# French national protocol for diagnosis and management of drug reaction with eosinophilia and systemic symptoms (DRESS) in adults and children.

S. Ingen-Housz-Oro, C. Bernier, H. Assier, F. Tétart, Frederic Dezoteux, A. Gaillet, B. Bensaid, A. Welfringer-Morin, N. de Prost, Delphine Staumont, et al.

► To cite this version:

S. Ingen-Housz-Oro, C. Bernier, H. Assier, F. Tétart, Frederic Dezoteux, et al. French national protocol for diagnosis and management of drug reaction with eosinophilia and systemic symptoms (DRESS) in adults and children. Annales de Dermatologie et de Vénéréologie, 2025, 152 (3), pp.103381. 10.1016/j.annder.2025.103381. hal-05325554

HAL Id: hal-05325554

https://lilloa.hal.science/hal-05325554v1

Submitted on 22 Oct 2025

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French national protocol for diagnosis and management of drug reaction with eosinophilia and systemic symptoms (DRESS) in adults and children

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S. Ingen-Housz-Oro<sup>a,b,*</sup>, C. Bernier<sup>c</sup>, H. Assier<sup>a</sup>, F. Tétart<sup>d</sup>, F. Dezoteux<sup>e</sup>, A. Gaillet<sup>f</sup>, B. Bensaid<sup>g</sup>, A. Welfringer-Morin<sup>h</sup>, N. de Prost<sup>f</sup>, D. Staumont-Sallé<sup>e</sup>, M. Tauber<sup>l</sup>, K. Bel Hareth<sup>a</sup>, P. Sanchez<sup>j</sup>, S. Guendouz<sup>k</sup>, C. Hua<sup>a</sup>, S. Fourati<sup>l</sup>, F. Schlemmer<sup>m</sup>, G. Gourier<sup>n</sup>, L. Nakad<sup>o</sup>, C. Hoffmann<sup>p</sup>, B. Milpied<sup>q</sup>, E. Collet<sup>r</sup>, A. Valois<sup>s</sup>, A. Soria<sup>t</sup>, V. Leroy<sup>u</sup>, N. Ortonne<sup>v</sup>, A. Colin<sup>a</sup>, C. Droumaguet<sup>w</sup>, E. Ferrat<sup>x</sup>, O. Gaudin<sup>y</sup>, P.-J. Mahé<sup>z</sup>, N. Joher<sup>aa</sup>, B. Badaoui<sup>ab</sup>, N. Bellon<sup>h</sup>, E. Sbidian<sup>a,b</sup>, O. Dereure<sup>ac</sup>, P. Wolkenstein<sup>a</sup>, B. Lebrun-Vignes<sup>ad</sup>, A. Barbaud<sup>t</sup>, V. Descamps<sup>ae</sup>, French National Reference Center for Toxic Bullous Diseases and Severe Drug Reactions TOXIBUL<sup>1</sup> and the FISARD group<sup>2</sup>

<footnote><sup>a</sup>Service de Dermatologie, Hôpital Henri Mondor, AP-HP, Créteil, France</footnote>

<footnote><sup>b</sup>Univers Paris Est Créteil EpiDermE, Créteil, France</footnote>

<footnote><sup>c</sup>Service de Dermatologie, CHU Nantes, Nantes, France</footnote>

<footnote><sup>d</sup>Service de Dermatologie, CHU Charles Nicolle, Rouen, France</footnote>

<footnote><sup>e</sup>Service de Dermatologie, CHU Lille, Lille, France</footnote>

<footnote><sup>f</sup>Médecine Intensive et réanimation, Hôpital Henri Mondor, AP-HP, INSERM, IMRB, Equipe CEpiA, Créteil, France</footnote>

<footnote><sup>g</sup>Service de Dermatologie, CHU Edouard Herriot, Lyon, France</footnote>

<footnote><sup>h</sup>Service de Dermatologie, Hôpital Necker, AP-HP Paris, France</footnote>

<footnote><sup>i</sup>Service d'Allergologie et Immunologie Clinique, Hôpital Lyon Sud, Hospices Civils de Lyon, Inserm U1111 CIRI, France</footnote>

<footnote><sup>j</sup>Service de pharmacovigilance, CHU Bordeaux, Bordeaux, France</footnote>

<footnote><sup>k</sup>Service de cardiologie, Hôpital Henri Mondor, AP-HP Créteil, France</footnote>

<footnote><sup>l</sup>Laboratoire de virologie, Hôpital Henri Mondor, AP-HP Créteil, France</footnote>

<footnote><sup>m</sup>Unité de pneumologie, Hôpital Henri Mondor, AP-HP Créteil, France</footnote>

<footnote><sup>n</sup>Service de pharmacovigilance, CHU Brest, Brest, France</footnote>

<footnote><sup>o</sup>Service des urgences, Hôpital Henri Mondor, AP-HP Créteil, France</footnote>

<footnote><sup>p</sup>Centre de traitement des brûlés, Hôpital National d'Instruction des Armées, Percy, Clamart, France</footnote>

<footnote><sup>q</sup>Service de dermatologie, CHU Bordeaux, Bordeaux, France</footnote>

<footnote><sup>r</sup>Service de dermatologie, CHU Dijon, Dijon, France</footnote>

<footnote><sup>s</sup>Service de dermatologie, Hôpital d'instruction des Armées, Toulon, France</footnote>

<footnote><sup>t</sup>Service de dermatologie and allergologie, hôpital Tenon, AP-HP, Sorbonne Université, Paris, France</footnote>

<footnote><sup>u</sup>Service d'hépatologie, Hôpital Henri Mondor, AP-HP Créteil, France</footnote>

<footnote><sup>v</sup>Département de pathologie, Hôpital Henri Mondor, AP-HP Créteil, France</footnote>

<footnote><sup>w</sup>Service d'endocrinologie, Hôpital Henri Mondor, AP-HP Créteil, France</footnote>

<footnote><sup>x</sup>Université Paris Est Créteil, Créteil, France</footnote>

<footnote><sup>y</sup>Cabinet de dermatologie, Paris, France</footnote>

<footnote><sup>z</sup>Réanimation chirurgicale et des brûlés, PTMC, CHU Nantes, Nantes, France</footnote>

<footnote><sup>aa</sup>Service de néphrologie, Hôpital Henri Mondor, AP-HP Créteil, France</footnote>

<footnote><sup>ab</sup>Laboratoire d'hématologie biologique, Hôpital Henri Mondor, AP-HP Créteil, France</footnote>

<footnote><sup>ac</sup>Service de dermatologie, CHU Montpellier, Montpellier, France</footnote>

<footnote><sup>ad</sup>Centre régional de pharmacovigilance, Hôpital Pitié-Salpetrière, AP-HP Paris, France</footnote>

<footnote><sup>ae</sup>Service de dermatologie, Hôpital Bichat, AP-HP Paris, France</footnote>

<footnote>* Corresponding author at: Service de dermatologie, Hôpital Henri Mondor, 1 rue Gustave Eiffel, 94000 Créteil, France.
E-mail address: saskia.oro@aphp.fr (S. Ingen-Housz-Oro), saskia.oro@aphp.fr (S. Ingen-Housz-Oro).</footnote>

<footnote n="1">1 Centre de référence TOXIBUL, filière FIMARAD, Hôpital Henri Mondor, AP-HP, Créteil, France.</footnote>

<footnote n="2">2 Groupe FISARD, Paris, France.</footnote>
# 1. Background: objectives of the care protocol, pathophysiology, and definition of the disease

The objective of this French National Diagnosis and Care Protocol (PNDS) is to provide healthcare professionals with guidance on optimal management and care pathways for adults and children with Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as DIHS—Drug-Induced Hypersensitivity Syndrome).

