key: cord-0931335-gkf3wez8
authors: Kim, Young; Latz, Christopher A.; DeCarlo, Charles S.; Lee, Sujin; Png, CY Maximilian; Kibrik, Pavel; Sung, Eric; Alabi, Olamide; Dua, Anahita
title: Relationship between Blood Type and Outcomes Following COVID-19 Infection
date: 2021-07-18
journal: Semin Vasc Surg
DOI: 10.1053/j.semvascsurg.2021.05.005
sha: c759e6080392b99c15daf5f278632cef4379c925
doc_id: 931335
cord_uid: gkf3wez8

Since the onset of the COVID-19 pandemic, a concentrated research effort has been undertaken to elucidate risk factors underlying viral infection, severe illness, and death. Recent studies have investigated the association between blood type and COVID-19 infection. This article aims to comprehensively review current literature and better understand the impact of blood type on viral susceptibility and outcomes.

The Coronavirus Disease 2019 (COVID-19) pandemic began in December 2019. An outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2 virus) began as a cluster of patients developing pneumonia of unknown origin linked to a seafood market in the city of Wuhan. 1 From there, COVID-19 quickly spread throughout the Wuhan region. Despite stringent measures to contain the viral outbreak, the illness continued to proliferate throughout China, overwhelming its hospitals resources and healthcare workers. 2 In January 2020, the first case of COVID-19 was reported in the United States. 3 The SARS-CoV-2 virus continued to spread through person-to-person transmission and swiftly escalated into a global emergency. 4, 5 Robust research efforts have been undertaken to determine risk factors for viral susceptibility and severe illness. 6 The importance of deciphering COVID-19-related risk factors has significant implications for triage and prognosis. To date, multiple, population-based studies have discovered patient-level factors associated with worse outcomes after contracting COVID-19 -including birth sex, race, ethnicity, age, obesity, and preexisting medical conditions. [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] Recent studies investigated blood type as a risk factor for COVID-19. [17] [18] [19] [20] [21] [22] [23] Blood type has been identified as a risk factor in many disease processes, ranging from malignancy 24, 25 to venous and arterial thromboembolism. [26] [27] [28] The most widely studied associations, however, have been in the realm of infectious diseases. Blood group antigens play a direct role in infection through various mechanisms. On a molecular level, they can serve as receptors and coreceptors for pathogens; and can also facilitate intracellular uptake of viral particles. 29 Clinically, blood types have been linked to bacterial, parasitic, and viral infections. [30] [31] [32] [33] [34] [35] [36] [37] One study, in particular, found that ABO polymorphism was associated with susceptibility to infection with severe acute respiratory syndrome coronavirus (SARS-CoV)-1. 30 Further investigations discovered a protective effect of anti-A antibodies against intracellular uptake of the SARS-CoV-1 virus. 38, 39 Using a cellular model of adhesion, Guillon et al. discovered that human anti-A antibodies inhibited interaction between angiotensin converting enzyme-2 (ACE-2)-dependent cellular adhesion to ACE-2 expressing cells. These results propose a molecular mechanism by which ABO polymorphism impacts susceptibility to SARS-CoV-1 infection and transmission. 38 These and other articles have led investigators to investigate whether an association exists between SARS-CoV-2 and blood antigen grouping. 40 Currently, nine large studies have analyzed the effect of blood type and COVID-19-related illness (Tables 1 and 2 ). [17] [18] [19] [20] [21] [22] [23] These studies span multiple countries with widely different patient populations.

The majority of these studies report an association between blood type and viral infection, although they differ with regard to which blood type portends susceptibility to infection. Among these studies, eight of nine articles associated blood type with COVID-19 susceptibility. Four studies found a correlation between blood type and severity of COVID-related illness, whereas five studies did not. The key findings of these studies are detailed below.

