Incidence of histoplasmosis in patients receiving TNF-alpha inhibitors: A systematic review and meta-analysis.

BACKGROUND: Immunobiological drugs such as TNF-α inhibitors are valuable in rescue therapy for autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease (IBD), but they increase the risk of infectious complications. Histoplasmosis is a significant concern in patients living in endemic regions, however, few studies have assessed the incidence of Histoplasma infection during therapy, and classic estimates may underestimate the risk. This study aimed to produce an updated risk estimate of histoplasmosis in patients on TNF-α blocking therapy. METHODS: This is a systematic review and meta-analysis of studies that contain parameters for calculating the risk of histoplasmosis in people who use TNF-α inhibitors, to produce a risk estimate. RESULTS: We identified 11 studies with the necessary parameters for inclusion in the meta-analysis, most of which were from North America. The incidence rate of histoplasmosis found was 33.52 cases per 100,000 patients treated with TNF-ɑ inhibitors (95% CI 12.28-91.46). Considering only studies evaluating monoclonal antibodies, the calculated incidence was 54.88/100,000 patients treated (95%CI 23.45-128.34). In subgroup analysis, the incidence was much higher in patients with IBD compared to rheumatic diseases. There was significant heterogeneity among the studies. CONCLUSION: The risk of histoplasmosis during TNF-α inhibitory therapy may be considerably higher than that found in classical estimates, especially in patients with IBD. There is a lack of studies evaluating histoplasmosis in large endemic areas, such as Central and South America.

A case report of gastrointestinal histoplasmosis in a patient treated with infliximab.

Histoplasmosis is an endemic mycosis in some areas of North and South America. This disease is usually asymptomatic, but it can result in severe and disseminated infection involving gastrointestinal tract, especially in immunocompromised individuals. We report a case of a 33-years-old Ecuadorian male treated with infliximab who developed disseminated histoplasmosis with gastrointestinal affection. Due to the non-specific presentation of gastrointestinal histoplasmosis, the diagnosis is often delayed and it causes poor outcomes. It is important to consider this diagnosis in immunocompromised patients with compatible symptoms, like patients on TNF inhibitors.

Cholestasis and disseminated histoplasmosis in a psoriatic patient on infliximab: case report and review of literature.

BACKGROUND: Histoplasma capsulatum is the most common endemic mycosis in the United States and frequently presents as an opportunistic infection in immunocompromised hosts. Though liver involvement is common in disseminated histoplasmosis, primary gastrointestinal histoplasmosis of the liver in absence of lung involvement is rare. Similarly, cholestatic granulomatous hepatitis in liver histoplasmosis is rarely seen. CASE PRESENTATION: We present a rare case of primary gastrointestinal histoplasmosis manifesting with acute granulomatous hepatitis and cholestasis in a 48-year-old female with psoriatic arthritis, receiving methotrexate and infliximab. The epidemiology, risk factors, clinical presentation, diagnosis, and treatment of histoplasmosis is discussed. Furthermore, we review the published cases of biopsy-proven disseminated histoplasmosis with cholestatic jaundice to highlight histoplasmosis involvement in the liver. CONCLUSION: Histoplasmosis should be considered in immunosuppressed patients with fever, chills, abdominal pain and cholestasis with progressive jaundice, particularly in subjects without evidence of biliary obstruction. Future studies are needed to accurately assess the risk of this fungal infection, specifically in patients on immunomodulatory therapy for autoimmune disease.

A case report of disseminated histoplasmosis and concurrent cryptococcal meningitis in a patient treated with ruxolitinib.

BACKGROUND: Ruxolitinib is a highly potent janus kinase inhibitor that places its users at risk for various bacterial infections and viral reactivation. However new reports are also emerging that suggest greater immunosuppression and risk for fungal disease. CASE PRESENTATION: We report the case of a 51 year-old veteran from Guam, treated with ruxolitinib for polycythemia vera, who developed disseminated histoplasmosis and concurrent cryptococcal meningitis. CONCLUSION: This case draws attention to the degree of immunosuppression that may be seen with this drug and the need for heightened vigilance for opportunistic infections in those treated with inhibitors of janus kinase/signal transducers and activators of transcription (JAK/STAT) such as ruxolitinib.

Histoplasmosis Following Systemic Immunomodulatory Therapy for Ocular Inflammation.

