[Suspected allergy to COVID-19 vaccines: A retrospective study of 320 patients]. / Suspicion d'allergie aux vaccins anti COVID-19 : étude rétrospective sur 320 patients.

Introduction: The health context with COVID-19 pandemic has led to fast development of many vaccines against the SarS-Cov-2 virus. Four of them are currently available in France and contain polyethylene glycol (PEG) or polysorbate 80 as excipients, already described as causing anaphylaxis. French recommendations have been suggested by allergology authorities and proposed a course of action in the event of a suspected allergy to these vaccines. Thus, allergies to excipients were the only contraindication to COVID-19 vaccination. Our main objective was to determine the impact of these allergology vaccine recommendations on the management of these patients. Our secondary objective was to determine prevalence of true allergies to these vaccines. Materials and methods: We conducted a unicentric descriptive retrospective study with all patients over 18 years of age referred for an allergological opinion before or after an injection of one of the anti-COVID-19 vaccines. Nineteen patients were classified into different interest groups, based on french recommendations. Results: The vast majority of patients did not require a pre-vaccination allergological assessment. Indeed, only 25 patients received skin tests prior to vaccination. The rest of patients were able to be vaccinated without allergological assessment. Patients not vaccinated due to allergy to excipients represent less than 1% of the population (n = 3/320). Conclusion: French recommendations made it possible to vaccinate the vast majority of patients included in our study. Allergy to PEG, polysorbate or their derivatives, the only contraindication to anti-COVID vaccination, according to the recommendations of February 2021, remains rare. Today, several authors propose tolerance inductions allowing the vaccination of patients allergic to PEGs or their derivatives with good tolerance.

Therapeutic management of adults with atopic dermatitis: comparison with psoriasis and chronic urticaria.

BACKGROUND: The therapeutic options in atopic dermatitis rely on consensus-based guidelines, also established for psoriasis and chronic urticaria. However, the therapeutic approach in atopic dermatitis, especially in the moderate-to-severe forms of the disease, seems less aggressive than in psoriasis and in chronic urticaria with a less frequent use of systemic agents. OBJECTIVES: To compare in real-life conditions the therapeutic management of adults with atopic dermatitis with those with psoriasis and chronic urticaria. METHODS: A transversal analysis was performed in May 2017, using retrospective data from a monocentric database. Data on epidemiology, severity, therapeutic educational intervention and systemic treatments were analysed from 401 patients with atopic dermatitis, compared with data from 230 patients with chronic urticaria and 535 patients with psoriasis. RESULTS: A high proportion (73%) of atopic dermatitis patients presented with a moderate-to-severe form of the disease compared to only 39% of chronic urticaria and 17% of psoriasis patients. Most of atopic dermatitis patients (78%) had completed a therapeutic educational programme, while the adherence was lower in chronic urticaria (35%) and in psoriasis (3%) patients. A systemic treatment, including biologicals, was recorded in 8% of atopic dermatitis patients, while it concerned 26% and 47% of chronic urticaria and psoriasis patients, respectively. CONCLUSIONS: We confirmed that atopic dermatitis treatment mostly relies on topical treatments. Only a minority of moderate-to-severe atopic dermatitis patients who are eligible for a systemic treatment receive such therapy. This may suggest promoting a more frequent use of systemic agents in moderate-to-severe atopic dermatitis.

[NSAID urticaria: Similar management to acute urticaria]. / Urticaire aux AINS : une prise en charge similaire à celle de l'urticaire aiguë.

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most common providers of immediate hypersensitivity reactions. Among these reactions, isolated acute urticaria is the most common clinical feature with a non-allergic origin. It is a pharmacological side effect resulting from the alteration of arachidonic acid metabolism induced by NSAIDs. Diagnosis of this acute urticaria is clinical, requiring no allergy testing. Currently, the recommended therapeutic management of NSAID urticaria is the avoidance of all NSAID with COX-1 inhibitor activity (even if when reintroduced, they are most often well tolerated) and the use of selective COX-2 inhibitors. This review focuses on urticaria reactions to NSAIDs, which are simple to manage.

Omalizumab in patients with chronic spontaneous urticaria nonresponsive to H1-antihistamine treatment: results of the phase IV open-label SUNRISE study.

