# French national protocol for diagnosis and management of epidermal necrolysis in adults (Stevens-Johnson syndrome and toxic epidermal necrolysis)

S. Ingen-Housz-Oro, I. Matei, A. Gaillet, J. Gueudry, K. Zaghbib, H. Assier, C. Hua, B. Bensaid, A. Colin, R. Ouedraogo, et al.

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## To cite this version:

S. Ingen-Housz-Oro, I. Matei, A. Gaillet, J. Gueudry, K. Zaghbib, et al., French national protocol for diagnosis and management of epidermal necrolysis in adults (Stevens-Johnson syndrome and toxic epidermal necrolysis). Annales de Dermatologie et de Vénéréologie, 2024, 151 (2), pp.103282. 10.1016/j.annder.2024.103282. hal-05478821

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Submitted on 27 Jan 2026

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Guidelines

# French national protocol for diagnosis and management of epidermal necrolysis in adults (Stevens-Johnson syndrome and toxic epidermal necrolysis)

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S. Ingen-Housz-Oro<sup>a,b,*,1</sup>, I. Matei<sup>a,1</sup>, A. Gaillet<sup>c,1</sup>, J. Gueudry<sup>d</sup>, K. Zaghbib<sup>e</sup>, H. Assier<sup>a</sup>, C. Hua<sup>a</sup>, B. Bensaid<sup>f</sup>, A. Colin<sup>a</sup>, R. Ouedraogo<sup>c</sup>, J. Redlich<sup>a</sup>, E. Courtois<sup>a</sup>, K. Chazelas<sup>a</sup>, E. Sbidian<sup>a,b</sup>, L. Nakad<sup>g</sup>, E. Bequignon<sup>h</sup>, N. Terkmane<sup>i</sup>, F. Gaultier<sup>j</sup>, F. Schlemmer<sup>k</sup>, G. Do-Pham<sup>l</sup>, A. Barbaud<sup>m</sup>, B. Lebrun-Vignes<sup>n</sup>, C. Hoffmann<sup>o</sup>, P.-J. Mahé<sup>p</sup>, R. Le Floch<sup>p</sup>, C. Bernier<sup>q</sup>, B. Vabres<sup>r</sup>, B. Milpied<sup>s</sup>, A. Delcampe<sup>d</sup>, F. Tétart<sup>t</sup>, M. Tauber<sup>u</sup>, D. Staumont-Sallé<sup>v</sup>, F. Dezoteux<sup>v</sup>, V. Descamps<sup>w</sup>, L. Misery<sup>x,y</sup>, A.-C. Bursztejn<sup>z</sup>, O. Dereure<sup>aa</sup>, E. Amazan<sup>ab</sup>, E. Le Bidre<sup>ac</sup>, S. Le Pallec<sup>ad</sup>, C. Lagier<sup>ad</sup>, A. Laroche<sup>ad</sup>, E. Ferrat<sup>ae</sup>, P. Wolkenstein<sup>a,af</sup>, N. de Prost<sup>c,af</sup>, French National Reference Center for Toxic Bullous Diseases and Severe Drug Reactions TOXIBUL<sup>ag</sup>

<footnote><sup>a</sup>Department of Dermatology, Henri Mondor, AP-HP, Créteil, France</footnote>

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

<footnote><sup>c</sup>Medical Intensive Care Unit, Henri Mondor Hospital, AP-HP, Créteil, France</footnote>

<footnote><sup>d</sup>Department of Ophthalmology, Charles Nicolle University Hospital, Rouen, France</footnote>

<footnote><sup>e</sup>Department of Psychiatry, Henri Mondor Hospital, AP-HP, Créteil, France</footnote>

<footnote><sup>f</sup>Department of Dermatology, Edouard Herriot Hospital, Lyon, France</footnote>

<footnote><sup>g</sup>Emergency Department, Henri Mondor Hospital, AP-HP, Créteil, France</footnote>

<footnote><sup>h</sup>Department of Otorhinolaryngology, Head and Neck Surgery, Créteil Intercommunal University Hospital, Créteil, France</footnote>

<footnote><sup>i</sup>Department of Ophthalmology, Henri Mondor, AP-HP, Créteil, France</footnote>

<footnote><sup>j</sup>Department of Oral Medicine and Oral Surgery, Henri Mondor Hospital, AP-HP, Créteil, France</footnote>

<footnote><sup>k</sup>Department of Pneumology, Henri Mondor Hospital, AP-HP, Créteil, France</footnote>

<footnote><sup>l</sup>Department of Internal Medicine, Centre Hospitalier Intercommunal de Créteil, Créteil, France</footnote>

<footnote><sup>m</sup>Sorbonne Université, INSERM, Institut Pierre Louis d'Épidémiologie et de Sante Publique, AP-HP Sorbonne Université, Tenon Hospital, Department of Dermatology and Allergology, Paris, France</footnote>

<footnote><sup>n</sup>Regional Pharmacovigilance Centre, Pitié-Salpêtrière Hospital, APHP, Sorbonne Université, Paris, France</footnote>

<footnote><sup>o</sup>Percy Military Hospital, Burn Center, Clamart, France</footnote>

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

<footnote><sup>q</sup>Department of Dermatology, CHU Nantes, Nantes, France</footnote>

<footnote><sup>r</sup>Department of Ophthalmology, CHU Nantes, Nantes, France</footnote>

<footnote><sup>s</sup>Department of Dermatology, CHU Bordeaux, Bordeaux, France</footnote>

<footnote><sup>t</sup>Department of Dermatology, Charles Nicolle University Hospital, Rouen, France</footnote>

<footnote><sup>u</sup>Université Lyon 1/INSERM U1111 – CIRI/Hospices Civils de Lyon, Allergologie et Immunologie Clinique, CHU Lyon-Sud, Pierre-Benite France</footnote>

<footnote><sup>v</sup>Department of Dermatology, CHU Lille, Univ Lille, INSERM U1286, Lille Inflammation Translational Research Institute (INFINITE), Lille, France</footnote>

<footnote><sup>w</sup>Department of Dermatology, Bichat Hospital, AP-HP, Paris, France</footnote>

<footnote><sup>x</sup>Univ Brest, LIEN, Brest, France</footnote>

<footnote><sup>y</sup>University Hospital of Brest, Department of Dermatology, Venereology and Allergology, Brest, France</footnote>

<footnote><sup>z</sup>Department of Dermatology, CHU Nancy, Nancy, France</footnote>

<footnote><sup>aa</sup>Department of Dermatology, INSERM U1058 « Pathogenesis and Control of Chronic Emerging Infections », University of Montpellier, Montpellier, France</footnote>

<footnote><sup>ab</sup>Department of Dermatology, CHU Martinique, Fort de France, France</footnote>

