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Background Supportive care is the cornerstone of management of adult and paediatric Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). However, consensus on the modalities of supportive care is lacking.Objectives Our aim in this international multicentric Delphi exercise was to establish a multidisciplinary expert consensus to standardize recommendations regarding supportive care in the acute phase of SJS/TEN.Methods Participants were sent a survey via the online tool SurveyMonkey, consisting of 103 statements organized into 11 topics: multidisciplinary team composition, suspect drug management, infection prevention, fluid resuscitation and prevention of hypothermia, nutritional support, pain and psychological distress management, management of acute respiratory failure, local skincare, ophthalmological management, management of other mucosa, and additional measures. Participants evaluated the level of appropriateness of each statement on a scale of 1 (extremely inappropriate) to 9 (extremely appropriate). The results were analysed according to the RAND/UCLA Appropriateness Method.Results Forty-five participants from 13 countries (on three continents) participated. After the first round, a consensus was obtained for 82.5% of the 103 initially proposed statements. After the second round, a final consensus was obtained for 102 statements.Conclusions We have reached an international Delphi-based consensus on best supportive care practice for SJS/TEN. Our expert consensus should help guide physicians in treating patients with SJS/TEN and thereby improve short-term prognosis and the risk of sequelae.

Epidermal necrolysis (EN, including Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN)) is mostly induced by drugs. Prevalence of lupus erythematosus (LE) is higher in EN than in general population (1.2 to 2%).1,2 Furthermore, flares of LE may present as EN (TEN-like LE).3-5 We aimed to describe EN in patients with clinical or biological LE to better characterize the relation between both diseases.

Background Necrotizing skin and soft-tissue infections (NSTI) are rare but potentially life-threatening and disabling infections that often require intensive care unit admission. Objectives To review all aspects of care for a critically ill individual with NSTI. Sources Literature search using Medline and Cochrane library, multidisciplinary panel of experts. Content The initial presentation of a patient with NSTI can be misleading, as features of severe systemic toxicity can obscure sometimes less impressive skin findings. The infection can spread rapidly, and delayed surgery worsens prognosis, hence there is a limited role for additional imaging in the critically ill patient. Also, the utility of clinical scores is contested. Prompt surgery with aggressive debridement of necrotic tissue is required for source control and allows for microbiological sampling. Also, prompt administration of broad-spectrum antimicrobial therapy is warranted, with the addition of clindamycin for its effect on toxin production, both in empirical therapy, and in targeted therapy for monomicrobial group A streptococcal and clostridial NSTI. The role of immunoglobulins and hyperbaric oxygen therapy remains controversial. Implications Close collaboration between intensive care, surgery, microbiology and infectious diseases, and centralization of care is fundamental in the approach to the severely ill patient with NSTI. As many aspects of management of these rare infections are supported by low-quality data only, multicentre trials are urgently needed.

The consequences of cardiac arrest (CA) on the gastro-intestinal tract are poorly understood. We measured the incidence of ischemic injury in the upper gastro-intestinal tract after Out-of-hospital CA (OHCA) and determined the risk factors for and consequences of gastrointestinal ischemic injury according to its severity.Prospective, non-controlled, multicenter study in nine ICUs in France and Belgium conducted from November 1, 2014 to November 30, 2018. Included patients underwent an esophago-gastro-duodenoscopy 2 to 4 d after OHCA if still intubated and the presence of ischemic lesions of the upper gastro-intestinal tract was determined by a gastroenterologist. Lesions were a priori defined as severe if there was ulceration or necrosis and moderate if there was mucosal edema or erythema. We compared clinical and cardiac arrest characteristics of three groups of patients (no, moderate, and severe lesions) and identified variables associated with gastrointestinal ischemic injury using multivariate regression analysis. We also compared the outcomes (organ failure during ICU stay and neurological status at hospital discharge) of the three groups of patients.Among the 214 patients included in the analysis, 121 (57%, 95% CI 50-63%) had an upper gastrointestinal ischemic lesion, most frequently on the fundus. Ischemic lesions were severe in 55/121 (45%) patients. In multivariate regression, higher adrenaline dose during cardiopulmonary resuscitation (OR 1.25 per mg (1.08-1.46)) was independently associated with increased odds of severe upper gastrointestinal ischemic lesions; previous proton pump inhibitor use (OR 0.40 (0.14-1.00)) and serum bicarbonate on day 1 (OR 0.89 (0.81-0.97)) were associated with lower odds of ischemic lesions. Patients with severe lesions had a higher SOFA score during the ICU stay and worse neurological outcome at hospital discharge.More than half of the patients successfully resuscitated from OHCA had upper gastrointestinal tract ischemic injury. Presence of ischemic lesions was independently associated with the amount of adrenaline used during resuscitation. Patients with severe lesions had higher organ failure scores during the ICU stay and a worse prognosis. Clinical Trial Registration NCT02349074 .

