key: cord-0702523-twi9ssnv
authors: Shokri, Pourya; Golmohammadi, Saeid; Noori, Maryam; Nejadghaderi, Seyed Aria; Carson‐Chahhoud, Kristin; Safiri, Saeid
title: The relationship between blood groups and risk of infection with SARS‐CoV‐2 or development of severe outcomes: A review
date: 2021-05-14
journal: Rev Med Virol
DOI: 10.1002/rmv.2247
sha: 06f1453f1764a35b3d967068d72b483b16b061c5
doc_id: 702523
cord_uid: twi9ssnv

The outbreak of coronavirus disease 2019 (COVID‐19), caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is considered a global catastrophe that has overwhelmed health care systems. Since initiation of the pandemic, identification of characteristics that might influence risk of infection and poor disease outcomes have been of paramount interest. Blood group phenotypes are genetically inherited characteristics whose association with certain infectious diseases have long been debated. The aim of this review is to identify whether a certain type of blood group may influence an individual’s susceptibility to SARS‐CoV‐2 infection and developing severe outcomes. Our review shows that blood group O protects individuals against SARS‐CoV‐2, whereas blood group A predisposes them to being infected. Although the association between blood groups and outcomes of COVID‐19 is not consistent, it is speculated that non‐O blood group carriers with COVID‐19 are at higher risk of developing severe outcomes in comparison to O blood group. The interaction between blood groups and SARS‐CoV‐2 infection is hypothesized to be as result of natural antibodies against blood group antigens that may act as a part of innate immune response to neutralize viral particles. Alternatively, blood group antigens could serve as additional receptors for the virus and individuals who are capable of expressing these antigens on epithelial cells, which are known as secretors, would then have a high propensity to be affected by SARS‐CoV‐2.

In late December 2019, the outbreak of coronavirus disease 2019 was observed with an unusual pneumonia in Wuhan, China. 1 It rapidly spread worldwide and was declared as a pandemic by the World Health Organization (WHO) on 11 March 2020. 2 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current global health crisis, and it has affected more than 143 million individuals and led to almost 3 million deaths across the world as of late April 2021. 3 COVID-19 primarily involves the lower respiratory tract and is characterized through a dry cough, fever, dyspnoea, and bilateral pneumonia. 4 It has been estimated that 23% of infected cases develop severe symptoms and 6% die due to complications of the disease, such as pneumonia and end-organ failure. 5 Advanced age, male sex, and comorbidities such as diabetes, hypertension, and renal disorders are related to the high SARS-CoV-2 infection rate. 6 The mechanism of SARS-CoV-2 infection mainly depends on spike protein since it utilizes angiotensin-converting enzyme 2 (ACE2) as receptor for cell entry. 7 Several host proteases could help the virus to invade the cells more efficiently. 7 Expression of ACE2 on various human cell surfaces gives SARS-CoV-2 the ability to infect multiple tissues. 8 The two other zoonotic coronaviruses that have caused epidemic infections in the past two decades are severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). 9 The long incubation period and highly contagious nature of COVID-19 are purported to be the primary reason for the substantially high death toll, despite the lower case mortality rate of SARS-CoV-2 in comparison with SARS-CoV and MERS-CoV. 10 For decades, blood group antigens were relegated just to compatibility testing for blood transfusions. However, clinical significance has expanded with relevance in pathogenesis of microorganisms and even providing the first line of defence against infectious agents through corresponding natural antibodies. ABO and Rh blood groups, are among factors that may offer susceptibility or resistance to viral invasion and also influence prognosis of infectious diseases. 11 Understanding the relationship between diseases that have caused pandemics and blood groups could be a useful risk factor to aid prediction of outcomes and establish efficient measures in combating the disease spread with respect to blood group distributions.

In this review, we sought to describe the relationship between blood groups and risk of infection with SARS-CoV-2 and developing unfavourable outcomes.

We searched PubMed database to identify publications from peerreviewed journals. We used Medical Subject Heading (MeSH) terms, including 'ABO Blood-Group System,' 'Rh-Hr Blood-Group System,' 'SARS-CoV-2,' and 'COVID-19' in combination with other free terms such as 'COVID-19,' 'SARS-CoV-2,' '2019-nCoV,' 'ABO blood types,' 'ABO factor,' 'ABO phenotype,' 'blood group,' 'Rhesus Blood Group System,' 'Rh factor,' 'antigen D,' and 'blood group antigens.' Also, medRxiv (https://www.medrxiv.org/) was searched for pre-prints articles with 'blood group AND COVID-19' key words. The search was conducted on March 11, 2021 and no search filters on publication type, language, time period, and other fields were implemented. Reference lists of all relevant publications were manually screened to identify further qualified studies.

