N. Moxham V. et al.De-isolation of COVID-19-positive hemodialysis patients in the outpatient setting: a single-center experience.Kidney Int. 2020; 98: 236-237Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar SARS-CoV-2 infection prevention and control measures for dialysis units are extrapolated from protocols that are derived from epidemiologic and respiratory viral transmission studies in the general population. For immunocompetent patients diagnosed with COVID-19, maintenance of contact and droplet isolation is recommended for 10 days from symptom onset.3Interim Guidance on Duration of Isolation and Precautions for Adults with COVID-19. Centers for Disease Control and Prevention (CDC), Atlanta, GA2021https://www.cdc.gov/coronavirus/2019-ncov/hcp/duration-isolation.htmlDate accessed: March 16, 2021Google Scholar These recommendations are supported by studies that have correlated shedding of cultivatable virus with viral copy number estimated by the cycle threshold (Ct) value from SARS-CoV-2 polymerase chain reaction (PCR) nucleic acid detection tests, the current gold standard for diagnosing COVID-19.4Bullard J. Dust K. Funk D. et al.Predicting infectious SARS-CoV-2 from diagnostic samples.Clin Infect Dis. 2020; 71: 2663-2666Crossref PubMed Scopus (647) Google Scholar, 5van Kampen J.J.A. van de Vijver D. Fraaij P.L.A. et al.Duration and key determinants of infectious virus shedding in hospitalized patients with coronavirus disease–2019 (COVID-19).Nat Commun. 2021; 12: 267Crossref PubMed Scopus (339) Google Scholar, 6Wolfel R. Corman V.M. Guggemos W. et al.Virological assessment of hospitalized patients with COVID-2019.Nature. 2020; 581: 465-469Crossref PubMed Scopus (4045) Google Scholar Cultivatable virus and the likelihood of forward transmission are inversely correlated with SARS-CoV-2 PCR Ct values. Consensus is emerging that no cultivatable SARS-CoV-2 can be recovered from COVID-19−positive patients with PCR Ct values above 25 to 30, depending on the assay used.4Bullard J. Dust K. Funk D. et al.Predicting infectious SARS-CoV-2 from diagnostic samples.Clin Infect Dis. 2020; 71: 2663-2666Crossref PubMed Scopus (647) Google Scholar, 5van Kampen J.J.A. van de Vijver D. Fraaij P.L.A. et al.Duration and key determinants of infectious virus shedding in hospitalized patients with coronavirus disease–2019 (COVID-19).Nat Commun. 2021; 12: 267Crossref PubMed Scopus (339) Google Scholar, 6Wolfel R. Corman V.M. Guggemos W. et al.Virological assessment of hospitalized patients with COVID-2019.Nature. 2020; 581: 465-469Crossref PubMed Scopus (4045) Google Scholar In patients with intact immune systems, Ct values generally rise to this level within 7 to 10 days after symptom onset; however, because of the sensitivity of the assay, the COVID-19 PCR itself may remain positive for weeks following the acute illness.3Interim Guidance on Duration of Isolation and Precautions for Adults with COVID-19. Centers for Disease Control and Prevention (CDC), Atlanta, GA2021https://www.cdc.gov/coronavirus/2019-ncov/hcp/duration-isolation.htmlDate accessed: March 16, 2021Google Scholar Thus, patients recovering from COVID-19 can shed SARS-CoV-2 nucleic acid for prolonged periods of time without harboring viable virus and may be considered noninfectious. Consequently, conversion to a negative COVID-19 PCR should not be used to guide public health and hospital isolation protocols for the general population. In contrast, COVID-19 patients who are immunosuppressed or who experience critical illness may shed cultivatable virus and remain infectious for even longer periods of time, in some cases up to 2 months after infection,7Rajakumar I. Isaac D.L. Fine N.M. et al.Extensive environmental contamination and prolonged severe acute respiratory coronavirus-2 (SARS CoV-2) viability in immunosuppressed recent heart transplant recipients with clinical and virologic benefit with remdesivir [e-pub ahead of print]. Infect Control Hosp Epidemiol.https://doi.org/10.1017/ice.2021.89Date accessed: March 12, 2021Google Scholar and therefore require special consideration. Patients with ESKD have impaired innate and adaptive immune systems that result in an increased risk of bacterial infection as well as generally blunted responses to vaccination.8Cohen G. Immune dysfunction in uremia 2020.Toxins (Basel). 