There was a significant amount of literature published about the relationship between blood type and SARS-CoV-2 and this field continues to evolve as the pandemic continues. For this comprehensive review, we included only peer-reviewed journal articles, articles in English and those published from March 2020 to January 2021. All articles were identified via searches on PubMed for terms including "COVID- 19" or "SARS-CoV-2" and "blood type", "severity COVID and blood type." The articles for reviewed by two reviewers for sample size, diversity of population and methodology to ensure a thorough, diverse representation of the literature. To minimize bias, single case reports and small case series were excluded. Zietz et al. also found that blood type groupings were associated with both risk of intubation and death. Zietz performed a retrospective cohort analysis using electronic health record data from the New York Presbyterian/Columbia University database. 23 were also at increased risk of infection, using type O as a reference. Rh-negative patients were at lower risk of infection compared with Rh-positive patients (ARD -2.7, 95% CI -4.7 to -0.8). With regard to intubation and death, type A blood was associated with decreased risk of both intubation (ARD -2.9, 95% CI -7.2 to 0.6) and death (ARD -1.6, 95% CI -4.9 to 1.6). Type AB individuals were at increased risk of both intubation (ARD 1.8, 95% CI -8.3 to 12.2) and death (ARD 1.4, 95% CI -6.9 to 8.9). Type B individuals were at increased risk of intubation (ARD 2.5, CI -2.7 to 7.5) but lower risk of death (ARD -2.6, 95% CI -6.6 to Other studies have also supported correlation between blood type with infection and illness in smaller populations. In Turkey, Gőker et al. found that blood type A was associated with higher rates of infection without any impact on severity of illness (n=186). 41 In a separate study, Kibler et al. found that patients with aortic stenosis status post transcatheter aortic valve replacement (n=22) with blood type A were more likely to become severely ill with COVID-19. 42 Given the small size of these and other, similar series, these studies did not weigh into our overall conclusions.

Five studies found that ABO blood type was not associated with severity of illness or mortality after infection. Barnkob et al. published the largest study to date overall, including a total of 841,327 subjects from Denmark. 43 Among tested subjects, 473,654 had ABO blood type data available, and 7,422

were positive for COVID-19. In this cohort, the majority (74%) of COVID-19 positive subjects had mild disease and did not require inpatient hospitalization. Data from tested subjects were compared with 2,204,742 non-tested individuals, which accounted for nearly 40% of the total Danish population. The authors found that individuals with type O blood were relatively protected from viral infection (RR 0.87, 95% CI 0.82-0.91). Unlike previous studies, however, there was no difference between ABO blood type and progression of illness to hospitalization or mortality (p>0.40 each). Rh typing was not collected in this analysis.

In our investigation, we performed a multi-institutional analysis across five hospitals in the New England region. 18 may be less susceptible. The authors did not report any association between blood type grouping and severity of illness, and covariate adjustment was not performed in this analysis.

In a confirmatory analysis, Dzik et al. analyzed ABO distribution among patients in both Wuhan and Boston. 44 Using Wuhan data already published by Zhao and Li, the authors did not find any associations between blood type and COVID-19-related severity of illness. 2, 22 This reaffirms the conclusions made by the original authors. In terms of their Boston data, Dzik's investigation is more comprehensively collected and analyzed in our study, as it utilizes the same database with fewer patients. Therefore, the study by Dzik et al. did not weigh into our discussion or conclusions.

Leaf et al. investigated critically ill patients with COVID-19 in the ICU setting. 19 In a multicenter cohort study, the authors examined SARS-CoV-2 positive patients admitted to ICUs from 67 hospitals across the United States. Among the 3239 critically ill patients during the study period, a total of 2033 patients had ABO blood group data available. Rh-type data was not reported in this analysis. Leaf et al. found that the distribution of ABO phenotypes in critically ill patients differed substantially from the expected distribution in healthy subjects. Among White patients, type A individuals were overrepresented (45.1% observed vs 39.8% expected) and type O individuals were under-represented (37.8% observed vs 45.2% expected) compared to healthy subjects. No differences were noted between observed and expected distributions of ABO blood groups in Black or Hispanic patients. Leaf et al. concluded that type A blood may be a risk factor among White patients with COVID-19-related critical illness while type O blood may be protective. Within this critically ill cohort, the mortality rate was 39.3% within 28 days, and ABO blood type did not affect mortality rates.

