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.