It is a practical tool for the attending physician, designed in collaboration with other specialists, to guide management of the condition. However, the PNDS cannot address all specific cases, comorbidities, therapeutic particularities, or hospital care protocols. It does not claim to cover all possible therapeutic approaches and cannot replace the individual responsibility of physicians toward their patients. It does, however, reflect the current state of knowledge on the optimal management of adult and pediatric patients with DRESS and will be updated as new data become available. This article is the English translation of the French PNDS for the management of DRESS, available on the French National Health Authorities (HAS) website, https://www.has-sante.fr/upload/docs/application/pdf/2024-11/def_corps_pnds_dress.pdf. The scientific rationale with corresponding references are available in French on the HAS website, https://www.has-sante.fr/upload/docs/application/pdf/2024-11/def_pnds_dress_argumentaire_v2.0_20062024_vf.pdf.

DRESS is a rare and potentially severe cutaneous adverse reaction (SCAR), with 10 cases per million in the general population, and 1 case per 10,000 new patients treated with antiepileptic drugs. Onset generally occurs 2 to 8 weeks after the introduction of the causative drug, but in certain cases DRESS may have a more rapid onset (e.g., a few days for iodinated contrast agents or beta-lactam antibiotics). The most frequently implicated drugs, often but not always being taken for the first time, include allopurinol, antiepileptic drugs (carbamazepine, oxcarbazepine, eslicarbazepine, phenytoin, lamotrigine), minocycline, antibacterial sulfonamides (cotrimoxazole, dapsone, sulfasalazine), abacavir, anti-tuberculosis drugs, vancomycin, and iodinated contrast media. The risk of polysensitization (sensitization to multiple drugs, not necessarily from the same class) is specific to this type of cutaneous adverse reaction. Some human leukocyte antigens (HLAs), which are major histocompatibility complex molecules, constitute risk factors, particularly in Asian populations (See Appendix S1 in online supplementary material).

DRESS is a type IVb hypersensitivity reaction mediated by T-helper type 2 (Th2) cells specific to the causative drug(s) and by eosinophils. CD8 + and CD4 + T cells produce interleukin 5 (IL-5) and the chemokine CCL11 (eotaxin 1), which recruit eosinophils, as well as IL-4 and IL-13, which amplify this recruitment. Cytotoxic CD8 + T cells also secrete TNF-α and IFN-γ, further potentiating type 2 immune response. Thymus and activation-regulated chemokine (TARC), also known as CCL17, which is secreted by keratinocytes and dendritic cells, may also play a role in immune response. Serum levels of CCL17 correlate with the clinical severity of DRESS. Recent studies have also implicated hyperactivation of the JAK/STAT pathway. These immunological characteristics have paved the way for identifying potential therapeutic targets for the disease. Similarly, an increase in regulatory T (T-Reg) cells has been observed during the acute phase of DRESS. This is followed by a gradual decline, with T helper (Th) 3/17 cells becoming predominant in the chronic phase and contributing to the late autoimmune complications described in patients. However, T-Reg cells have been demonstrated to exhibit abnormal function during the acute or resolution phases and may therefore contribute directly to the development of autoimmune complications.

DRESS is frequently associated with viral reactivation (herpes viruses such as human herpes virus [HHV]6, cytomegalovirus [CMV]

and Epstein-Barr virus [EBV]). The respective roles of the virus and the causative drug in the pathophysiology of this disorder remain unclear. The prevailing hypothesis is that the immune environment in DRESS promotes viral replication, which in turn exerts a deleterious amplifying effect.

DRESS typically begins with general symptoms (fever, flu-like syndrome, etc.), which may precede the eruption by several days. The eruption itself is characterized by infiltrated edema of the face and body, with variable presentations ranging from more or less infiltrated and extensive maculopapular rash to erythroderma. While the eruption may sometimes be subtle, this does not rule out the diagnosis. It is associated with lymph node enlargement and often high, persistent fever. Apart from occasional cheilitis or conjunctivitis, there is no mucosal involvement. Mechanical vesicles or bullae may occur as a result of edema. Pustules are observed in approximately 20% of cases. Purpura may also be noted, occasionally associated with more severe forms.

Though not universal, eosinophilia is a characteristic laboratory finding. Lymphocytosis may also be present, often accompanied by polymorphous, intensely basophilic lymphocytes (frequently misclassified in diagnostic tests as 'atypical' lymphocytes). Liver damage (cytolysis and/or cholestasis) is very common and varies in severity. Renal involvement typically presents with a combination of elevated creatinine, proteinuria, hematuria and eosinophiluria, indicative of interstitial nephritis. Other laboratory abnormalities, such as thyroid or pancreatic disturbances, may also be present. Persistent high fever should prompt the consideration of secondary macrophage activation syndrome.

DRESS owes its severity to visceral involvement, which can be life-threatening. In addition to hepatic and renal damage, pulmonary, cardiac (notably myocarditis), digestive (including pancreatic) and neurological involvement have been reported, along with hemodynamic failure (e.g., hypotension or shock).

Several scoring systems can provide retrospective confirmation of the diagnosis, with the RegiSCAR score being widely used (See Appendix S2 in the online supplementary material). DRESS can be classified into mild, moderate and severe forms (See Appendix S3 in the online supplementary material).

Diagnosis is based on the clinical features, the medication timeline, histological examination of the skin, the presence of eosinophilia and/or basophil lymphocytes, organ involvement, and in certain cases prolonged viral replication (as evidenced by positive polymerase chain reaction [PCR] for HHV6, EBV, or CMV).

Inpatient admission to a dermatology, internal medicine, or pediatrics department (for younger patients), or even to an intensive care unit (ICU) in the most severe cases, is imperative due to the severity of systemic symptoms and organ damage, which may progress even after discontinuation of the causative drug. Acute-phase mortality varies between 5% and 10%. It is essential that the suspect drug(s) and all other drugs belonging to the same class be strictly contraindicated.

The treatment of DRESS primarily relies on corticosteroids: topical clobetasol for mild or moderate forms, low-dose systemic corticosteroids for moderate DRESS, and high-dose systemic corticosteroids for severe DRESS. In all cases, corticosteroid doses should be tapered very gradually over several months to prevent relapses. In the most severe cases, adjunctive treatments (e.g., intravenous immunoglobulin [IVIg], antivirals or anti-interleukin (IL)-5/IL-5R) may be considered alongside corticosteroids. Sequelae such as autoimmune diseases, particularly thyroid disorders, have been reported. Follow-up allergy testing is useful to confirm causal relationship with a drug, especially where multiple medications are suspected. All cases of DRESS must be reported to the relevant pharmacovigilance authorities.
## 2. Diagnosis and initial assessment

### 2.1. Objectives

* Early diagnosis of DRESS;

* Prompt identification and discontinuation of the suspect drug(s);

* Rapid patient transfer to a specialized unit;

* Informing the patient and family. **2.2. Professionals involved**

The first professionals involved are likely to be the attending physician, a pediatrician, or an organ specialist, particularly prescribers of 'high-risk' drugs. However, in the early stages, an emergency physician and a hospital dermatologist or allergist specializing in dermatology (or even an ICU specialist in severe cases) will be brought in.

These professionals play a key role in early diagnosis and the implementation of initial treatment measures, including recognition and prompt discontinuation of the suspect drug(s).

The role of the emergency physician is to consider the possibility of DRESS, investigate signs of severity, contact the hospital dermatologist and/or the specialist unit, and initiate the first therapeutic measures (See Appendix S4 in the online supplementary material).

Early transfer of the patient to a specialized unit for the management of SCARs (dermatology, or failing that, internal medicine, or pediatrics in the case of children, with proximity to ICUs if DRESS is severe) is a priority as soon as the diagnosis and severity are confirmed: the patient's condition and the severity of the initial clinical and laboratory presentation (Fig. 1).

