Acute generalised exanthematous pustulosis induced by Pneumocystis jirovecii pneumonia prophylaxis with dapsone

Introduction

Acute generalised exanthematous pustulosis (AGEP) is a severe cutaneous adverse reaction (SCAR). Most cases are drug related; however, the condition has been associated with viral infections. ¹ Only one case of AGEP has been reported in an HIV-1 infected individual previously. ²

Case

A 34-year-old HIV-positive woman of African origin presented with a two-week history of a pustular skin rash, fever and malaise. This had started in the axilla and become generalised. She was diagnosed HIV positive in 2006 and her only exposure to short-term antiretroviral therapy was in 2006 and 2008 during pregnancy. CD4 count one month prior to admission was 176 cells/mm³. Despite multiple discussions she declined combination antiretroviral therapy (cART) as she felt physically well, however agreed to start Pneumocystis jirovecii pneumonia (PJP) prophylaxis. Three weeks prior to presentation she had been commenced on dapsone for PJP prophylaxis. Co-trimoxazole had been avoided due to slight anaemia and neutropenia which was felt to be secondary to untreated HIV infection and ethnicity.

On admission she was febrile (40℃), tachycardic and hypotensive. General systems examination was unremarkable. A widespread erythematous eruption with extensive non-follicular pustules was noted. Mucocutaneous sites were not involved. Haemoglobin was 7.6 g/dL; eosinophils were elevated at 0.67 × 10⁹/L, C-reactive protein 144 mg/L, alanine-amino transferase 160 U/L and creatinine 75 umol/L. Direct Coombs’ test was positive with raised reticulocytes supporting haemolysis. A venous methaemoglobin level was raised at 3.5% and chest radiography revealed subtle consolidation at the left costophrenic angle.

She was transferred to the high dependency unit for closer monitoring and commenced broad spectrum intravenous antibiotics and fluids. Dapsone was withdrawn in view of the severe rash and methaemoglobinaemia. Dermatology opinion raised the clinical suspicion of drug rash with eosinophilia and systemic symptoms (DRESS) or AGEP and skin biopsy was performed on day two of admission.

By day two of her admission, she remained systemically unwell with hypotension, tachycardia and progression of the rash. In view of her clinical deterioration intravenous hydrocortisone was commenced. Subsequent infective screen including serology for atypical pneumonia and Treponema pallidum, polymerase chain reaction testing for Epstein Barr virus, herpes simplex virus, cytomegalovirus, human herpes virus 6 (HHV-6) and multiple blood cultures, all of which were negative. Skin swab for bacterial culture was also negative. Methaemoglobin levels normalised following the withdrawal of dapsone. By day five the pustular rash began to desquamate (Figure 1) with a significant improvement in erythema and oedema. Her clinical condition improved and she made a full recovery. Skin biopsy supported the diagnosis of AGEP with histology revealing intraepithelial and subcorneal neutrophilic pustules with spongiosis. There was a perivascular infiltrate composed of eosinophils, neutrophils and lymphocytes (Figure 2). OPEN IN VIEWER

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Figure 2.

Skin biopsy demonstrating a subcorneal pustule (A). There is superficial dermal inflammation including lymphocytes, histiocytes and eosinophil polymorphs (B).

She is currently an outpatient having recently started cART. CD4 count is now 313 cells/mm³ and viral load 40 copies/mL. Her skin condition has fully resolved and she is now taking atovaquone for PJP prophylaxis.

Discussion

AGEP is a SCAR characterised by the rapid onset of a pustular eruption and erythema associated with fever and leukocytosis. ¹ First described by Beylot et al. ³ in 1980, the estimated incidence of AGEP is one to five cases per million per year. ¹ Antibiotics (beta-lactams and macrolides) are implicated in many cases although other medications and viral infections, such as HHV-6 have been reported.^3,4 Onset of symptoms is usually within a few days of initiating the culprit drug although this may be variable as in our case.

Erythema and pustules typically start on the face or intertriginous areas, gradually becoming generalised, with associated oedema. ⁵ Pyrexia characteristically accompanies the development of numerous small (<5 mm), sterile, non-follicular pustules. Additional findings may include atypical target-like lesions, purpura, vesicles, bullae and mucous membrane involvement.^1,3 Pustules resolve spontaneously within a few days of drug cessation. ⁵ Internal organs are generally not involved.

The clinical differential diagnosis includes AGEP, DRESS and acute pustular psoriasis of the von Zumbusch type. Diagnosis is based on clinical presentation and histology. Typical histopathological findings include subcorneal, intraepidermal pustules (spongiform or non-spongiform), oedema of the papillary dermis, perivascular infiltrates with neutrophils and exocytosis of some eosinophils.^1,5

Treatment involves withdrawal of the causative drug and supportive measures. Many cases are self–limiting; however, severe cases may require systemic steroids.^1,5 Prior to commencing high-dose steroids it is vital to exclude and/or cover for bacterial infections to reduce the risk of precipitating sepsis.

With regard to the pathogenesis of AGEP, histological and immunochemistry studies of the skin have suggested a role for the production of drug-specific T-cells (CD4⁺ and CD8⁺) and interleukin-8. ⁵ Although adverse drug reactions amongst HIV-infected patients are frequent,^6,7 AGEP is uncommon in the setting of HIV. It has been postulated that this may be related to immune dysregulation with insufficient activation of drug-specific CD4⁺ and CD8⁺ T cells. ⁸

Drug reactions in the setting of HIV and its treatment are common. This case illustrates a less common but important SCAR to recognise in our HIV cohort. It emphasises the need for future research into the role of drug-specific CD4⁺ and CD8⁺ T cells in the setting of HIV.