A
C
D
B
E
Jameleddine Zili, PhD Dermatology Department Fattouma Bourguiba University Hospital University of Monastir Monastir
Tunisia Research Laboratory LR20SP03A
REFERENCES
1. Bhat YJ, Hassan I, Sajad P, et al. Acute generalized exanthematous pustu- losis due to insect bites? Indian J Dermatol. 2015;60(4):422.
2. Ameur K, Youssef M, Belhadjali H, et al. Occupational acute generalized exanthematous pustulosis induced by disperse dyes in a textile. Contact Dermatitis. 2019;80(6):411-412.
3. Momin SB, Del Rosso JQ, Michaels B, et al. Acute generalized exanthematous pustulosis: an enigmatic drug-induced reaction. Cutis. 2009;83(6):291-298.
4. Tibballs J, Yanagihara AA, Turner HC, et al. Immunological and toxico- logical responses to jellyfish stings. Inflamm Allergy Drug Targets. 2011; 10(5):438-446.
5. Ermertcan AT, Demirer O, İnanir I, et al. Acute generalized exanthema- tous pustulosis with lymphangitis triggered by a spider bite. Cutan Ocul Toxicol. 2010;29(1):67-69.
A Case of Drug Reaction With Eosinophilia and Systemic Symptoms Caused by Mitotane: A Cytotoxic Drug Treating Adrenocortical Carcinoma
A 52-year-old Asian woman was referred and hospitalized with pruritic erythematous papules, patches, and fever. Four months prior, the patient underwent a right-sided adre- nalectomy because of adrenocortical cancer (ACC) and
J.Q. wrote the article. Q.Z. drew figure and table. X.J. edited the article. No competing financial interests exist.
A statement of all funding sources: the National Natural Science Foundation of China (82273559 and 82073473); the 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (ZYJC21036); Clinical Research Innovation Project, West China Hospital, Sichuan University (2019HXCX10); Sichuan University-Zigong Special Fund for University-Local Science and Technology Cooperation (2021CDZG-21).
DOI: 10.1089/derm.2023.0325
@ 2024 American Contact Dermatitis Society. All Rights Reserved.
initiated prednisone postoperatively. Six weeks before admis- sion, she commenced mitotane and concurrent radiation therapy. Approximately 1 month after initiating mitotane, the patient presented with widespread skin lesions. One week after the onset of symptoms, the patient developed fever (37.5℃, axillary) and abnormal liver function. Conse- quently, mitotane was discontinued after 5 weeks of usage, 1 week before admission. The patient reported no other medi- cation use or significant medical history.
Physical examination revealed erythematous papules, patches, and hyperpigmentation scattered over her trunk and extremities. Her face was slightly swollen with red patches (Fig. 1). No lymphadenopathy or mucosal site involvement was found.
Laboratory tests showed leukocytosis with eosinophilia (2.13×109/L, 18.9%), neutrophilia, monocytosis, atypical leukocytosis, elevated alanine aminotransferase (686 IU/ L), aspartate aminotransferase (399 IU/L), and C-reactive protein. Cytomegalovirus DNA test was positive and ele- vated during her hospitalization. Chest computed tomog- raphy scan showed increased and enlarged lymph nodes in axillary fossa. While examination for viral hepatitis, COVID-19, antinuclear antibody, thyroid function, elec- trocardiogram, abdominal ultrasound, and blood culture were negative.
During hospitalization, the patient experienced vomiting, and loss of appetite. Her maximum recorded body tempera- ture reached 39.1℃ (axillary). She remained hospitalized for 29 days, primarily receiving cyclosporin, prednisone, anti- infection therapy (cefuroxime, meropenem, ganciclovir, and valacyclovir), and symptomatic care. Cyclosporin and pred- nisone were continued for 3 months after her discharge.
Therefore, in accordance with RegiSCAR group criteria, 1 the patient scored 6, and a definite mitotane-induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome was diagnosed (Table 1).
DRESS is a rare and severe cutaneous drug-induced hyper- sensitivity, characterized by fever, lymphadenopathy, hemato- logical abnormalities, multisystem involvement, and viral reactivation, well known for its prolonged course.2 Currently,
mitotane is the primary postsurgery therapy3 for ACC, a rare and aggressive cancer with an overall 5-year survival rate ranging from 16% to 47%.3 However, once DRESS happens, immediate discontinuation of mitotane, the causative medica- tion, is necessary, and patients should receive immunosup- pressants such as high-dose corticosteroids and cyclosporin, which may impact the prognosis of the malignancy.