The diagnosis of DRESS and the patient's initial assessment are primarily conducted by a dermatologist, but must involve a multidisciplinary team depending on organ involvement and the patient's condition:

<figure><img src="image_4.png" /><figcaption>Fig. 1. Algorithm for transfer of patients with DRESS to the expert center.</figcaption></figure>
* dermatologist or allergist specializing in dermatology;

* pediatric dermatologist;

* pediatrician;

* hepatologist;

* nephrologist;

* pulmonologist;

* cardiologist;

* gastroenterologist;

* neurologist;

* psychiatrist, psychologist;

* ICU specialist;

* pathologist;

* biologists (specialized in hematology and virology);

* pharmacist;

* pharmacovigilance services;

* dietician;

* social worker;

* nurse.

The specialized team must include medical and paramedical staff trained in the management of SCARs and access to the necessary technology based on the organs involved.

## 2.3. Clinical diagnosis

DRESS usually begins 2 to 8 weeks after initiation of offending medication. However, cases of rapid-onset DRESS (less than 2 weeks) have been reported, particularly with antibiotics and iodinated contrast media (which can induce the syndrome within 1 to 4 days). A very short time to onset has also been observed in cases of accidental rechallenge with a drug that previously caused a rash or a prior episode of DRESS. Immunosuppression, recent systemic corticosteroid therapy or chronic kidney disease may alter the typical time to onset and must be considered when evaluating drug causality.

### 2.3.1. General signs and skin manifestations

The initial signs of DRESS are often nonspecific: fever, flu-like syndrome, myalgia, and general malaise. Fever, often high, is observed in over 90% of patients and generally precedes the eruption by a few days.

The initial clinical evaluation should include an assessment of vital signs: temperature, heart rate, blood pressure, respiratory rate, and oxygen saturation by pulse oximetry.

Dermatological manifestations typically begin with a variably pruritic morbilliform rash affecting the face, neck, upper extremities, and trunk. This rash may progress to diffuse infiltrated erythema covering more than 50% of the body surface area (BSA) or even erythroderma (erythema covering > 90% BSA). The rash may become edematous and, in some cases, purpuric (considered by some authors as a severity sign), with pustules, vesicles or blisters caused by edema. Infiltrated edema of the face, particularly involving the midfacial, periorbital and ear regions, is a characteristic feature. However, the rash may occasionally be fairly inconspicuous.

While mucosal involvement is possible, it is generally mild and limited to a single site (cheilitis, oropharyngeal enanthem or conjunctivitis). Forms showing phenotypic overlap with other severe cutaneous adverse reactions, including acute generalized exanthematous pustulosis and epidermal necrolysis have been reported.

A thorough physical examination reveals tender, often diffuse and supra-centimetric enlarged lymph nodes in half of cases. The examination should also evaluate potential involvement of the lungs, heart, digestive organs, and nervous system.

### 2.3.2. Visceral manifestations

All internal organs can be affected. These visceral manifestations and their intensity determine the severity of DRESS (mild, moderate,

or severe; see Appendix S3 in online supplementary material). These manifestations often appear at a distance from the initial onset of disease.

Hepatic involvement is the most common form of visceral damage, affecting 75% of patients. In 10% of cases, liver damage may precede the appearance of skin lesions. It can present as cytolysis, particularly in younger patients, or more commonly as cholestasis or a mixed profile. Hepatomegaly is rare. Severe liver damage is uncommon but can be life-threatening. Indicators of severity include transaminase levels > 15-fold the upper normal level (N), alkaline phosphatase levels > 5 N, or prothrombin time (PT) and factor V levels < 50%. In rare cases, fulminant hepatitis, characterized by PT < 50% and hepatic encephalopathy may occur and require emergency liver transplantation. Liver biopsy is generally unnecessary, but may be considered in cases of diagnostic uncertainty, particularly where the severity of hepatic involvement appears disproportionate to that of other organs.

Kidney damage is the second most common form of organ involvement after liver damage, occurring in 10–30% of cases. Age, pre-existing chronic kidney disease and allopurinol use are risk factors for kidney injury as a secondary manifestation of DRESS. Renal symptoms typically present as acute renal injury, occurring in isolation in nearly 90% of cases. Conversely, urinary manifestations are rare in the absence of renal impairment, accounting for less than 5% of cases. The most common histological presentation is tubulointerstitial nephritis. While eosinophiluria is inconsistent, its presence is particularly suggestive of this tubulointerstitial process. Apart from this organ-specific damage, functional acute kidney injury is often observed in the context of fever and erythroderma. It generally responds well to symptomatic treatment and should not be considered specific to DRESS or included in the RegiSCAR diagnostic criteria. However, a nephrologist should be involved with a view to a renal biopsy if the clinical course is unfavorable despite appropriate hydration and/or in the presence of urinary signs such as proteinuria or abnormal urine sediment. Oliguria or anuria indicative of severe renal impairment necessitates diuresis monitoring and close tracking of creatinine levels. Emergency renal replacement therapy (dialysis) is not uncommon, being required in up to 30% of patients with renal involvement in reported case series of DRESS.

Pulmonary manifestations are observed in 5–25% of cases and are more frequent with certain drugs, such as minocycline. They include acute interstitial lung disease, sometimes associated with pleuritis, which may progress to acute respiratory distress syndrome (ARDS). If performed, bronchoalveolar lavage, particularly in severe cases to rule out pulmonary infection, often reveals eosinophilic alveolitis.

Cardiac involvement may manifest as eosinophilic myocarditis or pericarditis. Myocarditis is potentially fatal, with mortality rates reaching up to 50%. It may occur around the time of diagnosis or develop weeks or even months after other symptoms of DRESS have resolved. Clinical manifestations that should raise concern include chest pain, tachycardia, dyspnea, and hypotension. However, symptoms may be atypical and include gastrointestinal signs. Diagnosis relies on clinical criteria, as well as electrocardiogram (ECG) abnormalities, elevated cardiac enzymes (particularly troponin) and echocardiography, rather than biopsy. Cardiovascular magnetic resonance imaging (MRI) can demonstrate myocardial inflammation. ECG abnormalities are observed in over 70% of cases, the most frequent being sinus tachycardia and ST-segment elevation, with possible arrhythmias or conduction disorders. Echocardiography may either be normal or reveal left ventricular dysfunction. Troponin levels are almost always elevated. ECG abnormalities, even minor or limited to sinus tachycardia, or elevated troponin levels warrant urgent cardiological evaluation.

Possible digestive involvement includes pancreatitis (identified clinically or via laboratory findings, sometimes delayed and severe, leading to diabetes), cholecystitis, gastroenteritis, or colitis with symptoms such as pain, diarrhea, bleeding, or gastrointestinal strictures.
Neurological complications, though rare, are diverse and may include encephalitis, meningitis, cerebrovascular accidents, or peripheral nerve damage.

Other potential manifestations include myositis, uveitis, and inflammation of the salivary glands.

Persistent high fever or laboratory abnormalities (e.g., pancytopenia, thrombocytopenia, extensive cytolysis, hyperferritinemia, hypertriglyceridemia or hypofibrinogenemia) should prompt evaluation for macrophage activation syndrome. The HScore (Saint Antoine Hospital score, available online at https://saintantoine.aphp.fr/score/) provides good predictive value. If the score is suggestive of macrophage activation syndrome, a myelogram (including viral PCR testing on bone marrow samples) can provide diagnostic guidance where contributive findings are present (e.g. presence of hemophagocytosis).

