Endemic and Pandemic Viral Illnesses and Cardiovascular Disease: Influenza and COVID-19


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Introduction

Over the past decade appreciation has grown that viral diseases can affect the cardiovascular system and contribute to cardiovascular disease (CVD). Influenza accounts for a substantial number of hospitalizations and deaths worldwide, and it has become increasingly evident that patients with CVD may have particular vulnerability to influenza-related complications and that influenza infection itself may contribute directly to CVD progression and events, including myocardial infarction (MI) and heart failure (HF). This association becomes even more evident when a large number of individuals in the population become infected, as has occurred several times in the past century in the setting of pandemics. In addition to influenza, other viruses, including respiratory syncytial virus (RSV), parainfluenza virus, adenovirus, human metapneumovirus, parvovirus, and enterovirus infections, have been implicated in CVD.

In late 2019, a novel coronavirus was found to be the cause of a cluster of cases of severe respiratory illness in Wuhan, China. This virus, SARS-CoV-2, and the disease it caused, COVID-19, quickly spread throughout the globe and was dubbed a global pandemic by the World Health Organization (WHO) on March 11, 2020. In addition to severe respiratory disease, often leading to a requirement for intensive care, mechanical ventilation, or death, this disease often affects the entire cardiovascular system, which may play a central role in the pathogenesis.

This chapter reviews the influence of endemic and pandemic viral infections, including influenza and COVID-19, on CVD. Several other viruses that directly affect the cardiovascular system, including parvovirus and coxsackie virus, are covered in other chapters (see Chapter 52, Chapter 55 ). Due to the rapidly changing nature of our understanding of the pathophysiology and therapeutic options for COVID-19, this chapter focuses on established pathophysiology and treatment options at the time of writing (September 15, 2021) and will be updated online as more information becomes available.

Influenza and Cardiovascular Risk and Disease

Influenza Virology

Influenza viruses are enveloped, negative-sense, single-stranded RNA viruses (∼13.5-kb genome) that are characterized based on surface antigens and exist as A and B strains. The hemagglutinin (HA) protein facilitates viral entry into the host cell and binds to the glycoprotein terminal sialic acid and glycolipid receptors. The neuraminidase protein (NA) facilitates viral release and affects viral evolution in concert with the HA protein. These two glycoproteins localize on the surface of the virus particle and are the main targets for protective antibodies generated from influenza virus infection or vaccination.

The segmental configuration of the influenza virus genome allows for reassortment, or interchange, of genetic RNA segments when two viruses of the same type infect the same cell. Thus influenza viruses undergo rapid antigenic drifts (defined as genetic variations in antigen structures stemming from point mutations in the HA and NA genes over time) and shifts (sudden genetic reassortment between two closely related influenza viral strains), which allow them to evade the host immune system. Although influenza B viruses primarily infect humans, the influenza A viruses (IAVs) are endemic in several species, including humans, birds, and pigs. Animal reservoirs offer a source of antigenically diverse HA and NA genes that can exchange between viral strains, creating virus variation, and occasionally forming novel influenza viruses that contain HA or NA segments from animals. Reassortment of the influenza A pdm09 virus in which the HA H2 and polymerase PB1 genes of the avian H2N2 virus were replaced by two new avian H3 and PB1 genes led to a pandemic in 2009. However, cases of swine- and avian-based zoonotic human transmission of influenza are rare, and are mainly confined to the avian H5N1 and H7N9 and the H3N2 variant viruses.

Pandemic influenza occurs every 20 to 50 years and stems from a viral strain that differs antigenically from previous strains. Because the human immune system is naive to the new virus, the overall lack of immunity in the population correlates with disease severity and excess mortality. Since 1918, the IAVs have caused four pandemics. The first and most severe pandemic in recent history, known as “Spanish influenza,” occurred in 1918, was caused by an H1N1 IAV strain, and led to approximately 500 million infections and 50 to 100 million deaths worldwide. In 1957, the “Asian influenza” caused by an H2N2 IAV strain resulted in ∼1.1 million deaths worldwide. In 1968, the “Hong Kong flu” caused by an A/H3N2 strain resulted in ∼1 million deaths worldwide. The fourth pandemic in 2009, caused by the influenza A (H1N1) pdm09 virus, led to 151,700 to 575,400 deaths worldwide from 2009 to 2010. Since that time, this novel IAV has continued to spread as a seasonal influenza virus. Influenza B co-circulates with influenza A each year. Typically, outbreaks of influenza A and B in the northern and southern hemispheres can lead to as many as 5 million cases of severe influenza and up to 500,000 deaths worldwide in a single season.

