Can arginine alleviate COVID-19? Original paper

The endothelium, a thin membrane lining cells and organs throughout the body, plays a critical role in regulating the immune response, including inflammation. SARS-CoV-2 is believed to target the endothelium, which may be how it affects multiple organs.

The amino acid arginine has many important functions in the body, including the production of proteins, hormones (e.g., growth hormone), and nitric oxide (NO). It is present in many foods, but your body can also synthesize it.

Endothelial cells control vascular contraction and relaxation via NO. In vitro evidence shows that arginine increases T-cell proliferation in cells extracted from COVID-19 patients,^[1] suggesting that arginine supplementation may be useful as an adjuvant therapy.

This first interim analysis of an ongoing randomized controlled trial assessed 101 adult patients who took either 1.66 grams of oral arginine or a placebo, twice daily, starting 7.8 days after symptom onset (on average). All 101 participants were receiving oxygen at the time of randomization and kept receiving standard treatment.

The inclusion criteria were as follows:

• Confirmed COVID-19
• Confirmed pneumonia
• Oxygen saturation of ≤93% on room air
• Ratio of alveolar oxygen partial pressure to fractional inspired oxygen (a measure of how well oxygen can move from the lungs to the blood) of ≤300 (200–300 is associated with mild, 100–200 with moderate, and <100 with severe acute respiratory distress syndrome)
• Lymphocytopenia (lymphocytes at <1,500/μL or <20% of white blood cells)

The primary outcome was reduced respiratory support (transition to less invasive assistance) measured on days 10 and 20 after randomization. The secondary outcomes were the length of hospitalization, the time to normalize the number of lymphocytes, and the time to achieve a negative COVID test.

Supplemental arginine did not produce any adverse effects.

By day 10, respiratory support was reduced in 71.1% of the arginine group and 44.4% of the placebo group. Adjusting for confounding variables revealed that the odds of a reduction in respiratory support were 6.6 times greater in the arginine group.

By day 20, there was no difference in respiratory support between groups, but the researchers think this was because most of the participants in the arginine group had likely been discharged from the hospital. Moreover, because of the relatively small number of participants, any difference found in this analysis may simply have failed to reach statistical significance.

The median hospital stay was 25 days in the arginine group and 46 days in the placebo group. No effects were found for the other secondary outcomes.

After randomization but prior to starting the treatment, 3 participants in the arginine group and 8 in the placebo group were transferred to the intensive care unit; all 11 passed away before they could start their assigned treatments. The between-group difference in mortality was statistically significant when these 11 participants were included (20.8% for placebo, 6.3% for arginine) but not otherwise (6.7% for placebo, 0% for arginine). In short, in any way that matters, the difference in mortality rate between the arginine group and the placebo group was not statistically significant.

When interpreting the results, one must consider the baseline differences between the two groups. Compared to the placebo group, the arginine group was younger (65.9 vs. 57.4) and had less hypertension (42.2% vs. 31.1% of the group), lower blood urea nitrogen (73.0 vs. 58.1 mg/dL), and worse respiratory status at baseline (which may have offered more room for improvement).

The median length of hospitalization for both groups had a very tight interquartile range, suggesting that the hospital may have had a protocol to discharge patients at specific time points.

This trial is ongoing — with 200 additional participants — so we may still learn more.

Some studies have associated low serum arginine with COVID-19 infection,^[2][3] and this is likely due to increased arginase activity.

Arginine levels (μmol/L) in COVID-19 patients with either moderate pneumonia or _acute respiratory distress syndrome_ (ARDS)

Source: Reizine et al. J Clin Immunol. 2021 Apr^[1]

Arginine levels (μmol/L) in adults and children with COVID-19

Source: Rees et al. Proc Natl Acad Sci U S A. 2021 Jun^[2]

Arginine levels (μmol/L) in patients with severe COVID-19 and in convalescent patients

Source: Dean et al. Front Immunol. 2021 Jul^[3]

Correlation is not causation, however, and increased arginase activity is not unique to COVID-19; it has been linked to CVD, cancer, diabetes, kidney disease, and immune system dysfunction — all of which are associated with poor COVID-19 outcomes.

Finally, let’s mention that while the present trial looked at arginine supplementation, arginine depletion has also been proposed as a potential antiviral mechanism, because preclinical evidence shows that arginine appears to be a key metabolite for viral replication.^[4] Arginine depletion has yet to be tested in COVID-19 patients, however.