Coronavirus Disease 19 (COVID-19) is an infectious disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which may present with fever, cough and dyspnea or asymptomatic infection in some cases. The SARS-CoV-2 belongs to the Coronaviridae family, being an enveloped RNA virus, which contains Spike (S) proteins on its surface that make it look like a crown (Corona). It has high homology to the coronavirus responsible for the SARS outbreak of 2003, Severe Acute Respiratory Syndrome Coronavirus 1 (SARS-CoV-1).1

Although most cases present with mild symptoms, the COVID-19 infection may lead to acute respiratory failure and death. This disease has caused worldwide health and economic impact, leading the international community to unite in trying to contain the virus through restrictive measures, research in potential drugs and mass vaccination. Despite these efforts, there is still a large number of new cases of the disease. Thus, it is important to continue searching for risk factors that might be associated with worse outcomes in persons infected by SARS-CoV-2.1

Individuals with comorbidities and the elderly are susceptible to severe COVID-19 infection, but one of the intriguing aspects of this disease is that healthy young people may sometimes present severe respiratory failure, while many people with comorbidities may be asymptomatic.2

One of the hypotheses to explain susceptibility to SARS-CoV-2 is linked to the ABO blood group system, represented by ABH oligosaccharide antigens A and B and antibodies against these antigens (anti-A and anti-B). These antigens are coded by autosomal codominant genes corresponding to alleles A and B in the ABO locus. The H antigen, coded by FUT1/FUT2/SEC1 genes, is responsible for exhibiting A and B antigens with a α−1,3-glycosidic bond. When the A allele is present, one N-acetyl-d-galactosamine (GalNAc) or, when the B allele is present, a d-galactose (Gal) is transferred to the H antigen.1 These antigens are mainly expressed on the surface of red blood cells, on the surface of endothelial and epithelial cells and in mucins secreted by exocrine glandules.

The main objectives of this systematic review were to investigate the association between the ABO blood group and the risk of COVID-19 infection and the association between the ABO blood group and the risk of suffering complications and death related to COVID-19.

This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines through the 2020 PRISMA Checklist and 2020 PRISMA Flow diagram. The protocol for this review was registered in the Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD42021245945. The research question was structured and refined using the PICO method (Population, Intervention/exposure, Comparison and Outcome), presented as follows: “Would the ABO blood group influence the risk of infection and clinical course of patients infected with SARS-CoV-2?”, as detailed in Tables 1 and 2.

PICO strategy for objectives 1 and 2 are as follows:

• PICO strategy for objective 1 (COVID-19 infection): P: Population at risk for SARS-CoV-2 infection (entire population); I: ABO blood group; C: Different blood groups by ABO classification system, and; O: COVID-19 infection.

• PICO strategy for objective 2 (COVID-19 severe infection): P: Population at risk for SARS-CoV-2 infection (entire population); I: ABO blood group; C: Different blood groups by ABO classification system, and; O: COVID-19 severe infection, hospitalization, admission to intensive care unit (ICU), need of mechanical ventilation, cardiovascular injury and mortality.

The initial search resulted in 798 articles across the following databases: PubMed, Embase, Scopus, Web of Science, Science Direct and Virtual Health Library. Then automation tools were applied (detailed in Figure 1), resulting in the exclusion of 195 articles. The next step was duplicate removal, which further excluded 340 articles. Subsequently, 263 studies were selected for title and abstract reading and 178 of those were excluded for lacking pertinence to the subject of our research, not fulfilling inclusion criteria or for matching any of the exclusion criteria, resulting in 85 manuscripts for full-text reading. Fifty-three matched the research question of this review and were included in the final analysis. Figure 1 details the search and selection flow-chart. Three study types were analyzed: Cohort studies (n = 22), Cross-sectional studies (n = 20) and case-control studies (n = 11).

Figure 1.

Search and selection flow-chart.

(0.41MB).

For objective 1 (risk of COVID-19 infection) 30 articles were analyzed (Table 4). Sample sizes ranged from 208 to 2211,894 participants, totaling 2212,102 participants. These studies were conducted in 19 countries and the majority were from Turkey (6 studies), China (3 studies) and Spain (3 studies). The mean age ranged from 5.8 years (5 months - 13.3 years) to 82 years (6.9 years).4,5 Regarding the type of studies found, 11 were cohort, 12, cross-sectional, and 7, case control. Different types of samples were found. Some involved hospitalized or discharged patients, while others evaluated outpatients.