The authors investigated all crew members from the French Navy nuclear aircraft carrier, Charles de Gaulle, who were exposed to a viral outbreak while on board. 45 Of the 1769 crew members, 1279 (76%) tested positive for COVID-19. After the ship returned to base, all members were quarantined and underwent medical monitoring for two weeks post-landing. In contrast with other studies, the median crewmember age was 28 years, 87% were men, and no significant medical comorbidities were reported.

No significant association was found between ABO or Rh blood groups with viral infection, progression to severe illness, or death after infection.

Eight of nine studies demonstrated an association between blood type and susceptibility to infection with SARS-CoV-2. Four of these nine studies also revealed an association with severity of illness.

Ray et al. found that subjects with type O and Rh-negative blood were protected from viral infection, severe illness, and mortality. 21 While the data is convincing, this study was limited by the inability to test critically ill patients who died quickly after hospital admission. Zietz et al. also found that ABO and Rh types were associated with infection, mechanical ventilation, and death. 23 This study was significantly limited by the circumstances of limited testing capability, however, with the majority of subjects being tested in an inpatient setting due to illness. Hoiland et al. focused primarily on critically ill subjects, reporting an association with blood types A and AB with risk of intubation, CRRT, and prolonged ICU stay. 17 This study was limited by a very small sample size, with missing blood group data in 25% of subjects.

In China, Zhao et al. reported type A subjects were at increased risk of infection and mortality, while type O subjects were protected from both outcomes. 22 Li et al. also found type A-associated susceptibility to viral infection, but did not find an association with mortality. 20 Both Zhao and Li's papers were limited by a small sample size of a single ethnic group. Moreover, given that both authors utilized data from the same hospitals during the same study period, there is potential for subject overlap between the two studies. A third study from China by Wu et al. supported these findings, noting an increased risk of infection with type A blood. 46 Of note, this third study from China (n=187) was much smaller in scale compared to the investigations by Zhao and Li (n=2153 and 2173 each) .

In the largest study to date, Barnkob et al. found a protective effect of type O blood with viral susceptibility. 43 We also found that subjects with type O and Rh-negative blood appeared to be at decreased risk for infection on multivariate analysis. 18 Unlike previous reports, neither Barnkob nor our study found any association between blood type and progression to severe illness or death. Our investigation was limited by small sample size and lead-time bias, however, with subjects analyzed early in their hospital course. Similarly, Leaf et al. also found that blood type O and Rh-negative subjects were at decreased risk of infection, with no association with mortality rates. 19 These results were also limited by small sample size, along with missing blood group data in approximately third of subjects.

Unlike other analyses, Boudin et al. did not find any association between ABO or Rh types with infection, severe illness, or death. 45 These results were impacted by the healthy patient population and high rate of infection (76%), however, and may not be reflective of normal societal conditions. Finally, all nine studies were retrospective analyses of observational data, and therefore subject to selection bias. A summary of key study limitations are detailed in Table 3 .

As a group, one collective limitation among this set of articles is the significant variability in testing of ABO and Rh blood types. Only three of the nine studies tested and analyzed Rh types, which are summarized in the next section. The proportion of ABO types represented appears to vary widely between studies (Table 1) , however, this appears to reflect the natural ABO blood group distribution within each individual study population. For example, Zhao and Li both report an AB blood group prevalence of over 10%, but this is representative of the Chinese population. 20, 22 Each of these studies should therefore be taken in context of their individual study populations and limitations (Table 3) .

The impact of Rh-type on COVID-19 infection deserves a special focus (Table 2) . Rh-type is the second most important blood group system after ABO typing. Like ABO types, Rh-type refers to proteins on surface of RBCs. 47 Clinically, this system plays an important role in blood transfusion and erythroblastosis fetalis. 47, 48 Recent studies also demonstrate a significant impact in COVID-19 infection and illness as well. As previously mentioned, of the nine studies included in this review, five studies investigated Rh blood type. Four of five studies found significant associations with Rh-negative blood grouping. 18, 19, 21, 23 Both Ray and Zietz found that subjects with Rh-negative blood type were at lower risk of viral infection, severe illness, and mortality after infection. Our study, along with Leaf's, also found that Rh-negative subjects were at lower risk of infection, but did not find any impact on COVID-19related illness or mortality. While overall results may be mixed, there is a consistent theme on Rh-type and susceptibility to COVID-19 infection.

