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American Journal of Kidney Diseases

Outcomes From Infections With Variant Strains of SARS-CoV-2 Among Patients Receiving Maintenance Hemodialysis

      To the Editor:
      Even though safe and effective vaccines have been developed for SARS-CoV-2, variants of concern continue to emerge.
      • Priesemann V.
      • Balling R.
      • Brinkmann M.M.
      • et al.
      An action plan for pan-European defence against new SARS-CoV-2 variants.
      ,
      • Kirby T.
      New variant of SARS-CoV-2 in UK causes surge of COVID-19.
      We present a comparison of 2 COVID-19 waves in 2 hemodialysis facilities. Patients in 1 hemodialysis facility (“wave 1”) were infected by nonvariant SARS-CoV-2 between July and October 2020. Patients from the second facility (“wave 2”) became ill between December 28, 2020, and January 10, 2021 and were infected by a variant SARS-CoV-2 from the B.1.362 lineage, termed IVUI-L452R (Israeli variant under investigation with L452R mutation). Genetic mutations were detected by next-generation sequencing. Detailed methods and figures showing timelines are in Item S1.
      This analysis includes 33 patients, 26 from wave 1 and 7 from wave 2. Baseline clinical characteristics were similar between the groups except for a higher frequency of diabetes and heart failure among wave 1 patients (Table S1).
      Table 1 and Fig 1 compare clinical presentation and disease severity. Five of 26 patients from wave 1 were asymptomatic and diagnosed by postexposure surveillance, while all patients from wave 2 were symptomatic.
      Table 1Clinical and Laboratory Data of Patients Infected With Nonvariant (Wave 1) and Variant (Wave 2) SARS-CoV-2
      CharacteristicWave 1 (n = 26)Wave 2 (n = 7)P
      Age, y65.8 ± 14.770.1 ± 12.10.5
      Male sex14 (54%)5 (71%)0.4
      Dialysis vintage, mo34.1 ± 27.757 ± 24.60.06
      Clinical presentation
       Asymptomatic infection19%0%0.2
       Fever62%71%0.9
       Cough15%43%0.1
       GI symptoms12%43%0.06
       Malaise28%71%0.04
      Statistically significant (or, for 0.05, borderline statistically significant).
       Confusion4%29%0.05
      Statistically significant (or, for 0.05, borderline statistically significant).
       Temperature, °C37.9 ± 0.838.1 ± 0.80.5
       Heart rate82.8 ± 14.486.6 ± 14.80.5
       Systolic BP, mm Hg146.1 ± 22.3150.1 ± 19.70.7
       Diastolic BP, mm Hg70.2 ± 12.272.6 ± 16.30.7
       Oxygen saturation (on room air), %94.7 ± 10.793 ± 6.40.7
      Laboratory data
       WBC count, × 103/μL5.4 ± 1.84.0 ± 1.60.08
       Lymphocytes, × 103/μL1.0 ± 0.50.4 ± 0.20.008
      Statistically significant (or, for 0.05, borderline statistically significant).
       Neutrophils, × 103/μL3.9 ± 1.63.2 ± 1.40.3
       Neutrophil-lymphocyte ratio5.1 ± 3.67.8 ± 3.60.07
       Hemoglobin, g/dL11.1 ± 1.711.1 ± 0.80.9
       Platelets, × 103/μL182.3 ± 73.3164.7 ± 840.6
       C-reactive protein, mg/dL7.7 ± 8.45.3 ± 20.5
       Total bilirubin, mg/dL0.5 ± 0.20.8 ± 0.50.04
      Statistically significant (or, for 0.05, borderline statistically significant).
       Albumin, g/dL3.3 ± 0.43.3 ± 0.30.9
       Ferritin, μg/L2,746 ± 2,7451,487 ± 1,0380.5
      Abbreviations and definitions: BP, blood pressure; WBC, white blood cell; GI symptoms, gastrointestinal symptoms (nausea, vomiting, or diarrhea).
      a Statistically significant (or, for 0.05, borderline statistically significant).
      Figure thumbnail gr1
      Figure 1COVID-19 severity distribution. Severity was ranked according to National Institutes of Health guidelines as asymptomatic, mild, moderate (with clinical or radiographic evidence of lower respiratory tract disease and oxygen saturation ≥94% while breathing room air), severe (saturation <94%, respiratory rate >30/min, infiltrates over 50% of lung volume), or critical (requiring invasive or noninvasive ventilation, in shock, or with organ failure) (). Distribution of severity differed significantly between patients in wave 1 and wave 2, P = 0.005.
      COVID-19 severity was significantly worse in patients from wave 2, with more with critical COVID-19 (71% vs 8%, P = 0.005, Fig 1), as well as borderline statistically significantly higher need for noninvasive ventilation (P = 0.05), mechanical ventilation (P = 0.05), and hemodynamic support (P = 0.05). Medical treatment is detailed in Table S2.
      In-hospital mortality was significantly higher among wave 2 patients (57% vs 8% in wave 1; P < 0.005), corresponding to an odds ratio of 16 (95% CI, 2-127.9). Overall mortality was also significantly higher for wave 2 patients (71.4% vs 15.4% for wave 1; P < 0.001) despite shorter follow-up (39 ± 4 vs 129 ± 54 days; P = 0.003).
      In this retrospective study, patients infected with IVUI-L452R SARS-CoV-2 had significantly poorer outcomes and higher mortality. Variant virus–associated COVID-19 differed from onset, as all patients were symptomatic, more frequently with malaise, and had worse lymphocyte and total bilirubin levels at presentation. Since all hemodialysis patients were screened for SARS-CoV-2 following outbreaks, we believe that all cases, including asymptomatic, were diagnosed.
      Concerns regarding SARS-CoV-2 variants relate to increased infectivity,
      • Korber B.
      • Fischer W.M.
      • Gnanakaran S.
      • et al.
      Tracking changes in SARS-CoV-2 spike: evidence that D614G increases infectivity of the COVID-19 virus.
      ,
      • Baric R.S.
      Emergence of a highly fit SARS-CoV-2 variant.
      potential resistance to vaccines, and emerging data linking specific genetic mutations to virulence.
      • Young B.E.
      • Fong S.W.
      • Chan Y.H.
      • et al.
      Effects of a major deletion in the SARS-CoV-2 genome on the severity of infection and the inflammatory response: an observational cohort study.
      However, varying medical capabilities and standards between different medical centers and patient heterogenicity can significantly confound such associations. Therefore, data from specific patient populations treated at the same medical center can add meaningful information.
      Patients from wave 2 were infected by SARS-CoV-2 from the B.1.362 lineage with an additional L452R mutation in the spike protein. Two other mutations associated with this variant are Q57H in the Orf3a protein, and T261I in Orf1. Both are associated with the globally prevalent viral clade 20C. IVUI-L452R is suspected by the Israeli Ministry of Health to be a potential variant of concern, and as such is currently under investigation.
      The Q57H mutation in Orf3a may be associated with increased infection rates and higher mortality.
      • Majumdar P.
      • Niyogi S.
      ORF3a mutation associated with higher mortality rate in SARS-CoV-2 infection.
      The L452R mutation alters the spike interface, promotes stronger virus-cell attachment through ACE2, and increases infectivity.