The major societal burden from influenza is caused by influenza A and B through seasonal outbreaks, mostly during winter months when transmission conditions are more favorable due to low temperatures and humidity. Most infections occur in the pediatric population, although the most severe cases occur in younger children or in older adults. Children appear to be the main transmitters of influenza virus, evidenced by reduced incidence of severe influenza among older adults when children are vaccinated.

Symptoms from influenza virus infection can vary from a mild upper respiratory disease limited to fever, sore throat, runny nose, cough, headache, muscle aches, and fatigue, to severe, in some cases leading to lethal influenza-induced pneumonia or due to a secondary bacterial infection. Influenza virus infection can also precipitate a wide range of nonrespiratory complications, including acute cardiovascular events.

Epidemiology of Influenza and Cardiovascular Disease

Several risk factors predispose patients to severe or lethal influenza infection. Due to lack of previous exposures, young children are more likely to develop worse symptoms and a higher fever and tend to shed larger amounts of virus for longer after being infected. Older adults are also at risk for more severe symptoms and infection-related complications, including hospitalizations, due to immunosenescence (reduced immune function with aging) and chronic conditions. In addition to extremes of age, other groups at risk for severe disease, hospitalization, or death include those with concomitant pulmonary or cardiac conditions, neuromuscular disease, diabetes mellitus, and conditions that render patients immunocompromised. Obesity is associated with enhanced viral replication, and those with morbid obesity have increased risk for secondary bacterial infections and a reduced immune response to influenza vaccination. Pregnancy is also a risk factor for severe disease, possibly related to altered immune function coupled with increased cardiopulmonary demand; the risk appears to increase more with each trimester.

Influenza and Acute Myocardial Infarction

Numerous observational studies utilizing case-control or case-only designs have reported associations between infection with influenza and other respiratory illnesses and acute MI, including a large self-controlled case series study including 115,112 individuals hospitalized for acute MI or stroke, which noted a fivefold increased risk for MI and a threefold increased risk for stroke within the first 3 days of an outpatient visit for various acute respiratory or urinary infections, including influenza. , Overall, influenza may account for between 3% and 6% of attributable risk for MI-related deaths. A patient-level study examining the relationship between laboratory-confirmed respiratory diagnosis and hospitalization for MI using insurance databases and public microbiology testing results found a 5-fold increased risk of acute MI within 7 days of influenza A and a 10-fold increased risk with influenza B. A significant time-dependent association was also detected with other respiratory viruses, including RSV, coronavirus, parainfluenza virus, adenovirus, human metapneumovirus, and enterovirus infections, adding to the evidence that various viral pathogens can precipitate atherothrombotic events.

Influenza and Heart Failure

Influenza is also associated with increased risk for HF events. Increased overall hospitalization rates have been observed during influenza seasons compared with non-influenza seasons (adjusted hazard ratio [HR], 1.11; 95% confidence interval [CI], 1.03 to 1.20; P = 0.005). In an analysis relating Centers for Disease Control and Prevention (CDC)-defined influenza-like illness (ILI) in four U.S. communities to rates of hospitalizations for HF or MI between 2010 and 2014, a 5% monthly absolute increase in influenza activity was associated with a 24% adjusted increase in hospitalizations for HF within the same month (incidence rate ratio (IRR), 1.24; 95% CI, 1.11 to 1.38; P < 0.001) ( Fig. 94.1 ). Patients with HF also have increased risk for other adverse outcomes when hospitalized with influenza. In over 8 million HF patients from a national inpatient sample, those with influenza (0.67%) had an increased risk for in-hospital mortality (odds ratio [OR], 1.15; 95% CI, 1.03 to 1.30), acute respiratory failure (OR, 1.95; 95% CI 1.83 to 2.07), and requirement for mechanical ventilation (OR, 1.75; 95% CI, 1.62 to 1.89).

