Glucose-6-Phosphate Dehydrogenase Deficiency and Coronavirus Disease 2019 Free

Abstract

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzyme defect and one of the most common X-linked genetic disorders worldwide [1]. An estimated 400 million people worldwide carry a mutation in the G6PD gene associated with enzyme deficiency, with marked ethnic and geographic differences. G6PD deficiency is prevalent in Africa, Asia, and the Middle East. In the United States, about 14% of African-American men are affected. The link between G6PD deficiency and infections in infancy has been recognized [2], and G6PD has been hypothesized to be a risk factor for severe coronavirus disease 2019 (COVID-19) [3]. Recently, 2 studies that looked for a statistical association between G6PD deficiency and COVID-19 severity obtained conflicting results. A large-scale study performed among US veterans found an increased likelihood of developing severe COVID-19 for veterans with G6PD deficiency [4]. However, a smaller study performed among hospitalized patients with COVID-19 reported that individuals with G6PD deficiency were less likely to develop a severe disease [5]. The present large-scale study, performed in a national healthcare provider in Israel, looked at the association between G6PD deficiency and risk of severe acute respiratory syndrome coronavirus 2 infection, COVID-19 severity, and long COVID-19.

METHODS

We performed a retrospective cohort study using electronic health records from Leumit Health Services (LHS), a nationwide healthcare provider in Israel. The study was approved by the LHS Institutional Review Board, with a waiver of informed consent. The study cohort was drawn from a pool of more than 700 000 individuals who were members of LHS before the onset of the pandemic in March 2020. The study involved the comparison of 2 matched groups of individuals who were followed until December 2022.

The G6PD deficiency group consisted of patients with a documented G6PD deficiency or a recorded laboratory test of G6PD activity performed in LHS, resulting in a measurement below 4 U/g Hg. In Israel, a G6PD biochemical test was performed for several decades on newborns from ethnic groups at risk or upon request. The control group was randomly selected among individuals without G6PD deficiency to match to G6PD-deficient individuals on gender, age, socioeconomic status category, and ethnic group, with a ratio of 10 controls for each included G6PD-deficient individual.

Descriptive statistics were used to describe the cohort demographic and clinical characteristics at baseline. COVID-19 outcomes were queried as of 31 December 2022. These were defined as COVID-19 infection status (assessed by the presence of a positive polymerase chain reaction laboratory test or recorded diagnosis of COVID-19 infection), presence of long COVID-19 (identified by the coded diagnosis “late effect of COVID-19 infection” recorded during a medical encounter), and COVID-19–related hospitalization and mortality events (extracted from the national COVID-19 database maintained by the Israeli Ministry of Health). The statistical association between binary variables was assessed using the Fisher exact test. Numerical variables were compared using the Mann–Whitney U test. Cohort data extraction was performed using programs developed by Leumit Research Institute in Python, Pandas, and SQL. Statistics were computed on deidentified data using R statistical software, version 4.0.4.

RESULTS

The cohort included 5996 individuals with G6PD deficiency (mean age, 28.3 years [standard deviation, 22.2]; 67.7% men) and 59 960 matched controls. The baseline participants' characteristics are presented in Table 1, and the COVID–19–related outcomes for the 2 groups are reported in Table 2. Cumulative rates of COVID-19 infection during the study period were significantly higher among G6PD-deficient individuals (47.3% vs 43.4% of matched controls; odds ratio [OR], 1.17; 95% confidence interval [CI], 1.11–1.23). Breakthrough infection (defined as infection occurring after at least 2 vaccine injections) rates were higher among G6PD-deficient patients than matched controls after full vaccination (P = .001) and after the third and fourth booster doses of Pfizer BNT162b2 mRNA vaccine (P = .002. and P = .02, respectively). Hospitalization rates for COVID-19 were higher among G6PD-deficient individuals (0.85% vs 0.46% of matched controls; OR, 1.86; 95% CI, 1.35–2.51). We observed higher rates of diagnosed long COVID-19 in the G6PD-deficient group (0.43% vs 0.27% of matched controls; OR, 1.60; 95% CI, 1.01–2.43). There were no significant differences in the rates of COVID-19 reinfection among G6PD-deficient patients.

