DISCUSSION
This study determined the relative risk of COVID-19 infection and disease outcomes with ABO blood type of hospitalized Filipino patients from Metro Manila, Philippines. To the best of the researchers’ knowledge, this is the first study conducted in Metro Manila, Philippines which explored the associations of ABO blood type with COVID-19 infection and disease outcomes of hospitalized patients. By and large, results indicated that ABO blood type independently predicted the risk COVID-19 infection and severity. Blood type A was 20% at greater risk for COVID-19 infection and had higher risk of developing asymptomatic-to-mild and severe-to-critical COVID-19 by 52% and 25%, respectively. Blood type AB, for this part, increased the risk of moderate COVID-19 by 62%. Blood type O, however, decreased the risk of COVID-19 infection by 19% as well as the risk of moderate COVID-19 by 54%. It was also noted that ABO blood type did not predict the risk of ICU admission, intubation, and mortality.
It is interesting to note that the distribution of blood types was consistent with previous studies, showing that most Filipinos were blood type O, followed by type A, type B, and type AB.11Analyses also showed that the most common clinical manifestations of confirmed COVID-19 patients were cough, dyspnea, and fever. These signs and symptoms are closely similar to the early manifestations noted in Wuhan, with fever as the most common symptomatology.12It should also be noted that although most patients had normal chest radiographic imaging, those with abnormal chest X-ray commonly presented with bilateral infiltrates, comparable with findings in Italy.13,14 In contrast, the commonly reported ground-glass opacity in chest CT scan and pleural line changes in chest sonography13 were not commonly seen among the included patients.
From the 43 different blood group systems recognized by the International Society of Blood Transfusion,15 the ABO blood classification is the most researched and associated with disease occurrence, including cardiovascular conditions, venous thromboembolism,16 rheumatologic diseases,17 malignancies and oncologic conditions, and infectious diseases.8 Among infectious diseases, tuberculosis,18 hepatitis, human immunodeficiency virus,19 and dengue20 have been associated with the ABO system.
Over the past years, research on the association of COVID-19 and ABO blood type have been conducted.4,6,21–26 In the study of Kim et al.,23 eight of the nine reviewed articles showed an association between ABO blood type and COVID-19 infection. Additionally, Muñiz-Diaz et al.23 noted that the risk of COVID-19 was 23% higher for blood type A but was 27% lower for blood type O. Earlier studies also showed a similar trend, wherein the risk of COVID-19 was higher with blood type A but was lower with blood type O,4,22,24–­26 and this was also observed in the genome-wide association study in Spain and Italy.27Consistent with our results, the risk of COVID-19 infection was 20% higher with blood type A, while there is a 19% lower risk with blood type O, and these associations were hypothesized to be due to the ABO antigens on red blood cells. These antigens are carbohydrates encoded by the antigen-coding gene in chromosome 925 and are synthesized through fucosylation of the core glycan and binding of fucose moiety at the non-terminal sugar residue end of the core glycan. This fucosylated core glycan, or H antigen, undergoes enzymatic activity through chromosome 9 and modifies the H antigen according to allelic variant. For blood type O, the allele gene product is devoid of enzymatic activity thus, cannot attach any terminal sugar at the H antigen. In contrast, blood type A receives a terminal N-acetylgalactosamine moiety, blood type B transfers a terminal galactose moiety, and blood type AB develops both moieties of blood type A and B.28 In COVID-19, its infection mechanism has been associated with the terminal galactosamine and galactose moieties in A and B antigens, respectively.29 The spike protein of SARS-CoV-2 virus binds with carbohydrates and has a strong affinity to galactosamine and galactose terminals thus, may facilitate viral binding and cellular uptake.4,7,29 It was also noted that Thr323 and Ser325 are glycosylation sites at the receptor-binding domain of the S1 subunit of SARS-CoV-2 virus hence, potentiating viral binding to host cell and infection.29
Notably, ABO blood type was associated with COVID-19 severity. Among the 327 confirmed COVID-19 patients, majority had moderate infection (41·28%) followed by severe-to-critical infection (35·17%). Factoring the effects of blood type, patients with blood type A were 52% and 25% at higher risk asymptomatic-to-mild and severe-to-critical COVID-19, respectively. Those with blood type AB were 62% at higher risk of moderate COVID-19, while blood type O reduced the risk of moderate infection by 54%. These associations, however, were not evident in previous studies.6,21,25 Nevertheless, despite insufficient evidence on the exact mechanisms for such associations, some studies proposed that it was attributed to increased activity and levels of angiotensin-converting enzyme 2 (ACE-2); Von Willebrand factor and Factor VIII; and, angiotensin-converting enzyme (ACE-1).30 The GATC haplotype of polymorphisms in the ABO gene increases ACE2 receptor activity, which is prevalent among non-O blood type.27 Thus, this upregulation promotes viral adherence and invasion of host cells of non-O blood types. In addition, patients with blood type O have lower ACE levels and have more protection against SARS-CoV-2 virus.30 It has also been proposed that the high levels of ACE1, Von Willebrand factor, and Factor VIII among patients with the A antigen predispose this population to severe forms of COVID-19, cardiovascular complications, and thromboembolic events.30
In our study, ABO blood type was not predictive of ICU admission, intubation, and mortality, even after controlling for significant confounders, which was parallel with the findings of various authors.21,25 However, some evidence showed significant associations between ABO blood type and COVID-19 disease outcomes. Ray et al.,27 for one, noted that blood type O had a protective effect against severe illness or death, decreasing the odds by approximately 15%. Hoiland et al.22 also estimated that the hazards of mechanical ventilation and mortality were 76% and 22% higher for blood types A and AB, respectively, compared to blood type O. In the study of Muñiz-Diaz et al.,24blood type O decreased the odds of mortality by 33%, while type A had 39% higher odds of mortality. However, the results of these studies did not account for certain factors which may affect the reported associations, such as ethnic origin, small sample sizes, and ancestry.22,24,26
This study has certain limitations. First, the COVID-19 variant was not included cognizant that certain variants have the propensity for severe forms of COVID-19. Second, some records of suspected COVID-19 cases were not included due to the lack of an RT-PCR result before their untimely death, especially at the start of the COVID-19 pandemic in the Philippines. Third, only Rhesus positive (Rh+) patients were included since the Filipino population is predominantly Rh+, with less than 1% being Rh–.11 Fourth, our study was conducted in select tertiary hospitals in Metro Manila and does necessary reflect the risk of the general healthy population. Finally, our study only included the admission COVID-19 severity and did not include the progression to higher levels of severity.