Acute generalised exanthematous pustulosis associated with shock

Abstract

A 23-year-old man with a history of end-stage renal disease was admitted to the hospital due to fever and shock, which occurred during his dialysis. One week prior, he developed an erythematous rash on his chest, face and back, associated with generalised eruption of pustules. In hospital, his status did not improve with norepinephrine and empirical broad-spectrum antibiotics. Following this, methylprednisolone was administered with remarkable improvement. Cultures revealed no infectious aetiology. Based on the morphology of the rash and a compatible skin biopsy, the diagnosis of acute generalised exanthematous pustulosis (AGEP) was established and considered the cause of his shock. The causative agent of his AGEP remained unknown. AGEP is a rare condition, most frequently associated with drug exposure. The removal of the offending agent is the treatment of choice. It can be complicated by shock in rare cases. In that scenario, systemic corticosteroids seem to improve outcomes greatly.

Background

Acute generalised exanthematous pustulosis (AGEP) (also known as toxic pustuloderma, pustular drug rash and pustular psoriasiform eruption with leucocytosis)¹ is a rare condition which presents with rapid onset of several non-follicular sterile pustules occurring diffusely on an oedematous and erythematous background.² The annual incidence is estimated at 1–5 cases per million people,³ and only a few cases described were associated with shock.^{2 4–8} AGEP is most frequently (90%) caused by drugs, but can also be caused by spider bites, herbal supplements or viral infections. Sometimes, the trigger remains unknown.^{1 2 9}

Case presentation

A 23-year-old man with a history of end-stage renal disease secondary to focal glomerulosclerosis was admitted to the hospital due to fever and shock during his dialysis session.

The patient has had end-stage renal disease since he was 6 years old when he developed nephrotic syndrome, secondary to focal glomerulosclerosis. At age 17, the patient underwent a cadaver donor kidney transplant. Due to medication non-compliance, he had allograft failure at age 19, forcing his return to dialysis. Due to allograft failure, the patient takes chronic tacrolimus 1 mg and prednisone 2.5 mg daily.

The patient was in his usual state of health until 1 week prior to admission when he developed an erythematous, intensely pruritic rash on his neck. In 4 days, the rash quickly progressed to his face, arms, chest and back. At that time, he presented to the emergency department. The patient had no other associated symptoms. There were no exacerbating factors. He denied recent travel, use of new foods, medications, detergents or perfumes. A skin biopsy was performed, and the patient was discharged with the provisional diagnosis of photoexacerbated allergic contact dermatitis.

One day prior to hospitalisation, he had a short episode of fever, with no other symptoms. On the day of admission, during his usual dialysis, the patient developed hypotension, tachycardia and fever. A fluid challenge was administered with no improvement. On transfer to the hospital, he was started on norepinephrine, cefepime and vancomycin for suspected septic shock. Despite the shock, the patient reported only being lightheaded but had no dyspnoea, diarrhoea, nausea or vomiting, rhinorrhea, sore throat or any pain. He had no urinary symptoms as he was fully anuric.

His admission vital signs were remarkable for fever (39.3°C) and tachycardia (136 bpm). On physical examination, there was a diffuse rash involving the face, neck, chest, abdomen and back, predominantly in the axillary folds and the forehead. The morphology of the rash consisted of confluent pinhead-sized papules and non-follicular pustules on an erythematous background (figure 1). Mild face oedema was also present. Purpuric lesions were present on his upper and lower extremities (figure 2), including the palms. No ulcers or erosions were seen in his mouth. His chest and abdominal examination, as well as his fistula, were unremarkable.

Figure 1.

Pustules can be seen on the left chest and axilla. The picture was taken 1 day after the initiation of methylprednisolone, and the erythematous background had already significantly improved.

Figure 2.

Right arm showing purpura. Similar lesions were also seen in his lower extremities and contralateral arm.

Investigations

The patient’s laboratory values on admission showed a mild leucocytosis (12×10⁹/L) with neutrophilia (11×10⁹/L) and no left shift or eosinophilia. They also showed an elevated C reactive protein, nine times the upper normal limit. All electrolytes and liver function tests were intact. Chest X-ray was unremarkable, and echo showed no vegetations.