Among 30 studies evaluating the risk of COVID infection associated with the ABO blood type, 21 studies found significant correlations. Most studies (14 studies), involving 105 to 7422 patients, found an increased proportion of blood group A in patients, compared to controls. Fewer studies showed an increased proportion of patients with blood group B (6 studies) or AB (6 studies). Most studies also found a reduced proportion of blood group O (15 studies, 105 – 7422 patients) in infected patients. A total of 10 studies found no statistically significant correlation between ABO status and COVID-19 infection.

Among studies with blood donors as controls (10 studies), most studies found a reduced proportion of patients with blood group O (4 studies, 302 - 854 patients). Fewer studies showed an increased proportion of patients with blood group A (3 studies), B (2 studies) or AB (2 studies). Two out of 10 studies found no statistically significant correlation between the ABO status and COVID-19 infection using blood donors as controls.

The majority of the studies (10 studies with 105 – 7422 patients) with non-blood donor controls (21 studies) found an increased proportion of blood group A in patients, compared to controls. Fewer studies showed an increased proportion of patients with blood group B (3 studies) or AB (3 studies). Most studies also found a reduced proportion of patients with blood group O (11 studies, 105 – 7422 patients). Seven studies using non-blood donors as controls found no statistically significant correlation between the ABO status and COVID infection.

For objective 2 (COVID infection severity), 35 articles were analyzed (Table 5). Sample sizes ranged from 43 to 5391,149 participants. The studies were conducted in 17 countries and the majority were from United States (6 studies), Turkey (5 studies) and Saudi Arabia (4 studies). Regarding the type of studies found, 16 were cohort, 13, cross-sectional, and 5, case control. We assessed studies including any of the three selected outcomes of interest (mortality, ICU and mechanical ventilation).

The mortality was evaluated in 30 studies. Seven studies found increased mortality in blood group A patients, 2, in blood group B patients, and 4, in blood group AB patients. One study also found reduced mortality in blood group O. The majority (21 studies) found no significant difference in mortality among ABO blood groups.

Admission to the ICU was evaluated in 10 studies. Most (9 studies) found no significant correlation between the ABO blood group and need for ICU admission. One study (with 330 patients) found an increased need for ICU admission in blood group AB patients.

Mechanical ventilation was analyzed in 10 studies. Most (6 studies) also found no significant difference between the ABO blood group and need for mechanical ventilation. Three studies found an increased need for mechanical ventilation in blood group A patients, 3, in blood group AB patients, and 1, in blood group B patients.

Analyzing all three severity outcomes, the majority of the studies found no significant difference in either mortality, ICU admission or need for mechanical ventilation associated with the ABO blood group in COVID-19 patients. Only 12 of the 35 studies found a significant correlation, mostly showing an increased mortality and need for mechanical ventilation in blood group A patients.

We performed a systematic review of the correlation between the ABO blood type and susceptibility to COVID-19 infection, both in terms of risk of infection and in terms of disease severity. The results of this review point to a possible increased risk of COVID-19 infection associated particularly with blood type A and a possible decreased risk of infection in blood type O, as most high-quality studies including either outpatients or hospitalized patients and with blood donors or non-blood donors as controls replicated this finding.

The relationship between the ABO blood group and risk of COVID-19 infection has been previously investigated by other review studies.6-9 Most reviews showed similar findings of an increased risk in group A patients and a decreased risk in group O. However, the present review includes a larger number of studies and more recently published papers, which might better reflect the present phase of the COVID-19 disease pandemic.

As for disease severity, results were conflicting, as most studies found no statistically significant correlations. Those that have found differences mostly reported increased mortality in group A patients. Admission to the ICU was mostly similar among ABO blood groups in all except one study and the need for mechanical ventilation was higher in blood group A and B in only 3 in 11 studies.4,5

Previously published reviews also bring conflicting results on this subject. One review has found increased mortality in group A versus non-A.6 Another study found lower risk of death in ABO group B patients.8 However, most reviews failed to demonstrate an increased mortality associated with any ABO blood group,4,9 similar to the findings of the present review, albeit with fewer articles included in the analysis. A definitive association of the ABO blood group distribution with mortality or severity outcomes remains to be proven.

Studies utilizing blood donors as controls carry a potential risk of bias, as the frequency of ABO blood group subtypes may be different between blood donors and the general population.1,2 Studies with blood transfusions could also influence outcomes due to different profiles between donors and transfusion recipients. One study by Muñiz-Diaz et al. (2020) reported 2 different samples, one with blood donor controls and another with non-blood donor controls and found different results, namely a significant difference (increased A and decreased O blood groups in patients) when comparing patients to blood donor controls and no significant difference when comparing transfusion recipients with COVID-19 infection to recipients without COVID-19 infection (non-blood donor controls).5 However, when summarizing all studies with blood donor controls and those with non-blood donor controls, results were largely similar (an increased risk in blood group A patients and a decreased risk in blood group O patients in most studies).