## 2.4. Histopathology

Skin biopsy is recommended in the diagnostic work-up of DRESS, particularly to rule out other disorders such as primary or secondary cutaneous T-cell lymphoma. However, the histopathological appearance of skin lesions varies significantly between cases and is not pathognomonic for DRESS, often mimicking viral maculopapular rashes.

The skin may exhibit various inflammatory profiles, including lichenoid interface dermatitis, eczematous or pustular patterns. Inflammatory skin lesions may sometimes be absent. The superficial dermal lymphocytic infiltrate is perivascular, and its density varies, ranging from minimal to dense infiltrates. The infiltrate may or may not contain eosinophils. Neutrophils and plasma cells may be present and extravasated red blood cells are quite common, but vasculitis is not observed. Misleading cases may be seen that mimic cutaneous lymphoma, due to significant lymphocyte exocytosis in the epidermis, dense dermal infiltrates or medium-sized atypical lymphocytes with deeply basophilic cytoplasm that may resemble Sézary cells.

In these cases, immunohistochemistry and T-cell clonality testing are recommended. The lymphocytes are mainly T cells, some CD8+ and cytotoxic (granzyme B+), without pan-T antigen loss. T-cell clonality testing is usually negative, though a dominant T clone may occasionally be identified.

If a lymph node biopsy is performed (only in cases of diagnostic uncertainty), the findings range from reactive hyperplasia to more suspicious infiltrates containing atypical lymphocytes that may suggest lymphoma. Correlation to clinical manifestations is therefore essential, and in such cases, as with suspicious skin biopsies, additional investigations (immunophenotyping by immunohistochemistry and T-cell clonality testing) are recommended.

Visceral biopsies are only performed in the event of diagnostic uncertainty. Liver biopsies typically show acute hepatitis with varying degrees of lobular inflammation, foci of necrotic hepatocytes and infiltrates that may be granulomatous, with eosinophils. Portal inflammation and cholestasis may also be present.

Renal biopsy most commonly reveals tubulointerstitial nephritis with edema and infiltrates composed of lymphocytes, histiocytes, eosinophils and plasma cells.

Endomyocardial biopsy reveals eosinophil-rich inflammatory infiltrate in the myocardium, either without necrosis (non-necrotizing eosinophilic myocarditis) or with necrosis (acute necrotizing eosinophilic myocarditis), the latter condition being particularly serious.

## 2.5. Initial laboratory work-up

### 2.5.1. First-line work-up

The minimum first-line laboratory work-up for suspected DRESS (to be repeated regularly based on the clinical course and detected abnormalities) includes:

* A complete blood count with a blood smear to identify reactive lymphocytes with intensely basophilic cytoplasm. Their presence is highly suggestive even in the absence of lymphocytosis. Eosinophilia is highly suggestive but inconsistent; it is absent in approximately 20% of cases or may appear later.

* Serum electrolytes, urea, creatinine and estimated glomerular filtration rate (eGFR).

* Urine electrolytes, proteinuria, and urine sediment.

* Complete liver panel (alanine transaminase (ALT), aspartate transaminase (AST), γ-glutamyl transferase (GT), alkaline phosphatase (ALP), and total and conjugated bilirubin).

* Coagulation studies, including Prothrombin Test (PT), supplemented by Factor V and vitamin K-dependent factors (II, VII, X) if PT is reduced.

* Troponin

* Infection work-up if fever is present (blood cultures, urine culture, PCR testing for SARS-CoV-2 and other respiratory viruses, and blood PCR or serologies for other viruses [e.g., human immunodeficiency virus, parvovirus] if viral infection is suspected).

* Quantitative viral PCRs for HHV6, EBV and CMV (performed in a hospital setting; not reimbursed in primary care; serological testing for these viruses is not considered worthwhile).

* Electrocardiogram

* Chest X-ray

### 2.5.2. Organ-specific work-up

This work-up is performed based on the organ damage detected or suspected upon physical examination or initial laboratory testing, in consultation with the relevant specialist if needed. It is then repeated as necessary based on the clinical course and detected abnormalities:

* Liver: PT, coagulation factors (Factor V and vitamin K-dependent factors) where PT is reduced; hepatitis A, B, C and E serologies; HSV PCR; abdominal ultrasound or Computed Tomography (CT) scan; liver biopsy where there is diagnostic uncertainty.

* Kidney: renal biopsy where there is diagnostic uncertainty.

* Lung: chest CT-scan, pulmonary function tests (after the acute episode in severe cases and/or if respiratory symptoms persist); bronchoscopy with bronchoalveolar lavage (cytological examination, microbiological testing tailored to the clinical context and severity).

* Heart: regular monitoring of troponin, brain natriuretic peptide (BNP)/pro-BNP, echocardiography, cardiovascular Magnetic Resonance Imaging (MRI).

* Pancreas: lipase, abdominal CT-scan, pancreatic MRI.

* Gastrointestinal tract: rectosigmoidoscopy with biopsy if colitis is suspected (particularly for CMV testing); stool culture (to rule out *Clostridium difficile* infection); endoscopy for strictures, abdominal CT-scan.

* Central nervous system: brain CT-scan or MRI, lumbar puncture.

* If macrophage activation syndrome is suspected: ferritin, triglycerides, fibrinogen; calculation of the HScore (hemophagocytic score). If the score suggests macrophage activation syndrome, a myelogram is performed.

* T-cell phenotyping and search for Sézary cells: in the event of uncertainty regarding epidermotropic T-cell lymphoma.

* Lymphadenopathy: lymph node biopsy is rarely indicated and is performed only in cases of diagnostic uncertainty if lymphoma is suspected.

### 2.5.3. Viral reactivation

DRESS is frequently associated with reactivation of herpesvirus (HHV6, EBV, CMV), although their precise role in its pathophysiology remains unclear. Viral replication, detected by quantitative PCR (not serology), peaks 2–4 weeks after the onset of DRESS, but may appear earlier during the initial transient lymphopenia and during subsequent
flare-ups. Testing should preferably be conducted in a hospital labora-
tory, as it is not reimbursed in primary care. In France, HHV6 and EBV
are the most commonly detected viruses (25–30%). CMV is less preva-
lent (< 10%). The frequency of positive viral replication depends on
the timing of testing: results are often negative at the time of diagnosis
of DRESS (except in patients seen very early) and become positive
within 2–4 weeks after onset of DRESS. Viral replication may involve
a single virus or multiple viruses in sequence.

Herpesvirus infections contribute to visceral damage. Viral PCR testing should be repeated if the clinical or laboratory course is unfavorable, as antiviral therapy (in particular, ganciclovir for CMV or HHV6, detailed later) may be considered in combination with corticosteroid therapy.

HHV6 replication (in particular, HHV6-B) is the most prevalent,
and evidence suggests it may begin in the skin before becoming detect-
able in the blood. It may be implicated in severe organ involvement or
macrophage activation syndrome. Monitoring of replicating viral load
is helpful where organ involvement is suspected. A detection threshold
of 200 copies/mL in whole blood is considered positive. However, this
threshold is only indicative due to variability between quantification
methods. There is no replication threshold predictive of severe organ
damage. A rare but notable situation is hereditary HHV6 chromosomal
integration (found in 1% of the population), where HHV6 is present in
all cells and hereditary. Such patients have positive HHV6 PCR results
in whole blood, with levels reaching several million copies/mL. Chro-
mosomal integration is diagnosed by a positive PCR result on a hair
follicle. The virus may reactivate transiently after drug exposure or
during immunosuppression.

CMV replication is rare but potentially serious where the viral load
is high, as it can be associated with organ damage such as liver injury.
As with HHV6, there is no predictive threshold for severe organ dam-
age due to variability in viral quantification methods. However, repli-
cation is generally considered significant and should be monitored if
the viral load exceeds 4 log IU/mL.