FIGURE 94.1, Association of timing of influenza season with hospitalizations for cardiovascular events.

Influenza and Arrhythmia Risk

The incidence of cardiac arrest and sudden cardiac death (SCD) show seasonal variation, increasing during the winter in line with peak influenza season, and the likelihood of survival to hospital discharge after cardiac arrest was lowest during the winter. , A study of 481,516 out-of-hospital cardiac arrests in Japan reported a significant association between cardiac arrests and severe influenza epidemics (relative risk [RR], 1.25; 95% CI, 1.16, 1.34), with a more pronounced effect within 7 days of reported peaks in influenza activity, consistent with previous data on associations of influenza with acute MI. Ventricular tachyarrhythmias detected by implantable cardioverter-defibrillators (ICDs) have exhibited seasonal variation, with positive associations observed during the winter and during increased influenza activity. ,

Because the risk of atrial fibrillation (AF) increases during winter months and colder temperatures, a population case-control study in Taiwan related newly diagnosed AF to influenza infection during the previous year (adjusted OR, 1.18; 95% CI, 1.014 to 1.378; P = 0.032). Individuals who received influenza vaccination had a reduced risk for AF compared with unvaccinated people (adjusted OR, 0.881; 95% CI, 0.836 to 0.928; P < 0.001).

Influenza and Myocarditis

Sporadic reports have linked myocarditis to influenza infection, varying from asymptomatic to fulminant myocarditis resulting in hemodynamic compromise, HF, or cardiogenic shock, requiring vasopressor or mechanical support. In cases of symptomatic myocarditis, patients typically present within 4 to 7 days of their illness with shortness of breath; pleuritic chest pain; and less frequently with hypotension, syncope, arrhythmia, or fulminant HF. Cases of fulminant myocarditis have been more common during pandemic influenza or during virulent years of seasonal influenza, as was the case during the 2009 H1N1 pandemic and during the particularly severe 2017/2018 influenza season. In case series, the majority of influenza-related myocarditis cases involved the A/H1N1 strain, followed by B-type and A/H3N2; HF was the most common complication (84% of cases), and over half of the cases required advanced cardiac support.

Pathophysiology of Influenza and Cardiovascular Disease

Influenza affects the cardiovascular system through multiple mechanisms. Influenza virus has been localized to human coronary endothelial and smooth muscle cells. Infection of mice with influenza A H3N2 virus led to severalfold increased expression of genes for monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8), tissue factor (TF), plasminogen activator inhibitor 1 (PAI-1), vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule (ICAM)-1, and E-selectin, whereas endothelial nitric oxide synthase (eNOS) expression decreased in endothelial cells. In Apo E -deficient atherosclerotic mice, influenza virus A H3N2 can reside in the atherosclerotic plaques and myocardium, and the virus has been cultured from aorta and myocardium a week after infection in high titers, comparable to pulmonary tissue. Infection also significantly increases plasma levels of proinflammatory cytokines and chemokines and can lead to an exaggerated cellular inflammatory response in atherosclerotic plaque, with a significant increase in plaque macrophage content. ,

Viable virus could be detected in the myocardium of mice infected with influenza A within 12 days of infection, with evidence of oxidative stress-induced mitochondrial damage resulting in a low-energy state. In addition, bacterial superinfection can complicate influenza infection, and likely contribute substantially to the risk in elderly individuals affected by influenza, and provide a rationale for administration of pneumococcal vaccine in this population. , The ability of influenza infection to directly infect arterial and myocardial tissues and to cause local arterial-level plus systemic proinflammatory effects, prothrombotic effects, and increases in pro-oxidative stress, in conjunction with nonspecific effects induced by demand ischemia, hypoxia, sympathetic stimulation, and myocardial depression, all contribute to an increased risk for multiple cardiovascular adverse outcomes ( Fig. 94.2 ).

FIGURE 94.2, Mechanisms of acute viral infections on the cardiovascular system.