As previously mentioned, Hoiland et al. reported an association with blood types A and AB with worse clinical outcomes. 17 While this study was limited by a very small sample size, the authors hypothesized that the presence of anti-A antibodies may play a key role in viral susceptibility. In their discussion, Hoiland et al. refer to a growing body of scientific work comparing SARS-CoV-1 and SARS-CoV-2 viruses. Both viral strains appear to share similar receptor-binding domains. 49 The anti-A antibody inhibits interaction between SARS-CoV-1 virus and the ACE-2 receptor 38 , suggesting that the ABO antibodies may influence SARS-CoV-2 infection as well. Other scientific reports have implicated viral infection with other factors, such as anti-A immunoglobin isotype 50 , ABO-type differences in von Willebrand factor 51 , and anti-A isohemagglutinin titers. 52 Interestingly, recent genomic analyses have identified specific gene clusters (3p21.31) as susceptibility markers in patients with COVID-19 and respiratory failure. Given the association of this specific locus with the ABO blood group locus, the authors suggest that this may be one mechanism for the involvement of ABO typing with COVID-19related illness. 40 While the complete mechanism remains yet to be fully elucidated, future studies in this field may help the development of prophylactic and therapeutic interventions for COVID-19 infection.

Since the onset of the COVID-19 pandemic, a concentrated research effort has been undertaken to elucidate risk factors underlying viral susceptibility and illness. Among these efforts, several recent studies have investigated the association between blood type and COVID-19 infection. Each of these reports provides important information with regard to understanding the underlying disease process.

While these reports may be inconsistent in their findings, certain trends are evident. Many studies report that blood type A may predispose one to increased susceptibility of infection with SARS-CoV-2, whereas type O and Rh-negative blood groups may be protective. While this appears to be an emerging trend, the impact of blood type on clinical outcomes remains unclear. At this point in time, there does not appear to be any relationship between blood type and COVID-19-related severity of illness or mortality. Current literature does not support blood type as part of a predictive model of viral illness or mortality, and ABO/Rh screening should not be utilized as a triage mechanism. Future investigations may focus on the creation of a global COVID-19 database to account for population-based differences in blood types and testing protocols. Moreover, further studies are necessary to understand the molecular mechanisms by which blood types may engender susceptibility to SARS-CoV-2 infection, and ultimately, develop countermeasures to viral infection and illness.

-ACE-2, angiotensin converting enzyme-2 -ARD, absolute risk difference -ARR, adjusted relative risk -CI, confidence interval -COVID-19, coronavirus disease 2019 -ICU, intensive care unit -OR, odds ratio -Rh, rhesus -SARS-CoV, severe acute respiratory syndrome coronavirus 21 Inability to test patients who died quickly due to critical illness Zhao et al. 22 Moderate sample size (n=2173), single ethnic group Li et al. 20 Moderate sample size (n=2153), single ethnic group, no covariate adjustment, potential subject overlap with Zhao et al. Hoiland et al. 17 Very small sample size (n=95), limited to ICU subpopulation, blood group data missing in 25% of ICU-admitted patients Leaf et al. 19 Moderate sample size (n=2033), blood group data missing in third of subjects Latz et al. 18 Moderate sample size (n=1289), lead time bias Zietz et al. 23 Selection bias for inpatient hospital population due to limited testing Barnkob et al. 43 ABO data available for only 62% of tested individuals, female sex overrepresented at 71% of negative and 67% of positive subjects Boudin et al. 45 Moderate sample size (n=1279), very high infection rate (76%), subjects not representative of general population (i.e. young, healthy)

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The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.