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ABO Blood Groups and SARS-CoV-2/COVID-19 Infection (version 2) by Fumiichiro Yamamoto

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Abstract

The title of this presentation is "ABO blood groups and SARS-CoV-2 infection". Scientific knowledge is depicted on the association between A and B glycan antigens of the ABO blood group system important in blood transfusion and cell/tissue/organ transplantation and the infection of the SARS-CoV-2 virus responsible for the ongoing epidemic of coronavirus disease COVID-19. Since the publication of the original note (version 1) on March 26, 2020, additional information and research data about SARS-CoV-2 virus and COVID-19 disease have been accumulating. Taking advantage of them, the note has been modified and revised to prepare this note (version 2). One major change is the addition of an alternative, and probably compatible, theory explaining the association of the ABO blood group polymorphism and the SARS-CoV-2 infectivity. Previously, the presence and/or absence of natural antibodies against A, B, and A,B antigens have been implicated to explain the association. However, in this version, potential roles in blood clotting of von Willebrand factor (vWF) and coagulation factor VIII (FVIII), whose serum-levels are differentially regulated by ABO polymorphism, have also been discussed (The title was modified on May 30 because version 2 was automatically removed from Search engine due to confusion with the original note).
The title of this presentation is “ABO blood groups and SARS-CoV-2 infection”.
Scientific knowledge is depicted on the association between A and B glycan
antigens of the ABO blood group system important in blood transfusion and
cell/tissue/organ transplantation and the infection of the SARS-CoV-2 virus
responsible for the ongoing epidemic of coronavirus disease COVID-19.
Since the publication of the original note (version 1) on March 26, 2020,
additional information and research data on SARS-CoV-2 virus and COVID-19
disease have accumulated. Taking advantage of them, the note was revised
(version 2) and posted online on May 21. However, since then a couple of
important findings have been made. These include the identification of ABO
gene locus to determine susceptibility to severe COVID-19 disease. I have
incorporated those new findings into this revision (version 3).
I have no financial interests to disclose. However, I would like to comment that
the opinions expressed in this presentation are those of the author and do not
reflect the opinions of Josep Carreras Leukemia Research Institute, where I
hold the title of Senior Group Leader.
In addition to the 7 topics mentioned in the original note, 2 additional topics (Nos.
8 and 9) have been added in version 2. Major changes in text are shown in
purple.
1. What is the ABO blood group system?
2. A and B antigens are expressed on cells other than RBCs.
3. Coronavirus Disease 2019 (COVID-19)
4. Coronaviruses and SARS-CoV-2
5. SARS-CoV-2 viruses express A and/or B antigens depending on the
ABO phenotype of cells in which they are produced.
6. Presence/absence of Anti-A, Anti-B, and/or Anti-A,B antibodies
affects individuals susceptibility to SARS-CoV-2 infection.
7. What is the biological implication of the association?
8. von Willebrand Factor (vWF) and blood-clotting Factor VIII (FVIII)
9. What is the clinical implication of the association?
Topics
The first topic is "What is the ABO blood group system?”
In 1900, Austrian immunologist Karl Landsteiner discovered ABO blood groups.
He separated the cellular component consisting mainly of red blood cells
(RBCs) and the liquid component (serum/plasma) of blood from himself and his
colleagues and mixed them in combinations. No changes were observed when
both components were derived from the same individuals. However,
agglutination of RBCs was observed in some combinations as shown by the
positive symbols in the figure and the table. If this occurs within the body, it is
problematic. Complement-mediated cell lysis may follow, and hemoglobin
molecules are released from the RBCs into the bloodstream. If the kidneys are
overwhelmed and do not function normally, the blood recipient may die. Thus,
blood typing and transfusion of "matched" blood, which does not cause RBC
agglutination, became the fundamental principle for the safe practice of
transfusion. Another important finding of the experiment is that individuals could
be classified into groups according to the agglutination pattern. You can see 3
different patterns in the table. The following year, Landsteiner's disciples found
the fourth group. And those 4 groups later became groups A, B, O and AB.
Group O can also be called as group 0 (zero) in some countries.
To explain the phenomenon of RBC agglutination, Landsteiner postulated two
antigens A and B, and the antibodies against those antigens, Anti-A and Anti-B,
respectively, in individuals who do not express these antigens. This rule is
currently known as the Landsteiner's Law. Accordingly, the agglutination of
RBCs is the result of immune reactions between antigens and antibodies. Group
A individuals express A antigens on their RBCs and possess Anti-B antibodies
in their sera. Group B individuals express B antigens on RBCs and possess
Anti-A antibodies in sera. Group AB individuals express A and B antigens on
RBCs, but do not possess Anti-A or Anti-B antibodies. On the other hand,
individuals in Group O do not express A or B antigens on RBCs, but they do
have Anti-A and Anti-B antibodies.
It is now known that O individuals also possess Anti-A,B antibodies that are
reactive to both A and B antigens, in addition to Anti-A and Anti-B. It should also
be remembered that these antibodies are polyclonal. In other words, they are
mixtures and are made of many different monoclonal antibodies that recognize
the same antigens.
To summarize, the ABO blood group system consists of A and B antigens and
antibodies against those antigens. Antigens A and B are not protein antigens
but oligosaccharide (glycan) antigens. Their chemical structures are shown on
this slide. They are similar but different. The A antigen has a GalNAc and fucose
attached to galactose, while B antigen has a galactose and fucose to galactose.
The frequencies of people with different ABO blood groups vary by ethnicity and
location. The table on the left shows the distribution among dozens of countries,
and the map on the right shows the distribution of group O individuals in the
world. It is evident that group O individuals prevail in Central and South America.
In Spain, for example, the frequencies of groups A, B, AB and O are 42, 10, 3
and 45%, respectively.
Antigens A and B were initially identified on human RBCs. However, depending
on the ABO phenotype of individual, they can also be expressed on other types
of cells, including the epithelial cells of the gastrointestinal and respiratory tracts
and the endothelial cells that underlie the blood vessels, in addition to the RBCs.
There are several diseases whose associations to the ABO polymorphism have
been demonstrated not only by statistical analysis but also by Genome-Wide
Association Studies (GWAS). In the gene targeted statistical approach it is
difficult to select the corresponding healthy population, which may mislead to
the wrong conclusion. However, analyzing hundreds of thousands to millions of
anonymous SNP (single nucleotide polymorphism) markers, the GWAS
approach is more objective and reliable because the SNP associations are
found, rather than examined. In addition to determining the presence or
absence of association, it can also evaluate how significant the association is
among numerous SNPs and also among 25,000 genes scattered over the
human genome. Those GWAS-certified disease associations include venous
thromboembolism (VTE), severe cerebral malaria, and gastric ulcer shown on
this slide. The potential molecular mechanisms responsible for these ABO
associations have been somewhat clarified.
ABO-dependent Disease Susceptibility
Venous thromboembolism (VTE, Economy class syndrome)
ABO-dependent plasma concentrations of von Willebrand Factor
(vWF) and Coagulation Factor VIII (FVIII)
Low concentrations in group O => Low disease incidence
Severe brain malaria
ABO-dependent adhesion of RBCs infected with malaria parasite
(Plasmodium falciparum)
Weak adhesion of group O RBCs => Low disease incidence
Gastric ulcer
One of Helicobacter pyloris adhesion receptors to stomach
epithelium is Lewis b (Leb). Functional A and B transferases convert
it to ALeband BLeb, to which the bacteria bind less efficiently.