Influenza Prevention and Therapy

The association between influenza and CVD has stimulated growing interest in the role of influenza vaccination in the prevention of CVD. Several observational and small randomized, clinical trials (RCTs) have suggested that influenza vaccination can protect from adverse cardiovascular outcomes. To prevent influenza illness the CDC recommends annual influenza vaccination for individuals 6 months or older, unless contraindicated. Each year the WHO and the CDC Advisory Committee on Immunization Practices make recommendations for the influenza vaccine composition based on circulating strains in the Southern Hemisphere. Because antigenic mismatch can occur due to antigenic drifts or virus mutations during the period of production of vaccines, vaccine effectiveness (VE) can vary each year, with VE in recent years between 20% and 70%; nevertheless, vaccines confer some protection even during years with a poor antigenic match.

A large meta-analysis of six RCTs (four blinded, two open label) assessed the benefit of influenza vaccination on reducing major adverse cardiovascular events, including cardiovascular death or hospitalization for MI, unstable angina, stroke, HF, or urgent coronary revascularization in 6734 individuals, with numerically fewer deaths in the vaccinated group. During a mean duration of follow-up of 7.9 months, the vaccine recipient group had fewer major adverse cardiovascular events compared with those who received placebo or no vaccination (RR, 0.64; 95% CI, 0.48, 0.86; P = 0.003), with an absolute risk difference of 1.74%. The effect was more pronounced in individuals with a recent acute coronary syndrome (ACS) compared with those without recent ACS.

In patients with HF, data on the effects of influenza vaccine on cardiac outcomes rely on observational studies due to the paucity of placebo-controlled trials. In a self-controlled case series from the United Kingdom between 1990 and 2013, vaccinated individuals had a lower risk for hospitalization from cardiovascular (IRR, 0.73; 95% CI, 0.71,0.76), respiratory infections (IRR 0.83, 95% CI 0.77, 0.90), or any cause (IRR, 0.96; 95% CI, 0.95, 0.98) relative to an adjacent vaccination-free year. Nevertheless, influenza vaccination in patients with HF remains low. In a post hoc analysis of the global PARADIGM-HF trial in over 8000 patients with HF with reduced ejection fraction (HFrEF), only 21% of patients with HF received influenza vaccination in the year of enrollment, with rates varying widely by country from less than 5% to 77%. Vaccination was associated with an adjusted reduced risk for mortality (HR, 0.81; 95% CI, 0.67, 0.97; P = 0.015), but not all-cause hospitalizations, cardiovascular death, HF, or cardiopulmonary- or influenza-related hospitalizations. Similar reduction in HF-related outcomes were observed in a nation-wide observational cohort study from Denmark of greater than 130,000 individuals, with reductions in death and hospitalizations. Observational data of influenza vaccination may indicate improved access to care, in addition to reflecting practice variation by region.

Influenza Vaccine Formulations

Influenza vaccine contains two strains from the A-lineage, A/H1N1 and A/H3N2, and either one or two strains from the B-lineage, B/Victoria or B/Yamagata, and are available in several formulations varying in their method of preparation (egg-based, cell culture, recombinant technology), in the amount of and number of vaccine antigens included, and in the presence of adjuvant. The CDC does not recommend preferentially one vaccine formulation over another, but it does emphasize the importance of annual vaccination. Immune responses to influenza vaccine are less robust among older individuals, which is a manifestation of immunosenescence. High-dose influenza vaccine that contains four times the amount of vaccine antigen as standard-dose influenza vaccine has been tested and approved in the United States and other regions for individuals age 65 or older. In a large, RCT of approximately 31,989 medically stable older adults, high-dose influenza vaccine reduced laboratory-confirmed symptomatic influenza by 24% compared with standard-dose vaccine, with a suggestion of reduced risk in serious events caused by cardiac or pulmonary causes (rate ratio, 0.82; 95% CI, 0.73 to 0.93).

The INVESTED trial compared high-dose vaccine with standard-dose vaccine in 5260 high-risk CVD participants; there was no reduction in cardiovascular or pulmonary hospitalizations. Participants were randomized to high-dose trivalent inactivated influenza vaccine or standard-dose quadrivalent inactivated influenza vaccine and treated for up to three influenza seasons. The primary composite endpoint, death or cardiopulmonary hospitalization, did not differ between vaccine groups (HR, 1.06; 95% CI, 0.97, 1.17; P = 0.21), and results were consistent across secondary endpoints and within prespecified subgroups, although high-dose vaccine was associated with more mild vaccine-related adverse events such as injection site pain, swelling, and myalgias. The low rates of hospitalizations ascribed to influenza or pneumonia were low overall, suggesting a modest attributable risk of these types of events to the overall risk for hospitalizations in this high-risk patient group.