2020; 12: 439Crossref Scopus (40) Google Scholar The ability of COVID-19−positive ESKD patients to clear SARS-CoV-2 and thus the risk of infectious virus shedding is unknown. Thus, isolation protocols for COVID-19 dialysis patients are not clearly established. Given the possibility of extended shedding of noninfectious viral nucleic acid, prolonged isolation becomes impractical, especially if conversion to a negative COVID-19 PCR is used as a criterion for discontinuing precautions. We performed a quality assurance/quality improvement project using COVID-19 PCR Ct values as a surrogate to assess the risk of infectious virus shedding in COVID-19−positive ESKD patients, with the objective of informing a discontinuation of isolation protocol for patients in our dialysis units. Alberta Kidney Care South reported 49 cases of COVID-19 in a population of 1332 ESKD patients on dialysis (3.7%) from March 2020 to December 2020. This corresponded to 36 of 1031 (3.5%) hemodialysis and 13 of 301 (4.3%) peritoneal dialysis patients. There were 7 deaths, giving a case-fatality rate of 14.2%. Of 49 COVID-19 dialysis patients, 20 had at least 2 COVID-19 PCR tests over 10 days or longer and were included in the analysis. Baseline characteristics of these patients are shown in Table 1. The median age was 61 years (range 31−86 years), 75% were male, and 80% were on hemodialysis. We used the Ct values of the COVID-19 PCR as a surrogate for the presence of cultivatable SARS-CoV-2. Of the 20 patients with serial COVID-19 PCR tests, 4 patients (20%) required admission to the intensive care unit (ICU) with mechanical ventilation, and 2 patients (10%) died. The Ct values as measured over time for the 20 patients are presented in Figure 1. Approximately 2 weeks from the first positive COVID-19 PCR, 19 of 20 patients reached Ct values >28, consistent with no infectivity or infectivity with no forward transmission potential. One patient with a persistent COVID-19 PCR Ct value <28 was a solid organ allograft recipient and chronically immunosuppressed with prednisone and mycophenolate mofetil. Two COVID-19−positive patients on prednisone monotherapy had adequate recovery in their Ct value to consider them unlikely to be carrying viable virus and hence noninfectious within a 14-day timeframe. In 4 patients, Ct values appear to have had an initial downward trend, presumably due to testing in the very early phase of the disease when viral copy numbers are still relatively low. Finally, only 1 patient had a nondetectable COVID-19 PCR after 14 days. Despite these results, half the patients were still symptomatic or hospitalized at the time of follow-up testing (Table 1).Table 1Characteristics of the study population (N = 20)DemographicsValueAge, yr, median (range)61 (30–86)Male:Female15:5Hemodialysis: peritoneal dialysis16:4Cause of kidney diseaseaSome patients had multiple listed etiologies of kidney disease. Hypertension/diabetes (%)14 (70) Glomerulonephritis (%)4 (20) Other (%)5 (25)Diabetes15 (75)Medications ACEI/ARB (%)11 (55) ImmunosuppressantsbImmunosuppressant medications were prednisone (2), prednisone, and mycophenolate mofetil (1). (%)3 (15)Immunocompromising comorbidity Solid organ transplant (%)1 (5) OthercOther immunocompromising comorbidities including autoimmune conditions requiring treatment. (%)2 (10)Symptoms at presentation Yes (%)18 (90) Unknown (%)2 (10)Intensive care unit admission4 (20)Status at follow-up testing SymptomsYes (%)5 (25)No (%)6 (30)Unknown (%)4 (20) Hospitalized5 (25)ACEI, angiotensin-converting-enzyme inhibitor; ARB, angiotensin receptor blocker.a Some patients had multiple listed etiologies of kidney disease.b Immunosuppressant medications were prednisone (2), prednisone, and mycophenolate mofetil (1).c Other immunocompromising comorbidities including autoimmune conditions requiring treatment. Open table in a new tab ACEI, angiotensin-converting-enzyme inhibitor; ARB, angiotensin receptor blocker. In a retrospective study of 90 SARS-CoV-2−positive in vitro samples probed for the E-gene, Bullard et al. could not demonstrate infectivity of patients with Ct values >24 and symptom duration of >8 days.4Bullard J. Dust K. Funk D. et al.Predicting infectious SARS-CoV-2 from diagnostic samples.Clin Infect Dis. 2020; 71: 2663-2666Crossref PubMed Scopus (647) Google Scholar Their study was limited primarily to non-immunocompromised adult patients in a community context. In a similar report limited to patients with mild COVID-19, Wolfel et al. also concluded that cultivatable virus could not be detected more than 14 days after onset of symptoms.6Wolfel R. Corman V.M. Guggemos W. et al.Virological assessment of hospitalized patients with COVID-2019.Nature. 