Clinical diagnosis and management of drug reaction with eosinophilia and systemic symptoms (DRESS) in children: An EAACI position paper

Abstract

Background

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare but severe cutaneous adverse drug reaction encountered in both adults and children with a significant mortality rate. A number of guidelines or consensus reports have been published for optimal diagnosis and treatment of DRESS in adults, but none specifically for children. It is increasingly evident that there are significant differences in drug pharmacokinetics, metabolism, co‐occurring infections, comorbidities, clinical manifestations, and severity of drug allergies between children and adults, as well as across different pediatric age groups.

Aim

This position paper aimed to evaluate and compare all the available data related to clinical features, diagnosis, and treatment of DRESS in adults and children in an attempt to identify the differences and gaps, and produce recommendations on diagnosis and treatment of this fatal disorder in children.

Materials and Methods

A search of MEDLINE (via PubMed) and Web of Science from 2000 to 2024, including studies that assessed children with DRESS syndrome, was performed. In the absence of pediatric‐specific data, studies involving adults or mixed populations (both adults and children) were also analyzed. Among a total of retrieved 5264 records, following duplicate removal and full‐text assessment, a total of 493 manuscripts related to DRESS were included in the report and recommendation generation. The recommendations for the clinical diagnosis and treatment of DRESS in children were formulated in accordance with the directionality and strength guidelines suggested by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group and related research.

Results

Among retrieved records, there was only one randomized controlled trial, one meta‐analysis, one systematic review, six retrospective comparative studies on treatment, and one systematic review on the accuracy of skin tests in DRESS. All of these studies were conducted in adults, rarely involving children, and none were exclusively performed in pediatric populations. Comparison of systematic case reviews revealed that some aspects of clinical features, prognosis, and mortality in children differed from those in adults. The diagnosis of DRESS is based on several clinical and laboratory criteria, which have been developed for adult patients but have not been validated for children. Causality assessment tools, in vivo skin tests, and in vitro tests have been used widely in adults to identify the culprit drugs in DRESS, while these tools are more rarely employed or reported in children. Adult guidelines or consensus reports recommend a severity‐based, stepwise treatment approach for DRESS, whereas no such severity classification or treatment algorithms exist exclusively for children, leading to inconsistent management with numerous instances of overtreatment and undertreatment.

Conclusion

There is very limited evidence‐based data on the diagnosis and management of DRESS both in adults and in children. Until more evidence becomes available, we propose a diagnostic algorithm, a DRESS severity classification, and a severity‐based tailored treatment approach, all adapted to pediatric needs together with issued recommendations to enable physicians to provide better care and reduce morbidity and mortality in pediatric patients.

Key message.

Appropriate diagnosis and treatment of DRESS are critical in children. Current diagnostic criteria and treatment approaches in clinical practice are largely derived from studies and recommendations based on adult populations. However, the clinical presentation of DRESS in children appears to differ from that in adults, often featuring a milder course and lower mortality rates. The applicability and validity of existing diagnostic criteria in pediatric populations remain uncertain, although RegiSCAR scoring is widely used. In light of the limited evidence‐based information on pediatric DRESS, including diagnostic criteria and treatment modalities, our recommendations are primarily informed by the evaluation of sparse pediatric data, some adult studies, comparisons of clinical features between adults and children, and expert opinion and clinical practice. This position paper aims to propose a diagnostic perspective and a rational and efficient treatment algorithm that could reduce the risk of complications and mortality while minimizing the risks of undertreatment or overtreatment in children.

1. INTRODUCTION

Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug‐induced hypersensitivity syndrome (DIHS), is a rare but severe cutaneous adverse drug reaction (SCAR) characterized by both skin and systemic symptoms, with a significant mortality rate. ¹ The pathophysiology of this delayed reaction remains incompletely understood but involves an interplay between altered drug metabolism, interactions between the drug and its metabolites with the immune system leading to T‐cell activation, transient immune suppression, deficits in regulatory pathways with reactivation of latent herpesvirus infections, and a genetic predisposition associated with certain human leucocyte antigen (HLA) haplotypes. ² , ³ , ⁴ , ⁵ , ⁶ , ⁷

DRESS is often referred to as the “chameleon” of drug hypersensitivity reactions (DHR) because of its highly variable and unpredictable clinical course, often mimicking many other diseases commonly encountered in clinical practice. ¹ , ⁸ , ⁹ , ¹⁰ The increased prevalence of infections and clinical entities, such as Kawasaki disease, further complicates the differential diagnosis in children. ¹¹ , ¹² , ¹³

The diagnosis of DRESS relies on several clinical and laboratory criteria that were developed for adult patients. However, comparative studies have shown that clinical features and prognosis in children differ from those in adults. ⁹ , ¹⁴ , ¹⁵ , ¹⁶ Although the applicability and validity of the current diagnostic criteria—namely the European Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) ¹⁴ and the Japanese J‐SCAR ¹⁵ —in children are unknown, the RegiSCAR criteria are widely used in clinical practice.

Causality assessment tools, ¹⁷ , ¹⁸ in vivo skin tests, and in vitro tests have been used to identify culprit drugs in DRESS, with low to moderate sensitivity in adults. ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ However, these tools are more rarely employed or reported in children. ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ , ²⁹ Since drug provocation tests are generally contraindicated in DRESS, the specificity of skin tests and in vitro tests remains uncertain. ²² , ³⁰ , ³¹

A number of adult guidelines or consensus reports, mostly based on expert opinion and some comparative studies, recommend a severity‐based, stepwise treatment approach for DRESS. ²¹ , ³² , ³³ , ³⁴ As there are no practical guidelines specific to pediatric patients with DRESS, they are generally treated according to adult practices, which may not be suitable for all ages within childhood, or based on individual clinician experiences. ³⁵ , ³⁶ , ³⁷ Accordingly, a recent multicentre survey revealed significant knowledge gaps in the recognition, diagnosis, and management of severe drug hypersensitivity reactions among physicians. ³⁸

The main objective of this task force (TF) was to identify the needs for the recognition and management of pediatric DRESS by reviewing extensive data on epidemiology, clinical and laboratory features, diagnosis, treatment, and short‐ and long‐term management. After identifying the gap in the availability of a pediatric DRESS severity classification and tailored treatment, a severity‐based algorithm was developed as a proposal for practical treatment. The TF issued recommendations on the diagnosis, classification, and management of DRESS in children to enable physicians to provide better care and reduce morbidity and mortality in pediatric patients.

2. METHODOLOGY

This TF on pediatric SCARs, which commenced in August 2023 by participation of 11 researchers, agreed on the methodological protocol for an extensive literature review and analysis, and thereafter on the production of a first position paper on DRESS. MEDLINE (via PubMed) and Web of Science were searched from database inception to December 26, 2023, including studies that assessed children with DRESS syndrome. The search queries are detailed in Table S1. In the absence of pediatric‐specific data, studies involving adults or mixed populations (both adults and children) were also analyzed. Given the limited information available on pediatric DRESS, we included all types of studies, such as randomized controlled trials (RCTs), cohort studies, case–control studies, case series, and case reports. Furthermore, systematic reviews, guidelines, position papers, and consensus reports concerning children or adults were consulted. Studies published before 2000 were excluded due to the obscurity of this diagnosis in earlier literature and the generally low quality of these papers. We continued to track evidence published after the initial search in a non‐systematic manner until September 2024.

The recommendations for the clinical diagnosis and treatment of DRESS in children were formulated in accordance with the directionality and strength guidelines suggested by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group and related research. ³⁹ , ⁴⁰ , ⁴¹ Recommendations were included in the manuscript only after achieving consensus, defined as at least 80% agreement among panel members. Details of methodology and formulation of recommendations can be found in supporting information (Tables S1A and S1B).

Among a total of retrieved 5264 records, following duplicate removal and full‐text assessment specifically focused on DRESS, a total of 493 manuscripts related to DRESS were included in the report and recommendation generation. Among these, there was one randomized controlled trial (RCT), which was prematurely terminated, ⁴² one meta‐analysis, ⁴³ one systematic review, ⁴⁴ six retrospective comparative studies on treatment, ⁴³ , ⁴⁵ , ⁴⁶ , ⁴⁷ , ⁴⁸ , ⁴⁹ and one systematic review on the accuracy of skin tests in DRESS. ²² All of these studies were conducted in adults, rarely involving children, ²² , ⁴⁵ , ⁵⁰ and none were exclusively performed in pediatric populations.

One of the limitations of this systematic analysis was that treatment recommendations depended on limited evidence obtained from mostly adult studies together with a very limited number of studies in children. In addition, we did not use the evidence‐to‐decision framework to formulate recommendations, which would have required gathering evidence across 12 criteria for each question, including desirable and undesirable effects, values and preferences, resources required, and acceptability. ⁵¹ , ⁵²

3. EPIDEMIOLOGY AND RISK FACTORS

The rarity of DRESS limits the feasibility of large population‐based studies. Most data on pediatric DRESS come from isolated case reports, small case series, and pharmacovigilance records, which likely underestimate its true incidence and prevalence. The estimated incidence ranges from 1:1000 to 1:10,000 exposures to various medications ³ , ⁵³ , ⁵⁴ , ⁵⁵ , ⁵⁶ , ⁵⁷ and has been reported as 0.9:100,000 inhabitants or 10:1000,000 in the general population. ⁵⁸ , ⁵⁹ In hospitalized patients, the incidence ranges from 2.18 to 40:100.000 inpatients. ⁵⁶ , ⁶⁰ , ⁶¹ , ⁶² Most studies focus on adult or mixed populations and do not provide separate data for pediatric cases, but allow comparison of hazard ratios. ⁶³ During a 42‐month Spanish study (2012–2015) conducted through a Pharmacovigilance Program for Laboratory Signals, a calculated incidence rate of 3.89 cases per 10,000 patients overall and 2.88 cases per 10,000 pediatric patients was found. ⁶² A recent study on pediatric SCARs in a hospital setting reported an overall incidence of 0.31% among pediatric inpatients (50/15,684), with the specific incidence of DRESS being 0.11%. ²⁷ These findings challenge the general notion that the incidence of DRESS is lower in children than in adults. Although some adult studies observed a higher incidence of DRESS in women, ¹ , ⁵³ , ⁶¹ , ⁶³ , ⁶⁴ pediatric studies showed no significant gender predilection. ⁹ , ²⁵ , ³⁵ , ³⁶ , ³⁷ , ⁶⁵