BACKGROUND: Omalizumab is approved as an add-on therapy for the treatment of chronic spontaneous urticaria (CSU) in patients with inadequate response to H1-antihistamine treatment. The urticaria control test (UCT) is a reliable, concise tool developed as an alternative to the 7-day urticaria activity score (UAS7) - the standard for CSU disease activity assessment. OBJECTIVES: This prospective, open-label, phase IV study evaluated the efficacy and safety of omalizumab in French adult patients with CSU nonresponsive to H1-antihistamine treatment. MATERIALS AND METHODS: Patients [n = 136; stratified 1 : 2 (with angio-oedema : without angioedema)] received omalizumab 300 mg subcutaneously every 4 weeks for 12 weeks. Study assessments included UCT, UAS7, angio-oedema activity score and d-dimer levels (exploratory objective). RESULTS: At Week 12, 74·6% of the patients achieved disease control [UCT score ≥ 12 (primary endpoint)] and 67·7% of patients showed well-controlled disease (UAS7 ≤ 6). There was a strong negative correlation between UCT score and UAS7 at Week 12 (Spearman's correlation coefficient -0·839). Mean plasma d-dimer concentration was elevated at baseline (1002·1 ng mL-1 ) and decreased notably at Week 8 (455 ng mL-1 ). Among the nine patients with a very high baseline d-dimer concentration (> 3000 ng mL-1 ), eight were responders (UAS7 ≤ 6) at Week 12. CONCLUSIONS: Omalizumab was efficacious in patients with CSU nonresponsive to H1-antihistamines. The UCT was a reliable tool for disease assessment and the scores correlated well with UAS7. This study does not support the usefulness of d-dimer to monitor long-term disease prognosis in adult urticaria; however, it may indicate patients who respond to omalizumab.

Epidermolysis bullosa simplex generalized severe induces a T helper 17 response and is improved by apremilast treatment.

BACKGROUND: Epidermolysis bullosa simplex generalized severe (EBS-gen sev) is a genetic disorder caused by mutation in the KRT5 or KRT14 genes. Although it is usually considered a mechanical disease, recent data argue for additional inflammatory mechanisms. OBJECTIVES: To assess the inflammation in the skin of patients with EBS-gen sev. METHODS: A first immunohistochemical retrospective study was performed on frozen skin samples from 17 patients with EBS-gen sev. A second multicentre prospective study was conducted on 10 patients with severe EBS-gen sev. Blister fluid and epidermis were processed for immunochemical analysis and quantitative real-time polymerase chain reaction. Cytokine expression was analysed in blister fluid and compared with that in controls. RESULTS: Histological analysis showed a constant dermal perivascular CD4+ lymphocyte infiltrate in skin biopsies of both blister (n = 17) and rubbed skin (n = 5), an epidermal infiltration of neutrophils and eosinophils in 70% of cases, and increased immunostaining for CXCL9 and CXCL10 in blistering skin. High levels of T helper 17 cytokines were detected in lesional skin. Three adult patients with EBS-gen sev were treated with apremilast, with a dramatic improvement of skin blistering and good tolerance. CONCLUSIONS: Our study demonstrates the importance of inflammation in patients with EBS-gen sev and underlines the key role for T helper 17 cells in its pathogenesis. In addition, this study provides promising new therapeutic approaches for this disabling disorder.

Angioedema in chronic spontaneous urticaria is underdiagnosed and has a substantial impact: Analyses from ASSURE-CSU.

