Discussion

Our finding of acute arginine depletion in COVID-19 among adults is consistent with findings from a recent study of 26 severely ill adults in France (6). We identify arginine depletion in both children with SARS-CoV-2 infection and those with MIS-C. Predicated on prior work describing the pathophysiology of arginine depletion (3⇓–5), we hypothesize that arginine depletion in COVID-19 and MIS-C may contribute to endothelial dysfunction, T cell dysregulation, and coagulopathy that have been observed in COVID-19. Further studies evaluating the role of arginine in the pathophysiology of COVID-19 and MIS-C, in particular, are merited.

Low arginine-to-ornithine ratio and GABR suggest increased arginase activity and potentially impaired arginine synthesis, respectively (7), in COVID-19 and MIS-C. Furthermore, as adult controls with anti-SARS-CoV-2 antibodies who recovered from COVID-19 had normal arginine bioavailability, arginine depletion during COVID-19 appears to be transient. Although there was no correlation between arginine concentration and lymphocyte counts, a trend with arginine bioavailability ratios was observed, likely limited by a relatively small sample size. Ultimately, a majority of COVID-19 patients had low arginine levels, which has been implicated in T cell dysfunction. With arginine concentrations of <50 μM, stimulated T cells have demonstrated reduced expression of the CD3ζ chain, the primary signaling chain in the T cell receptor complex, impairing T cell proliferation and IFN-γ production (4).

A recent study proposed arginine depletion and the use of arginase therapies as potential treatments for COVID-19 (8). However, our data suggest this may potentially exacerbate COVID-19 illness, given the extant arginine depletion in COVID-19. Studies evaluating arginine as a potential therapy for COVID-19 are merited. If arginine supplementation shows promise in the treatment of COVID-19, it may serve as an additional treatment option in resource-limited settings without access to vaccines or therapies for COVID-19.

Multiple amino acid anomalies beyond arginine were noted in patients with COVID-19 that may provide insight into metabolic derangements and could have clinical consequences. Compared to controls, glutamine, an arginine precursor that becomes essential during critical illness (5), was significantly lower in adult patients with COVID-19 but not among the pediatric cohort. Tryptophan, a serotonin precursor, was reduced by nearly 50% in COVID-19 patients, which may have neuropsychiatric implications (9). Phenylalanine was high, while citrulline was low in COVID-19 patients, implicating potential dysfunction of tetrahydrobiopterin, an essential nitric oxide synthase cofactor (3, 5). Decreased energy metabolism, through both the tricarboxylic acid cycle and the citric acid cycle, is suggested by COVID-19 amino acid profiles. These data confirm metabolic derangements identified in adults with SARS-CoV-2 infection (10) that may also affect children with COVID-19 and MIS-C.

Although our observations are open avenues for potential therapies for COVID-19 and MIS-C targeting arginine augmentation, our study has limitations. We did not identify the mechanism(s) underlying arginine depletion, which potentially includes reduced protein consumption in ill patients with poor oral intake, renal dysfunction, or increased metabolism via arginase. We also did not determine the impact of low arginine bioavailability on nitric oxide production, which could be assessed in future studies by measuring flow-mediated vasodilation. We compared pediatric samples to an adult control group; however, plasma arginine concentrations in our adult samples are similar to those in pediatric controls (11). Furthermore, our relatively small sample size may have precluded our analysis reaching statistical significance, even in the presence of true biological phenomena.