We read with great interest the study by Bertin et al [1] exploring the involvement of antiphospholipid (aPL) antibodies in a cohort of SARS-COV 2 patients. The authors observed that the levels of IgG anticardiolipin were significantly associated with severe COVID-19 manifestations (odds ratio [OR] = 6.50; P = 0.009).

Les cliniciens sont generalement familiers avec le concept de VILI (ventilator induced lung injury), dont les principaux determinants mecaniques sont le volotrauma et l’atelectrauma. Le volotrauma depend du volume insuffle par le ventilateur et du volume pulmonaire disponible pour la ventilation. Sur le plan conceptuel comme experimental, l’effort inspiratoire spontane du patient est a meme de generer un volume courant identique a celui genere par le ventilateur et ainsi d’exposer au meme risque de volotrauma. De plus, des donnees experimentales recentes ont decrit des consequences physiologiques additionnelles, potentiellement deleteres, de la survenue d’un effort inspiratoire important chez un patient presentant une atteinte lesionnelle pulmonaire sous-jacente (par exemple phenomene de « pendelluft », atelectrauma des regions dependantes, augmentation de la pression transmurale vasculaire). Ces effets physiologiques sont de nature a aggraver les lesions pulmonaires preexistantes, perturbant davantage l’hematose et la mecanique respiratoire, et donc stimulant d’autant plus la commande respiratoire. Ce cercle vicieux au sein duquel le patient s’auto-inflige des lesions pulmonaires a ete recemment conceptualise sous le terme de P-SILI (patient selfinflicted lung injury). La reconnaissance des situations a risque de P-SILI en pratique clinique permet d’apporter une reponse therapeutique adaptee. Parfois, la ventilation controlee constitue alors un traitement protecteur.

International audience; Background: Epidermal necrolysis is a rare and severe cutaneous adverse reaction to drugs with long-term somatic consequences and potentially underrecognized psychological complications.Objectives: To assess the prevalence and risk factors of post-traumatic stress disorder (PTSD) in Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in a population of adults undergoing psychiatric evaluation.Methods: In this prospective study, we included adult patients admitted at the acute phase of SJS/TEN to our dermatology department from June 2009 to February 2013. The main objective was to assess the prevalence of PTSD at 6 months after the acute disease phase, defined by a PTSD Checklist score > 44. Secondary objectives were to investigate risk factors of PTSD in the medical history of patients and characteristics of the disease at the acute phase by the Peritraumatic Dissociative Experience Questionnaire (PDEQ) and Peritraumatic Distress Inventory (PDI) and the degree of impairment on the Sheehan Disability Scale.Results: We initially included 32 of 80 patients admitted during the study period. At 6 months, seven of 30 still followed up had a PTSD Checklist score > 44, suggesting a PTSD prevalence of 23%; 23 (77%) patients had a hydroxyzine prescription at the acute phase. The main risk factors associated with PTSD at 6 months were psychological results at the acute phase.Conclusions: Despite frequent prescription of hydroxyzine at the acute phase, almost one-quarter of patients with SJS/TEN had PTSD at 6 months. A systematic psychiatric evaluation should be offered regularly for at least 1 year after the acute disease phase.

International audience

Background Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are associated with various sequelae. Chronic pain, one of these sequelae, has never been systematically evaluated. Objectives and methods To assess the persistence of pain in a single-centre cohort of 113 consecutive patients with SJS/TEN. From this cohort, 81 patients were interviewed more than 1 year after the initial episode and included in the study. Data were collected according to standardized questionnaires. Results From the 81 interviewed patients, 52 patients (64%) were painless and 29 patients (36%) were painful. Chronic pain syndrome was associated with a more severe initial acute phase of the disease (larger extent of detachment, higher SCORTEN, increased rate of admission in ICU and complications, and longer hospital stay). Pain was mainly located at the level of eyes (55%), mouth and lower limbs (38-41%), with a moderate daily intensity on average (4.7/10). The 'affective' descriptors prevailed over the 'sensory' descriptors, with the exception of burning and itching sensations. Finally, regarding provoked pain, mechanical allodynia (to brushing and pressure) was more marked than thermal allodynia. Discussion The persistence of chronic pain after SJS/TEN is a common phenomenon. Sensory descriptors are consistent with sensitization of both small-diameter nerve fibres (burning and itching sensations) and large-diameter nerve fibres (mechanical allodynia), but the affective-emotional components of pain largely predominate. Conclusions Complex mechanisms lead to persistent pain as long-term sequela of SJS/TEN, among which mechanisms, psychological factors related to post-traumatic stress disorder probably play a key role.

