Abstract :

The severe pneumonia caused by the human coronavirus (hCoV)-SARS-CoV-2 has inflicted heavy casualties, especially among the elderly and those with co-morbid illnesses irrespective of their age. The high mortality in African-Americans and males, in general, raises the concern for a possible X-linked mediated process that could affect the viral pathogenesis and the immune system. We hypothesized that G6PD, the most common X-linked enzyme deficiency, associated with redox status, may have a role in severity of pneumonia. Retrospective chart review was performed in hospitalized patients with COVID19 pneumonia needing supplemental oxygen. A total of 17 patients were evaluated: six with G6PD deficiency (G6PDd) and 11 with normal levels. The two groups (normal and G6PDd) were comparable in terms of age, sex, co-morbidities, and laboratory parameters—LDH, IL-6, CRP, and ferritin, respectively. Thirteen patients needed ventilatory support ; 8 in the normal group and 5 in the G6PDd group (72% vs.83%). The main differences indicating increasing severity in normal vs. G6PDd groups included G6PD levels (12.2 vs. 5.6, P = 0.0002), PaO2/FiO2 ratio (159 vs. 108, P = 0.05), days on mechanical ventilation (10.25 vs. 21 days P = 0.04), hemoglobin level (10 vs. 8.1 P = 0.03), and hematocrit (32 vs. 26 P = 0.015). Only one patient with G6PDd died; 16 were discharged home. Our clinical series ascribes a possible biological role for G6PDd in SARS-CoV2 viral proliferation. It is imperative that further studies are performed to understand the interplay between the viral and host factors in G6PDd that may lead to disparity in outcomes.

Key Points

• COVID19 studies show higher mortality in men, due to severe pneumonia and ARDS, indicating possible X-linked mediated differences
• G6PD, the most common X-linked enzymopathy, highly prevalent in African Americans and Italians, maintains redox homeostasis.
• Preclinical studies using G6PD deficient (G6PDd) cells infected with human coronavirus (hCoV), show impaired cellular responses, viral proliferation and worsening oxidative damage.
• Retrospective chart review in hospitalized patients with COVID19 pneumonia needing supplemental oxygen shows differences between the two groups (Normal and G6PDd) in hematological indices; the G6PDdgroup demonstrated prolonged PaO2/FiO2 ratio, and longer days on mechanical ventilation indicating the severity of the pneumonia.

Introduction

The novel coronavirus SARS-CoV2 that causes coronavirus disease 2019 (COVID19) has approximately afflicted over 72 million people worldwide [1,2,3,4], including approximately 16.2 million in the USA as of December 2020. Among 1482 patients hospitalized reported by COVID19–Associated Hospitalization Surveillance Network (COVID-NET), 74.5% were aged ≥ 50 years, and 54.4% were male [2, 5, 6]. The male predominance hints at X linked related differences in the predilection to the severity of illness. One such possibility is the X-linked glucose-6-phosphate dehydrogenase (G6PD) deficiency (G6PDd), the most common enzymopathy, commonly manifesting as hemolysis due to oxidative stress [7,8,9]. With over 200 mutations identified in G6PDd, mainly in the coding regions, causing various degrees of deficiency, it is found in high frequency among African Americans, Mediterranean, and Asians [8]. The gene encoding G6PD is located near the telomeric region of the distal arm of the X chromosome (band Xq28), a well-documented hot spot of a group of genes that includes fragile X, color vision, hemophilia A, and congenital dyskeratosis [8]. The G6PD gene results in many biochemical variants and the deficiency of the gene product-G6PD, which is the rate-limiting enzyme in the pentose-phosphate pathway [8, 9]. The variants are grouped into four classes: (a) Class I variants comprise the most severe form of G6PDd and lead to chronic non-spherocytic hemolytic anemia, and typically occurs with enzyme activity < 10% of normal; (b) Class II variants typically have < 10% residual enzyme activity, but no hemolytic anemia; and (c) Class III and IV variants (10–60% and 60–150% activity, respectively) have milder phenotypes and hemolysis occurs only after extreme oxidative stress [10]. Very severe G6PDd is sporadic and rare, whereas less severe deficiencies are polymorphic, and more common in tropical areas, postulated to be evolved as protection against malaria [7, 8]. Males are more commonly affected when hemizygous and can be either phenotypically normal or deficient [10]. Homozygous females are as deficient as the hemizygous males, whereas heterozygous females are mosaics with intermediate levels of deficiency as a result of random X-chromosome inactivation (lyonization) [11]. We report here clinical scenarios of six COVID19 positive patients, with no previous respiratory issues with G6PDd, who required longer ventilatory support and ICU care compared to 11 matched controls. Given the role of G6PD in altering redox homeostasis [12], we hypothesize that the deficiency further enhances oxidative stress by uncontrolled production of reactive oxygen species (ROS) during this rapidly evolving inflammation caused by the SARS-CoV-2 virus and host immune system, leading to abnormal pulmonary vascular performance and respiratory decline. This case series warrants a systematic investigation of the role played by G6PD in this unrelenting COVID19-induced pneumonitis.

Methods

We reviewed the charts of 17 consecutive patients who were admitted to the Houston Methodist hospital and ICU with confirmed COVID19 infection, and where G6PD levels were available with consent, between March 15 and May 15, 2020. Clinical data were obtained through an Institutional Review Board (IRB) approved protocol PRO00025607 that allowed review of medical records. The main inclusion criteria included adults > 18 years old with a diagnosis of COVID19 within 24 h of admission to the hospital and where G6PD levels were obtained. G6PD was considered low if the recorded values were below the laboratory cut-off value of 9.6 U/g Hb; < 4.5 was considered severe, values between 4.5 and 9.6 as mild, and all other values as normal. Of note, G6PD testing as obtained as baseline in patients as hydroxychloroquine (HCQ) was the first line of treatment per the institutional protocol at the time of the study. Both groups received a 5-day course of HCQ and completed the course by the time G6PD result was reported. The G6PDd patients (3 severe and 3 mild) were compared to the normal cohorts (where the G6PD values were > 9.6) in 2:1 matching for age, gender, and co-morbidity. The data reported here have follow-up available through June 20, 2020; each patient had at least 21 days of follow-up.

Statistical analysis

Descriptive statistics were used to summarize the data; results are reported as means and medians, as appropriate. The unpaired t test was performed using GraphPad Prism 8 for macOS version 8.4.2 (464), April 7, 2020, GraphPad Software, San Diego California USA, www.graphpad.com. All comparisons were one-tailed; a P value of less than 0.05 was considered significant.