2020; 581: 465-469Crossref PubMed Scopus (4045) Google Scholar Although van Kampen et al. further suggest that symptom severity should be considered, they concluded that both quantitative viral RNA load assays and serological assays may be sufficient to step down infection control precautions.5van Kampen J.J.A. van de Vijver D. Fraaij P.L.A. et al.Duration and key determinants of infectious virus shedding in hospitalized patients with coronavirus disease–2019 (COVID-19).Nat Commun. 2021; 12: 267Crossref PubMed Scopus (339) Google Scholar Finally, a study in cardiac transplant patients found nonviable virus correlated with Ct values between 25 and 30.7Rajakumar I. Isaac D.L. Fine N.M. et al.Extensive environmental contamination and prolonged severe acute respiratory coronavirus-2 (SARS CoV-2) viability in immunosuppressed recent heart transplant recipients with clinical and virologic benefit with remdesivir [e-pub ahead of print]. Infect Control Hosp Epidemiol.https://doi.org/10.1017/ice.2021.89Date accessed: March 12, 2021Google Scholar Several studies have reported prolonged (>2 weeks) COVID-19 PCR positivity in patients on dialysis. Dudreuilh et al. found that 41.2% of their patients had persistent positive PCR testing at 14 days, whereas De Vriese and Reynders noticed that COVID-19 survivors needed 34 to 44 days from symptom onset to first negative test.2Dudreuilh C. Kumar N. Moxham V. et al.De-isolation of COVID-19-positive hemodialysis patients in the outpatient setting: a single-center experience.Kidney Int. 2020; 98: 236-237Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar,9De Vriese A.S. Reynders M. IgG Antibody response to SARS-CoV-2 infection and viral RNA persistence in patients on maintenance hemodialysis.Am J Kidney Dis. 2020; 76: 440-441Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar Only De Vriese and Reynders reported Ct values, with most patients reaching a Ct value of ~25 by 15 to 21 days, although the specific test characteristics were not disclosed. Interestingly, effective production of anti−SARS-CoV-2 IgG levels correlated directly with rising COVID-19 PCR Ct values in these patients.9De Vriese A.S. Reynders M. IgG Antibody response to SARS-CoV-2 infection and viral RNA persistence in patients on maintenance hemodialysis.Am J Kidney Dis. 2020; 76: 440-441Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar Both groups have also recommended specific de-escalation plans for COVID-19−positive patients on hemodialysis. Dudreuilh et al. recommended serial testing in afebrile patients starting at 7 days after initiation until at least 2 negative tests (48 hours apart).5van Kampen J.J.A. van de Vijver D. Fraaij P.L.A. et al.Duration and key determinants of infectious virus shedding in hospitalized patients with coronavirus disease–2019 (COVID-19).Nat Commun. 2021; 12: 267Crossref PubMed Scopus (339) Google Scholar Based on this review of Ct values in a COVID-19−positive chronic dialysis cohort, all patients without immunosuppressive therapy were found to have levels above 28 at 14 days from the first positive COVID-19 PCR test, suggesting a very low likelihood of infectivity. Our results and those of De Vriese and Reynders9De Vriese A.S. Reynders M. IgG Antibody response to SARS-CoV-2 infection and viral RNA persistence in patients on maintenance hemodialysis.Am J Kidney Dis. 2020; 76: 440-441Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar suggest that SARS-CoV-2 kinetics in ESKD patients are similar to those in the general population, and that dialysis patients with mild to moderate COVID-19 infection mount a sufficient immune response to this virus. Thus, contact and droplet isolation procedures can be safely discontinued for COVID-19−positive patients in the dialysis unit as per the general population, without the requirement for conversion to a negative COVID-19 PCR. Special consideration, however, must be given to ESKD patients on immunosuppressive therapy, with severe disease or ongoing symptoms. The authors declared no competing interests except Dr. Conly. Dr. Conly reports financial support from Alberta Health Services, the University of Calgary, Pfizer Inc. and non-financial support from Centers for Disease Prevention and Control. Dr. Conly hold grants from the WHO outside this work. He is also a member of the WHO Infection Prevention and Control Research and Development Expert Group for COVID-19 and the WHO Health Emergencies Programme (WHE) Ad-hoc COVID-19 IPC Guidance Development Group, both of which provide multidisciplinary advice to the WHO, for which no funding is received and from which no funding recommendations are made for any WHO contracts or grants. Download .pdf (.14 MB) Help with pdf files Supplementary File (PDF) Supplementary Methods