Wallis and colleagues  conducted a large systematic review to identify granulomatous disease in coincidence with TNF-a inhibition. In addition to TB, several endemic and opportunistic fungal infections were identified: systemic candidiasis, histoplasmosis, coccidioidomycosis, Cryptococcus, and aspergillosis and other bacterial and mycobacterial pathogens. The incidence of these granulomatous infections was found to be greater than two times higher (P < .0001) with infliximab than with etanercept and reported in the first 3 months after initiation of treatment. As with TB, in mycotic infection, TNF inhibition interferes with granuloma formation and apopto-sis of infected macrophages occurs, which undermines the host's ability to protect against disseminated infection. Beaman  demonstrated that TNF-a potentiates antifungicidal capability of human monocytes. Active discovery and dialog are needed to establish screening and empiric treatment guidelines.
Coccidioidomycosis is caused by a dimorphic fungus existing as a mold in soil and dust and is endemic to the southwestern United States and Mexico.
Its spores are aerosolized by occupational and recreational disruption of soil with transmission occurring by inhalation. It causes potentially fatal illness presenting as a flulike illness or pneumonia with fever, cough, headaches, rash, and myalgia. Immunocompromised patients may fail to recover developing chronic pulmonary infection or widespread disseminated infection with central nervous system involvement potentially leading to permanent neurologic damage.
Through a retrospective comparative study of five rheumatology practices and one medical center in areas endemic for coccidioidomycosis, Bergstrom and colleagues  demonstrated statistically significant increased risk of patients with inflammatory arthritis being treated with anti-TNF-a agents (P %.01). From 1998 to 2003 (57 months), 13 symptomatic cases were identified. Twelve cases involved infliximab with onset 2 to 48 weeks from initiation of treatment and one etanercept case with onset at 96 weeks. None of these patients had comorbid conditions that might put them at higher risk, such as HIV, diabetes, or pregnancy. All patients were on meth-otrexate and one patient was on prednisone and cyclosporine. Before TNF inhibition, two patients had a previous history of coccidioidomycosis, 12 patients had normal pretreatment chest radiographs, no patient had documentation of skin manifestations, and six patients had documentation of negative serology, which confounds arguments that the initial presentation to rheumatology was for an acute primary infection of coccidioidomycosis causing "desert arthritis'' mistaken for RA. Two deaths were identified, one of which was caused by posthumous recognition of the pathogen in which antifungal treatment was never initiated. This particular case illustrates the imperative nature in maintaining a high index of suspicion and obtaining thorough birth and travel histories. The findings of Bergstrom and colleagues  are corroborated by a greater than six times increased risk established by Wallis and colleagues  (P = .013) using completely different methods of investigation.
Suggested preventive measures are screening history for residence in endemic areas, central nervous system infections, and chest radiograph and consideration of serology testing of IgM and IgG and then again every 3 months. Patient education regarding transmission and symptoms should be conducted . History of meningitis in an endemic area or a suggestive history demands vigilance. Screening serology by some transplant centers is performed in endemic areas. A positive screening results in fluconazole prophylaxis . Active disease warrants discontinuation of TNF inhibition keeping in mind that relapse rate of disease is high on discontinuation of antifungals .
Histoplasmosis, another life-threatening infection to which patients under TNF inhibition are potentially predisposed, is one of the most prevalent mycoses in the United States with the most highly endemic areas being in the Ohio and Mississippi River valleys. Transmission is by inhalation of spores with disruption of soil containing contaminated bird or bat droppings.
Histoplasmosis infection is often asymptomatic in presentation and self-limited. Immunocompromised people are at higher risk of becoming symptomatic, however, and may succumb to substantial morbidity with disseminated disease [5,55-57]. TNF-a is important in both primary and secondary histoplasmosis infection. Inhibition of TNF-a in mouse models conferred 100% mortality with coincident histoplasmosis infection .
By May 2002, 22 acute life-threatening cases were identified in the United States by the FDA AERS  and by September 2002, 40 cases were further identified . Four remarkable cases were additionally described in the literature [5,56]. These cases illustrate the vast potential for underestimation of postmarketing surveillance because correspondence with the authors suggests these cases were unlikely to have been reported to AERS. Initial presentation was predominantly fever, malaise, weight loss, and cough, with pulmonary nodules or diffuse interstitial pneumonitis, thrombocytopenia, neutropenia, and pancytopenia. Presentation was exceptional in one patient who presented with granulomatous hepatitis. Five patients of the 22 cases reported by May died. Wallis and colleagues  established a greater than seven times increased risk (P < .001) with infliximab over etanercept.
Suggested screening in patients with history of residence in endemic areas is a chest radiograph with urine histoplasmin antigen at baseline and every 3 months [48,56]. If active histoplasmosis is identified, anti-TNF-a treatment should cease. Pre-emptive or reinitiated treatment during TNF inhibition should be considered with suggestive history . Patients should be counseled on activities associated with transmission of disease (exploring caves, cleaning chicken coops, shifting soil). Further investigation is needed in this area to formulate guidelines.