<footnote><sup>ac</sup>Department of Dermatology, University François Rabelais, Hospital of Tours, Tours, France</footnote>

<footnote><sup>ad</sup>Patients' Association AMALYSTE, Paris, France</footnote>

<footnote><sup>ae</sup>University Paris-Est Créteil, INSERM, IMRB, Equipe CEpiA, Créteil, France</footnote>

<footnote><sup>af</sup>University Paris-Est Créteil, UPEC, Créteil, France</footnote>

<footnote><sup>ag</sup>French National Reference Center for Toxic Bullous Diseases and Severe Drug Reactions TOXIBUL, Filière FIMARAD, Créteil, France</footnote>

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

<footnote n="1">¹ Equally contributors.</footnote>
# 1. Objectives and disease definition

This article is the English translation of the French national protocol for disease diagnosis and management (Protocole National de Diagnostic et de Soins, PNDS) updated in September 2023 by the French reference center for toxic bullous dermatoses and severe drug reactions TOXIBUL (https://toxibul.fr/), to provide healthcare professionals with detailed guidelines on the optimum management and care pathway required to treat an adult with epidermal necrolysis (EN, including Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis, TEN, or Lyell's syndrome). The French version of this PNDS is available on the National Health Authorities (Haute Autorité de Santé, HAS) website, https://www.has-sante.fr/upload/docs/application/pdf/2023-11/pnds lyell 2023 version finale has.pdf. This protocol concerns only patients with EN, and is based on regularly updated literature data (see scientific rationale, updated in 2023, available in French on the HAS website, https://www.has-sante.fr/upload/docs/application/pdf/2023-11/argumentaire pnds necrolyse epidermique 2023.pdf).

The updated version of this PNDS does not cover EN in children. Indeed, a PNDS has been dedicated since 2022 to EN in children (https://www.has-sante.fr/upload/docs/application/pdf/2021-11/fimarad pnd sle v2.2 synthese.pdf).

PNDS is a practical tool to which the primary care physician, jointly with other specialists, can refer for the management of the disease, particularly upon mapping the clinical pathway, in conjunction with the consulting physician and the patient.

However, the PNDS cannot cover all specific cases, all comorbidities, all therapeutic particularities and all hospital care protocols. One cannot infer from its design its capacity to cover all possible management approaches, nor can it substitute for the individual responsibility of the physician towards their patient. Nonetheless, the tool summarizes the current knowledge on the optimum management of adult patients with EN.

Epidermal necrolysis (EN) includes Stevens-Johnson syndrome (SJS, detached/detachable skin surface <10%), toxic epidermal necrolysis, TEN, or Lyell's syndrome, detached/detachable skin surface ≥30%), and SJS/TEN overlap (detached/detachable skin 10-29%, evaluated by Wallace's rule of nines or the palm method, which represents 1% of the body surface). EN is a very rare disease (incidence of 2-6 cases/million inhabitants, depending on the country). In adults, the disease typically occurs more in females of 40-50 years old, and its incidence increases with age. The average mortality rate in the acute phase is 15-20%, and tends to increase with age, presence of comorbidities, and extensive sloughing. SCORTEN and ABCD-10 scores have similar performances in terms of predicting acute-phase mortality.

In 85-90% of cases, EN is caused by medicines and usually occurs within 4-28 days (maximum 56 days) of medicine intake (usually the first in life). Some medicines are traditionally known as drugs with high risk of inducing EN (e.g., aromatic anti-epileptics and lamotrigine, allopurinol, sulfonamide antibiotics, oxicams, nevirapine) and other new drugs have recently been identified as such (anticancer drugs and immunotherapies, in particular). Additionally, certain populations have shown genetic susceptibility to certain molecules (e.g., human leucocyte antigen (HLA) B15.02 and carbamazepine, HLA B58.01 and allopurinol in the Asian population), hence recommendations for pre-therapeutic screening in those populations. In other cases, EN can be triggered by an autoimmune reaction, notably in lupus, or can be idiopathic, which often affects young adults. Infectious causes, typically involving *Mycoplasma pneumoniae*, are rare in adults.

The disease evolves in two phases:

- **The acute phase:** is sudden and can be life threatening depending on the extent of cutaneous and mucosal lesions. Respiratory

and septic complications determine the prognosis. To date, no immunomodulatory treatment has been proven effective in reducing mortality or accelerating healing. Supportive care in a specialized center remains the cornerstone of treatment.

- **The chronic phase:** accompanied with multiple sequelae in almost all (90%) patients with a lasting impact on quality of life. The physical sequelae involve most often the skin (dryness, abnormal pigmentation, extensive scarring, nail abnormalities, cutaneous pain), eyes (dry eye, chronic conjunctivitis, trichiasis, symblepharons, corneal abnormalities, with potential impairment in vision leading sometimes to blindness), mouth (dryness, dental alterations), genital organs (preputial and vaginal synechiae), more rarely the digestive tract (esophageal stenosis), and bronchi (bronchiolitis obliterans), and more generally, sequelae related to prolonged stays in intensive care units. The psychological sequelae are common and may significantly affect the patient's ability to resume a normal social, family, and professional life (anxiety, depression, sleep disorders, nightmares, fear of medication, and even post-traumatic stress disorder). The management of such sequelae is time-consuming, multidisciplinary, and has to be coordinated by the dermatologist of the reference center.

# 2. Diagnosis and initial evaluation

## 2.1. Objectives

- Achieve early diagnosis

- Organize rapid transfer of patients to specialized units

- Inform patients and their families

## 2.2. Healthcare professionals involved

The first healthcare professional the patient visits may be the primary care physician or the organ specialist, that is, the person who prescribed the culprit drug. However, the patient condition could deteriorate rapidly and an emergency physician or hospital dermatologist may become involved as the first- or second-line physicians.

Emergency physicians, intensive care doctors (depending on the initial severity), and hospital dermatologists play a key role in establishing the early diagnosis and implementing the initial management measures, e.g., recognizing the culprit drug and discontinuing its use.

It is of utmost importance to transfer the patient to a center specialized in the management of severe drug reactions (a center with dermatology and intensive care unit facilities), once the diagnosis and disease severity are established. In such emergencies, the reference center and the local specialized center can be contacted beforehand, e.g., via telemedicine, to seek their opinion on EN diagnosis, the transfer decision, and procedure. Patient transfer to a specialized center has already proven its prognostic value. This decision relies on many parameters related to patient's characteristics and the severity of the initial presentation of the disease (see Appendix 1, supplementary material available online).

