Fungal Infections Associated with Sphingosine 1-Phosphate Receptor Modulators: Immunological Mechanisms, Clinical Patterns, and Management Considerations

Fungal infections constitute a large portion of serious infections worldwide and are increasing, partially due to new immunomodulatory therapies, such as Sphingosine-1-Phosphate (S1P) receptor modulators, including fingolimod for the treatment of multiple sclerosis (MS). Fingolimod antagonizes multiple S1P receptors, including S1PR1, S1PR3, S1PR4, and S1PR5, resulting in immunological alterations that may increase susceptibility to invasive fungal infections (IFIs). Our PubMed-based literature search identified 43 published cases and a 60-patient case series describing invasive fungal infections in patients receiving S1P receptor modulators. Of these, cryptococcosis was the most frequently documented infection, followed by histoplasmosis and coccidioidomycosis. Most published cases involved patients on fingolimod, whereas evidence for the other medications in this class is extremely limited. Currently, there are no standardized fungal screening protocols. A baseline complete blood count with differentials should be obtained before the initiation of S1P receptor modulator therapy. Patients should also be monitored clinically for signs and symptoms of fungal infection. Primary antifungal prophylaxis and routine serum cryptococcal antigen testing are not currently recommended. Management of suspected IFIs should focus on diagnostic workup to identify the causative organism and extent of organ involvement to determine the appropriate antifungal therapy. Decisions regarding interruption or discontinuation of MS therapy should be individualized according to the clinical syndrome, infection severity, and risk of MS rebound. This narrative review synthesizes the available mechanistic and clinical evidence on invasive fungal infections in patients with multiple sclerosis receiving S1P receptor modulator therapy.