Strong adhesion to group O cells => High disease incidence
The plasma concentration of von Willebrand factor (vWF) is 25% lower in group
O individuals compared to group non-O individuals. Coagulation Factor VIII
(FVIII) crucial for blood clotting is stable in blood only when bound with vWF.
Consequently, the lower concentration of vWF results in a lower concentration
of FVIII, causing a lower incidence of VTE.
Plasmodium falciparum infection causes malaria. Red blood cells infected with
parasites clog the brain capillaries and cause cerebral malaria. Epidemiological
studies showed a 25% higher incidence of severe brain malaria in non-O type
children. The mechanism was examined using a histochemical method. Groups
A and O RBCs infected with the parasites were allowed to bind to tissue sections.
Differential adhesion to the capillaries was observed, with stronger binding of
group A RBCs than group O RBCs, suggesting that this difference in adhesion
causes a differential occurrence in cerebral malaria.
One of the receptors for Helicobacter pylori adhesion to the stomach epithelium
is a glycan called Lewis b (Leb). When functional A or B glycosyltransferase(s)
are produced by functional A or B alleles, these enzymes modify Leb to ALeb or
BLeb by transferring a GalNAc or galactose, respectively. The decrease in the
binding of Helicobacter pylori to the gastric epithelium was experimentally
demonstrated by this modification, which explains a higher incidence of gastric
ulcer in individuals of type O.
Although not in this slide, an increased susceptibility of non-O individuals to
gastric/pancreatic cancer has also been reported. In case of pancreatic cancer,
the ABO association has also been demonstrated by GWAS. The molecular
mechanisms remain to be experimentally determined.
We all know about coronavirus disease 2019 (COVID-19) because this ongoing
pandemic disease has been drastically affecting our daily routine, infecting and
sacrificing many people. The disease is caused by the coronavirus called
"severe acute respiratory syndrome coronavirus 2", SARS-CoV-2 in short. The
disease was initially identified in Wuhan in China, but has since spread
worldwide. Common symptoms include fever, cough, and shortness of breath.
Although most infected people show no or mild symptoms, some progress to
severe pneumonia, multiple organ failure, and even death. (Chen N, et al.
Epidemiological and clinical characteristics of 99 cases of 2019 novel
coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020. Feb
15;395(10223):507-513. doi: 10.1016/S0140-6736(20)30211-7).
* An infectious disease caused by "severe acute respiratory
syndrome coronavirus 2" (SARS-CoV-2)
* First identified in 2019 in Wuhan, China, and has since spread
globally, resulting in the 201920 coronavirus pandemic.
* Fever, cough, and shortness of breath are common symptoms,
whereas muscle pain, sputum production and sore are less
common.
* While the majority of cases result in no or mild symptoms,
some progress to severe pneumonia, multi-organ failure, and
death. (Wikipedia)
Coronavirus disease 2019 (COVID-19)
The virus is transmitted primarily through respiratory droplets released by
coughing and sneezing, although people can become infected through physical
contact with contaminated materials. Unfortunately, there are no licensed
effective vaccines available at this time (July 7, 2020).
* The infection is typically spread via respiratory droplets
produced during coughing and sneezing although it also results
from physical contact to contaminated materials.
* Time from exposure to onset of symptoms is generally between
2 and 14 days, with an average of 5 days.
* Recommended measures to prevent infection include
frequent hand washing, maintaining distance from others (social
distancing), and keeping hands away from the face.
* At this moment there is no vaccine or specific antiviral
treatment effective for COVID-19. (Wikipedia)
Coronavirus disease 2019 (COVID-19)
The number of infected and also the number of dead have increased
dramatically in many countries.
Please verify updated data provided by the Johns Hopkins University Center for
Science and Systems Engineering (CSSE), the World Health Organization
(WHO), or any other reliable source.
Older people are at a high risk of COVID-19, and over 90% of the deaths
occurred in those older than 60 years. More than 50% of all deaths were people
aged 80 years or older also. Eighty percent of deaths have occurred of
individuals with at least one underlying comorbidity, in particular with
cardiovascular diseases/hypertension and diabetes, but also with a variety of
other chronic underlying conditions. Male COVID-19 patients tend to have
worse prognosis than female patients: Higher chances of being hospitalized to
ICU and death resulting from the disease. In Spain for instance, seven out of 10
individuals found infected with SARS-CoV-2 are female, but 70% of those
hospitalized to ICU and 60% of those who died of the disease are male. And
this tendency of poor prognosis for men has been observed in more than 30
countries.
* Older adults are at a significantly increased risk of severe
COVID-19 disease, and over 90% of the deaths occurred in
people older than 60 years.
* Eighty percent of deaths occurred in people with at least one
underlying comorbidity, in particular those with cardiovascular
diseases/hypertension and diabetes, but also with a variety of
other chronic underlying conditions.
* Male COVID-19 patients tend to have worse prognosis than
female patients: Higher chances of hospitalization to ICU and
death resulting from the disease.
Coronavirus disease 2019 (COVID-19)
An excessive reaction of the immune system by cytokine storm may attack own
tissues and transform COVID-19 into a multi-organ disease. SARS-CoV-2
exhibits a wide organotropism, especially to such organs as lung, kidney and
heart. In addition, the viral infection may directly damage those vital organs and
impair their functions.
The name “coronavirusderives from its morphology reminiscent of the solar
corona. SARS-CoV and MERS-CoV responsible for Severe Acute Respiratory
Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) epidemics,
respectively, are also members of coronaviruses, in addition to coronaviruses
that cause the common cold.
* The name coronavirusis derived from the Latin word
corona, which refers to the characteristic appearance
reminiscent of a solar corona around the virus particles, due
to the surface covering with club-shaped Spike (S) proteins.
* Human coronaviruses have been involved in serious
respiratory tract infections, including SARS-CoV responsible
for Severe Acute Respiratory Syndrome (SARS) in
2003, MERS-CoV responsible for Middle East Respiratory
Syndrome (MERS) in 2012, and SARS-CoV-2 responsible
for COVID-19 in 2019-2020.
Coronaviruses
(Wikipedia)
The morphology of coronaviruses is illustrated in the left figure, and the electron
micrograph of SARS-CoV-2 viruses is shown on the right.
COVID-19 is caused by severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2). The virus is a positive-sense single-stranded RNA virus. The
size of the genome is approximately 30 kilobases long and contains
approximately 10 genes. The genome sequence has been determined from
hundreds of isolates and has been found to be highly homologous to SARS-
CoV and MERS-CoV and other human coronaviruses, as well as to
coronaviruses in bats and pangolins.
* Severe acute respiratory syndrome coronavirus 2 (SARS-
CoV-2) is a positive-sense single-stranded RNA virus with the
30kb genome size and 10 or so genes.
* It is contagious in humans and is the cause of the ongoing
pandemic of coronavirus disease 2019 (COVID-19).
* SARS-CoV-2 has close genetic similarity to bat
coronaviruses, from which it likely originated. An intermediate
animal reservoir such as a pangolin is also thought to be
involved in its introduction to humans.
(Wikipedia)
Severe Acute Respiratory Syndrome Coronavirus 2
SARS-CoV-2 is encapsulated with the host cell membrane. Viral Spike (S)
proteins are glycoproteins embedded in the membrane, and they are "coronas"
of viral particles.
