Evaluation of cytokine profile and HLA association in benznidazole related cutaneous reactions in patients with Chagas disease.
BACKGROUND
Benznidazole is the drug of choice for Chagas disease. The major drawback of this drug is the high adverse events rate, being cutaneous reactions the most frequent one, leading to definitive withdrawal of treatment in 15%-30% of patients.


METHODS
Prospective observational study where adult Chagas disease patients accepting to receive benznidazole (100 mg/8 hours for 60 days) were included. The objective was to characterize the skin toxicity of benznidazole in patients with Chagas disease, determine the serum cytokine profile, and evaluate the potential association with specific HLA alleles and benznidazole concentration. Serum cytokine levels were measured at day 0, 15, and 60 of treatment. Class I and II HLA alleles were determined. When cutaneous reaction was detected, a skin biopsy was performed. Serum benznidazole concentration was determined at the time of cutaneous reaction, or at day 15 of treatment.


RESULTS
Fifty-two patients were included, 20(38.5%) had cutaneous reaction, and median time of appearance was 9 days. Skin biopsies showed histopathological findings consistent with drug eruption. Patients with cutaneous drug-reaction had higher proportion of eosinophilia during treatment, and higher interleukin (IL)-5 and IL-10 serum concentrations at day 15 of treatment than those without cutaneous reaction. Treatment interruption (that included moderate-severe cutaneous reactions) was more frequent in patients carrying HLA-B*3505 allele (45.5% vs 15.4%, P = .033). No differences in benznidazole serum concentration were found.


CONCLUSIONS
Benznidazole related cutaneous reaction rate is high, and it was produced by a delayed hypersensitivity reaction with a Th2 response. Carrying HLA-B*3505 allele could be associated with moderate-severe cutaneous reaction.
Department of Infectious Diseases, Universitat Autònoma de Barcelona, PROSICS Barcelona.
Fernando
F
Salvador
Department of Infectious Diseases, Universitat Autònoma de Barcelona, PROSICS Barcelona.
Adrián
A
Sánchez-Montalvá
Immunology Division.
Mónica
M
Martínez-Gallo
Allergy Section, Department of Internal Medicine.
Anna
A
Sala-Cunill
Immunology Division.
Laura
L
Viñas
Immunology Division.
Marina
M
García-Prat
Department of Dermatology.
Gloria
G
Aparicio
Department of Infectious Diseases, Universitat Autònoma de Barcelona, PROSICS Barcelona.
Augusto
A
Sao Avilés
Metabolics Platform, High Technology Unit, Vall d'Hebron Research Institute.
M Ángeles
MÁ
Artaza
Department of Pathology, Vall d'Hebron University Hospital, Barcelona, Spain.
Berta
B
Ferrer
Department of Infectious Diseases, Universitat Autònoma de Barcelona, PROSICS Barcelona.
Israel
I
Molina
D000328:Adult; D000483:Alleles; D014355:Chagas Disease / Q000188:drug therapy* / Q000276:immunology* / Q000469:parasitology; D016207:Cytokines / Q000097:blood* / Q000276:immunology; D003875:Drug Eruptions / Q000235:genetics / Q000276:immunology*; D005260:Female; D005805:Genes, MHC Class I; D005802:Genes, MHC Class II; D015235:HLA-B Antigens / Q000235:genetics; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000139:chemically induced* / Q000276:immunology; D016753:Interleukin-10 / Q000097:blood; D015848:Interleukin-5 / Q000097:blood; D008297:Male; D009593:Nitroimidazoles / Q000009:adverse effects* / Q000276:immunology / Q000633:toxicity; D011446:Prospective Studies; D012867:Skin / Q000276:immunology / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology; D014344:Trypanocidal Agents / Q000009:adverse effects*; D014349:Trypanosoma cruzi / Q000187:drug effects
D016207:Cytokines; D015235:HLA-B Antigens; C508609:IL10 protein, human; D015848:Interleukin-5; D009593:Nitroimidazoles; D014344:Trypanocidal Agents; D016753:Interleukin-10; C009999:benzonidazole
Chagas disease; Trypanosoma cruzi; benznidazole; cutaneous drug reaction