[Antihistamines : An ongoing narrative]. / Antihistaminiques : une histoire sans fin.

Histamine is responsible for many processes mediated by different receptors expressed on a variety of cells. The discovery of the first H1 antihistamines in the 1940s led to the development of numerous H1 and H2 antagonists with a broad application in many indications. The recent identification of two new histamine receptors (H3, H4) in the 1980s and 2000s led to the market authorization in Switzerland of new drugs since 2018. The purpose of this review is to provide a brief overview of the physiology of histamine, the recent development of new compounds in this field, antihistamine drug indications and relevant side effects.

L'histamine possède de nombreuses propriétés physiologiques, tant centrales que périphériques, via son action sur différents récepteurs. La découverte des premiers antihistaminiques H1 dans les années 1940 stimula le développement de nombreux autres antagonistes H1, puis H2, utilisés dans diverses spécialités médicales. L'identification plus récente de deux récepteurs à l'histamine (H3, H4) dans les années 1980 et 2000 relança le développement de nouveaux composés avec, en Suisse, une première autorisation de mise sur le marché en 2018. L'objectif de cet article de revue est de présenter brièvement la physiologie de l'histamine, l'histoire du développement des antihistaminiques, leurs utilisations actuelles, ainsi que leurs effets indésirables notables.

[64Cu]Cu-PEG-FUD peptide for noninvasive and sensitive detection of murine pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease resulting in irreversible scarring within the lungs. However, the lack of biomarkers that enable real-time assessment of disease activity remains a challenge in providing efficient clinical decision-making and optimal patient care in IPF. Fibronectin (FN) is highly expressed in fibroblastic foci of the IPF lung where active extracellular matrix (ECM) deposition occurs. Functional upstream domain (FUD) tightly binds the N-terminal 70-kilodalton domain of FN that is crucial for FN assembly. In this study, we first demonstrate the capacity of PEGylated FUD (PEG-FUD) to target FN deposition in human IPF tissue ex vivo. We subsequently radiolabeled PEG-FUD with 64Cu and monitored its spatiotemporal biodistribution via µPET/CT imaging in mice using the bleomycin-induced model of pulmonary injury and fibrosis. We demonstrated [64Cu]Cu-PEG-FUD uptake 3 and 11 days following bleomycin treatment, suggesting that radiolabeled PEG-FUD holds promise as an imaging probe in aiding the assessment of fibrotic lung disease activity.

[Understanding hypersensitivity reactions to monoclonal antibodies]. / Comprendre les réactions d'hypersensibilité aux anticorps monoclonaux.

Biologic drugs are complex molecules synthesized by a living organism. Their use is increasingly prevalent across all medical specialties, exposing a growing number of patients to potential adverse reactions. In this review, we discuss the new classification of hypersensitivity reactions, along with the specific characteristics of monoclonal antibodies. We also address the available diagnostic tools and discuss the management of those reactions, including for patients requiring the continuation of these biologic drugs.

Les médicaments biologiques sont des molécules complexes synthétisées par un organisme vivant. Ils sont de plus en plus utilisés dans toutes les spécialités médicales, exposant ainsi les patients à des réactions indésirables. Dans cet article, nous abordons la nouvelle classification des réactions d'hypersensibilité ainsi que les caractéristiques spécifiques des anticorps monoclonaux. Nous évoquons également les outils diagnostiques disponibles et discutons de la prise en charge, y compris pour les patients nécessitant la poursuite de l'administration des médicaments biologiques.

[Management of allergic rhinitis in general practitioner's office]. / Prise en charge de la rhinite allergique au cabinet du généraliste.

In Switzerland, almost 20 % of the population suffers from allergic rhinitis, which has a major impact on patients' quality of life. Allergen avoidance remains the most effective measure but is not always possible. Intranasal corticosteroids, oral antihistamines, or combination of intranasal corticosteroids and antihistamines remain first-line pharmacological treatments. In case of refractory symptoms, despite well-managed symptomatic treatment, when the patient wishes a more long-term effect or for prevention of asthma, the patient can be referred to the allergologist for specific immunotherapy. The specific immunotherapy is the only treatment option that targets the underlying pathophysiology of allergy and therefore shows disease-modifying effects.

