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Case Report/Case Series
March 2015

Acute Generalized Exanthematous Pustulosis Caused by Dihydrocodeine Phosphate in a Patient With Psoriasis Vulgaris and a Heterozygous IL36RN Mutation

Author Affiliations
  • 1Department of Dermatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
  • 2Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
JAMA Dermatol. 2015;151(3):311-315. doi:10.1001/jamadermatol.2014.3002
Abstract

Importance  Acute generalized exanthematous pustulosis (AGEP) is a rare and severe type of drug eruption. Dihydrocodeine phosphate is a semisynthetic opioid analgesic. Recently, recessive mutations in IL36RN have been identified in generalized pustular psoriasis (GPP). To date, 4 cases of AGEP and IL36RN mutation without previous history of psoriasis vulgaris (PV) have been reported.

Observations  A woman in her 60s with PV presented with diffuse erythema, nonfollicular pustules, and fever. She had been treated with dextromethorphan hydrobromide hydrate, amoxicillin hydrate, clarithromycin, dihydrocodeine phosphate, tipepidine hibenzate, and tulobuterol tape for a cough and common cold. Based on histopathologic results and a positive result in a drug provocation test with dihydrocodeine phosphate, she was diagnosed with AGEP. A heterozygous IL36RN mutation c.28C>T (p.Arg10X) was also confirmed by mutation analysis.

Conclusions and Relevance  This is the first report of dihydrocodeine phosphate–induced AGEP. In this case, helper T cells, type 17, might have been activated because of morphine and underlying PV, followed by increased production of interleukin (IL) 36. However, because of the IL36RN mutation, IL-36 signaling was uncontrolled, which might have resulted in the occurrence of AGEP. An IL36RN mutation might underlie several different pustular skin eruptions, including AGEP and GPP, and further accumulation of patient data is required.

Introduction

Acute generalized exanthematous pustulosis (AGEP) is a rare and severe type of drug eruption. It is characterized by acute, extensive, sterile pinhead-sized nonfollicular pustules, erythema, edema, fever, and leukocytosis with neutrophilia.1 Dihydrocodeine phosphate is a semisynthetic opioid analgesic used mainly in cough medicines in Japan.2 Herein, we report the first case to our knowledge of AGEP caused by dihydrocodeine phosphate in a patient with psoriasis vulgaris (PV) and a heterozygous IL36RN mutation. We also discuss the possible causal mechanism of AGEP in this particular case.

Report of a Case

This study was approved by the Nagoya University Graduate School of Medicine institutional review board. Patient written informed consent was obtained, in compliance with the Declaration of Helsinki principles.

A woman in her 60s with a history of urticaria-type drug eruption caused by phenytoin consulted a physician about erythematous eruptions all over her body. At age 22 years, she had been diagnosed with PV and had been treated with topical steroids and topical vitamin D analogs. She had also been treated with oral nonsteroidal anti-inflammatory drugs (NSAIDs) for 10 years for arthralgia of the knees.

More immediately prior to presentation, she had been treated with dextromethorphan hydrobromide hydrate for 12 days, amoxicillin hydrate for 8 days, and clarithromycin, dihydrocodeine phosphate, tipepidine hibenzate, and tulobuterol tape for 2 days for a cough and common cold. Three days before presentation, she noticed the eruptions. Therefore, she stopped using clarithromycin, dihydrocodeine phosphate, tipepidine hibenzate, and tulobuterol tape of her own volition while continuing to take dextromethorphan hydrobromide hydrate and amoxicillin hydrate.

Initial physical examination revealed fever (temperature, 37.5°C) and diffuse erythema over the whole body with predominant localization in the intertriginous folds (Figure 1A). Hundreds of nonfollicular pustules on the erythema were diffusely spread over the upper arms and lateral chest areas (Figure 1B and C). The erythematous and scaly lesions on the posterior region of the neck were consistent with PV. There were no mucosal lesions associated with Stevens-Johnson syndrome.

Figure 1.
Clinical Findings at the First Visit
Clinical Findings at the First Visit

A, Diffuse erythema on the chest and abdomen. B, Diffuse erythema with pustules on the left lateral chest. C, A close-up view showing nonfollicular pustules.

The white blood cell count (15 400/μL; normal range, 3400-7300/μL), including neutrophils (13 890/μL; normal range, 1214-5110/μL), and serum levels of C-reactive protein (CRP) (7.75 mg/dL; normal range, 0-0.2 mg/dL) were all elevated. (To convert white blood cells and neutrophils to number of cells × 109/L, multiply by 0.001; to convert CRP to nanomoles per liter, multiply by 9.524.) Liver and kidney function and eosinophil percentage were within normal limits. Lymphocyte transformation findings for amoxicillin hydrate (stimulation index, 1.5; normal, <1.8) and dihydrocodeine phosphate (stimulation index, 1.0; normal, <1.8) were negative. No microbial growth from cultures of pustules was seen.