BACKGROUND: ASSURE-CSU revealed differences in physician and patient reporting of angioedema. This post hoc analysis was conducted to evaluate the actual rate of angioedema in the study population and explore differences between patients with and without angioedema. METHODS: This international observational study assessed 673 patients with inadequately controlled chronic spontaneous urticaria (CSU). Physicians abstracted angioedema data from medical records, which were compared with patient-reported data. Patients in the Yes-angioedema category had angioedema reported in the medical record and a patient-reported source. For those in the No-angioedema category, angioedema was reported in neither the medical record nor a patient-reported source. Those in the Misaligned category had angioedema reported in only one source. Statistical comparisons between Yes-angioedema and No-angioedema categories were conducted for measures of CSU activity, health-related quality of life (HRQoL), productivity and healthcare resource utilization (HCRU). Regression analyses explored the relationship between Dermatology Life Quality Index (DLQI) score and angioedema, adjusting for important covariates. RESULTS: Among evaluable patients, 259 (40.3%), 173 (26.9%) and 211 (32.8%) were in the Yes-angioedema, No-angioedema and Misaligned category, respectively. CSU activity and impact on HRQoL, productivity, and HCRU was greater for Yes-angioedema patients than No-angioedema patients. After covariate adjustment, mean DLQI score was significantly higher (indicating worse HRQoL) for patients with angioedema versus no angioedema (9.88 vs 7.27, P < .001). The Misaligned category had similar results with Yes-angioedema on all outcomes. CONCLUSIONS: Angioedema in CSU seems to be under-reported but has significant negative impacts on HRQoL, daily activities, HCRU and work compared with no angioedema.

The burden of chronic spontaneous urticaria is substantial: Real-world evidence from ASSURE-CSU.

BACKGROUND: Chronic spontaneous urticaria (CSU) can be debilitating, difficult to treat, and frustrating for patients and physicians. Real-world evidence for the burden of CSU is limited. The objective of this study was to document disease duration, treatment history, and disease activity, as well as impact on health-related quality of life (HRQoL) and work among patients with inadequately controlled CSU, and to describe its humanistic, societal, and economic burden. METHODS: This international observational study assessed a cohort of 673 adult patients with CSU whose symptoms persisted for ≥12 months despite treatment. Demographics, disease characteristics, and healthcare resource use in the previous 12 months were collected from medical records. Patient-reported data on urticaria and angioedema symptoms, HRQoL, and work productivity and activity impairment were collected from a survey and a diary. RESULTS: Almost 50% of patients had moderate-to-severe disease activity as reported by Urticaria Activity Score. Mean (SD) Dermatology Life Quality Index and Chronic Urticaria Quality of Life Questionnaire scores were 9.1 (6.62) and 33.6 (20.99), respectively. Chronic spontaneous urticaria markedly interfered with sleep and daily activities. Angioedema in the previous 12 months was reported by 66% of enrolled patients and significantly affected HRQoL. More than 20% of patients reported ≥1 hour per week of missed work; productivity impairment was 27%. These effects increased with increasing disease activity. Significant healthcare resources and costs were incurred to treat CSU. CONCLUSIONS: Chronic spontaneous urticaria has considerable humanistic and economic impacts. Patients with greater disease activity and with angioedema experience greater HRQoL impairments.

Comparative histological analysis of drug-induced maculopapular exanthema and DRESS.

BACKGROUND: Cutaneous adverse drug reactions frequently present as a benign maculopapular exanthema (MPE) with a rapid healing. Sometimes systemic signs are present, which could represent a more severe or systemic MPE (sMPE) or even be the initial phase of a drug reaction with eosinophilia and systemic symptoms (DRESS). Histopathology associated with MPE, sMPE and DRESS has not been well characterized. OBJECTIVES: To study the cutaneous histopathological changes associated with MPE, sMPE and DRESS. METHODS: A retrospective clinicopathological analysis of 13 cases of MPE, 13 of sMPE and 45 of DRESS, collected in one centre from 2005 to 2013. RESULTS: The number of histopathological changes per section increased gradually from MPE to sMPE and DRESS. Prevalence of spongiosis, dermal lymphocytes, eosinophils and neutrophils did not differ between MPE, sMPE and DRESS. Keratinocyte damage, rare in MPE, was regularly found in sMPE and frequent in DRESS. The density of the inflammatory infiltrate increased progressively from MPE to sMPE and DRESS. Atypical lymphocytes were absent in MPE, present in sMPE and more frequent in DRESS. Deep dermal involvement and leukocytoclastic vasculitis were only observed in DRESS. LIMITATIONS: This was a retrospective study. CONCLUSIONS: Numerous histopathological changes per section in drug-induced exanthema should alert for a more severe form of cutaneous adverse drug reactions, i.e. DRESS.

[Fixed drug eruption to clarithromycin: The importance of challenge tests in diagnosis]. / Érythème pigmenté fixe à la clarithromycine : importance des tests de provocation pour le diagnostic.

