In an April 8 MedPage Today article, Mark Zucker, MD, asked the question as to why there is differential susceptibility to COVID-19 infection. In other words, why do some people become severely ill while others are asymptomatic? He raised the issue of possible genetic determinants in susceptibility and response to the coronavirus.
This is a question that I have been pondering as well, particularly as to whether there may be a link between glucose-6-phosphate dehydrogenase (G6PD) deficiency and susceptibility to, and virulence of, COVID-19 infection. G6PD deficiency is a common, X-linked recessive genetic condition that affects some 400 million people worldwide. It is the most common human enzyme defect. G6PD is an important catalyst in the pentose phosphate pathway, in which glucose is converted to pentose sugars and NADPH is produced. NADPH serves an important role in ridding cells of free oxygen radicals, thereby reducing oxidative stress and preventing cell destruction. Most cells in the body contain mitochondria, which also generate NADPH. However, red blood cells lack mitochondria and, therefore, rely upon the pentose phosphate pathway for generating this . As a result, the primary clinical effects of G6PD deficiency are neonatal jaundice and acute hemolytic anemia, particularly after exposure to certain drugs, other chemicals, and infectious agents. However, G6PD deficiency has also been found to affect neutrophils, oocyte genesis and development, and cause .
This disorder is commonly found in people from the Mediterranean region, Africa, and Asia. , may be affected. There are at least 186 allelic variants of G6PD deficiency, which result in various phenotypic presentations. They are classified in categories from I to V, based on the level of residual G6PD activity and clinical manifestations, with I representing lowest G6PD activity and more . Mediterranean variants produce than do African variants.
Since the onset of the COVID-19 pandemic, we have seen that people in Italy and Spain have been significantly affected by this illness, with and . This compares with a worldwide case mortality rate of . With regard to G6PD deficiency, the global prevalence is 4.9%. The prevalence in Italy ranges from 0 to 3%, although the mean prevalence in Sardinia is 7.5%, with some areas there showing . Contemporary nationwide data are more difficult to obtain for Spain. However, a 1969 study of showed a prevalence ranging from 0.32% to 1.53%. In the United States, reports have shown that African Americans may be than the rest of the population, and 10% of African-American males are affected by G6PD deficiency.
Is there any evidence to support a correlation or causal relationship between G6PD deficiency and COVID-19 infection susceptibility or severity of illness? Oxidative stress is known to increase viral proliferation and virulence. A study published in 2008 looked at another human coronavirus, HCoV229E, and its effect on G6PD-deficient cells. The investigators found that G6PD-deficient cells were more susceptible to HCoV229E infection and cell death. Addition of an antioxidant . Two researchers from Estonia released a manuscript preprint last week in which they conclude that COVID-19 stimulates a pro-inflammatory systemic response, which is pro-oxidant, and inhibits anti-inflammatory (anti-oxidant) response. This results in an imbalance/overproduction of free oxygen radicals, which further sustains the systemic inflammatory response syndrome. The situation would be made worse in patients with G6PD deficiency, in which these free oxygen radicals.
It is possible that there is no correlation between G6PD deficiency and COVID-19 infectivity and virulence. The death rates in Italy and Spain, and among African Americans, may be due to other medical co-factors or reflect disparate socioeconomic determinants of health. However, in the past few weeks, I have been contacted by individuals in this country and abroad, who are either G6PD deficient or are parents of children (mostly male) with G6PD deficiency, and who are concerned as to whether there is a connection between this disorder and severity of illness with COVID-19. They are strongly in favor of more research to learn about a possible connection. One mother of a child with G6PD deficiency has created a petition to be sent to the NIH, the CDC, and the WHO .
I agree with them. In order to accomplish this, though, it would be necessary to test some subset of patients to determine whether they have G6PD deficiency since many may not be aware that they have the disorder. Criteria would have to be established as to which patients should be tested, perhaps based on their initial presentation or progression of illness with COVID-19. In the past few years, there have been substantial advances in testing for , with the result that point of care and is now available. Although this adds another step and cost in caring for ill patients, it may well be worth it if a strong correlation is established between G6PD deficiency and susceptibility to and severity of illness with this coronavirus. The knowledge would enable caregivers to monitor these patients more aggressively to circumvent further decline in their conditions. And, in doing the research, we may gain a better understanding about the characteristics of this novel coronavirus itself and effective ways to treat it.
a pathologist and former hospital executive, is a member of the graduate teaching faculty in the Master of Health Administration Program, School of Health Sciences, in the Herbert H. & Grace A. Dow College of Health Professions at Central Michigan University in Mount Pleasant.