En Suisse, près de 20 % de la population sont atteints de rhinite allergique et cette dernière impacte de manière importante la qualité de vie des patients. L'éviction des allergènes reste la mesure la plus efficace mais n'est pas toujours possible. Les corticostéroïdes intranasaux, les antihistaminiques per os, ainsi que les combinaisons de corticostéroïdes et d'antihistaminiques intranasaux demeurent les traitements pharmacologiques de première ligne. En cas de symptômes réfractaires, lorsque le patient souhaite un effet à long terme ou dans un contexte de prévention de l'asthme, il peut être référé chez l'allergologue pour une immunothérapie spécifique. C'est la seule option thérapeutique ciblant la physiopathologie sous-jacente de l'allergie et avec un effet modificateur sur la maladie.

[Urticaria : updates of a chronic condition]. / Urticaire : nouveautés et chronicité.

Urticaria is a frequent disease and exist in an acute or chronic form. The pathophysiology, focused on mast cells and histamine among other mediators, is an active research field but still poorly understood. The medical care focus on the avoidance of triggers and aggravating factors. The recommended drug therapy has not changed. The acknowledgment of chronic urticaria as a chronic disease is essential according to the last international recommendations. Acknowledging the disease morbidity and consequences, in a private, social or professional environment, allows better medical care for patients. The latter should get support on the long term, thanks to multiple diagnostic and therapeutic guidance tools.

L'urticaire est une maladie fréquente pouvant être aiguë ou chronique. Sa physiopathologie, centrée sur les mastocytes et de multiples médiateurs dont l'histamine, fait l'objet de nombreuses recherches mais reste encore mal connue. La prise en charge se concentre sur l'éviction des facteurs déclencheurs et aggravants. Les traitements médicamenteux recommandés n'ont pas changé. La reconnaissance de l'urticaire chronique en tant que maladie chronique est centrale dans les dernières recommandations internationales. La reconnaissance de la morbidité et des conséquences de la maladie, dans les cadres privé, social ou professionnel, permet une meilleure prise en charge des patient-es. Ces dernier-ères devront être accompagné-e-s sur le long terme, grâce à plusieurs outils diagnostiques et d'accompagnement thérapeutique.

[Allergology: what's new in 2022]. / Allergologie : ce qui a changé en 2022.

The study of reactions to SARS-CoV-2 vaccines has marked a large part of the literature in the last two years, using the basophil activation test (BAT) as a potential diagnostic tool for reactions to Covid-19 vaccines. In allergic rhinoconjunctivitis, lirentelimab (a humanised monoclonal antibody against lectin 8), reduces patients' symptoms and atopic comorbidities. In severe asthma, tezepelumab (human monoclonal antibody) reduces the annual asthma exacerbation rate over 52 weeks. In terms of diet, the new EAACI guidelines recommend avoiding cow's milk supplementation in infants during the first three days of life to reduce the risk of cow's milk allergy.

L'étude des réactions aux vaccins contre le SARS-CoV-2 a marqué une grande partie des publications de ces deux dernières années, en utilisant le test d'activation de basophiles (BAT) comme outil de diagnostic potentiel pour les réactions aux vaccins contre le Covid-19. Sur le plan de la rhinoconjonctivite allergique, le lirentélimab (anticorps monoclonal humanisé contre la lectine 8) diminue les symptômes des patients et ses comorbidités atopiques. Sur le plan de l'asthme sévère, le tézépélumab (anticorps monoclonal humain) en diminue le taux d'exacerbations annuelles sur 52 semaines. Sur le plan alimentaire, les nouvelles directives EAACI (Académie européenne d'allergie et d'immunologie clinique) recommandent d'éviter la supplémentation en lait de vache chez les nourrissons au cours des 3 premiers jours de vie pour en diminuer le risque d'allergie.

Intradermal Testing With COVID-19 mRNA Vaccines Predicts Tolerance.