BACKGROUND: Determining the substance responsible for recurrent fixed drug eruption (FDE) may be difficult in the case of patients on multiple medication. Allergy testing may prove invaluable in such situations, as we demonstrate herein with an original case. PATIENTS AND METHODS: A 49-year-old man presented a rash on the seventh day of treatment with esomeprazole, clarithromycin and amoxicillin prescribed for gastritis involving Helicobacter pylori. The condition regressed spontaneously within a few days, but left three areas of hyperpigmentation. The patient subsequently reported four further episodes consisting of stereotypical reactivation in the areas of the three initial lesions and occurring 24hours after use of clarithromycin (2 episodes) and amoxicillin (2 episodes). The patient resumed proton pump inhibitor therapy (esomeprazole) without incident. Based on history taking, an initial diagnosis was made of multiple fixed drug eruption involving amoxicillin and clarithromycin. The initial skin allergy investigations were negative (patch-tests for amoxicillin and clarithromycin on healthy skin on the patient's back and on the affected area). After discussion, we decided to reintroduce the suspected drugs in succession. Beginning with clarithromycin, 12h after a single dose of 250mg, we noted an erythematous reaction on the pigmented areas, together with a burning sensation. In an identical challenge test with amoxicillin (500mg), the latter drug was perfectly well tolerated, ruling out the diagnosis of FDE to amoxicillin and thus the diagnosis of multiple FDE suggested by the patient history. DISCUSSION: FDEs to macrolides are rare, and herein we report a new case. Our observation confirms the diagnostic value of challenge tests in FDE. These tests should only be performed in the event of non-severe FDE, in other words not in bullous or systemic reactions, and they often constitute the only diagnostic approach possible, since skin tests are rarely positive during investigation for FDE.

Drug reaction with eosinophilia and systemic symptoms (DRESS): clinicopathological study of 45 cases.

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare and severe adverse drug reaction. Large detailed studies of histopathological features of DRESS are sparse and suggest an association between keratinocyte damage and the severity of visceral involvement. OBJECTIVES: To describe the dermatopathological features in a large series of DRESS and their possible association with clinical features and the severity of the disease. METHODS: A retrospective analysis of the clinicobiological and dermatopathological features in a monocentric cohort of patients with DRESS. RESULTS: From January 2005 to January 2013, 45 patients were validated as probable or definite cases of DRESS. The median age was 64 years (range 3-87). The most frequent clinical and biological features included: fever ≥38.5°C (95%), facial oedema (72%), enlarged lymph nodes (51%), visceral involvement (75%), blood eosinophilia (97%) and atypical lymphocytes (82%). Severe DRESS occurred in 24% and a fatal outcome in 6% of patients. Histopathological analysis showed that no specific histopathological pattern was characteristic for DRESS. However, several changes in different cutaneous compartments were observed in 2 of 3 of cases. Spongiosis (55%) and keratinocyte damage (53%) were the most common epidermal changes. Spongiosis was associated with non-severe DRESS (P = 0.041) whereas confluent keratinocyte necrosis correlated with severe DRESS (P = 0.011). Vascular changes were frequent (88%). A moderate dermal perivascular lymphocytic infiltrate was invariably present, containing eosinophils, neutrophils and/or atypical lymphocytes in 57% of cases. CONCLUSIONS: Epidermal changes are indicative for the severity of DRESS.

[Diversity of cutaneous bacteria decreases inflammation]. / Plus il y a de bactéries différentes, moins il y a d'inflammation : la révolution microbiotique.

Human microbiota includes all microorganisms, saprophytes and pathogens that colonize our bodies. Recent advances in metagenomic analysis techniques have expanded our knowledge of the microbiota and fundamentally changed our view of its relationships with the immune system. The commensal flora appears to be essential to the development of the immune system, and the diversity of the microbiota is correlated with good health status of individuals. These findings open up new conceptual and therapeutic approaches in chronic inflammatory diseases.

Role of obesity on the thickness of primary cutaneous melanoma.