* SARS-CoV-2 virus is
membrane-encapsulated
and has four structural
proteins: S (spike), E
(envelope), M (membrane),
and N (nucleocapsid). The
N protein holds the RNA
genome, and the S, E,
and M proteins together
create the viral envelope.
(Wikipedia)
SARS-CoV-2 Virus
Spike (S)
Glycoprotein
Glycans
(A, B, A&B, -)
S proteins mediate viral association with cells. They have 23 potential N-linked
glycosylation sites, of which at least 13 were shown to be glycosylated. Both the
SARS-CoV and SARS-CoV-2 S proteins have been experimentally
demonstrated to physically interact with cell-surface angiotensin-converting
enzyme 2 (ACE2).
* Spike (S) protein is a large transmembrane protein that
mediates cellular binding (Li W, et al. 2006).
* The S protein possesses 23 N-linked glycosylation sites, and
the glycosylation has been confirmed of 13 of these sites
(Krokhin O, et al. 2003; Ying W, et al. 2004).
* SARS-CoV was shown to bind human cell-surface
angiotensin-converting enzyme 2 (ACE2) with high affinity (Xiao
X, et al. 2003; Wong SK, et al. 2004).
* The S proteins association with ACE2 protein was also
shown of SARS-CoV-2 (Wrapp D, et al. 2020).
SARS-CoV Spike Protein
The transmembrane protease called TMPRSS2 was shown to cleave S proteins
to expose the fusion peptides whereby viruses fuse with host cells. The viral
RNA genome is introduced and used to make viral particles. The three-
dimensional structures of the S proteins from SARS-CoV-2, in addition to those
from SARS-CoV, have been determined in open and closed configurations.
* Transmembrane protease TMPRSS2 cuts open the Spike
protein, exposing a fusion peptide. The virus then releases RNA
into the cell, producing viral copies that are disseminated to
infect more cells (Hoffman M, et al. 2020, Matsuyama S, et al 2020).
SARS-CoV-2 Spike Protein
(NCBI)
Closed state =>
(MMDB ID: 185171 PDB ID: 6VXX)
<= Open state
(MMDB ID: 185172 PDB ID: 6VYB)
Certain genetic factors have been shown to influence susceptibility to SARS.
These include haplotypes at the locus of the major histocompatibility complex
encoding human leukocyte antigens (HLAs) and those at the ABO blood group
locus. A lower risk of individuals in group O was observed.
Major histocompatibility complex (MHC) locus
The HLA-B*4601 haplotype was associated with severity of
SARS infection in a group of Taiwanese patients (Lin M, et al,
2003).
The HLA-B*0703 and HLA-DRB1*0301 haplotypes were
associated with severity of SARS infection in a group of
Hong Kong Chinese patients (Ng MH, et al. 2004).
ABO blood group locus
Blood type O was associated with a lower risk of SARS-
CoV infection (Cheng et al. 2005).
Genetic Factors Influencing SARS-CoV Infection
SARS-CoV viruses infect and proliferate in epithelial cells of the respiratory and
digestive tracts. Separately, those epithelial cells express A and/or B glycan
antigens, depending on the ABO phenotype of the individual. However, it
remained to be determined whether the S proteins produced in cells expressing
A and/or B antigens are glycosylated to carry those antigens or not. It was also
unknown whether Anti-A, Anti-B, and Anti-A,B antibodies could block the
physical interaction between S proteins on viral particles and ACE2 proteins in
the cell membrane. It was, therefore, necessary to examine the validity of these
assumptions.
A and/or B Antigen Expression on SARS-CoV
Fact:
* SARS-CoV replicates in epithelial cells of the respiratory and
digestive tracts that have the ability to synthesize A and/or B
glycan antigens, depending on individuals ABO phenotype.
Assumptions:
* The S proteins produced in A, B, or AB individuals could be
decorated with A, B, or A/B glycan antigens, respectively.
* Anti-A, Anti-B, and Anti-A,B antibodies could bind to the A, B,
and A/B antigens on the S proteins, respectively, and block
the interaction between S and ACE2 proteins.
In 2008, Le Pendu and colleagues published an article entitled "Inhibition of the
interaction between the SARS-CoV Spike protein and its cellular receptor by
anti-histo-blood group antibodies" (Guillon P, et al. 2008. Glycobiology, 18(12):
1085-1093. https://doi.org/10.1093/glycob/cwn093).
.
Inhibition of Interaction between S & ACE2 Proteins
Inhibition of the interaction between the SARS-CoV Spike protein
and its cellular receptor by anti-histo-blood group antibodies
GuillonP, et al. (2008). Glycobiology, 18(12): 1085-1093.
https://doi.org/10.1093/glycob/cwn093
Abstract
Severe acute respiratory syndrome coronavirus (SARS-CoV) is a highly pathogenic emergent virus which replicates in cells that
can express ABH histo-blood group antigens. The heavily glycosylated SARS-CoV spike (S) protein binds to angiotensin-
converting enzyme 2 which serves as a cellular receptor. Epidemiological analysis of a hospital outbreak in Hong Kong revealed
that blood group O was associated with a low risk of infection. In this study, we used a cellular model of adhesion to
investigate whether natural antibodies of the ABO system could block the S protein and angiotensin-converting
enzyme 2 interaction. To this aim, a C-terminally EGFP-tagged S protein was expressed in chinese hamster ovary cells
cotransfected with an α1,2-fucosyltransferase and an A-transferase in order to coexpress the S glycoprotein ectodomain and the
A antigen at the cell surface. We observed that the S protein/angiotensin-converting enzyme 2-dependent adhesion of these
cells to an angiotensin-converting enzyme 2 expressing cell line was specifically inhibited by either a monoclonal or human
natural anti-A antibodies, indicating that these antibodies may block the interaction between the virus and its receptor, thereby
providing protection. In order to more fully appreciate the potential effect of the ABO polymorphism on the epidemiology of
SARS, we built a mathematical model of the virus transmission dynamics that takes into account the protective effect of ABO
natural antibodies. The model indicated that the ABO polymorphism could contribute to substantially reduce the virus
transmission, affecting both the number of infected individuals and the kinetics of the epidemic.
In this article, the authors described the results of the experimental cell model
and also the data obtained from the analysis of the dynamics of viral
transmission. In the former, they designed Chinese hamster ovary cells that
express cell surface SARS-CoV (and not SARS-CoV-2) S proteins carrying A
antigens by co-transfecting eukaryotic expression constructs of appropriate
genes. The newly generated cells were first shown to bind to Vero E6 cells that
express cell surface ACE2 proteins through the S-ACE2 interaction. The
authors then showed that a mouse Anti-A monoclonal antibody, as well as
human polyclonal natural Anti-A antibodies, blocked the binding. In the latter,
they constructed a mathematical model of viral transmission and examined the
kinetics of SARS epidemic. Substantially reduced viral submission due to ABO
polymorphism was calculated.
Cell model experiments:
* Chinese hamster ovary cells were engineered to express, on
cell surface, S proteins carrying A glycan antigens.
* The adhesion of those cells to Vero E6 cells expressing ACE2
was specifically inhibited by a mouse monoclonal Anti-A
antibody or human natural Anti-A antibodies.
Analysis of viral transmission dynamics:
* The mathematical model indicated that the ABO polymorphism
could substantially reduce viral transmission, affecting both the
number of infected individuals and the kinetics of the epidemic.