      Tchesnokova V, Kulakesara H, Larson L, et al. Acquisition of the L452R mutation in the ACE2-binding interface of Spike protein triggers recent massive expansion of SARS-Cov-2 variants. bioRxiv. Preprint posted online February 22, 2021. https://doi.org/10.1101/2021.02.22.432189.

      This supports plausible mechanisms that can explain the deleterious effects of infection with variant viruses.
      Major limitations of this study include its retrospective nature and small sample size. Rates of heart failure and diabetes, risk factors for critical COVID-19,
      • Berlin D.A.
      • Gulick R.M.
      • Martinez F.J.
      Severe Covid-19.
      were higher among wave 1 patients. Since this was not a controlled trial and because of continually emerging data, therapeutic approaches differed between waves. Convalescent plasma was used in wave 1 but accumulated data have failed to ascertain therapeutic benefit.
      • Simonovich V.A.
      • Burgos Pratx L.D.
      • Scibona P.
      • et al.
      A randomized trial of convalescent plasma in Covid-19 severe pneumonia.
      Glucocorticoids, which significantly reduce mortality from severe COVID-19,
      • Berlin D.A.
      • Gulick R.M.
      • Martinez F.J.
      Severe Covid-19.
      were used more often in wave 2. Thus, differences in comorbidities and treatment were unlikely to explain differences in outcomes between the waves.
      Comprehensive mutation analysis was not performed for all wave 1 patients. However, several samples tested negative for variants of concern as part of outbreak surveillance, and the mutations identified in the variant viruses were very uncommon in Israel during the wave 2 outbreak.
      • Miller D.
      • Martin M.A.
      • Harel N.
      • et al.
      Full genome viral sequences inform patterns of SARS-CoV-2 spread into and within Israel.
      Also, the different outcomes could not be explained by variations in national morbidity and mortality rates, which were comparable between the waves (Item S1). Despite these limitations, our findings that relate viral genetic variation to clinical outcomes will inform future investigations. All patients were treated in a single medical center, which strengthens our results. Of note, no hemodialysis patients have been treated for COVID-19 in our hospital since February 2021, following nationwide vaccination that prioritized hemodialysis patients. We believe this should encourage vaccination of this population in other countries. In addition, previous reports of COVID-19 in hemodialysis patients demonstrated highly variable outcomes. We believe genetic typing of SARS-CoV-2 infection may prove important in interpreting outcomes in future studies.

      Article Information

      Authors’ Contributions

      Research area and study design: OW, SB, NN, KCH; data acquisition: OW, OM, NZ, AF, KCH; data analysis and interpretation: OW, OM, NZ, SB, KCH; statistical analysis: OW, KCH; supervision or mentorship: OW, SB, KCH. Each author contributed important intellectual content during manuscript drafting or revision and agrees to be personally accountable for the individual’s own contributions and to ensure that questions pertaining to the accuracy or integrity of any portion of the work, even one in which the author was not directly involved, are appropriately investigated and resolved, including with documentation in the literature if appropriate.

      Support

      None.

      Financial Disclosure

      The authors declare that they have no relevant financial interests.

      Acknowledgements

      We thank Faye Schreiber, MS (Meir Medical Center) for editing the manuscript.

      Peer Review

      Received March 28, 2021. Evaluated by 3 external peer reviewers, with direct editorial input from a Statistics/Methods Editor, an Associate Editor, and the Editor-in-Chief. Accepted in revised form June 27, 2021.

      Supplementary Material

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