Antiviral Therapies for Influenza

In addition to vaccination, antiviral agents may reduce the likelihood of influenza-related cardiovascular events, although available data are mostly observational. A large, propensity-matched, retrospective analysis of adults with a prior diagnosis of CVD suggested that treatment with oseltamivir in the first 48 hours after a diagnosis of influenza confers a significant reduction in the incidence of recurrent cardiovascular events (OR, 0.417; 95% CI, 0.349 to 0.498), and at least one other retrospective study suggested potential benefit of oseltamivir in preventing stroke and transient ischemic attack (TIA) (HR, 0.56; 95% CI, 0.42 to 0.74).

SARS-CoV-2 and COVID-19

Coronavirus Virology and Epidemiology

Coronaviruses (Coronavirinae subfamily) fall into four groups of alpha, beta, gamma, and delta coronaviruses by phylogenetic clustering. Alpha and beta coronaviruses cause infection in humans. Coronaviruses contain four major structural proteins: the spike (S) protein, the nucleocapsid (N) protein, the membrane (M) protein, and the envelope (E) protein. The spike protein, which resembles a crown in cross section and for which the viruses are named, mediates the attachment of the virus to the host cell receptor and subsequent fusion of the virus and cell membrane.

First discovered in the 1960s, the coronavirus family includes seven strains with the ability to infect humans ( eFig. 94.1 ). Four viruses (i.e., HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1) generally cause mild and self-resolving infections. Three other coronaviruses can cause severe and potentially fatal infections ( Table 94.1 ): severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). ,

TABLE 94.1
Comparison of Coronaviruses with an Epidemic Potential
Virus Receptor Incubation Period Prevalence of Underlying Cardiovascular Disease Average case fatality rate
SARS-CoV ACE2 2-11 days 10% 10%
MERS-CoV DPP4 2-13 days 30% 30%
SARS-CoV-2 ACE2 2-14 days Up to 20% in hospitalized patients 2%-4% (Highly variable, based on multiple factors)

EFIGURE 94.1, Timeline of discovery of coronaviruses.

Severe Acute Respiratory Syndrome Coronavirus and Middle East Respiratory Syndrome

The SARS-CoV virus causing SARS infection first emerged in November 2002 in the Guangdong Province of China, likely related to a zoonotic transmission from the wild-animal markets. The virus most likely originated from bats with an intermediate host of civet cats. SARS-CoV binds to and uses the angiotensin-converting enzyme 2 (ACE2) to enter host cells. ACE2 is abundantly expressed on the surfaces of endothelial cells of arteries, arterial smooth muscle, pericytes, and the epithelium of the respiratory tract and small intestine. Primarily transmitted from symptomatic patients via respiratory droplets, SARS has an incubation period of 2 to 11 days after exposure, and it affected 8096 people in 29 countries in 2003 with 774 cases of death reported worldwide (and 8 nonfatal cases in the United States). Cardiovascular complications reported with SARS in small case series included tachycardia, hypotension, bradycardia, ACS, MI, and thromboembolic events. ,

The MERS-CoV outbreak emerged in Saudi Arabia (SA) in June 2012. This virus also likely originated in bats with dromedary camels acting as the intermediate host for transmission to humans. MERS-CoV enters the host cells through a serine peptidase, dipeptidyl peptidase 4 (DPP4), and is transmitted from patients via respiratory secretions through close contact with an incubation period of 2 to 13 days. , MERS-CoV has been reported in about 2500 cases in 26 countries with a case fatality rate of 34.4%. , A systematic review of 637 patients with MERS-CoV showed a high prevalence of comorbidities among these patients including cardiac diseases (30%), hypertension (50%), diabetes (50%), and obesity (16%).

