Toxic epidermal necrolysis after immune checkpoint inhibition, case report, and review of the literature

Figures & data

Table 1. Two patient cases with TEN following ICI.

Patient No./sex/age	Oncological history	Skin and mucosal manifestations	BU admission	Treatment, day^a	Outcome
1/F/54	2014: stage pT2bN0Mx melanoma right arm. Apr. 2019: axillary lymphadenectomy: stage IIIB, pT2bN2bM0. Jul. 2019: 1. Adjuvant Nivolumab. Aug. 2019: Subcutaneous and muscular metastases. BRAF+, PD-L1 neg. Sept. 2019: Ipi/Nivo. Jan. 2020: Near-complete response.	Jan. 2020 (03.01): maculopapular rash involving face and trunk. Admitted 17.01: symmetric, generalized exanthema, confluent and deep red on trunk, some soft bullae. Nikolsky’s sign positive. Involvement of eyes (conjunctival injection, mild chemosis, small conjunctival defect), palate and vaginal mucosa.	Admitted 16 days after appearance of rash. SCORTEN 3: 35% mortality risk. Exfoliation of epidermis 30% (later > 90%). Biopsy confirmed TEN. Other potential culprit drugs: TMP-SMZ started 7 days prior to rash, Pantoprazole started 2 weeks prior.	Dermatology: d1: Prednisolone 40 mg × 2, Cyclosporin 3.2 mg/kg/day. d3: IV Methylprednisolone 60 mg × 2, immunoglobulins × 3. Ophtalmology: d1: Chloramphenicol, Ultracortenol. Infection: d9: Cefotaxime 2 g × 3 (S. aureus). d14: Cloxacillin (3 weeks).	Critically ill until signs of re-epithelialization seen at day 13 after admission. Discharged after 5.5 weeks. 9 months later new soft tissue metastases, followed by brain metastases 3 months later. Currently doing well on BRAF/MEK inhibitor.
2/M/34	Jun. 2021: right-sided nephrectomy for renal cell carcinoma with sarcomatoid features. pT3a. Aug. 2021: cauda equina syndrome. CT: bone, lung, liver, and subcutaneous metastases, thus stage IV. IMDC unfavorable risk group. Radiation therapy 3 Gy × 12 L5-S3. 1. Ipi/Nivo 24.09.	Sep. 2021 (21.09): unspecific macular itchy rash on back, worsened by excessive sweating. 29.09: symmetric, generalized exanthema, confluent and erythematous on back, urticarial lesions in intertriginous areas. Nikolsky′s sign positive. Involvement of eyes (conjunctival injection, chemosis, corneal epithelial defects), oral, nasal and genital mucosa	Admitted 11 days after appearance of rash. SCORTEN 3: 35% mortality risk. Exfoliation of epidermis 30% (later 80%–90%). Biopsy confirmed TEN. Other potential culprit drugs: Pivmecillinam started 3 days prior to rash exacerbation, Piperacillin/Tazobactam started 2 days prior to rash exacerbation.	Dermatology: d1: IV Methyl-prednisolone 60 mg × 1. d2: Cyclosporin 4.5 mg/kg/day (decline kidney function: d7 Mycophenolic mofetil). d4: IV Methylprednisolone 100 mg × 1. Ophtalmology: d2: Chloramphenicol. d5: Ultracortenol, d7: Prokera bilaterally. Infection: d2: Vancomycin, Fluconazole (prophylaxis). d5: Anidulafungin. d6: Ganciclovir (CMV-infection). d17: Gentamicin, Clindamycin, Ciprofloxacin, Anidulafungin (neutropenic infection. Bone marrow toxicity suspected due to Ganciclovir). d23: Meropenem.	Signs of re-epithelialization seen at day 6 after admission. Critically ill, sedated and on a ventilator for 12 days. After initial slow improvement, worsened general condition on ICU day 20. Decided not to re-intubate. Patient died on ICU day 24. Complicating factors: disease progression, bone marrow toxicity, systemic inflammation, possible infection.

Course of events.

^aDays from TEN diagnosis.

CMV: cytomegalovirus; CT: computed tomography; Gy: gray; ICU: intensive care unit; IMDC: International metastatic RCC database consortium; Ipi/Nivo: ipilimumab plus nivolumab; IV: intravenous; PD-L1: programmed death-ligand 1; PET-CT: positron emission tomography-computed tomography; SCORTEN: severity-of-illness score for toxic epidermal necrolysis; TEN: toxic epidermal necrolysis; TMP-SMZ: trimethoprim/sulfamethoxazole.

Figure 1. Two patient cases with TEN following ICI. (A) Pt. 1 at day 1 after admission to the BU. (B) Pt. 1 at day 10. (C) Pt. 1 at day 18. (D) Pt. 2 before admission to the BU. Generalized polymorphic eruption with dark red skin and positive Nikolsky’s sign (arrows). (E) Pt. 2 at day 4. Total epidermiolysis on the back. (F) Pt. 2 at day 8. (G) Skin biopsy from Pt. 1 showing intact stratum corneum, while full thickness epidermal necrosis is seen (arrow). Numerous necrotic keratinocytes at all levels of the epithelium is obvious. (H) Skin biopsy from Pt. 2 showing less apoptotic keratinocytes scattered through the epithelium (arrow). Subepidermal bulla formation can be seen (star), with infiltrate of inflammatory cells.

Data availability statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.