[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.

[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.

[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.

[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.

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.

[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.

[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.

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.

Non-IgE-Dependent Hypersensitivity to Rocuronium Reversed by Sugammadex: Report of Three Cases and Hypothesis on the Underlying Mechanism.

We present 3 cases of pseudoallergic (anaphylactoid) reactions to perioperatively administered rocuronium, which rapidly resolved after sugammadex injection. Allergological workup showed no evidence for immediate-type hypersensitivity to the drugs used for anesthesia, including rocuronium. However, rocuronium induced an irritative reaction in skin tests in all 3 patients and in 3 healthy individuals. This reaction was specifically suppressed by adding sugammadex at a 1:1 molecular proportion to rocuronium before the skin tests. This observation suggests that the patients suffered from a pseudoallergic reaction, and indicates that sugammadex might act via the inhibition of non-IgE mediated MRGPRX2 (Mas-related G-protein-coupled receptor member X2)-triggered mast cell degranulation induced by rocuronium.

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.

Immunoglobulin deficiency in patients with chronic rhinosinusitis: Systematic review of the literature and meta-analysis.

BACKGROUND: Several studies have shown a high prevalence of immunoglobulin deficiencies in patients with chronic rhinosinusitis (CRS). OBJECTIVE: We sought to perform a systematic review and meta-analysis to estimate this prevalence more precisely and to identify patients who need substitution treatment. METHODS: All case series published after 1990 describing patients with CRS, which was defined as symptomatic rhinosinusitis for more than 12 weeks and documented immunoglobulin deficiencies (including deficiencies of IgG with subclasses, IgA, and IgM; specific antibody deficiencies; and potential common variable immunodeficiency), were retrieved. A meta-analysis of the proportion of any combination of common variable immunodeficiency, IgG deficiency, IgA deficiency, and IgM deficiency in patients with CRS was performed by using logit transformation of the prevalence. Recurrent CRS was defined as rhinosinusitis not controlled by appropriate conservative management for 4 months, and difficult-to-treat CRS was defined as noncontrollable rhinosinusitis despite successful sinus surgery and appropriate conservative management for at least 1 year. RESULTS: The meta-analysis revealed a prevalence of pooled IgG, IgA, and IgM deficiencies in 13% of patients with recurrent CRS and 23% of patients with difficult-to-treat CRS. The prevalence of IgG subclass deficiency (5% to 50%) and specific antibody deficiency (8% to 34%) was increased in patients with CRS, as was the prevalence of respiratory allergies in patients with recurrent CRS (31% to 72%). CONCLUSION: Immunoglobulin deficiency is a frequent condition in patients with CRS. An even higher prevalence of atopy was observed in patients with recurrent CRS. Therefore immunoglobulin titers and accurate allergy diagnostic workups are strongly recommended in these patients to provide specific treatments for symptom alleviation. However, there is a need for larger prospective studies addressing the effect of specific therapeutic interventions for CRS.

[Treatment of drugs-associated non-hereditary angioedema mediated by bradykinin]. / Allergologie. Traitement de l'angiœdème à bradykinine non héréditaire d'origine médicamenteuse.

Angioedema is a deep intradermal or sub-cutaneous edema, which can be mediated by histamine, bradykinin or mixture of both components. The aims of this review are to describe the clinical approach and diagnosis of non-hereditary bradykinin-mediated angioedema induced by drugs such as: angiotensin-converting inhibitor, sartan, gliptins, rapamycin or some thrombolytic reagents and renin inhibitors. Furthermore, we will discuss the drug management of these angioedema, which is mainly based on C1 inhibitor concentrate or icatibant administration.

[Benefits of gluten-free diet: myth or reality?]. / Benfaits du régime sans gluten: mythe ou réalité?

Non celiac gluten sensitivity may explain digestive and general symptoms in patients without celiac disease but this recently described entity is controversial. The role of gluten in comparison to other nutriments such as saccharides and polyols (FODMAPs) remains debated. If a gluten-free diet is clearly indicated in celiac disease and wheat allergy, it remains debatable in non-celiac gluten sensitivity given weak and contradictory evidence. There is no strong evidence for a strict indication to a gluten-free diet in endocrinological, psychiatric, and rheumatologic diseases, or to improve performance in elite sports.

[Omalizumab in the treatment of chronic urticaria: what's new in 2013?]. / Allergologie. Omalizumab dans le traitement de l'urticaire chronique: quoi de neuf en 2013 ?

In 2013, new crucial data dealing with the treatment options for chronic idiopathic and physical urticaria have been published. In this article, after a short introduction where we discuss the classification and the pathogenesis of the disease, we will focus on the therapeutic approach in patients with chronic urticaria. In particular, considering the data available on the treatment with omalizumab, we will discuss the indications and treatment modalities of chronic urticaria.

[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.

T cell-mediated acute localized exanthematous pustulosis caused by finasteride.

A 21-year-old man presented with multiple erythematous nonfollicular papules partially confluent to plaques on his breast and lower abdomen that had been present for 1 month. Grouped pustules were present under the right breast. The patient had been taking finasteride over the past 3 months for androgenetic alopecia. His medical history was negative for psoriasis. Our initial differential diagnosis included dyskeratosis follicularis Darier, allergic contact dermatitis, infectious folliculitis, varicella zoster virus infection, fixed drug eruption, and IgA pemphigus. The white blood cell count and differential were within the normal limits. Results of viral cultures and PCR, as well as bacterial and fungal cultures of skin lesions proved negative. A lesional biopsy specimen showed a slight psoriasiform acanthosis in association with spongiosis and infiltration of both the epidermis and dermis by neutrophils and eosinophils, resulting in formation of subcorneal, intraepidermal, and subepidermal pustules. The results of direct immunofluorescence were negative, excluding an IgA pemphigus. The result of a lymphocyte transformation test was positive for finasteride. On the basis of the time relationship between the administration of finasteride and the development of the skin disease in combination with symptoms resolution on cessation of the drug, the histologic findings, and the positive lymphocyte transformation test result, we consider this to be an unusual type of acute generalized exanthematous pustulosis defined as acute localized exanthematous pustulosis caused by finasteride. Within 4 weeks after withdrawal of finasteride, the rash resolved without any specific therapy. Transient discrete residual hyperpigmentation and scaling were present. The patient refused an oral provocation challenge.