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- general medicine (see internal medicine)
- blood bank & transfusion medicine
- immunology
- infectious diseases
Similar to the SARS-CoV experience,1 a possible link between ABO blood groups with COVID-19 susceptibility and severity has been shown in multiple observational studies.2–4 Gérard et al 5 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 anti-A antibodies in COVID-19 susceptibility. In fact, it was known that anti-A antibodies can block the adhesion of SARS-CoV S-protein to ACE2 expressing cell lines.6 Given the genomic similarity between SARS-CoV-2 and SARS-CoV, it might be prudent to hypothesise a protective role of anti-A antibodies against COVID-19 severity as well. However, existing clinical evidence in this regard is controversial. Hoiland et al 7 had reported that critically ill COVID-19 patients with blood groups A and AB (lacking anti-A antibodies) were more likely to require mechanical ventilation and prolonged intensive care compared with patients with B/O (with anti-A 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.8 Other studies found no association between ABO blood groups and COVID-19 severity/mortality.9–12 We aimed to summarise the available literature and provide a pooled analysis of the effect of A/AB (without anti-A antibodies) on clinical outcomes in COVID-19 patients compared with B/O (with anti-A antibodies) blood groups.
This meta-analysis was conducted and reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement.13 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 “SARS-CoV-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 non-English language, non-peer-reviewed 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 Newcastle-Ottawa 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 Mantel-Haenszel (M-H) fixed-effects model. Heterogeneity was quantified as low, moderate and high with upper limits of 25%, 50% and 75% for I2 respectively. Studies with moderate-to-high heterogeneity were reanalysed using the M-H random-effects model. A two-tailed 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 meta-analysis, pooling data retrieved from 233 006 patients with COVID-192–4 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.7 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, I2=59%, random-effects 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, I2=0%, fixed-effects model) (figure 2).
Supplemental material
Supplemental material
Forest plot showing the odds of severe outcomes in COVID-19 patients having blood groups A/AB (without anti-A antibodies) versus those having blood groups B/O (with anti-A antibodies). M-H, Mantel-Haenszel.
Forest plot showing the odds of mortality in COVID-19 patients having blood groups A/AB (without anti-A antibodies) versus those having blood groups B/O (with anti-A antibodies). M-H, Mantel-Haenszel.
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 anti-A antibodies) as compared with B/O groups (with anti-A antibodies). However, in the meta-analysis 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.8
The present study findings do have certain limitations. Most of the studies included in the meta-analysis 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 death. However, we did perform a sensitivity analysis with mortality being the sole severe outcome. Finally, the relationship between COVID-19 severity and anti-A antibodies is indeed far from simple. Several other factors can act as potential confounders, including the immunoglobulin subtype of antibodies,5 presence of ACE1/C3 polymorphisms19 and variable levels of factor VIII/VWF levels.20
In conclusion, this preliminary, yet updated meta-analysis negates the possible significant association between the lack of anti-A antibodies (A/AB blood group), and poor clinical outcomes in patients with COVID-19. However, further studies on predefined endpoints in hospitalised patients (especially with critical COVID-19 disease), adjusting for possible covariates, are warranted to provide a reliable estimate of the risk.
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Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
SB and MB contributed equally.
Correction notice This article has been corrected since it first published. The provenance and peer review statement has been included.
Contributors SB and MB are the primary authors. SB, MB and RP had helped in literature search and data collection. All the authors had approved the final version of the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.