Permanent renal sequelae secondary to drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome induced by quetiapine

Abstract

We describe a Caucasian man in his late 60s who was admitted to the intensive care unit (ICU) with a history of cardiogenic shock secondary to an acute myocardial infarction. The patient’s baseline serum creatinine levels were 0.9–1 mg/dL. On day 7 of the admission treatment with quetiapine was initiated due to a delirium episode. The next day the patient developed an erythematous-maculopapular rash and fever, with eosinophilia in the blood count. Over the following days the patient experienced an acute deterioration of kidney function requiring continuous renal replacement therapy. The skin lesions and eosinophilia resolved after withdrawal of quetiapine and systemic steroid therapy was administered. The patient was discharged from the ICU with a serum creatinine level of 2.6 mg/dL. Three months later, blood tests showed no recovery of the kidney function. According to the Naranjo adverse drug reaction probability scale, this event would be classified as 'probable' DRESS syndrome and, based on the RegiSCAR scoring system, was classified as 'definite' DRESS syndrome.

Background

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome is a rare and potentially life-threatening adverse drug-induced reaction. The estimated prevalence of the syndrome ranges from 1 in 1000 to 1 in 10 000 drug exposures, and mortality has been estimated to be up to 10%.¹

The acronym designated by Bocquet et al ² consists of a severe skin eruption, fever, haematological abnormalities (eosinophilia or atypical lymphocytes in peripheral blood) and internal organ involvement (hepatitis being the most common followed by nephritis, pneumonitis, colitis, encephalitis, pancreatitis, thyroiditis or myocarditis).

DRESS syndrome can be assessed as a spectrum ranging from a mild rash with systemic eosinophilia that responds favourably to withdrawal of the offending drug to multiple organ involvement with high mortality and the need for immunosuppressive treatment. Death typically results from myocarditis and severe hepatitis leading to liver failure.³

The presence of delirium in critically ill patients is associated with a poor prognosis since it prolongs the duration of mechanical ventilation and intensive care unit (ICU) and hospital stay, as well as long-term cognitive impairment, increased likelihood of transfer to long-term care facilities and death. The pathophysiology of delirium is not fully understood; of the available pharmacological strategies, antipsychotics represent the most common treatment for ICU delirium.⁴ Quetiapine is an atypical antipsychotic drug approved for the treatment of schizophrenia and bipolar disorder and has been used off-label for the treatment of delirium in critically ill patients.⁵

We present the case of a patient who developed permanent renal failure secondary to DRESS syndrome induced by quetiapine.

Case presentation

A Caucasian man in his late 60s was admitted to the ICU with a history of cardiogenic shock secondary to an acute myocardial infarction that required haemodynamic support with an intra-aortic balloon pump and venoarterial extracorporeal membrane oxygenation (ECMO). The patient denied the chronic consumption of alcohol, recreational drugs or alternative therapies. His past medical history included non-insulin-dependent type 2 diabetes mellitus, high blood pressure and hypercholesterolaemia. Chronic medication included enalapril 20 mg orally daily and atorvastatin 10 mg orally daily. Baseline serum creatinine was 0.9–1 mg/dL and the glomerular filtration rate was >60 mL/min/1.73 m².

On admission to the ICU a physical examination was performed. The patient was 170 cm tall, weighed 95 kg and had a body mass index of 32.9 kg/m². Clinical examination showed a patient with a Glasgow Coma Scale of 2/15. He required invasive mechanical ventilation, anticoagulant and antiaggregant therapy was initiated with unfractionated heparin and aspirin, and 1 g of intravenous (IV) cefazolin every 8 hours was administered as antimicrobial prophylaxis.

On the second day of admission, atrial fibrillation was documented and treated with a loading dose of 900 mg IV amiodarone followed by a maintenance dose of 200 mg orally daily. Two days later a respiratory infection was suspected (chest X-ray and raised levels of inflammatory markers), so antibiotic escalation was required with piperacillin-tazobactam (4/0.5 g IV every 8 hours) and nebulised gentamicin (200 mg every 12 hours). At the same time, the patient experienced non-oliguric renal failure (blood urea nitrogen 238 mg/dL, serum creatinine 2 mg/dL, estimated glomerular filtration rate 31 mL/min/1.73 m²) that required continuous renal replacement therapy (CRRT). Three days later (day 5 of admission) the patient experienced neurological and respiratory improvement and mechanical ventilation was withdrawn.

On day 8 the patient developed an erythematous-maculopapular rash which initially appeared on the upper chest area and spread to the trunk and extremities (figure 1), with a temperature of 38°C. Blood tests revealed eosinophilia in the peripheral blood count. Quetiapine (25 mg orally daily) had been initiated 12 hours before due to a delirium episode. DRESS syndrome was suspected and, initially, the patient received topical corticosteroids (prednicarbate) with minimal effectiveness. Two days later the rash and the systemic eosinophilia worsened so piperacillin-tazobactam and nebulised gentamicin were discontinued and, instead, aztreonam (2 g IV every 6 hours) and clindamycin (600 mg IV every 8 hours) were initiated as well as prednisone 10 mg orally daily.