Once transferred to the specialized center for EN management, the diagnosis process and the initial evaluation of the patient in the acute phase are collaboratively undertaken by many healthcare professionals, such as: dermatologist, intensivist, pulmonologist, infectious diseases specialist, ophthalmologist, ear-nose and throat (ENT) specialist, stomatologist, gynecologist, urologist, gastroenterologist, psychiatrist, psychologist, pathologist, allergist, pharmacist, pharmacovigilance/drug safety specialist, dietician, social workers, nurses.

The specialized team to which the patient is referred must have an intensive care unit (which may be a burn center Intensive Care
Unit (ICU), depending on local healthcare organization) in the vicinity in addition to the following resources:

- Medical and paramedical staff trained to manage such cases;

- Adapted ICU beds;

- Heating system (temperature kept between 28 and 32 °C);

- Preparedness to perform complex skin management procedures under analgesia or sedation, if needed;

- Supportive departments (notably radiology and microbiology laboratory).

## 2.3. Clinical diagnosis

The diagnosis of EN is mainly clinical. Digital photographs are taken (with patient consent) and sent to the specialized center to help confirm the diagnosis before transfer, and to monitor the evolution of lesions in the acute phase. A seemingly mild rash detected at an early stage may raise alarm in the presence of these signs: intense cutaneous and/or mucosal pain, high fever, feeling unwell (fatigue), widespread mucosal lesions (mouth, eyes, genito-anal area), purpuric macules or atypical targets, cutaneous vesicles and/or bullae, Nikolsky's sign, or even sheet-like epidermal detachments.

Clinical features used for diagnosis and initial clinical evaluations:

- Fever, fatigue;

- Skin and mucosal pain;

- Diffuse purpuric macules or atypical targets sparing the extremities (usually start on the trunk, unlike in erythema multiforme);

- Vesicles, bullae;

- Sheet-like epidermal sloughing;

- Nikolsky's sign (upper skin layers slip away when rubbed)

- Widespread mucosal involvement (membranous and pseudomembranous conjunctivitis, enanthem, bullae, mucosal erosion affecting the mouth, nasopharynx, oropharynx, and genitalia).

The clinical examination should also cover history taking [age, independence, past history of drug allergy, comorbidities, and active cancer (and its prognosis), being immunocompromised, etc.], vital signs [temperature, blood pressure, pulse, respiratory rate, oxygen saturation, weight (compared with ideal body weight)], and non-invasive investigations for pharyngo-laryngeal (dysphonia, aphagia, dyspnea) and tracheobronchial (bronchial congestion, productive cough, dyspnea) involvement. The larynx is more rarely affected in EN than the oral cavity or the oropharynx, but its involvement is often associated with tracheobronchial lesions, hence the high risk of respiratory complications.

The diagnosis of EN is basically clinical with no need for other paraclinical investigations (biological or imaging) to confirm it.

Skin biopsy (see below) confirms the diagnosis and rules out autoimmune bullous dermatosis. Establishing the diagnosis of EN should not be delayed waiting for histological results.

## 2.4. Histopathology

Skin biopsy and histopathological examination of the eroded skin, and direct immunofluorescence (DIF) of the healthy peripheral skin confirm EN diagnosis and rule out other bullous diseases that have similar clinical presentation (e.g., linear IgA bullous dermatosis).

Skin histology is highly suggestive (but not pathognomonic of EN) if shows full-thickness epidermal necrosis. DIF is negative.

## 2.5. Initial blood work

Emergency blood work should include: complete blood count, serum electrolytes, bicarbonates, urea, creatinine, and creatinine clearance, liver function test (LFT) with alanine aminotransferase (ALAT), aspartate amino transferase (ASAT), gamma glutamyl transferase (GGT), alkaline phosphatase, total and conjugated bilirubin, blood sugar, C Reactive Protein, calcium and phosphorus levels, creatine phosphokinase (CPK), lactate deshydrogenase, albumin level, prothrombin time, blood arterial lactate if hemodynamic or respiratory failures are suspected, arterial blood gases.

In addition to the biological markers, SCORTEN and ABCD-10 prognostic scores (see Appendix 2, supplementary material available online) are used to evaluate more severe forms of EN: lymphopenia, hypophosphatemia, hypoalbuminemia, high LDH, and laryngeal lesions.

## 2.6. Causality assessment

The management of EN necessitates early identification and discontinuation of the culprit medicine(s). For such the following data should be collected:

- **Chronology of events in the 4 weeks preceding EN**: intercurrent illness, prescription of new drugs, radiological examinations with injection of radio contrast media, self-medication, etc.);

- **First signs of EN**: index date, signs that are sometimes non-specific: fever, fatigue, flu-like illness, oral, genital, or ocular pain, occurring 2-3 days before the development of the skin lesions;

- **Precise chronology of medicines intake in the month preceding hospitalization** by comparing all possible sources (patient, family and friends, primary care doctor, pharmacy, health insurance records, etc.). A clear distinction must be made between the patient's usual medications and the new ones, the only to be suspected, without omitting inhaled or topical medications, iodinated radio contrast media, etc. It is important to plot a chronological timeline of medicines intake.

EN typically occurs between 4 and 28 days after introduction of the causative agent. Longer periods of up to 56 days have sometimes been observed, particularly in patients with chronic renal or hepatic failure. Imputability analysis must take into account the drug half-life (the drug remains in the body for five half-lives after its discontinuation). Drugs taken to treat the first signs of EN (e.g., paracetamol, non-steroidal anti-inflammatory drugs (NSAID)) are often wrongly incriminated, as they constitute a protopathic bias, hence the importance of correctly notifying the index date. If there is any doubt about the causative agent, it is advisable to rapidly contact a pharmacovigilance center, and/or the nearest specialized or reference center. The imputability algorithm, ALDEN can help determine the culprit drug(s) (see Appendix 3, supplementary material available online).

**Overall, 10-15% of EN cases have no known drug origin. For such, other tests should be performed to explore the etiology of the disease:**

- Toxicological analysis: to exclude occult drug intake

- *Mycoplasma pneumoniae* IgG and IgM serology (at early stage and three weeks after), and polymerase chain reaction (PCR) for *M. pneumoniae* on nasopharyngeal swabs;

- Serology: tests for other atypical respiratory pathogens (e.g., *Chlamydia pneumoniae*) according to clinical presentations;

- PCR for Enterovirus (rare forms mimicking severe hand-foot-and-mouth disease);
- Antinuclear antibodies, anti-DNA, and anti-soluble nuclear antigens (search for underlying systemic lupus erythematosus);

- Anti-skin specific antibodies if an autoimmune bullous disease is suspected.

**Other tests are also performed to assess the patient general condition:**

- Serology for human Immunodeficiency virus (HIV), hepatitis B, and hepatitis C;

- Beta-human chorionic gonadotropin (hCG) in women of child-bearing age;

- Specific HLA screening if EN was triggered by a drug with known genetic susceptibility (e.g., carbamazepine in HLA B15.02-carrying patients or allopurinol in HLA B58.01-carrying Asian patients).

