Histoplasmosis after Treatment with Anti–Tumor Necrosis Factor-α Therapy

Abstract

Anti-tumor necrosis factor-alpha (TNF-alpha) antibodies are frequently used to treat inflammatory diseases. However, these drugs also have immunosuppressive effects. We report on three patients who developed disseminated histoplasmosis on therapy with TNF-alpha inhibitors. In vitro assays were used to characterize the role of these agents in host defense against Histoplasma capsulatum. Intracellular proliferation of H. capsulatum was measured in alveolar macrophages and peripheral monocytes of normal volunteers in the presence and absence of the TNF-alpha antibody, infliximab. Both infliximab and control antibody enhanced fungal growth in monocytes and alveolar macrophages, suggesting this was a nonspecific antibody response. Despite similar intracellular fungal loads in the presence of both antibodies, lymphocyte proliferation in response to blood monocytes and alveolar macrophages infected with H. capsulatum was inhibited by the addition of physiologic doses of infliximab, whereas control antibody had no effect. The production of H. capsulatum-induced interferon-gamma and TNF-alpha was assessed in 5-day cultures containing lymphocytes and alveolar macrophages or monocytes. Interferon-gamma secretion was significantly reduced in the presence of infliximab. In summary, patients receiving anti-TNF-alpha therapy are at risk for developing disseminated histoplasmosis. This may be due to a defect in the TH1 arm of cellular immunity.

Characterization of theHistoplasma capsulatum-Induced Granuloma

“…9A) and the absence of anti-CD3-induced TNF-␣ production (Table I) show that the primary cellular source of TNF-␣ is the macrophage, and T cells contribute little if any to local TNF-␣ levels. Therapeutic anti-TNF-␣ treatments induced reactivation of latent H. capsulatum infection in some patients, emphasizing the role of this mediator in control of the yeast and preventing dissemination (8,10,61). The granuloma has strong Th1-type and very little Th2-type cytokine activity (Table I).…”

Dendritic cell interactions withHistoplasmaandParacoccidioides

“…While the disease course is typically indolent in immunocompetent hosts, it is more likely to be severe in immunocompromised individuals such as patients with advanced HIV infection, hematologic malignancies or those receiving chemotherapy, corticosteroids or anti-TNF-a therapies. [31][32][33] A high inoculum can cause life-threatening disease in immunologically intact individuals. 34 Hence, the spectrum of disease manifestations range from asymptomatic to an acute respiratory illness with flu-like symptoms to life-threatening disseminated disease with high fever and respiratory compromise 30,31,35 The infection is acquired via inhalation of microconidia or small mycelial fragments into the terminal bronchioles and alveoli where the fungus transform into its yeast phase.…”

TNFα blockade in human diseases: Mechanisms and future directions

“…Studies in animal models demonstrate that TNFα plays a critical role in defense against infections due to histoplasma, cryptococcus, coccidiodes, candida, aspergillus and pneumocystis [87][88][89]. Studies in three patients with histoplasmosis associated with INF use showed that INF interfered with the host's helper T cell response to histoplasma antigens [90].…”