Background: The newly developed mRNA-based COVID-19 vaccines can provoke anaphylaxis, possibly induced by polyethylene glycol (PEG) contained in the vaccine. The management of persons with a history of PEG allergy or with a suspected allergic reaction after the first dose remains to be defined. Methods: In this real-life study, we defined two cohorts of individuals: one pre-vaccination including 187 individuals with high-risk profiles for developing anaphylaxis and a second post-vaccination including 87 individuals with suspected allergic reactions after the COVID-19 mRNA vaccine. Upon negative skin test with an mRNA vaccine, a two-step (10-90%) vaccination protocol was performed. Positive skin tests were confirmed with the basophil activation test (BAT). Results: Among 604,267 doses of vaccine, 87 suspected allergic reactions (5 after the booster) were reported to our division for further investigations: 18/87 (21%) were consistent with anaphylaxis, 78/87 (90%) were female, and 47/87 (54%) received the BNT162b2 mRNA vaccine. Vaccine skin tests were negative in 96% and 76% of the pre- and post-vaccination cohorts, respectively. A two-step vaccination was tolerated in 232/236 (98%) of individuals with negative tests. Four individuals experienced isolated asthmatic reactions during the two-step challenge. Vaccine-positive skin tests were consistently confirmed by BAT; CD63 and CD203c expression was selectively inhibited with ibrutinib, suggesting an IgE-dependent mechanism. Conclusion: Sensitization to SARS-CoV-2 mRNA vaccines can be detected with intradermal testing. Significantly more individuals were sensitized to mRNA vaccines in the post-vaccination cohort. A two-step 10-90%-vaccination protocol can be safely administered upon negative skin testing.

Atopy as an independent predictor for long-term patient and graft survival after kidney transplantation.

Background: Atopy is a genetic condition predisposing individuals to develop immunoglobulin E (IgE) against common allergens through T-helper 2 (Th2) polarization mechanisms. The impact of atopy on graft survival in solid organ transplantation is unknown. Methodology: We analyzed 268 renal allograft recipients from the Swiss Transplant Cohort Study, a prospective multicenter cohort studying patients after solid organ transplantation, with a 9-year median follow-up (IQR 3.0). We used the Phadiatop assay to measure IgE antibodies against a mixture of common inhaled allergens (grass, tree, herbs, spores, animals, and mites) to identify pre-transplantation atopic patients (>0.35 KU/L). Results: Of 268 kidney transplant recipients, 66 individuals were atopic (24.6%). Atopic patients were significantly younger than non-atopic patients (49.6 vs 58.0 years old, P = 0.002). No significant difference was found for gender, cold/warm ischemia time, preformed donor-specific antibodies (DSA), HLA mismatches, induction and maintenance immunosuppressive therapy, CMV serostatus, or cause of kidney failure. Patient and graft survival at ten years of follow-up were significantly better in the atopic group, 95.2% versus 69.2% patient survival (P < 0.001), and 87.9% versus 60.8% graft survival (P < 0.001), respectively. A multivariate Cox analysis revealed that atopy predicted recipient and graft survival independently of age and living donor donation. Finally, we found similar rates of biopsy-proven acute cellular and antibody-mediated rejections between atopic and non-atopic recipients. Conclusion: Atopy was associated with better long-term patient and graft survival, independently of age and living donor donation after kidney transplantation. Yet, atopy should not be used as a predictor for acute rejection.

[A first-line guide to the evaluation of « Penicillin Allergy ¼ in general medical practice]. / Proposition de prise en charge de l'« allergie à la pénicilline ¼ en médecine interne et de premier recours.

« Penicillin allergy ¼ is a common finding in patient's medical files (up to 10 %). Although it is important not to neglect such records (due to the serious and life-threatening reactions an allergic patient may suffer from), most of the time these reported notions of allergy are wrong and lead to the unfortunate avoidance of all betalactamins. This in turn leads to increased risks of antibiotic resistance and increased health costs. This review aims to summarize the current knowledge on penicillin allergy epidemiologic data and proposes a first-line guide for general practitioners to the evaluation of the patient with a history of « penicillin allergy ¼.