## 2.7. Differential diagnosis

- **Other toxic bullous dermatosis:** generalized bullous fixed-drug eruption (patients aged over 75, less marked health deterioration, well-demarcated patches, little or no mucosal involvement, recurrence); drug-induced linear IgA bullous dermatosis (DIF is indicated); severe bullous lichenoid eruption caused by checkpoint inhibitors (cancer patients on immunotherapy, lichenoid lesions associated with bullae, little mucosal involvement, and particularly little ocular involvement, and less health deterioration);

- **Other severe skin eruptions:** acute generalized exanthematous pustulosis (confluent pustules, develop often in skin folds, evolve into fine superficial sloughing (pseudo-Nikolsky's sign), little or no mucosal involvement, revealed by histological examination); DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms, typically no skin detachment or mucosal involvement, but overlap syndrome is possible);

- **Autoimmune bullous dermatosis:** idiopathic linear IgA bullous dermatosis, pemphigus vulgaris, paraneoplastic pemphigus (histology and DIF, serum antibodies);

- **Other autoimmune diseases:** the presentation of subacute lupus erythematosous (SLE) can exceptionally resemble that of TEN (known SLE or newly discovered with other clinical or laboratory signs of SLE, positive anti-SSA, proteinuria, hypocomplementemia, etc.). However, discovering “lupus-like” biological signs during the course of EN is sometimes fortuitous especially in the absence of other SLE clinical or biological signs, which makes it difficult to assert the pathogenicity of the antibodies. Similarly, some dermatomyositis cases exceptionally show TEN-like presentation;

- **Staphylococcal epidermolysis:** Staphylococcal Scalded-Skin Syndrome (SSSS), very superficial detachment, often affects peri-orificial areas, absence of mucosal erosions, histological examination shows more superficial cleavage, presence of focus of infection;

- **Thermal or caustic burns:** contact dermatitis caused by Nigella sativa oil (which can cause “contact” EN, sometimes severe with targets and skin detachments, but typically without mucosal involvement) or essential oils; caustic dermatitis (history, absence of mucosal erosions, characteristic skin lesions, histological examination); severe phytophotodermatosis (history, absence of mucosal lesions).

## 2.8. Classification, nosology, and severity assessment

EN classification depends on the total body surface area affected by newly formed or established bullous or erosive lesions (detached and detachable surface [erythematosus or purpuric skin

with positive Nikolsky's sign]). The nosological spectra of EN include:

- **Stevens-Johnson syndrome (SJS):** detached/detachable skin surface is <10%;

- **SJS/TEN Overlap syndrome:** detached/detachable skin surface is 10-29%;

- **Toxic epidermal necrolysis, TEN, or Lyell's syndrome:** detached/detachable surface is ≥30%.

Upon admission to the specialized center/ward, it is paramount to give the patients and their relatives full information on the disease and its severity. A next of kin must be named and patient's confidentiality must be respected in front of the relatives especially when the causative drug is virtually disease-specific (e.g., antiretroviral). Patients and their families must be informed that the disease may worsen in the first 10-15 days, possibly leading to ICU admission. A brochure providing informations on the disease, including contact details of patients' communities/organizations should be given to family members together with proper psychological support.

The average premature mortality rate (6 weeks from the start of EN) is 15-20% (ranging from 10 to 40-50%, depending on the extent of skin detachment and early complications). Death is mainly caused by sepsis (of cutaneous, respiratory or, more rarely, digestive origin) and/or multi-organ failure (in particular secondary to specific visceral damage, infectious complication, or hypovolemia) possibly brought by decompensation of a pre-existing condition. SCORTEN is a prognostic score recorded in the first 3 days after admission that comprises seven clinical and biological parameters to evaluate the risk of mortality. More recently described, the 5-point ABCD-10 score is an equivalent predictor of mortality (see Appendix 2, supplementary material available online).

## 3. Management of the acute phase

The treatment relies primarily on supportive care since no etiological treatment has been proven effective in halting the progression of detachment, accelerating healing, and reducing mortality.

### 3.1. Objectives

- To identify the drug (or drugs) that has probably caused the disease, stop it urgently, and permanently contraindicate it to prevent recurrence;

- To reduce acute-phase mortality and morbidity;

- To prevent and limit long-term complications.

### 3.2. Healthcare professionals involved

The therapeutic management of the acute phase is a collaborative work of a multidisciplinary team coordinated by the expert physician (usually a dermatologist) of the EN-specialized center. At admission and on the front line:

- Dermatologist;

- Intensivist;

- **Ophthalmologist:** systematically conducts urgent assessment on admission and several times a week depending on the severity of the ocular lesions (see Appendix 4, supplementary material available online, initial grading of the severity of the acute phase ophthalmological damage with regular reassessments);

- **ENT specialist:** examines the oropharynx and systematically explores the entire pharyngo-larynx via fibroscopy, ideally
within the first 72 h. However, an ENT examination may be requested on admission in the presence of warning signs (congestion, productive cough, dysphonia, dyspnea, especially in patients at high risk of developing severe forms or are immunocompromised). Laryngeal involvement (edema, erosions) can be predictive of subsequent pulmonary damage on the short-term, hence the importance of respiratory monitoring. Any worsening of dysphagia or odynophagia during the first days should prompt ENT reassessment looking for lesion deterioration or superinfection. Ear examination should not be neglected given the high risk of otitis externa caused by skin lesions in the external auditory canal. Ear suction will also be useful at the time of re-epithelialization to aspirate skin scales that might cause ear pain;

- Psychiatrist, psychologist;

- Dietitian;

- Nurse trained in the management of this disease.

Other healthcare professionals might be needed in the acute phase: allergist; pharmacist; pulmonologist; infectious disease specialist; stomatologist; gynecologist; urologist; gastroenterologist; social workers.

### 3.3. How to deal with high-risk medicines

It is imperative that any suspect drug be discontinued as early as possible, with due attention to maintaining continuity of healthcare. The list of suspect drugs is very long, but fewer than 10 are responsible for almost half of all cases in Europe.

The high-risk drugs are:

- Aromatic anti-epileptics: carbamazepine, oxcarbazepine, esilcarbazepine, phenobarbital, phenytoin;

- Lamotrigine;

- Allopurinol;

- Sulfonamide anti-bacterial drugs (especially co-trimoxazole and sulfasalazine);

- Nevirapine

- Oxicams, a class of NSAID;

There are other high-risk drugs, such as proton pump inhibitors and certain cancer immunotherapies. A thorough drug history is therefore needed and should exclude no drug.