International audience; Background: Most cases of Stevens-Johnson syndrome and toxic epidermal necrolysis are drug-induced. A small subset of cases remain with unknown aetiology (idiopathic epidermal necrolysis [IEN]).Objective: We sought to better describe adult IEN and understand the aetiology.Methods: This retrospective study was conducted in 4 centres of the French national reference centre for epidermal necrolysis. Clinical data were collected for the 19 adults hospitalized for IEN between January 2015 and December 2019. Wide toxicology analysis of blood samples was performed. Histology of IEN cases was compared with blinding to skin biopsies of drug-induced EN (DIEN, 'controls'). Available baseline skin biopsies were analysed by shotgun metagenomics and transcriptomics and compared to controls.Results: IEN cases represented 15.6% of all EN cases in these centres. The median age of patients was 38 (range 16-51) years; 68.4% were women. Overall, 63.2% (n = 12) of cases required intensive care unit admission and 15.8% (n = 3) died at the acute phase. Histology showed the same patterns of early- to late-stage EN with no difference between DIEN and IEN cases. One toxicology analysis showed unexpected traces of carbamazepine; results for other cases were negative. Metagenomics analysis revealed no unexpected pathological microorganism. Transcriptomic analysis highlighted a different pro-apoptotic pathway in IEN compared to DIEN, with an overexpression of apoptosis effectors TWEAK/TRAIL.Conclusions: IEN affects young people and is a severe form of EN. A large toxicologic investigation is warranted. Different pathways seem involved in IEN and DIEN, leading to the same apoptotic effect, but the primary trigger remains unknown.

Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) can lead to severe ophthalmologic sequelae. The main risk factor is the severity of the initial ocular involvement. There are no recommendations for ocular management during acute phase.We conducted a national audit of current practice in the 11 sites of the French reference center for toxic bullous dermatoses and a review of the literature to establish therapeutic consensus guidelines. We sent a questionnaire on ocular management practices in SJS/ TEN during acute phase to ophthalmologists and dermatologists. The survey focused on ophthalmologist opinion, pseudomembrane removal, topical ocular treatment (i.e. corticosteroids, antibiotics, antiseptics, artificial tear eye drops, vitamin A ointment application), amniotic membrane transplantation, symblepharon ring use, and systemic corticosteroid therapy for ophthalmologic indication. Nine of 11 centers responded. All requested prompt ophthalmologist consultation. The majority performed pseudomembrane removal, used artificial tears, and vitamin A ointment (8/9, 90%). Combined antibiotic-corticosteroid or corticosteroid eye drops were used in 6 centers (67%), antibiotics alone and antiseptics in 3 centers (33%). Symblepharon ring was used in 5 centers (55%) if necessary. Amniotic membrane transplantation was never performed systematically and only according to the clinical course. Systemic corticosteroid therapy was occasionally used (3/9, 33%) and discussed on a case-by-case basis.The literature about ocular management practice in SJS/ TEN during acute phase is relatively poor. The role of specific treatments such as local or systemic corticosteroid therapy is not consensual. The use of preservatives, often present in eye drops and deleterious to the ocular surface, is to be restricted. Early amniotic membrane transplantation seems to be promising.

International audience

International audience

Background There is no consensus on the treatment of drug reaction with eosinophilia and systemic symptoms (DRESS). At our center, systemic steroids (SS) are used for severe cases while topical steroids (TS) are used for mild and moderate forms. Objectives To investigate the short-term outcome for patients with DRESS receiving SS as first-line therapy before being transferred to our department and then switched to TS after admission. Methods A retrospective monocenter study in DRESS patients (RegiSCAR score ≥ 4) transferred to our dermatology department from a different setting between 07/2012 and 06/2018 and who had received SS before being transferred. Epidemiological, clinical and laboratory data were collected, as well as details of treatment modalities and outcome. Results Twenty patients were included. On admission to our department, 4 were assessed as having severe DRESS and continued on SS, while 16 were assessed as mild/moderate DRESS and were switched to TS. Among these 16 patients, the outcome on TS was favorable for 12 and quickly unfavorable for 4, who had to be switched back to SS. Retrospective analysis of the initial data (before transfer) showed that these 4 patients had previously had a greater number of severity criteria than the other 12. Conclusion Caution is needed not only when deciding to initiate SS in DRESS but also on withdrawal of these drugs. Our series suggests that when SS are used as first-line therapy in DRESS patients with initial severity criteria, they should not be withdrawn quickly for a switch to TS, even where progression appears favorable, due to the risk of relapse.