DRESS is typically associated with fewer drugs compared to other cutaneous adverse drug reactions. Current evidence indicates that the two most commonly implicated drug classes in pediatric patients are anticonvulsants and antibiotics. ⁹ , ²⁵ , ²⁷ , ³⁶ , ³⁷ , ⁵⁴ , ⁶⁵ , ⁶⁶ , ⁶⁷ These are also frequently associated with DRESS in adults, alongside nonsteroidal anti‐inflammatory drugs, allopurinol, and antiretrovirals. ¹ , ¹⁰ , ⁵³ , ⁵⁴ , ⁶¹ , ⁶³ , ⁶⁸ , ⁶⁹ , ⁷⁰ Among antibiotics, sulphonamides, vancomycin, and beta‐lactams (BLs) are the primary culprits. For anticonvulsants, aromatic drugs—particularly carbamazepine—are the main agents responsible. ²⁵ , ²⁶ , ²⁷ Recent findings have suggested an interesting association between DRESS and the use of aromatic ring‐containing drugs, regardless of whether they are anticonvulsants. ⁵³

The results of studies investigating the role of genetic risk factors in DRESS are variable. In Han Chinese populations, a significant association has been identified between allopurinol‐induced DRESS and the HLA‐B*58:01 allele. ⁷¹ Similarly, a correlation has been observed between the HLA‐A*31:01 genotype and carbamazepine‐induced DRESS in European‐Caucasian, Japanese, and Chinese populations, but with a low predictive value for screening. ⁷² , ⁷³ , ⁷⁴ , ⁷⁵ Associations have been demonstrated between the HLA‐B*51:01 and HLA‐C*14:02 genotypes and phenytoin‐induced DRESS in Thai children ⁷⁶ ; the HLA‐A*31:01 and HLA‐B*15:02 genotypes have been linked to carbamazepine‐induced SCARs in Caucasian children ⁷⁷ and an association has also been reported between the CYP2C19*2 genotype and phenytoin‐induced DRESS in Thai children. ⁷⁸

4. CLINICAL FEATURES AND COMPLICATIONS

DRESS is a severe DHR characterized by the appearance of fever, skin rash, and organ involvement. ¹ , ³ , ²⁵ In the last few years, systematic case reviews of pediatric DRESS covering the last 60 to 70 years have been published. ⁹ , ³⁶ , ³⁷ , ⁶⁵ A comparison of the mean values of surveyed pediatric cases to those of adult systematic case reviews ¹⁰ , ⁵⁴ is provided in Table 1, in an attempt to exhibit similarities and dissimilarities in clinical features and prognosis between children and adults. Most of these studies have included cases with a RegiSCAR score ≥4, except two which also included possible (score 2 or 3) DRESS cases. ⁹ , ⁵⁴ Additionally, pediatric DRESS case series involving 10 or more cases are given in detail in our supplemental material, in order to inform the reader that variable frequencies of presentations also existed in the pediatric literature (Table S2).

TABLE 1.

Comparison of clinical and laboratory features between children and adults with DRESS.

	Systematic case reviews in children 9 , 36 , 37 , 65	Systematic case reviews in adults 10 , 54 , 79
General characteristics
Sample size (n of patients)	130, 37 148, 36 354, 65 644 9	141, 79 151, 10 172 54
Restriction of cases to a RegiSCAR score ≥4	Yes, 36 , 37 , 65 No 9	Yes, 10 , 79 No 54
Age (years)	8.7 (0.05–17) 37 *** , 8.8 ± 4.9 65 ** , 9.5 (5–14) 9 **** , 10 (0.17–17) 36 , ***	40.7 ± 20.9 54 ** , 44.5 (23–61) 10 **** , 57.0 (18.1–93.0) 79
Latency period (days) )	18.9 (7–120) 65 *** , 23.2 (0.42–112) 36 *** , 23.8 (3–60) 37 , *** 24 (14–28) 9 ****	24 (16–35), 10 24.5 (1–160) 79 * , 27 ± 16 54 **
F/M ratio	0.8, 36 0.92, 9 1.03, 37 1.07 65	0.90, 54 0.96, 10 1.43 79
Main drugs involved #
Antibiotics	18, 9 30.8, 37 31, 65 33.6 36	8.6, 54 30, 10 43.3 79
Anticonvulsants	49, 65 50, 37 51, 9 52.6 36	24.1, 79 27, 10 45 54
Skin involvement type #
Erythrodermia	5.4, 37 13.8, 36 53 65	9, 10 42.6, 79 54 54
Maculopapular rash	25, 65 62, 9 69.7, 36 89.2 37	60, 54 66, 10 78 79
Pruritus	32.3 37	44 10
Vesicles/bullae/pustules	6 65	16 10 ,22.7 79
Facial edema	28 9 31, 65 51.5 37	39 54 , 44 10 , 71.6 79
Skin involvement >50% BSA	54, 9 71.7 36	44, 10 51.8 79
Mucosal involvement	20, 65 24 9	16, 10 24.8 79
Systemic involvement #
Fever	67, 65 76, 9 93.9, 36 96.2 37	64, 54 82.9, 79 95 10
Enlarged lymph nodes in more than 2 sites	54, 9 55, 65 70.9, 36 74.6 37	54.6, 79 56, 54 62 10
Liver involvement	73, 9 , 65 80, 37 84.5 36	81.6, 79 88, 10 94 54
Kidney	12, 9 , 65 15.4, 37 16.9 36	8, 54 32, 10 39.7 79
Pulmonary	7.7, 37 14, 65 18, 9 20.9 36	5, 54 12, 10 12.1 79
Heart	2.7, 36 3.1, 37 5, 65 9 9	2, 54 3, 10 7.9 79
Nervous system	7 9	2 54
GIS(pancreas and/or intestines)	5.5, 36 11 (pancreas 2), 9 34 65	8 (pancreas 1), 10 2.1 (pancreas) 79
Haemophagocytosis	<3 65	7.8 79
Laboratory findings #
Eosinophilia	58, 65 60, 9 70,3 36 90 37	66, 54 84.4, 79 87 10
Atypical lymphocytes	28, 9 35, 65 40.8 37	27, 54 33 10
Leucopenia	11, 9 14.2 36	NR
Leucocytosis	28, 9 45.9, 36 66 65	36 79 (lymphocytosis)
Thrombocytopenia	< 3, 65 10, 9 14.2 36	NR
Anemia	0.8 (hemolytic), 37 <3, 65 15 9	NR
Viral reactivation #
HHV‐6	5, 9 33, 36 42.9, 37 46 65	15, 10 25, 79 80 54
CMV	1, 9 3.4 65	9.6 79
EBV	1, 9 1.7 65	23 79

^# Values are given in percent (%) of reported cases

^*Median (range)

^**Mean ± SD.

^***Mean (range).

^****Mean (IQR).

Although DRESS can occur in children of any age, even under 1 year, ²⁷ , ³⁶ , ⁸⁰ , ⁸¹ systematic case studies report a mean age of onset around 8 to 10 years. ³⁵ , ³⁶ , ³⁷ , ⁶⁵ The latency period for DRESS is similar in adults and children, with a mean of 3 to 4 weeks after initiating a new medication, ²⁵ , ⁶⁵ , ⁸¹ although longer periods have been reported with anticonvulsants ³⁶ , ³⁷ , ⁸² , ⁸³ and shorter periods of a few days with antibiotics. ²⁵ , ⁸⁴

The skin is the primary organ involved, with maculopapular rash, erythroderma, and facial edema being the most common manifestations ⁹ , ¹⁰ , ⁶⁵ , ⁸⁰ (Table 1). Skin involvement >50% body surface area (BSA) is more frequently reported in children when compared to adults. Mucosal involvement, mostly oral and/or ocular, is observed in almost a quarter of children, in similar rates to adults. ⁹ , ⁶⁵ Fever, liver involvement, lymphadenopathy, and eosinophilia are among the most common systemic features both in children and adults, though these may be absent in 10% to 30% of cases. ³⁶ , ³⁷ , ⁸¹ Systematic case reviews demonstrated that children tended to have a higher rate of involvement of more than two affected organ systems when compared to adults. ⁹ , ¹⁰ Hepatitis is the most frequently observed liver complication, although cholestasis may also occur both in adults and children. ⁹ , ³⁶ , ⁶⁵ , ⁸² Pulmonary manifestations [cough, shortness of breath, interstitial pneumonia, and/or pleural effusion] are reported in up to 20% of pediatric series, slightly higher than adults. ²⁵ , ³⁶ , ³⁷ , ⁶⁵ Renal involvement [acute kidney injury, renal failure and/or proteinuria] more frequently affected adults, while rates of gastrointestinal involvement (vomiting, diarrhea, abdominal pain, and less frequently, colitis, oesophagitis, or pancreatitis) and cardiac involvement [tachycardia, electrocardiographic(ECG) abnormalities, myocarditis, cardiogenic shock] were similar (Table 1). Cardiac involvement is very important and associated with significant mortality. ⁹ , ²⁵ , ³⁵ , ³⁷ , ⁶⁰ Neurological symptoms, such as decreased consciousness, seizures, confusion, and irritability, were more frequently noted in small children (<6 years of age) than in older ones or adults, in parallel to pre‐existing seizure disorders. ⁹ Meningitis, encephalitis, and peripheral neuropathy have also occasionally been reported. ⁹ , ²⁵ However, these features are not consistently replicated in other case reviews. It should be emphasized that data was not reported for respiratory, renal, gastrointestinal, pancreatic, and neurological involvement in all pediatric series. Since some patients may have subtle symptoms of important organ involvement, a high degree of alertness is warranted and tests such as amylase, lipase, troponin, electrocardiography, chest x‐rays, computerized tomography, and/or magnetic resonance imaging should be employed immediately when suspected. The clinical description of pediatric DRESS patients may also be biased due to missing mild cases in the literature, its low incidence rate, and the absence of appropriate diagnostic criteria for this age group.

Herpes virus, especially herpes virus‐6 (HHV‐6), cytomegalovirus (CMV) and Epstein–Barr virus (EBV) reactivations presenting a few weeks after the start of treatment are characteristic of, and play a crucial role in the development and/or progression of DRESS. ¹ , ⁷ , ¹⁴ , ¹⁵ Cytomegalovirus reactivation can be associated with pneumonia, peritonitis, sepsis, colitis, intestinal bleeding, fulminant disease, and even mortality if unrecognized. ¹⁵ , ³⁴ , ⁴⁵ , ⁴⁶ , ⁵⁹ On the other hand, it has been proposed that long‐lasting EBV and HHV‐6 reactivation could be associated with the later development of autoimmune disease. ¹⁵ , ³⁴ , ⁴⁴ , ⁴⁶ Comparison of systematic case reviews reveals that HHV‐6 reactivation rates are almost similar in adults and children, while these figures for CMV and EBV ⁹ , ²⁷ , ⁶⁵ are much lower and/or more rarely reported in children than in adults. (Table 1) Hence, the role of CMV and EBV reactivations on complications and prognosis is more obscure for the pediatric age group and an important area to be investigated.