The risk of EN is particularly high with certain drugs in certain populations, which justifies pre-therapeutic screening in those populations. For instance, Asian people carrying HLA B15:02 are at risk for EN upon taking carbamazepine, similarly with those carrying HLA B58:01 upon taking allopurinol (non-exhaustive list, see Appendix 5, supplementary material available online).

Medications that are vital/essential to the patient and not suspected should not be stopped (recovery despite their continuation will avoid any reluctance to use them in the future). On the other hand, a patient treated for EN can still use a high-EN risk drug if the latter is vital/essential for the patient and not suspected, under supervision of the pharmacovigilance department if necessary.

### 3.4. General guidelines

Patients with ≥10% of detached/detachable skin surface should be placed in heated rooms where temperature is kept between 28 and 32 °C to limit caloric losses and catabolism. They should be handled very carefully to avoid worsening skin sloughing.

Patients are put on analgesics on admission since EN is often associated with severe cutaneous and/or mucosal pain. The visual

analogue scale (VAS; 0 to 10) is used to score pain. If VAS score is ≥4/10, morphine should be introduced, with initial titration followed by patient-controlled analgesia (PCA); failing that, a continuous drip of morphine is set supplemented by a bolus dose prior to each skin treatment session. Paracetamol is useful in case of high intolerable fever.

Patients in the acute phase of EN experience considerable anxiety, often worsened by the repeated skin dressings, thus must be promptly assessed after admission by a psychiatrist and/or a psychologist. To alleviate this anxiety, it is often beneficial to prescribe anxiolytics, such as hydroxyzine (unless contraindicated due to drug side effects). However, the effectiveness of anxiolytics in preventing psychological sequelae, in particular post-traumatic stress syndrome, has not been proven yet. Overall, such sequelae occur much easier in patients who already have a past history of anxiety or anxiety-depression. Psychological support must be provided to the patient, and his family if necessary, on a regular basis throughout the hospital stay.

Heparin is necessary to prevent thrombo-embolic complications, as it is the case with all bedridden patients.

For intravenous infusions, a peripheral catheter is preferred and should be set on an intact skin area and changed regularly. Nonetheless, in patients with larger detached skin surface areas who require larger amounts of fluid resuscitation therapy, a central catheter is indicated.

Intravenous fluid and electrolyte resuscitation therapies must be adjusted according to the degree of skin losses (acute skin failure secondary to epidermal detachment).

The amount of fluid therapy to give within the first 24 h can be estimated using various formulas. The modified Brooke formula (from Pruitt BA et al. J Trauma 1971) defines the minimum fluid intake in the first 24 h, and is calculated as follows:

$$ \text{Volume in first 24 h, } V_{24h} = (1.5 \text{ mL} \times \text{ of detached/detachable skin surface} \times \text{ kg body weight})/\text{day, where } V_{24h} \text{ represents the volume of crystalloids to be infused over 24 h in mL. Other formulas may also be used. The fluid volume should thereafter be adapted to the urine output volume (target 0.5-1 mL/kg/h) measured every 4-8 h, and the evolution of biological markers (urea, creatinine, serum protein, urinary electrolytes), with the possibility of adding supplementary doses (e.g., 500-1000 mL of crystalloids over 1-4 h) whenever appropriate. Crystalloids (isotonic saline or Ringer's lactate) are the most commonly used fluid therapies. If the patient is kept fasting, carbohydrate intake will initially be covered with a solution of 10% glucose (e.g., 1000 mL/24 h, to which 4-8 g/L NaCl is added depending on plasma osmolarity), then parenteral nutrition will be administered if necessary.} $$

Respiratory monitoring (respiratory rate, oxygen saturation) is crucial during the acute phase owing to the high risk of respiratory-specific (ENT and tracheobronchial) and non-specific (fluid-electrolytes overload, respiratory infections) complications. Monitoring is clinical and radiological. If in doubt, consult an intensivist (see below).

In most cases, oral food intake is hindered by the significant oral mucosal erosions, and is quantitatively insufficient to cover the increasing caloric needs precipitated by the severe skin sloughing (caloric and protein losses through the skin), hence the need for continuous enteral feeding via nasogastric tube. An ENT physician could help insert the nasogastric tube in these critical patients, who often have extensive nasal and oral erosions. The only contraindication to enteral feeding is esophageal damage. In the latter case, parenteral feeding is used instead until the esophageal mucosa has healed. Enteral caloric intake is gradually increased and adapted to the patient's needs as assessed by the dietitian. Blood glucose level should be regularly monitored and kept between 8 and 12 mmol/L, if necessary, by insulin shots.
### 3.5. Prevention of infections

The risk of nosocomial infections should be drastically reduced by applying rigorous asepsis and antisepsis rules. Strict application of "standard" hygiene precautions, particularly hand hygiene, is important. However, the way in which skin treatment is carried out (sterile or non-sterile scrubs and gloves) depends on the habits of the healthcare teams. Strict asepsis rules must be applied for invasive procedures.

The high risk of infection justifies regular bacteriological and, if in doubt, mycological sampling of the skin (superficial swabs or, if possible, skin cultures every 48-72 h and/or, if available, quantitative bacterial cultures, until epithelialization), urine (urinalysis), blood (blood cultures of direct sample and of central catheter line, if applicable), and bronchial secretions in intubated patients.

Antiseptics (antiseptic baths or water-diluted chlorhexidine spray and rinsing) are used to cleanse skin lesions on a daily basis.

Fecal collectors may be useful, particularly in intensive care units, to avoid soiling buttock lesions and to limit bacterial colonization.

Prophylactic antibiotics are not recommended. In case sepsis is detected or strongly suspected, the antibiotic therapy to prescribe has to take into account the results of the latest bacterial profiling, the portal of entry (detached skin, mostly), though not exclusive (possibility of translocation of germs of digestive origin and treatment-associated urinary tract infection). Bacterial profiling has an excellent negative predictive value for *Staphylococcus aureus* and *Pseudomonas aeruginosa*.

### 3.6. Topical skin treatment

Skin lesions management is long and complex and requires special nursing skills, as well as the use of analgesic and even anxiolytic before each session. It is highly recommended to avoid traumatic manipulations of the skin by using suitable beds ("flu-idized", "air mattress", or equivalent). No debridement or scrubbing of the denuded wounds is allowed.

After disinfection with chlorhexidine antiseptic (baths or sprays) followed by rinsing, large bullae are to be punctured and covered, as for erosions, with non-adherent dressings (e.g. hydrocellular, interfaces, etc.) or petroleum jelly several times a day. Topical wound care practices are extremely diverse, and the literature data are not in favor of any. Some centers cover wounds with bandages, while others do not. Topical antibiotics (silver sulfadiazine, fusidic acid, etc.) are not routinely recommended since they can cause sensitization and antibiotic resistance. Exceptionally, their use might be discussed for very limited surface applications over short periods, guided by the antibiotic susceptibility testing to improve germs targeting. Topical corticosteroids are not recommended either.

