Association of Glucose-6-Phosphate Dehydrogenase Deficiency With Outcomes in US Veterans With COVID-19.

Importance: The underlying biological risk factors for severe outcome due to SAR-CoV-2 infection are not well defined. Objective: To determine the association between glucose-6-phosphate dehydrogenase (G6PD) deficiency and severity of COVID-19. Design, Setting, and Participants: This retrospective cohort study included analysis of 24 700 veterans with G6PD enzyme testing prior to January 1, 2020, obtained through the US Veterans Health Administration national databases. These veterans were cross-referenced with the Veterans Administration COVID-19 Shared Data Resource for SARS-CoV-2 testing from February 15, 2020, to January 1, 2021. The final study population consisted of 4811 veterans who tested positive for SARS-CoV-2. Statistical analysis was performed from June to December 2021. Exposures: G6PD deficiency. Main Outcomes and Measures: COVID-19 severe illness, as defined by the Centers for Disease Control and Prevention: hospitalization, need for mechanical ventilation and/or intensive care unit admission, or in-hospital mortality after a positive SARS-CoV-2 test. Results: Among 4811 veterans in the Veterans Health Administration who had historical G6PD enzyme activity test results and SARS-CoV-2 positivity included in this study, 3868 (80.4%) were male, 1553 (32.3%) were Black, and 1855 (39%) were White; 1228 (25.5%) were 65 years or older and 3583 (74.5%) were younger than 65 years. There were no significant differences in age, body mass index, or Charlson Comorbidity Index were present between the veterans with G6PD deficiency and without G6PD deficiency. Among these veterans with SARS-CoV-2 infection, G6PD deficiency was more prevalent in Black male veterans (309 of 454 [68.1%]) compared with other racial and ethnic groups. Black male veterans less than 65 years of age with G6PD deficiency had approximately 1.5-fold increased likelihood of developing severe outcomes from SARS-CoV-2 infection compared with Black male veterans without G6PD deficiency (OR, 1.47; 95% CI, 1.03-2.09). In the small subset of White male veterans with G6PD deficiency, we observed an approximately 3.6-fold increased likelihood of developing severe outcomes from SARS-CoV-2 infection compared with White male veterans aged 65 years or older without G6PD deficiency (OR, 3.58; 95% CI, 1.64-7.80). This difference between veterans with and without G6PD deficiency was not observed in younger White male veterans or older Black male veterans, nor in smaller subsets of other male veterans or in female veterans of any age. Conclusions and Relevance: In this cohort study of COVID-19-positive veterans, Black male veterans less than 65 years of age and White male veterans 65 years of age or older with G6PD deficiency had an increased likelihood of developing severe COVID-19 compared with veterans without G6PD deficiency. These data indicate a need to consider the potential for G6PD deficiency prior to treatment of patients with SARS-CoV-2 infection as part of clinical strategies to mitigate severe outcomes.

The Association of Baseline Plasma SARS-CoV-2 Nucleocapsid Antigen Level and Outcomes in Patients Hospitalized With COVID-19.

BACKGROUND: Levels of plasma SARS-CoV-2 nucleocapsid (N) antigen may be an important biomarker in patients with COVID-19 and enhance our understanding of the pathogenesis of COVID-19. OBJECTIVE: To evaluate whether levels of plasma antigen can predict short-term clinical outcomes and identify clinical and viral factors associated with plasma antigen levels in hospitalized patients with SARS-CoV-2. DESIGN: Cross-sectional study of baseline plasma antigen level from 2540 participants enrolled in the TICO (Therapeutics for Inpatients With COVID-19) platform trial from August 2020 to November 2021, with additional data on day 5 outcome and time to discharge. SETTING: 114 centers in 10 countries. PARTICIPANTS: Adults hospitalized for acute SARS-CoV-2 infection with 12 days or less of symptoms. MEASUREMENTS: Baseline plasma viral N antigen level was measured at a central laboratory. Delta variant status was determined from baseline nasal swabs using reverse transcriptase polymerase chain reaction. Associations between baseline patient characteristics and viral factors and baseline plasma antigen levels were assessed using both unadjusted and multivariable modeling. Association between elevated baseline antigen level of 1000 ng/L or greater and outcomes, including worsening of ordinal pulmonary scale at day 5 and time to hospital discharge, were evaluated using logistic regression and Fine-Gray regression models, respectively. RESULTS: Plasma antigen was below the level of quantification in 5% of participants at enrollment, and 1000 ng/L or greater in 57%. Baseline pulmonary severity of illness was strongly associated with plasma antigen level, with mean plasma antigen level 3.10-fold higher among those requiring noninvasive ventilation or high-flow nasal cannula compared with room air (95% CI, 2.22 to 4.34). Plasma antigen level was higher in those who lacked antispike antibodies (6.42 fold; CI, 5.37 to 7.66) and in those with the Delta variant (1.73 fold; CI, 1.41 to 2.13). Additional factors associated with higher baseline antigen level included male sex, shorter time since hospital admission, decreased days of remdesivir, and renal impairment. In contrast, race, ethnicity, body mass index, and immunocompromising conditions were not associated with plasma antigen levels. Plasma antigen level of 1000 ng/L or greater was associated with a markedly higher odds of worsened pulmonary status at day 5 (odds ratio, 5.06 [CI, 3.41 to 7.50]) and longer time to hospital discharge (median, 7 vs. 4 days; subhazard ratio, 0.51 [CI, 0.45 to 0.57]), with subhazard ratios similar across all levels of baseline pulmonary severity. LIMITATIONS: Plasma samples were drawn at enrollment, not hospital presentation. No point-of-care test to measure plasma antigen is currently available. CONCLUSION: Elevated plasma antigen is highly associated with both severity of pulmonary illness and clinically important patient outcomes. Multiple clinical and viral factors are associated with plasma antigen level at presentation. These data support a potential role of ongoing viral replication in the pathogenesis of SARS-CoV-2 in hospitalized patients. PRIMARY FUNDING SOURCE: U.S. government Operation Warp Speed and National Institute of Allergy and Infectious Diseases.

Emerging Mechanisms of Pulmonary Vasoconstriction in SARS-CoV-2-Induced Acute Respiratory Distress Syndrome (ARDS) and Potential Therapeutic Targets.

The 1918 influenza killed approximately 50 million people in a few short years, and now, the world is facing another pandemic. In December 2019, a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused an international outbreak of a respiratory illness termed coronavirus disease 2019 (COVID-19) and rapidly spread to cause the worst pandemic since 1918. Recent clinical reports highlight an atypical presentation of acute respiratory distress syndrome (ARDS) in COVID-19 patients characterized by severe hypoxemia, an imbalance of the renin-angiotensin system, an increase in thrombogenic processes, and a cytokine release storm. These processes not only exacerbate lung injury but can also promote pulmonary vascular remodeling and vasoconstriction, which are hallmarks of pulmonary hypertension (PH). PH is a complication of ARDS that has received little attention; thus, we hypothesize that PH in COVID-19-induced ARDS represents an important target for disease amelioration. The mechanisms that can promote PH following SARS-CoV-2 infection are described. In this review article, we outline emerging mechanisms of pulmonary vascular dysfunction and outline potential treatment options that have been clinically tested.