DRESS typically follows a prolonged clinical course, taking 2–6 weeks for resolution, though this varies widely depending on severity, treatment response, and complications. ²⁵ , ³⁵ , ³⁷ , ⁸⁰ , ⁸² , ⁸³ Acute complications include severe infections, steroid side effects, organ failure, and intensive care unit admission. ²⁵ , ²⁶ , ³⁵ , ³⁶ , ³⁷ , ⁸¹ The course of the DRESS syndrome frequently shows various episodes of complete or partial relapses or recurrences, despite removing the culprit drug. Possible causes are rapid corticosteroid dose tapering (occurs within 2 days after reduction); the administration of new drugs or dose increase of a previously tolerated drug (occurs within 3 days), viral reactivations, and spontaneous forms without obvious cause. ³ , ³⁴ , ³⁵ , ⁵⁰ , ⁶⁹ Flare‐ups or relapses, defined as the reappearance or worsening of symptoms during recovery, occur in 1.5 to 6.8% of children, primarily during steroid tapering. ³⁵ , ³⁷ Recurrence, defined as a new episode of DRESS after full recovery due to re‐exposure to the original culprit drug or a different drug, was reported in 2.5% of children. ³⁵ Comparison of systematic case reviews revealed that relapses occur more frequently in adults than children, probably related to higher virus reactivation rates. ¹⁰ , ³⁵ , ³⁷ , ⁶⁵ , ⁷⁹ (Table 2). Afiouni et al. identified that pediatric DRESS patients with relapse or recurrences had more comorbidities including neuropsychiatric disorders, more frequent organ involvement, and more severe signs and symptoms. ⁶⁵ Additionally, initial systemic steroid treatment (82% vs. 48%) and intravenous immunoglobulin (IVIG) treatment (24% vs. 10%) were more prevalent in relapsing children in this series. ⁶⁵

TABLE 2.

Comparison of treatment modalities and prognosis between children and adults with DRESS.

	Pediatric case Series (n ≥ 10) 25 , 26 , 27 , 66 , 80 , 81 , 82 , 83 , 84	Systematic case reviews in children 35 , 36 , 37 , 65	Systematic case reviews in adults 10 , 54 , 79
Sample size (n of patients)	10, 82 10, 83 11, 84 16, 66 17, 27 18, 26 22, 81 32, 80 49 25	130, 37 148, 36 354, 65 644 35	141, 79 151, 10 172 54
Treatments
Only supportive (with or without TCS)	0, 82 , 84 6.1, 25 9, 80 12.5, 66 13.6, 81 35.3, 27 100 26	10.8, 37 21.4, 35 29 65	0, 79 5, 10 22 54
Only TCSs (without SCS)	0, 82 , 84 9.4, 80 30.6 25	6.3 36	9, 10 25.5 79
Systemic CSs (1–2 mg/kg/g, po or iv)	55.1, 25 56, 80 56.3, 66 64.7, 27 80, 82 86.4, 81 100 26 , 84	57, 65 75.6, 35 85.3, 36 88.5 37	73, 79 78, 54 86 10
Pulsed MP 30 mg/kg, iv	0, 26 , 27 , 66 , 81 , 84 3, 80 20 82	NR separately	NR separately
IVIG	0, 26 , 27 , 81 , 82 , 84 12.2, 25 12.5 (wsc), 66 15.6 (wsc), 80 20 83	2.8 (wsc), 35 11.9, 36 12.3, 37 13 65	0, 79 6, 10 9 54
IVIG + SCS	0, 26 , 27 , 80 , 81 , 82 , 84 18.7 66	9.8 35	NR, 10 0, 79 5.8 54
Antiviral	0, 25 , 26 , 27 , 66 , 81 , 82 , 84 3.1 80	0, 36 1, 65 1.5 37	NR, 10 , 54 5.7 79
Cyclosporine	0, 26 , 27 , 66 , 80 , 81 , 82 , 84 3.1, 80 4.1 25	0, 36 , 37 , 65 1.1 35	0, 79 3 10
Other immunomodulatory drug	0, 25 , 26 , 27 , 66 , 81 , 82 , 84 3.1 80 (1 case:6‐MP)	0, 36 , 37 , 65 NR 35	0, 10 , 54 2.8 79 (4 cases:anti‐IL‐5R)
Plasmapheresis/ plasma exchange	0 25 , 26 , 27 , 66 , 80 , 81 , 82 , 84	0, 35 , 65 0.7, 36 2.3 37	0, 54 1 10
N‐acetyl cysteine	NR	NR	NR
Prognosis
Relapses	4.5, 81 5.6, 26 6.3, 80 10, 83 20, 82 22.4 25	1.5, 37 2.5 (recurrence), 35 4.8, 65 6.8 (flare‐up) 35	8.5, 79 13 10
Any long‐term sequelae	4.5, 81 6.2, 66 9.4, 80 10.8, 25 20 82 , 83	3.3, 53 4.2, 35 8, 65 10.8 37	NR
Any autoimmune sequalae	3.1, 80 4.5, 81 6.2, 66 10.2, 25 20 82 , 83	3.3, 35 3.7, 65 8.5 37	3, 10 12.1 79
Diabetes type 1	0, 81 , 82 , 83 3.1, 80 6.2 66	1.1, 35 2.3 37 , 65	NR separately
Autoimmune thyroid disease	3.1, 80 4, 25 4.5, 81 10 82 , 83	1.4, 35 , 65 3.8 37	5.7 79
Mortality	0, 27 , 66 , 80 , 82 , 83 , 84 4, 25 4.5, 81 5.6 26	3.0, 35 , 36 , 65 5.4 37	5.2, 54 7.1, 79 9 10

Note: Values are given percent (%) of reported cases.

Abbreviations: 6‐MP, 6 mercaptopurin; anti‐IL‐5R, anti‐interleukin (IL)‐5R antibodies; IVIG, Intravenous immunoglobulin; MP, Methylprednisolone; NR, Not reported; SCS, Systemic corticosteroid; TCS, Topical corticosteroid; wsc, without systemic corticosteroid.

Although complete recovery is generally expected, some patients, even after complete resolution, may develop long‐term(months to years) complications, particularly autoimmune diseases such as type 1 diabetes mellitus, thyroid disease, alopecia, vitiligo, systemic lupus erythematosus, adrenal insufficiency, autoimmune hemolytic anemia, and type III polyglandular autoimmune syndrome, and also non‐autoimmune complications such as chronic organ disease, recurrent herpesvirus reactivations, opportunistic infections, steroid side effects, multiple drug hypersensitivity, and psychiatric disturbances. ²⁵ , ³⁵ , ³⁷ , ⁴⁷ , ⁶⁵ , ⁸¹ , ⁸² , ⁸³ , ⁸⁵ Some evidence suggested that autoimmune sequelae were more frequent and occurred earlier in young patients compared to adults, ⁴⁷ , ⁸⁵ but larger systematic case reviews reveal that the rates were almost similar, between 3 to 10%, in both age groups (Table 2).

The general comparison of systematic case reviews suggests that children can manifest a wide range of systemic manifestations, and adult and pediatric DRESS cases are not strikingly different in the spectrum of manifestations. However, certain clinical features, organ involvement rates, and virus reactivation patterns, as discussed above, are different from adults ⁹ , ¹⁰ , ²⁵ , ³⁶ , ⁸⁰ , ⁸⁵ (Tables 1 and 2).

5. DIAGNOSIS

5.1. Clinical diagnosis and differential diagnosis

The diagnosis of DRESS is currently based on characteristic clinical features, laboratory findings, and scoring systems that incorporate these elements. Skin histopathology, while not diagnostic, is often utilized to exclude alternative diagnoses. ¹⁴ , ⁸⁶ , ⁸⁷

Two main diagnostic criteria for DRESS are widely recognized: the RegiSCAR criteria ¹⁴ and the Japanese J‐SCAR criteria ¹⁵ both originally developed through adult studies. In Europe and many other regions, the RegiSCAR criteria are the most commonly used, with diagnostic thresholds as follows: 2–3 as a possible case, 4–5 as a probable case, and a score >5 as a definite case ¹⁴ , ⁸⁸ (See Figure S3). These thresholds reflect the severity of DRESS, with probable and definite cases representing the full clinical spectrum of the disease. Adult guidelines and most adult case series, as well as pediatric systematic case reviews, consider only cases scoring 4 or above as DRESS. ¹⁰ , ¹⁴ , ²¹ , ³² , ³⁶ , ³⁷ , ⁵⁴ , ⁶⁵ , ⁸⁰ , ⁸⁸

However, it is important to note that these criteria were initially designed for research purposes and have not been validated for routine clinical practice, particularly in specific populations such as children or immunosuppressed patients. ⁹ , ¹⁶ Pediatric systematic case reviews have highlighted significant differences between children and adults, including patterns of organ involvement, rates of viral reactivation, and laboratory abnormalities that raise questions about the suitability of RegiSCAR and other diagnostic criteria for use in pediatric populations ⁹ (Table 1). Nonetheless, this TF currently recommends using RegiSCAR criteria also for children, until new criteria validated for this age group are available, but the limitations for pediatric patients should be recognized.

DRESS can mimic or overlap with various other diseases, including infections, collagen vascular diseases, cytokine storm syndromes, malignancies, and other SCARs, needing careful differentiation both at initial presentation and during subsequent management. ³ , ⁷ , ⁸ , ¹¹ , ¹³ , ¹⁴ In children, the frequent occurrence of primary viral infections—such as those caused by EBV, CMV, parvovirus, measles, rubella, echovirus, influenza, and parainfluenza—further complicates accurate diagnosis. These infections often imitate the clinical and laboratory features of mild to moderate DRESS, challenging the applicability of current diagnostic criteria. ⁶ , ¹¹ , ¹³ , ¹⁴ , ⁸⁹ , ⁹⁰ , ⁹¹ , ⁹² , ⁹³ RegiSCAR criteria emphasize the exclusion of alternative causes, particularly infectious diseases. ¹⁴ , ⁸⁸ However, formal laboratory testing to rule out these conditions is not systematically performed and is often absent in many published pediatric studies. ⁹ , ³⁶ , ³⁷ , ⁶⁵

Beyond the limitations of current diagnostic criteria, there is an evolving understanding of DRESS as a condition that exists on a broader spectrum, ranging from mild cases with rashes and minor symptoms to severe, life‐threatening multiorgan dysfunction and fatalities. ¹⁶ , ⁹⁴ Recent studies in adults have identified patients with DRESS‐like features or conditions such as severe maculopapular exanthema or drug‐related rash with eosinophilia with a RegiSCAR score <4, hence not meeting the threshold for probable or definite DRESS, but some of them exhibited morbidity comparable to major DRESS cases with occasional mortality and distinct clinical features. ¹¹ , ¹² , ⁸⁷ , ⁹⁵ , ⁹⁶ It is not clear yet if these are precursor forms of DRESS or different entities. The pediatric implications of these findings are not yet fully understood, though they are likely more complex than in adults. This underscores the need for a similar approach in defining and managing children across an extended DRESS spectrum. ¹¹ , ¹² , ¹³ , ³⁵ , ⁹⁴