La « notion d'allergie à la pénicilline ¼ dans les dossiers des patients est une trouvaille assez fréquente (jusqu'à 10 %) et généralement erronée. Cette dernière peut mener à une sous-utilisation des bêtalactamines avec des conséquences négatives sur l'émergence de germes résistants, la prise en charge et les coûts médicaux. D'un autre côté, il s'agit néanmoins d'un diagnostic à ne pas ignorer ni à banaliser (notamment devant une anamnèse incomplète) étant donné la sévérité des réactions qu'une exposition pourrait occasionner. Cet article propose un résumé des connaissances actuelles des données épidémiologiques sur le sujet, et un algorithme de prise en charge en première intention des « notions d'allergie à la pénicilline ¼.

Management of allergy transfer upon solid organ transplantation.

Allergy transfer upon solid organ transplantation has been reported in the literature, although only few data are available as to the frequency, significance, and management of these cases. Based on a review of 577 consecutive deceased donors from the Swisstransplant Donor-Registry, 3 cases (0.5%) of fatal anaphylaxis were identified, 2 because of peanut and 1 of wasp allergy. The sera of all 3 donors and their 10 paired recipients, prospectively collected before and after transplantation for the Swiss Transplant Cohort Study, were retrospectively processed using a commercial protein microarray fluorescent test. As early as 5 days posttransplantation, newly acquired peanut-specific IgE were transiently detected from 1 donor to 3 recipients, of whom 1 liver and lung recipients developed grade III anaphylaxis. Yet, to define how allergy testing should be performed in transplant recipients and to better understand the impact of immunosuppressive therapy on IgE sensitization, we prospectively studied 5 atopic living-donor kidney recipients. All pollen-specific IgE and >90% of skin prick tests remained positive 7 days and 3 months after transplantation, indicating that early diagnosis of donor-derived IgE sensitization is possible. Importantly, we propose recommendations with respect to safety for recipients undergoing solid-organ transplantation from donors with a history of fatal anaphylaxis.

[The efficacy of omalizumab in the treatment of chronic rhinosinusitis with nasal polyps: a discussion of 2 refractory cases]. / Efficacité de l'omalizumab dans la polypose nasale: à propos de deux cas.

Nasal polyposis is a specific phenotype of chronic rhinosinusitis (CRS). Some cases can be managed with topical and infrequent use of systemic steroids, while many patients require surgery. Despite postoperative, regular steroid administration, recurrences may be found especially in patients suffering from Aspirin exacerbated respiratory disease (AERD), a particularly severe form of CRS with polyps, asthma and non-steroid-anti-inflammatory-drug (NSAID) intolerance. We report two cases of difficult-to-treat AERD patients following revision surgery, treated with monoclonal anti-IgE antibody (omalizumab) and successful control of the disease and symptoms. Omalizumab may be a promising alternative in selected cases of CRS with nasal polyps to avoid overuse of systemic steroids and frustrating repetition of paranasal sinus surgeries.

La rhinosinusite chronique (RSC) touche 15 % de la population et se caractérise par l'obstruction et l'écoulement nasaux pendant plus de trois mois. Les formes sévères de la RSC sont associées à la présence de polypes nasaux. Le traitement de première ligne sont des corticoïdes topiques, qui ne sont pas toujours efficaces et certains patients ont besoin de plusieurs cures de stéroïdes per os et chirurgies nasales répétitives pour stabiliser la maladie. Ce cercle vicieux s'observe souvent dans le syndrome de Widal (polypes, asthme et intolérance aux AINS). On rapporte deux cas de Widal avec interruption de cette boucle, obtenue par l'application de l'anticorps monoclonal anti-IgE omalizumab. L'omalizumab pourrait être une alternative dans certains cas de RSC pour limiter la surutilisation de stéroïdes et la répétition frustrante de chirurgie nasale.

[Allergology and clinical immunology]. / Allergologie et immunologie clinique.

Hereditary angioedema (HA) is a disabling and potentially fatal condition. The management of HA includes treatment of acute attacks, short-term prophylaxis to prevent an attack, and long-term prophylaxis to minimize the frequency and severity of recurrent attacks. In this article, we will present new therapeutic alternatives for long term prophylaxis. Glucocorticoids (GC) usage leads to a number of severe side-effects. In giant cell arteritis, the use of tocilizumab in conjunction with low doses of GC reduces the number of relapses. In ANCA-associated vasculitis the use of an anti-C5R (avacopan) alone or in conjunction with low doses of GC results in similar remission rates to those induced by high dose GC.