There are a number of carbohydrates and proteins on human red blood cell (RBC) membranes that are known as blood group antigens. 12 According to the World Blood Transfusion Association, about 341 antigens have been identified and categorized into 41 blood group systems. 13 ABO blood group system, as discovered by Landsteiner, is the most important blood group system. 14 The sequential additions of carbohydrates to an oligosaccharide backbone resulted in formation of three antigens, including A, B, and H. 15 Adding a terminal residue to the oligosaccharide backbone, creates the H antigen which then acts as a precursor for formation of A and B antigens. 15 ABO gene encodes two glycosyltransferase enzymes that attach N-acetylgalactosamine or D-galactose to H antigen to produce A and B antigens, respectively. 15 In the case of no glycosyltransferase expression, the H antigen serves as an O phenotype. 15 Group O is the most frequent blood group globally, followed by group A, B, and then AB. 16 However, the distribution of these phenotypes widely varies in different populations and is mostly attributed to epidemics that have occurred in the past, so blood groups that were more resistant against disease tended to be naturally selected over time. 17 ABO phenotypes are a common target of epidemiological studies since they are genetically determined traits and the frequency of their distribution varies noticeably across ancestry groups. 18 Accordingly, multiple investigations have been conducted to identify the possible relationship between blood groups as genetic risk factors for various human diseases, especially infectious diseases. 11 A relationship between blood groups and diseases was first postulated in 1917 to investigate an association between ABO blood types and tuberculosis. 19 Since then, many studies have supported the hypothesis that blood groups could be related to the risk of occurrence and progression of several diseases, including cardiovascular disorders, diabetes, neurological diseases, and cancers of the gastrointestinal system. 20, 21 In the case of infectious diseases, it has been shown that individuals with blood group O are at higher risk of being infected with norovirus, HBV, Vibrio cholerae, and dengue virus. [22] [23] [24] [25] [26] Conversely, individuals with non-O blood groups were at higher risk of severe Plasmodium falciparum infection than those with blood group O. 27 Moreover, the efficacy of infectious disease related vaccines may be influenced by blood group distribution in the target population. 28, 29 The mechanism in which blood group antigens may confer susceptibility or protection from infectious agents or influence the evolution of diseases have yet to be elucidated. However, there is some underlying evidence to suggest that blood group antigens may play a key role as receptors and/or cofactors for several infectious agents 11, 30 including Norwalk virus and Helicobacter pylori which interact with ABO antigens to successfully bind with gastric mucosa. 31, 32 Furthermore, various pathogens are capable of expressing blood group antigens identical or cross-reactive epitopes on their surfaces. 11 Therefore, natural antibodies against ABO antigens may act as part of innate immunity that can attenuate infection. 11 The next general blood group category is the Rhesus (Rh) system, determined by the presence or absence of Rh or D antigen. Unlike the ABO system, Rh phenotypes are associated with few diseases, most of which are haemolytic diseases of newborns that occur as a consequence of Rh mismatching between mother and offspring. 33 

The initial idea of a relationship between blood groups and corona- 34 Given that the epidemic was controlled rapidly, the former finding was not sufficiently debated nor corroborated by further research at the time.

More investigations are now underway to better understand if there is the same association between blood groups and the emerging virus, due to SARS-CoV-2 and SARS-CoV sequences being very similar and given that both utilize ACE2 for cell entry. 35 A recent Italian-Spanish genome-wide association study found that polymorphisms at two susceptibility loci, including 9q34.2 and 3p21.31, contributed to SARS-CoV-2 induced respiratory failure that was significant at the genome-wide level. 36 The ABO gene resides on 9q34.2 locus, which suggests that the ABO blood group system has potential implications for SARS-CoV-2 infection. 36 Several reports have come to a conclusion that O blood group subjects are at lower odds of testing positive for COVID-19, whereas those with non-O blood groups, particularly group A, have higher susceptibility to the infection. 35 55 Moreover, populations living in endemic malaria regions appear to have a lower incidence of COVID-19. 56, 57 One potential explanation for this restricted spread is high prevalence of blood group O in malaria-endemic regions, which have been selected due to protective effects against Plasmodium falciparum. 27,58 Therefore, since O blood group carriers are somewhat resistant to SARS-CoV-2 infection, reduced spread of the infection would reasonably be expected in these regions. 59, 60 It is noteworthy to mention that the impact of blood groups on Although all studies in this area have been performed on adult patients, NCT04682912 is recruiting approximately 2,000 children under the age of 18 years who were documented positive for SARS-CoV-2 through PCR assay in order to examine the possible link of blood groups with SARS-CoV-2 infection in such groups of patients. 63 

ABO blood group antigens are expressed not only on erythrocytes but also widely distributed along the mucosal membrane of the gastrointestinal tract, respiratory and reproductive systems, and in their secretions. 64 Expression of such antigens on epithelial cell surfaces and secretions is genetically determined by FUT2 gene, encoding fucosyltransferase 2 enzyme. 65 Based on synthesis of this enzyme, approximately 80% of the population are 'secretor' and 20% are 'non-secretors'. 65 Expression of blood group antigens on mucosal cells have raised some questions about whether the interactions with infectious agents play a role on entry processes of pathogens. In this case, it was shown that in non-secretors, lack of blood type antigen expression on mucosal cells offers some degree of protection from several pathogens, which then potentially bind to these antigens on mucosal surfaces. [65] [66] [67] Recently, it has been shown that the receptor binding domain (RBD) of SARS-CoV-2 spike protein exhibited only low-level affinity for binding to A, B, and H antigens on RBCs but, when exposed to blood group antigens expressed on respiratory epithelial cells, a high SHOKRI ET AL.

