A Correlation between ABO and Rh Blood Groups with Clinical Characteristics in Patients with Coronavirus Disease 19

Pratik Panda^1*, Jijnasha Mishra¹, Abhishek Joshi¹ and Ashok Mehendale²

^*Correspondence: Pratik Panda, Department of Community Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Medical Sciences (Demmed to be University) Sawangi (Meghe) Wardha, Maharashtra, India, Email:

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Introduction

Novel Corona virus Pneumonia (NCP) better known as corona virus disease 19 was originally discovered by Wuhan in December 2019 and has since propagated across the nation. Over 80,000 persons had been infected by early March 2020, with nearly 3,200 deaths in China [1]. On January 30^th, 2020, Kerala, India's first coronavirus disease 19 positive case was reported [2]. As a result, the number of instances increased dramatically as. A sum total of 14,37,788 samples suspected to be infected were dropped to the National Institute of Virology (NIV), Pune, and an associated testing facility, in accordance to a data released by the Indian Council of Medical Research (ICMR) on May 8, 2020. 56,342 of them were tested positive for SARS-CoV-2, [3]. Coronavirus disease 19 which has recently spread across multiple nations is now compared to different epidemics of respiratory illnesses happened in past such as Severe Acute Respiratory Syndrome (SARS) of 2003, and Middle East Respiratory Syndrome (MERS) of 2012. The pervasive transmittance of SARS-CoV-2 in several nations is analogous to the proceeding pandemic of SARS and Middle East Respiratory Syndrome (MERS) that turned up in 2003 and 2012 in China and Saudi Arabia correspondingly [4]. SARS-CoV causes SARS and till date COVID-19 has no specific satisfactory therapy. Coronavirus is more contagious than the first SARS-CoV.

With growing knowledge about the virus and on-going extensive molecular research, it’s evident that there are multiple risk and protective factors towards morbidity and mortality in coronavirus disease 19 [5].

Most importantly, recent studies from different countries across the world have reported significant association in immuno-pathogenesis of the disease severity in terms of morbidity, mortality and duration of hospital stay with the blood group systems concluding that subjects with blood type o and Rh positive status have relatively at lower risk than non-blood group O (e.g. blood group A) and Rh negative status for coronavirus disease 19 infection [6]. The exact underlying mechanism is still not clear.

In our present study we have sought to analyse multiple standard studies done in the recent past and draw out conclusions in context of affiliation of blood group types with grievous outcome of coronavirus disease, our results might provide important information regarding the treatment options and effective management.

Literature Review

Epidemiology of corona virus disease

Microbiology of coronavirus: Coronaviruses is a RNA virus, belongs to Coronaviridae family, Nidovirales order is subdivided into for genera namely alpha, beta, gamma, delta variants of which alpha and beta variants infect humans and beta variant being the main culprit of the resulted pandemic [7]. These are single-stranded, non-segmented, positive sense RNA viruses. This virus resumes roughly spherical shape with diameter about 100-150 nm electron microscope [8]. The club shaped projections over the external surface of the virus represents its spike protein. Coronavirus possess an un-segmented RNA genome of molecular weight nearly 30 kb. This RNA genome contains approximately 2900-3200 base pairs and serves as messenger RNA (mRNA) and encodes for several structural and non-structural viral proteins. There are four important structural proteins viz. Nprotein, E-protein, M protein and spike protein (S) [9]. Out of all structural proteins, Spike protein (S) portrays critical part in determining host immune response and tissue tropism for the virus [10]. The spike protein has two subunits S₁ helps for binding to host tissues and S₂ for fusion. The virus after entry into upper respiratory tract binds to Acetyl Cholinesterase 2 (ACE 2) receptors present in the airways (in airway epithelium and type 2 pneumocystis) by means of Receptor binding domain (RCD) present in S₂ subunit of spike-protein. The nucleo capsid of this virus is covered within a viral envelope and assumes helical symmetry [11]. International Committee on Taxonomy of Viruses (ICTV) titled the virus as SARSCoV- 2 (Severe Acute Respiratory Syndrome Coronavirus-2) [12].

