WASHINGTON — Coccidioides species represent a serious threat to patients taking tumor necrosis factor-α inhibitors, Dr. Andrew Racette said at the annual meeting of the American Academy of Dermatology.
Drugs that inhibit tumor necrosis factor-α (TNF-α) are very effective in treating inflammatory rheumatic and autoimmune diseases, but also decrease resistance to granulomatous pulmonary infections, particularly tuberculosis (Clin. Infect. Dis. 2004;38:1261–5).
However, less information has been published about patients receiving TNF-α inhibitor therapy who develop pulmonary infections caused by Coccidioides, a fungus endemic to the southwestern United States. While most TB cases seen in patients taking TNF-α inhibitors are reactivations of quiescent disease, most of the coccidioidomycosis infections in these patients appear to be new primary infections, said Dr. Racette, a second-year dermatology resident at Western University of Health Sciences, Phoenix.
A total of 31 patients who developed coccidioidomycosis infections while taking TNF-α inhibitors were identified via questionnaires sent to rheumatologists and dermatologists in the Phoenix area. Fourteen were taking infliximab, 10 etanercept, and 7 adalimumab. At the time they developed their infection, 25 were taking other concurrent immunosuppressive medications, including methotrexate, prednisone, and leflunomide. Six patients—four on etanercept and one each on infliximab and adalimumab—were on no other medications.
The patients had a mean age of 57 years (range 29–80) and an average time to infection of 21 months (range 2–73). Most (21) were being treated for rheumatoid arthritis, 3 for psoriatic arthritis, 2 for psoriasis, and 1 patient each for other disorders including ankylosing spondylitis, gout, and Crohn's disease.
Only 1 of 31 patients had a known cocci infection prior to initiating TNF-α inhibitor treatment. Of 20 patients who had chest x-rays prior to treatment, two had abnormal results (left upper lung nodules). Of 17 who had serologies prior to TNF-α inhibitor treatment, all were negative.
The most common presenting symptoms were cough (61%), fever (48%), and fatigue (29%). A nonspecific rash was present at diagnosis in 26%, while another 26% were asymptomatic. The diagnosis was made by serology alone in 17 patients and by pathologic evidence (culture, cytopathology, or biopsy) in the other 14.
All but one were treated with fluconazole 200 mg twice daily (orally for outpatients and intravenously for inpatients). Intravenous amphotericin B was given to patients in the ICU, while one outpatient and one inpatient received voriconazole.
After the infection resolved, 12 patients restarted their medication—6 on infliximab, 3 on etanercept, and 3 on adalimumab. Of those, there was one recurrence of coccidioidomycosis infection, in a patient who was taking etanercept 25 mg twice weekly, prednisone 7 mg/day, and fluconazole 200 mg twice daily who later died of respiratory failure. Eight patients were hospitalized for their infections, three had dissemination of disease, three were treated in the ICU with intubation and mechanical ventilation, and two died.
Based on this case series and published literature, the following recommendations can be made for managing patients living in the southwestern United States who are going to be starting TNF-α inhibitors and those who are already on them, Dr. Racette said:
▸ Do pretreatment screening. This should include a history of prior coccidioidomycosis infection and work environment. Patients who work outdoors are at increased risk. A chest x-ray and Coccidioides serologies should be done to rule out any asymptomatic infection that likely would be exacerbated by the TNF-α inhibitor.
▸ Monitor patients during therapy. This includes asking the patient about cough, fever, and fatigue at each visit. A physical exam also should be performed. Annual chest x-rays and cocci serologies may be worthwhile in higher-risk groups, such as elderly patients and those who work outside, but more data are needed, he said.
▸ Decide whether to resume TNF-α therapy. This is debatable because of the risk for reactivation. It may be safe if patients continue fluconazole and as long as their complement fixation titer remains negative. Surveillance every 2–3 months is key.