### 3.7. Eye management

Bedside ophthalmological examination is paramount within the first 24 h to assess the severity of ocular damage, adapt symptomatic treatment, and determine the frequency of monitoring, generally several times a week or even every day for the mechanical removal of conjunctival pseudo-membranes or the management of symblepharons. For routine practice, and to optimize the dialogue between dermatologist and ophthalmologist, a 3-stage grading system for the severity of ocular damage is set up to record ophthalmological examination at the bedside (see Appendix 3, supplementary material available online).

Symptomatic treatment aims to protect the cornea and maintain adequate lubrication of the ocular surface to minimize further damage.

Topical treatment is applied every 2-4 h, or even every hour in the most severe cases, and mainly consists in using preservative-free eye drops and/or vitamin A ointment. The use of preservative-free antiseptic eye drops, antibiotics and corticoids should be discussed with the ophthalmologist on a case-by-case basis, and regularly reassessed.

For the most severe cases, the opinion of an EN-expert ophthalmologist of the reference or specialized centers should be sought. Amniotic membrane transplantation might be considered if technically feasible. The effectiveness of symblepharon rings has not been proven yet.

### 3.8. Management of other mucosal erosions

Similarly, rigorous clinical assessment of mucosal lesions is essential in the acute phase, and done on a daily basis for accessible sites, such as the mouth and external auditory canals. As for the other sites, examination by specialists is performed at least once during the acute phase (ENT [remember the prognostic importance of looking for laryngeal lesions on admission], gynecological, anal, etc.). Oral mucosa lesions are treated with antiseptic and analgesic mouthwashes, whereas genital lesions with petroleum jelly several times a day (vaseline tampon to prevent vaginal stenosis in women). Aspiration of the external auditory canals is also recommended at the time of re-epithelialization to remove epidermal scales that might cause otalgia and to reduce the risk of secondary otitis that might develop in the presence of oozing lesions and subsequent maceration.

### 3.9. Management in ICU

#### 3.9.1. Overall management

Around 25% of EN patients are admitted to ICU during their hospital stay. The indications for ICU admission are:

- **Close monitoring** of cases with skin sloughing that already exceeds 30%, or expected to reach it due to rapid spreading, cases with high-dose morphine-dependent or morphine-resistant hyperalgesia, sepsis, or bronchial congestion;

- **Absolute indication for ICU admission**, e.g., hemodynamic instability, acute respiratory distress, consciousness disorders, or any other organ failure requiring ICU admission.

Withholding of life-sustaining therapies should be discussed on a case-by-case basis and anticipated, particularly in elderly patients and in those with severe associated comorbidities associated with poor outcomes.

- **Hemodynamic monitoring and renal failure management**

Fluid resuscitation is the cornerstone of EN management and is basically derived from that of burn management. The amount of fluid required to rehydrate patients in the first 24 h can be estimated using numerous resuscitation formulas, none of which is optimal. Typically, the amount of fluid loss in EN patients is less than that in burn patients, therefore we suggest using the modified Brooke formula (see above). The volume of infused fluid is reassessed several times a day using several monitoring tools (clinical, biological, and echocardiographic), preferably non-invasive given the high risk of infection. There is no specific recommendation for albumin substitution, but it may reasonably be customized to each patient, in particular those with severe hypoalbuminemia (<20 g/L), and if associated with shock.

The indications for vasopressor support and other replacement therapies (opotherapy) are similar to those in non-EN patients (bearing in mind the high degree of dose dependency in EN
patients in terms of fluid volumes). Acute renal failure is a common complication (30%) of EN. Need for renal replacement therapy (9% of patients), more frequent when allopurinol is responsible for EN, is associated with poor prognosis (80% mortality).

- Respiratory distress management

Mechanical ventilation is required in around 25% of patients and as a rule, the greater the skin sloughing, the higher the need for mechanical ventilation. Non-invasive ventilation is not a priori recommended due to facial skin lesions and the risk of aspiration that can happen in the presence of ENT lesions. However, there are no data on the use of non-invasive ventilation (NIV) in EN.

Oro-tracheal intubation is often difficult, and must be anticipated and performed in a suitable environment. The usual indications for oro-tracheal intubation include respiratory distress, shock, and coma. Sedation is recommended in patients with uncontrolled pain (hinders treatment of mucocutaneous lesions). EN patients presenting clinical signs of specific tracheobronchial epithelial lesions (difficult-to-drain bronchial hypersecretion, laryngeal damage seen by nasofibroscopy, dyspnea, and hypoxemia within 48 h of diagnosis) should probably be intubated early since they are at high risk of developing acute respiratory failure secondary to upper airway obstruction with which intubation becomes all the more difficult.

Invasive mechanical ventilation facilitates the use of bronchoscopy, ideally within the first 24 h. In more than a third of cases, bronchoscopy helps diagnose specific tracheobronchial lesions characterized by initial focal or even extensive damage of the proximal bronchial epithelium. In such cases, bronchoscopy suctions, usually performed daily for the first few days, may help prevent or relieve atelectasis developed secondary to mucous plug formation. Bronchoscopy can also be used for laboratory investigations purposes to draw samples (bronchial aspirates, protected distal sampling, and bronchoalveolar lavage).

The use of prone position and extracorporeal membrane oxygenation (ECMO) is not specifically contraindicated. Overall, the prognosis of invasively ventilated EN patients remains poor, with an ICU mortality rate reaching 50%.

- Neuropsychological management

General anesthesia may be required for pain control. Analgesia should be multimodal, preferably using ketamine. The equimolar oxygen-nitrous oxide mixture (MEOPA) or methoxyflurane are good alternatives to opioids in ICU, particularly upon treating lesions of limited surface area. Active prevention of post-traumatic distress syndrome should be considered on admission to ICU by providing psychological support.

- Prevention of infectious complications

Risk factors for sepsis in EN include the extent of skin detachment, diabetes, hypothermia, prior use of corticosteroids, and admission to ICU. Overall, 27% of patients admitted to ICU develop bacteremia, the main infectious complication of EN. To date, there have been no detailed information on the incidence of ventilator-associated pneumonia, but the prolonged ventilation and the commonly detected bronchial damage in these patients suggest a high incidence in them.

To prevent these infections, the treatment of skin lesions should continue inside the ICU, same as outside it, and be repeated several times a day. Whenever possible, a peripheral catheter should be inserted, preferably on an intact skin surface. When central catheter becomes necessary, better use antibiotics- or antiseptic-coated (e.g., silver sulfadiazine, minocycline-rifampicin, chlorhexidine)

catheters (unless contraindicated due to the offending drug). These catheters should be changed only if a complication is suspected (e.g., infection, malfunction), and not routinely.