Anti-A Antibodies Blocked S -ACE2 Interaction
On March 11, 2020, a manuscript was published on medRxiv, the Health
Sciences preprint server (Zhao J, et al. Relationship between the ABO Blood
Group and the COVID-19 Susceptibility. medRxiv preprint
https://doi.org/10.1101/2020.03.11.20031096). It is titled, "Relationship between
the ABO blood group and the COVID-19 susceptibility". Strictly speaking, the
content may not be entirely reliable because it has not yet undergone scientific
review. However, I read the preprint anyway. I will comment on the manuscript
in detail in the following slides.
It was concluded that people with blood groups A and O have a significantly
higher and lower risk of acquiring COVID-19, respectively.
.
Relationship between the ABO Blood Group and the COVID-19
Susceptibility
Jiao Zhao et al. medRxiv preprint doi: https://doi.org/10.1101/2020.03.11.20031096.
CONCLUSION:
* People with blood group A have a significantly higher risk for
acquiring COVID-19 compared with non-A blood groups.
* People with blood group O have a significantly lower risk for the
infection compared with non-O blood groups.
ABO Polymorphism and SARS-CoV-2 Infection
Another paper was posted on medRxiv on April 11, 2020 (Zietz M, et al. Testing
the association between blood type and COVID-19 infection, intubation, and
death. medRxiv preprint https://doi.org/10.1101/2020.04.08.20058073). Taking
advantage of healthcare data in the New York Presbyterian (NYP) hospital
system available on 1559 individuals with known blood type tested for SARS-
CoV-2 (682 COV+), the authors assessed the association between ABO+Rh
blood type and SARS-CoV-2 infection status, intubation, and death. A higher
proportion of blood group A and a lower proportion of group O were observed
among COV+ patients compared to COV-, though in both cases the result was
statistically significant only in Rh positive blood groups. In a meta-analysis of
NYP data with previously-reported data from China, enrichment for A and B
groups and depletion of O group were observed among COVID-19 patients
compared to the general population. No strong evidence of association was
obtained between blood group and intubation or death among COVID-19
patients.
ABO Polymorphism and SARS-CoV-2 Infection
Testing the association between blood type and COVID-19
infection, intubation, and death
Zietz M, et al. medRxiv preprint https://doi.org/10.1101/2020.04.08.20058073
Abstract
The rapid global spread of the novel coronavirus SARS-CoV-2 has strained existing healthcare and testing resources, making the
identification and prioritization of individuals most at-risk a critical challenge. A recent study of patients in China discovered an
association between ABO blood type and SARS-CoV-2 infection status by comparing COVID-19 patients with the general
population. Whether blood type is associated with increased COVID-19 morbidity or mortality remains unknown. We used
observational healthcare data on 1559 individuals tested for SARS-CoV-2 (682 COV+) with known blood type in the New York
Presbyterian (NYP) hospital system to assess the association between ABO+Rh blood type and SARS-CoV-2 infection status,
intubation, and death. We found a higher proportion of blood group A and a lower proportion of blood group O among
COV+ patients compared to COV-, though in both cases the result is significant only in Rh positive blood types. We show
that the effect of blood type is not explained by risk factors we considered (age, sex, hypertension, diabetes mellitus, overweight
status, and chronic cardiovascular and lung disorders). In a meta-analysis of NYP data with previously-reported data from China,
we find enrichment for A and B and depletion of O blood groups among COVID-19 patients compared to the general
population. Our data do not provide strong evidence of associations between blood group and intubation or death among
COVID-19 patients. In this preliminary observational study of data currently being collected during the outbreak, we find new
evidence of associations between B, AB, and Rh blood groups and COVID-19 and further evidence of recently-discovered
associations between A and O blood groups and COVID-19.
Another paper was posted on medRxiv on April 17, 2020 (Zeng X, et al.
Association between ABO blood groups and clinical outcome of coronavirus
disease 2019: Evidence from two cohorts. medRxiv preprint
https://doi.org/10.1101/2020.04.15.20063107). The frequency of blood group O
individuals among patients with COVID-19 was found lower in the critical cohort
(26.5%) than the reference Chinese population comprised of half a million Han
individuals (33.2%) or the mild cohort (32.5%), suggesting that group O
individuals did not progress to the critically ill stage as often.
The frequencies of group A patients in the mild and critical cohorts, 35.8% and
39.2%, respectively, were, on the other hand, significantly higher than the
reference population (p=0.000 and p=0.005, respectively), confirming that
group A individuals may be more vulnerable to SARS-CoV-2 infection.
Furthermore, group A has an increased risk with an OR value of 1.40 and 1.63
in the mild and critical cohorts, respectively. Nonetheless, group A was not
associated with acute respiratory distress syndrome (ARDS) and death,
whereas an association was observed of the age (≥60 years) of patients with
ABO Polymorphism and SARS-CoV-2 Infection
Association between ABO blood groups and clinical outcome of
coronavirus disease 2019: Evidence from two cohorts
Zeng X, et al. medRxiv preprint doi: https://doi.org/10.1101/2020.04.15.20063107.
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become the third most common coronavirus
that causes large-scale infections worldwide. The correlations between pathogen susceptibility and blood type
distribution have attracted attention decades ago. The current retrospective study aimed to examine the
correlation between blood type distribution and SARS-CoV-2 infection, progression, and prognosis in
patients with coronavirus disease 2019 (COVID-19). With 265 patients from multiple medical centers and two
established cohorts, we found that the blood type A population was more sensitive to SARS-CoV-2.
Moreover, the blood type distribution was not relevant to acute respiratory distress syndrome
(ARDS), acute kidney injury (AKI), and mortality in COVID-19 patients. These findings are indicative
of coping with the great threat since it probed the relationship between blood types and ARDS, AKI, and mortality, in
addition to susceptibility in COVID-19 patients.
ARDS (OR=6.22) or death (OR=9.23) in the multivariable logistic regression
analysis although the limited number of enrolled patients may be responsible.
Two correspondences were published in the British Journal of Hematology. Like
Zhao and colleagues, Li and colleagues analyzed the COVID-19 cases in
Wuhan, China and came to the same conclusion that group A and group O
individuals are at higher and lower risk, respectively, of acquiring COVID-19
disease.
Gerard and colleagues analyzed Zhao’s data from the point of Anti-A or Anti-B
antibodies instead of A and B antigens and showed that people with Anti-A
antibodies are less represented in patients with COVID-19. Because group O
and group B patients were underrepresented and overrepresented, respectively,
it was concluded that Anti-A from O is more protective than Anti-A from B.
Most recently, on June 8, genetic testing company 23andMe released
preliminary data from its ongoing COVID-19 genetic study, drawing on
information obtained from the survey of more than 750,000 participants. The
percentage (%) reporting COVID-19 was calculated from individual ABO blood
groups: 1.3%, 1.4%, 1.5%, and 1.5% among all the participants, and 3.2%,
3.9%, 4.0%, and 4.1% among professional health care workers for groups O, A,
B, and AB, respectively. The protective effect of group O was observed against
acquisition (OR = 0.86, p < 0.0001) and hospitalization due to infection (OR =
0.81, p = 0.05) in the entire population and also enhanced among health
professionals (OR = 0.81, p < 0.0001). The results appear to have demonstrated
the powerful nature of this novel approach to studying genetic associations
based on genome sequencing and survey questions. With its large number of
participants, the approach may be extremely powerful if genome sequences are
analyzed for GWAS study. However, it would have been better if the results were
first published in a paper that has undergone a traditional peer review process
to examine the comprehensiveness of statistical methods and the accuracy of
data analyzed.
