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In certain groups of men, glucose-6-phosphate dehydrogenase (G6PD) deficiency was linked with an increased likelihood of severe COVID-19, a Veterans Affairs cohort study found.

In Black men under 65, for example, those with the common enzyme deficiency had a roughly 1.5-fold higher risk for severe illness (OR 1.47, 95% CI 1.03-2.09), reported Lavannya Pandit, MD, MS, of the Michael E. DeBakey VA Medical Center in Houston, and colleagues.

And in white men 65 and over, those with G6PD deficiency had a 3.6-fold higher likelihood of severe outcomes (OR 3.58, 95% CI 1.64-7.80), which in the study was defined as the need for hospitalization, mechanical ventilation, or intensive care, or death.

"This study is the first to present epidemiologic evidence that putatively link a biologic mechanism of impaired cellular responses in G6PD deficiency to increased COVID-19 severity," Pandit and colleagues wrote in . "Our analysis revealed a strong association between G6PD deficiency and COVID-19 severity, modified by race and age."

In the U.S., anywhere from 4% to 7% of people are , but that percentages rises to 10% to 14% for Black men. G6PD enzyme activity is moderated by hyperglycemia, and associations have been observed between G6PD deficiency and risk for diabetes.

One of the challenges with COVID-19 has been understanding why certain individuals experience severe, life-threatening conditions, and others don't, the researchers said. While ancestry, socioeconomic status, healthcare utilization, and comorbid conditions are all variables that have been associated with worse illness, "the contribution of biology toward disease severity has been minimally explored. As a result, despite almost 3 years of observational data, the biologic bases of susceptibility to SARS-CoV-2 infection and risks of severe outcomes after infection are largely unknown."

The findings, they concluded, highlight "the need to review and determine possible underlying inherent genetic risks, such as G6PD deficiency, prior to illness or early in treatment course as a strategy to mitigate negative outcomes."

Pandit's team examined data on 4,811 veterans in the Veterans Health Administration who had a positive COVID-19 test and had been tested for G6PD deficiency. Most (80.4%) were men, one-third were Black, 39% were white, and three-fourths were under age 65. Of those, 454 were positive for G6PD deficiency (418 men and 36 women), 68% of whom were Black men.

Although the genetic metabolic abnormality is an X-linked condition, and thus more commonly affects men, the researchers noted that hemizygous males and heterozygous females can also be affected.

In discussing why a link was only seen among the younger population of Black men in their study, Pandit and co-authors posited that "increased COVID-19 severity may not be measurable in the older Black male population possibly due to other underlying comorbidities in this population (diabetes and chronic kidney disease, for example) that may already confer a ceiling effect on severity, and that ceiling effect may not be additionally altered (increased) by G6PD deficiency."

As to the differences in risk between the white and Black groups, they suggested that it could come down to different alleles (G6PD-Mediterranean vs G6PD-A, for example), though Department of Defense testing does not universally determine genetic variants.

Limitations cited by the researchers included that comorbidity data were obtained through ICD-10 codes, which may be misclassified, and demographic factors such as race were self-identified. "Additional study is warranted by including Medicare and Medicaid information and additional confounding factors, including healthcare policy messaging, access to care, and usage of non-prescribed and prescribed medications outside of the [Veterans Health Administration]," they added.

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