Hypersensitivity to Folic Acid and/or Folinic Acid—A Review of Clinical Cases, Potential Mechanism, Possible Cross-Allergies and Current Diagnostic Options

Folic acid and its derivatives (e.g., folinic acid) are a group of water-soluble compounds collectively known as vitamin B9. Synthetic folic acid is a component of dietary supplements, medications and other pharmaceuticals and fortified foods. Folinic acid (5-formyltetrahydrofolic acid) is the active metabolite of folic acid. It is used to treat vitamin B9 deficiency and as an adjunct to various combination therapies. Hypersensitivity reactions to folic acid or folinic acid are rare and occur following exposure to synthetic folic acid or its derivatives but not on natural folates. In people allergic to folates, cross-reactions are possible following exposure to folic acid analogues (including antifolates, e.g., methotrexate). The mechanism of hypersensitivity to folic acid and/or folinic acid has not been clearly established. Both IgE-dependent and non-IgE-dependent hypersensitivity reactions are likely. It is possible that folic or folinic acid is either an immunogen or a hapten. Diagnosing hypersensitivity to folic/folinic acid is difficult. There are no validated in vitro or in vivo diagnostic tests. The basophil activation test (BAT) appears to be a promising tool for diagnosing folate allergy. The aims of the manuscript were to review published clinical cases of hypersensitivity reactions to folic or folinic acid, potential mechanisms of these reactions and possible cross-allergies, and current diagnostic possibilities of folate hypersensitivity.