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This article is part of our May 2023 Immune Health special issue. (link removed).
reference
Tosato M, Calvani R, Picca A. 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.Nutrients. 2022;14(23):4984.
Study objective
To determine the effects of oral L-arginine and vitamin C supplementation on physical performance, measured by a 6-minute walk test, in subjects with long Covid disease (according to World Health Organization (WHO) criteria). Secondary outcomes included assessment of muscle strength, endothelial function, and fatigue associated with supplementation with these two nutrients.
Key to take away
Oral supplementation with 3.2 g L-arginine and 1 g liposomal vitamin C for 28 days significantly improved physical performance, muscle strength, endothelial function and fatigue in adults with long Covid.
design
Single-center, single-blind, placebo-controlled, randomized clinical trial
Participant
The study was conducted in an outpatient clinic in Rome, Italy. Participants were adults with a previous SARS-CoV-2 infection (severe acute respiratory syndrome coronavirus 2), confirmed by polymerase chain reaction (PCR) testing, a negative swab test for at least 4 weeks before enrollment, and with long Covid symptoms (according to WHO criteria). for long Covid).
The average age of participants was 50.5 years (20–60 years), and 65.2% were women. The median time from Covid-19 diagnosis to start of the study was 254 days. About half of participants were hospitalized with active Covid, with 8.7% in intensive care.
The researchers included 50 patients in the study and randomized them equally between the intervention and placebo arms. Two participants withdrew from each arm before the start of the intervention. At baseline, the intervention and placebo groups were similar in anthropometric, clinical and functional characteristics.
Interventions
The intervention consisted of 1.66 g L-arginine and 500 mg liposomal vitamin C taken orally twice daily (Bioarginina).®C, Farmaceutici Damor, Naples, Italy). The same manufacturer made the placebo. The form of the dietary supplement and placebo was unclear (e.g., potency, capsule, other).
Evaluated study parameters
To assess the primary outcome of exercise capacity, researchers measured distance walked in a 6-minute walking test. They conducted this test at baseline and on day 28 in a marked indoor hallway.
To assess the secondary outcome of muscle strength, the researchers used a hydraulic, hand-held dynamometer to measure handgrip strength.
To assess the secondary measure of endothelial function, they performed a flow-mediated dilation test, which essentially measured the change in brachial artery dilatation after 5 minutes of forearm ischemia created by a blood pressure cuff.
The researchers measured the secondary end result of fatigue persistence with the question: "I felt like everything I did was an effort." The answer “most of the time or all the time” indicated persistent fatigue. This is item 7 on the Center for Epidemiological Studies Depression Scale1and is used to measure physical frailty2as it is more related to fatigue than depression.3
Primary outcome
The primary outcome of this intervention study was to determine the effect of oral supplementation of L-arginine with liposomal vitamin C on distance walked during the 6-minute walk test as a measure of physical performance.
Key findings
This study was 80% powered to detect a difference of at least 35 meters in the 6-minute walk test. This difference corresponds to a minimal clinically significant difference.
The effects of the intervention were measured on day 28. The mean serum L-arginine concentration increased in the intervention group compared to placebo (+60.2 μM vs. +11.0 μM;P=0.02).
The primary endpoint, mean distance on the 6-minute walk test, increased by 30 meters in the intervention group, while there was no change in the placebo group (P=0.001). The mean difference between groups was 50 meters (95% CI: 20.0–80.0 m; effect size = 0.56).
There were also statistically significant differences in secondary endpoints.
Handgrip strength increased by 3.4 kg compared to a 1.0 kg increase with placebo (P=0.03). The mean difference was 3.4 kg (95% CI: 0.5–9.4 kg; effect size = 0.37). Flow-mediated dilatation increased by 14.3% in the intervention group compared to 9.4% in the placebo group (P=0.03). The mean difference was 3.4% (95% CI: 0.4–6.5; effect size = 0.66).
On day 28, 8.7% of the intervention group reported fatigue compared to 80.1% of the placebo group (P≤0.0001). There was a high degree of correlation between the primary endpoint and all secondary endpoints.
transparency
The authors received no external funding for this study and the authors declared no conflicts of interest. The supplement was donated by the manufacturer, who had no role in the design or interpretation of the study.
Implications and limitations for practice
According to the Centers for Disease Control and Prevention, one in five American adults who have Covid-19 will develop Long Covid.4The consequences of a long Covid illness are significant in terms of reduced quality of life, reduced work productivity and an increased risk of chronic diseases.
Although the pathophysiology of Long-Covid is not fully understood, there are several findings that support the hypothesis that changes in L-arginine metabolism underlie some Long-Covid symptoms. L-arginine is metabolized by both nitric oxide synthase and arginase. The metabolism of nitric oxide synthase produces nitric oxide (NO). NO is an essential component of endothelial function, the dysfunction of which impairs vascular tone, increases thrombosis and leads to inflammation.5When L-arginine is preferentially metabolized by arginase, less is available to form NO. As a result, there is an impairment of endothelial function, an increase in thrombosis and inflammation. Previous studies have shown that Covid-19 infection results in decreased L-arginine with upregulated arginase activity.6.7Based on these findings, the idea of supplementing L-arginine to make more of it available for metabolism to NO is logical. Additionally, vitamin C supplementation increases intracellular tetrahydrobiopterin, which in turn is required by nitric oxide synthase to produce NO.8
Consistent with this underlying hypothesis, this study demonstrated that oral supplementation with L-arginine and liposomal vitamin C improved endothelial function. Not surprisingly, researchers found improvements in the associated clinical outcomes of improved physical performance (6-minute walking distance), increased muscle strength and reduced fatigue in adults with long Covid. What is particularly encouraging is that these clinically significant results were achieved in a relatively short time, just one month, and with moderate doses. The researchers note that L-arginine supplementation has been shown in other studies to improve aerobic and anaerobic fitness, particularly in untrained individuals.9This clearly describes the population of people with Long Covid.
Given the favorable safety profile for both L-arginine and vitamin C, and in light of the significant morbidity associated with long-Covid, this relatively simple supplementation strategy deserves clinical testing. This study is limited by the relatively small number of participants and the fact that the study was conducted at a single center. Although these results should be considered preliminary, these results provide a clinically viable strategy for a group of patients for whom few validated options exist.