PURPOSE: Histoplasmosis is a known complication of systemic immunosuppressive therapy, particularly among patients who are receiving tumor necrosis factor α inhibitors. There are limited data on the development of disseminated or pulmonary histoplasmosis among patients who are receiving systemic immunosuppressive medication for noninfectious ocular inflammation. DESIGN: Retrospective case series. METHODS: We reviewed all patients with uveitis or scleritis who subsequently developed pulmonary or disseminated histoplasmosis at the Mayo Clinic in Rochester, Minnesota between September 1, 1994 and July 1, 2017, with a 3:1 age- and sex-matched control cohort who did not develop histoplasmosis. This was a single institutional study examining patients that developed histoplasmosis after the initiation of systemic immunomodulatory therapy (IMT). Patients had to develop either disseminated or pulmonary histoplasmosis while receiving systemic immunosuppressive therapy and have an ophthalmic examination at Mayo Clinic Rochester. The control group was comprised of patients who received systemic IMT for ocular inflammation but did not develop histoplasmosis. RESULTS: Nine cases of histoplasmosis were identified: 2 disseminated and 7 pulmonary. Both patients with disseminated histoplasmosis were taking tumor necrosis factor α inhibitors. Seven of the 9 patients received systemic antifungal medication, including both disseminated cases. Over a median follow-up of 4.4 years, none of the patients died, and there were no recurrences of histoplasmosis. When compared to the control cohort, there was no correlation between length of time on IMT and the risk of histoplasmosis. CONCLUSIONS: Ocular inflammation patients on systemic immunomodulatory therapy may develop pulmonary or disseminated histoplasmosis. Most cases require treatment with systemic antifungal medication, but it might not be necessary to stop systemic immunomodulatory medication for ocular inflammation. Ophthalmologists should be aware that patients receiving systemic immunomodulatory therapy have a higher risk of developing Histoplasma infections. Prompt diagnosis and treatment using the expertise of an infectious diseases specialist may ensure low mortality for these patients.

A Case of Disseminated Histoplasmosis in a Patient with Rheumatoid Arthritis on Abatacept.

Biologic agents are effective treatments for rheumatoid arthritis but are associated with important risks, including severe infections. Tumor Necrosis Factor (TNF) α inhibitors are known to increase the risk of systemic fungal infections such as disseminated histoplasmosis. Abatacept is a biologic agent with a mechanism different from that of TNFα inhibitors: It suppresses cellular immunity by competing for the costimulatory signal on antigen-presenting cells. The risk of disseminated histoplasmosis for patients on abatacept is not known. We report a case of abatacept-associated disseminated histoplasmosis and review the known infectious complications of abatacept. While the safety of resuming biologic agents following treatment for disseminated histoplasmosis is also not known, abatacept is recommended over TNFα inhibitors for rheumatoid arthritis patients with a prior serious infection. We discuss the evidence supporting this recommendation and discuss alternative treatments for rheumatoid arthritis patients with a history of a serious infection.

Opportunistic Infections in Biological Therapy, Risk and Prevention.

Patients being treated with biological therapies are at increased risk for serious infections, including opportunistic infections. Although more is known about opportunistic infection risk with older biologics, such as antitumor necrosis factor drugs, there is less knowledge of opportunistic infection risk with newer biological therapies. The incidence of certain opportunistic infections (tuberculosis, herpes zoster, pneumocystosis) has been rigorously evaluated in large observational studies. However, data are more limited for other infections (histoplasmosis, nontuberculous mycobacteria). Infectious morbidity and mortality may be preventable with screening and prophylaxis in select populations.

Proactive infectious disease approach to dermatologic patients who are taking tumor necrosis factor-alfa antagonists: Part I. Risks associated with tumor necrosis factor-alfa antagonists.

Tumor necrosis factor-alfa levels are linked to disease severity in patients with inflammatory conditions, such as psoriasis. Inhibitors of this cytokine are commonly used with significant success in the treatment of such inflammatory disorders. Their use, however, can be plagued by infectious complications. An awareness of potential infections associated with these therapies is critical in order to maximize preventive efforts both before and during therapy. This review provides a guide for dermatologists caring for patients in need of this type of biologic therapy to preemptively address the infectious risks. Part I of this continuing medical education article reviews background information on the various infectious risks associated with tumor necrosis factor inhibitor therapy and appropriate historical data to obtain in the context of pretherapy evaluations.

Proactive infectious disease approach to dermatologic patients who are taking tumor necrosis factor-alfa antagonists: Part II. Screening for patients on tumor necrosis factor-alfa antagonists.

Tumor necrosis factor-alfa levels are linked to disease severity in patients with inflammatory conditions, such as psoriasis. Inhibitors of this cytokine are commonly used with significant success in the treatment of such inflammatory disorders. Their use, however, can be plagued by infectious complications. An awareness of potential infections associated with these therapies is critical in order to maximize preventive efforts both before and during therapy. This review provides a guide for dermatologists caring for patients in need of this type of biologic therapy to preemptively address the infectious risks. Part II of this continuing medical education article reviews recommended screening methods for patients undergoing evaluations for tumor necrosis factor inhibitor therapy for psoriasis or other dermatologic diseases, and discusses possible prophylactic strategies to use, including the appropriate use of immunizations.

