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International audience; BackgroundNeuromuscular blocking agents (NMBAs) are among the leading cause of perioperative anaphylaxis, and most of these reactions are IgE mediated. Allergic sensitisation induced by environmental exposure to other quaternary ammonium-containing compounds, such as pholcodine, has been suggested. The aim of this study was to assess the relationship between pholcodine exposure and NMBA-related anaphylaxis.MethodsALPHO was a multicentre case-control study, comparing pholcodine exposure within a year before anaesthesia between patients with NMBA-related perioperative anaphylaxis (cases) and control patients with uneventful anaesthesia in France. Each case was matched to two controls by age, sex, type of NMBA, geographic area, and season. Pholcodine exposure was assessed by a self-administered questionnaire and pharmaceutical history retrieved from pharmacy records. The diagnostic values of anti-pholcodine and anti-quaternary ammonium specific IgE (sIgE) were also evaluated.ResultsOverall, 167 cases were matched with 334 controls. NMBA-related anaphylaxis was significantly associated with pholcodine consumption (odds ratio 4.2; 95% confidence interval 2.3–7.0) and occupational exposure to quaternary ammonium compounds (odds ratio 6.1; 95% confidence interval 2.7–13.6), suggesting that apart from pholcodine, other environmental factors can also lead to sensitisation to NMBAs. Pholcodine and quaternary ammonium sIgEs had a high negative predictive value (99.9%) but a very low positive predictive value (

Difficult to control severe asthma is characterized by the persistence of inacceptable symptoms of asthma despite a continuous treatment with at least high doses of inhaled steroids and long acting bronchodilators. The diagnosis is done after a period of observation and some investigations that will allow confirm the diagnosis of asthma, eliminate alternative diagnosis and etiological forms that would be difficult to treat intrinsically (allergic broncho-pulmonary aspergillosis, Churg and Strauss disease, chronic eosinophilic pneumonia, occupational asthma). At the end of this period devoted to diagnosis a systematic approach is set up to take care of these patients. Therapeutic education includes action plans and measures for triggering factors avoidance in order to prevent exacerbations. Comorbidities such as rhinitis, nasal polyposis, gastro-oesophageal reflux and obesity are taken into account. Lastly, the treatment must be adapted according to the patient's preferences and aims, and to the asthma severity. Ultimately in steroid-dependent asthma, the lowest efficient dose is tracked continuously. For these patients, new molecules are needed.

Exacerbations of asthma are the main cause of asthma morbidity. They induce acute respiratory failure, and sometimes death. Two immunological signals acting in synergy are necessary for inducing asthma exacerbations. The first, triggered by allergens and/or unknown agents leads to the chronic Th2 inflammation characteristic of asthma. The second, caused by either viral infection, allergens, pollutants or a combination of these, results in an acute Th1 and Th2 inflammation precipitating symptoms. In both, innate and adaptive immunities are involved, providing a series of potential targets for therapy. Molecules associated to the first, chronic inflammation constitute targets for preventing therapies, when these related to the second, acute signal provide the rationale for curative treatments. Toll like receptors and bronchial epithelial cell-derived cytokines, engaged upstream of inflammation constitute interesting candidates for future treatments. The great heterogeneity of asthma has to be taken into account when considering targets for therapy to identify clusters of responders and nonresponders, and an integrative system biology approach will be necessary to go further.

Exacerbations represent a major clinical issue in asthma management, leading to hospitalizations, acute respiratory failure and sometimes death. They induce the main costs of asthma management in terms of care recourse and loss of working days. Their mechanisms must be carefully elucidated to design new drugs able to prevent them. Exacerbations are mainly caused by viral infection, and also allergen and pollutant exposure. These triggers induce exacerbations in asthmatic subjects already displaying a chronic bronchial inflammation caused itself by allergy, pollutants and/or perhaps infection. Exacerbations therefore result from two additive immunological signals. Both signals involve innate immunity via the activation of epithelial and dendritic cells. The first signal induces chronic epithelium damage and activation. By stimulating cytokine production and coreceptors expression by dendritic cells, it determines the type of inflammatory response leading to T cell activation and polymorphonuclear cells homing and activation. The second signal acutely enhances the chronic inflammation and eventually adds a distinct type of inflammation to the first chronic response. These mechanisms will be discussed in the context of the various triggers involved, both from an epidemiologic and immunologic point of view.

Summary Appeared at the beginning of the 20th century, allergen-specific immunotherapy (SIT) has long been used in allergic rhinitis and asthma without any knowledge of its mechanisms of action or any tangible proof of its efficacy. However, from the beginning of the era of evidence-based medicine, a number of placebo-controlled studies have been published and reached a sufficient number to assess the cellular events induced by SIT and allow meta-analysis to provide guidelines based on proofs. Controlled studies and meta-analysis concerned not only subcutaneous immunotherapy but also the sublingual route, demonstrating an effect of SIT on symptoms and medication use. Most recently sublingual tablets were proposed in allergic rhinitis. This paper reviews the mechanisms of SIT, the evidence of efficacy of SIT from the injective to the sublingual route and reminds the current guidelines.