A. Didier

Drugs and other agents involved in anaphylactic shock occurring during anaesthesia. A French multicenter epidemiological inquiry

An epidemiological inquiry was carried out in departments of anaesthesia and immunology in French University and General Hospitals, as well as among those who were already known to have an allergo-anaesthesia outpatient clinic. This inquiry aimed to find out how many patients had undergone diagnostic investigations after as well as an anaphylactoid reaction during an anaesthetic in 1990 and 1991, as well as the demographic data, the kind of assessment, the accident mechanism and the drugs involved. Twenty-one French centres replied to the questionnaire and a series of 1,585 patients tested over a two-year period was thus collected. There were three female patients to one male. The reactions occurred mostly in the adult (80%), but 9% were observed in children. Allergological tests for IgE-dependent anaphylaxis were the skin tests (21 centres), combined with radioimmunological assays of specific serum antibodies to muscle relaxants (10 centres), propofol (9 centres), latex (5 centres), leukocyte histamine release (9 centres) and human basophil degranulation test (4 centres). The criteria for a positive result were the same for all centres. Among these 1,585 patients, 813 were recognized as having had a reaction of immunological origin (52%). The substances involved were identified in these 813 patients as being muscle relaxants (70%), latex (12.6%), hypnotics (3.6%), benzodiazepines (2.0%), opioids (1.7%), colloids (4.7%), and antibiotics (2.6%). Suxamethonium was responsible for 43% of the IgE-dependent reactions involving a muscle relaxant, vecuronium for 37%, pancuronium for 13%, alcuronium for 7.6%, atracurium for 6.8% and gallamine for 5.6%.(ABSTRACT TRUNCATED AT 250 WORDS)

A Proof-of-Concept, Randomized, Controlled Trial of Omalizumab in Patients With Severe, Difficult-to-Control, Nonatopic Asthma

BACKGROUND While up to 50% of patients with severe asthma have no evidence of allergy, IgE has been linked to asthma, irrespective of atopic status. Omalizumab, an anti-IgE monoclonal antibody, is reported to significantly benefit a subset of patients with severe, persistent, allergic asthma. Therefore, we investigated whether omalizumab has biologic and clinical effects in patients with refractory nonatopic asthma. METHODS Forty-one adult patients who, despite daily treatment with or without maintenance oral corticosteroids, had severe, nonatopic, refractory asthma according to GINA (Global Initiative for Asthma) step 4, were randomized to receive omalizumab or placebo in a 1:1 ratio. The primary end point was the change in expression of high-affinity IgE receptor (FcεRI) on blood basophils and plasmacytoid dendritic cells (pDC2) after 16 weeks. The impact of omalizumab on lung function and clinical variables was also examined. RESULTS Compared with placebo, omalizumab resulted in a statistically significant reduction in FcεRI expression on basophils and pDC2 (P < .001). The omalizumab group also showed an overall increase in FEV1 compared with baseline (+250 mL, P = .032; +9.9%, P = .029). A trend toward improvement in global evaluation of treatment effectiveness and asthma exacerbation rate was also observed. CONCLUSIONS Omalizumab negatively regulates FcεRI expression in patients with severe nonatopic asthma, as it does in severe atopic asthma. Omalizumab may have a therapeutic role in severe nonatopic asthma. Nonetheless, our preliminary findings support further investigation to better assess the clinical efficacy of omalizumab. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT01007149; URL: www.clinicaltrials.gov and European Clinical Trials Database, EudraCT; No.: 2009-010937-38; URL: https://www.clinicaltrialsregister.eu.

EAACI: A European Declaration on Immunotherapy. Designing the future of allergen specific immunotherapy

