COVID-19 illness: Different comorbidities may require different immunological therapeutic targets.

BACKGROUND: The SARS-CoV-2 pandemic has led to more than 6,870.000 deaths worldwide. Despite recent therapeutic advances, deaths in Intensive Care Units still range between 34 and 72%, comprising substantial unmet need as we move to an endemic phase. The general agreement is that in the first few days of infection, antiviral drugs and neutralizing monoclonal antibodies should be adopted. When the patient is hospitalized and develops severe pneumonia, progressing to a systemic disease, immune modifying therapy with corticosteroids is indicated. Such interventions, however, are less effective in the context of comorbidities (e.g., diabetes, hypertension, heart failure, atrial fibrillation, obesity and central nervous system-CNS diseases) which are by themselves associated with poor outcomes. Such comorbidities comprise common and some distinct underlying inflammatory pathobiology regulated by differential cytokine taxonomy. METHODS: Searching in the PubMed database, literature pertaining to the biology underlying the different comorbidities, and the data from the studies related to various immunological treatments for the Covid-19 disease were carefully analyzed. RESULTS: Several experimental and clinical data have demonstrated that hypertension and atrial fibrillation present an IL-6 dependent signature, whereas diabetes, obesity, heart failure and CNS diseases may exhibit an IL-1a/b predominant signature. Distinct selective cytokine targeting may offer advantage in treating severe COVID-19 illness based on single or multiple associated comorbidities. When the patient does not immediately respond, a broader target range through JAKs pathway inhibitors may be indicated. CONCLUSIONS: Herein, we discuss the biological background associated with distinct comorbidities which might impact the SARS-CoV-2 infection course and how these should to be addressed to improve the current therapeutic outcome.

Effects of l-Arginine Plus Vitamin C Supplementation on l-Arginine Metabolism in Adults with Long COVID: Secondary Analysis of a Randomized Clinical Trial.

Altered l-arginine metabolism has been described in patients with COVID-19 and has been associated with immune and vascular dysfunction. In the present investigation, we determined the serum concentrations of l-arginine, citrulline, ornithine, monomethyl-l-arginine (MMA), and symmetric and asymmetric dimethylarginine (SDMA, ADMA) in adults with long COVID at baseline and after 28-days of l-arginine plus vitamin C or placebo supplementation enrolled in a randomized clinical trial, compared with a group of adults without previous history of SARS-CoV-2-infection. l-arginine-derived markers of nitric oxide (NO) bioavailability (i.e., l-arginine/ADMA, l-arginine/citrulline+ornithine, and l-arginine/ornithine) were also assayed. Partial least squares discriminant analysis (PLS-DA) models were built to characterize systemic l-arginine metabolism and assess the effects of the supplementation. PLS-DA allowed discrimination of participants with long COVID from healthy controls with 80.2 ± 3.0% accuracy. Lower markers of NO bioavailability were found in participants with long COVID. After 28 days of l-arginine plus vitamin C supplementation, serum l-arginine concentrations and l-arginine/ADMA increased significantly compared with placebo. This supplement may therefore be proposed as a remedy to increase NO bioavailability in people with long COVID.

Effects of l-Arginine Plus Vitamin C Supplementation on Physical Performance, Endothelial Function, and Persistent Fatigue in Adults with Long COVID: A Single-Blind Randomized Controlled Trial.

Long COVID, a condition characterized by symptom and/or sign persistence following an acute COVID-19 episode, is associated with reduced physical performance and endothelial dysfunction. Supplementation of l-arginine may improve endothelial and muscle function by stimulating nitric oxide synthesis. A single-blind randomized, placebo-controlled trial was conducted in adults aged between 20 and 60 years with persistent fatigue attending a post-acute COVID-19 outpatient clinic. Participants were randomized 1:1 to receive twice-daily orally either a combination of 1.66 g l-arginine plus 500 mg liposomal vitamin C or a placebo for 28 days. The primary outcome was the distance walked on the 6 min walk test. Secondary outcomes were handgrip strength, flow-mediated dilation, and fatigue persistence. Fifty participants were randomized to receive either l-arginine plus vitamin C or a placebo. Forty-six participants (median (interquartile range) age 51 (14), 30 [65%] women), 23 per group, received the intervention to which they were allocated and completed the study. At 28 days, l-arginine plus vitamin C increased the 6 min walk distance (+30 (40.5) m; placebo: +0 (75) m, p = 0.001) and induced a greater improvement in handgrip strength (+3.4 (7.5) kg) compared with the placebo (+1 (6.6) kg, p = 0.03). The flow-mediated dilation was greater in the active group than in the placebo (14.3% (7.3) vs. 9.4% (5.8), p = 0.03). At 28 days, fatigue was reported by two participants in the active group (8.7%) and 21 in the placebo group (80.1%; p < 0.0001). l-arginine plus vitamin C supplementation improved walking performance, muscle strength, endothelial function, and fatigue in adults with long COVID. This supplement may, therefore, be considered to restore physical performance and relieve persistent symptoms in this patient population.