In France, at the end of the sixth year of medical studies, students take a national ranking examination including progressive clinical case-based multiple-choice questions (MCQs). We aimed to evaluate the ability of these MCQs for testing higher-order thinking more than knowledge recall, and to identify their characteristics associated with success and discrimination.We analysed the 72 progressive clinical cases taken by the students in the years 2016-2019, through an online platform.A total of 72 progressive clinical cases (18 for each of the 4 studied years), corresponding to 1059 questions, were analysed. Most of the clinical cases (n=43, 60%) had 15 questions. Clinical questions represented 89% of all questions, whereas basic sciences questions accounted for 9%. The most frequent medical subspecialties were internal medicine (n=90, 8%) and infectious diseases (n=88, 8%). The most frequent question types concerned therapeutics (26%), exams (19%), diagnosis (14%), and semiology (13%). Level 2 questions ("understand and apply") accounted for 59% of all questions according to the Bloom's taxonomy. The level of Bloom's taxonomy significantly changed over time with a decreasing number of level 1 questions ("remember") (P=0.04). We also analysed the results of the students among 853 questions of training ECNi. Success and discrimination significantly decreased when the number of correct answers increased (P0.0001 both). The success, discrimination, mean score, and mean number of discrepancies did not differ according to the diagnosis, exam, imaging, semiology, or therapeutic type of questions.Progressive clinical case-based MCQs represent an innovative way to evaluate undergraduate students.

Les urgences dermatologiques nécessitant une admission en réanimation sont rares mais associées à une mortalité élevée et à de lourdes séquelles à long terme. Elles sont essentiellement représentées par les infections nécrosantes des tissus mous (également appelées : dermohypodermites bactériennes nécrosantes-fasciites nécrosantes [DHBN-FN]) et par les toxidermies graves que sont les nécrolyses épidermiques (comprenant le syndrome de Lyell ou nécrolyse épidermique toxique [NET], le syndrome de Stevens-Johnson [SJS] et le DRESS (drug reaction with eosinophilia and systemic symptoms)). Elles ont pour caractéristiques communes un diagnostic souvent difficile, la nécessité d’une approche multidisciplinaire et de soins paramédicaux lourds et spécifiques, imposant fréquemment le transfert dans un centre expert. Le traitement des DHBN-FN est médicochirurgical, associant un débridement chirurgical précoce et une antibiothérapie probabiliste à large spectre. La présence de signes de gravité locaux (nécrose, crépitation, douleur intense) ou généraux (sepsis, choc septique) est une indication d’urgence à l’exploration chirurgicale. Sa précocité est le principal facteur pronostique modifiable, les recommandations de thérapeutiques complémentaires (immunoglobulines intraveineuses, oxygénothérapie hyperbare, pansement à pressions négatives, ...) reposant à ce jour sur un faible niveau de preuve. L’élément essentiel de la prise en charge des toxidermies graves est la recherche et l’arrêt du médicament imputable, facteur essentiel du pronostic. Le SJS et le NET, en général associés à une ou plusieurs atteintes muqueuses, entraînent dans les formes les plus graves une défaillance cutanée aiguë. La prise en charge repose sur les soins de support (correction des troubles hydroélectrolytiques, prévention de l’hypothermie, prévention et traitement des épisodes infectieux, analgésie et anxiolyse, soins locaux). Les complications infectieuses et respiratoires sont les principales causes de décès à la phase aiguë. Aucun traitement spécifique n’a fait la preuve de son efficacité à ce jour. Le diagnostic de DRESS est difficile, et la prise en charge doit être multidisciplinaire. Sa gravité tient aux possibles atteintes viscérales associées (hépatique, rénale et cardiaque) qui justifient dans les formes graves d’une corticothérapie urgente.