5.2. Causality Assessment and Testing for identification of the culprit

Causality assessment in DRESS is essential due to the high risk of life‐threatening reactions upon reexposure to the culprit or cross‐reactive drugs. During the acute phase, causality assessment tools (CATs) such as Naranjo's assessment scale ¹⁷ or the World Health Organization‐Uppsala Monitoring Centre (WHO‐UMC) scale ¹⁸ can be used; however, their sensitivity for drug causality assessment in children with DRESS remains mostly unclear. However, a pediatric study found that the Naranjo scale was useful for assessing DRESS caused by anticonvulsant monotherapy but also highlighted its limitations. ⁹⁷ Additionally, a recent systematic review found that consistency between CAT scores and skin testing results was just 37.4% for the patch test (PT) and 36.5% for the intradermal test (IDT) in DRESS cases. ²²

In vivo and in vitro tests are valuable for identifying the primary culprit and also evaluating less suspected drugs, cross‐reactivity, and neosensitizations. These tests should be conducted 3 to 6 months after resolution to minimize the risk of DRESS relapse or false‐negative results due to prolonged steroid treatment. ¹⁹ , ²⁰ , ²¹ , ⁹⁸ However, in selected cases where urgent treatment decisions are necessary, earlier testing (after at least 6 weeks) has been found both useful and safe in some studies. ²⁶ , ⁹⁹ , ¹⁰⁰ , ¹⁰¹ In cases of ambiguous DRESS, in vivo testing can be performed after 6 weeks. ⁹⁶

The primary in vivo diagnostic tests for DRESS include PT and IDT with delayed reading (d‐IDT); PT should always be performed first due to its superior safety profile. ¹⁹ , ²⁵ , ³² , ⁹⁹ The recommended test techniques, maximum non‐irritant concentrations, and dilutions used in adult DRESS cases can also be applied to children until pediatric‐specific data becomes available. ¹⁹ , ¹⁰² , ¹⁰³ , ¹⁰⁴ In vivo tests carry the risk, although rare, of recurrence of DRESS. A flare during PT, such as mild skin rashes, occurs in up to 20% of adults, ¹⁰⁵ , ¹⁰⁶ , ¹⁰⁷ but systemic reactions are rare and have been mainly reported with tuberculosis(TB) drugs in patients with HIV infection undergoing early testing due to treatment urgency. ¹⁰⁸ , ¹⁰⁹ Pediatric studies confirmed the safety of PTs in DRESS with no reported reactions or flares in available series. ²⁵ , ²⁶ , ²⁷ , ²⁸ , ¹¹⁰ (Table S3). If PT results are negative, d‐IDTs can be performed, especially with low suspicion drugs, in patients receiving multiple drug regimens or when evaluating alternative treatment options. Although testing with highly suspected or cross‐reactive drugs may rarely induce systemic reactions, ¹¹¹ , ¹¹² , ¹¹³ , ¹¹⁴ , ¹¹⁵ other studies have demonstrated their safety, and sometimes higher sensitivity in adult DRESS. ¹⁹ , ²² , ¹¹⁶ , ¹¹⁷ Intradermal tests are rarely used in pediatric DRESS due to difficulties in practical application and safety concerns, especially in younger children. However, recent reports of approximately 20 IDTs performed with antibiotics in children with DRESS have not revealed any systemic reaction or recurrence ²⁵ , ²⁶ , ²⁷ , ¹¹⁸ , ¹¹⁹ (Table S3).

Patch tests' sensitivity in DRESS depends on the tested drug, but specificity is not known. ¹⁹ , ²² , ²⁸ , ⁹⁵ , ⁹⁹ , ¹⁰⁷ , ¹¹⁶ , ¹¹⁷ In a systematic analysis of 217 PTs and 52 IDTs performed in DRESS cases, including mostly adults but also children, the positivity rates were 58.4% in PTs, 66.5% in d‐IDTs, and 25% in skin prick tests. ²² The sensitivity of these tests in pediatric DRESS series is reported to be between 33.0 to 71.4% for PTs with antiepileptics and antibiotics ²⁵ , ²⁶ , ²⁷ , ²⁸ , ⁶⁶ , ¹¹⁰ , ¹¹⁵ and 22.0 to 75.0% for a limited number of IDTs with antibiotics ²⁵ , ²⁶ , ²⁷ , ²⁸ (Table S3). These figures align with adult and mixed‐series DRESS data (Table S3), as well as a systematic review. ¹⁹ , ²² , ⁹⁵ , ¹¹⁵ , ¹²⁰ , ¹²¹

In vivo skin testing has low sensitivity and age and safety limitations in DRESS, leading to increased interest for in vitro tests. ¹²² , ¹²³ The lymphocyte transformation test (LTT) and enzyme‐linked immunospot (ELISpot) assay are the most commonly used, with some studies suggesting they are more sensitive than skin tests for certain drugs. ²³ , ¹²³ , ¹²⁴ These tests offer advantages such as patient safety, the ability to test multiple suspected drugs, and, in the case of ELISpot, higher sensitivity when performed in the acute phase (within 2 weeks) of DRESS. ¹²³ , ¹²⁵ , ¹²⁶ , ¹²⁷ However, technical difficulties such as the necessity to work with radioactive material (3H‐thymidine) for LTT and sophisticated laboratory equipment and personnel requirements limit their use in clinical practice. ²³ , ¹²⁵ , ¹²⁶ , ¹²⁷ In children, the role of in vitro tests in DRESS has been explored in some study populations. ²³ , ²⁴ , ²⁵ , ²⁷ , ²⁹ , ¹²⁸ Cabanas et al. found that the sensitivity and specificity of LTT (3H‐thymidine) in the recovery phase of DRESS were 73% and 82%, respectively, while in the acute phase, they were lower (40% and 30%). ²³ The highest sensitivity was observed for anticonvulsants, anti‐TB drugs, and beta‐lactams (BL). ²³ In children, the LTT positivity rate was found to be between 50% and 75% during the recovery of DRESS in some studies. ²⁵ , ²⁷ ELISpot is another promising test for identifying culprit drugs in DRESS, with sensitivity values from 52% to 77.8%, in comparison to values from 7% to 66.7% for LTT in adults, while specificity for these tests was reported to be between 95% and 100%. ²⁴ , ¹²⁶ , ¹²⁷ A key difference is that ELISpot is useful for confirming culprits during the acute symptomatic phase of DRESS, whereas LTT is more reliable in the recovery phase after 3 to 6 months. ¹²⁶ , ¹²⁷ Some pediatric studies also support the use of drug‐specific cytokine production assays as rapid diagnostic tools during the acute phase, and in immunosuppressed patients. ²⁹ , ¹²⁵ The combination of different in vivo and in vitro methods has been shown to increase diagnostic sensitivity up to 90% in mixed populations with DRESS. ²⁴ , ²⁹ , ¹²⁹

Despite these advances, CATs, skin tests, and in vitro tests are not always sensitive enough, meaning negative results do not exclude a drug's responsibility or sensitization. Drug provocation testing (DPT), which is the gold standard for diagnosing non‐severe reactions, is contraindicated in DRESS, especially with highly suspected or cross‐reactive ones. ³⁰ , ³¹ However, some authors suggest that in special circumstances, such as HIV patients or essential medications like anti‐TB agents, drugs with a low probability of being responsible and with negative skin test results can be reintroduced cautiously in specialized centers after weighing the benefits and the risks of recurrence. ³¹ , ¹³⁰ , ¹³¹ , ¹³² On the other hand, some research suggested that desensitization may be a safer and more effective approach to reintroducing anti‐TB drugs in DRESS patients when compared to graded challenge testing or switching to alternative medications, with success rates of up to 85% in adults and adolescents. ¹²¹ , ¹³³ The authors have suggested that desensitization may reduce reaction severity or induce tolerance due to the dose‐dependent T‐cell response observed in DRESS. ¹²¹ , ¹³⁴ However, these are high‐risk procedures that require expert oversight and strict safety protocols and should not be attempted in routine practice.

Pharmacogenomic risk factors may play an important role in identifying patients at risk for DRESS. Certain HLA alleles have been strongly associated with the condition in specific ethnic populations, as mentioned in the epidemiology section, which have shown negative predictive values up to 100%, but low positive predictive values. ⁷¹ , ⁷³ , ⁷⁴ , ⁷⁵ , ⁷⁶ , ⁷⁷ , ¹³⁵ , ¹³⁶ , ¹³⁷ Some clinical pharmacogenetics consortiums and working groups recommend HLA‐allele‐specific screening for the prevention of serious reactions with some drugs in special ethnic groups such as HLA‐B*57:01 for abacavir, HLA*B15:02 and HLA‐A*31:01 for carbamazepine, HLA‐B*13:01 for dapsone, and HLA‐B*58:01 for allopurinol. ⁴ , ⁷² , ¹³⁸ , ¹³⁹ However, since HLA testing does not always provide reliable predictive results, it cannot replace clinical evaluation and testing in identifying the culprit drug.

Based on the available evidence from studies in both children and adults, this TF developed an algorithm and recommendations on diagnosis and culprit identification in pediatric DRESS (Figures 1 and 2, Table 3). The TF recommends using the Naranjo and/or WHO‐UMC scales for causality assessment in the acute stage (and/or during retropective evaluation), but vigilance about the low sensitivity and the pitfalls of these scales is needed. The TF recommends performing, after at least 3 to 6 months after resolution of DRESS, PTs with all suspected drugs and alternatives, as an initial testing procedure. If the PTs are negative, d‐IDT with low suspicion and/or alternative drugs, especially antibiotics, is recommended. In selected cases of absolute necessity, d‐IDT with culprit and/or cross‐reactive drug(s), especially antibiotics, in diluted concentrations can be performed, but caution for reactivation is highly warranted. The TF suggests performing in vitro tests, especially LTT during the recovery phase and ELISpot analysis during both the acute and recovery phases for identification of culprit drugs, if technically feasible. The TF recommends against performing DPT with suspected drug(s) and cross‐reactive medications. Any positivity in any step should be accepted as confirmed drug allergy and these drug(s) and cross‐reactive ones should be prohibited lifelong. Very essential drugs (especially anti‐tuberculosis agents) with low probability of being the culprit and negative in skin tests and in vitro tests can be re‐administered in specialized centers with a very cautious protocol, after balancing the benefits and risks of recurrence. ¹³⁰ , ¹³¹ , ¹³²

FIGURE 1.

Proposed work‐up for identification of culprit drug(s) in childhood DRESS. WHO‐UMC:World Health Organization‐Uppsala Monitoring Centre causality assessment scale. d‐IDT: Intradermal test with delayed reading. DPT: Drug provocation test. CR: Cross‐reactive. * For in vitro tests: At least 4 weeks after steroid cessation; for in vivo tests: At least 3–6 months after resolution. **In infants and small children, it is suggested to perform IDTs only if strongly needed after careful consideration of the individual case. ***This procedure can only be performed in highly specialized centers because of the high risk of recurrence.

FIGURE 2.