Pattern of disease in COVID-19: Appertaining to ongoing epidemiological surveys, the IP is 1-14 days and classically 3-7 days, but there are several circumstances in which an IP more than 14 days were recorded [13]. The Eclipse period (time required to generate intracellular virions) is around 10 hours. After a review of multiple reports on disease course in coronavirus disease 19 it is quite evident that individuals are infectious, in course the IP, and the ones without any clinical symptoms could also transmit the disease. Droplet infection and intimate are the considerable modes of spread for the virus [14]. The clinical course of disease although is unpredictable and varies from person to person. However, majority of persons having infected with coronavirus disease 19 develop go through three stages, namely stage of early infection which usually lasts up to 5 days, in which individuals are mostly asymptomatic to start with or might develop mild unspecific features of viral illness like fever, dry cough, headache, sore throat and fatigue. The second stage is also called as pulmonary stage, usually lasts for about 10 days which is characterised by respiratory symptoms such as tachypnea, dyspnoea, hypoxemia in which patient ultimately lands into respiratory failure. In severe cases, affected individuals go through third stage i.e. stage of hyper inflammation; in thus stage the affected individual can undergo Acute Respiratory Distress Syndrome (ARDS), multi system organ dysfunction, septic shock [15]. Deaths were mostly due to Acute Respiratory Distress Syndrome (ARDS) and multi system organ dysfunction and the cause was attributed to extensive release of cytokines after Coronavirus disease infection commonly known as cytokine storm. In the later stages, many patients conditions deteriorated rapidly later on the virus was found to have multi organ tropism [16].

Cytokine storm is believed to be one of the most considerable contributors of ARDS and multisystem organ dysfunction resulting in majority of deaths due to the disease.

As the molecular basis for the cytokine storm is further studied, multiple factors have been found that predisposes an individual to cytokine storm, one of such factors is the individual’s blood type.

We have performed a review with meta-analysis and wide ranging retrospective study from various standard articles on the susceptibility of subjects with different blood types with prognosis of coronavirus disease 19.

Hypothesis suggesting possible mechanisms of susceptiveness of ABO and Rh blood groups to SARSCoV- 2 infection

The existence of A and B antigens over the surface of mature erythrocytes forms the foundation for ABO system [17]. ABO blood group comprises of three independent allelic types dominant A and B and O recessive, it is regulated by ABO gene situated on the long arm of the chromosome-9. (9q34.2), this gene code for glycosyltransferases (different for A and B) the enzyme glycosyltransferases plays a role in transfer functional groups with sugar residues to the acceptor H substance (glycosyltransferase A adds N-acetyl galactosamanine whereas glycosyltransferase B adds d-glucose residues), and thereby resulting in formation of A and B antigens respectively. In contrast, O allele does not encode a nonfunctional enzyme, and leaves behind a non-functional H substance and thus does not form any antigens [18]. Hence, it is the type of antigen that an individual possess determines its blood group (e.g. individuals with A antigen are designated as blood group A).

ABO antibodies are natural antibodies starts to develop soon after birth and reaches peak levels by 5-8 years and decline after 5^th decades. These antibodies are synthesised in reaction to exposure of the missing antigen by environment or by food carbohydrate antigens that closely resemble to blood antigens [19]. Hence A blood group individuals have circulating Anti B in the serum, blood type-B. Subjects have anti-A and blood type-O has both anti-A and anti-B. Previous reports demonstrated ABO blood type and susceptiveness to various viral illnesses such as SARS, HIV, Helicobacter pylori, SARS, West Nile virus, Hepatitis B [20]. Several studies have proposed the presence of anit-A anti-body in the serum inhibits binding of Spike protein of Coronavirus to bind to ACE 2 receptors present in airways of host thereby lowers degree of infectivity by the virus in non-type-A (blood types O and B) than blood type-A [21].

Another hypothesis which confers lower immunity to blood group A is the antigenic structure of an antigen. OGlycosylation modification of S protein of Coronavirus is believed to have some role in immuno-pathogenesis of the disease. As the virus cannot survive in the extracellular environment, it uses the host’s mechanisms by binding to ‘a’ like antigens via serine-loaded domains. This confers a relative protection to the virus as the host with blood type-A is not able to develop innate response or acquired immunoglobulins due to clonal section, glycoside accommodation. Hence blood type-A subjects becomes targets for the virus [22].

Furthermore, it has also seen that non blood group O individuals have relatively more degree of Factor VII and VWF (von-will brand factor), interleukins such as IL-6 and also levels of the molecules mediating the leucocyte adhesion the endothelium such as ICAM 1, sP-selectin were found to be lower. These molecules have also been described to cause inflammatory and cardio vascular diseases [23].

Rh gene

Rh blood group system is most polymorphic and much more complex than ABO blood group system. Rh gene is positioned on the long arm of chromosome-1 (1p36). It is made up of 2 separate genes namely, RHD and RHCE. Each of genes contains 10 exons. Both the genes encode for Rh proteins which may have D and C/E antigens [24].

Rh-positive subjects have D-antigen in RBC membrane while Rh-negative subjects have either absent Rh genes or unexpressed Rh gene.

Association of diseases with Rh blood groups are very in comparison with abo blood group system. For example haemolytic diseases of new-born occur when mismatch occurs in between mother and the progeny. Similar evidences have proved that Rh-positive subjects have protective effect in counter to latent toxoplasmosis [25].

