Voriconazole Exposure and Risk of Cutaneous Squamous Cell Carcinoma, Aspergillus Colonization, Invasive Aspergillosis and Death in Lung Transplant Recipients

Abstract

Voriconazole is a triazole antifungal used to prevent and treat invasive fungal infections after lung transplantation, but has been associated with an increased risk for developing cutaneous squamous cell carcinoma (SCC). Despite widespread use, there are no clear guidelines for optimal prophylactic regimens that balance its competing risks and benefits. We conducted a retrospective cohort study of all lung transplant recipients at the University of California, San Francisco transplanted between October 1991 and December 2012 (n=455) to investigate whether voriconazole exposure impacted development of SCC, Aspergillus colonization, invasive aspergillosis, and all-cause mortality. Voriconazole exposure was associated with a 73% increased risk for developing SCC (HR=1.73; 95% CI: 1.04–2.88; p=0.03), with each additional 30-day exposure at the standard dose increasing the risk by 3.0% (HR=1.03; 95% CI: 1.02–1.04; p<0.001). Voriconazole exposure reduced risk of Aspergillus colonization by 50% (HR=0.50; 95% CI: 0.34–0.72; p<0.001), but we were underpowered to detect risk reduction for invasive aspergillosis. Voriconazole exposure significantly reduced all-cause mortality among subjects who developed Aspergillus colonization (HR=0.34; 95% CI: 0.13–0.91; p=0.03), but had no significant impact on those without colonization. Physicians should consider patient-specific factors that modify the potential risks and benefits of voriconazole in the care of lung transplant recipients.

Effect of voriconazole on risk of nonmelanoma skin cancer after hematopoietic cell transplantation

“…12,13 However, voriconazole is associated with cutaneous toxicities, including photosensitivity, 14 and along with its metabolite, voriconazole N-oxide (VNO), it sensitizes keratinocytes to ultraviolet A light and may induce DNA damage and inhibit repair mechanisms. 15 Although the association between voriconazole and NMSC has been established in the population of solid organ transplant recipients, 16,17 less is known about patients who have undergone HCT. Therefore, we sought to determine the effect of voriconazole on post-HCT risk for NMSC.…”

PharmGKB summary

“…SCC can lead to numerous cutaneous lesions, which may require surgery, and in some case, be fatal; voriconazole use is associated with a 73% increased risk of the disease in lung transplant recipients [52]. The authors of the study on CYP2C19 UMs and SCC suggest that the increased risk of SCC may be due to a link between the voriconazole N-oxide metabolite and DNA damage [22].…”

Routine comprehensive Aspergillus screening of bronchoalveolar lavage samples in lung transplant recipients

“…When applying routine PCR and/or GM screening, healthcare professionals should exercise clinical judgment and reserve treatment to cases of suspected infection. Nonetheless, some reports argue that Aspergillus colonization is a risk factor for future invasive infection in LTRs and might be associated with excess mortality; therefore, the increased diagnostic rate of colonization, though not an indication for treatment, may be of clinical importance as well.…”