Acute Eruption in a Child With Acute Lymphoblastic Leukemia

A 6-year-old girl with B-cell acute lymphoblastic leukemia in the maintenance phase, presented with a 1-month history of painful lower-lip lesions and pruritic, erythematous lesions on the face and dorsal aspects of the hands. Her maintenance chemotherapy consisted of 6-mercaptopurine and methotrexate; she had not undergone hematopoietic stem cell transplantation (HSCT). She had been receiving oral voriconazole, 100 mg every 12 h for 3 months, as secondary prophylaxis following an invasive pulmonary aspergillosis during induction. Lesions began as painful blisters on the lower lip vermilion that evolved into crusted erosions (Figure 1) during a febrile upper respiratory tract infection. Although the systemic symptoms resolved before dermatologic assessment, the eruption worsened despite topical emollients and barrier creams, extending to the perioral area, cheeks, eyelids (Figure 2), and dorsal hands (Figure 3). Examination revealed sharply demarcated scaly erythematous plaques on photoexposed areas, along with erosive cheilitis limited to the lower lip. Polymerase chain reaction testing for HSV-1, HSV-2, EBV and CMV was negative. Laboratory testing during the febrile illness showed ALT of 210 IU/L (0–39), AST of 197 IU/L (0–41) and a peak serum voriconazole level of 5.2 μg/mL (therapeutic range 1.0–5.5). Liver transaminases subsequently normalized while the cutaneous eruption progressed. The findings were consistent with a voriconazole-induced mucocutaneous phototoxic reaction based on lesion distribution, voriconazole levels at the upper end of the therapeutic range, absence of systemic findings, and negative viral testing. Prednicarbate 0.25% cream was applied once daily for 2 weeks, followed by tacrolimus 0.03% ointment 2–3 times weekly, with marked improvement in the labial, facial, and hand lesions. Strict photoprotection, including broad-spectrum sunscreen and sun protective clothing, was implemented. In collaboration with the Department of Infectious Diseases, voriconazole was replaced with posaconazole due to cutaneous toxicity and unstable drug levels. Tacrolimus was discontinued after 2 months, with sustained improvement and no recurrence. Voriconazole, a second-generation triazole antifungal, is widely used for its oral bioavailability and broad-spectrum activity [1]. In the United States, it is FDA approved for patients ≥ 2 years to treat invasive fungal infections (IFIs) caused by Aspergillus, Candida, Fusarium, and Scedosporium species [2]. Although not approved for prophylaxis, it is used off-label in high-risk settings, including allogeneic HSCT. Despite concerns about phototoxicity [1] and the selection of resistant non-Aspergillus species [3], an adult meta-analysis of primary antifungal prophylaxis trials ranked voriconazole favorably for allogeneic HSCT when efficacy and tolerability were considered together (whereas posaconazole ranked highest for acute myeloid leukemia or myelodysplastic syndrome) [4]. Pediatric data are limited: in a retrospective, single-center cohort of allogeneic HSCT recipients receiving itraconazole, voriconazole, and posaconazole as prophylaxis, no proven or probable IFIs occurred, and voriconazole had the highest rates of possible IFIs (6%) and potentially drug-related adverse events (14%) [5]. Cutaneous adverse effects of voriconazole are well described in immunocompromised pediatric patients, with a time-dependent progression: acute sunburn-like lesions, photoonycolysis, and pseudoporphyria within the first year of treatment; accelerated photoaging with lentigines, elastosis, and actinic keratoses within 2–3 years; and, rarely, squamous cell carcinoma (SCC) after prolonged exposure (3–4 years), especially in chronically immunosuppressed patients. The mean age at diagnosis of SCC is 15 years [1, 6-8]. Phototoxicity is common, occurring in up to 20% of pediatric patients and 46% of those treated for ≥ 6 months [1]. Unlike methotrexate mucositis, which affects non-keratinized mucosa without photodistribution, voriconazole phototoxicity involves sun-exposed skin in two-thirds of cases, the vermilion border in one-third, and mucocutaneous forms in 3% [1, 2]. Risk factors include fair skin and cumulative drug dose, with an 8.8% increased risk per additional 10 g of voriconazole [1]. Patients receiving the drug as prophylaxis may be at greater risk. Histopathology shows epidermal necrosis with vacuolar interface changes, keratinocyte apoptosis, and a superficial perivascular lymphocytic infiltrate with occasional eosinophils, consistent with a phototoxic reaction [9]. The pathogenesis of voriconazole-induced phototoxicity is attributed to its active metabolite, voriconazole N-oxide, which acts as a chromophore absorbing UVA and UVB radiation. Moreover, its inhibition of CYP3A4/5 and CYP2C9 may increase endogenous photosensitizers, such as vitamin A derivatives [6]. Prolonged immunosuppression—common in patients receiving voriconazole—may contribute to accelerated photoaging and higher non-melanoma skin cancer (NMSC) risk [1], often more aggressive than in patients not exposed to the drug [10]. Despite the frequency and severity of these cutaneous toxicities, discontinuation of voriconazole is uncommon. Only 5% of patients discontinued voriconazole after the first phototoxic reaction; among those who continued therapy, 45% experienced a subsequent phototoxic reaction [1]. Still, only 8% discontinued treatment following recurrence [1]. Counseling on sun protection is infrequent, and dermatology referral occurred in just 6% of cases [1]. Patients and caregivers should receive strict, year-round photoprotection counseling before treatment initiation, and those with recurrent phototoxic reactions or high NMSC risk should be referred to dermatology for surveillance and consideration of alternative antifungal therapy [1]. This case illustrates a classic cutaneous phototoxic reaction to voriconazole, with well-demarcated erosive cheilitis on the lower lip and erythematous-squamous plaques on photoexposed areas of the face and dorsal hands, closely resembling previously described presentations [5]. Its characteristic morphology and distribution provide visual diagnostic clues to facilitate early recognition and appropriate management. The authors declare no conflicts of interest.