Figure 1.

Erythematous-maculopapular rash.

Despite the changes in treatment, the patient did not show any improvement so amiodarone was withdrawn (day 15 of admission), suspecting it could be causing the eosinophilia. Despite this, there was an increase in the eosinophil count. On day 18 of admission the patient reached the maximum peak of eosinophilia (figure 2). The patient's medication was then rechecked and quetiapine was discontinued. Simultaneously, kidney function remained altered and interstitial nephritis was suspected. Corticosteroids were increased to 1 mg/kg/day with IV methylprednisolone. After all these changes, the skin lesions and eosinophil count started to decrease for the first time.

Figure 2.

Evolution of the eosinophil count during the ICU admission.

On day 20 of the admission the patient received a single dose of 25 mg quetiapine to treat a new episode of delirium, and a new increase in blood eosinophils was observed on the following day. Quetiapine was then permanently suspended. ECMO was removed on day 22 and the patient was discharged from the ICU on day 29.

Investigations

To define more accurately the DRESS syndrome, a scoring system known as the RegiSCAR scoring system has been developed.⁶ RegiSCAR constitutes the European registry of severe cutaneous adverse reactions (SCAR) including Stevens–Johnson syndrome, toxic epidermal necrolysis, acute generalised exanthematous pustulosis and DRESS. One of the aims of this registry is to delineate each of these SCARs as distinct entities. In this respect, the RegiSCAR scoring system has been designed to grade DRESS cases as 'no', 'possible', 'probable' or 'definite' case. Scores of 5 or more are classified as definite. Based on the signs and symptoms of our case, it could be classified as definite (score of 7) (table 1).

Table 1.

Registry of severe cutaneous adverse reaction diagnosis score for drug rash and eosinophilia with systemic symptoms to quetiapine

Items	Answer	Score
Fever (≥38°C)	Yes	0
Enlarged lymph nodes (≥2 sites, >1 cm)	No	1
Atypical lymphocytes	Unknown	0
Eosinophilia
700–1499 or 10–19.9%
≥1500 0≥20%	Yes	2
Skin rash
Extent >50%	Yes	1
At least 2: oedema, infiltration, purpura, scaling	Yes	1
Biopsy suggesting DRESS	Unknown	0
Internal organ involvement
1	Yes	1
≥2
Resolution in >15 days	Yes	0
At least 3 biological investigations done and negative to exclude alternative diagnosis	Yes	1
Final score		7

DRESS, Drug Reaction with Eosinophilia and Systemic Symptoms.

Treatment

The first step in the treatment of DRESS syndrome is the discontinuation of the suspected drug. Supportive therapeutic approaches must also be initiated, and a moderate-to-high dose of systemic corticosteroids is generally essential for treatment.⁷

During the patient's admission in the ICU, the clinical pharmacist carried out medication reconciliation and daily checked the medical and medication history. No drug interactions were found. The clinical pharmacist reviewed the patient’s treatment in order to determine which drug was the cause of DRESS syndrome and if there were any drug interactions. Antimicrobial agents have been reported to be one of the most common drugs related to DRESS syndrome,³ which is why treatment with piperacillin-tazobactam was discontinued first and treatment with oral corticoid was initiated (10 mg oral prednisone daily). Despite these changes, the rash and the eosinophilia kept increasing, so the clinical pharmacist then rechecked the medication and it was decided to discontinue treatment with amiodarone, but the symptoms did not improve.

The clinical pharmacist searched and identified in the literature some cases that related DRESS syndrome with atypical antipsychotics,^8–14 so quetiapine treatment was withdrawn and the corticosteroid dose was increased up to 1 mg/kg/day (methylprednisolone 90 mg IV). After these changes the skin lesions resolved completely and the eosinophil count started to decrease for the first time. High doses of corticosteroids were maintained for 2 weeks and were then gradually reduced until complete withdrawal after 6 weeks of treatment.

Outcome and follow-up

The patient was discharged from the ICU after 29 days with no skin signs and normal eosinophil count. Serum creatinine remained high (2.6 mg/dL). Three months later, during the follow-up visit, tests showed no recovery of the kidney function. The suspicion of the adverse reaction was reported to the Spanish Pharmacovigilance Centre.

