Therapeutic Prospects for Th-17 Cell Immune Storm Syndrome and Neurological Symptoms in COVID-19: Thiamine Efficacy and Safety, In-vitro Evidence and Pharmacokinetic Profile

Abstract

AbstractIntroductionEmerging infectious diseases, especially the coronavirus disease identified in 2019 (COVID-19), can be complicated by a severe exacerbation in the Th17 cell-mediated IL-17 proinflammatory immune storm. This enhanced immune response plays a major role in mortality and morbidity, including neurological symptoms. We hypothesized that countering the cytokine storm with thiamine may have therapeutic efficacy in lowering the Th17 cell proinflammatory response. We used an in vitro study and corroborated those results in disease controls (DC). We developed an effective dose range and model for key pharmacokinetic measures with the potential of targeting the cytokine storm and neurological symptoms of COVID-19.Study Participants and MethodsWe investigated the effect of a three-week 200 mg dose of thiamine in lowering the Th17 response in sixteen DC (proinflammatory origin due to heavy alcohol drinking) patients; and eight healthy control/volunteers (HV) as a pilot clinical-translational investigation. To further investigate, we performed an in vitro study evaluating the effectiveness of thiamine treatment in lowering the Th17 proinflammatory response in a mouse macrophage cell line (RAW264.7) treated with ethanol. In this in vitro study, 100 mg/day equivalent (0.01 µg/ml) thiamine was used. Based on recent publications, we compared the results of the IL-17 response from our clinical and in vitro study to those found in other proinflammatory disease conditions (metabolic conditions, septic shock, viral infections and COVID-19), including symptoms, and dose ranges of effective and safe administration of thiamine. We developed a dose range and pharmacokinetic profile for thiamine as a novel intervention strategy in COVID-19 to alleviate the effects of the cytokine storm and neurological symptoms.ResultsThe DC group showed significantly elevated proinflammatory cytokines compared to HV. Three-week of 200 mg daily thiamine treatment significantly lowered the baseline IL-17 levels while increased IL-22 levels (anti-inflammatory response). This was validated by an in vitro macrophage response using a lower thiamine dose equivalent (100 mg), which resulted in attenuation of IL-17 and elevation of IL-22 at the mRNA level compared to the ethanol-only treated group. In humans, a range of 79-474 mg daily of thiamine was estimated to be effective and safe as an intervention for the COVID-19 cytokine storm. A literature review showed that several neurological symptoms of COVID-19 (which exist in 45.5% of the severe cases) occur in other viral infections and neuroinflammatory states that may also respond to thiamine treatment.DiscussionThe Th17 mediated IL-17 proinflammatory response can potentially be attenuated by thiamine. Thiamine, a very safe drug even at very high doses, could be repurposed for treating the cytokine/immune storm of COVID-19 and the subsequent neurological symptoms observed in COVID-19 patients. Further studies using thiamine as an interventional/prevention strategy in severe COVID-19 patients could identify its precise anti-inflammatory role.