BACKGROUND Necrotizing soft-tissue infections (NSTIs) are life threatening, requiring broad-spectrum antibiotics. Their aetiological diagnosis can be limited by poor performance of cultures and administration of antibiotics before surgery. OBJECTIVES We aimed (i) to compare 16S-targeted metagenomics (TM) and unbiased semiquantitative panmicroorganism DNA- and RNA-based shotgun metagenomics (SM) with cultures, (ii) to identify patients who would best benefit from metagenomics approaches and (iii) to detect the microbial pathogens in surrounding non-necrotic 'healthy' tissues by SM-based methods. METHODS A prospective observational study was performed to assess the analytical performance of standard cultures, TM and SM on tissues from 34 patients with NSTIs. Pathogen identification obtained with these three methods was compared. RESULTS Thirty-four necrotic and 10 healthy tissues were collected from 34 patients. The performance of TM was inferior to that of the other methods (P < 0·05), whereas SM performed better than standard culture, although the result was not statistically significant (P = 0·08). SM was significantly more sensitive than TM for the detection of all bacteria (P = 0·02) and more sensitive than standard culture for the detection of anaerobic bacteria (P < 0·01). There was a strong correlation (r = 0·71, Spearman correlation coefficient) between the semiquantitative abundance of bacteria in the culture and the bacteria-to-human sequence ratio in SM. Low amounts of bacterial DNA were found in healthy tissues, suggesting a bacterial continuum between macroscopically 'healthy' and necrotic tissue. CONCLUSIONS SM showed a significantly better ability to detect a broader range of pathogens than TM and identify strict anaerobes than standard culture. Patients with diabetes with NSTIs appeared to benefit most from SM. Finally, our results suggest a bacterial continuum between macroscopically 'healthy' non-necrotic areas and necrotic tissues. What's already known about this topic? Necrotizing soft-tissue infections (NSTIs) are characterized by rapidly progressive necrosis of subcutaneous tissues and high mortality, despite surgical debridement combined with broad-spectrum antibiotics. The spectrum of potentially involved pathogens is very large, and identification is often limited by the poor performance of standard cultures, which may be impaired by previous antibiotic intake. Metagenomics-based approaches show promise for better identification of the pathogens that cause these infections, but they have not been evaluated in this medical context. What does this study add? Shotgun metagenomics (SM) showed higher sensitivity than 16S rRNA gene sequencing and a better ability than culture to detect anaerobic bacteria. As a result, a significant proportion of infections with bacteria, such as Pasteurella multocida or Clostridium perfringens, were detected only by SM. SM bacterial quantification enabled better detection of low amounts of bacterial DNA from macroscopically 'healthy' tissue, suggesting a subclinical infectious extension. What is the translational message? The high analytical performance of SM shown in this study should allow its future implementation for the diagnosis of necrotizing fasciitis, complementing or replacing routine methods. The large amount of data, including additional information on antimicrobial resistance, virulence profiles and metabolic adaptation of the pathogens, will improve microbiological documentation. Our results will improve our understanding of infectious pathophysiology in the future, leading to potentially better medical care.

Le syndrome de detresse respiratoire aigue (SDRA) correspond a la forme la plus grave de l’insuffisance respiratoire aigue hypoxemique et est associe a une mortalite hospitaliere de l’ordre de 40 %. Il s’agit d’une entite heterogene dont la definition clinicoradiologique a ete revue en 2012 lors de la conference de Berlin. Le substrat histologique le plus frequemment associe au SDRA est le dommage alveolaire diffus (DAD), mais un large panel de lesions histologiques a ete rapporte, suggerant que le SDRA ne peut etre reduit au DAD. Des facteurs de risque « communs » ont ete proposes par la conference de Berlin et sont retrouves dans plus de 90 % des cas. Il existe cependant d’authentiques SDRA pour lesquels aucun facteur de risque n’est identifie et pouvant necessiter une approche therapeutique ciblee. Une demarche diagnostique standardisee est alors indispensable.

Background Necrotising soft-tissue infections (NSTI) are rare, life-threatening conditions. Objectives We aimed to assess whether admitting hospital characteristics were associated with NSTI mortality. Methods We studied the French nationwide hospital discharge database (retrospective national cohort). All patients admitted in 2007-2012 with an ICD-10 code of necrotising fasciitis were eligible. We extracted data on the patients (age, sex, ICU admission, co-morbidities) and hospitals (public vs private proprietary; for public hospitals, teaching, yes/no; and number of NSTI admissions, ≥3 NSTI cases/year, yes/no). Multivariable analyses were performed to identify independent predictors of day-28 mortality and in-hospital mortality using mixed logistic regression and Cox proportional hazards models, respectively. Results We identified 1537 patients (915 males) with a median age of 60 (IQR, 48-75) years, admitted to 326 hospitals, public (82%) and admitting fewer than three NSTI cases/year (93%). Overall, 364 patients died (23·7%; 95%CI, 21·6-25·9). Patients treated in public teaching centres with ≥3NSTI cases annually had lower day-28 mortality (adjusted odds ratio [aOR], 0·68; 95%CI, 0·46-0·99; p=0·045) and in-hospital mortality rates than patients treated in local hospitals, even after adjusting for potentially relevant individual risk factors. No significant association was found between mortality and inter-hospital transfer. Conclusions Our finding highlighted an increased survival in teaching centres with high NSTI volume procedures. If confirmed in other settings, these findings reinforce the importance of expertise in early diagnosis and management of this condition. This article is protected by copyright. All rights reserved.