Allergy today is a public health concern of pandemic proportions, affecting more than 150 million people in Europe alone. In view of epidemiological trends, the European Academy of Allergy and Clinical Immunology (EAACI) predicts that within the next few decades, more than half of the European population may at some point in their lives experience some type of allergy.Not only do allergic patients suffer from a debilitating disease, with the potential for major impact on their quality of life, career progression, personal development and lifestyle choices, but they also constitute a significant burden on health economics and macroeconomics due to the days of lost productivity and underperformance. Given that allergy triggers, including urbanization, industrialization, pollution and climate change, are not expected to change in the foreseeable future, it is imperative that steps are taken to develop, strengthen and optimize preventive and treatment strategies.Allergen specific immunotherapy is the only currently available medical intervention that has the potential to affect the natural course of the disease. Years of basic science research, clinical trials, and systematic reviews and meta-analyses have convincingly shown that allergen specific immunotherapy can achieve substantial results for patients, improving the allergic individuals’ quality of life, reducing the long-term costs and burden of allergies, and changing the course of the disease. Allergen specific immunotherapy not only effectively alleviates allergy symptoms, but it has a long-term effect after conclusion of the treatment and can prevent the progression of allergic diseases.Unfortunately, allergen specific immunotherapy has not yet received adequate attention from European institutions, including research funding bodies, even though this could be a most rewarding field in terms of return on investments, translational value and European integration and, a field in which Europe is recognized as a worldwide leader. Evaluation and surveillance of the full cost of allergic diseases is still lacking and further progress is being stifled by the variety of health systems across Europe. This means that the general population remains unaware of the potential use of allergen specific immunotherapy and its potential benefits.We call upon Europe’s policy-makers to coordinate actions and improve individual and public health in allergy by: Promoting awareness of the effectiveness of allergen specific immunotherapyUpdating national healthcare policies to support allergen specific immunotherapyPrioritising funding for allergen specific immunotherapy researchMonitoring the macroeconomic and health economic parameters of allergyReinforcing allergy teaching in medical disciplines and specialtiesThe effective implementation of the above policies has the potential for a major positive impact on European health and well-being in the next decade.

Update on the roles of distal airways in asthma.

The present review is the summary of an expert workshop that took place in Vence (France) in 2007 on the role of distal airways in asthma. The evidence showing inflammation and remodelling in distal airways, and their possible involvement in asthma control and natural history, was reviewed. The usefulness and limitations of various techniques used for assessing distal airways were also evaluated, including pulmonary function tests and imaging. Finally, the available data studying the benefit of treatment better targeting distal airways in asthma was examined. It was concluded that both proximal and distal airways were involved in asthma and that distal airways were the major determinant of airflow obstruction. Inflammation in distal airways appeared more intense in severe and uncontrolled asthma. Distal airways were poorly attained by conventional aerosol of asthma medications owing to their granulometry, being composed of 3–5 μm particles. Both proximal and distal airways might be targeted either by delivering medications systemically or by aerosol of extra-fine particles. Extra-fine aerosols of long-acting β-agonists, inhaled corticosteroids or inhaled corticosteroid/long-acting β-agonist combinations have been shown in short-term studies to be not inferior to non-extra-fine aerosols of comparators. However, available studies have not yet demonstrated that extra-fine inhaled medications offer increased benefit compared with usual aerosols in asthmatic patients.

Update on the roles of distal airways in COPD

This review is the summary of a workshop on the role of distal airways in chronic obstructive pulmonary disease (COPD), which took place in 2009 in Vence, France. The evidence showing inflammation and remodelling in distal airways and the possible involvement of these in the pathobiology, physiology, clinical manifestations and natural history of COPD were examined. The usefulness and limitations of physiological tests and imaging techniques for assessing distal airways abnormalities were evaluated. Ex vivo studies in isolated lungs and invasive measurements of airway resistance in living individuals have revealed that distal airways represent the main site of airflow limitation in COPD. Structural changes in small conducting airways, including increased wall thickness and obstruction by muco-inflammatory exudates, and emphysema (resulting in premature airway closure), were important determinants of airflow limitation. Infiltration of small conducting airways by phagocytes (macrophages and neutrophils), dendritic cells and T and B lymphocytes increased with airflow limitation. Distal airways abnormalities were associated with patient-related outcomes (e.g. dyspnoea and reduced health-related quality of life) and with the natural history of the disease, as reflected by lung function decline and mortality. These data provide a clear rationale for targeting distal airways in COPD.

Immediate- and delayed-type allergic reactions to amide local anesthetics: clinical features and skin testing†

Amide type local anesthetic agents are among the most commonly used drugs in medicine. Several adverse drug reactions (ADRs) have been previously described with their use. Among them, allergic reactions are considered rare. The aim of this study was to describe the main characteristics of ADRs induced by amide type local anesthetic drugs.

Mild asthma: an expert review on epidemiology, clinical characteristics and treatment recommendations

This review is the synthesis of a working group on mild asthma. Mild asthma includes intermittent and persistent mild asthma according to the Global Initiative for Asthma (GINA) classification, and affects between 50% and 75% of asthmatic patients. Mild asthma is more frequent, more symptomatic, and less well controlled in children than in adults. Cohort studies from childhood to adulthood show that asthma severity usually remains stable over time. Nevertheless, mild asthma can lead to severe exacerbations, with a frequency ranging from 0.12 to 0.77 per patient‐year. Severe exacerbations in mild asthma represent 30–40% of asthma exacerbations requiring emergency consultation. In mild asthma, inflammation and structural remodelling are constant, of varying intensity, but nonspecific. Therapy with inhaled corticosteroids (ICS) decreases bronchial inflammation, but has only a slight effect on structural remodelling, and, when stopped, inflammation immediately recurs. Permanent low‐dose ICS therapy is the reference treatment for persistent mild asthma. Effectiveness is to be reassessed at 3 months, and if it is insufficient the patient is no longer considered mildly asthmatic, and treatment has to be stepped up. As mild asthma is the most frequent form of the disease, diagnosis and management require physicians’ particular attention.