For example, in this case, the patient received no treat- ment for ACC until 3 months after discharge due to cyclo- sporin and prednisone. Subsequently, she was enrolled in a clinical trial to undergo carrilizumab and apatinib therapy. This case serves as a reminder to oncologists to pay attention to DRESS, a rare adverse effect of mitotane, when treating ACC patients. For dermatologists managing patients with drug eruptions induced by mitotane, it is important to con- sider the possibility of DRESS and exercise caution when reducing corticosteroid doses.
Furthermore, doctors from these 2 departments should collab- orate to determine treatment regimens for ACC patients who develop mitotane-induced DRESS during and after their recov- ery. Decisions regarding the exploration of alternative therapies, as well as strategies to minimize the immunosuppressive effects of prolonged drug administration, which should be tapered grad- ually to mitigate the risk of relapse, need further investigation.
Jinxin Qi Department of Dermatology and National Clinical Research Center for Geriatrics West China Hospital Sichuan University Chengdu China
Laboratory of Dermatology Clinical Institute of Inflammation and Immunology Frontiers Science Center for Disease-Related Molecular Network West China Hospital
Sichuan University Chengdu China
TABLE 1. RegiSCAR Criteria for Drug Reaction With Eosinophilia and Systemic Symptoms/Drug- Induced Hypersensitivity Syndrome and Patient Data
| Score | RegiSCAR Criteria | Our Patient | |||||
|---|---|---|---|---|---|---|---|
| -1 | 0 | 1 | 2 | Min. | Max. | ||
| Fever ≥38.5°C | No/U | Yes | -1 | 0 | 0 | ||
| Enlarged lymph nodes | No/U | Yes | 0 | 1 | 0 | ||
| Eosinophilia | No/U | 0 | 2 | 2 | |||
| Eosinophils | 0.7-1.499×109/L | ≥1.5×109/L | 2 | ||||
| Eosinophils, if leukocytes <4.0x109/L | 10-19.9% | ≥20% | 2 | ||||
| Atypical lymphocytes | No/U | Yes | 0 | 1 | 1 | ||
| Skin involvement | -2 | 2 | 1 | ||||
| Skin rash extent (% body surface area) | No/U | >50% | 1 | ||||
| Skin rash suggesting DRESS | No | U | Yes | 0 | |||
| Biopsy suggesting DRESS | No | Yes/U | 0 | ||||
| Organ involvementª | 0 | 2 | 1 | ||||
| Liver | No/U | Yes | 1 | ||||
| Kidney | No/U | Yes | 0 | ||||
| Lung | No/U | Yes | 0 | ||||
| Muscle/heart | No/U | Yes | 0 | ||||
| Pancreas | No/U | Yes | 0 | ||||
| Other organ | No/U | Yes | 0 | ||||
| Resolution ≥15 days | No/U | Yes | -1 | 0 | 0 | ||
| Evaluation of other potential causes | |||||||
| Antinuclear antibody | 0 | ||||||
| Blood culture | 0 | ||||||
| Serology for HAV/HBV/HCV | 0 | ||||||
| Chlamydia/mycoplasma | |||||||
| If none positive and ≥3 of above negative | Yes | 0 | 1 | 1 | |||
| Total score | 4 | 9 | 6 | ||||
ª After exclusion of other explanations: 1, 1 organ; 2, 2 or more organs. Final score <2, no case; final score 2-3, possible case; final score 4-5, probable case; final score >5, definite case.
DRESS, drug reaction with eosinophilia and systemic symptoms; HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; U, unknown/ unclassifiable.
Qian Zhang Department of Plastic, Aesthetic, Reparative and Reconstructive Surgery West China Second University Hospital Sichuan University Chengdu China
Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University) Ministry of Education Chengdu China
Xian Jiang Department of Dermatology and National Clinical Research Center for Geriatrics West China Hospital Sichuan University Chengdu China
Laboratory of Dermatology Clinical Institute of Inflammation and Immunology Frontiers Science Center for Disease-Related Molecular Network West China Hospital Sichuan University Chengdu China jiangxian@scu.edu.cn
REFERENCES
1. Kardaun SH, Sidoroff A, Valeyrie-Allanore L, , et al. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symp- toms: does a DRESS syndrome really exist? Br J Dermatol 2007;156(3): 609-611.
2. Cardones AR. Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. Clin Dermatol 2020;38(6):702-711.
3. Puglisi S, Calabrese A, Basile V, et al. New perspectives for mitotane treatment of adrenocortical carcinoma. Best Pract Res Clin Endocrinol Metab 2020;34(3):101415.