Aspergillosis presents on a spectrum of allergic in the immunocompetent to invasive in the immunocompromised, which is often fatal. Aspergillus sp. is ubiquitous and is transmitted to human hosts by inhalation of spores found on dead or decaying leaves and vegetation, compost, or grain. Development of serious disease is extremely uncommon in immunocompetent people. In mouse models, TNF-a prevents dissemination from lungs to vital organs and mortality, which otherwise was shown to be >40% and 0% in noninhibited mice . TNF-a seems to enhance an early event in host defense system against invasion by Aspergillus and a late event via superoxide anion production resulting in hyphal damage and destruction .
In 2001, three cases of invasive aspergillosis associated with TNF-a inhibition were reported. The first case was a young man with fistulizing Crohn's disease who developed symptoms of high fever, productive cough, and dyspnea 5 days following initial intravenous infusion of infliximab without other immunesuppressants. Massive bilateral infiltrates were found on chest radiograph, he died 1 month later of multiorgan failure and septic shock. Despite antifungal treatment, serial cultures and autopsy revealed invasive growth of Aspergillus fumigatus . The second case was a 73-year-old woman with chronic obstructive pulmonary disease and 10-year history of RA with recent initiation of infliximab, fluctuating doses of prednisone (5-10 mg), and leflu-nomide. Two months after initiation she was treated for right upper lobe pneumonia discovered on chest radiograph. Another 2 months later she presented afebrile with cough productive of white clumps and recent 20-lb weight loss. Obstructive right upper and middle lobe infiltrates were found on CT of chest and bronchoscopy revealed A fumigatus . The third case reported involved a 55-year-old woman with a 10-year history of RA being treated with etanercept and 5-mg prednisone daily for 10 months when she presented with high fever, dyspnea, and productive cough and ultimately respiratory failure and pneumopyothorax. Bronchoscopy revealed A fumiga-tus . By September 2002, there were 30 cases of aspergillosis (20 inflixi-mab, 10 etanercept) reported without clinical description. Although more cases of infliximab were reported, this was not statistically significant . Subsequently, a case has been reported with aspergillosis, disseminated TB, and cutaneous herpes simplex infection during treatment of RA with infliximab and methotrexate .
Marty and colleagues  discovered a significantly increased risk of invasive fungal infection (adjusted P = .004) in patients treated with infliximab for severe graft-versus-host disease after bone marrow transplantation. Prophylaxis against filamentous fungi is strongly suggested in this scenario. De Rosa and colleagues  suggest adherence to use of masks in high-risk patients when in close proximity to construction.
Cryptococcal infection is transmitted by inhalation of yeast or spores from soil or dust with contaminated bird droppings. The most common presentation is with pneumonia or disseminated disease with central nervous system involvement. Cryptococcus sp. is encapsulated yeast with worldwide distribution. Infection carries an overall mortality rate of 12% and permanent neurologic damage can ensue after resolution of infection . Mouse models reveal inhibition of TNF-a preventing pulmonary clearance of Cryp-tococcus neoformans .
Wallis and colleagues  found 19 cases of Cryptococcus infection in association with TNF-a blockade. Subsequently, there have been five additional [48,67-70] case reports published, one of which describes possible zoonotic transmission from a pet bird . All cases were associated with infliximab with onset from time of treatment being 3 to 5 weeks. Wallis and colleagues  found no significant increase of cryptococcal infection between infliximab and etanercept. It is important to recognize that invasive cryptococcal disease can occur with negative cerebrospinal fluid or serum cryptococcal antigen and culture as supported by two case reports [67,68] and a high index of suspicion is critical for prevention of devastating sequelae . There is no discussion of preventive guidelines found on review of literature. It seems a reasonable approach to treat patients with a history of cryptococcal infection with suppressive antifungal therapy during TNF blockade as done in AIDS treatment protocol.
Pneumocystis pneumonia is caused by a ubiquitous fungus Pneumocystis jiroveci (formerly carinii). This pathogen is of no consequence in healthy individuals. In patients who are immunocompromised, however, illness begins insidiously with dry cough and flulike symptoms leading to dyspnea at rest, rapidly leading to respiratory failure and death. Only 12 cases of P jiroveci pneumonia have been described with methotrexate alone since the advent of its use . By June 2001, there were at least 15 cases associated with anti-TNF-a therapy. Ten of these cases were with infliximab onset being between one and three doses with three deaths (one United States). Eight cases were with etanercept time to onset being 1 to 4 months with three deaths (all United States) . HIV status was either reported as negative or not commented on. There were six apparently additional cases published worldwide associating P jiroveci pneumonia with infliximab use [73-78]. In vitro and mouse studies suggest TNF blockade prevents both clearance and control of the pneumocystis organism by the host defense system and results in more severe infection [79-81].
Some experts encourage evaluation for prophylaxis on an individual basis considering lymphocyte count and dose and duration of immunosuppressant treatment [32,77]. Prophylaxis is with TMP-SMX or dapsone, atovaquone, or inhaled pentamidine if allergic to sulfa. There is a paucity of data at this time for formal recommendations.
Although there is a paucity of description in the literature of biologic associated candidiasis , Wallis and colleagues  quantify almost a fivefold increase in systemic Candida with infliximab over etanercept (P = .046) and 2.3 increase with any candidial presentation (P = .006) in the United States. TNF knockout mice had increased susceptibility to both oral and systemic candidiasis . This is an area requiring further investigation.
Other fungal and protozoal pathogens have been associated with TNF-a inhibition in case reports, such as disseminated sporotrichosis , toxoplasmosis , and a fatal case of myositis involving Brachiola algerae via mosquito vector .
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