Another important progress has been made in the Genome-Wide Association
Study (GWAS) of COVID-19 disease. On June 17, a paper was published in the
New England Journal of Medicine describing the results of COVID-19 GWAS
study, which was previously posted online on the medRxiv preprint server. In
the work described in that paper, the authors analyzed 8,582,968 single
nucleotide polymorphism (SNP) markers from 835 COVID-19 patients and
1,255 control participants from Italy and 775 patients and 950 control
participants from Spain for the COVID-19 association.
Cross-replicating associations were identified between the COVID-19 disease
and rs11385942 at chromosome 3p21.31 and rs657152 at 9q34, which were
genome-wide significant (p<5×10-8) in the meta-analysis of both study panels,
odds ratio [OR], 1.77; 95% confidence interval [CI], 1.48 to 2.11; p=1.14×10-10
and OR 1.32 (95% CI, 1.20 to 1.47; p=4.95×10-8), respectively. The association
signal at 9q34 was located at the ABO blood group locus.
Unlike the statistical analysis examining the association of the ABO
polymorphism and COVID-19 disease, this GWAS discovered the ABO
association with COVID-19. Consequently, it was a more objective finding.
Furthermore, the results showed that the ABO gene is one of the most important
genes whose SNP polymorphism makes differential susceptibility COVID-19
disease.
A blood-group-specific analysis demonstrated a higher risk for group A
individuals (OR=1.45, 95% CI, 1.20 to 1.75, p=1.48×10-4) and a protective effect
for group O individuals (OR=0.65, 95% CI, 0.53 to 0.79, p=1.06×10-5).
What is the biological
implication of the association?
The SARS-CoV-2 viruses produced in individuals of groups A, B, AB and O
express A, B, A and B, and none of the antigens, respectively. People in groups
A, B, AB and O have Anti-B, Anti-A, neither and Anti-A/Anti-B/Anti-A,B
antibodies, respectively. Therefore, these antibodies can react to the
corresponding antigens and inhibit, at least partially, interpersonal infection
between certain individuals with different ABO phenotypes. These situations
resemble "matched" and "mismatched" combinations of blood transfusion. For
example, SARS-CoV-2 viruses produced in individuals from group A can
express A antigens and infect individuals from groups A and AB without such
antigen-antibody reactions. However, infection of these viruses to individuals in
groups B or O who possess Anti-A antibodies may be somewhat inhibited.
Similarly, SARS-CoV-2 viruses that express B antigens can infect individuals
from group B or AB. However, infection in group A or O individuals possessing
Anti-B antibodies may be somewhat limited. The infectivity of SARS-CoV-2
viruses is shown schematically on this slide. Red arrows indicate viral infectivity,
while black broken arrows show some degree of infectivity block.
The ABO distribution in Wuhan in China, described in Zhao et al, was used to
calculate the frequencies of individuals with different ABO phenotypes infected
with the SARS-CoV-2 virus, assuming random encounters. The numbers in red
show the frequencies of "matched" combinations, while the numbers in black
show the frequencies of "unmatched" combinations. The sum of values in red
and the sum of values in black are 0.564039 and 0.435961, respectively.
In case that no inhibition (0%) is assumed of the “unmatchedcombinations,
infectivity is calculated by the sum of frequencies in each row, which is
equivalent to the frequency of individuals showing that ABO type. For example,
the frequency of group O individuals among the infected is calculated to be 0.34
{(0.108829 + 0.084262 + 0.030794 + 0.114515) / (0.564039 + 0.435961)}. In
case that 100% inhibition is assumed, only the values in red are considered.
The frequency of group O individuals among the infected is calculated to be
0.2030 (0.114515 / 0.564039). In case that 75% inhibition is assumed, only 25%
SARS-CoV-2 Infectivity
ABO Phenotype of Virus
A B AB O
0.32 0.25 0.09 0.34
ABO Type of
Individual
A0.32 0.103427 0.080078 0.029266 0.108829
B0.25 0.080078 0.062001 0.022659 0.084262
AB 0.09 0.029266 0.022659 0.008281 0.030794
O0.34 0.108829 0.084262 0.030794 0.114515
of the values in black are considered. Therefore, the frequency of group O
individuals among the infected is calculated to be 0.2533 [{0.114515 + 0.25 x
(0.108829 + 0.084262 + 0.030794)} / (0.564039 + 0.25 x 0.435961)].
Using the data in the table on the previous slide, the expected ABO distribution
in individuals infected with SARS-CoV-2 was calculated. Five sets of
frequencies with 0, 25, 50, 75 and 100% inhibition are shown. Data at 0%
inhibition correspond to those from the healthy population in the Wuhan region.
The actual frequencies determined from the infected and hospitalized patients
are shown in the rightmost column. It seems clear that people with O type have
a lower risk of SARS-CoV-2 infection. However, inhibition of infection mediated
by Anti-A, Anti-B, and/or Anti-A,B antibodies is unlikely to be 100% effective.
In summary, the Anti-A, Anti-B, and Anti-A,B antibodies appear to decrease the
chance of SARS-CoV-2 infection. However, inhibition is not 100% efficient.
Once infection is established, SARS-CoV-2 viruses are produced that exhibit
the same ABO phenotypes as infected individuals, and those antibodies are no
longer useful in inactivating newly produced viruses. Ironically, O individuals
with a lower risk of SARS-CoV-2 infection can produce type O SARS-CoV-2
viruses that are more effective in infecting individuals with any ABO phenotype.
* Anti-A, Anti-B, and Anti-A,B antibodies may decrease
individuals chance of infection to SARS-CoV-2 virus, resulting
in a lower susceptibility of type O individuals.
* Blockage may be complete or not. However, once infection
is established, individuals produce viruses of their own ABO
types, and Anti-A, Anti-B, and/or Anti-A,B antibodies they
possess may no longer neutralize newly produced viruses.
* O individuals may have a lower risk of viral infection, but
type O SARS-CoV-2 viruses they produce may infect to their
own cells as well as individuals with any ABO phenotypes.
SARS-CoV-2 Infectivity
Anti-A, Anti-B and Anti-A,B antibodies of the IgA class may be primarily
responsible for the inhibition of SARS-CoV-2 infection for mucosal immunity,
although natural antibodies of other classes (IgM and IgG) may also function.
Inhibition results in a decrease in the value of R0, the expected number of cases
generated directly by a case. In other words, the R0 value would have been
greater if the inhibition did not exist. Furthermore, inhibition is estimated to be
more efficient in heterogeneous populations in the ABO phenotype and less
efficient in homogeneous populations, such as Amerindians in Central and
South America where type O is prevalent.
* Anti-A, Anti-B and/or Anti-A,B IgA antibodies in the respiratory
tract may be primarily responsible for mucosal immunity
although those of IgM and IgG classes may also function.
* The inhibition of SARS-CoV-2 viral infection may diminish the
R0 value, namely, the expected number of cases directly
generated by one case in a population susceptible to infection.
* The inhibition in viral transmission is less effective in a
population homogeneous in the ABO phenotype, for instance,
Amerindians in Brazil and other countries in the Central/South
America where type O is prevalent.