Airway management is similar to that applied to non-EN patients. Particular attention should be paid upon using heated humidifiers whose effectiveness may be compromised in highly febrile patients. If a heated humidifier malfunctions or is suspected of malfunctioning, in a patient with a body temperature >38.5 °C, a heat and moisture exchanger filter should be used instead.

Better not to repeat bronchoscopy systematically as this could lead to mucosal bleeding and formation of fibrin plugs.

- Management of metabolic and digestive complications

To avoid excessive heat and caloric losses, the patient is preferably placed in a room with anteroom where it will be possible to maintain room temperature between 28 and 32 °C. Patient's temperature should be measured every 4 h, preferably core body temperature (using temperature-sensing indwelling bladder catheter for intubated patients). If hypothermia persists despite a room temperature kept between 28 and 32 °C, a warming blanket could be added. Inversely, and unless the patient temperature exceeds 40 °C (exceptional risk of malignant hyperthermia requiring thermal control measures to be discussed for each patient), the room must be continuously heated even if the patient is febrile (fever leads to greater heat loss through the skin).

Occasionally, the digestive system is affected (10% of cases), which leads, in severe forms, to a high mortality rate (45%). EN may affect the esophagus and/or the small intestine or colon. Symptoms include abdominal pain, profuse diarrhea, melena or rectal bleeding. In such cases, the feeding methods are similar to those used for ICU non-EN patients. The energy target may initially be hypocaloric/protein-based (6 kcal/kg/day) for the first few days, especially in the most severe cases, then increased to 25-35 kcal/kg/day, depending on the recovery phase. The feeding is preferably enteral except in case of endoscopically-detected esophageal-gastro-duodenal mucosal lesions where parenteral nutrition should be temporarily installed. Enteral nutrition can be resumed whenever mucosal healing is observed, or at the end of a healing period estimated according to the case severity. Gastric residual volume monitoring is not recommended.

### 3.10. Etiology-oriented treatment

To date, there has been no solid evidence in the literature, based mainly on retrospective series or small, uncontrolled studies, to recommend immunomodulatory treatment for etiological purposes in the acute phase of EN.

Systemic corticosteroids, intravenous immunoglobulins, cyclosporine, anti-Tumor Necrosis Factor or other immunosuppressants, and hematopoietic growth factors, although used by some centers, alone or in combination, have not proven their usefulness. Moreover, in comparison with exclusive supportive care, none of these therapeutic classes has yet been shown, by studies of good methodological quality, to be effective in reducing mortality, halting the spread of sloughing, or accelerating muco-cutaneous healing (https://www.has-sante.fr/upload/docs/application/pdf/2023-11/argumentaire_pnds_necrolyse_epidermique_2023.pdf). Thalidomide is contraindicated as it is associated with excess mortality.

Therapeutic trials are difficult to conduct because of the rarity of the disease. Their aim is to rapidly stop the progression of skin detachment, accelerate muco-cutaneous healing, and reduce acute-phase mortality. In patients without an obvious drug trigger, and in case of a high clinical suspicion level of M. pneumoniae infection, empiric antibiotic therapy including macrolides should be ini-
tiated. Negative nasopharyngeal PCR test and serology (IgM) might help discussion treatment discontinuation.

### 3.11. Information to the patient and the primary care physician at hospital discharge

Upon leaving the hospital, patients are provided with a discharge summary indicating the suspected or proven cause of their illness, the risk of complications, the need for follow-up, and the possibilities for subsequent use of medication.

A written document listing the contraindicated and authorized drug(s) should also be given to the patient (allergy card and a comprehensive list of prohibited drugs), together with contact details of the expert center. It may also be useful to give the patient a fact sheet on the disease to provide healthcare professionals, whom the patient may visit later on, with general information on this rare and poorly-known disease.

The primary care physician must be informed that the polymorphism, frequency and severity of EN complications require systematic follow-up, sometimes for several years, and of which the cost and duration may justify a request for optimal health insurance coverage.

## 4. Follow-up and management of complications

As soon as the acute phase is over, the dermatologist of the expert center, jointly with the primary care physician, organize the follow-up schedule according to the nature and severity of complications. The minimum follow-up duration is one year, depending on the needs of each patient.

The follow-up includes:

- **Screening and management of complications** by experienced specialists in conjunction with the reference or specialized center, as well as the primary care physician.

- **Allergy management:** allergy skin tests are carried out at the reference or specialized center to identify the culprit drug, if several drugs are initially suspected, and to suggest alternatives in case the culprit drug was an essential medicine for the patient.

### 4.1. Objectives

- To detect complications, particularly ocular and psychological, at an early stage so as to initiate effective therapeutic measures to mitigate their severity and hinder their evolution;

- To provide patients with all the help they need to enjoy the best possible quality of life;

- To manage future use of medication (guided by allergy skin testing);

- To keep patient updated with advances on disease-related knowledge;

- To help patients obtain full coverage of their healthcare claims

### 4.2. Healthcare professionals involved

The follow-up and screening for complications are a multidisciplinary task essentially undertaken by the primary care physician and the dermatologist of the expert center.

In addition to the referent dermatologist, the following healthcare professionals are also involved: ophthalmologist (professional the most frequently involved); gynecologist or urologist; stomatologist/odontologist (prevention and correction of dental ailments); ENT specialist; psychiatrist and/or psychologist; pulmonologist (pulmonary function tests and lung imaging); gastroenterologist (endoscopy); plastic surgeon or dermatologist (laser/reconstruction

surgery); neurologist and/or pain management specialist (investigation and treatment of skin pain); other organ specialists, whenever needed; dietician or nutritionist; physiotherapist; nurse.

The healthcare professionals inform patients about the help and support they can have from patients' associations and advocacy groups.

The hospital social worker can help patients with the administrative paperwork of the local social service and administrative bodies, and provide career guidance and information on disability-related legislations and services. The social worker liaises with the dermatologist to help the patient file a claim for disability benefits (e.g., disabled adult allowance), should these prove necessary. Organizations for the visually impaired and blind, and centers for people with low vision, offer rehabilitation programs for the visually impaired to help them with their daily life.

Healthcare professionals involved in allergy skin testing are the dermatologist or allergist of the reference center, expert in allergy testing in EN, and the pharmacist (for test preparation).

### 4.3. Follow-up planning

Follow-up visits will be regular during the first year, for example at 1 or 2 months after hospital discharge, then at 6 months and 1 year. Depending on the sequelae observed in that period, the follow-up visits can be made more or less frequent. In some cases, the follow-up visits may still be necessary decades after the acute phase.