Corticosteroid therapy has a variable effect on viral replication: it
has no effect on EBV replication, may control HHV6 replication
through its lymphopenic effect (since HHV6 replicates within T cells),
though this is sometimes insufficient, and can be deleterious to CMV
replication.

2.6. Causality assessment

A chronological timeline should be drawn up, listing all drugs
taken by the patient (even as a one-off) in the 8 weeks prior to the
onset of DRESS. Any dosage increases should also be listed. The
patient's history of drug allergies should be documented.

The typical time to onset of DRESS is 2 to 8 weeks after initiation of
the suspect drug, but shorter or even very short delays have been
reported (see above). The date of DRESS onset (the ‘index date’)
may correspond to the appearance of non-dermatological signs (e.g.,
general signs, visceral signs such as digestive symptoms, or laboratory
abnormalities, particularly eosinophilia).

There is no causality score specifically adapted to DRESS. All drugs
suspected of causing DRESS must be discontinued following the intrin-
sic causality assessment (compatible chronology, symptoms consistent
with the diagnosis of DRESS and exclusion of other possible causes).
Conversely, medications taken for more than 12 weeks are not consid-
ered suspect and may be continued if necessary.

Extrinsic causality (based on bibliographic evidence and the noto-
riety of the drug) is important for ranking the risk level of suspect
drugs. Allergy tests performed after the acute phase of DRESS can help
identify the molecule(s) responsible and, in certain cases, may lead to
the consideration of cautious rechallenge of drugs yielding negative
tests (see chapter 4.6).

Reporting to pharmacovigilance is mandatory and ensures health
monitoring of the risk of SCAR.

2.7. Differential diagnosis

The diagnosis of DRESS can be challenging, particularly in the early
stages or when dermatological presentations are poorly defined. The
main differential diagnoses to consider in the presence of a DRESS
eruption are:

* Other cutaneous adverse reactions (maculopapular rash, acute generalized exanthematous pustulosis, early-stage epidermal necrolysis)

* Viral infection (particularly in children)

* Bacterial infection such as scarlet fever (especially in children) or toxin-producing infections

* Other causes of erythroderma (eczema, psoriasis, cutaneous T-cell lymphoma)

* Lymphoma, particularly angioimmunoblastic lymphoma

* Kikuchi disease

* Kawasaki disease (especially in children)

* Pediatric multisystem inflammatory syndrome linked to SARS-CoV-2

The drug causality assessment, laboratory tests and skin biopsy sup-
port the diagnosis.

2.8. Classification and assessment of severity

The severity of DRESS is primarily dependent on visceral involve-
ment. Skin involvement does not define the severity of DRESS, but
major facial edema and/or purpura are sometimes associated with sev-
ere DRESS.

A recent international consensus differentiates between three
stages of DRESS severity: mild, moderate and severe (see Appendix
S3 in online supplementary material). In summary:

* Mild DRESS is characterized by the absence of visceral involvement and minor liver abnormalities (transaminases < 4 N).

* Severe DRESS is characterized by severe hepatic damage (transam-
  inases > 15 N and/or Factor V < 50%), and/or acute kidney
  injury (with rapid deterioration of renal function or classified as
  KDIGO III [kdigo.org]), damage to certain organs (e.g., lung, heart,
  digestive organs, central nervous system), and/or the presence of
  macrophage activation syndrome.

* Moderate DRESS is characterized by intermediate clinical presentations.

3. Management during the acute stage

3.1. Objectives

Treatment of DRESS is an emergency. The goal is to limit the risk of progression to a severe, potentially fatal form of the disease.

The mortality rate for DRESS in the acute phase is 5–10%, with
15% of patients requiring intensive care. Age, renal impairment, sev-
ere visceral damage, macrophage activation syndrome and CMV repli-
cation are associated with risk of ICU admission and increased
morbidity and mortality.

The goals of management and treatment are to:

* Identify and urgently discontinue the drug(s) suspected of causing the disease, with permanent contraindication to prevent recurrence.
* Transfer the patient to a department accustomed to managing SCARs and close to an ICU in case of progression to severe DRESS (Fig. 1). The risk of secondary worsening of DRESS should not be overlooked, even after discontinuation of the causative drug.

* Investigate and treat potential visceral damage repeatedly over time (delayed onset is possible) to reduce morbidity and mortality in the acute phase.

* Test for viral reactivations contributing to visceral damage so that specific antiviral treatment can be initiated if necessary.

## 3.2. Professionals involved

Therapeutic management of the patient in the acute phase relies on multidisciplinary cooperation coordinated by the expert physician (usually a dermatologist) in a center specializing in the management of SCARs.

Front-line professionals upon admission comprise:

* dermatologist (or allergist specializing in dermatology); pediatric dermatologist if the patient is a child;

* hospital pediatrician if the patient is a child;

* organ specialists as needed: hepatologist, nephrologist, cardiologist, pulmonologist, gastroenterologist, neurologist, etc.;

* intensive care specialist if there is severe organ damage;

* psychiatrist, psychologist;

* pathologist;

* biologists (specialized in hematology and virology);

* dietician;

* nurses trained in dermatological care.

Other professionals involved as needed in the acute phase:

* allergist;

* pharmacist;

* pharmacovigilance services;

* social worker.

## 3.3. Medication management

It is imperative to discontinue all suspect medications as early as possible while ensuring continuity of care. Where discontinuation of a suspect drug poses a significant and immediate risk of exacerbating a comorbidity (e.g., stopping an antiepileptic drug, or an antibiotic in the context of a serious infection), the discontinuation and potential substitution must be carried out in consultation with the specialist managing the underlying condition.

The list of drugs associated with DRESS is extensive, but fewer than 10 molecules or drug classes account for most cases in Europe:

* Aromatic anti-epileptics: carbamazepine, oxcarbazepine, eslicarbazepine, phenobarbital, phenytoin; lamotrigine;

* Allopurinol;

* Antibacterial sulfonamides (cotrimoxazole, dapsone, sulfasalazine);

* Abacavir;

* Beta-lactam antibiotics (particularly penicillin);

* Minocycline;

* Vancomycin.

However, any drug can cause DRESS. The causality assessment must therefore be meticulous and thorough, not ruling out any potential culprit drug, even where the time to onset is short (e.g., iodinated contrast media).

The risk of DRESS is particularly high with certain drugs in specific populations, justifying pre-treatment screening policies for at-risk groups. For example, individuals of Asian descent carrying HLA

B15:02 (associated with carbamazepine-induced DRESS) or HLA B58:01 (associated with allopurinol-induced DRESS, see Appendix S1 in the online supplementary material) are particularly at risk.

Discontinuation of non-suspect essential treatments (i.e., medications introduced more than 12 weeks prior) should be avoided, as recovery despite their continuation helps to rule out any future reluctance to use them.

Conversely, a drug deemed to have a 'high risk' of inducing DRESS may be used or continued if it is indispensable and not suspected in the patient's case, with input from a pharmacovigilance center if necessary.

## 3.4. General measures

The room should be maintained at between 25 and 28 °C if the patient presents with erythroderma. The management of skin symptoms includes baths or showers with mild soap and emollients several times a day.

Oral hydration is often sufficient in the absence of acute kidney injury. An intravenous drip should be inserted if the patient cannot drink, has a high fever and/or has acute kidney injury or severe organ damage. Vascular access is primarily via a peripheral venous catheter, which should be changed regularly, with an area of healthy skin prioritized for catheter placement. The primary method of achieving adequate hydration is the use of crystalloid solutions (isotonic saline or Ringer's lactate).

Where fever management is challenging, paracetamol may be prescribed, except in cases of significant cytolysis, where its use is contraindicated.

During DRESS, the prescription of new drugs should be restricted to the strict minimum due to the risk of polysensitization associated with this condition.