SARS-CoV-2 Infectivity
Anti-A, anti-B and anti-A,B antibodies can inhibit the interaction between viral S
proteins and cellular ACE2 receptors. However, this is not the end result.
Inhibition can trigger prevention of SARS-CoV-2 viral entry and opsonization
into host cells and the following neutralization in a complement-mediated
manner. The generation of cytotoxic T cells may be promoted, and the
acquisition of immunity against other viral antigens may follow. Therefore,
pleiotropic effects may occur.
Anti-A, Anti-B and/or Anti-A,B antibodies may inhibit the
interaction between the viral S proteins and cellular ACE2
receptors.
This may trigger:
* Prevention of the entry and opsonization of SARS-CoV-2
virus into cells and the viral neutralization in a complement-
mediated manner.
* Generation of cytotoxic T cells may be promoted.
* Acquisition of immunity against other viral antigens may
follow.
SARS-CoV-2 Infectivity
von Willebrand Factor (vWF)
and blood-clotting Factor VIII
(FVIII)
Under physiological conditions, the vascular endothelium produces many
substances that contribute to hemostasis, fibrinolysis, and regulation of vascular
tone and permeability. One such substance is the multimeric glycoprotein
named von Willebrand factor (VWF). The mature vWF molecule is composed of
50 to 100 monomers and can reach an ultimate size of up to 20 MDa. The
majority of vWFs are synthesized in vascular endothelial cells and released into
plasma, whereas about 10% are synthesized by bone marrow megakaryocytes
and stored primarily in the alpha granules of circulating platelets. vWF plays a
crucial role in platelet adhesion, aggregation, and fibrin clot formation, by acting
as a carrier protein and stabilizer for Factor VIII (FVIII).
* The von Willebrand factor (vWF) is a multimeric adhesive
glycoprotein that is important for platelet-platelet and platelet-
vessel hemostatic interactions.
* The majority of vWFs are synthesized in vascular endothelial
cells and released into plasma.
* Approximately 10% of vWFs are synthesized by bone
marrow megakaryocytes and stored primarily in the alpha
granules of circulating platelets.
von Willebrand Factor (vWF)
People with high levels of Coagulation Factor VIII (FVIII) are at increased risk
for thrombosis and pulmonary embolism. FVIII is a protein essential for blood
clotting. It is produced in liver sinusoidal cells and also in endothelial cells
present throughout the body. FVIII is encoded by the gene F8, and the mutations
in that gene result in a recessive X-linked coagulation disorder hemophilia A. In
plasma, FVIII is stable and retains the pro-coagulant activity only when it is
bound with a carrier protein vWF. When FVIII is activated, it separates from vWF
and interacts with Factor IX (FIX), setting off a chain of additional reactions that
form a blood clot.
* Factor VIII (FVIII) is an essential blood-clotting protein
produced in liver sinusoidal cells and also endothelial cells
throughout the body.
* Defects in the F8 gene encoding FVIII result in hemophilia A,
a recessive X-linked coagulation disorder.
* In blood, FVIII is bound with vWF. However, when FVIII is
activated, it separates from vWF and interacts with Factor IX
(FIX), setting off a chain of additional chemical reactions that
form a blood clot.
Coagulation Factor VIII (FVIII)
Both the vWF and FVIII are risk factors for the development of atherosclerotic
diseases. Because FVIII is stable in blood only when it binds to vWF, plasma
concentrations of vWF and FVIII are strongly correlated with each other.
In the healthy population, plasma vWF antigen level varies widely (50-200
IU/dL) with the mean value of 100 IU/dL. Plasma vWF and FVIII levels may or
may not be higher in males than females (this is controversial). The mean
concentration of plasma FVIII in 232 men was reported to be 6.5% higher than
in 178 women (p=0.05) (Preston AE, 1964). In fasting morning samples, a
statistically significant male-female difference was reported in vWF activity also:
the average level for males was 139±17% vs 69±9% for females (p=<.0005)
(Sarji KE, 1975). However, this sex difference was not supported in a later study
where higher vWF and FVIII levels were found in females than males (Conlan
MG, 1993). In that multivariate analysis, associations were also observed with
race and diabetes. People from African origin had vWF and FVIII levels 15 to
* Both the vWF and FVIII are risk factors for the development of
atherosclerotic diseases.
* Because FVIII is stable in blood only when it binds to vWF,
plasma vWF and FVIII levels are strongly correlated with each
other.
* Plasma vWF and FVIII levels tend to be higher in old
individuals than young ones, and also higher in males than
females although the latter may not always be true.
* The associations have also been observed of plasma vWF
and FVIII levels with race and diabetes.
Plasma vWF and FVIII Concentrations
18% higher than people from European origin, and diabetics had 11 to 18%
higher than non-diabetics.
Plasma vWF and FVIII levels also seem to be higher in old people than young
people (Albánez S, 2016). In a normal population, vWF plasma level increases
by approximately 17IU/dL per decade (Ridz N, 2015). An increased plasma vWF
level is observed by a variety of stimuli such as hypoxia and inflammatory
cytokines among others.
As previously mentioned, susceptibility to venous thromboembolism (VTE),
which is also called as Economy class syndrome, varies among individuals with
different ABO phenotypes, with group O individuals showing a 25% decrease in
the disease incidence. In addition to age, sex, race, and diabetes, plasma vWF
and FVIII concentrations are also dependent on the ABO polymorphism, as
demonstrated in these graphs (Albánez S, et al. Aging and ABO blood type
influence VWF and FVIII levels through interrelated mechanisms. J. Throb.
Haemost. 2016, https://doi.org/10.1111/jth.13294).
The mean level for blood group O individuals is 75 IU/dL and the normal range
is 36-157 IU/dL, which is 25-35 IU/dL lower than individuals with other ABO
groups. Accordingly, a 25% decrease is observed in plasma vWF and also FVIII
levels in group O individuals. The graph in the left shows the distribution of the
plasma vWF level of individuals with different ages. Blood group non-O and O
individuals are marked in closed and open circles, respectively. Similar
vWF, FVIII & ABO Polymorphism
(Albánez S, et al. Aging and ABO blood type influence VWF and FVIII
levels through interrelated mechanisms. J. Throb. Haemost. 2016)
distribution is shown of the plasma FVIII level in the right graph. Statistically
significant differences were observed between group non-O and O individuals.
Plasma levels of vWF and FVIII are dependent on age and ABO polymorphism.
And higher vWF and FVIII concentrations are related to an increased risk of
deep-vein thrombosis in subjects of non-O blood groups than in those of group
O.
vWF, FVIII & ABO Polymorphism
(Albánez S, et al. Aging and ABO blood type influence VWF and FVIII levels through
interrelated mechanisms. J. Throb. Haemost.2016, DOI: 10.1111/jth.13294)
What is the clinical implication
of the association?
Systemic endothelial activation and injury are important causes of multi-organ
system failure, and vWF serves as a useful marker of endothelial activation and
injury.
Plasma vWF concentrations are associated with clinical outcomes in acute lung
injury (ALI) and acute respiratory distress syndrome (ARDS). They are
significantly greater in ARDS patients and non-survivors than patients without
ARDS and survivors, respectively. Higher vWF levels are also associated with
fewer organ failure–free days, a longer duration of mechanical ventilation, and
probably with sepsis. According to stepwise logistic regression analysis, vWF
was independently associated with in-hospital death.
