Drug for Fungal Infections in Lung Transplant Recipients Increases Risk for Skin Cancer, Even Death

Their study appears online Sept. 3, 2015, in the American Journal of Transplantation.

“It is important for physicians to be aware of the impact of voriconazole on these outcomes,” said senior author Sarah Arron, MD, PhD, associate professor of dermatology and director of the UCSF High Risk Skin Cancer Clinic. “We recommend that all providers counsel lung transplant recipients on skin cancer risk and photoprotection in addition to scheduling routine skin cancer screening with a trained dermatologist after transplantation. Lung transplant programs should also consider patient-specific risk factors when deciding on the type, dose and duration of antifungal prophylaxis regimens.”

Skin cancer is the most common malignancy following solid organ transplants, primarily due to immunosuppression, with recipients experiencing a greater than 65-fold increased risk of developing cutaneous squamous cell carcinoma (SCC) compared to the general population. These carcinomas are aggressive and can lead to numerous lesions, resulting in multiple debilitating surgeries and increased risk of death.

Lung transplant recipients are particularly susceptible to SCC due to older age at transplant and more intensive immunosuppression. They also have high rates of fungal infections after transplant, which can result in significant morbidity and mortality.

First approved in 2002, voriconazole is used to prevent and treat invasive fungal infections like those caused by the Aspergillus fungi, especially in patients with compromised immune systems such as following a lung or other organ transplant. The Aspergillus fungi can cause aspergillosis, a variety of diseases often occurring in people with healthy immune systems but having an underlying illness such as tuberculosis or chronic obstructive pulmonary disease (COPD).

However, SCC is a serious side effect of voriconazole, which has no clear guidelines for prophylaxis regimens despite its widespread use.

In their study, Arron and her colleagues evaluated all UCSF single-lung, double-lung or heart-lung transplant recipients receiving a transplant between October 1991 and December 2012. These 455 individuals were analyzed for voriconazole exposure and its impact on SCC, Aspergillus colonization, invasive aspergillosis and all-cause mortality.

The researchers found that voriconazole exposure resulted in a 73 percent greater risk for SCC, with each additional 30-day exposure increasing the risk by 3 percent.

Further, the drug significantly reduced the risk of Aspergillus colonization, especially in the first year after transplant, but not aspergillosis. It also reduced all-cause mortality among those transplant recipients who developed Aspergillus colonization but had no significant impact on those without colonization.

“Among lung transplant recipients with risk factors for SCC, including those with older age, male sex and white race or those in whom prolonged voriconazole administration may not have clear benefit, transplant physicians should consider limiting exposure to high doses of voriconazole or using alternative pharmacologic options that do not pose an increased risk for SCC,” said lead author Matthew Mansh, MD, who did the work as a doctoral student at Stanford University that included a research year in the UCSF Department of Dermatology.

Other UCSF contributors to the American Journal of Transplantation study were Max Binstock, dermatology research coordinator; Kiyanna Williams, dermatology medical student; Farhaan Hafeez, dermatology medical student; Julie Kim, dermatology medical student; David Glidden, PhD, professor of epidemiology and biostatistics; Rebecca Boettger, PharmD, pharmacist; Steven Hays, MD, associate professor of medicine and lung transplant program medical director; Jasleen Kukreja, MD, MPH, associate professor of surgery and surgical director of the lung transplant program; Jeffrey Golden, MD, professor of medicine and associate medical director of lung transplantation; Peter Chin-Hong, MD, professor of medicine; and Jonathan Singer, MD, assistant professor of medicine. Maryam Asgari, MD, of Kaiser Permanente Northern California, also contributed.

Funding was provided by a Stanford University Medical Scholars Research Grant; National Institutes of Health National Center for Advancing Translational Sciences through the UCSF Clinical and Translational Science Institute; NIH National Heart, Lung, and Blood Institute; and the UCSF Nina Ireland Lung Disease Program.

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