A biopsy specimen of the erythema with pustule on the left lateral chest showed an intracorneal pustule containing large numbers of neutrophils and epidermis with mild elongation of rete ridges (Figure 2A and B). High magnification showed a thin granular layer and a few necrotic keratinocytes in the epidermis, liquefaction degeneration of the basal layer, and lymphocytic perivascular infiltrate with admixed neutrophils in the superficial dermis. No Kogoj spongiform pustules were observed (Figure 2C). A biopsy specimen of the scaly erythematous lesion on the posterior region of the neck showed parakeratosis with thinning of the granular layer and hyperplasia of the epidermis with regular elongation of rete ridges and dilation and tortuosity of the blood vessels in the dermal papillae, consistent with PV in a patient undergoing treatment with topical steroids and topical vitamin D analogs (Figure 2D).

Figure 2.
Hematoxylin-Eosin–Stained Histopathologic Specimens From Erythema With a Pustule on the Chest and a Scaly Erythematous Lesion on the Neck
Hematoxylin-Eosin–Stained Histopathologic Specimens From Erythema With a Pustule on the Chest and a Scaly Erythematous Lesion on the Neck

A-C, Chest specimens. A, Intracorneal pustule and epidermis showing mild elongation of rete ridges (original magnification ×40). B, Intracorneal pustule with large numbers of neutrophils (original magnification ×400). C, Thinned granular layer and a necrotic keratinocyte in the epidermis; liquefaction degeneration of the basal layer; and lymphocytic perivascular infiltrate with admixed neutrophils in the superficial dermis (original magnification ×200). D, Neck specimen, parakeratosis with thinning of the granular layer and hyperplasia of the epidermis with regular elongation of rete ridges and dilation and tortuosity of the blood vessels in the dermal papillae (original magnification ×100).

On the basis of her history, clinical features, blood test results, and histologic findings, AGEP or generalized pustular psoriasis (GPP) was suspected. Treatment with all medications was stopped, and she was hospitalized.

In the hospital, she was treated with oral epinastine hydrochloride, 20 mg/d; topical clobetasone butyrate, 0.05%, on her neck; and difluprednate, 0.05%, on her trunk and extremities. The fever, pustules, and erythema resolved within 3, 5, and 12 days, respectively, and she was discharged.

In an outpatient setting, patch and scratch-patch tests were performed using dextromethorphan hydrobromide hydrate, 30%, amoxicillin hydrate, 10% and 20%, clarithromycin, 20%, dihydrocodeine phosphate, 1% and 10%, tipepidine hibenzate, 10% and 20% (all doses in petrolatum), and tulobuterol tape, according to the guidelines of the International Contact Dermatitis Research Group. All patch and scratch-patch test results were negative.

Subsequently, the patient was hospitalized, and oral challenge tests were performed using 1/10, 1/5, 1/2, and full therapeutic doses of dextromethorphan hydrobromide hydrate, amoxicillin hydrate, clarithromycin, and tipepidine hibenzate and a 1/10 therapeutic dose of dihydrocodeine phosphate. The test reactions to dextromethorphan hydrobromide hydrate, amoxicillin hydrate, clarithromycin, and tipepidine hibenzate were all negative. However, skin eruptions were reproduced over the whole body within 20 hours after taking dihydrocodeine phosphate at a 1/10 therapeutic dose (Figure 3). At this time, the body temperature and most laboratory test results were within normal limits, including findings of a complete blood cell count and tests for liver and kidney function, but serum levels of CRP (0.91 mg/dL) were slightly elevated. Based on these results, a diagnosis of AGEP caused by dihydrocodeine phosphate was made. The eruptions disappeared spontaneously within 6 days of the test, and the patient was discharged.

Figure 3.
Clinical Findings After a Drug Provocation Test
Clinical Findings After a Drug Provocation Test

At 20 hours after taking dihydrocodeine phosphate at 1/10 therapeutic dose, diffuse erythemas were confirmed on the chest and abdomen.

In an outpatient setting, DNA was extracted from venous blood samples. All coding regions and associated splice sites of the IL36RN locus were amplified by polymerase chain reaction, and Sanger sequencing was performed. A heterozygous mutation c.28C>T (p.Arg10X), which is one of the GPP-causing founder mutations in Japanese people, was confirmed (Figure 4).3

Figure 4.
IL36RN Sequence Data of the Patient
IL36RN Sequence Data of the Patient

Arrow indicates c.28C>T (heterozygous) mutation.

Discussion

To our knowledge, the present case and one described by Matsuzawa et al2 are the only reports in the English language literature of drug eruptions induced by dihydrocodeine phosphate. In Matsuzawa et al.2 the patient showed erythema multiforme major. AGEP is usually caused by penicillins, macrolides, pristinamycin, quinolones, chloroquine, anti-infective sulfonamides, terbinafine, diltiazem, carbamazepine, spiramycin, and metronidazole.4 The main differential diagnosis is GPP,4 and AGEP might be difficult to differentiate from GPP both clinically and histopathologically.5 However, the presence of eosinophils, necrotic keratinocytes, and a mixed interstitial and mid-dermal perivascular infiltrate, and the absence of tortuous or dilated blood vessels, favor a diagnosis of AGEP.5

