A new study by researchers from the University of Otago-New Zealand, University of California, Davis-USA, The University of Alabama at Birmingham-USA, University of Queensland-Australia and the Birmingham VA Medical Center- has found high doses of Vitamin B9 or folic acid were associated with increased COVID-19 risk.
ccording to the study team, folic acid, a B vitamin that’s used widely to fortify foods and lower the risk of birth defects, may carry a hidden risk for those who take huge quantities of it.
The study findings showed that individuals were more likely to get COVID-19 and to die from COVID-19 if they had been taking high doses of vitamin B9.
The research objective was initially to determine if methotrexate or folic acid prescription was associated with differential risk for COVID-19 diagnosis or mortality.
The study findings were published in the peer reviewed journal: BMJ Open
In this population-based analysis, we report association with a 1.5-fold increased risk for COVID-19 diagnosis and 2.6-fold increased risk for COVID-19-related death among those who had been prescribed folic acid supplementation. The prescription of methotrexate was not associated with an increased risk of diagnosis of COVID-19 and we were not able to make an estimate for COVID-19-related death in the small sample of those prescribed methotrexate only.
Notably, those prescribed methotrexate and folic acid did not have an increased risk for COVID-19 diagnosis or associated death, indicating that methotrexate might attenuate the increased risk for COVID-19 diagnosis and related death, which were associated with the prescription of folic acid alone.
In the context of SARS-Cov-2 infection, it is established that hijacking of cellular metabolic pathways is important for viral replication.17 Zhang et al described that SARS-CoV-2 remodels host folate and one-carbon metabolism at the post-transcriptional level to support de novo purine synthesis, bypassing viral shutoff of host translation.8
This suggests that viral replication could be sensitive to folate inhibitors, such as methotrexate. Intracellular glucose and folate are depleted in SARS-CoV-2-infected cells, and viral replication is exquisitely sensitive in vitro to inhibitors of folate and one carbon metabolism, notably methotrexate.8
Stegmann et al, based on cell culture experiments, reported that methotrexate alone or in combination with remdesivir limits the replication of SARS-CoV-2.18 With the caveat that our study is observational epidemiology and causality cannot be inferred, our study does support the possibility that external folate supply facilitates the production of large amounts of virus, contributing to clinical infection and mortality.
With the same caveat on inference of causality from observational data, our study also supports the notion that SARS-CoV-2 replication is enhanced by folate supply based on our finding that coprescription of an antifolate (methotrexate) attenuated the association of supplementation with folic acid with COVID-19 outcomes.
There is also evidence that inadequate folate status may be harmful in the context of host resistance to infection with SARS-CoV-2. In addition to the well-recognised complication of anaemia, folate deficiency has other detrimental health effects, including suppression of immune function.19
Additional support for the possibility that adequate folate status is important in COVID-19 outcomes is provided by the observation that folate deficiency was associated with poorer outcomes in a cohort of patients with COVID-19.20 It is important to note that it is possible that in the study by Itelman et al,20 if increased folate levels were causal of COVID-19 diagnosis and poor outcomes, that the association with lower folate levels could have been caused by selection (collider) bias.21
Vitamin B12 deficiency has also been proposed as a factor related to poor COVID-19 outcomes, presumed to be through the induction of functional folate deficiency.22 A drug–protein structure interaction analysis raises the possibility that folate blocks the 3CL hydrolase enzyme, which may affect viral entry and replication.23 It is therefore possible that both inadequate and excessive amounts of folate may be detrimental to host resistance to SARS-CoV-2 infection and that there may be an optimal range of physiological folate status related to host resistance to COVID-19 infection and severity.
Data from the COVID-19 Global Rheumatology Alliance describe that a number of immunomodulatory drugs used in rheumatology are associated with an increased risk of infection and death compared with methotrexate.7 Being on no DMARD, therapy was associated with an increased risk of death with COVID-19 (OR 2.11 (1.48–3.01)), which could be interpreted as either a protective effect of methotrexate or an increased risk for death associated with poor rheumatic disease control.
The authors of the study additionally noted that people not on DMARD therapy had increased use of glucocorticoids meaning that confounding by indication cannot be ruled out as an explanation.24 Methotrexate was also associated with lower odds for death when compared with sulfasalazine, other immunosuppressants and rituximab. In no case was methotrexate associated with an increased risk for death.
The COVID-19 Global Rheumatology Alliance study did not explore the effect of folic acid supplementation in the setting of methotrexate, although it is highly likely that almost all patients on methotrexate also were receiving folic acid supplementation. Considering the widespread use of folic acid supplements and proposals to abandon entirely tolerable upper intake levels for folic acid,25 it would be prudent to monitor the effect of increased folic acid intake at a population level on COVID-19 morbidity and mortality, particularly at the upper end of folic acid intake.