key: cord-337602-5evfkk70 authors: Focosi, Daniele title: Anti‐A Isohemagglutinin titers and SARS‐CoV2 neutralization: implications for children and convalescent plasma selection date: 2020-06-09 journal: Br J Haematol DOI: 10.1111/bjh.16932 sha: doc_id: 337602 cord_uid: 5evfkk70 I read with interest the recent article by Li et al (1) detailing the risk for COVID‐19 pneumonia and ABO blood group. After demonstration that group O healthcare workers were less likely to become infected with SARS‐CoV (2), a research group proved that anti‐A blood group natural isoagglutinins inhibit SARS‐CoV entry into competent cells (3) and could opsonize viral particles leading to complement‐mediated neutralization (4). Since SARS‐CoV2 uses the same receptor as SARS‐CoV, anti‐A isoagglutinins are expected to have similar effects against SARS‐CoV2: accordingly, clusters of glycosylation sites exist proximal to the receptor‐binding motif of the SARS‐CoV and SARS‐CoV2 S protein (5). Accepted Article competent cells (3) and could opsonize viral particles leading to complement-mediated neutralization (4) . Since SARS-CoV2 uses the same receptor as SARS-CoV, anti-A isoagglutinins are expected to have similar effects against SARS-CoV2: accordingly, clusters of glycosylation sites exist proximal to the receptor-binding motif of the SARS-CoV and SARS-CoV2 S protein (5) . Several recent publications from China, USA, Turkey, Spain and Italy have shown that the odd ratios for acquiring COVID-19 is higher in blood group A than in blood group Owhen compared to healthy controls (Table 1) , while no statistically significant difference was found for groups B and AB. . Most importantly, the Italian-Spanish genome-wide association study identified the rs657152 polymorphism in the ABO locus on chromosome 9q34 (and only another polymorphism in chromosome 3p21.31) as the only susceptibility locus for respiratory failure in COVID-19 (6) , suggesting that, in addition to disease acquisition, ABO blood group could also affect disease severity. Blood group A and ABO polymorphisms (rs495828, gene promoter, and rs8176746, exon 7) predispose to COVID-19 severity via increased ACE activity (7-9) and cardiovascular disorders (10, 11) . In a multivariate regression analysis for predicting COVID-19 prevalence, C3 and ACE1 polymorphisms were more important confounders in the spread and outcome of COVID-19 in comparison with A allele (12) . But an alternative explanation should be considered. Under this model, transmission from group O individuals and between individuals of the same group will always be maximal. High titer isoagglutinins can prevent transmission, while low-titer isoagglutinin could lead to milder disease presentations (13) . COVID-19 has more severe clinical presentations and outcome in elderly and in males : intriguingly, elderly males are known to experience greater reductions in isoagglutinin titers than females (14) . Studies are This article is protected by copyright. All rights reserved Accepted Article hence ongoing to evaluate correlations between isoagglutinin titers and outcome in blood group O and B patients. Since the phenomenon apparently does not benefit group B patients (15), I suggest that only anti-A IgG (which are more prevalent than IgM in group O patients, and occur at titers > 1:16 in about 70%), but not anti-A IgM (which are more prevalent than IgG in group B patients), could confer benefit. Apart from specificity, steric hindrance could affect receptor saturation from different antibody isotypes, making IgM less ideal for masking. Since A1 subgroup accounts for more than 80% of A group, investigations should specifically focus on anti-A1 IgG. It is known that passively acquired maternal isoagglutinins are rare in infants after the first month of life (16) , but levels of anti-A isoagglutinins are already about 25% of the adult levels at month 3 and reach 90% of the adult level at 3 years, peaking at age 5-10, with individuals of 80 years of age and over showing reduced levels similar to those seen in 6-to 12-month-old infants (17) . So the isoagglutinin titer hypothesis does not explain why infants are generally spared by severe COVID19. A lot of additional co-factors could also explain the association, such as crossprotection from childhood vaccinations, lack of antibodydependent enhancement (ADE) due to missing original antigenic sin (OAS) for other betacoronaviruses (18) , or stable Fc fucosylation (19) . If confirmed, this hypothesis will have implications for convalescent plasma therapy, since anti-A1 IgG could confer additional benefit over anti-SARS-CoV2 neutralizing antibodies: in fact, while preserving ABO match compatibility, it could be wiser to prefer blood group O donors for CP in COVID-19. In the meanwhile, it seems wiser to titer anti-A isoagglutinins in group O CP donations (or to preserve frozen plasma aliquots for later investigations), and to preferentially choose group O units. In view of the growing worldwide trends at manufacturing hyperimmune serum from convalescent plasma, it should also be This article is protected by copyright. All rights reserved Accepted Article considered that hyperimmune serum, arising from pooled diverse ABO groups, contains far lower anti-A isoagglutinin titer than an average O-group convalescent donation. I declare that I have no conflict of interest related to this manuscript. Association between ABO blood groups and risk of SARS-CoV-2 pneumonia ABO Blood Group and Susceptibility to Severe Acute Respiratory Syndrome Inhibition of the interaction between the SARS-CoV Spike protein and its cellular receptor by anti-histo-blood group antibodies HIV-1 incorporates ABO histo-blood group antigens that sensitize virions to complement-mediated inactivation Structural, glycosylation and antigenic variation between 2019 novel coronavirus (2019-nCoV) and SARS coronavirus (SARS-CoV) The ABO blood group locus and a chromosome 3 gene cluster associate with SARS-CoV-2 respiratory failure in an Italian-Spanish genome-wide association analysis Quantitative variation in plasma angiotensin-I converting enzyme activity shows allelic heterogeneity in the ABO blood group locus Rs495828 polymorphism of the ABO gene is a predictor of enalapril-induced cough in Chinese patients with essential hypertension Pleiotropic effect of common variants at ABO Glycosyltranferase locus in 9q32 on plasma levels of pancreatic lipase and angiotensin converting enzyme ABO(H) blood groups and vascular disease: a systematic review and meta-analysis Novel association of ABO histoblood group antigen with soluble ICAM-1: results of a genome-wide association study of 6,578 women C3 and ACE1 polymorphisms are more important confounders in the spread and outcome of COVID-19 in comparison with ABO polymorphism Harnessing the natural anti-glycan immune response to limit the transmission of enveloped viruses such as SARS-CoV-2 Antibody titers in Group O platelet donors. Asian journal of transfusion science COVID-19 & ABO blood group: another viewpoint. British journal of haematology Clearance of maternal isohemagglutinins from infant circulation (CME) The development of ABO isohemagglutinins in Taiwanese Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals Afucosylated immunoglobulin G responses are a hallmark of enveloped virus infections and show an exacerbated phenotype in Relationship between the ABO Blood Group and the COVID-19 Susceptibility Association between ABO blood groups and clinical outcome of coronavirus disease 2019: Evidence from two cohorts The effects of blood group types on the risk of COVID-19 infection and its clinical outcome. Turkish journal of medical sciences