Supplementary folic acid associated with higher risk of COVID-19 diagnosis and mortality

In a recent study published in the journal BMJ Open, researchers investigated the impact of folic acid supplements and methotrexate, in combination or individually, on disease severity and mortality in coronavirus disease 2019 (COVID-19) cases.

Study: Folic acid and methotrexate use and their association with COVID-19 diagnosis and mortality: a case–control analysis from the UK Biobank. Image Credit: Pixel-Shot / Shutterstock

Background

Folate, or vitamin B9, plays a vital role in various cellular functions, including amino acid synthesis in protein metabolism and nucleic acid metabolism for the synthesis of deoxyribonucleic acids (DNA) and ribonucleic acids (RNA). However, studies have shown that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hijacks the host cell’s folate and glucose reserves to replicate the viral genome. This viral replication is reported to be sensitive to folate inhibitors such as methotrexate, which is widely prescribed as a chemotherapy agent and a first-line disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis (RA).

Folic acid — the oxidized form of folate — is prescribed as a supplement to pregnant women and as a treatment for conditions such as sickle cell anemia and epileptic seizures. In the United States and 80 other countries, folic acid is used to fortify foods, and the United Kingdom intends to follow suit. Considering the current and future widespread use of folic acid supplements, it is important to understand the role of folic acid in aiding SARS-CoV-2 replication and exacerbating COVID-19 severity.

About the study

The present study carried out a case-control analysis to determine the differential COVID-19 diagnosis and mortality risk associated with the use of folic acid supplements and methotrexate medications. The dataset obtained from the UK Biobank (UKBB) consisted of information from 380,380 participants who had been prescribed folic acid, methotrexate, anticonvulsants, iron supplements, and other medications such as statins. The availability of body mass index (BMI) measure, Townsend deprivation index, and smoking status data also determined the selection of participants.

Participants were considered COVID-19 positive based on a positive PCR test for SARS-CoV-2 and an International Classification of Diseases (ICD)-10 code for confirmed or probable COVID-19. Of the 380,380 participants selected from UKBB, 26,033 were COVID-19 positive cases, of whom 820 had succumbed to the disease.

The data were also grouped according to ethnicity, sex, age (below 60 and above 74 years), and additional comorbidity factors such as RA and sickle cell anemia. The association of the prescription data with COVID-19 diagnosis and mortality was analyzed. Statistical models were adjusted for demographic factors, comorbidities, and other medications.

Results

The study results indicate a 1.5-fold increase in COVID-19 diagnosis risk and a 2.5-fold increase in COVID-19-related mortality risk associated with folic acid supplement prescriptions. Patients on prescribed methotrexate and folic acid supplements were not at increased risk of COVID-19 diagnosis or death, indicating that methotrexate could play an antagonistic role against the deleterious effect of folic acid in COVID-19 patients.

Methotrexate was not associated with an increased risk of COVID-19 diagnosis. However, given the small sample size of mortality cases who were prescribed methotrexate in the absence of folic acid supplements, the researchers could not determine the mortality risk associated with a prescription of only methotrexate.

Rheumatoid arthritis patients who were not on DMARD therapy were at an increased risk of COVID-19-related mortality, which could indicate the absence of the protective effect of methotrexate, confounded by indications due to other medications or poor disease management. Compared to medicines like sulfasalazine, rituximab, and other immunosuppressants, methotrexate showed lower odds of COVID-19-related mortality.

The study also presents information highlighting the importance of optimum folate levels. Folate deficiency has been linked to suppression of immune function and poor outcomes in some COVID-19 patients. Low vitamin B12 levels linked to folate deficiency have also been associated with COVID-19 severity. The authors believe that host resistance to COVID-19 might depend on an optimal range of folate in the body, with both deficiency and excess being detrimental to the resistance against SARS-CoV-2.

Some of the limitations to the analysis include (1) the inability to account for other treatment methods such as antivirals and monoclonal antibodies affecting the outcome in COVID-19 patients and (2) the difficulty in generalizing the findings of the study to the larger population as the sample set was dominated by middle-aged (older than 45 years) white European participants.

Conclusions

To summarize, with caveats on the inference of causality, the study supports the hypothesis that high folate levels resulting from folic acid supplements could increase the risk of COVID-19 diagnosis and death. Methotrexate, a folate antagonist, provides some protective effect against the detrimental effects of folic acid in COVID-19 patients. Still, the widespread, use of folic acid supplements highlights the need for more thorough studies on the role of folic acid in COVID-19 progression.