In mouse experiments, functional regulation of vWF was shown to ameliorate
acute ischemia-reperfusion kidney injury also.
vWF, ALI, ARDS & Multi-organ System Failure
* Playing a role in cross-talk between inflammation and
thrombosis, plasma vWF is a marker of systemic endothelial
activation and injury important in multi-organ system failure.
* At the time of intubation, median edema fluid and plasma
vWF concentrations are significantly higher (two-fold increase)
in non-survivors versus survivors, predicting the clinical
outcomes in acute lung injury (ALI), acute respiratory distress
syndrome (ARDS), and fewer organ failurefree days.
* In mouse experiments, functional regulation of vWF
ameliorates acute ischemia-reperfusion kidney injury.
The vast majority of lung damage was previously thought to have resulted from
viral pneumonia, but the roles blood clotting may play have recently gained
more attention. Coagulation may occur because of damage to cells lining blood
vessels that results from the viral infection and the immune system’s
inflammation-causing response. Actually, high incidence of thrombotic
complications including pulmonary embolism, a potentially deadly blockage in
arteries of the lungs, have been observed in critically ill ICU patients (30% with
COVID-19 versus 1.3% without COVID-19). The blood clots are visible, being
formed in patientsarterial catheters and filters used to support failing kidneys.
Blood flow is impeded in the lungs, causing difficulty in breathing. Viruses
including HIV, dengue and Ebola are prone to cause blood cell clumping. And
this pro-clotting activity seems to be more pronounced in patients infected with
SARS-CoV-2. Apparently, the infection causes excessive inflammation, hypoxia,
immobilization, and diffuse intravascular coagulation, and COVID-19 patients
seem to be predisposed to venous and arterial thromboembolisms. And these
may be, partially at least, responsible for the sudden change of patients who
otherwise appear well to develop severe blood-oxygen deficiency and
COVID-19 & Blood Clotting
* High incidence was observed of thrombotic complications in
critically ill ICU patients with COVID-19.
* COVID-19 may predispose to swift and sometimes fatal
venous and arterial thromboembolism due to excessive
inflammation, hypoxia, immobilization and diffuse intravascular
coagulation.
* More pernicious are the clots that impede blood flow in the
lungs, causing difficulty in breathing.
* Potential treatments to block blood clotting were proposed to
COVID-19 patients admitted to the ICU.
deteriorate dramatically. Clots may also be formed in other parts of the body,
potentially damaging vital organs including the heart, kidneys, and liver. It is,
therefore, possible that people are dying from undiagnosed pulmonary emboli
and other clotting-related events.
Accordingly, potential need for treatments to block inflammation and blood
clotting has been proposed for all COVID-19 patients admitted to the ICU (Klok
FA, et al. Incidence of thrombotic complications in critically ill ICU patients with
COVID-19. Thromb Res. 2020 Apr 10.
https://doi.org/10.1016/j.thromres.2020.04.013).
Systemic anticoagulation may improve clinical outcomes among patients
hospitalized with COVID-19. However, the effects do not seem to be spectacular.
Although a median survival was longer (21 days versus 14 days) among
patients who received anticoagulation, compared with patients who did not
receive anticoagulation, in-hospital mortality was similar (22.5% versus 22.8%)
Furthermore, patients who received anticoagulation had more bleeding events
(3% versus 1.9%) than those who did not.
A study was published in NEJM (Mandeep R, et al. Cardiovascular Disease,
Drug Therapy, and Mortality in Covid-19. NEJM 2020. DOI:
10.1056/NEJMoa2007621), confirming previous observations that the
underlying cardiovascular disease is associated with an increased risk of in-
hospital death in hospitalized patients with Covid-19: coronary artery disease
(10.2% vs. 5.2% among those without disease; OR=2.70), heart failure (15.3%
vs. 5.6%; OR=2.48), and cardiac arrhythmia (11.5% vs. 5.6%; OR=1.95). In
addition, an age greater than 65 years (mortality of 10.0% vs. 4.9% among those
≤65 years of age; OR=1.93), chronic obstructive pulmonary disease (14.2% vs.
5.6%; OR=2.96), and current smoking (9.4% vs. 5.6% among former smokers
or nonsmokers; OR=1.79) have also been associated with COVID-19 mortality.
Angiotensin-converting enzyme (ACE) inhibitors dilate blood vessels,
increasing blood flow and lowering blood pressure. Evaluation of the
relationship of cardiovascular disease and drug therapy with in-hospital death
did not confirm previous concerns regarding a potential harmful association with
the use of ACE inhibitors (2.1% vs. 6.1%; OR=0.33) or the use of angiotensin-
receptor blockers (ARBs) (6.8% vs. 5.7%; OR=1.23). Surprisingly, the use of
ACE inhibitors seems to protect, rather than harm, patients.
Unfortunately, the paper was retracted by the majority of authors because
the original data provided by an author in Surgisphere was not verified.
Another paper published by the same research team in The Lancet
reporting that COVID-19 patients treated with Hydroxychloroquine (HCQ)
had an increased risk of dying, which was attributed to the drug’s side
effects on the heart, was also retracted.
Currently, there are no vaccines targeting COVID-19. However, intensive efforts
have been devoted to development. The COVID-19 Vaccine & Therapeutics
Tracker lists 152 vaccine developments and 28 in human clinical trials.
For instance, the US biotech firm Moderna revealed the first data from a human
trial on May 18: Its COVID-19 vaccine triggered an immune response in people
and protected mice from lung infections with SARS-CoV-2. Additional studies
being carried out in the UK, China, and other countries also reveal the safety
and promise of their vaccine candidates. However, it remains to be seen if those
vaccines can really protect humans from COVID-19.
In addition to vaccination, passive immunization is also under development.
Human monoclonal antibodies against the SARS-CoV-2 virus have been
prepared. Monoclonal antibodies have also been made from Lama glama. And
convalescent plasma has been collected from patients previously infected with
SARS-CoV-2 and recovered from COVID-19 to treat patients by administration.
The COVID-19 Vaccine & Therapeutics Tracker lists 297 candidate drugs in
development with 211 in human clinical trials. Antiviral drugs that inhibit COVID-
19 infection have been searched intensively for the past few months, primarily
from the list of FDA-approved drugs for other diseases. Although various drugs,
such as Favipiravir and Ciclesonide, received much media attention, to date no
successful drugs that decrease COVID-19 mortality have been identified.
However, Remdesivir was shown to shorten the time to recovery in adults
hospitalized with COVID-19 due to lower respiratory tract infection, and has
recently received FDA approval. Combinations of various medications have also
been tried, such as interferon beta-1b, Lopinavir-ritonavir (an HIV drug), and
ribavirin (an oral hepatitis C drug). Potential use of anti-malarial drugs, such as
Quinine and Hydroxychloroquine, and anti-HIV drugs has also been examined
for possible COVID-19 treatment, but the WHO has recently suspended clinical
trials of those medications due to the absence of antiviral effects.
Doctors should focus better on reducing the number of seriously ill patients who
require extreme respiratory care. In this way, the burden on healthcare and
society will be lessened.
The lungs are sponge-shaped tissues with alveoli at the ends of the trachea.
The interstitium is the wall of the alveoli, and a mesh network of thin tubes that
surround it are important for gas exchange, taking in oxygen and taking out
carbon dioxide. In patients with COVID-19 pneumonia, the walls of the alveoli
were found thickened and fluid accumulated in the alveoli showing "pulmonary
edema". This is a finding of acute respiratory distress syndrome (ARDS) with
severe respiratory failure.