General approach to management of DRESS in children. Management during the acute‐subacute phase, which may extend to weeks, includes diagnosis by scoring, differential diagnosis, identification of culprit(s) and cessation, an algorithmic treatment according to severity classification, and close follow‐up for complications and flare‐ups until full resolution. Afterwards, these children should be closely followed up for months, and in vivo and in vitro tests should be employed to identify the responsible drug(s), which should be avoided lifelong.

TABLE 3.

Task force recommendations on diagnosis and culprit identification in children with DRESS.

Recommendation	Strength of recommendation
Diagnosis and differential diagnosis
1. The TF recommends to use current RegiSCAR criteria for diagnosis of DRESS in children, until specific criteria specific for this age group have been developed, but the limitations for pediatric patients should be recognized Patients with a RegiSCAR score ≥4 are recommended to be regarded as having DRESS and a severity classification to Grade 1, 2 or 3 should be made (see Table 4) Patients with a RegiSCAR score of 2–3 are recommended to be regarded as having an indeterminate form between systemic maculopapular exanthema and DRESS; named as AMBIGUOUS DRESS(see Table 4) and included in the evaluation and management protocol with close follow‐up	Strong
2. The TF recommends to perform a detailed study for differential diagnosis of infectious disorders (including primary herpes viridae infections, which are highly prevalent in children) and other disorders, such as rheumatologic diseases, cytokine storm syndromes, malignancies or other SCARs	Strong
Causality assessment
1. The TF recommends to use the Naranjo and/or World Health Organization‐Uppsala Monitoring Centre (WHO‐UMC) scales for causality assessment in the acute stage (or during retropective evaluation), but vigilance about the low sensitivity and the pitfalls of these scales is needed	Strong
Identification of responsible drug(s)
1. The TF recommends to perform in vivo skin tests for identification of culprit drug(s), co‐ or, neo‐sensitizations, and finding safe alternatives They should be performed after at least 3 to 6 months after resolution in Grade 1, 2 or 3 DRESS, in order to avoid relapse and/or false negatives from prolonged corticosteroid treatment If there is absolute need, tests can be done earlier in these cases, but recurrence risk increases In ambiguous DRESS cases with rapid resolution, in vivo tests can be performed after 6 weeks	Strong
2. The TF recommends to perform first patch tests (PT) with all suspected drugs and for choice of alternatives However, children with HIV may carry a higher risk for recurrence during patch tests	Strong
3. The TF suggests to perform intradermal tests with delayed reading (d‐IDT) with suspected drug(s), especially antibiotics, if the PTs are negative	Conditional
4. The TF recommends to perform intradermal tests with delayed reading (d‐IDT) with low suspicion and/or alternative drugs, especially antibiotics, if the PTs are negative	Strong
5. The TF suggests to perform in vitro tests, especially lymphocyte transformation test during recovery phase and ELISpot analysis during both the acute and recovery phase for identification of culprit drugs, if technically feasible	Conditional
6. The TF recommends against performing drug provocation tests (DPT) with highly suspected drug(s) and cross‐reactive medications	Strong
7. The TF suggests that very essential drugs (especially anti‐tuberculosis agents) with low probability of being the culprit and negative in skin tests, can be re‐administered in specialized centers with a very cautious protocol, after balancing the benefits and risk of recurrence*	Conditional
8. The TF recommends to perform a full diagnostic work‐up, including PT, d‐IDT and in vitro tests, in children with ambiguous DRESS who resolved rapidly without progression and/or complications, A cautious provocation test can be performed with suspected drugs if these tests are negative	Strong
9. The TF suggests to perform HLA testing in special ethnic groups for high risk medications such as carbamazepine, allopurinol and dapsone, as a supportive, but not diagnostic, tool	Conditional

^*Drug reintroduction protocols (Ref. 130, 131, 132).

6. TREATMENT

Management of pediatric DRESS remains an inconsistent and challenging aspect of clinical practice due to the absence of diagnostic criteria, severity classifications, controlled studies, and evidence‐based treatment strategies specific to children. ²⁵ , ³⁵ , ¹⁴⁰ , ¹⁴¹ Current management strategies for DRESS in adults are predominantly severity‐ or score‐based, but also rely on expert opinion or consensus in most reports. ²¹ , ³² , ³³ , ³⁴ Only a limited number of prospective or retrospective controlled studies have been conducted in adults ⁴² , ⁴³ , ⁴⁴ , ⁴⁵ , ⁴⁶ , ⁴⁸ , ⁴⁹ and none in children. It is increasingly evident that there are significant differences in drug pharmacokinetics, metabolism, co‐occurring infections, comorbidities, clinical manifestations, and severity of DRESS between children and adults, as well as across different pediatric age groups ⁹ , ¹⁴¹ , ¹⁴² (Table 1). However, in pediatric practice, treatment approaches often rely on extrapolation from adult treatment modalities. These are applied empirically despite the lack of evidence‐based knowledge or a consistent correlation between disease severity and the use of specific treatment strategies. ³⁵ , ³⁶ , ³⁷ , ⁶⁵ Comparison of employed treatment modalities in case series and systematic case reviews of children and adults with DRESS is given in Table 2, which reveals that supportive therapy (without systemic steroids) and immunomodulatory IVIG treatment were more frequently employed in children, while topical steroids (instead of systemic steroids), antivirals, cyclosporine, and other immunomodulatory treatments were more rarely used, when compared to adults.

6.1. Basic Principles

Management of DRESS involves not only medical treatment but also comprehensive short‐ and long‐term monitoring to detect relapses and address complications that may require further interventions (Figure 2). All patients with a high suspicion of DRESS should be hospitalized and closely monitored until all signs and symptoms resolve. Following discharge, intermittent follow‐up visits should continue for several months to ensure complete recovery and to monitor for potential late complications. ²¹ , ³² , ³³ Prompt identification and discontinuation of the causative and suspected drug(s) (within 6 weeks prior to disease onset) are critical. All medications in the same class, as well as potentially cross‐reactive drugs, should be strictly avoided until diagnostic testing is performed to confirm safety. ²⁵ , ³² , ³³

6.2. Choosing safe treatments during the acute stage

Antibiotics, particularly BLs, and aromatic anticonvulsants are the most frequent triggers of DRESS in children. ⁹ , ³⁶ , ³⁷ , ⁶⁵ Studies of BL cross‐reactivity patterns in SCARs, particularly DRESS, reveal that the “penicillin ring” plays a more significant role in immune responses than R1 side chain structures, ²⁶ , ¹⁴³ , ¹⁴⁴ , ¹⁴⁵ in contrast to the side chain specific patterns in non‐SCAR IgE‐ and T cell‐mediated reactions. ¹⁴⁶ Consequently, all β‐lactams should be avoided when the culprit drug belongs to this class. Cumulative data from previous cross‐reaction studies on delayed BL reactions suggest that aztreonam may be a relatively safe alternative for patients with penicillin‐ or cephalosporin‐induced DRESS; however, these findings are based on a limited number of cases. ¹⁴⁵ , ¹⁴⁷ , ¹⁴⁸ , ¹⁴⁹

Cross‐reactivity between aromatic anticonvulsants is notably high, reaching 50%–70% among certain molecules in both severe and mild delayed hypersensitivity reactions, while non‐aromatic molecules are generally not associated with cross‐reactivity. ¹⁵⁰ , ¹⁵¹ , ¹⁵² , ¹⁵³ , ¹⁵⁴ Non‐aromatic anticonvulsants are typically reported as safe alternatives for pediatric and adult patients with hypersensitivity to aromatic anticonvulsants. ¹⁵¹ , ¹⁵² , ¹⁵⁵ , ¹⁵⁶ However, in DRESS patients, unexpected reactions with both aromatic and non‐aromatic anticonvulsants, as well as benzodiazepines, may occur. These reactions may be attributed to the natural unpredictable course of DRESS, including flare‐ups, neosensitizations, and/or the development of multiple drug hypersensitivity (MDH) to newly introduced, non‐cross‐reactive drugs. ¹⁴⁴ , ¹⁵⁷ , ¹⁵⁸ , ¹⁵⁹ , ¹⁶⁰ , ¹⁶¹ , ¹⁶² , ¹⁶³ , ¹⁶⁴

When alternative treatments are essential, drugs with distinctly different chemical structures should be selected. ³² , ¹⁴⁴ Additionally, DRESS patients are at an increased risk for flare‐up reactions, confirmed neo‐sensitizations and/or MDH to unrelated drugs, especially during the acute phase and the first few months following the initial reaction, with incidences of reaching up to 29%. ¹⁹ , ²⁵ , ⁶⁵ , ¹¹⁶ , ¹⁶⁵ , ¹⁶⁶ Therefore, besides discontinuing the culprit drug(s) and cross‐reactive agents, empiric use of antibiotics, analgesics, or any other drugs should be avoided as much as possible during the acute and subacute phases. ³ , ³² , ¹⁶⁷

6.3. Supportive Therapy

Basic supportive treatments for pediatric DRESS include skin care, adequate nutrition, H1‐antihistamines to manage severe pruritus, fluid and electrolyte replacement, and close monitoring for disease progress. ²¹ , ³² When large pediatric DRESS series and systematic case reviews are evaluated altogether, it is seen that from none ⁸² , ⁸⁴ to 100% ²⁶ with a mean of 10.8% to 29% of children received only supportive therapy, without systemic steroids, although this approach was not always effective. ²⁵ , ²⁶ , ²⁷ , ³⁵ , ³⁶ , ³⁷ , ⁶⁵ , ⁶⁶ , ⁸⁰ , ⁸¹ , ⁸² , ⁸⁴ Rates of systemic corticosteroid (SCS) use were high and often similar in adults and children (Table 2).

6.4. Topical Corticosteroids

Corticosteroids, whether topical (TCSs) or systemic (SCSs), should be initiated in all patients with confirmed DRESS due to the inflammatory nature of the illness. ³ , ¹⁴ , ²¹ In pediatric cases, TCSs are generally considered and reported within supportive therapies. ³⁵ , ³⁷ , ⁶⁵ Some pediatric series have separately reported the use of TCSs, albeit without specifying potency, as the sole treatment in 6.3% ³⁶ to 30.6% ²⁵ of children, with complete recovery (Table 2). However, in adult populations, TCSs are regarded as a fundamental treatment modality. The reported rates of TCS use as the sole therapy are higher in adults, ranging from 9.0% to 25.5% ¹⁰ , ⁸⁰ (Table 2). Findings from retrospective studies in both adults and children suggest that supportive care combined with TCSs is an effective treatment option for patients with mild DRESS,although there is not a clear information on the dosing of TCSs in children with DRESS. This approach has been associated with shorter hospital stays, fewer infectious and non‐infectious complications, and reduced rates of viral reactivation, particularly CMV, as well as fewer relapses compared to patients treated with SCSs alone. ²⁵ , ⁴³ , ⁴⁵ , ⁴⁶ , ⁶⁰ , ⁶⁵ Recent adult DRESS treatment guidelines recommend the use of very high or high‐potency TCSs as a first‐line treatment for mild, ¹⁵ , ²¹ non‐severe, ³³ or non‐serious ³² cases. However, in pediatric practice, the indications for TCSs and the appropriate potency levels remain undefined. In children, TCSs are often used empirically as part of supportive care rather than as a targeted therapeutic intervention.