Introduction La douleur chronique est une sequelle de la necrolyse epidermique (NE) dont la physiopathologie reste a determiner. Nous avons mene une evaluation neurophysiologique pour etudier l’implication eventuelle de lesions des fibres nerveuses de petit diametre qui transmettent les informations douloureuses depuis l’epiderme. Materiel et methodes Dans cette etude monocentrique retrospective, nous avons selectionne a partir de la base informatique du service des explorations neurophysiologiques (2011–2019) les patients pour lesquels ces tests avaient ete realises pour bilan de douleurs chroniques apres NE. A partir des dossiers, nous avons recueilli les donnees de la phase aigue et a la date des tests neurophysiologiques : localisation de la douleur, intensite (EVA 0–10), duree, impact, composante affective–emotionnelle, caracteristiques sensorielles (brulures, picotements, allodynie mecanique). Les tests neurophysiologiques comprenaient l’enregistrement de potentiels evoques nociceptifs et la mesure de seuils sensitifs thermiques (chaud/froid) et de conductance cutanee. Resultats Dix patients ont ete inclus, explores en mediane 2 ans (1–13) apres la phase aigue. Les tests neurophysiologiques etaient normaux dans 5 cas et en faveur d’une neuropathie des petites fibres (NPF) dans 5 cas. Les caracteristiques demographiques et de phase aigue ne differaient pas entre les deux groupes. L’EVA mediane etait de 6 (3–8). La douleur impactait la vie quotidienne dans 7 cas, presentait une composante emotionnelle dans 6 cas, et, au plan sensoriel, etait a type de brulure (6 cas), picotement (7 cas) ou allodynie mecanique (5 cas). Il n’y avait pas de difference entre les deux groupes pour la localisation et l’intensite de la douleur, son impact (3 patients/5 vs 4/5), sa composante emotionnelle (3/5 vs 3/5) ou sensorielle : sensations de brulure (3/5 vs 4/5), picotements (4/5 vs 3/5) ou allodynie mecanique (2/5 vs 3/5, Tableau 2 ). Trois patients de chaque groupe avaient des antecedents pouvant etre associes a une NPF. Discussion Les caracteristiques des patients en phase aigue et au stade douloureux ne differaient pas selon le resultat des tests neurophysiologiques (presence d’une NPF ou non). Ainsi, l’aspect lesionnel de l’atteinte des petites fibres, evalue par ces explorations, n’est pas un determinant de la chronicisation de la douleur. Les phenomenes de sensibilisation des afferences sensitives peripheriques ou des structures d’integration centrales joueraient un role beaucoup plus important dans la persistance de la douleur apres NE. Des etudes histologiques pourraient etre informatives pour mieux comprendre la sensibilisation peripherique possiblement liee a la repousse axonale lors de la cicatrisation. Pour la sensibilisation centrale, des composantes affectives–emotionnelles et les sequelles psychologiques propres a la NE semblent impliquees.

Introduction Les maladies immunologiques (lupus, dermatomyosite) sont des facteurs de risque de necrolyse epidermique (NE) medicamenteuse. D’autre part, en poussee aigue, elles peuvent mimer une NE. Cependant, le cadre nosologique des NEs avec auto-immunite peut etre difficile a statuer. Materiel et methodes Cette etude retrospective multicentrique a inclus les adultes avec NE de 07/2014 a 03/2020, avec antecedent de connectivite et/ou auto-anticorps (Ac) decouverts au moment de la NE (AAN, anti-DNA, anti-ECT, dot-myosite), qu’il y ait ou non un medicament (mdt) suspect. Les histologies ont ete relues en aveugle. Resultats Dix-huit patients ont ete inclus (17 F, âge median 47 ans), dont 4 avec lupus connu, 2 avec syndrome de Sjogren primaire, 2 avec photosensibilite. Sept (39 %) ont ete vus au printemps/ete. Onze (61 %) avaient un mdt suspect (ALDEN entre 3, possible et 6, certain). Le decollement median etait de 28 % (2-60 %). Une atteinte cephalique nette etait notee dans 12 cas. L’atteinte muqueuse etait constante. Trois patients sont decedes, 5 ont eu des sequelles severes. Trois situations ont ete observees : – Dans 5 cas : lesions annulaires, necrotiques, franche predominance cephalique, rare atteinte oculaire, connectivite connue, pas de mdt suspect. Les Ac etaient des AAN (n = 3, titre median 1/640), anti-ADN (n = 2), anti-SSA (n = 5), anti-MDA5 (n = 1). Ils ont recu un traitement specifique de la connectivite en phase aigue de la NE ; – Dans 10 cas : NE sans particularite clinique, frequente atteinte oculaire, mdt suspect dans 8 cas (80 %, ALDEN 4 a 6). Les Ac etaient des AAN (n = 8 titre median 1/800), anti-ADN (n = 1), anti-SSA (n = 6), anti-RNP (n = 1), anti-TIFF1γ (n = 1). Aucun n’a recu de traitement specifique en phase aigue. A distance, les Ac ont persiste sans manifestation clinique ; – Pour 3 patientes : NE sans particularite, au cours d’une poussee de lupus, avec mdt suspect : cotrimoxazole (n = 2, ALDEN 6), AINS (ALDEN 3). La nosologie a ete difficile a trancher. Au plan histologique, il n’y avait pas de difference significative entre les groupes, meme si une tendance a une mucinose dermique et moins de lesions lichenoides pilaires a ete observee dans le groupe 1. Un patient (groupe 1) avait une bande lupique en IFD. Discussion La presence d’une auto-immunite au cours d’une NE fait discuter 3 situations : – une NE immunologique, « non toxique », sur connectivite connue ou non (« lupus-Lyell »), melant au decollement des lesions annulaires, necrotiques, peu d’atteinte oculaire, justifiant un traitement specifique de la connectivite ; – une NE medicamenteuse, ou les Ac semblent fortuits (precessifs ? epitope spreading ?), n’imposant pas de traitement specifique de connectivite ; – une situation difficile a trancher (« lupus-Lyell » ou NE medicamenteuse favorisee par le lupus) chez des patients severes. L’indication d’un traitement immunomodulateur d’une NE avec auto-immunite doit etre pesee selon le cadre nosologique.