## 3.5. Corticosteroid therapy

Therapeutic management of DRESS, irrespective of the presence of viral reactivation, relies primarily upon local (cutaneous) or oral corticosteroid therapy, depending on the degree of severity of DRESS (see criteria in Appendix S3 in the online supplementary material).

* **For mild DRESS**, topical treatment with high potent corticosteroids (class IV) such as clobetasol (approximately 30 g per day) is sufficient, and is applied to the whole body, except the face, until the rash has completely cleared. A potent corticosteroid (class III) such as betamethasone may be used on the face. The assistance of a nurse is often required to ensure optimal compliance. Thereafter, tapering should be very gradual, over a period of 6 weeks to 3 months, to avoid relapses.

* **For moderate DRESS**, topical corticosteroid therapy with clobetasol can be used in the same way, but with increased clinical and laboratory monitoring. In the event of worsening clinical symptoms and/or laboratory findings, a switch to oral corticosteroid therapy is required. Alternatively, oral corticosteroids at a dose of 0.5 mg/kg/day can be initiated from the outset for an average duration of 1 month, with gradual tapering over 3 months.

* **For severe DRESS**, oral or intravenous corticosteroid therapy at 1 mg/kg/day prednisone equivalent is indicated, for an average duration of 1 month, with a very gradual taper over 3 to 6 months.

Pulse administration of corticosteroids is not recommended, as it appears to be associated with more frequent viral reactivation, persistent symptoms, and higher mortality.

The usual precautions for monitoring prolonged topical or systemic corticosteroid therapy should be observed.
In some cases, such as patients with severe sepsis in ICU, modifications to the route of administration and dose of corticosteroid therapy may be required (following multidisciplinary discussion).

If DRESS occurs during pregnancy, the same recommendations concerning corticosteroid therapy apply, with appropriate obstetric-gynecologic monitoring.

## 3.6. Other treatments

### 3.6.1. Antivirals

The role of antivirals in the therapeutic strategy for DRESS is still debated. There are no clinical trials demonstrating their efficacy.

The use of antivirals, in combination with corticosteroids, is discussed on a case-by-case basis during multidisciplinary meetings at expert centers, in the following cases: severe DRESS, organ involvement that does not improve with high-dose systemic corticosteroid therapy, and high viral load (no consensus threshold, see above). The viruses concerned are CMV (approved for this indication) and HHV6 (off-label). It is therefore important to investigate these reactions repeatedly to be able to offer antiviral treatment in the aforementioned severe cases. The molecules used are ganciclovir (intravenous), valganciclovir (oral) or foscarnet (intravenous), with monitoring of tolerability (particularly hematological), until the viral load becomes negative.

### 3.6.2. Intravenous immunoglobulin

Intravenous immunoglobulins (IVIg) must not be used alone in DRESS (ineffective and poorly tolerated).

However, in cases of steroid-refractory DRESS or in DRESS associated with high viral replication, the addition of IVIg to systemic corticosteroid therapy may be considered. The usual dose is 1 to 2 g/kg, administered over 2 to 5 days, with the rate adjusted according to the patient's tolerance. Tolerability must be monitored (risk of thrombosis, acute kidney injury, lymphocytic meningitis, eczematous rash, etc.).

### 3.6.3. Anti-IL-5/IL-5R

Anti-IL-5 antibodies (e.g., mepolizumab in single or repeated doses of 300 mg every 4 weeks for 3 months) or anti-IL-5R antibodies (e.g., benralizumab in single or repeated doses of 30 mg) are emerging options for the treatment of DRESS. To date, they have only been used as adjuncts to systemic corticosteroids in severe steroid-refractory or steroid-dependent DRESS. However, the involvement of the IL-5 pathway in the pathophysiology of DRESS suggests that these treatments could potentially serve as first-line steroid-sparing therapies in the future. Case reports in the literature show that IL-5/IL-5R inhibitors can rapidly reduce circulating eosinophilia and control cutaneous and visceral involvement, including myocarditis. Currently, there is no evidence to support their use as monotherapy without the use of corticosteroids.

In routine practice, mepolizumab or benralizumab may be considered in cases of severe, steroid-refractory or steroid-dependent DRESS, where adjunctive therapy to corticosteroids is needed. These treatments have a favorable safety profile.

A further French clinical trial should help to better define the place of benralizumab as a first-line treatment for DRESS in combination with topical or systemic corticosteroids.

### 3.6.4. Other treatments

In exceptional cases, immunosuppressive agents such as cyclosporine or Janus Kinase (JAK) inhibitors may be considered for severe steroid-refractory DRESS.

Indeed, a short course of cyclosporine as an adjunct to corticosteroids may help accelerate control of DRESS and reduce hospital

stays. Anecdotal reports describe the use of JAK inhibitors, cyclophosphamide, or mycophenolate mofetil.

Methotrexate and omalizumab (anti-IgE) may have potential as steroid-sparing treatments in patients with steroid-dependent chronic cutaneous DRESS.

### 3.6.5. Psychological support

DRESS can be a traumatic experience for patients due to the sudden impact on their body appearance, the intensity of systemic symptoms and the anxiety caused by the potential severity of the disease. This justifies offering routine and early psychological support to patients and their families from the acute phase onward.

## 3.7. Intensive care management

Approximately 15% of DRESS patients require ICU admission due to various types of organ failure, including myocarditis, nephritis, hepatitis, or shock. Shock with multi-organ failure can occur independently of cardiac damage and may be life-threatening.

Mortality associated with these complications varies between studies, but is generally high, particularly in cases involving shock or cardiac damage (20-47%).

The management of DRESS patients in an ICU requires a multidisciplinary approach and an aggressive therapeutic strategy to stabilize organ dysfunction. This includes non-specific supportive care, such as catecholamines, non-invasive or invasive ventilation, and dialysis, along with etiological treatment involving high-dose corticosteroids +/- adjuvant therapies (e.g., IVIg, anti-IL-5/IL-5R, antivirals, etc.).

DRESS-associated myocarditis, which affects women twice as often as men and typically occurs in the early stages of the disease, is potentially severe and can lead to cardiogenic shock. The older the patient and the shorter the interval between drug exposure and DRESS onset (less than 15 days), the poorer the prognosis. Early admission to an ICU for monitoring and specific management is warranted.

Myocarditis should be suspected in the presence of elevated troponin levels and evocative ECG abnormalities. Urgent cardiological evaluation, including cardiac ultrasound or MRI, is essential to confirm the diagnosis and rule out differential diagnoses such as ischemic heart disease, particularly in patients with cardiovascular risk factors. Once myocarditis is confirmed, the patient should be admitted to cardiac intensive care or the ICU for high-dose corticosteroid therapy, standard heart failure treatment and symptomatic measures. In severe cases of refractory cardiogenic shock, venoarterial extracorporeal membrane oxygenation (VA-ECMO) may be indicated. If recovery is not achieved with VA-ECMO, long-term ventricular assistance or cardiac transplantation may be necessary. It is important to consult with a heart transplant/assistance team as soon as ECMO is initiated. It should be noted that some patients may present with acute circulatory failure without cardiac dysfunction.

Respiratory involvement, although rare, is variable, ranging from mild dyspnea to acute respiratory distress syndrome (ARDS). Its presence is associated with a more severe clinical course and an increased risk of mortality. Oxygen therapy is required in cases of severe parenchymal involvement, and orotracheal intubation with invasive mechanical ventilation may be necessary in the most severe cases. Patients under 60 years of age and those with DRESS onset within 30 days of drug exposure are at higher risk for ARDS.

DRESS can also cause acute kidney injury due to immuno-allergic nephritis, with dialysis required in 30% of cases. The criteria for initiating dialysis in these cases are the same as those traditionally used for acute kidney injury in ICU patients.

