Pustulosis acuta generalisata following chemotherapy in an HIV-positive patient

Introduction

A 35-year-old man presented in August 2012 to the emergency department with a two-day history of a pruritic papulopustular rash symmetrically located on both arms and extended from the hands to the proximal aspect of his upper limbs, preserving the shoulder area (Figure 1). On examination, temperature was 36.6℃, blood pressure, pulse, oxygen saturation and electrocardiogram (ECG) were normal. The patient reported having a sore throat with mild fever 14 days before the appearance of the skin manifestations, but the symptoms spontaneously resolved in one week. His current medications consisted of tenofovir + emtricitabine, darunavir/ritonavir and low-molecular weight heparin as thrombosis prophylaxis after an episode of port-a-cath thrombosis. OPEN IN VIEWER

The patient had a history of cleared HBV infection and HIV infection diagnosed in 2006 and had been treated since March 2012 with tenofovir + emtricitabine and darunavir/ritonavir. He was diagnosed with a seminoma (stage IIC) in July 2011 and in August 2011 he underwent orchifunicolectomy followed by three cycles of chemotherapy with cisplatin, etoposide and bleomycin, the last of which was administered one month before presentation to the emergency department. His antiretroviral therapy (ART) was discontinued during all chemotherapy cycles because of potential combined toxicities and pharmacological interactions. He was admitted to our hospital 40 days before the appearance of the aforementioned rash during his third and last chemotherapy cycle for an episode of febrile neutropenia (G4 toxicity, requiring 7 G-CSF injections) and cutaneous HSV infection treated with ceftriaxone, fluconazole and acyclovir. During this hospitalization his CD4 cell count was 454 cells/mm³ (28.4%) and HIV-RNA was 9878 cp/ml.

The emergency physician prescribed cetirizine, cutaneous gentamicin + betametasone and valaciclovir and discharged the patient home.

Three days after being discharged from the emergency department, the lesions increased in number involving the palms bilaterally and the left conjunctiva (Figure 2). Some lesions evolved to multiple confluent papulopustules. The patient also reported diffuse arthralgias involving especially the lower limbs. His physical examination was unremarkable. The right knee was red, warm, swollen and tender as were both ankles. OPEN IN VIEWER

The full blood count, liver, renal function tests and urinalysis were normal; C-reactive protein was 48.2 mg/dl (reference range: 2–6 mg/dl), erythrocyte sedimentation rate was 35 mm/h (reference range: 1–15 mm/h); absolute granulocyte count was 2900 cells/mm³, CD4 cell count was 616 cells/mm³ (32.4%) and HIV-RNA was <37 cp/ml.

Serology for HCV, VZV, Adenovirus, Salmonella, Brucella, Mycoplasma, RPR and TPHA were negative; serology for HSV, CMV and Parvovirus B19 documented previous infections. Serology for Coxsackievirus was slightly positive with a 1 : 16 titer (reference range: <1 : 8). Rheumatoid factor and anti-nuclear antibody tests yielded negative results. Anti-Streptolysin O titer was 371 UI/ml (reference range: 20–250 UI/ml).

The key feature is a history of previously untreated streptococcal pharyngitis associated with inflammatory joint involvement, cutaneous manifestations and elevated inflammatory markers. Although post-streptococcal disorders are uncommon in adult patients, the clinical picture suggested a possible immunologic reaction involving streptococcal antigens, such as pustulosis acuta generalisata.

Amoxicillin-clavulanate was then administered for 10 days. After four days, the skin rash began to resolve; on examination knees and ankles were still tender and warm, but the patient reported less pain and an increased range of motion.

One month later, the cutaneous and articular manifestations were completely resolved; anti-streptolysin O titer rose to 520UI/ml and inflammatory markers decreased (ESR 18, CRP 2.5).

Discussion

Streptococcus pyogenes is a Gram-positive coccus which represents the only species included in Lancefield group A streptococci (GAS). GAS are responsible for pharyngitis and other suppurative infections linked to various post-infectious syndromes. Both streptococcal pharyngitis and acute rheumatic fever typically occur in children between 5 and 14 years of age, ¹ but adults of all ages can be infected. The signs and symptoms of group A streptococcal pharyngitis are similar to those found in other pharyngeal infections, and diagnosis is usually made thanks to throat cultures or positive rapid antigen detection tests. ¹

Acute rheumatic fever is an immune-mediated disorder which follows an untreated streptococcal infection. The diagnosis is based on Jones' criteria, ² and requires two major criteria or one major and two minor criteria plus supporting evidence of current or recent GAS infection (throat culture or rapid antigen test positive for GAS or documentation of an elevated or rising serum anti-streptococcal antibody titre). ³ Major criteria are carditis, polyarthritis, chorea, erythema marginatum and subcutaneous nodules, while minor manifestations are arthralgia (if no arthritis), fever, elevated acute phase reactants (C-reactive protein and erythrocyte sedimentation rate) and a prolonged PR interval seen on ECG.

Pustulosis acuta generalisata, or post-streptococcal pustulosis (PAG) is a term coined by Braun-Falco et al. ⁴ to describe a post-streptococcal condition characterized by scattered symmetrical eruption of sterile pustules with an inflammatory halo typically affecting hands, feet, and, to a lesser extent, arms, legs and trunk. The pustules may also be confluent and may arise on normal skin. Other common features include an elevated ESR, leukocytosis, fever and arthropathy. Similar cases of adult patients who developed, subsequently to tonsillitis, PAG with joint involvement were previously described.^5,6 Differential diagnosis includes acute generalized exanthematous pustulosis (AGEP) and generalized pustular psoriasis (GPP).

Our patient had no history of possible recent enteroviral infections and had not recently assumed any new medications, thus excluding AGEP. Furthermore, he had no history or signs compatible with psoriasis, making a diagnosis of GPP unlikely.

The patient had a history of recent immune-suppression (derived from both chemotherapy and his HIV-positive status) followed by an immune-reconstitution caused by the re-introduction of ART and the completion of chemotherapy cycles, which could have led to an aberrantly high response to streptococcal antigens, thus causing typical post-streptococcal sequelae as arthritis, elevated inflammatory markers and cutaneous manifestations.