6.5. Systemic Corticosteroids

Systemic corticosteroids (SCSs), though not supported by high‐quality evidence, are the primary treatment for moderate to severe DRESS cases according to adult guidelines. ¹⁵ , ²¹ , ³² , ³³ Systematic case reviews revealed their use in 65% to 86% of adult, ¹ , ¹⁰ , ⁵⁴ , ⁸⁰ and 57% to 88.5% of pediatric ³⁵ , ³⁶ , ³⁷ , ⁶⁵ DRESS cases.(Table 2). However, the precise threshold for initiating SCSs and their impact on recovery, complications, and mortality remain unclear in children. ³⁵ , ³⁶ , ³⁷ , ⁶⁵ A key concern is the controversial role of SCSs in managing drug‐induced hepatitis. In both pediatric and adult cases, SCSs may not be sufficient to prevent liver transplantation or death. ⁵⁴ , ¹⁶⁸ , ¹⁶⁹ , ¹⁷⁰ While SCSs generally lead to rapid clinical improvement within days and favorable outcomes in most cases, their use is associated with significant complications. Among these, short‐ and long‐term infectious risks, such as sepsis and reactivation of HHV‐6 and CMV, which are linked to poor prognosis and mortality, immune reconstitution inflammatory syndrome (IRIS) and frequent relapses during SCS tapering are major problems. ⁴⁵ , ⁴⁶ , ⁶⁰ , ¹⁷¹ , ¹⁷² , ¹⁷³ Pediatric case series have shown that relapses often prolong SCS therapy to weeks or even months, hence resulting in a vicious cycle of complications. ²⁵ , ⁸⁰ , ⁸¹ , ⁸² , ¹⁴⁰ Some studies suggest that pediatric patients treated with SCSs experience higher rates of relapses, ⁶⁵ autoimmune complications ³⁵ and ICU admission ²⁵ compared to those who did not receive SCSs.

Pulse methylprednisolone (PMP) therapy (30 mg/kg/day IV for 3 days) has been reported to be effective in some refractory severe DRESS cases in both adults and children. ⁸⁰ , ¹⁷⁴ , ¹⁷⁵ , ¹⁷⁶ , ¹⁷⁷ While PMP provides strong anti‐inflammatory effects and rapid clinical recovery, abrupt dose reduction—from 30 mg/kg/day to 1–2 mg/kg/day—may trigger inflammatory responses, such as viral reactivation, DRESS relapse, and/or IRIS. ⁴⁴ , ¹⁷² , ¹⁷³ Notably, autoimmune complications, but not infectious complications, were more frequent in patients treated with PMP than in those receiving standard SCS therapy, particularly in children. ⁴⁴ , ⁴⁷ , ¹⁷⁸ , ¹⁷⁹ Reflecting these concerns, new adult guidelines do not include PMP among primary treatment options. ²¹ , ³² , ³³ , ³⁴

All of these findings highlight the need to balance the benefits of SCSs in controlling inflammation and preventing autoimmune complications against their risks, including infectious complications and long‐term adverse effects in children. In non‐severe cases, a careful risk–benefit analysis should be conducted before initiating SCS therapy.

6.6. Intravenous Immunoglobulin Treatment

The role of IVIG therapy in DRESS remains uncertain due to the absence of controlled clinical trials, with existing evidence primarily derived from case reports and case series. IVIG has been hypothesized to compensate for decreased immunoglobulin levels, enhance immune defense against herpes virus infections, and exert anti‐inflammatory effects similar to those observed in autoimmune disorders. ¹⁸⁰ , ¹⁸¹ While the use of IVIG as a standalone treatment for DRESS is not recommended, ²¹ , ³² , ¹⁸² several reports in both adults and children support its use as an adjunct to SCSs. IVIG in a dose of 1–2 g/kg over 2–7 days has shown efficacy in steroid‐resistant cases or in managing flare‐ups during steroid tapering. ⁵⁰ , ¹⁴⁰ , ¹⁸³ , ¹⁸⁴ , ¹⁸⁵ , ¹⁸⁶ , ¹⁸⁷ , ¹⁸⁸ However, most studies have not included long‐term follow‐up to monitor for autoimmune complications.

Adult guidelines include IVIG as a second‐line treatment for complicated or refractory DRESS cases. ²¹ , ³² , ³³ Analysis of pediatric DRESS cases reveals that IVIG is employed more frequently in children, particularly those under 6 years of age. Reported rates of IVIG use range from 9.8% to 13% ³⁵ , ³⁶ , ³⁷ , ⁶⁵ in pediatric systematic case reviews, compared to rates between 0% ⁷⁹ and 9% ⁵⁴ in adult systematic reviews (Table 2). On the other hand, pediatric case series showed a wide variation in IVIG use, with rates ranging from 0% ²⁷ , ⁸¹ , ⁸² , ⁸⁴ to as high as 20%, ⁸³ reflecting significant differences in treatment practices across countries (Table 2).

Despite numerous favorable reports of IVIG in both adults and children, concerns remain about the potential for autoimmune reactions and also other side effects. ¹⁸² These risks may be partially prevented by the concurrent use of SCSs. ¹⁷⁸ , ¹⁷⁹ , ¹⁸⁹ Further studies are needed to clarify the efficacy and long‐term outcomes of IVIG therapy in DRESS, particularly in pediatric populations.

6.7. Antiviral Treatment

Previous studies have indicated that viral reactivations, particularly of CMV and HHV‐6, may contribute to several complications in DRESS. Early initiation of antiviral therapy could be highly effective in preventing infectious complications and reducing mortality. ⁴⁵ , ¹⁷² , ¹⁹⁰ , ¹⁹¹ , ¹⁹² , ¹⁹³ , ¹⁹⁴ Current adult guidelines recommend adding antiviral therapy to other treatments in cases of severe visceral involvement and/or life‐threatening signs, if major viral reactivation with a high viral load is confirmed. ²¹ , ³² , ³³ , ³⁴

The role of viral reactivations in the severity and progression of pediatric DRESS remains unclear. Systematic reviews of pediatric DRESS have reported rates of viral reactivation (including HHV‐6, CMV, and/or EBV) ranging from 1% ⁹ to 46%. ⁶⁵ However, the corresponding rates of antiviral treatment in these studies were 0% ³⁵ and 1%, ⁶⁵ respectively, with no data provided on the relationship between virus detection and treatment decisions (Table 2). There is only one case report of a 3‐month‐old infant with DRESS caused by antiepileptic medications who fully recovered following ganciclovir therapy for proven CMV hepatitis. ¹⁹⁵ However, a major limitation of antiviral therapy in DRESS is the significant toxicity associated with currently available antiviral agents. ¹⁷² , ¹⁹² , ¹⁹⁶ Although adult studies showed the beneficial effects of antiviral therapy in proven reactivations, there is an urgent need for further studies to determine the role of viral reactivations in pediatric DRESS and to clarify the potential benefits and risks of this treatment in this population.

6.8. Other Second‐line Therapies

Cyclosporine, a potent immunosuppressive agent, has emerged as a promising treatment option for DRESS in recent years. ¹⁹⁷ , ¹⁹⁸ , ¹⁹⁹ , ²⁰⁰ Studies in adults, including case reports and series, have demonstrated that cyclosporine can achieve rapid and successful outcomes either as a short course (5–7 days) first‐line therapy or as a prolonged treatment in corticosteroid‐resistant or corticosteroid‐dependent cases. ¹⁹⁸ , ¹⁹⁹ , ²⁰⁰ Comparative studies have further shown that cyclosporine leads to faster resolution of clinical symptoms, lower complication rates ⁴⁸ and no relapses during tapering when compared to SCSs. ⁴⁹ Cyclosporine has not been associated with significant adverse effects except in patients with severe renal involvement. ⁴⁸ , ⁴⁹ , ¹⁹⁸ , ²⁰¹ Current adult guidelines recommend cyclosporine as a second‐line therapy for severe, steroid‐refractory, or steroid‐dependent DRESS cases. ²¹ , ³²

In pediatric DRESS, recent evidence supports the use of cyclosporine as an adjuvant in corticosteroid‐resistant cases and, less commonly, as a corticosteroid‐sparing agent with favorable responses in most cases, ³⁵ , ⁸⁰ , ¹⁹⁸ , ²⁰² , ²⁰³ , ²⁰⁴ though some cyclosporine‐resistant cases have been reported. ²⁵ , ²⁰⁵ A systematic review ³⁵ and 2 pediatric series have reported cyclosporine use in 1.3%, ³⁵ 3.1%, ⁸⁰ and 4.1% ²⁵ of cases, with good outcomes (Table 2). These findings highlight cyclosporine's potential as an effective option for challenging pediatric DRESS cases, complementing its established role in treating other immune‐mediated conditions. ²⁰⁶ , ²⁰⁷ , ²⁰⁸ , ²⁰⁹ , ²¹⁰

Other immunomodulatory agents, such as cyclophosphamide, tumor necrosis factor (TNF)‐α inhibitors, and anti‐interleukin (IL‐5) agents, such as mepolizumab, have been occasionally used in adults with refractory or severe DRESS ²¹¹ , ²¹² , ²¹³ , ²¹⁴ , ²¹⁵ and very rarely in children. ⁸⁰ , ²¹⁶ Mepolizumab, which had been approved for asthma over 6 years of age, seems to be one of the most promising second‐line agents in severe DRESS in children also. ²¹⁵

In cases of severe DRESS with life‐threatening complications, such as multiorgan involvement, respiratory failure, or cardiac involvement, mechanistic therapies like therapeutic plasma exchange (plasmapheresis) may be considered when other treatments fail. Case reports, predominantly in children but also in adults, have described dramatic and sustained clinical responses to plasmapheresis as an adjuvant therapy in very severe and potentially fatal cases. ¹⁰ , ³⁷ , ¹⁷⁷ , ²¹⁷ , ²¹⁸ , ²¹⁹ , ²²⁰ , ²²¹ , ²²²

7. SEVERITY‐BASED CLASSIFICATION AND TREATMENT OF DRESS IN CHILDREN

In recent years, new scoring systems and severity classifications for DRESS have been developed for adults. ²¹ , ³² , ¹⁷² , ²²³ , ²²⁴ Only one severity classification was also reported in children, which failed to show any significant relation to clinical features and prognosis. ⁸¹ Recent adult guidelines recommended treating DRESS cases with a RegiSCAR score ≥4 according to disease severity classifications and/or scores. ²¹ , ³² , ³³ , ³⁴ , ²²⁵ This highlights the urgent need for a severity‐based treatment strategy specifically tailored for pediatric patients. Unfortunately, high‐quality pediatric data to guide risk stratification, evaluation, and evidence‐based treatment remain lacking.