BACKGROUND: Thick primary cutaneous melanoma (PCM) is associated with older age, male sex, being single, a low educational level, self-detection and general practice detection, nodular melanoma (NM) and acral lentiginous melanoma (ALM) types; and are found in the head-neck and lower limb locations. Obesity plays a direct role on melanoma tumour growth, as it has been shown in animal models, but its role in the thickness of PCM remains unknown. OBJECTIVES: We investigated the impact of obesity on the thickness of invasive PCM. METHODS: A cross-sectional study was performed in a prospective cohort for which we collected several clinical and histological data already known to be associated with thick PCM and the Body Mass Index from new cases of invasive PCM which were referred to the dermatology department in Valence. RESULTS: Four hundred and twenty-seven patients were studied. In an univariate analysis, thick PCM was associated with low educational level, obesity, identification by the patient or the general practitioner (GP), location on the cephalic extremity, in a non-visible area of the body, the NM and ALM type, and an ulceration. In a multivariate analysis, NM, ulceration, topography of the melanoma and identification of the melanoma by the patient or GP were significantly associated with thick melanoma. When including only clinical features in the model, low educational level, mode of melanoma identification and obesity were significantly associated with a risk of thick melanoma. CONCLUSIONS: Obesity is a clinical independent risk factor of thick PCM. For health policies, governments should pay greater attention to detect melanoma in obese patients. Our results encourage the basic research on tumoural growth mechanisms due to obesity in melanoma.

[Pathophysiology of urticaria]. / Physiopathologie de l'urticaire.

Urticaria is a dermal edema resulting from vascular dilatation and leakage of fluid into the skin in response to molecules released from mast cells. The major mediator responsible for urticaria is histamine. However, the clinical spectrum and pattern of lesions indicate that other molecules, including prostaglandins, leukotrienes, cytokines, and chemokines, produced at different times after mast cell activation contribute to the polymorphism of this symptom and the variable evolution of this disease. It is a common practice to distinguish immunological and nonimmunological urticaria. Immunological urticaria is a hypersensitivity reaction mediated by antibodies and/or T-cells that results in mast cell activation. Although immunoglobulin (Ig) E-mediated type I hypersensitivity (HS) was long postulated to be the major immunological pathway associated with mast cell activation, interaction between IgEbound mast cells and allergens is unlikely to be the mechanism by which urticaria develops in most patients. It is now well established that urticaria may result from the binding of IgG auto-antibodies to IgE and/or to the receptor for IgE molecules on mast cells, thus corresponding to a type II HS reaction. These auto-immune urticarias represent up to 50 % of patients with chronic urticaria. Mast cell activation can also result from type III HS through the binding of circulating immune complexes to mast cell-expressing Fc receptors for IgG and IgM. Finally, under certain circumstances, T-cells can induce activation of mast cells, as well as histamine release (type IV HS). Nonimmunological urticarias result from mast cell activation through membrane receptors involved in innate immunity (e.g., complement, Toll-like, cytokine/chemokine, opioid) or by direct toxicity of xenobiotics (haptens, drugs). In conclusion, urticaria may result from different pathophysiological mechanisms that explain the great heterogeneity of clinical symptoms and the variable responses to treatment.

[Recurrent pyoderma gangrenosum-like ulcers induced by oral anticoagulants]. / Ulcérations récidivantes à type de pyoderma grangrenosum induites par les antivitamines K.

BACKGROUND: Other than the classic skin necrosis induced by oral anticoagulants (OAC) in patients with protein C and S deficiencies, other types of OAC induced-skin ulcers are little known. Herein, we describe an original case of recurrent pyoderma gangrenosum (PG)-like ulcers induced by OAC. PATIENTS AND METHODS: A 70-year-old female heart-transplant recipient presented deep, hyperalgesic and quickly-spreading necrotic ulceration of the right leg 6 weeks after starting oral anticoagulant therapy with fluindione. Histological analysis revealed dermal infiltrate containing polynuclear neutrophils, which accords with the histopathological diagnosis of leukocytoclastic vasculitis or PG. Infectious, autoimmune and thrombophilic causes were ruled out. Fluindione was withdrawn and the ulcer healed completely within a month. Six months later, right leg ulceration recurred two weeks after the patient resumed fluindione but healed within 1 month of discontinuation of the drug. An OAC from another chemical family (warfarin) was then introduced, with further recurrence of ulceration after 2 weeks of treatment. DISCUSSION: The chronology of events and the negativity of aetiological explorations allowed a diagnosis to be made of OAC-induced skin ulcer, a rare complication of which the pathophysiology is unclear. This is the first case of PG-like ulcers induced by OAC.

