Dear Editor,
Severe cutaneous drug reactions like acute generalised exanthematous pustulosis (AGEP) is characterised by acute onset of erythematous and oedematous eruptions with non-follicular sterile pustules, accompanied by fever mainly due to antibiotics while drug reaction with eosinophilia and systemic symptoms (DRESS) is characterised by generalised skin rash, lymphadenopathy, hypereosinophilia, lymphocytosis, and internal organ involvement mainly caused by aromatic anticonvulsants, allopurinol. Herein, we describe AGEP-DRESS overlap in a patient who developed features of AGEP and sequentially followed by DRESS, following oral diclofenac. AGEP-DRESS overlap,1 which is defined as cases simultaneously or sequentially qualifying for both diagnoses.
A 45-year-old female patient was being treated with the tablet diclofenac for the past four days. She presented with fever of two days duration and multiple tiny pustules superimposed on erythema over extremities and trunk with flexural preponderance, relatively sparing face, palms, and soles, associated with severe burning sensation. There was no history of sore throat, insect bites, or similar rash in the past. Patient had tachycardia, fever 101 °F with no lymphadenopathy.
Dermatological examination revealed multiple discrete 1–2 mm non-follicular pustules on an erythematous base over the trunk, arms, and thighs (Fig. 1a). Investigations revealed total leukocyte count of 24,600/mm3 with 90% neutrophils, ESR-82 mm of fall in first hour, and mildly deranged liver enzymes. Procalcitonin, ANA, RA factor, ASO titre, Serological tests for dengue, HIV 1&2, hepatitis A, B, and C, and RT PCR for COVID-19 were negative. Pustules were sterile and showed multiple polymorphonuclear cells. Cultures from the pustule, blood, and urine were also sterile. Skin biopsy from the representative lesion showed sub-corneal pustules predominantly composed of neutrophils along with spongiosis of the underlying epidermis in the absence of parakeratosis and supra-papillary thinning (Fig. 2a).
Fig. 1.
(A) shows multiple discrete pustules over erythematous base involving back. (B) shows swelling and erythema over face (C) shows multiple erythematous plaques involving legs without pustules.
Fig. 2.
(A) (100×) Epidermis shows sub-corneal pustules composed of neutrophils and cell debri associated with spongiosis. The upper dermal capillaries show perivascular inflammatory cells composed of lymphocytes, neutrophils and eosinophils suggestive of features of AGEP. (B) (400×) Epidermis shows moderate spongiosis associated with exocytosis by lymphocytes & eosinophils along with occasional necrotic keratinocytes suggestive of features of DRESS.
By day 6, initial lesions had started healing with exfoliation; however, patient continued to have cephalo-caudal progression of new lesions with changed morphology at previously uninvolved sites along with high-grade fever, facial oedema, oral mucosal petechial haemorrhages, and bilateral axillary and inguinal lymphadenopathy, with multiple erythematous plaques and few targetoid lesions, along with the absence of pustules (Fig. 1b and c). Repeat investigations showed leucocytosis, mild transaminitis, raised ESR, and positive CRP. Biopsy from targetoid lesion on the leg showed spongiosis, exocytosis of eosinophils, occasional necrotic keratinocytes, and marked papillary oedema with the absence of sub-corneal pustule suggesting DRESS (Fig. 2b). Patient fulfilled Regi SCAR criteria (probable case) of DRESS also with a score of 04.
Hence, the patient was diagnosed with AGEP-DRESS overlap. She was continued on a high dose of steroids to which she responded completely over the next fortnight. It is planned to taper the steroids over next three months. Informed consent of patient was obtained for the use of images for publication purpose.
Only 2% adverse drug reactions are adverse which include AGEF and DRESS.2 AGEP is characterised by acute onset pinpoint-sized, non-follicular, sterile pustules, on oedematous erythematous skin, with flexural preponderance, two to four days after the intake of culprit drug usually associated with a fever above 38 °C, and a neutrophil count of more than 7 × 109/μl with no internal organ involvement.
DRESS is characterised by fever, facial oedema, lymphadenopathy, and morbilliform eruption, which may progress to a widespread erythematous rash, two to six weeks after the intake of drug. Eosinophilia and atypical lymphocytic cells are a hallmark of this condition. However, there are case reports about DRESS without eosinophilia.3
Diagnostic criteria for both AGEP and DRESS individually take into consideration three aspects, namely lesional morphology, disease course, and histological features. Patients are differentiated into possible/probable/definite cases depending on the extent of involvement of the above features. Most patients of AGEP remain stable after withdrawal of the offending drug, with only a few cases reported with hemodynamic instability.4 Although, lymphadenopathy with systemic involvement, more extensive cutaneous involvement in the form of erythematous plaques on extremities and facial oedema in case of AGEP, and histologic findings on skin biopsy, given rise to suspicion of DRESS, as has been reported in case reports.5 On reviewing the literature, only few cases of true AGEP-DRESS overlap,1,5,6 which is defined as cases simultaneously or sequentially qualifying in full for both diagnoses, fulfilled in our case too. The most common drugs associated with AGEP include penicillin and related antibiotics while DRESS is most frequently associated with aromatic anticonvulsants and allopurinol.
Diclofenac sodium is a Non steroidal anti-inflammatory drugs (NSAIDs) and is a derivative of phenylacetic acid causing adverse cutaneous manifestations ranging from stomatitis, photosensitivity, hypersensitivity reactions, and urticaria.7 AGEP and DRESS have common pathogenesis involving T cells, likely explaining the overlap features in two different entities. T cells recruit and activate monocytes, eosinophils, or neutrophils and release various cytokines and chemokines. Granulysin is the dominant cytokine in SJS/TEN, IL5 in DRESS, and IL-8, IL-17, and IL-22 in AGEP. Pichler et al. suggested sub-classifying delayed hypersensitivity reactions into T-cell reactions, which through the release of certain cytokines and chemokines specifically activate and recruit monocytes (type IVa), eosinophils (type IVb), or neutrophils (type IVD). The complex immune reactions in overlap pattern can be combined to explain clinical ambiguities among SCARs.8
Because two SCARs (AGEP and DRESS) are causing typical clinical manifestations of AGEP initially and then fulfilling criteria of DRESS sequentially in our case, following drug administration, physicians must consider such manifestations while dealing with the drug reaction cases as it will determine patient care and prognosis.
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Patients informed consent was obtained.
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Disclosure of competing interest
The authors have none to declare.
Acknowledgements
None.
References
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