In this position paper, the consensus of the TF members has led to the development and recommendation of a severity classification and corresponding treatment algorithm for pediatric DRESS after systematic analysis of all relevant literature. The recommendations were based on recent systematic case reviews, special clinical reports of children, observational or comparative study results involving adults and, less frequently, children, and general principles from adult guidelines. ⁹ , ²¹ , ²² , ²⁵ , ³² , ³⁵ , ³⁶ , ³⁷ , ⁴² , ⁴³ , ⁴⁴ , ⁴⁵ , ⁴⁶ , ⁴⁷ , ⁴⁸ , ⁴⁹ , ⁵⁰ , ⁶⁰ , ⁶⁵ , ¹⁷⁷ , ¹⁷⁸ , ¹⁸⁷ , ¹⁸⁸ , ¹⁹⁵ , ¹⁹⁸ , ²⁰² , ²⁰³ , ²⁰⁴ , ²²⁰ , ²²¹ , ²²² (Table 4, Figure 3).

TABLE 4.

Severity classification and treatment recommendations for children with suspected DRESS.

Classification of severity	Clinical criteria	Recommended management at admission*
AMBIGUOUS DRESS	All must be fullfilled RSS: 2–3 Rash compatible with DRESS and fever, any organ involvement and/or eosinophilia within few days to < 12 weeks of drug exposure Good general condition Normal vital signs other than fever Liver and kidney function tests below limits of injury No danger signs (see below)	Ambulatory or hospitalization Supportive therapy Moderate potency TCSs** until resolution and therafter, gradual tapering during a few weeks Close clinical, laboratory and RSS follow‐up until recovery IF; Increase in score and/or clinical deterioration; Manage as Grade 1–3 DRESS
GRADE 1 DRESS	All must be fulfilled RSS ≥4 Good general condition Normal vital signs other than fever No, or minimal (ALT <5 × ULN or ALP <2 × ULN) liver involvement No, or minimal (below AKI definition) kidney involvement No other organ involvement No danger signs (see below)	Hospitalization Supportive therapy High‐potency TCSs** until resolution and therafter gradual tapering during 6 wks‐3 months Close clinical, laboratory and RSS follow‐up until recovery IF; no response in 1 week, or clinical deterioration; Manage as Grade 2 DRESS
GRADE 2 DRESS	All must be fullfilled; RSS ≥4 Good general condition Normal vital signs other than fever No danger signs (see below) At least one of criteria (1) or (2) fulfilled; (1) Criteria for drug‐induced liver injury(DILI) (any of the following): ALT (and/or AST,if no muscle pathology) ≥ X5 ULN ALP ≥ X2 ULN (if no bone pathology) on 2 consecutive occasions TB ≥ X 2 ULN together with ≥X3 increase in ALT, simultaneously Symptomatic hepatitis*** AND; No signs and laboratory criteria of coagulopathy,ascites and/or hepatoencephalopathy (see danger signs) (2) Criteria for acute kidney injury (any of the following): SCr 1.5–1.9 X baseline (or ULN) or an increase by ≥0.3 mg/dL within 48 hrs An increase in sCr by 150‐200 % over 7 days Decrease in GFR ≥25% to 75% from baseline or normal value for age A reduction in urine output (<0.5 mL/kg/h for 6–12 hrs but not exceeding 12 hrs) AND; No signs and laboratory criteria for acute renal failure (see danger signs)	Hospitalization Supportive therapy Systemic corticosteroids prednisone, or prednisolone po (1 to 1.5 mg /kg/d, until resolution, therafter gradual tapering during 6 weeks–3 months) Close clinical, laboratory and RSS follow‐up until recovery IF no response in 1 week, or clinical deterioration; ADD: IVIG 1–2 g/kg for 3–5 days
GRADE 3 DRESS	RSS ≥4 AND ANY ONE of the following DANGER SIGNS: (1) Altered conscious levels and/or vital signs (other than fever) (2) Haematologic: Pancytopenia, thrombocytopenia (<50,000 /dL), severe anemia (Hemoglobin <7 g/dL), neutropenia (neutrophil count <500/dL), hemophagocytosis, and/or bone marrow failure (3) Presence (or high risk of) acute liver failure (all must be fullfilled): No known evidence of chronic liver disease Biochemical evidence of severe liver injury (Elevated ALT/ALP reaching criteria for DILI and TB ≥ 2XULN) Ascites, and/or, hepatic‐based coagulopathy defined as any one of the following; PT ≥15 s or INR ≥1.5, not corrected by Vitamin K, in the presence of clinical HE, PT ≥20 s or INR ≥2.0 regardless of the presence or absence of clinical HE (4) Acute renal failure (any of the following): Increase in serum Cr by ≥3 times baseline or increase in sCr to ≥ 4.0 mg/dl eGFR decrease of ≥75% of baseline or to < 35 ml/min/1.m2 Urine output <0.3 mL/kg/h for ≥24 hours or anuric for ≥12 h (5) Acute respiratory failure with hypoxemia and/or hypercarbia (6) Other important organ involvement of any degree: Heart, lung, nervous system, pancreas, GI tract (7) Multi‐organ failure	Hospitalization Supportive therapy Start SCS + IVIG combined treatment at admission Give intravenous methylprednisolone as the first SCS (2 mg/kg/d for 3–5 days), then continue with po prednisone (or prednisolone)in a dose of 2 mg/kg/d, until resolution. Therafter gradual tapering during 8 wk‐ 6 months Consultation with organ specialists Close clinical, laboratory and RSS follow‐up until recovery ICU admission if hemodynamic imbalance and/or respiratory failure IF NO RESPONSE; ADD Cyclosporine po or iv Plasmapheresis Cyclosporine po or iv Other mechanical treatments such as RRT

Abbreviations: AKI, Acute kidney injury; ALP, Alkaline phosphatase; ALT, Alanine transferase; AST, Aspartate transferase; eGFR, estimated glomerular filtration rate; GI, gastrointestinal; HE, Hepatic encephalopathy; ICU, Intensive care unit; INR, International normalized ratio; IVIG, Intravenous immunoglobulin; PT, Prothrombin time; RRT, Renal replacement therapy; RSS, RegiSCAR score; sCr, Serum creatinine; SCS, Systemic corticosteroids; TB, Total bilirubin; TCS, Topical corticosteroids; ULN, Upper limit of normal.

^*These treatments are recommended at initial encounter, afterwards the management should continue according to disease progress as seen in Figure 3.

^**See Table S4 and Figure S1 for potency and dose of topical corticosteroids for children. The recommended TCS dose is 20 g/m²/day adopted to body surface area of the child, 1 or 2 times a day, for extensive cutaneous involvement. ²²⁶ , ²²⁷ The amount to be applied for different body compartments should be chosen by FTU criteria ²²⁶ , ²²⁷ (see Figure S2 for description). In adolescents very high potency TCSs can be preferred.

^***Symptomatic hepatitis: Presence of symptoms attributed to hepatitis such as fatigue, nausea, vomiting, right upper quadrant pain, itching, skin rash, jaundice, weakness, anorexia, and weight loss together with any increase in liver function tests. ²²⁸ , ²²⁹ Definition of drug‐induced liver injury in children. ¹⁶⁸ , ²²⁸ Definition of acute kidney injury in children. ²³⁰ , ²³¹ , ²³² Definition of acute liver failure in children. ²²⁹ Definition of acute renal failure in children. ²³⁰ , ²³¹ , ²³²

FIGURE 3.

Algorithmic treatment of DRESS according to severity in children. BSA, Body surface area; FTU, Finger tip unit; IVIG, Intravenous immunoglobulin; NAC, N‐acetylcysteine; RSS, RegiSCAR score. ^aFor severity classification and danger signs see Table 4. ^bSupportive therapy: Emollients, nutritional support, fever management, antihistamines, and fluid‐electrolyte monitorization and replacement. ^cIn adolescents, very high potency TCSs can be preferred. See Table S4 for drug and doses. ^dGood clinical response in the short term is defined as follows: Resolution of fever, marked cutaneous improvement, decrease of more than 50% in baseline liver enzyme values or creatinine level at admission, and regression in other symptoms and signs within one to 2 weeks (Ref. 223). ^eTreatment resistance is defined as: No change or increase in RegiSCAR scores and/or no improvement in clinical and laboratory features after 7–14 days(expected mean duration for response to corticosteroids in children of full‐dose systemic or topical corticosteroids (Ref. 36, 81). In severe cases, the waiting duration for commencing other treatments can be shorter. ^fSlow tapering; 10%–15% of total daily dose/1 week (Ref. 171).

The proposed severity classification includes four categories: Ambiguous DRESS, Grade 1 DRESS, Grade 2 DRESS, and Grade 3 DRESS, which are explained in detail in Table 4. One of the most important variables that determine the severity of DRESS is the degree of organ involvement and injury. The criteria for defining different levels of DRESS severity were adapted to children by international pediatric liver and kidney injury and failure criteria. ¹⁶⁸ , ²²⁸ , ²²⁹ , ²³⁰ , ²³¹ , ²³² Recommendations for the general management and treatment of pediatric DRESS are outlined in Tables 5 and 6. In situations where there was insufficient or little evidence, but strong clinical expertise or consensus, recommendations were formulated as a "suggestion" with a recommendation strength of conditional. The recommended drugs and their pediatric dosing for different severity grades are derived from related pediatric guidelines and given in Table S4. ²⁰⁹ , ²²⁶ , ²²⁷ , ²³³ , ²³⁴ , ²³⁵ , ²³⁶

TABLE 5.

Task force (TF) recommendations on general management of DRESS in children.

Recommendation	Strength of recommendation
1. The TF recommends that any child with a suspicion of DRESS should be evaluated for disease severity criteria and presence of danger signs at admission (Table 4, Figure 3)	Strong
2. The TF recommends that children suspected of DRESS be hospitalized and clinical and laboratory manifestations should be closely followed‐up during hospitalization Children with ambiguous DRESS can be hospitalized or closely followed up as an outpatient, if there is strong confidence of cautious household care	Strong
3. The TF recommends to stop and avoid all suspected drugs and cross reactive medications until testing is accomplished	Strong
4. The TF recommends to minimize the use of any further drugs, including antipyretics and antibiotics, and try to create a medication‐free interval for days to weeks after DRESS onset, unless they are absolutely indicated	Strong
5. The TF recommends a wisely and safe drug selection process, if it is mandatory to start any new medication for the underlying disease or complications during hospitalization or therafter, until test results The TF recommends to choose an alternative drug that do not have any chemical structure similarity to the suspected culprit The TF recommends against the administration of another beta‐lactam(BL) molecule during the acute–subacute period of a BL‐related DRESS, since a high rate of cross reaction to other BLs in unpredictable patterns have been reported in BL‐induced DRESS The TF suggests against to start a new antiepileptic drug in antiepileptic‐induced cases, if clinically possible. When it is mandatory, the TF recommends to start a non‐aromatic antiepileptic drug when the culprit is an aromatic one. When the culprit is a non‐aromatic drug the TF recommends to start a non‐aromatic antiepileptic with a different chemical structure. If possible, the TF suggests to perform a HLA testing before commencing a new antiepileptic drug	Strong/conditional
6. The TF recommends close follow‐up for flare‐up or relapse of manifestations within a few days, if any new drug, even a non cross‐reactive one, is started	Strong

TABLE 6.

