ABO blood groups and severe outcomes in COVID-19: A meta-analysis

Similar to the SARSCoV experience, a possible link between ABO blood groups with COVID-19 susceptibility and severity has been shown in multiple observational studies. Gérard et al have further noted that people with B and/or O blood groups were less represented among COVID-19 patients, thereby highlighting the possible beneficial role of antiA antibodies in COVID-19 susceptibility. In fact, it was known that antiA antibodies can block the adhesion of SARSCoV Sprotein to ACE2 expressing cell lines. Given the genomic similarity between SARSCoV-2 and SARSCoV, it might be prudent to hypothesise a protective role of antiA antibodies against COVID-19 severity as well. However, existing clinical evidence in this regard is controversial. Hoiland et al had reported that critically ill COVID-19 patients with blood groups A and AB (lacking antiA antibodies) were more likely to require mechanical ventilation and prolonged intensive care compared with patients with B/O (with antiA antibodies). However, a genomewide association study of severe COVID-19 patients showed that those with blood group A had a higher risk of severe disease, while blood group O had a protective effect. Other studies found no association between ABO blood groups and COVID-19 severity/ mortality. We aimed to summarise the available literature and provide a pooled analysis of the effect of A/AB (without antiA antibodies) on clinical outcomes in COVID-19 patients compared with B/O (with antiA antibodies) blood groups. This metaanalysis was conducted and reported according to the Preferred Reporting Items for Systematic reviews and MetaAnalyses (PRISMA) statement. We (SB and MB) independently performed a systematic search of the literature across the PubMed database from inception till 30 November 2020, using the following keywords interposed with appropriate Boolean operators: “COVID-19” OR “SARSCoV-2” AND “ABO blood groups”. Observational studies of case–control or cohort design were selected. Studies reporting the absolute rate of occurrence of severe outcomes (number of patients requiring intubation or number of patients with dyspnoea where intubation data not reported) or intubation and/or deaths or deaths among confirmed COVID-19 patients with A/AB versus B/O blood groups were included in analysis. Studies conducted only in critically ill patients with COVID-19 were excluded. Reviews, commentaries, articles in nonEnglish language, nonpeerreviewed articles/ preprints and studies with incomplete data were also excluded. Any discrepancy was solved by a discussion with a third reviewer (RP). Study quality was assessed using the NewcastleOttawa scale. Statistical analysis was performed using the RevMan V.5. 4 software following data extraction. Being a dichotomous variable, the difference in the rate of occurrence of the reported clinical outcomes (events) in COVID-19 patients with A/AB versus B/O blood groups were calculated using the OR with 95% CIs after implementation of the MantelHaenszel (MH) fixedeffects model. Heterogeneity was quantified as low, moderate and high with upper limits of 25%, 50% and 75% for I respectively. Studies with moderatetohigh heterogeneity were reanalysed using the MH randomeffects model. A twotailed p<0.05 was considered to be statistically significant. After a scrupulous literature search and a meticulous study selection process, we included nine observational studies in our metaanalysis, pooling data retrieved from 233 006 patients with COVID-19 10 11 14–17 (online supplemental figure 1). Of note, we had excluded the studies by Hoiland et al and Leaf et al that were conducted only in critically ill COVID-19 patients. 18 Characteristics of all the studies along with quality assessment have been demonstrated in online supplemental table 1). The pooled analysis showed that there was no significant difference in severe clinical outcomes in patients with A/AB blood groups compared with those with B/O groups (OR 1.09; 95% CI 0.91 to 1.29, p=0.35, I=59%, randomeffects model) (figure 1). Sensitivity analysis of studies that had reported only mortality as the severe outcome also showed no significant difference (OR 1.07; 95% CI 0.93 to 1.24, p=0.35, I=0%, fixedeffects model) (figure 2). We found no significant differences in the unadjusted mortality and/or severity outcomes (defined by intubation or dyspnoea) related to COVID-19 in patients with blood groups A/AB (with no antiA antibodies) as compared with B/O groups (with antiA antibodies). However, in the metaanalysis performed among Spanish and Italian cohorts after adjusting for age and gender, odds for having severe COVID-19 disease (defined by respiratory failure) was higher in A/AB groups as compared with B/O groups (OR: 1.51, 95% CI 1.25 to 1.83). Nevertheless, no difference in ABO blood groups was observed among patients requiring any form of mechanical ventilation. The present study findings do have certain limitations. Most of the studies included in the metaanalysis had a retrospective design. Adjustment for age, gender and comorbidities were either not reported, or reported for each blood group separately. Hence, pooled analysis using adjusted ORs could not be done. Besides, the clinical outcomes reported across the included studies were variable, ranging from dyspnoea to intubation to