Patient assessment methods varied among studies. We only extracted data regarding the ABO group distribution among infected and non-infected subjects for objective 1 (the risk of COVID-19 infection). For objective 2 (the severe COVID-19 infection), we extracted data regarding mortality, admission to the ICU and the need for mechanical ventilation for analysis, regardless of other clinical outcomes evaluated by the selected studies. This was an attempt to draw more homogenous conclusions based on heterogenous studies.

The mechanisms responsible for this correlation between ABO blood groups and the susceptibility to COVID-19 infection are still unclear. Guillon et al. (2008) demonstrated that viral S proteins co-localize with the ABO group A antigens and that anti-A antibodies could inhibit the adhesion between the S protein and host cell ACE2 receptors that initiate viral invasion.10 This could explain why type O patients (who have both anti-A and anti-B antibodies) might be protected from infection and also why type A patients (who do not possess anti-A antibodies) might be at greater risk. Deleers et al. (2021) reported that COVID-19-infected patients had significantly lower levels of anti-ABO antibodies, reinforcing the hypothesis that these antibodies might have a protective role. Indeed, lower susceptibility to infection in group O patients has been previously reported for SARS-CoV, another member of the Coronavirus family.11

Another hypothesis to explain a relationship between the ABO blood group and COVID-19 disease outcomes involves the risk of thromboembolic complications. Group O individuals have lower levels of pro-thrombotic von Willebrand factor (vWF) and may be partially protected against COVID-associated thrombosis, an important mechanism in many complications leading to worse outcomes.12 This is in line with the findings from Ladikou et al. (2020) and Sardu et al. (2020), included in the present review, which have shown higher levels of vWF in non-O patients associated with worse outcomes.12,13

The present study has several limitations. We have found high heterogeneity among the studies, regarding different populations, study designs, sample sizes, control groups, follow-up periods and outcome measures. For this reason, we did not perform a meta-analysis of the results. Limiting the analysis to less heterogeneous studies with a low risk for bias might have reduced sample size significantly. Also, the studies analyzed lacked important information, such as participant vaccination status and SARS-CoV2 variant reported, which might impact the outcomes. Due to the time in which our assessment was performed, most patients were not infected with the Omicron variant, that is presently the dominant variant worldwide. Results with the Omicron variant, including BA.1 and BA.2 variants, might have been different.

This review summarizes all available studies to date regarding the association between the ABO blood group and susceptibility to COVID-19 infection and disease severity. A rigorous methodology was used to analyze and synthesize data and the risk for bias and quality of evidence were systematically assessed. Many previous reviews were published in an earlier time during the pandemic and thus, included fewer studies. Another strength of our review is that we only included studies with laboratory-confirmed SARS-CoV-2 infection. We have also tried to approach the susceptibility to infection and disease severity as different objectives, selecting studies that utilized these specific outcomes for each analysis.

Understanding patient susceptibility to COVID-19 infection according to the ABO blood group could help us in identifying new risk factors to be incorporated in prognostic tools and triage algorithms. Comprehension of the mechanisms by which this susceptibility is manifested might also open new treatment possibilities by providing novel therapeutic targets or utilizing naturally occurring protective factors associated with ABO blood group antigens or antibodies.

Future studies specifying the vaccination status and identifying particular SARS-CoV-2 variants, especially the dominant Omicron variants, and the susceptibility of these patients according to the ABO blood group might further optimize the COVID-19 risk stratification and treatment.

Qualitative assessment of available information suggests that the blood group A may be a risk factor for the COVID-19 infection and that the blood group O may have a protective effect. Based on all evidence available at this point, we were unable to determine a clear association between the ABO blood group and COVID-19 associated mortality. These conclusions were based on highly heterogenous evidence and furthermore, contain several biases. Moreover, they do not reflect the predominance of omicron variants and of vaccinated subjects, which characterize the present moment of the pandemic. Further studies are needed to assess the actual impact of the ABO blood group on the risk and severity of the COVID-19 infection.

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DMBS, DABSA, PRN, JLBS and DABSA contributed to the article conception and wrote the manuscript; DMBS, DABSA, RBM, EMBS, FCSN, MSNP and VCVG contributed to the data collection and analysis. DMBS, DABSA, MSNP, PRN, PBN and GFA read, revised and approved the final version of the manuscript.