Task force recommendations on treatment of DRESS in children.

Recommendation	Strength of recommendation
1. The TF recommends that all children with a suspicion of DRESS should be started supportive therapy, including a warm and humid environment, gentle skin care with emollients and dressings, nutritional supplementation, fever management (preferably by mechanic cooling), H1‐antihistamines if there is severe pruritus, and fluid and electrolyte replacement, if necessary	Strong
2. The TF recommends that selection of initial treatments should be made according to the severity degree of the reaction (Table 4, Figure 3)	Strong
3. The TF suggests to start moderate* potency topical corticosteroids (TCS) in cases where the RegiSCAR score is 2–3 (Ambiguous DRESS), in addition to supportive care and close follow‐up for progression	Conditional
4. The TF recommends to start high potency TCS* in children with Grade 1 DRESS After TCSs are started, close clinical and laboratory follow up for reevaluation of severity should be done. In the absence of gradual recovery and/or presence of deterioration, systemic corticosteroids (SCSs) should be started Once the disease is under control, TCSs should be tapered slowly in 6 weeks to 3 months The TF suggests against to use very high potency TCSs in children because of higher risk of side effects and unconfirmed superiority to high potency TCSs In adolescents, very high potency TCSs can be considered	Strong
2. The TF recommends to begin systemic corticosteroids, especially prednisone or prednisolone, in doses of 1 to 2 mg/kg/day in children with Grade 2 and above DRESS The dose may be chosen according to severity of presentation In the presence of danger signs and/or concern about intestinal absorption, intravenous methylprednisolone 2 mg/kg/day should be given at the beginning, with rapid transition to oral SCSs in a few days If there is serious liver involvement, which can cause a derangement in metabolism of prednisone, methylprednisolone or prednisolone can be chosen The dose should be continued until resolution of symptoms and laboratory parameters Upon resolution, the dose should be slowly and gradually (10%–15% of total daily dose/week) tapered down during a period of at least 6 weeks to 3 months (6 months in Grade 3 DRESS), in order to reduce the occurrence of disease flare‐ups and reactivations with dose reduction If relapse occurs when tapering corticosteroids, it should be returned to previous dose and tapered more slowly If this is not effective, herpes virus reactivations should be checked first. If negative, then corticosteroid sparing agents such as IVIG or cyclosporine can be added If a favorable response a is not obtained within one to 2 weeks, this should be interpreted as a steroid resistance and other second‐line treatments appropriate for children should be consecutively added (see Figure 3)	Strong
3. The TF suggests against to give high dose (30 mg/kg, iv) pulse methylprednisolone therapy in children with DRESS, considering risk of frequent flares upon cessation and autoimmunity encountered with this regimen In rare circumstances, such as severe organ failure and /or high risk of fatality, where very abrupt response to treatment is needed, this regimen can be employed for 3 days with transition to conventional treatment afterwards	Conditional
4. The TF recommends to add intravenous immunoglobulin (IVIG) 1–2 g/kg for 3–5 days, as an add‐on therapy to SCSs, IF; The disease severity is increasing or resolution of symptoms is not encountered in spite of adequate dose of SCSs; or Frequent relapses occur during tapering of SCSs and flares cannot be controlled by slowing the tapering rate; or The severity of DRESS is Grade 3 at admission	Strong
5. The TF recommends against to give IVIG alone without SCSs in DRESS	Strong
6. The TF suggests to add iv ganciclovir (or, alternatively, oral valganciclovir)* in doses recommended for children, IF; A major viral reactivation (HHV‐6 or CMV) is confirmed by high viral loads and accompanied by life‐threatening signs; or It is suspected that viral reactivation contributes to severe complications (e.g., encephalitis, hemophagocytosis, or severe erosive colitis) Upon starting antiviral treatment, the TF suggestss to sustain the dose of SCSs and not to taper, until antigenemia is completely cleared	Conditional
7. The TF recommends to use cyclosporine* as a second‐line anti‐inflammatory agent in children, IF; There is severe organ involvement resistant to SCS and IVIG combination; or Patient has contraindications to SCSs; or Patient has steroid‐dependency with frequent relapses when SCSs are tried to be tapered The dose should be chosen according to indication.	Strong
8. The TF suggests against the use of second‐line immunosuppressives other than cyclosporine and newly introduced biological treatments in children with DRESS, until strong evidence is obtained The only exception may be use of mepoluzimab in children over 6 years of age with very severe disease uncontrollable with other antiinflammatory treatments	Conditional
9. The TF recommends to add plasmapheresis to other treatments in very severe DRESS cases resistant to other treatments, especially if there is life threatening organ involvement, such as myocarditis, liver failure and/or respiratory failure	Strong
10. The TF recommends that organ‐specific specialist consultation should be employed in patients with important organ disease, such as renal, cardiac, neurologic and severe liver involvement for alternative treatment choices and replacement therapies	Strong
11. The TF recommends that all children with a presumptive diagnosis of DRESS should be closely followed up through all treatment steps during acute and subacute periods and for long term complications during weeks to months after the disease resolves	Strong

^a A favorable clinical response in short‐term is defined as follows: resolution of fever, marked cutaneous improvement, and decrease of more than 50% in baseline liver enzyme values or creatinine level at admission (Ref. 223).

^*See Table S4 for drugs and doses.

8. FOLLOW‐UP AND PROGNOSIS

Since DRESS is characterized by a prolonged course and long‐term complications, as discussed in previous sections, regular follow‐up consultations should commence immediately after discharge and continue for at least 6 months to three or more years. Thereafter, follow‐up should be arranged based on the patient's needs. Regular testing, including complete blood cell counts with differentials, liver and renal function tests, virologic studies, autoantibodies, and thyroid function tests, should be performed. Additional examinations should be conducted as necessary, and psychological evaluation and support should be provided if required. ²¹ , ¹⁷⁹ , ²³⁷

DRESS is a potentially fatal disease, with death occurring during the acute phase or weeks to months later due to complications. ³ , ¹⁷² , ¹⁹² , ²¹¹ Fortunately, comparisons between pediatric and adult systematic reviews revealed lower mortality rates in children that ranged between 3% and 5.4%, ³⁵ , ³⁶ , ³⁷ , ⁶⁵ while no deaths were reported in six pediatric series. ²⁷ , ⁶⁶ , ⁸⁰ , ⁸² , ⁸³ , ⁸⁴ (Table 2). In adults, increasing age together with an increase in comorbid conditions, higher rates of herpes virus reactivations, and employment of more aggressive treatment regimens may predispose to more severe disease and higher mortality than in children. ⁷⁹ , ¹⁷² , ¹⁷⁸ In most pediatric deaths, the primary causes were multi‐organ failure, single‐organ failure, or sepsis, ³⁵ , ³⁶ , ³⁷ with no apparent age‐related trend. ³⁵ Some systematic case analyses revealed that, among children who died from DRESS, 12.5% received supportive care only, and 54.1% were treated exclusively with SCSs without additional immunosuppressive agents or other interventions, which may point out the contribution of undertreatment to mortality in severe pediatric cases. ³⁵ , ³⁷ Hence, a severity‐based stepwise treatment approach, which was proposed in this paper, is an absolute necessity also in children.

AUTHOR CONTRIBUTIONS

Semanur Kuyucu and Eva Gomes chaired the EAACI Pediatric Severe Cutaneous Adverse Drug Reactions (SCAR) Task Force, including a total of 11 researchers from seven countries. Relevant to this paper on DRESS. Semanur Kuyucu, chair of the TF, performed the conception and design of the present study on DRESS, contributed to the analysis and reviewing process of search results, analysis of data, and writing on diagnosis, treatment, and prognosis, elaboration of severity classification, and diagnostic and treatment algorithms, formulation of recommendations, and evidence grading, and handled the submission process. Natalia Blanca‐Lopez contributed to the analysis and reviewing process of search results, writing on clinical manifestations and prognosis, generation of the comparative table on clinical manifestations and prognosis of pediatric and adult studies on DRESS, critical reviewing, and approval of diagnostic and treatment algorithms and recommendations. Luis Moral contributed to the analysis and reviewing process of search results, writing on clinical manifestations and prognosis, generation of the comparative table on clinical manifestations and prognosis of pediatric and adult studies on DRESS, critical reviewing, and approval of diagnostic and treatment algorithms and recommendations. Jean‐ Christoph Caubet contributed to the analysis and reviewing process of search results, writing partly on diagnosis, critical reviewing, and approval of diagnostic and treatment algorithms and recommendations. Bernardo Sousa‐Pinto performed the search strategy on SCARs and DRESS, made formal analysis, contributed to the reviewing process of search results, writing of methodology, contributed to formulation and wording and critical reviewing of recommendations and evidence grading, and gave graphical support. Özge Yılmaz Topal contributed to the analysis and reviewing process of search results, analysis of data regarding epidemiology and writing the epidemiology section, generation of the comparative table on diagnostic test results of pediatric and adult studies on DRESS, management of references, and approval of diagnostic and treatment algorithms and recommendations. Francesca Mori contributed to the analysis and reviewing process of search results and critical reviewing and conception, and approval of diagnostic and treatment algorithms and recommendations. Marina Atanaskovic‐Markovic contributed to the analysis and reviewing process of search results and critical reviewing and approval of diagnostic and treatment algorithms and recommendations. Eva Gomes, secretary of the TF, contributed to the conception and design of the study, to the analysis and reviewing process of search results, the general structure of the paper, the analysis of data regarding epidemiology and writing of the epidemiology section, the approval of diagnostic and treatment algorithms and recommendations, the formulation of recommendations and evidence grading, and the critical reviewing. TF members took part in methodology generation, critical appraisal and discussions on every step of the study during eight online meetings with attendance of majority in most. All contributors approved the final version.

FUNDING INFORMATION

This Position Paper was supported by the European Academy of Allergy and Clinical Immunology (EAACI) under the EAACI Pediatric Severe Cutaneous Adverse Drug Reactions(SCARs) [Task Force and Drug Allergy Interest Group] [Budget code number: 40709] (Years:2024 and 2025).

CONFLICT OF INTEREST STATEMENT

The authors have no conflict of interest to declare.

PEER REVIEW

The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer‐review/10.1111/pai.70103.

Supporting information

Data S1.

Kuyucu S, Blanca‐Lopez N, Caubet J‐C, et al. Clinical diagnosis and management of drug reaction with eosinophilia and systemic symptoms (DRESS) in children: An EAACI position paper. Pediatr Allergy Immunol. 2025;36:e70103. doi: 10.1111/pai.70103