-3 affinity was found toward binding to blood group A antigen in comparison with B and H antigens. 68 Consistently, Valenti et al. determined that in non-O blood group patients affected by SARS-CoV-2, non-secretor phenotype was significantly associated with reduced need of mechanical ventilation and intensive care unit (ICU) admission as compared to secretor phenotypes (OR = 0.57; 95% CI: 0.37-0.87; p = 0.007), whereas it did not reach statistical significance for blood group O patients. 69 Therefore, secretor phenotype in group A carriers may play a fundamental role in SARS-CoV-2 invasion to host respiratory cells and further progression of the disease. However, this conclusion may be challenged by a previous study in which no correlation was found between FUT2 gene and COVID-19 prevalence nor mortality. 70 Thus, clarifying the exact role of secretor status on SARS-CoV-2 infection requires further investigations.

The majority of studies concluded that ABO blood groups cannot 55 In a systematic review and meta-analysis of five studies, a statistically significant association has been found in the case of blood group A and a higher risk of mortality due to SARS-CoV-2 infection, while no association was observed in other blood groups. 37 Takagi et al. performed a meta-regression analysis on data of 101 nations, with blood group distribution data available online. 79 In addition to blood group proportions, total number of confirmed COVID-19 cases and deaths in these nations in a whole population of ∼7 billion were almost 9 million and 450,000, respectively. 79 It showed that blood group O was independently associated with lower SARS-CoV-2 mortality (p = 0.02). 79 The data of all the studies evaluating this association are summarized in Table 1 .

The inherent mechanisms explaining protection from or predisposition to SARS-CoV-2 infection are not yet clear, although there are multiple possibilities.

Viral interaction with ACE2 for facilitating cell entry might be possible with other host molecules such as blood group antigens, which in turn affect the susceptibility of different blood type carriers to getting infected by SARS-CoV-2. A recent in vitro study indicated that when the SARS-CoV-2 exposed to ABO antigens expressed on respiratory epithelial cells, the RBD showed a significant preference for binding to A antigen compared to B and H antigens (p < 0.001). This highlights the potential role of A antigen expressing on epithelial cells over the development of SARS-CoV-2 infection. 68

In 2008, Guillon et al. demonstrated that the adhesion of SARS-CoV spike protein to ACE2 could be inhibited by natural anti-A antibodies. 88 The same can be extended to SARS-CoV-2. 89 

Blood group O is associated with a lower risk of unfavourable outcomes in patients with COVID-19. 55 -7 assumed to be a result of this phenomenon. 98, 99 Moreover, it was reported that levels of angiotensin-converting enzyme (ACE), which is responsible for converting angiotensin I to angiotensin II, is lower in blood group O carriers. 100 Angiotensin II could promote inflammatory responses and also induce high blood pressure. 101 

Since the initiation of COVID-19 pandemic, there has been a great deal of concern regarding rapid expansion of low-quality research and investigations. This is especially evident in literature attempting to identify a possible link between blood types and susceptibility to Moreover, in the case of blood group comparison between infected and non-infected individuals, a great number of studies obtained the control population from blood donors that are typically recruited from people in group O due to their universal compatibility, therefore it may have resulted in overestimation of O carriers in control groups. 103 Consequently, the results of such studies should be interpreted with great caution.

Taken together, if we assume that there is a real connection be- 

Although the association between blood groups and outcomes of COVID-19 is not certain, it is speculated that non-O blood group carriers with COVID-19 are at higher risk of developing severe outcomes. The interaction between blood groups and SARS-CoV-2

infection is hypothesized to be as result of natural antibodies against blood group antigens. Also, the severity of disease and disease complications may be influenced by secretor status and ABO antibody titer. Further preclinical and clinical studies are warranted

to draw a precise conclusion on the association between blood groups and SARS-CoV-2 infection.

None.

No conflict of interest declared.

Data sharing is not applicable to this article as no new data were created or analysed in this study.

No ethical approval required for this article.

None.

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P.S., S.G., M.N., and S.A.N. prepared the first draft of the manuscript; K.C.C. and S.S. critically revised and edited the manuscript; S.S. supervised this project. All authors reviewed and approved the final version of the manuscript.

https://orcid.org/0000-0002-8692-9720Saeid Safiri https://orcid.org/0000-0001-7986-9072