Severe Acute Respiratory Syndrome CORONAVIRUS 2 and COVID-19

On December 31, 2019, a cluster of 27 cases of pneumonia of unknown etiology was reported in Wuhan, China. Patients had symptoms of viral pneumonia including fever, cough, chest discomfort, dyspnea, and bilateral lung infiltrates. The exact source of the initial infection remains unclear, although most of the initial cohort had an epidemiologic link to a wet market in Wuhan. The first genome sequence of the novel causative coronavirus was published on January 10, 2020, and the virus was later named SARS-CoV-2. Human-to-human transmission was confirmed by January 20, 2020, and the disease reached epidemic peak in China by February 2020. On March 11, 2020, the WHO officially declared the global outbreak of COVID-19 as a pandemic. By late March 2021, COVID-19 had affected 127 million and killed over 2.7 million individuals worldwide, and it has caused over 30 million infections and about 550,000 deaths in the United States.

SARS-CoV-2 belongs to the beta-CoVs group and shows about 89% nucleotide identity with bat virus and 79% with human SARS-CoV, and similarly uses ACE2 as the receptor to enter the host cell. Transmission of SARS-CoV-2 occurs mainly by contact with an infected person or contaminated surface, exposure to virus-containing respiratory droplets, and exposure to virus-containing aerosols (<5 μm). Fecal-oral transmission is also a rare route of transmission.

The SARS-CoV-2 infection in adults can be either symptomatic or asymptomatic, and asymptomatic individuals still have the ability to transmit the disease. There are fewer symptomatic cases in children of 15 years old or younger. The primary symptoms of COVID-19 are fever, cough, and shortness of breath, although the full spectrum of symptoms is broad, and can include muscle pain, anorexia, malaise, sore throat, nasal congestion, anosmia, dyspnea, and headache. Symptoms may appear in as few as 2 days or as long as 14 days after exposure ( Fig. 94.3 ). The detected viral load is similar in asymptomatic and symptomatic COVID-19 patients, which explains the high potential for transmission of the virus from asymptomatic or minimally symptomatic patients to other persons. COVID-19 is associated with multiple extrapulmonary manifestations ( Fig. 94.4 ). Gastrointestinal symptoms such as diarrhea, abdominal pain, and vomiting occur in 2% to 10% of COVID-19 patients, and SARS-CoV-2 patients’ feces often contain viral RNA.

FIGURE 94.3, Clinical course and manifestations of COVID-19.

FIGURE 94.4, Extrapulmonary manifestations of COVID-19.

As an RNA virus, SARS-CoV-2 is susceptible to mutation during replication. Mutations that persist after rounds of replication lead to the emergence of new variants , and those with different phenotypic characteristics are termed strains. Three different nomenclature systems are used for naming and tracking SARS-CoV-2 variants. The World Health Organization (WHO) has introduced a simpler method of using Greek alphabet letters to identify variants of concern and variants of interest ( eTable 94.1 ). Early in the pandemic, a novel variant, D614G, increased the efficacy of the virus to replicate and its ability to interact with the ACE2 receptor. Another variant, termed alpha variant, was initially identified in the United Kingdom and has additional mutations in the spike protein and is more easily transmissible with possibly higher mortality. The beta variant first identified in South Africa, also with mutations in the spike protein, shows high potential for transmissibility and is less likely to be effectively neutralized by convalescent serum, and might be less responsive to early vaccines based on the original circulating virus. The highly contagious delta variant, initially detected in India, has caused significant mortality, and first-generation vaccines may offer less protection against it.

Overall, the emergence of new variants is a cause for concern because they may have higher transmissibility, higher virulence, less susceptibility to treatments using monoclonal antibodies, and the potential ability to evade the body’s innate or acquired immune responses, as well as the response to vaccines. Additional booster vaccine doses might become necessary to protect against them. It is yet not clear if new variants will have a different impact on the cardiovascular system.

eTable 94.1
The World Health Organization (WHO) SARS-CoV-2 Variant of Concern (VOC)
WHO label Pango lineages GISAID clade Earliest documented samples Date of designation as VOC
Alpha B.1.1.7 GRY United Kingdom, Sept 2020 18-Dec-2020
Beta B.1.351
B.1.351.2
B.1.351.3
GH/501Y.V2 South Africa, May 2020 18-Dec-2020
Gamma P.1
P.1.1
P.1.2
GR/501Y.V3 Brazil, Nov2020 11-Jan-2021
Delta B.1.617.2
AY.1
AY.2
AY.3
G/478K.V1 India, Oct 2020 11-May-2021

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