Invasive fungal infections in pediatric patients treated with tumor necrosis alpha (TNF‐α) inhibitors

Abstract

Macromolecular immunosuppressive monoclonal antibodies and fusion proteins directed against molecules or cells involved in inflammation and immunity represent a recent and important addition to our therapeutic armamentarium. Tumor necrosis alpha (TNFα) is a cytokine involved in systemic inflammation and clinical utilization of its antagonists has revolutionized treatment of juvenile rheumatoid and psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, and plaque psoriasis. Clinical utility has also been demonstrated for use against steroid-refractory graft-vs-host disease and other immune-mediated conditions. Currently, five anti-TNFα agents are approved by the European Medicines Agency (EMA), including the monoclonal anti-TNF antibodies infliximab, adalimumab, golimumab and certolizumab pegol along with etanercept, a TNFα-receptor/IgG-Fc fusion protein. Theoretical considerations related to their mode of action and clinical observations suggest that opportunistic infectious complications should be seriously considered as possible adverse events of macromolecular immunosuppressants. The purpose of this review is to critically analyze the literature on invasive fungal infections (IFIs) occurring in association with TNFα inhibitors alone or in combination with other immunosuppressive agents, with a focus on pediatric patients, and to provide a framework of evaluating the risk for IFIs in this population.

ESCMID-ECMM guideline: diagnosis and management of invasive aspergillosis in neonates and children

“…Similar incidence rates have been reported among paediatric HSCT patients by other studies [9e13]. The overall case-fatality rates of IA in children with cancer and those receiving a transplant ranges between 20% and 50% but is highly determined by the extent of invasive disease and the severity of immunosuppression [4,14,15]. Incidences of IA range from 26% to 45% in children with chronic granulomatous disease (CGD), and IA is the single most common infectious cause of death [16].…”

Fungal infections in patients with inflammatory bowel disease: A systematic review

“…TNF‐a inhibitors inhibit TNF‐a, a central mediator in immunity with important roles in inflammatory cell migration and maturation, granuloma formation and production of inflammatory cytokines . TNF‐a inhibition increases susceptibility to invasive fungal infection by defects in cellular immune response due to reduced interferon‐γ production, decreased expression of pattern recognition receptors like Toll‐like receptors and leucocyte apoptosis . Even though their mechanism of immunosuppression greatly varies, it involves alteration in intracellular signalling, inhibition of cytokine production and reduced leucocyte adhesion and migration .…”

Inflammatory Cytokines Stabilize SOXC Transcription Factors to Mediate the Transformation of Fibroblast‐Like Synoviocytes in Arthritic Disease

“…Direct targeting of proinflammatory cytokines with biologic compounds is a prevalent strategy in current clinical practice to reduce or delay permanent joint degeneration. This strategy, however, is neither ideal nor sufficient, because global interference with the immune system results in unwanted effects such as development of drug resistance, infections, and cancers . We demonstrated that down‐regulating the expression of SOXC genes in the synovial lining and articular chondrocytes significantly reduced synovitis and articular cartilage erosion.…”