Severe liver damage can also occur. In fulminant cases, the use of N-acetylcysteine may be considered, all hepatotoxic treatments (e.g.,
paracetamol) must be discontinued, and emergency liver transplantation should be considered.

### 3.8. Specific considerations in children

The incidence of DRESS in children is poorly understood and is likely underestimated.

In published pediatric series, half of all drugs associated with DRESS are antiepileptics (carbamazepine, phenobarbital, phenytoin, and lamotrigine) and around one-third are antibiotics (sulfonamides, beta-lactams, and vancomycin), followed by sulfasalazine and nonsteroidal anti-inflammatory drugs. The average time between the introduction of the suspect drug and the first symptoms of DRESS ranges from 9 to 28 days, depending on the series. Symptoms tend to appear more quickly (< 15 days) where the suspect drug is an antibiotic.

The median age of occurrence of DRESS in children ranges from 8 to 11.5 years, depending on the series, with rare cases reported in infants as young as 5 weeks.

As in adults, the clinical presentation typically begins with high fever and marked asthenia, followed, or accompanied by a cutaneous rash, most commonly morbilliform. Erythroderma develops in 5–44% of cases. Facial edema is present in 30–65% of cases, and mucosal involvement, mainly buccal cheilitis, is described in 50% of cases. Lymph node enlargement is observed in 30–65% of cases.

Organ involvement occurs in 91% of cases. The liver is the most frequently affected organ (84%), followed by the lungs (interstitial pneumonia, 8–21%), kidneys (interstitial nephropathy, 15%), and heart (myocarditis, 3%). Neurological and digestive involvement are possible but far less common. Macrophage activation syndrome is more common in children than in adults.

The clinical course is slow, with symptoms typically resolving after more than two weeks. Relapses are common, even in the absence of reintroduction of the causative drug. The risk of death is 4–5%, depending on the series.

Differential diagnoses of DRESS in children include:

* Viral infections (primary infections), which are more frequent than in adults and should always be investigated with comprehensive testing:

- EBV serology (anti-VCA IgM, anti-VCA IgG, anti-EBNA IgG), CMV (IgM and IgG), parvovirus B19 (IgM and IgG);

- PCR for EBV, CMV, parvovirus B19, HHV6, adenovirus and enterovirus;

* Toxin-induced bacterial infections, such as scarlet fever;

* Kawasaki disease, characterized by fever, rash, impairment of general condition, mucosal involvement (conjunctivitis, cheilitis), and lymph node enlargement;

* Pediatric multisystem inflammatory syndrome linked to SARS-CoV-2;

* Inflammatory diseases, such as juvenile arthritis or Still's disease;

* Hematological disorders, especially in the presence of macrophage activation syndrome.

The treatment of pediatric DRESS is similar to that for adults. Systemic corticosteroids are frequently used in case series (85% of cases) at doses of 0.5–1 mg/kg/day. Corticosteroid therapy should be continued for several months, with a gradual taper to prevent rebound effects upon discontinuation. Class III (potent) or IV (very potent) topical corticosteroids have shown good efficacy in mild cases of DRESS, initially with daily application over the entire body. The frequency of application is then gradually reduced. In some cases, corticosteroid pulses, antivirals, IVIg or cyclosporine have been proposed, but no robust

studies have established the role of these therapies in the treatment of DRESS in children.

Immediate complications depend on the affected organs. Hepatitis is the most common, but severe cases and deaths are due primarily to cardiac involvement (myocarditis), central nervous system involvement, or macrophage activation syndrome.

In the medium term, corticosteroid-induced complications have been reported, especially with prolonged use: arterial hypertension, steroid-induced diabetes, adrenal insufficiency, and growth retardation.

Dermatological sequelae are primarily characterized by hyperpigmentation, particularly in children with dark phototypes.

Autoimmune complications appear to be more common in children than in adults, with reported cases of autoimmune thyroiditis, mainly Hashimoto's thyroiditis but also Graves' disease. These complications can occur within three years of the onset of DRESS. Cases of type 1 diabetes have also been reported, mainly within two months after DRESS. Anecdotal cases of type 3 autoimmune polyendocrine syndromes (thyroiditis, type 1 diabetes and Vogt-Koyanagi-Harada disease [associated with vitiligo, uveitis, deafness and alopecia]), hemolytic anemia, lupus or arthritis have also been reported in the literature. It is therefore essential to inform parents and the attending physician of the potential for autoimmune complications. Clinical monitoring (e.g. for lupus, vitiligo, alopecia, symptoms of polyuria-polydipsia syndrome, weight loss) and laboratory monitoring (blood glucose, thyroid stimulating hormone (TSH) and possibly antinuclear antibodies) are recommended during the first few years following DRESS.

Prolonged recovery and relapses are also more common in children.

In the pediatric population, it is important to be alert to the psychological impact of DRESS not only on the child, but also on the parents and sometimes the siblings. Specific psychological support should be offered.

As in adults, the allergological work-up includes patch testing, potentially followed by delayed intradermal testing depending on the suspect drugs (see section 4.6). Cautious drug rechallenge should only be considered for medications essential to the child's care and only at highly specialized centers.

### 3.9. Discharge information for patients and their attending physicians

At discharge, the patient and their attending physician must be given personalized information regarding the suspected or confirmed cause of DRESS, the risk of sequelae, the need for follow-up, and future use of medications.

Patients should be given a written document listing contraindicated and authorized medications (an allergy card and the most comprehensive list of prohibited drugs possible). The temporary allergy card issued at hospital discharge can be updated following allergy tests.

Patients and their general practitioners should be informed that DRESS treatment lasts several months, and that corticosteroid therapy must not be stopped too early or abruptly. The prescription given at the expert center must be strictly followed.

A 'therapeutic education' program should be implemented to support the patient. It should provide guidance on managing corticosteroid therapy, preventing side effects, tapering doses gradually, using the allergy card, handling medications in the future, and addressing residual symptoms.

Photoprotection (sunscreen and protective clothing) is required until cutaneous signs completely disappear and should be extended in cases of residual pigmentary disorders.

Patients and their GPs should also be informed of the risk of autoimmune sequelae, for which screening should be performed during the year following the acute phase (see above).
Finally, patients should be advised to seek urgent medical attention if they experience chest pain or dyspnea, even long after the acute phase, to avoid missing potential myocarditis.

## 4. Follow-up, management of sequelae and allergy testing

Follow-up begins as soon as the acute phase resolves. It should be coordinated by the dermatologist in collaboration with the attending physician. Follow-up should last at least one year, depending on each patient's needs.

### 4.1. Objectives

The objectives of follow-up are:

* Gradual tapering of corticosteroid therapy (topical or systemic) over several months, depending on the severity of DRESS (see above);

* Screening for corticosteroid-related complications (weight gain, diabetes, hypertension, osteoporosis, adrenal insufficiency, etc.);

* Screening for potential rebound or relapse of DRESS;

* Assessing the tolerability of possible adjuncts to corticosteroid therapy;

* Screening for and managing late sequelae and complications, particularly autoimmune ones, with specialist consultation if needed;

* Allergological management: skin testing conducted in an expert center specialized in cutaneous adverse drug reactions to identify the causative drug where multiple medications were initially suspected, and proposing alternatives or cautious rechallenge of essential medications.

### 4.2. Professionals involved

The key figures in the follow-up of DRESS treatment and screening for sequelae are the dermatologist or pediatric dermatologist at the expert center, in collaboration with the patient's GP or pediatrician.

Depending on the complications of DRESS and visceral damage sustained during the acute phase, multidisciplinary follow-up with organ specialists may be necessary.

Counseling by a psychologist or psychiatrist may also be required throughout the care process.

