Association of Rhesus factor blood type with risk of SARS-CoV-2 infection and COVID-19 severity.

Abstract

Substantial attention has been paid to ABO blood type as a potential risk factor for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) susceptibility and coronavirus disease 2019 (COVID-19) severity, but this association remains controversial.1 Less attention has been paid to whether Rhesus (Rh) factor is associated with COVID-19 risk. We analysed a prospectively collected database to address this question. To test whether blood factor RhD is associated with SARS-CoV-2 susceptibility and/or COVID-19 severity. This was a prespecified population-based cohort study to independently test for associations of blood RhD factor and common socioeconomic factors with SARS-CoV-2 susceptibility and COVID-19 severity. The study was approved by the Intermountain Healthcare Institution Review Board (IRB) with a waiver of consent. Intermountain Healthcare is an integrated, non-profit healthcare system that comprises 24 hospitals and 215 clinics in Utah, Idaho, and Nevada. At the onset of the COVID-19 pandemic, Intermountain prospectively initiated a SARS-CoV-2/COVID-19-specific electronic records database. We searched this database for patients who were tested for SARS-CoV-2 between 3 March 2020 and 24 May 2021 and had a recorded RhD blood type (N = 180 564). Infectivity was determined by SARS-CoV-2-specific polymerase chain reaction of nasal swabs or saliva samples. For multiple tests, the first positive test was chosen, otherwise the first negative test was used. We also searched the Intermountain electronic medical record database for all Intermountain subjects with blood typing pre-COVID (2000–2018) to determine population wide RhD and ABO distributions. We compared virus-positive versus -negative, hospitalised versus non-hospitalised, and intensive care unit (ICU) versus non-ICU patients. The Student’s t-test and the chi-square statistic were used to assess differences between Rh groups. Multivariable adjusted odds ratios (adjORs) and 95% confidence intervals (CIs) were determined by logistic regression adjusted for age, sex, race, ABO blood type, and comorbidities. Patient demographics stratified by RhD factor and hospital disposition are shown in Table 1 and baseline characteristics by COVID-19 presence and severity in Table 2. RhD frequencies increased progressively from COVID test-negative to infected, to hospitalised, to ICU patients. Similarly, the established demographic factors of age, male sex, and non-White race increased progressively from test negative to ICU care patients. Outcome frequencies and adjusted ORs by RhD type are shown in Table 3. RhD-positive patients showed modestly greater susceptibility to SARS-CoV-2 infection (adjOR 1.09, 95% CI 1.05–1.13), and RhD-positive, infected patients were substantially more likely to be hospitalised with COVID-19 (adjOR 1.26, 95% CI 1.14–1.40) and require ICU care (adjOR 1.25, 95% CI 1.04–1.52). Analyses restricted to White race gave similar results (not shown). Our control, population-wide blood type distribution, determined in 581 248 subjects, was comparable to that of our COVID-19 test cohort, both for RhD positivity (84.8% vs. 85.2%) and for ABO types1 (A, 40.4% vs. 40.3%; O, 46.8% vs. 47.2%; B, 9.4% vs. 9.2%; AB, 3.4% vs. 3.3%), indicating a lack of important selection bias in the COVID-19 database sample. Hospitalised 5674 Non-hospitalised 27 804 ICU patients 1728 Non-ICU patients 3946 The variable susceptibility to and severity of SARS-CoV-2/COVID-19 across populations have generated interest in underlying causes and associations. Blood groups may represent one of these factors. Early reports from China and Europe reported greater susceptibility to SARS-CoV-2 infection and/or COVID-19 severity with blood group A and lower risk with blood group O. However, subsequent reports, including from the USA, did not confirm these associations.2, 3 Similarly, our large Intermountain experience found no evidence for blood group A as a risk factor for infection versus group O (adjOR 0.97, 95% CI 0.93–1.01) or for hospitalisation (adjOR 0.89, 95% CI 0.80–0.99).1 RhD has been proposed to be a SARS-CoV-2/COVID-19 risk factor, but it has not been thoroughly studied or highlighted. A Canadian population cohort study reported blood type O and RhD-negative status to be protective for SARS-CoV-2 infection and COVID-19 severity.4 In contrast, a Danish population-based study did not find RhD to impact susceptibility to SARS-Cov-2 infection or to COVID-19 severity, whereas blood type O was modestly protective against infection but not disease severity.5 A smaller New York study reported mixed findings for ABO blood type but found a positive association with RhD factor.3 Thus, our results uniquely establish a positive risk association of RhD positivity with SARS-CoV-2 susceptibility and COVID-19 severity independent of an association with ABO blood type (previously reported1). Mechanistically, Rh factor is important for blood type compatibility and immune response. The risk of haemolytic disease of RhD-positive newborns mismatched to their RhD-negative mothers is a well-known example. Antigenic interactions between Rh factor and SARS-CoV-2 have not been reported but represent a worthwhile research topic. A limitation of this observational study is that it can neither determine causality nor provide a mechanism of the association of Rh-factor with COVID-19, which will require further study. In summary, our large, prospectively generated COVID-19 population-based database has demonstrated RhD positivity to be a risk factor for SARS-CoV-2/COVID-19 susceptibility and severity. Rh factor determination may usefully contribute to individual and population risk prediction. Additional studies will be helpful in determining whether this finding represents a causal or a non-causal association. We acknowledge the assistance of Brianna Ronnow, Intermountain Healthcare, for assistance with manuscript submission, who was otherwise uncompensated. None. Jeffrey L. Anderson designed the research study, performed the research, analysed the data, and wrote the paper. Heidi T. May designed the research study, performed the research, analysed the data, and wrote the paper. Stacey Knight designed the research study, analysed the data, and wrote the paper. Tami L. Bair performed the research. Benjamin D. Horne designed the research study, analysed the data, and wrote the paper. Kirk U. Knowlton designed the research study and wrote the paper.