L'angiœdème héréditaire (AH) est une maladie invalidante et potentiellement mortelle. La prise en charge de l'AH comprend le traitement des crises aiguës, la prophylaxie à court terme pour prévenir une attaque et la prophylaxie à long terme pour minimiser la fréquence et la gravité des crises récurrentes. Nous discutons les nouvelles alternatives thérapeutiques pour la prophylaxie à long terme. L'utilisation des glucocorticoïdes (GC) est grevée d'effets secondaires multiples et graves. Dans l'artérite gigantocellulaire l'adjonction d'un anti-IL6 à des doses faibles de GC a permis de réduire le nombre de rechutes. Dans les vascularites à ANCA, un anti-C5R (avacopan) a permis de réduire la quantité de GC nécessaire pour atteindrela rémission.

Current Perspectives on Erythema Multiforme.

Recognition and timely adequate treatment of erythema multiforme remain a major challenge. In this review, current diagnostic guidelines, potential pitfalls, and modern/novel treatment options are summarized with the aim to help clinicians with diagnostic and therapeutic decision-making. The diagnosis of erythema multiforme, that has an acute, self-limiting course, is based on its typical clinical picture of targetoid erythematous lesions with predominant acral localization as well as histological findings. Clinically, erythema multiforme can be differentiated into isolated cutaneous and combined mucocutaneous forms. Atypical erythema multiforme manifestations include lichenoid or granulomatous lesions as well as lesional infiltrates of T cell lymphoma and histiocytes. Herpes simplex virus infection being the most common cause, other infectious agents like-especially in children-Mycoplasma pneumoniae, hepatitis C virus, Coxsackie virus, and Epstein Barr virus may also trigger erythema multiforme. The second most frequently identified cause of erythema multiforme is drugs. In different studies, e.g., allopurinol, phenobarbital, phenytoin, valproic acid, antibacterial sulfonamides, penicillins, erythromycin, nitrofurantoin, tetracyclines, chlormezanone, acetylsalicylic acid, statins, as well as different TNF-α inhibitors such as adalimumab, infliximab, and etanercept were reported as possible implicated drugs. Recently, cases of erythema multiforme associated with vaccination, immunotherapy for melanoma, and even with topical drugs like imiquimod have been described. In patients with recurrent herpes simplex virus-associated erythema multiforme, the topical prophylactic treatment with acyclovir does not seem to prevent further episodes of erythema multiforme. In case of resistance to one virostatic drug, the switch to an alternative drug, and in patients non-responsive to virostatic agents, the use of dapsone as well as new treatment options, e.g., JAK-inhibitors or apremilast, might be considered.

Current Perspectives on Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are considered a delayed-type hypersensitivity reaction to drugs. They represent true medical emergencies and an early recognition and appropriate management is decisive for the survival. SJS/TEN manifest with an "influenza-like" prodromal phase (malaise, fever), followed by painful cutaneous and mucous membrane (ocular, oral, and genital) lesions, and other systemic symptoms. The difference between SJS, SJS/TEN overlap, and TEN is defined by the degree of skin detachment: SJS is defined as skin involvement of < 10%, TEN is defined as skin involvement of > 30%, and SJS/TEN overlap as 10-30% skin involvement. The diagnosis of different degrees of epidermal necrolysis is based on the clinical assessment in conjunction with the corresponding histopathology. The mortality rates for SJS and TEN have decreased in the last decades. Today, the severity-of-illness score for toxic epidermal necrolysis (SCORTEN) is available for SJS/TEN severity assessment. Drugs with a high risk of causing SJS/TEN are anti-infective sulfonamides, anti-epileptic drugs, non-steroidal anti-inflammatory drugs of the oxicam type, allopurinol, nevirapine, and chlormezanone. Besides conventional drugs, herbal remedies and new biologicals should be considered as causative agents. The increased risk of hypersensitivity reactions to certain drugs may be linked to specific HLA antigens. Our understanding of the pathogenesis of SJS/TEN has improved: drug-specific T cell-mediated cytotoxicity, genetic linkage with HLA- and non-HLA-genes, TCR restriction, and cytotoxicity mechanisms were clarified. However, many factors contributing to epidermal necrolysis still have to be identified, especially in virus-induced and autoimmune forms of epidermal necrolysis not related to drugs. In SJS/TEN, the most common complications are ocular, cutaneous, or renal. Nasopharyngeal, esophageal, and genital mucosal involvement with blisters, erosions as well as secondary development of strictures also play a role. However, in the acute phase, septicemia is a leading cause of morbidity and fatality. Pulmonary and hepatic involvement is frequent. The acute management of SJS/TEN requires a multidisciplinary approach. Immediate withdrawal of potentially causative drugs is mandatory. Prompt referral to an appropriate medical center for specific supportive treatment is of utmost importance. The most frequently used treatments for SJS/TEN are systemic corticosteroids, immunoglobulins, and cyclosporine A.