Hepatitis and pneumonitis during adalimumab therapy in Crohn disease: mind the histoplasmosis!

CONTEXT: Tumor necrosis factor-alpha (TNF-α) inhibitor therapy plays a pivotal role in the management of moderate to severe inflammatory bowel disease. Because of the role of TNF-α in the host defenses, anti-TNF therapy has been associated with an increase the risks of granulomatous infections. OBJECTIVE: To report the first case of adalimumab-associated invasive histoplasmosis presenting as an acute hepatitis-like syndrome and febrile pneumonitis in a patient with Crohn's disease. METHOD: Case report of a patient with progressive histoplasmosis confirmed by percutaneous fine needle aspiration biopsy lung and urine Histoplasma antigen. RESULTS: We present the case of a young man with CD who developed pneumonia and acute hepatitis-like features caused by Histoplasma capsulatum infection during adalimumab therapy. To the best of our knowledge, this acute hepatitis-like manifestation has never been reported as a presentation of the histoplasmosis in patients with Crohn's disease. CONCLUSIONS: This case underscores the potential risk for serious infection that may arise in this setting and should alert clinicians to the need to consider the histoplasmosis diagnosis in patients presenting with acute hepatitis-like syndrome associated with prolonged febrile illness or pneumonitis during therapy with anti-TNF-α antibodies.

Acute pulmonary histoplasmosis in a patient with uveitis after infliximab therapy.

The purpose of this study is to report a case of disseminated histoplasmosis in a patient with uveitis, after treatment with infliximab. The method employed in this study is single case report. Infliximab can be useful in controlling idiopathic uveitis, but can give rise to disseminated histoplamosis, especially in patients living in geographic areas where histoplasmosis is endemic. Clinicians should be aware of the possibility of rapid onset histoplasmosis in patients receiving anti-tumor necrosis factor agents. In such cases, these agents should be immediately stopped, investigations performed, and appropriate treatment started.

Infliximab-induced disseminated histoplasmosis in a patient with Crohn's disease.

BACKGROUND: A 56-year-old female with a 30-year history of ileocolic Crohn's disease presented with a 1-month history of bloody diarrhea and decreased caliber of stools; physical examination revealed a broad indurated anal fissure. The patient had been receiving antimetabolite therapy with 6-mercaptopurine and maintenance therapy with infliximab for over a year. INVESTIGATIONS: Physical examination; proctoscopy; perianal and anal canal biopsy; chest CT; blood and stool analysis, measurement of serum histoplasmosis antibodies and urine histoplasmosis antigen levels; fungal culture and Gomori's methenamine silver staining of resected tissue specimens. DIAGNOSIS: Disseminated histoplasmosis. MANAGEMENT: Proctocolectomy and end ileostomy followed by treatment with liposomal amphotericin and then oral itraconazole. A palmar space abscess required multiple debridements, and a muscle flap to cover the defect.

Reactivation histoplasmosis after treatment with anti-tumor necrosis factor alpha in a patient from a nonendemic area.

Histoplasma capsulatum (HC) is a thermally dimorphic ascomycete that is a significant cause of respiratory infections (>80%) in endemic areas (Midwest and southeast USA), but infections are rare in non-endemic areas. Most primary HC infections are subclinical or self-limited. While reactivation Histoplasmosis has been reported in the setting of immunosuppression, it remains unclear whether remote primary latent infection represents risk of endogenous reactivation after anti-tumor necrosis factor (TNF)-alpha therapy. We report a case of a patient who developed reactivation Histoplasmosis after receiving anti-TNF-alpha. To our knowledge, this is the first clear report of reactivation of "latent" Histoplasmosis after anti-TNF-alpha therapy.

Serious infections associated with anticytokine therapies in the rheumatic diseases.

The ability to target and neutralize macrophage-derived inflammatory cytokines, particularly tumor necrosis factor-alpha (TNF-alpha), has emerged in recent years as one of the most important advances in the treatment of rheumatoid arthritis, Crohn's disease, and several other systemic inflammatory diseases. In rheumatoid arthritis, for example, these biological agents rapidly reduce signs and symptoms of joint inflammation and profoundly slow the progression of joint damage. However, data that have emerged following Food and Drug Administration approval of these agents have alerted clinicians to an increased likelihood of opportunistic infections in patients treated with these agents, particularly tuberculosis. The effect of TNF inhibition on the frequency of infection with more common bacterial pathogens is less clear. Animal models of tuberculosis and other opportunistic infections have demonstrated the importance of TNF-alpha in controlling and containing intracellular pathogens. The spectrum of infections reported to date in the setting of anti-TNF-alpha treatment is reviewed here. In addition, relevant animal data illustrating potential mechanistic roles for TNF-alpha in host responses to infection are also reviewed.

Histoplasmosis after treatment with anti-tumor necrosis factor-alpha therapy.

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.