Discussion

The diagnosis of DRESS syndrome is challenging, given its variable presentation. The main clinical features are rash, fever, haematological abnormalities and organ involvement, all of which are highly non-specific. Rechallenging with the suspected drug is considered the gold standard for drug eruptions; however, it cannot be used to confirm the culprit drug for DRESS due to the possible life-threatening consequences.¹⁵

The pathophysiology of DRESS remains unknown, but suspected factors include reactivation of viral infections, genetic predisposition and impaired drug metabolism pathways in certain patients. Many drugs have been reported to be a causative agent of DRESS syndrome. However, only a limited number of them are frequently encountered as culprits, including anticonvulsants, antimicrobial agents, antipyretic agents and others.¹⁶

We found only one report of DRESS syndrome induced by quetiapine in the available literature. In that case, the causality by the RegiSCAR scoring system was possible with a score of 3.⁸ We also found a case report of myocarditis associated with DRESS syndrome caused by treatment for bipolar disorder with quetiapine and lithium, but in this case it was not possible to determine which drug was responsible for the DRESS-associated myocarditis.⁹ In 2016 the US Food and Drug Administration (FDA) issued a safety communication about the atypical antipsychotic olanzapine causing a rare but severe skin reaction that can progress to affect other parts of the body known as DRESS syndrome. A search of the FDA Adverse Event Reporting System (FAERS) database identified 23 reported cases of DRESS syndrome with olanzapine worldwide since 1996.¹⁰ Before that, in 2014, the FDA issued the same alert with ziprasidone, a second-generation antipsychotic medication, because the FAERS had received six reports of ziprasidone-associated DRESS.¹¹ There are several published case reports of patients experiencing DRESS syndrome with other atypical antipsychotics like clozapine.^{12 13} There have not been any alert reports from the FDA with quetiapine, although information from the data submitted by the WHO global adverse drug reaction database (Vigibase) indicates that 46 cases of DRESS syndrome linked to quetiapine have been reported.¹⁴ Consequently, quetiapine could share this adverse effect with other atypical antipsychotics.

The causality of DRESS syndrome as an adverse drug reaction due to the administration of quetiapine was also evaluated using the algorithm of Naranjo et al,¹⁷ obtaining a final score of 7. According to this value, the likelihood of quetiapine-induced DRESS syndrome was classified as probable.

The liver is the most frequently affected organ, with elevated serum alanine aminotransferase found in approximately 70% of patients with DRESS syndrome. The kidney is also commonly affected, with 11% of patients exhibiting renal disease. In most cases there is only mild renal impairment, which usually resolves after the withdrawal of the offending drug.³ In our patient, liver function tests did not show any abnormalities; however, the renal function was altered requiring renal replacement therapy during the patient's admission in the ICU, CRRT was administered for the first time 4 days before the rash and the eosinophilia appeared. The decision to start CRRT was triggered by non-oliguric renal failure (blood urea nitrogen 238 mg/dL, serum creatinine 2 mg/dL, estimated glomerular filtration rate 31 mL/min/1.73 m²). Four days later the rash developed an erythematous-maculopapular pattern. At that time the urea nitrogen level had decreased, which allowed us to withdraw the CRRT. Forty-eight hours later the patient experienced anuria. Blood tests showed an increase in serum creatinine (4.3 mg/dL) and a deterioration in the estimated glomerular filtration rate to 13 mL/min/1.73 m²; blood urea nitrogen was 93 mg/dL. CRRT was then restarted and maintained until day 12 when the urine volume was restored. Despite all these manoeuvres, recovery of renal function was incomplete so the nephrologist suspected a drug-induced interstitial nephritis. However, a renal biopsy could not be performed to disclose drug-induced interstitial nephritis because the patient was receiving treatment with an infusion of heparin. After discharge from the ICU, renal function remained altered with an estimated glomerular filtration rate of 26 mL/min/1.73 m² and serum creatinine of 2.6 mg/dL. Three months later, during the follow-up visit, tests showed no recovery of the glomerular filtration rate (25 mL/min/1.73 m²) with serum creatinine of 2.7 mg/dL.

Conclusion

We report a case of DRESS syndrome probably induced by quetiapine. Eosinophilia and skin lesions fully resolved after the discontinuation of quetiapine and corticosteroid therapy, but the patient developed chronic kidney disease. It is essential for healthcare professionals to be aware of the possibility of this adverse reaction, which can cause permanent disability, and to communicate it to the pharmacovigilance system when suspected.

Learning points.

• The use of the RegiSCAR scoring system should be considered to define severe cutaneous adverse reactions like Stevens–Johnson syndrome, toxic epidermal necrolysis, acute generalised exanthematous pustulosis and DRESS syndrome.

• This case of DRESS syndrome suggests that this adverse event might be associated with atypical antipsychotics, so it is essential to be aware of this severe adverse reaction when using them to treat delirium in patients in the ICU because of off-label use, the comorbidities that these patients have and the importance of a rapid on-site treatment strategy.

• Collaborative working relationships between pharmacists and physicians are essential to promote better patient care and the safe use of medicines.

• It is essential to communicate adverse reactions to the pharmacovigilance system.

Ethics statements

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