Potential influence of G6PD deficiency on COVID-19 therapies
Chloroquine (CQ), a 4-aminoquinoline drug, is commonly used in the treatment of malaria and amoebiasis [122,123]. It is also used for treating autoimmune diseases, including lupus erythematosus and rheumatoid arthritis, due to its capacity for modulating inflammation and the immune response [124,125]. The effect of CQ on certain viruses is inconclusive. A positive response is observed with CQ in chikungunya, HIV, and HCV infections [126–129], whereas it is not effective in influenza and dengue infections [126,130]. Hydroxychloroquine (HCQ) is a derivative of chloroquine and its treatment for COVID-19 is currently being evaluated in clinical trials [131]. The potential use of HCQ against COVID-19 may raise safety issues in certain populations [132]. Recent reports suggest that CQ or HCQ is possibly linked to hemolysis in G6PD deficiency [133–135]. However, two large retrospective studies indicated that no episode of hemolysis was found after HCQ treatment among G6PD-deficient individuals [136,137]. Hence, the claim that oxidant hemolysis due to chloroquine exposure in G6PD-deficient individuals remains unsettled [138].
Despite the efforts of developing vaccines against COVID-19, studies show that the elderly are less responsive to immune stimulation. During aging, the depletion of naïve T cells and B cells weakens the immune defense against invading pathogens. Moreover, chronic and low-grade inflammation in the elderly, known as inflammaging, leads to a reduced ability to external stimulation. These events result in an impaired response to infection and dampen the reaction to vaccines [139]. Nevertheless, some anti-aging therapies show promising results related to enhancing the anti-viral response in the elderly. An mTOR inhibitor reduces infection, improves vaccination responses, and enhances the anti-viral response in the elderly [140]. Metformin is a common diabetic drug that indirectly inhibits mTOR and extends life span in animals [141]. The mortality rate drops in hospitalized patients with COVID-19 who have received metformin [142,143]. Senolytic drugs reduce inflammation and selectively remove senescent cells during aging [144]. These anti-aging compounds can exert their function in promoting healthspan by maintaining redox homeostasis and alleviating oxidative stress [145–147]. These compounds administered to the elderly with COVID-19 may reduce their mortality and improve recovery [148–151]. This opens the possibility of reducing the signs of aging or immunosenescence in the elderly population with drugs such as calorie restriction mimetics and senolytics before vaccination [152,153]. In particular, the elderly with G6PD deficiency may benefit from these treatments through boosting their antioxidative defense and immune responses.