A black box warning was issued by the FDA in 2008, after reviewing 240 reports of histoplasmosis in patients treated with TNF-α inhibitors, most from areas where H capsulatum is endemic, and in at least 21 of these reported cases the infection was not diagnosed until a late stage.[36] Even though these studies were valuable in establishing the notion of a higher risk for histoplasmosis in patients on TNF-blocking therapy, most subsequent publications do not provide all the data that would allow the calculation of an incidence rate. The gene discussed is TNF; the disease is infection.