In the absence of sequelae at 1-year, systematic follow-up is probably no longer justified unless requested by the patient. In general, patients and their primary care physicians are given the contact details of a specialist to reach in case of deterioration.

Allergy skin tests are ideally performed within the first three to six months after the acute phase.

EN sequelae are often multiple and have a major impact on quality of life, hence the importance of providing comprehensive and multidisciplinary care by the referring dermatologist. Having good listening skills and empathy increases the likelihood of achieving such objectives.

Management of EN sequelae relies on proper history taking and clinical examination, both conducted by experienced specialists.

- Careful and detailed history taking covering the patient's general condition, the quality/quantity of food intake, ability of the patient to resume daily activities, family, professional, and social life, mood status, quality of sleep, etc.;

- Body weight (compared with that before illness);

- Dermatological examination of the skin (pigmentation disorders, hypertrophic scars, eruptive nevi, photosensitivity, skin pain), skin appendages (nails, hair), and mucous membranes (particularly buccal and genital);

- Systematic ophthalmological examination looking for, in particular, dry-eye syndrome, symblepharons, eyelash abnormalities, and a slit-lamp examination on which the future monitoring and treatment will depend;

- Buccal examination looking for dry mouth and dental abnormalities;

- Gynecological examination looking for vulvovaginal synechiae and dry vagina;

- ENT examination;

- Chest examination and pulmonary function test (spirometry, plethysmography, DLCO measurement, 6-min walk test, etc.) preferably 1 to 3 months after the acute phase, especially in cases of serious tracheobronchial disorders, acute respiratory distress syndrome, or residual respiratory symptoms. Patient's follow-up will be adapted according to the disease clinical course and the results of the initial assessment;
- Psychiatric and/or psychological evaluation with suitable follow-up;

- Make sure that the patient has their allergy card.

The role of the social worker is crucial in helping the patients with their administrative paperwork, which can sometimes last a very long time: 100% health insurance coverage, reimbursement of expenses of transport to the specialized centers, resuming professional activity, management of any disability, compensation claims, etc.

### 4.4. Management of skin sequelae

Pigmentation disorders are the most common complications. They partially fade in the first two years after the acute phase, but rarely disappear completely, especially on dark skin. Photoprotection is therefore necessary for at least two years (Sun Protective Factor 50+ sunscreens, protective clothing, avoiding exposure to the sun between noon and 4 pm in summer). There are no recommendations for the management of hypertrophic scars. Cosmetic surgery or laser treatment may be discussed on a case-by-case basis.

Nails are often affected in the acute phase, and may grow back thin, soft, and distally dystrophic. Hardening nail polish may be useful.

### 4.5. Management of ophthalmological sequelae

Patients with severe ophthalmological complications will be managed by a team specialized in ocular surface diseases at the specialized center.

General recommendations for ocular treatment in the chronic phase, that should be adapted to each patient, include:

- Preservative-free artificial tears and vitamin A ointment several times a day

- +/− Local antiseptics/antibiotics (short-term treatment)

- +/− Local antibiotics-corticoids (short course)

- +/− Cyclosporine or tacrolimus eye drops

- +/− Autologous serum eye drops

- Removal of rubbing eyelashes

Gas-permeable scleral lenses have shown a significant beneficial effect on pain and photophobia, and significantly improved vision and quality of life by correcting the EN-induced irregular astigmatism and ensuring corneal hydration and protection.

Amniotic membrane transplantation is discussed for persistent corneal ulcers.

It is important to keep contact with the community ophthalmologist since the latter can often be called upon, particularly for the removal of ingrown eyelashes.

### 4.6. Management of psychological sequelae

At each follow-up visit, the dermatologist should ask the patient about the presence of persistent psychological symptoms or the development of new psychiatric complications: anxiety-depression or post-traumatic stress symptoms, sleep disorders, night-mares, etc.

If necessary, psychological support or even regular psychiatric follow-up should be offered. The prescription of psychotropic medication is left at the discretion of the psychiatrist. The latter and/or the psychologist could also consider alternative management approaches, such as hypnosis, sophrology, or relaxation, even though have not been specifically evaluated in EN cases. Patients and their families need to be informed of the various support and information options available to them: organizations, communities, and blogs dedicated to this disease.

### 4.7. Management of other sequelae

Other complications are rare, could affect other organs/tissues, and require management approaches customized to each patient, as follows:

- Mouth and teeth: sialagogues, periodontal and dental care;

- Esophagus: esophageal dilation (sometimes repeated), and adapted diet;

- Genitals: moisturizers, emollients, topical corticoids, vaginal dilators, surgery to cut vaginal bridges, etc. The gynecologist will also assess what contraception method to use whenever appropriate;

- Lungs: diffusion disorders are common, generally asymptomatic, and proportional to the severity of skin damage, whereas restrictive ventilatory impairments are occasional. Bronchiolitis obliterans is rare in adults and its management and follow-up should be adapted to the severity of the bronchial damage and its complications (superinfections, functional disability).

### 4.8. Causality investigations, allergy skin testing

Allergy skin tests must be carried out by an allergist or dermatologist expert in skin testing in severe drug reactions. There is no precise recommendation on the testing time, i.e., they can be performed as early as 6 weeks after recovery from the acute phase, indeed the earlier, the better so as not to lose test sensitivity. Their main purpose is to identify which drug is the culprit in patients who were on multi-drug treatment, in order to remove certain contraindications and/or seek alternatives depending on the expected benefit for the patient. Tests are essentially performed *in vivo* (cutaneous) as *in vitro* tests are not available in most centers and are controversial.

In routine clinical practice, only patch tests are recommended. There are no large-scale data on intradermal testing, but some suggest it. On the whole, skin tests are well tolerated and there is no risk of EN reactivation. Reintroduction of any drug, never the one highly suspected of triggering EN, should be discussed in an expert multidisciplinary meeting held in the specialized center or reference center.

Patch tests have low sensitivity in EN (20% positivity rate; may be higher if performed on previously affected skin). A negative test therefore does not preclude the drug from causation.

Contraindications should concern only molecules judged to be responsible and those that are chemically similar (to prevent possible cross-reaction) including their topical forms. Meanwhile and pending a better understanding of the role of genetic factors, it is advisable to extend this contraindication to first-degree relatives. There is no reason to contraindicate any other drugs known to induce EN if not suspected for the present case.

In addition, medication adverse reactions should be systematically reported as quickly as possible to the relevant regional pharmacovigilance center.

## Disclosure of interest

The authors declare that they have no competing interest.

## Appendix A. Supplementary material

Supplementary material to this article can be found online at https://doi.org/10.1016/j.annder.2024.103282.