Limited operation for severe multisegmental bilateral bronchiectasis

BACKGROUND Some patients exhibiting severe multisegmental bilateral bronchiectasis are no longer improved with antibiotic treatment and drainage and, most of the time, operation is contraindicated. In our institution, limited operation has been offered to select patients for this indication. We report our data regarding the feasibility and utility of such a procedure. METHODS We studied 16 patients who underwent surgical removal of nonlocalized disease between 1990 and 1999. We report the mortality and morbidity rates of this surgical procedure and the clinical, bacteriological, and functional data for each patient. RESULTS There was no mortality and the morbidity was low (18%, all with favorable outcome). Symptoms such as hemoptysis, sputum production, or dyspnea were also improved. The recurring infections decreased in frequency in 8 patients and disappeared completely in 5 others. The bacteriological data assessment revealed disappearance of germs in 4 patients and persistence of chronic colonization in others. Postoperative spirometric data were not worsened and postoperative computed tomographic scans did not show progression of lesions not removed. CONCLUSIONS These results suggest that, in properly selected patients, lasting symptomatic improvement can be achieved by resection. Limited operation may be indicated in nonlocalized bilateral bronchiectasis, provided that a target can be identified. This procedure is supported by physiopathologic arguments and is particularly relevant to patients with bronchiectasis with cystic and functionless territories.

Alternative processing of the U2 small nuclear RNA produces a 19-22nt fragment with relevance for the detection of non-small cell lung cancer in human serum.

RNU2 exists in two functional forms (RNU2-1 and RNU2-2) distinguishable by the presence of a unique 4-bases motif. Detailed investigation of datasets obtained from deep sequencing of five human lung primary tumors revealed that both forms express at a high rate a 19–22nt fragment (miR-U2-1 and -2) from its 3′ region and contains the 4-bases motif. Deep sequencing of independent pools of serum samples from healthy donors and lung cancer patients revealed that miR-U2-1 and -2 are pervasively processed in lung tissue by means of endonucleolytic cleavages and stably exported to the blood. Then, microarrays hybridization experiments of matched normal/tumor samples revealed a significant over-expression of miR-U2-1 in 14 of 18 lung primary tumors. Subsequently, qRT-PCR of miR-U2-1 using serum from 62 lung cancer patients and 96 various controls demonstrated that its expression levels identify lung cancer patients with 79% sensitivity and 80% specificity. miR-U2-1 expression correlated with the presence or absence of lung cancer in patients with chronic obstructive pulmonary disease (COPD), other diseases of the lung – not cancer, and in healthy controls. These data suggest that RNU2-1 is a new bi-functional ncRNA that produces a 19–22nt fragment which may be useful in detecting lung cancer non-invasively in high risk patients.

Safety and tolerability of 5-grass pollen tablet sublingual immunotherapy: pooled analysis and clinical review

Introduction: The 5-grass pollen tablet (Oralair®, Stallergenes, Antony, France) is a once-daily preseasonal and coseasonal sublingual immunotherapy (SLIT) that is effective in controlling the symptoms of allergic rhinoconjunctivitis and in reducing the need for symptomatic medication. Areas covered: The body of safety data gathered from the 5-grass pollen tablet clinical development program, post-approval studies, and more than 6 years of real-life experience demonstrates the safety and tolerability profile of the 5-grass pollen tablet across all age groups. Adverse events (AEs) are generally mild or moderate in severity, and rarely lead to treatment discontinuation. AEs also tend to decline in frequency and severity over time and with repeated treatment. The most frequent treatment-emergent AEs are local-site oropharyngeal reactions (e.g., oral pruritus, throat irritation, tongue pruritus, mouth edema, ear pruritus), which are consistent with the sublingual route of administration. Expert opinion: The first dose of the 5-grass pollen tablet should be administered under the supervision of an experienced physician, to allow for optimal monitoring and timely management of AEs, should they occur. The 5-grass pollen tablet can be administered at home after the first dose, and patients and carers should be educated on how to manage adverse reactions, unplanned treatment interruptions and situations in which SLIT should be withheld.