All infectious exams were negative, such as blood cultures, Epstein-Barr virus, herpesvirus 6, parvovirus B19, rubella, syphilis, coronavirus (non-COVID-19), influenza, metapneumovirus, parainfluenza, respiratory syncytial virus, rhinovirus, Bordetella parapertussi, Chlamydophila pneumonia, Mycoplasma pneumoniae, adenovirus, HIV, and hepatitis B and C. A smear preparation of the pustules was not performed.

The skin biopsy done at his visit to the emergency department showed a drug reaction or grade 1 graft versus host disease (figure 3).

Figure 3.

Skin with mild basal vacuolar alteration, superficial perivascular lymphocytic infiltrate with few interstitial and perivascular eosinophils. The differential includes a drug reaction and grade 1 graft versus host disease.

Differential diagnosis

The differential diagnosis for the case included generalised pustular psoriasis (GPP), drug reaction with eosinophilia and systemic symptoms (DRESS) and AGEP.

GPP has a generalised rash that lasts for several days, with recurrence over the years. Patients with pustular psoriasis usually have arthritis and a history of psoriasis.^{2 8 10} The rash in our patient had an acute onset and was predominantly in the folds. He also had no history of arthritis or psoriasis. Although this is the typical presentation, GPP can also occur acutely in patients without any history of psoriasis or arthritis, and the histology might not reveal any psoriatic changes, making the differential diagnosis challenging.¹¹ In those cases, the healing time can help differentiate GPP from AGEP. In GPP, the clinical course is chronic, with frequent flare-ups, whereas in AGEP, the pustules regress in days leaving a post-pustular desquamation.¹¹

DRESS commonly exhibits a papulovesicular or papulopustular rash. Although it can have a pustular component, that is unusual, and it is less prominent than the pattern presented in the case. Also, DRESS requires organ dysfunction for the diagnosis such as hepatitis, pneumonitis and myocarditis,^{3 10} that were not seen in our patient.

Finally, AGEP is characterised by the development in hours or days of hundreds of pinhead-sized non-follicular pustules on an erythematous background.^{3 7} It can also be associated with fever, neutrophilia, facial oedema and lower extremity purpura.^{2 3 9} Due to the morphology of the lesions and the clinical course, a provisional diagnosis of AGEP was established.

Treatment

While in the intensive care unit (ICU), patient remained intermittently febrile and constantly tachycardic. Due to the clinical suspicion of AGEP, a new skin biopsy was performed. After the first day in the ICU, he was started on methylprednisolone 60 mg daily. The systemic inflammatory response decreased, and haemodynamic stability was restored. His rash improved significantly, leaving a collaret-shaped postpustular desquamation (figure 4). He stayed a total of 24 hours in the ICU, receiving norepinephrine.

Figure 4.

After 2 days of methylprednisolone, the pustules on the left chest and axilla can no longer be appreciated (upper right on the image). A pinpoint desquamation is seen in his abdomen.

The biopsy showed a subcorneal pustule, papillary dermal oedema and spongiosis (figure 5). With this, it was possible to apply the European Study of Severe Cutaneous Adverse Reactions scoring system,³ which led to a definitive AGEP diagnosis (table 1).

Figure 5.

Skin with subcorneal pustule, papillary dermal oedema, spongiosis and mild superficial perivascular lymphohistiocytic infiltrate with rare eosinophils.

Table 1.

The patient’s score based on the European Study of Severe Cutaneous Adverse Reactions scoring system for the diagnosis of acute generalised exanthematous pustulosis

Criteria	Description	Score
Morphology
Pustules	Compatible	1
Erythema	Compatible	1
Distribution or pattern	Typical	2
Postpustular desquamation	Yes	1
Total score (0 to 7)		5
Course
Mucosal involvement	No	0
Acute onset (≤10 days)	Yes	0
Resolution ≤15 days	Yes	0
Fever ≥38°C	Yes	1
Neutrophilia	Yes	1
Total score (–8 to +2)		2
Histology
Skin histology	Subcorneal pustule, papillary oedema, spongiosis	3
Total score (–10 to +3)		3
Overall score (−18 to +12)		10

The patient was regarded as not having an infection, and antibiotics were stopped on the third day. At that time, he started developing a worsening of his leucocytosis (up to 17×10⁹/L), with left shift and eosinophilia (2.6×10⁹/L). Also, he had an elevation of his liver enzymes (AST: 227 U/L, ALT: 313 U/L). Despite those laboratory abnormalities, the patient was asymptomatic. The pustules and the desquamation improved within 2–5 days after the initiation of corticosteroid. He was discharged on day 6 of hospitalisation on a prednisone taper with residual purpura.

