The Food and Drug Administration (FDA) has directed the manufacturers of the four tumor necrosis factor (TNF)-[alpha] blockers-adalimumab (Humira), certolizumab pegol (Cimzia), etanercept (Enbrel), and infliximab (Remicade)-to strengthen the product label warnings indicating that the drugs can increase the risk of serious opportunistic fungal infections. TNF-[alpha] blockers prevent the inflammatory and immune responses that normally occur as a result of endogenous TNF cytokine activity. They are approved for use in a variety of conditions, including rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, plaque psoriasis, ankylosing spondylitis, and Crohn's disease, in which TNF stimulation is a significant cause of both pathologic inflammation and joint destruction. The FDA evaluated 240 reports of a serious fungal infection called histoplasmosis in patients taking adalimumab, etanercept, and infliximab. Environmental factors appear to play a part because the majority of the patients were from the Ohio River and Mississippi River valleys, where the fungus is common. (Histoplasmosis is also called Ohio River Valley fever, and it is most common in the southeastern, mid-Atlantic, and central United States.) One case of histoplasmosis occurred with certolizumab pegol. Other fungal infections (coccidioidomycosis and blastomycosis) were also reported.

Histoplasmosis, caused by the inhalation of airborne particles of the Histoplasma capsulatum fungus from the soil where it grows, can produce no symptoms, or it can present as an acute illness with fever, chills, cough, and chest pain upon inhalation; a chronic illness with cough, shortness of breath, chest pain, fever, excessive sweating, and hemoptysis (symptoms that are similar to those of pulmonary tuberculosis); or a disseminated illness with fever, headache, stiff neck, skin lesions, and mouth sores. TNF-[alpha] blockers suppress the immune system's ability to defend against the fungi, leaving those taking them at greater risk for histoplasmosis, including the disseminated form of the infection, in which the blood, meninges, adrenal glands, and other organs can be involved. Histoplasmosis also can produce joint pain, skin nodules, and rash. The labeling of the drugs has always included a black box warning indicating the risk of serious, sometimes fatal, infections, including fungal infections, but its emphasis on the risk of tuberculosis has led to delayed recognition and treatment of histoplasmosis, according to the FDA.

Nurses should carefully assess for cough and shortness of breath, persistent fever, fatigue, and exacerbated joint pain in patients taking any of the TNF-[alpha] blockers. They should evaluate for histoplasmosis any patients presenting with these symptoms who live in or have recently visited areas in which histoplasmosis is common. Affirmative assessment findings warrant a complete workup for histoplasmosis, and a confirmed diagnosis will most likely mean patients will have to stop taking the drug until the infection is treated. Nurses should warn patients taking TNF-[alpha] blockers and their families of the risk of fungal infections and their symptoms and instruct them to carefully read the medication guide that accompanies filled prescriptions for TNF-[alpha] blocker drugs.

FDA: manufacturers of TNF-blocker drugs must highlight risk of fungal infections [press release]. FDA News 2008 Sep 14. http://www.fda.gov/bbs/topics/NEWS/2008/NEW01879.html.