Fungal infection risks associated with the use of cytokine antagonists and immune checkpoint inhibitors

Abstract

The revolutionary success of biologic agents in treating various malignant and autoimmune conditions has been met with increased risk of opportunistic infections due to perturbations in immunity. In patients receiving biologic-containing regimens, the risk of fungal infection is less well-understood, and there is a lack of established guideline on the standard of care in terms of screening and prophylaxis. In this article, we reviewed the risk of fungal infections associated with cytokine antagonists, including anti-tumor necrosis factor (TNF) agents and interleukin (IL) antagonists, and immune checkpoint inhibitors. The risk of fungal infection in this group of patients is drug-, pathogen-, host-, and context-dependent. Among the biologic agents reviewed, anti-TNF agents are associated with highest number of reported cases of fungal infection, especially histoplasmosis. In fact, infection due to all dimorphic fungi except Talaromyces marneffei have been reported in patients receiving TNF-α inhibitors, despite their widespread use in T. marneffei-endemic regions. The risk is higher with TNF-α inhibitors that block both the membrane-bound and soluble forms of TNF-α, i.e., infliximab and adalimumab, compared with etanercept which inhibits the soluble form only. In addition to the preferential suppression of Th1 pathway and granuloma formation leading to genuinely higher risk of infection, the longer history and extensive use of infliximab coupled with the endemicity of histoplasmosis in the United States lead to an apparent increase in reported cases. IL-17 antagonists lead to a moderate increase in mucocutaneous candidiasis, but not the risk of life-threatening mycosis, consistent with the essential role of Th17 cells in mucosal defense. Immune checkpoint inhibitors, on the other hand, do not significantly increase the risk of invasive fungal infections when used alone and may even be of therapeutic value in the treatment of severe and refractory mycosis.

Impact statement

The risk of opportunistic infections due to fungi is relatively less well addressed in patients receiving biologic agents, compared with other opportunistic bacterial and viral infections. There is a lack of consensus guideline on the screening, prophylaxis, and management of fungal infection in patients anticipated to receive or actively receiving biologic therapy. In addition, invasive mycosis in immunocompromised patients is associated with high mortality and morbidity. This review highlighted the risk of fungal infection in patients receiving cytokine antagonists and immune checkpoint inhibitors, two big categories of biologic agents that are widely used in the treatment of various autoimmune and malignant conditions, often in combination with other immunomodulatory or immunosuppressive agents but also as standalone therapy. The adverse outcomes of opportunistic fungal infection in these patients can be reduced by heightened awareness, active case finding, and prompt treatment.