Reclassifying Anaphylaxis to Neuromuscular Blocking Agents Based on the Presumed Patho-Mechanism: IgE-Mediated, Pharmacological Adverse Reaction or "Innate Hypersensitivity"?

Approximately 60% of perioperative anaphylactic reactions are thought to be immunoglobulin IgE mediated, whereas 40% are thought to be non-IgE mediated hypersensitivity reactions (both considered non-dose-related type B adverse drug reactions). In both cases, symptoms are elicited by mast cell degranulation. Also, pharmacological reactions to drugs (type A, dose-related) may sometimes mimic symptoms triggered by mast cell degranulation. In case of hypotension, bronchospasm, or urticarial rash due to mast cell degranulation, identification of the responsible mechanism is complicated. However, determination of the type of the underlying adverse drug reaction is of paramount interest for the decision of whether the culprit drug may be re-administered. Neuromuscular blocking agents (NMBA) are among the most frequent cause of perioperative anaphylaxis. Recently, it has been shown that NMBA may activate mast cells independently from IgE antibodies via the human Mas-related G-protein-coupled receptor member X2 (MRGPRX2). In light of this new insight into the patho-mechanism of pseudo-allergic adverse drug reactions, in which as drug-receptor interaction results in anaphylaxis like symptoms, we critically reviewed the literature on NMBA-induced perioperative anaphylaxis. We challenge the dogma that NMBA mainly cause IgE-mediated anaphylaxis via an IgE-mediated mechanism, which is based on studies that consider positive skin test to be specific for IgE-mediated hypersensitivity. Finally, we discuss the question whether MRGPRX2 mediated pseudo-allergic reactions should be re-classified as type A adverse reactions.

Hereditary haemorrhagic telangiectasia: to transplant or not to transplant - is there a right time for liver transplantation?

BACKGROUND & AIMS: Hereditary haemorrhagic telangiectasia is characterized by arterio-venous malformations (AVM). It frequently involves the liver without clinical symptoms, but may lead to biliary ischaemia, portal hypertension, or fatal high-output heart failure. The indication of liver transplantation is controversial. METHODS: Herein, we report the case of a 65-year-old female patient with a 'double Osler syndrome' consisting of hereditary haemorrhagic telangiectasia (HHT) and type I hereditary angioedema diagnosed at the age of 25 and 22 years respectively. RESULTS: Hereditary angioedema was treated with danazol for several decades until multiple hypoechogenic liver masses were detected. Albeit danazol treatment was replaced by C1 esterase inhibitor infusions, hepatocellular carcinoma was diagnosed at the age of 64 and the patient was listed for liver transplantation. HHT was marked by recurrent epistaxis until the age of 63 when severe intestinal bleeding occurred. At the age of 65, severe dyspnoea (NYHA class IV) developed and rapidly progressive high-output cardiac failure was diagnosed. Despite argon plasma coagulation to control bleeding from intestinal angiodysplasia, and treatment with bevacizumab to inhibit angiogenesis, the patient died from severe gastrointestinal bleeding associated with cardiogenic shock at the age of 66 before being transplanted. CONCLUSION: The indication to list this patient for liver transplantation was debated several times before the diagnosis of hepatocellular carcinoma because of good general condition and low MELD score. Precise guidelines for screening and management of patients with hepatic HHT need to be better defined.