EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Currently, our world is facing an outbreak of the 2019 novel coronavirus (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and tremendous efforts are being made to develop drugs to treat and vaccines to prevent the disease. At present, there are no specific antiviral drugs or vaccines for COVID-19.¹

Almost all countries in the world face the risk of having an enormous burden of COVID-19 disease; however, up to now, some countries are affected more than others, including China, the United States, Italy, Spain, France, England, Holland, and Belgium, where the infection incidence is high and with increased mortality. When we look at the numbers of total confirmed cases of COVID-19 per million people on April 3, 2020 (the date the paper was written), it seems that the global COVID-19 pandemic has spared some countries like India, Pakistan, countries of the African continent, and South America.2 Many confounding factors can affect these results, including age distribution of the country, the accessibility of health services, the diagnostic facilities, the living environment, and cultural responses toward isolation precautions; however, the major gaps in disease burden between these 2 groups of countries cannot be explained by any of these factors. Of note, gathering epidemiologic data to understand what causes these differences among countries is not easy.

A main difference among these countries may be another infectious agent, which can cause high seroprevalence among populations in countries that have endemic disease or are vaccinated routinely, such as hepatitis A virus (HAV), another RNA virus. In Africa, Asia, and Central and Southern America, hepatitis A is still endemic, where seroprevalence reaches 100%. In contrast, in industrialized countries, hepatitis A has become uncommon as socioeconomic conditions and hygiene standards have increased.³ In a study from Morris-Cunnington and associates,⁴ the overall HAV seroprevalence was shown to be 19% in the English population and only 9% when individuals immunized previously were excluded. As we know, during aging, remodeling of the immune system can occur, which may cause changes in humoral, cellular, and innate immunity. These changes may cause decreases in quality of immune responses in elderly individuals.⁵ The loss of humoral and cellular immunity to hepatitis A vaccine in the elderly who live in relatively developed countries may have led to an increased number of patients and mortality by COVID-19.

Interestingly, we have found that the rate of COVID-19 is quite low among our dialysis patients. We have 21 dialysis centers across the country, with 2420 patients on hemodialysis and 30 patients on peritoneal dialysis. Only 3 patients have been diagnosed with COVID-19, which makes roundly 1 per 1000. In a randomized study of 227 of the 2420 dialysis patients at Baskent University who were analyzed with the ELISA Architect Plus i 1000SR, 215 patients (94.7%) were shown to be HAV antibody positive (unpublished data). At Baskent University Health Centers, we will continue to carry out this study as it reveals important results.

Our theory can be further supported by the Princess Diamond cruise ship experience. After arriving in Yokohama, Japan, the ship was placed under quarantine for COVID-19. Of the total 3711 passengers and crew members, 634 people tested positive among 3063 tests performed over 15 days. The infected people were from 28 countries, with most being from 6 countries, namely, Japan, United States, China, Philippines, Canada, and Australia. Among the infected patients, 50.5% were asymptomatic, which was the highest asymptomatic ratio that has been reported.⁶ The low frequency of symptomatic disease on the ship, which contained mainly elderly tourists, may be explained by their stimulated immunity before they started the cruise trip: that is, a hepatitis A vaccine was recommended for international travel in areas with high HAV endemicity.⁷ The data on HAV seropositivity of infected and noninfected patients from the Diamond Princess could provide evidence for our hypothesis.

Another group of individuals who seem to be spared from COVID-19 are children. In a study by Wu and associates,8 of 72 314 evaluated patients with COVID-19 from Wuhan, only 1% of patients were under 10 years old. In a recent study from Dong and colleagues9 that evaluated 2143 children with COVID-19, half of the children had slight upper respiratory tract symptoms, whereas one-third had signs of pneumonia; the severity of illness revealed that young children, particularly infants < 1 year of age, were vulnerable. This may also be attributed to the eventual decrease of maternal anti-HAV antibodies toward age 1 year; as we know, the hepatitis A vaccine is administered after 1 year of age, at ages 12 to 18 months, in many countries. The immature cellular immune system during infancy may have also contributed to this result.

Immunopathologic Aspects of Hepatitis A Infection
Hepatitis A virus causes immune reactions and immune complex diseases in humans. The infection is still seen endemically in some countries. It is an asymptomatic disease in early childhood, causing humoral and cellular immunity in patients. Viral replication occurs in hepatocyte cytoplasm, and hepatocellular damage and destruction of hepatocytes are mediated by cellular cytotoxicity. Interferon-gamma (IFN-γ) seems to have an important role in clearance of infected hepatocytes.¹⁰ The infection causes a variety of immune complex diseases, such as arthralgia, leukocytoclastic vasculitis, glomerulonephritis, cryoglobulinemia, optic neuritis, myocarditis, toxic epidermal necrolysis, transverse myelitis, and aplastic anemia, which are rarely seen in other viral diseases. These complications show high immunologic trigger after HAV infection.

Hepatitis A Vaccine
The hepatitis A vaccine is highly immunogenic. It causes seropositivity in 95% of adults after a single dose and in 97% of adults and 100% of children after 2 doses. This vaccine also causes HAV-specific proliferation of mononuclear cells in peripheral blood and release of IFN-γ.^11,12 The vaccine response continues for 20 years.¹³

The immune response caused by the hepatitis A vaccine may be protective against COVID-19 infection by a possible adaptive immune cross-reaction. Patients with asymptomatic COVID-19 disease could indirectly indicate those with protection from HAV seropositivity. The hepatitis A vaccine may help to keep the COVID-19 infection at mucosal colonization levels and prevent lower respiratory tract involvement and fatality.

Our early results need to be tested via in vitro and molecular studies; however, the situation our world is facing is urgent. Various therapies that may have the slightest chance to rescue COVID-19 patients with respiratory insufficiency are being tried without precise clinical proof. Scientists from all over the world are united in efforts to develop a specific vaccine for COVID-19. We think that, until the development of a specific vaccine for SARS-CoV-2, the stimulation of the immune system with a present vaccine, namely, the hepatitis A vaccine, can be beneficial to prevent further fatalities.

Volume: 18 Issue: 2 April 2020

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