DISCUSSION

This large population study shows that G6PD-deficient individuals carry a higher risk of COVID-19 infection, of COVID-19 hospitalization, and of developing long COVID-19. These results are concordant with the increased risk of severe COVID-19 requiring hospitalization observed among US veterans with G6PD deficiency [4]. A smaller study performed among hospitalized patients with COVID-19 found a decreased risk of critical illness for patients with G6PD deficiency [5]. One possible explanation for these apparently conflicting results could be that G6PD-deficient patients have a relatively more severe presentation, leading to increased hospitalization rates. Conversely, G6PD-deficient patients who were included in the hospital study had fewer risk factors for severe disease than their G6PD-sufficient counterparts and were thus less likely to evolve into critical illness. Indeed, this latter study reported lower rates of diabetes mellitus (12.8% vs 20.8%), hypertension (22.2% vs 25.9%), renal disease (9.4% vs 12.8%), and lung disease (6% vs 9.9%) among the 117 hospitalized patients with G6PD deficiency. In addition, body mass, a major risk factor that correlates with diabetes, hypertension, and renal disease, was not reported.

Some limitations of our study need to be mentioned. First, as a retrospective study, we could not exclude possible inaccuracies in clinical records, missing data, or potential confounders that could be differently distributed between cases and controls. G6PD deficiency is a genetic trait present in individuals of Middle Eastern and African descent, and malaria has been historically prevalent in these countries. Other genetic traits or environmental factors could overlap with G6PD deficiency and have a confounding effect on COVID-19 outcomes. For instance, G6PD deficiency may be more prevalent among individuals with higher skin melanin content, and this could notably affect vitamin D levels. Nevertheless, the large number of patients included and the fact that the 2 groups were carefully matched and their data retrieved systematically from electronic health records should minimize the extent of bias.

In this study, G6PD deficiency was identified biochemically. There was no information regarding the specific mutations involved in the G6PD deficiency, and we were not able to assess the association between specific G6PD mutations and COVID-19 risk. Different mutations in the G6PD gene may affect the severity of G6PD deficiency and could play a role in the spectrum of severity of illness with COVID-19. Future research based on genetic biobanks could further analyze associations between specific G6PD mutations and COVID-19 risk.

Several mechanisms could explain the higher susceptibility of individuals with G6PD deficiency. Nicotinamide adenine dinucleotide phosphate (NADPH) is critical for the regeneration of glutathione and reactive oxygen species (ROS) and plays an essential role in the production of reactive nitrogen species and nitric oxide [6]. In airway epithelial cells, immune inflammation induces G6PD activity with the concomitant increase in glutathione, ROS, nitrotyrosine, and NADPH oxidase 2 (NOX2) [7]. In experimental models, G6PD inhibition suppresses airway inflammation in airway epithelial cells induced by lipopolysaccharides and the ROS derived from NOX2 [8]. Dysregulated redox systems and nuclear factor kappa B (NF-κB) signaling in G6PD-deficient cells have been associated with increased susceptibility to coronavirus infection through HSCARG protein [9]. Moreover, G6PD-deficient patients produce lower levels of proinflammatory cytokines, interleukin (IL)-6, and IL-1β in peripheral mononuclear cells [10], and their granulocytes display diminished bactericidal activity and increased susceptibility to infection [11]. The higher susceptibility to infections in G6PD patients may likewise be associated with reduced expression of prostaglandin E2 and cyclooxygenase-2 [12], defective neutrophil extracellular trap formation, and impaired inflammasome activation observed in neutrophils of G6PD-deficient individuals [13, 14].

The increased risk of severe disease and long COVID in G6PD-deficient individuals identified in this study warrants further investigation. We encourage clinicians to consider this condition in their treatment plans for G6PD-deficient patients and consider early treatment with antivirals in at-risk patients.

Notes

Disclaimer. The information presented here does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government.

Financial support. This work was supported in part by the Intramural Research Program, National Institutes of Health, National Cancer Institute, Center for Cancer Research.

References

Author notes