Because overproduction of cytokines and their release from immune cells
gathered in the interstitium of the lungs damage capillary cells and cause a
tubular leakage of fluid into the alveoli, preventing overreaction of the immune
system can provide a treatment option. In addition to glucocorticoids and other
general immunosuppressive drugs, more sophisticated drugs are also available,
including the humanized anti-IL6 receptor monoclonal antibody Tocilizumab and
Sarilumab, and JAK inhibitor Baricitinib. However, it is evident that the use of
those candidate drugs for susceptible patients with COVID-19 pneumonia will
require extreme caution. A treatment breakthrough has quite recently been
reported: in a large clinical trial, a cheap and widely available steroid,
dexamethasone, has been shown to reduce deaths by one-third among critically
ill patients with COVID-19.
As for the inhibition of thin tube leakage, the usefulness of an unapproved drug
candidate named "FX06", which was developed by an Austrian venture
company, is examined. FX06 is a peptide derived from fibrin involved in blood
coagulation. The drug was previously used in a patient who needed a human
respiratory system due to Ebola's exothermic fever, and the tube leak was
reported to improve, resulting in lifesaving. Additionally, the safety of the drug
has been confirmed in clinical trials in patients with more than 200 muscular
infarctions.
Antiviral drugs that have a virus-reducing effect, drugs that dampen an
overactive immune response, and drugs that prevent tubular leakage can also
be used together to obtain synergistic effects.
In addition, systemic anticoagulants, statins, ACE inhibitors, and other
antihypertensive drugs may or may not demonstrate that they improve clinical
outcomes among patients hospitalized with COVID-19 if treatment conditions
are well elaborated. It should also be mentioned that administration of
anticoagulants may cause blood pressure problems and intestinal bleeding.
Considering that herd immunity is difficult to achieve without hundreds of
thousands to millions of additional deaths worldwide, the development of
effective vaccines and/or drugs to COVID-19 is urgent and vital for society.
In addition to a differential susceptibility to SARS-CoV-2 infectivity of individuals
with different ABO blood groups due to Anti-A, Anti-B, and Anti-A,B natural
antibodies, the ABO polymorphism may also affect the infectivity and severity of
COVID-19 disease through differential ABO-dependent plasma concentrations
of vWF and FVIII important in blood clotting.
ABO & SARS-CoV-2/COVID-19
* ABO polymorphism may directly affect SARS-CoV-2 infectivity.
=> Anti-A, Anti-B, and Anti-A,B natural antibodies may inhibit
the binding of viral Spike proteins to the ACE2 receptors of the
human host cells, resulting in a lower SARS-CoV-2 infectivity in
group O individulals.
* ABO polymorphism may indirectly affect COVID-19 severity.
=> ABO-dependent plasma levels of vWF and FVIII involved in
blood clotting may result in a differential risk for deep vein
thrombosis and pulmonary embolism, causing more severe
COVID-19 disease symptoms in group non-O individuals.
I hope that I have convinced you to agree with the concept that the ABO
polymorphism fights against the SARS-CoV-2/COVID-19 pandemic.
ABO & SARS-CoV-2/COVID-19
* ABO polymorphism may directly affect SARS-CoV-2 infectivity.
=> Anti-A, Anti-B, and Anti-A,B natural antibodies may inhibit
the binding of viral Spike proteins to the ACE2 receptors of the
human host cells, resulting in a lower SARS-CoV-2 infectivity in
group O individulals.
* ABO polymorphism may indirectly affect COVID-19 severity.
=> ABO-dependent plasma levels of vWF and FVIII involved in
blood clotting may result in a differential risk for deep vein
thrombosis and pulmonary embolism, causing more severe
COVID-19 disease symptoms in group non-O individuals.
You can also get helpful information about ABO groups and SARS-CoV infection
in the documents in this list, in addition to the literature mentioned in the text.
Under the current state of emergency, our institute is closed and we are forced
to work at home. Actually, due to fear of infection, my wife and I have been
locked up at home since March13, 2020. The WHO says that we can protect
ourselves from being infected with the SARS-CoV-2 virus by washing hands
frequently, maintaining social distance, avoiding touching eyes, nose and mouth,
and practicing respiratory hygiene. We can easily comply with these
recommendations to help end the COVID-19 pandemic soon.
There was an incident I would like to report here. My wife and I went out of our
apartment only three times since the Spanish lockdown on March 15, to buy the
groceries. We wore protective masks and gloves. I tried to breathe less in order
to avoid the inhalation of SARS-CoV-2 viruses during the purchase trip. Our
apartment is located on the 3rd floor (corresponding to the 4th floor in the US
standard) in a building without an elevator. My wife carried a light load (ca 10kg)
of purchases and went up first. I followed her with a heavy load (ca. 20kg). While
I was walking upstairs, I became too sleepy and fell asleep around the 1st floor.
My wife realized that something went wrong and came down to find out that I
was unconscious, gasping for air. She hit and shook me to wake me up without
success, and asked neighbors for help. When I regained consciousness, I was
placed on a sofa of a neighbor and someone else was calling for an ambulance.
In fear of SARS-CoV-2 infection at the hospital, I asked to cancel the ambulance.
One of the neighbors kindly carried up the groceries to our apartment. What
happened was oxygen-deficiency because I did not breathe right with a mask
and the oxygen in the body was lost due to a hard labor carrying a heavy load
upstairs. Fortunately, no serious damage was made. The news that several
junior high students have died during physical exercise wearing a mask in China
reminds me of the fact that people need to breathe even in fear of infection. I
also realized my vulnerability because I am old and my physical parameters are
at or above the upper borderlines of normal ranges for obesity, cholesterol,
blood pressure, blood sugars, etc. Keeping healthy and alive is not easy.
At this opportunity I would like to thank doctors, nurses and other health
professionals for caring for the sick. I would also like to thank everyone who
dedicates their time and efforts to keep society functioning even in these
circumstances. I would also like to thank Miyako Yamamoto for helping me
prepare this presentation (both the original and revised versions). Due to limited
accessibility to scientific literature, concerns about viral infection, and a restless
mind, errors and shortcomings may still exist. Lastly, I would like to thank you
for your attention.
Article
Full-text available
Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide as a pandemic throughout 2020. Since the virus uses angiotensin-converting enzyme 2 (ACE2) as a receptor for cellular entry, increment of ACE2 would lead to an increased risk of SARS-CoV-2 infection. At the same time, an association of the ABO blood group system with COVID-19 has also been highlighted: there is increasing evidence to suggest that non-O individuals are at higher risk of severe COVID-19 than O individuals. These findings imply that simultaneous suppression of ACE2 and ABO would be a promising approach for prevention or treatment of COVID-19. Notably, we have previously clarified that histone deacetylase inhibitors (HDACIs) are able to suppress ABO expression in vitro. Against this background, we further evaluated the effect of HDACIs on cultured epithelial cell lines, and found that HDACIs suppress both ACE2 and ABO expression simultaneously. Furthermore, the amount of ACE2 protein was shown to be decreased by one of the clinically-used HDACIs, panobinostat, which has been reported to reduce B-antigens on cell surfaces. On the basis of these findings, we conclude that panobinostat could have the potential to serve as a preventive drug against COVID-19.
ResearchGate has not been able to resolve any references for this publication.