Introduction La necrolyse epidermique (NE, syndrome de Stevens–Johnson et necrolyse epidermique toxique), est induite par un medicament dans 85 % des cas. Le delai d’apparition le plus classique est de 4 a 28 jours. Les bases de pharmacovigilance (PV) collectent les declarations d’effets indesirables transmises par des medecins ou non-medecins (pharmaciens, avocats, consommateurs) et permettent de generer des signaux concernant des medicaments suspects. Cependant certains biais peuvent influencer l’imputabilite du/des medicament(s) suspect(s). Notre objectif etait d’identifier les classes medicamenteuses les plus sujettes a des biais. Materiel et methodes Nous avons utilise Vigibase, la base de PV mondiale de l’OMS, en incluant les molecules suspectes de NE entre 2016 et 2020, et rapportees au moins 10 fois afin d’eviter les fluctuations d’echantillonnage. Une analyse non supervisee de type classification hierarchique sur composante principale a ete realisee. Afin d’apprecier si un medicament pouvait etre soumis a un biais, nous avons inclus les variables associees a la qualite du rapport notifiant le cas comme le delai d’apparition et le rapporteur (medecin ou non). Resultats Cent cinquante-deux medicaments ont ete inclus. La classification a permis d’identifier 3 classes (CL) : – ‘CL1′ (n = 41) correspondant aux medicaments preferentiellement rapportes par des medecins et associes a un delai d’apparition compatible (4–28 jours), constituee de molecules a forte notoriete comme l’allopurinol et la nevirapine ; – ‘CL2′ (n = 42), correspondant aux medicaments preferentiellement rapportes par des medecins et associes a un delai d’apparition – enfin ‘CL3′ (n = 69), regroupant des medicaments rapportes par des non-medecins, avec un delai d’apparition frequemment inconnu, correspondant aux anticancereux et antiepileptiques. Discussion Cette etude n’exclut pas la causalite d’un medicament mais renseigne sur les biais qui peuvent impacter l’imputabilite medicamenteuse. Les biais peuvent resulter par exemple de la qualite du rapporteur (ex : avocats ou consommateurs dans certains pays a forte pression juridique) ou du delai d’apparition, trop court ou non renseigne. La CL2 semble etre soumise au biais protopathique (medicament considere a tort comme suspect alors qu’il est donne pour les premiers signes de la maladie) compte tenu d’un delai d’apparition trop court. La CL3 semble etre soumise a un biais d’information (exposition medicamenteuse ou diagnostic incertains), qui impacte la qualite des notifications. Ainsi, lors de l’analyse d’une association entre un medicament et une NE, ces biais doivent etre consideres avant de conclure a un lien de causalite, pour ainsi mieux guider les contre-indications medicamenteuses.