Allergy tests are conducted by an allergologist/dermato-allergologist experienced in allergy testing for SCARs, with support from a pharmacist for test preparation.

### 4.3. Follow-up procedures

Clinical and laboratory follow-up should be tailored to the severity of DRESS. The patient should attend a follow-up consultation one month after discharge and then every three months until corticosteroid therapy is discontinued, and the condition has resolved. Monitoring should continue for at least one year following the onset of DRESS to screen for autoimmune complications.

* Clinical monitoring: weight, growth curve in children, blood pressure, skin involvement, visceral manifestations of DRESS, and signs of autoimmune disease.

* Laboratory monitoring of DRESS: complete blood count, renal function, and a comprehensive liver panel should initially be done weekly, then at longer intervals, until all abnormal lab results arising from DRESS have normalized; monitor viral replication as needed.

* HLA typing: specific HLA typing if the causative drug is associated with a high-risk population.

* Management of prolonged corticosteroid therapy: specific monitoring, adherence to a low-salt and low-sugar diet, monitoring of fast-ing blood glucose, particularly before or two hours after meals, bone densitometry, and dental check-ups.

* Screening for autoimmune diseases at least once in the year following DRESS and in the event of suggestive symptoms: thyroid work-up (TSH, thyroid peroxidase antibody test, and thyroglobulin test), fasting blood glucose, antinuclear antibodies.

- In addition to thyroiditis, diabetes, and lupus erythematosus, other autoimmune diseases have been reported, including vitiligo, alopecia and Addison's disease. These are most often observed in young patients and/or in cases of strong HHV6 viral reactivation. They are detected clinically.

- Patients with pre-existing autoimmune diseases may experience flare-ups and require closer monitoring than usual.

- Patients with pre-existing renal disease may require lifelong hemodialysis after DRESS.

### 4.4. Management of relapses

It is difficult to define a 'typical' median duration of DRESS, whatever its severity, as there are no accepted criteria for defining its clinical course. In addition, the course of DRESS is punctuated by flare-ups of varying intensity and frequency, which can occur several months after the first symptoms and may occur without any reintroduction of the causative drug. However, here again, there is no universally accepted definition of a DRESS flare-up or recurrence. A flare-up or recurrence is often defined as a worsening of clinical (skin or deep organ) and/or laboratory findings, the reappearance of such findings after a period of control, or the development of new organ involvement.

Factors contributing to 'long' or 'chronic' DRESS and relapses must be identified:

* Drug-related factors: attention should be paid 1/ to the occasionally inadvertent resumption of the suspect drug or of a drug with a similar chemical structure; 2/ to cross-sensitization to a different drug introduced during the acute phase.

* Treatment-related factors: excessively rapid tapering of oral or systemic corticosteroids.

* Viral factors: HHV6, EBV or CMV replication.

* Immunological factors: underlying immune dysfunction.

In cases of 'long' or 'chronic' DRESS, or with repeated flare-ups, the use of steroid-sparing immunosuppressants may be discussed on a case-by-case basis at an expert center or within a multidisciplinary consultation: cyclosporine, methotrexate (for chronic cutaneous DRESS, in the absence of liver damage), mycophenolate mofetil, cyclophosphamide, and rituximab.

In certain highly comorbid patients, however, the use of these conventional immunosuppressants exposes them to the risk of severe infectious complications.

The use of targeted immunomodulatory therapies may then be discussed in a multidisciplinary consultation at an expert center, particularly biologics targeting IL-5 (mepolizumab) or its receptor (benralizumab), IL-4/IL-13 (dupilumab), or IgE (omalizumab).

### 4.5. Management of autoimmune complications

Autoimmune complications most often arise at a distance from the acute phase of DRESS and may persist over time or even be irreversible. They are not rare (3 to 5% of all cases of DRESS described in the literature) and are not always correlated with the severity of DRESS.

The risk factors for immune complications are poorly understood. They include:
* Young age;

* Pre-existing immune dysfunction;

* Viral replication (notably HHV6, EBV);

* Prolonged corticosteroid therapy and use of IVIg.

Screening for the most common autoimmune complications (thyroiditis and type 1 diabetes) should be performed routinely over a period of at least one year (see section 4.3).

Their management requires multidisciplinary collaboration, mainly involving the following specialists:

* An endocrinologist for:

- Thyroiditis, whether or not symptomatic (Hashimoto's disease, Graves' disease);

- Type 1 diabetes: fulminant non-autoimmune type 1 diabetes (due to β-cell destruction) or, more rarely, autoimmune diabetes. The distinction between the two forms is based on clinical findings and testing for GAD (glutamic acid decarboxylase), IA2, ZnT8 or insulin autoantibodies (IAA, in children). Beware of the risk of ketoacidosis in these types of insulin-dependent diabetes;

- Autoimmune polyendocrine syndromes, described mainly in children.

* A dermatologist for vitiligo, alopecia, chronic urticaria and bullous pemphigoid.

* A hepato-gastroenterologist for rare cases of autoimmune hepatitis and enteropathy.

## 4.6. Allergological work-up

An allergological work-up, carried out at an expert center by a dermatologist or dermato-allergologist familiar with the management of SCARs, is very useful in DRESS, particularly where there is more than one suspect drug. In France, only in vivo skin tests are performed (see Appendix S5 in online supplementary material). In vitro tests such as lymphocyte transformation tests or ELISpot assays are not routinely performed.

Patch tests are the first stage of testing. They show good sensitivity in DRESS (around 60%), but they must be interpreted with caution due to the frequent polysensitization specific to this type of reaction and their lack of sensitivity for certain molecules, even where their involvement has been confirmed (e.g., allopurinol, rifampicin, cotrimoxazole). They are performed according to standard recommendations (i.e., active substance diluted to 10% or finished product diluted to 30% in petroleum jelly, prepared extemporaneously by the testing team or by hospital pharmacies, or marketed by Chemotechnique Diagnostics, Vellinge, Sweden), in consultation, and

read at 2 or 3 days, 4 days, and, depending on the molecule in question, at 7 days if necessary.

If the patch tests are negative, additional intradermal testing is performed (intradermal reaction if an injectable form of the drug is available at the dilutions recommended in the literature, otherwise prick-testing using the same drug as for the patch tests), with delayed readings between 24 h and 3 days, or even up to 7 days.

If all tests are negative, and only if there is a major therapeutic benefit for the patient, rechallenge or substitution tests will be discussed in a multidisciplinary consultation. These tests must be carried out very cautiously, with very gradually escalating doses (starting at $10^{-4}$ or $10^{-2}$, depending on the team, up to the full dose, with 7 days between doses or 3 days for anti-tuberculosis drugs), under close clinical and laboratory supervision in a hospital setting. The drugs that can be used as part of such a strategy are:

- Alternatives to the suspect drug (substitution drug), belonging to the same family, after they have been tested with negative results (e.g., suspected penicillin and introduction of a third-generation cephalosporin). However, if a molecule from the same therapeutic class but with a different structure, and thus without cross-reactivity, is to be introduced (e.g., suspected rifampicin and introduction of moxifloxacin, sometimes to reassure the patient and the healthcare team), the drug is administered at the usual therapeutic dose from the outset.

- One of the chronologically suspect drugs (rechallenge test), only if there is no other alternative, if tests are negative for this molecule, and if there is at least one other suspect drug that will not be reintroduced. This is facilitated by the presence of another suspect molecule with a positive test or a well-established profile. Caution remains essential given the frequent polysensitization observed in DRESS, justifying very gradual dose escalation.

## Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

## Acknowledgments

Mrs Tiffanie Akiki and Mrs Cécile Remy Gaboriau.

## Appendix A. Supplementary material

Supplementary data to this article can be found online at https://doi.org/10.1016/j.annder.2025.103381.