Fungal Infections Complicating Tumor Necrosis Factor α Blockade Therapy

Abstract

Tumor necrosis factor α (TNF-α) blockade has emerged as a useful therapy for collagen vascular diseases or graft-vs-host disease. Fungal infections complicating such therapy have been reported sporadically. MEDLINE and PubMed databases (from January 1, 1966, to June 1, 2007) were searched for reports of invasive fungal infections (IFIs) associated with the 3 available anti-TNF-α agents, ie, infliximab, etanercept, and adalimumab. Of the 281 cases of IFI associated with TNF-α inhibition, 226 (80%) were associated with infliximab, 44 (16%) with etanercept, and 11 (4%) with adalimumab. Fungal infections associated with infliximab occurred a median of 55 days (interquartile range [IQR], 15-140 days) after initiation of therapy and 3 infusions of the medication (IQR, 2-5), whereas those associated with etanercept occurred a median of 144 days (IQR, 46-240 days) after initiation of therapy. The median age of patients was 58 years (IQR, 44-68 years), and 62% were male. Use of at least 1 other immunosuppressant medication, typically a systemic corticosteroid, was reported during the course of the fungal infection in 102 (98%) of the 104 patients for whom data were available. The most prevalent IFIs were histoplasmosis (n=84 [30%]), candidiasis (n=64 [23%]), and aspergillosis (n=64 [23%]). Pneumonia was the most common pattern of infection. Of the 90 (32%) of 281 cases for which outcome information was available, 29 fatalities (32%) were recorded. Tumor necrosis factor α blockade is associated with IFI across a range of host groups. A high index of suspicion in patients treated with TNF-α antagonists is recommended because the course of such infections can be serious or fulminant, and rapid access to health care should be provided. Surveillance of IFIs complicating TNF-α blockade and other biologic therapies is warranted through well-organized prospective patient registries. Tumor necrosis factor α (TNF-α) blockade has emerged as a useful therapy for collagen vascular diseases or graft-vs-host disease. Fungal infections complicating such therapy have been reported sporadically. MEDLINE and PubMed databases (from January 1, 1966, to June 1, 2007) were searched for reports of invasive fungal infections (IFIs) associated with the 3 available anti-TNF-α agents, ie, infliximab, etanercept, and adalimumab. Of the 281 cases of IFI associated with TNF-α inhibition, 226 (80%) were associated with infliximab, 44 (16%) with etanercept, and 11 (4%) with adalimumab. Fungal infections associated with infliximab occurred a median of 55 days (interquartile range [IQR], 15-140 days) after initiation of therapy and 3 infusions of the medication (IQR, 2-5), whereas those associated with etanercept occurred a median of 144 days (IQR, 46-240 days) after initiation of therapy. The median age of patients was 58 years (IQR, 44-68 years), and 62% were male. Use of at least 1 other immunosuppressant medication, typically a systemic corticosteroid, was reported during the course of the fungal infection in 102 (98%) of the 104 patients for whom data were available. The most prevalent IFIs were histoplasmosis (n=84 [30%]), candidiasis (n=64 [23%]), and aspergillosis (n=64 [23%]). Pneumonia was the most common pattern of infection. Of the 90 (32%) of 281 cases for which outcome information was available, 29 fatalities (32%) were recorded. Tumor necrosis factor α blockade is associated with IFI across a range of host groups. A high index of suspicion in patients treated with TNF-α antagonists is recommended because the course of such infections can be serious or fulminant, and rapid access to health care should be provided. Surveillance of IFIs complicating TNF-α blockade and other biologic therapies is warranted through well-organized prospective patient registries. 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In the largest series of granulomatous infections complicating TNF-α blockade reported to date, several fungal infections were described without further details about the clinical course of the patients.58Wallis RS Broder MS Wong JY Hanson ME Beenhouwer DO Granulomatous infectious diseases associated with tumor necrosis factor antagonists.Clin Infect Dis. 2004 May 1; 38 (Epub 2004 Apr 15.): 1261-1265Crossref PubMed Scopus (496) Google Scholar This series could have been biased, as the authors admit, by potential overreporting or underreporting of events, unconfirmed diagnoses, absence of a control population, and imprecise calculations of event rates. This review focuses on available published data about fungal infections complicating anti-TNF-α therapy with an emphasis on pathogenesis and clinical information. The MEDLINE and PubMed databases (from January 1, 1966, to June 1, 2007) were searched for reports of invasive fungal infections (IFIs) associated with TNF-α blockade. The terms infliximab, etanercept, and adalimumab were used along with terms describing specific IFIs, ie, Molds, Mould, Aspergillus, Aspergillosis, zygomycetes, zygomeces, zygomycosis, mucormycosis, yeast, Candida, Candidiasis, Cryptococcus, Cryptococcosis, tinea, endemic fungi, blastomyces, blastomycosis, coccidioides, coccidioidomycosis, Histoplasma, histoplasmosis, Sporothrix schenckii, and sporotrichosis. All identified articles were reviewed as well as articles identified through the search that describe the effects of TNF-α inhibition on immune function, especially as these effects concerned immunity against fungal pathogens. Further, current knowledge about fungal pathogen-associated immunity was reviewed to identify areas where TNF-α inhibition is important. Fungal infections described were grouped by major category, ie, molds, yeasts, and IFIs caused by endemic and dimorphic fungi. Pneumocystis jiroveci pneumonias (PCPs) were excluded. 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