These findings, except the presence of eosinophils, correspond to those in the present case. According to the differentiation between AGEP and GPP,1 the present case showed the history of PV, the predominant distribution pattern of the intertriginous folds, the shorter duration of pustules and fever, the history of drug reaction, the recent drug administration, and the histopathologic findings that all favored the diagnosis of AGEP rather than GPP. According to the AGEP validation score of the EuroSCAR study group,1 the total score in the present case was 10 (pustules, +2; erythema, +2; distribution/pattern, +2; postpustular desquamation, +1; mucosal involvement, 0; acute onset, 0; resolution ≤15 days, 0; fever ≥38°C, 0; polymorphonuclear neutrophils ≥7000/μL, +1; and histology, +2) . Therefore, the present case was interpreted as definite AGEP. Because our patient had been treated with oral NSAIDs for arthralgia of the knees, the body temperature might not have risen above 38°C. From these results and the positive drug provocation test findings, we are confident that this is the first report of dihydrocodeine phosphate–induced AGEP.

Recently, recessive mutations in IL36RN, which encodes the anti-inflammatory interleukin (IL)-36 receptor antagonist (IL-36Ra), have been identified in GPP3,6,7; IL-36Ra blocks IL-36, including IL-36α, β, and γ. In the case of the IL36RN mutation, IL-36 signaling is uncontrolled, and enhanced production of IL-6, IL-8, IL-1α, and IL1β occurs.8 Mutations in IL36RN are found in a majority of GPP cases not accompanied by PV and in about 10% of GPP cases accompanied by PV.3 However, it is uncertain whether the mutation is also a marker for AGEP.

Navarini et al9 have reported that these phenomena might give rise to pustular eruptions in GPP, and IL36RN mutations might also underlie some forms of AGEP. In their report, 4 patients with AGEP and IL36RN mutations without a history of PV were described. Three heterozygous (c.338C>T; c.338C>T; and c.142C>T) and 1 homozygous (c.80T>C) single-nucleotide substitutions in IL36RN were identified. The IL36RN-mutated cases were associated with exposure to amoxicillin in 2 cases, clindamycin-rifampicin in 1 case, and piroxicam in a case from the literature. In addition, our research group10 has reported GPP triggered by amoxicillin in monozygotic twins with compound heterozygous IL36RN mutations.

Herein, we present a case of AGEP associated with exposure to dihydrocodeine phosphate in a patient with a heterozygous IL36RN mutation. This mutation might underlie several different pustular skin eruptions that can occur spontaneously or in association with exogenous factors such as drugs, as seen in the present case.

Interleukin 17 is closely associated with the pathogenesis of PV. Helper T (TH) cells, type 17, are overrepresented in lesions from patients with PV, and lesional TH17 cells produce IL-17 without stimulation.11 The anti–IL-17 monoclonal antibody ixekizumab improves the clinical symptoms of PV.12 Carrier et al13 have reported increased gene expression of IL-36 in a TH17-dominant psoriasislike animal model and in cultured primary human keratinocytes by IL-17A and tumor necrosis factor (TNF), and IL-22 synergized with IL-17A and TNF. Furthermore, IL-36 directly induced the production of proinflammatory mediators such as TNF, IL-6, and IL-8 in the keratinocytes.13

AGEP serves as a valuable model for characterizing T cells, with production of IL-8 leading to neutrophilic inflammation.14 Opioid receptor agonists are known as modulators of innate and adaptive immune responses, and functional activity of TH17 cells is significantly increased with chronic morphine exposure.15

In the present case, TH17 cells may have been constantly activated because of the underlying PV. In addition, the TH17 cells may have been further activated by morphine, a metabolic product of dihydrocodeine phosphate, followed by increased production of IL-36. However, because of the IL36RN mutation, IL-36 signaling was uncontrolled, and the production of proinflammatory mediators, such as IL-8, was induced by keratinocytes, which might have resulted in the occurrence of AGEP.

Conclusions

The pathogenesis of dihydrocodeine phosphate–induced AGEP with the IL36RN mutation is still unclear, and a singular case is insufficient to establish a clear explanation. Therefore, further accumulation of patient data, including data related to the IL36RN mutation, and careful observation of the clinical course are required to improve the understanding of AGEP associated with the IL36RN mutation.

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Article Information

Accepted for Publication: August 9, 2014.

Corresponding Author: Noriaki Nakai, MD, PhD, Department of Dermatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan (nnakai@koto.kpu-m.ac.jp).

Published Online: November 19, 2014. doi:10.1001/jamadermatol.2014.3002.

Author Contributions: Dr Nakai had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Nakai, Sugiura, Akiyama, Katoh.

Acquisition, analysis, or interpretation of data: Nakai, Sugiura, Akiyama.

Drafting of the manuscript: Nakai.

Critical revision of the manuscript for important intellectual content: Nakai, Sugiura, Akiyama, Katoh.

Administrative, technical, or material support: Nakai, Sugiura.

Study supervision: Sugiura, Akiyama, Katoh.

Conflict of Interest Disclosures: None reported.

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