Introduction L’atteinte pulmonaire precoce de la necrolyse epidermique (NE, syndromes de Stevens–Johnson et necrolyse epidermique toxique) est liee a une atteinte specifique tracheobronchique de la maladie et peut necessiter le recours a la ventilation mecanique (VM). En dehors des constatations endoscopiques revelant un decollement de la muqueuse tracheobronchique, la physiopathologie de cette atteinte specifique a la phase aigue n’a ete que peu etudiee. Nous avons explore les caracteristiques de patients necessitant le recours a la VM a la phase aigue de la NE. Materiel et methodes Dans cette etude retrospective monocentrique, nous avons analyse les caracteristiques cliniques et du liquide bronchoalveolaire (LBA) de 15 patients admis en reanimation et mis sous VM pour NE en les comparant a 15 patients « temoins » apparies en âge et sexe, mis sous VM pour un syndrome de detresse respiratoire aigue (SDRA) d’origine infectieuse. Le dosage des cytokines (TNFα, IFNγ, IP10, IL8, IL10, IL6, IL13, GM-CSF, RAGE) dans le LBA a ete realise par technique Luminex (Human Magnetic Luminex assay, RD p = 0,7). Cependant, la composition du LBA etait differente : macrophagique chez les patients atteints de NE (mediane 74 % [50–80 %] vs 34 % [18–53] ; p = 0,001), neutrophilique chez les patients SDRA (mediane 53 % [40–75] vs 18 % [6–46] ; p = 0,002). Le pourcentage de lymphocytes n’etait pas different. Les concentrations alveolaires d’IL-13 etaient significativement superieures (p = 0,0056) et celles d’IL-6, d’IL-10 et de RAGE significativement inferieures (respectivement p = 0,0002 ; p = 0,047 ; p = 0,004) chez les patients NE comparativement aux SDRA. Les cytokines de type TH1 (TNFα, IFNγ, IP10, IL8, GM-CSF) n’etaient pas differentes. Les concentrations des cytokines dans le LBA des NE ne differaient pas selon la presence ou non d’un decollement bronchique macroscopique. Discussion Cette etude exploratoire met en evidence que, outre le phenomene de decollement tracheobronchique, il existe une inflammation pulmonaire au cours de la NE en phase aigue. Le profil inflammatoire des NE se distingue du SDRA par : – une agression tissulaire moins importante (moindre production IL6 et de RAGE) ; – la predominance d’infiltration macrophagique ; – une production accrue d’IL-13 en faveur d’un profil plus Th2. Cette inflammation alveolaire pourrait d’une part participer a la gravite du tableau initial, et d’autre part faire le lit des sequelles tardives observees a type de trouble de diffusion.

Introduction Les sequelles sont frequentes, multiples et parfois graves chez les patients survivant apres syndrome de Stevens-Johnson (SJS) ou de Lyell. Neanmoins, tres peu d’etudes se sont interessees au vecu de ces sequelles et a l’impact de la maladie sur la qualite de vie (QDV) a long terme chez ces patients. Nous avons conduit une etude observationnelle chez 51 patients avec pour objectif principal de decrire le SF36 et ses composantes physique (P) et mentale (M), selon qu’il y ait eu ou non un sejour en reanimation en phase aigue (rea/pas rea). Materiel et methodes Dans cette etude monocentrique, les patients survivant apres SJS/Lyell pris en charge entre 2010 et 2017, joignables, et parlant francais ont ete contactes par telephone entre 11/2017 et 03/2018 et questionnes sur leur mode de vie depuis la maladie, leur ressenti des sequelles (echelle numerique EN 0–10) et leur QDV selon plusieurs scores, dont le SF36 (composantes P et M), des scores psychologiques, et la QDV estimee par le patient sur une EN 0–100. Outre l’objectif principal, le SF36 des patients admis en reanimation (rea) etait aussi ete compares a une population controle, survivants de choc septique, apres appariement âge/sexe. Resultats Cinquante-sept patients (38 femmes, âge median 48 ans) ont ete inclus, dont 19 etaient passes en rea. Le delai median entre la phase aigue et la passation du questionnaire etait de 3,6 ans (2–6). Les composantes P et M du SF36 etaient inferieures a la population generale (z-scores a −0,44 et −0,34 respectivement), avec une difference significative pour la composante P entre patients rea/pas rea ( Tableau 1 ). Les scores d’anxiete et de depression etaient eleves chez 54 % et 21 % des patients, et pres de 50 % avaient des manifestations de stress post-traumatique. L’EN mediane de QDV etait de 65/100, sans difference rea/pas rea. Chez les patients rea, les scores P et M du SF36 etaient aussi alteres que ceux des survivants de choc septique ( Figs. A et B ). Les patients decrivaient les sequelles suivantes : cutanees (77 %), oculaires (70 %), psychologiques (60 %), dentaires (49 %), genitales (30 %), et respiratoires (18 %), avec une EN entre 5 et 6 pour toutes. 44 % avaient des depenses non remboursees pour au moins 2 types de sequelles, 46 % ont du changer d’activite professionnelle, 20 % ont vu leur vie familiale modifiee, et 32 % ont demande une allocation adulte handicape. Discussion Cette etude montre l’impact majeur du SJS/Lyell sur la QDV a long terme. Les patients rea avaient un impact physique encore plus important, et similaire a ceux survivants de choc septique. Les sequelles psychologiques etaient frequentes. Le ressenti des sequelles etait eleve, la vie familiale et professionnelle souvent bouleversee, et les depenses non remboursees frequentes. Conclusion Cette etude confirme la necessite d’un suivi multidisciplinaire prolonge apres un SJS/Lyell, integrant un suivi social.