[Measles-Mumps-Rubella vaccination of an egg-allergic child sensitized to gelatin]. / Bonne tolérance de la vaccination rougeole-oreillons-rubéole chez un enfant allergique à l'œuf et sensibilisé à la gélatine.

The Measles-Mumps-Rubella (MMR) vaccine is often postponed in egg-allergic patients due to fear of anaphylactic reaction at the time of injection of this vaccin produced on egg derivates. However, this vaccine is recommended by health authorities, especially in case of increased measles incidence, and international recommendations indicate that there is no need for predictive allergological work-up and that the MMR vaccine is well tolerated in egg-allergic patients. We report on the case of a 12-year-old child with severe immediate-type egg allergy. Immediate-reading intradermal skin tests performed prior to the MMR vaccine were positive. Subsequent allergological work-up revealed a gelatin sensitization, and the child tolerated injections of the vaccine given according to a tolerance induction protocol. Gelatin is used as a stabilizer in numerous vaccines and may be responsible for immediate-type hypersentivity reactions to gelatin-containing vaccines. In case of reaction induced by the MMR vaccine, one needs to explore a potential gelatin sensitization/allergy. The MMR vaccine should be given and is well tolerated in patients with immediate-type egg hypersensitivity, even when gelatin sensitization is combined.

Molecular allergens in the diagnosis of latex allergy.

BACKGROUND: Molecular allergens enable the definition of sensitization profiles in allergic patients. AIM: To validate the most helpful allergens for the diagnosis of latex allergy in different clinical situations. METHODS: 130 patients suspected to be allergic to latex with positive IgE against natural rubber latex (NRL) have been studied: 97 were confirmed as latex allergic (among which 55 professionally exposed to latex and 35 with a peranaesthetic anaphylactic shock) and 33 were only sensitized to latex without clinical allergy. Each serum was tested for IgE against 9 recombinant latex allergens and bromelain using Phadia ImmunoCAP 250. RESULTS: rHev b 6.01, 6.02, 2 and 5 were the major allergens in the allergic population. An excellent correlation (94%) was observed between IgE against rHev b 6.01 and latex prick test positivities. IgE against rHev b 1, 3 and 5 were more frequent and their levels significantly higher in patients with peranaesthetic anaphylactic shock. Among the asymptomatic patients (29/33 allergic to pollen), NRL IgE positivity is explained by the presence of anti-rHev b 8 and/or anti-carbohydrate IgE. CONCLUSIONS: rHev b 6.01 and rHev b 5 specific IgE are of major interest to confirm latex allergy diagnosis. rHev b 5 is particularly useful in case of monosensitization where clinical symptoms and latex skin prick tests may be discordant, rHev b1 and rHev b 3 are interesting to document multi-operated and peranaesthetic latex allergy. Finally, rHev b 8 is a helpful marker to highlight latex/pollen cross-reactivity which improves the specificity of the serological tests.

[Delayed-type hypersensitivity to heparin: diagnosis and therapeutic management]. / Hypersensibilité retardée aux héparines : diagnostic et prise en charge thérapeutique.

Heparin is widely used as an anticoagulant and is indicated in the prevention and treatment of thromboembolic disorders. Heparin-induced delayed-type hypersensitivity presents as eczematous lesions, either at the injection site or generally, and affects 7.5% of patients on heparin. This poses diagnostic and therapeutic issues, since an alternative anticoagulant treatment is essential and the risk of cross-reactivity may be as high as 80%, depending on the type of heparin used. If delayed-type hypersensitivity is suspected, heparin-induced thrombocytopenia must first be ruled out, and heparin should be stopped. Fondaparinux is currently the first-line alternative, with a risk of cross-reactivity estimated at only 10%. The switch from a low-molecular-weight heparin (LMWH) to another LMWH is no longer recommended. The use of unfractionated heparin, danaparoid or hirudin may be warranted in the event of recurrence with fondaparinux, and an immuno-allergological work-up is needed to specify the exact profile of cross-allergies.