Outcome and follow-up

In the follow-up, 10 days after the discharge, the patient had no symptoms and his leucocytosis, as well as the elevation of his liver enzymes resolved. All skin lesions were completely resolved.

Discussion

AGEP was first described in 1968¹² and recognised as a disease in 1980.¹³ It is characterised by an erythematous oedematous rash that commonly starts in the intertriginous areas or on the face. On top of this background erythematous rash, hundreds of non-follicular sterile pustules arise,³ with mucosal involvement occurring in 20% of cases.^{3 9}

Facial oedema, lower extremity purpura, atypical target lesions and blisters are not common but have been described.⁹ Our patient presented with the classic described rash, and lower and upper extremity purpura (figure 2).

The rash characteristically occurs in hours or days,⁷ and is associated with fever in 80% of the cases.^{2 3} In the present case, the rash developed over a week. In another case report,⁷ AGEP also developed weeks after initiation of the offending agent, potentially because the patient was using corticosteroids. Our patient was using 2.5 mg of prednisone as well as tacrolimus, which could potentially also explain the delayed course. Cutaneous lesions usually resolve in 4–10 days and are followed by pinpoint or collaret-shaped desquamation,^{1 3 10} which can be seen in this case (figure 4).

The offending drug or trigger was not identified in our patient. The patient believes that the rash and pustules significantly worsened with the administration of the vancomycin. However, at that time, he already had the rash and was haemodynamically unstable. It is unclear if indeed the vancomycin worsened the pre-existing AGEP or if the redness of the rash was simply exacerbated due to red man syndrome. Nevertheless, vancomycin is described to cause AGEP,⁷ which is reported to be associated with shock.^{5 7 8}

Regarding laboratory abnormalities, neutrophilia (>7×10⁹/L) is present in 80% of the cases,^{2 3} and eosinophilia in 30%.^{1 3} Mild acute renal injury and hepatic dysfunction are not frequent but have also been described, being typically transient.^{1 2} In the present case, eosinophilia and a transient hepatic dysfunction appeared only after clinical improvement.

Frequently, the smear preparation of the pustules is sterile.^{1 3} The culture of the smear preparation can help to exclude infectious skin diseases. Unfortunately, this evaluation was not performed.

The diagnosis of AGEP was made by the scoring system proposed by Sidoroff et al,³ which takes into account the morphology of the rash, the course and histological aspect. Patients who score from 1 to 4 have a possible diagnosis, 5–7 probable and 8–12 definitive. Our patient scored 10, a definitive diagnosis.

AGEP can lead to distributive shock.^{2 4–8} Since our patient presented with fever and haemodynamic instability, our initial hypothesis was septic shock. As antibiotics led to no clinical improvement and the extensive investigation for an infectious aetiology was negative, this suspicion seemed unlikely. His haemodynamic instability and systemic inflammatory response syndrome completely resolved after a few hours on a corticosteroid, as reported in two other cases.^{2 7} This very pronounced response to the methylprednisolone, without any other alternative diagnosis, made us conclude that the AGEP was the cause of the shock, rather than an accompanying symptom.

Learning points.

• Acute generalised exanthematous pustulosis (AGEP) should be suspected in patients presenting with fever, erythema and pustules. The use of the European Study of Severe Cutaneous Adverse Reactions scoring system can help establish the diagnosis and avoid inappropriate treatments.

• Although uncommon, AGEP can be associated with shock. The removal of the offending agent and the initiation of corticosteroids can significantly improve the clinical course and prevent unnecessary use of antibiotics.

• Mild and transient eosinophilia and hepatotoxicity can occur in AGEP, and present later during the disease.