Hypothesis suggesting a role of ABO Blood group with severity of coronavirus disease 19

Angiotensin Converting Enzyme 2 (ACE 2) is molecule attributed as in transmission of the SARS-CoV-2 resulting in severe acute respiratory syndrome. A significant relation was found between ABO blood group and ACE 2 activity. GATC halo type which is prevalent amongst non-blood type O subjects (e.g. blood group a) is found to have some association with ACE activity. And hence it is understandable that non-blood type-O individuals (e.g. blood group a) have lower levels of ACE 2 activity in comparison with blood type-O subjects and thereby imparting relative higher risk to COVID-19 infection [26].

Further, as recent studies have proved that corona virus infection is not only limited to only respiratory tract but is a multi-system inflammatory disorder resulting in an aggressive inflammatory response leading on to release of large amounts of inflammatory cytokines commonly known as cytokine storm. The cytokine profile of COVID-19 positive patients were analysed and it was noted there has been have elevated circulating levels of IL1β, TNF-alpha, IL-6, IL-12, IFNγ, IP10 and MCP1 in patients with significant pulmonary inflammation and multi organ failure [27]. Further studies have shown that Inter-Leukin-6 is a crucial inflammatory cytokine. Which is over expressed following COVID-19 infection which then triggers formation of acute phase reactants such as C-Reactive Protein (CRP).

Persistent with this, blood type-O. subjects have demonstrated more degree of IL-6 than non-blood type-O subjects. Hence a positive association between secretions of IL-6 with ACE 2 levels is expected [28].

A Genome Wide Association Study (GWAS) was conducted which demonstrated increased circulating levels of IL-6 in subjects with blood type-O [29].

In contrast, the A allele of blood of blood group A have been shown to have increased risk for cardiovascular diseases in COVID-19. This an allele codes for an antigen of blood A. A antigen plays some role in preventing P selection and ICAM 1 molecules from enzymatic digestion and therefore facilitates binding of leukocytes to endothelial cells of blood vessels, which subsequently dampens the circulation and on the other hand promotes leucocyte adhesion and thereby inflammation, following an oxidative stress caused by COVID-19 infection [30].

All of these factors collectively predispose individuals with blood type A for having more adverse cardio vascular events than those of blood group O.

Results

The affiliation of a particular blood type with the seroprevalence of the disease was studies thoroughly and it was observed that there was a direct correlation in between occurrence of a blood-type and the COVID-19. Fatality rate, suggesting a potential protective factor of O Blood type against coronavirus disease 19 related fatality on a contrary, the preponderance of blood type is directly correlated with coronavirus disease 19. Fatality/million demonstrating a blood type as risk factor in corona virus disease 19 infection.

The observed and expected occurrence of Rh-phenotype (D) reflected no statistically relevant likeliness. However, Rh negative individuals appear to have a higher mortality than Rh positive individuals.

Discussion

Following several reports of association between risk and susceptibility of coronavirus disease between blood group distributions we collected and analysed data from various documents in PubMed, Googlescholar and Med scape and it has been shown a definite correlation in between ‘ABO’ and ‘Rh’ type with prevalence and severity of SARS-CoV-2. On the risk scale, a positive had highest risk of infection followed by a positive, whereas O positive individuals had lowest risk.

With time and on-going research, we have found out one of the certain risk factors that could be associated with the susceptibility of an individual to SARS-CoV-2 and prognosis of the disease. Several researches have shown to have strong degree of correlation of COVID-19 infectivity with blood group factors in terms of morbidity and mortality. Out of over 39 blood group systems and 350 antigens recognised by I.S.B.T ‘ABO’ blood grouping is widely accepted [31].

ABO gene is a highly polymorphic gene located at the long arm of chromosome-9. (q34.2) and hence vulnerabilities may be because of natural immunoglobulin or pro-thrombotic events with nongroup and one of the halo type of gene abo polymorphism i.e. GATC is prevalent among non-blood type-O subjects and is positively correlation with ace activity.

Several studies previously have demonstrated link between various other diseases with ABO blood types such as HIV, Helicobacter pylori, SARS, West Nile virus, Hepatitis B. For ABO, the possible mechanism being abo antigens serving as receptors or co-receptors for pathogens and molecular mimicry by common epitome shared by blood a group antigens with that of the pathogen. Moreover, growing evidence suggest that the antibody anti-A plays a crucial role in inhibiting binding of RCM to ACE-2 receptors thereby conferring protection to non-blood group A subjects.

Within the infected population of coronavirus disease 19, individuals with positive Rhesus factor had lower risk of infection than the negative ones. However, does not have much significance in deciding the prognosis of the disease.

Conclusion

Prognosis of coronavirus disease-19 is related with subjects blood type, Blood type-O. Rh-positive type may protect, while blood group and individuals with negative Rh status are at higher risk relatively.

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