Optimal step doses for drug provocation tests to prove beta-lactam hypersensitivity.

BACKGROUND: Drug provocation tests (DPT) are commonly performed as part of ß-lactam (BL) allergy workup, in case of negative skin tests (ST) and in the absence of contraindications. The recommendations of learned societies have created a frame for DPT performance, but protocols vary widely between centres, generating various hypothesis-driven protocols (i.e. empirical dosing, driven by both safety concerns and practical aspects). METHODS: The primary objective of this retrospective analysis was to detect eliciting dose thresholds (reactive doses) during BL DPT, using the survival analysis method, in order to suggest optimal step doses. Our secondary objective was to evaluate the safety of our 30-min incremental 1-day protocol. The study included all the patients explored in the Allergy Unit of the University Hospital of Montpellier (France), between September 1996 and July 2015 for a suspicion of drug hypersensitivity reaction to BLs, with negative ST and positive DPT. RESULTS: During the study period, 182 positive DPT (accounting for 171 hypersensitive patients) were analysed. We identified eliciting thresholds, and we suggest the following steps for DPT to BLs: 5-15-30-50% of daily therapeutic dose (with additional lower steps for index reactions of anaphylaxis). We confirm the safety of 1-day protocol for immediate and mild nonimmediate reactors, for both children and adults, with a surveillance period of 2 h after the last administered dose, and a prolonged surveillance after discharge of 48 h. CONCLUSION: This data-driven approach in designing DPT protocols is a step forward in improving DPT standardization, starting with the most frequently tested drugs, BL antibiotics.

Google Trends terms reporting rhinitis and related topics differ in European countries.

Google Trends (GT) searches trends of specific queries in Google and reflects the real-life epidemiology of allergic rhinitis. We compared Google Trends terms related to allergy and rhinitis in all European Union countries, Norway and Switzerland from 1 January 2011 to 20 December 2016. The aim was to assess whether the same terms could be used to report the seasonal variations of allergic diseases. Using the Google Trend 5-year graph, an annual and clear seasonality of queries was found in all countries apart from Cyprus, Estonia, Latvia, Lithuania and Malta. Different terms were found to demonstrate seasonality depending on the country - namely 'hay fever', 'allergy' and 'pollen' - showing cultural differences. A single set of terms cannot be used across all European countries, but allergy seasonality can be compared across Europe providing the above three terms are used. Using longitudinal data in different countries and multiple terms, we identified an awareness-related spike of searches (December 2016).

[Using cancer case identification algorithms in medico-administrative databases: Literature review and first results from the REDSIAM Tumors group based on breast, colon, and lung cancer]. / Recherche d'algorithmes d'identification des cancers dans les bases médico-administratives : premiers résultats des travaux du groupe REDSIAM Tumeurs sur les cancers du sein, du côlon-rectum et du poumon.

BACKGROUND: The development and use of healthcare databases accentuates the need for dedicated tools, including validated selection algorithms of cancer diseased patients. As part of the development of the French National Health Insurance System data network REDSIAM, the tumor taskforce established an inventory of national and internal published algorithms in the field of cancer. This work aims to facilitate the choice of a best-suited algorithm. METHOD: A non-systematic literature search was conducted for various cancers. Results are presented for lung, breast, colon, and rectum. Medline, Scopus, the French Database in Public Health, Google Scholar, and the summaries of the main French journals in oncology and public health were searched for publications until August 2016. An extraction grid adapted to oncology was constructed and used for the extraction process. RESULTS: A total of 18 publications were selected for lung cancer, 18 for breast cancer, and 12 for colorectal cancer. Validation studies of algorithms are scarce. When information is available, the performance and choice of an algorithm are dependent on the context, purpose, and location of the planned study. Accounting for cancer disease specificity, the proposed extraction chart is more detailed than the generic chart developed for other REDSIAM taskforces, but remains easily usable in practice. CONCLUSIONS: This study illustrates the complexity of cancer detection through sole reliance on healthcare databases and the lack of validated algorithms specifically designed for this purpose. Studies that standardize and facilitate validation of these algorithms should be developed and promoted.

Respiratory hypersensitivity reactions to NSAIDs in Europe: the global allergy and asthma network (GA2 LEN) survey.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most prevalent drugs inducing hypersensitivity reactions. The aim of this analysis was to estimate the prevalence of NSAID-induced respiratory symptoms in population across Europe and to assess its association with upper and lower respiratory tract disorders. METHODS: The GA2 LEN survey was conducted in 22 centers in 15 European countries. Each of 19 centers selected random samples of 5000 adults aged 15-74 from their general population, and in three centers (Athens, Munich, Oslo), a younger population was sampled. Questionnaires including questions about age, gender, presence of symptoms of asthma, allergic rhinitis, chronic rhinosinusitis, smoking status, and history of NSAID-induced hypersensitivity reactions were sent to participants by mail. Totally, 62 737 participants completed the questionnaires. RESULTS: The mean prevalence of NSAID-induced dyspnea was 1.9% and was highest in the three Polish centers [Katowice (4.9%), Krakow (4.8%), and Lodz (4.4%)] and lowest in Skopje, (0.9%), Amsterdam (1.1%), and Umea (1.2%). In multivariate analysis, the prevalence of respiratory reactions to NSAIDs was higher in participants with chronic rhinosinusitis symptoms (Odds Ratio 2.12; 95%CI 1.78-2.74), asthma symptoms in last 12 months (2.7; 2.18-3.35), hospitalization due to asthma (1.53; 1.22-1.99), and adults vs children (1.53; 1.24-1.89), but was not associated with allergic rhinitis. CONCLUSION: Our study documented significant variation between European countries in the prevalence of NSAID-induced respiratory hypersensitivity reactions, and association with chronic airway diseases, but also with environmental factors.

Integrated care pathways for airway diseases (AIRWAYS-ICPs).

The objective of Integrated Care Pathways for Airway Diseases (AIRWAYS-ICPs) is to launch a collaboration to develop multi-sectoral care pathways for chronic respiratory diseases in European countries and regions. AIRWAYS-ICPs has strategic relevance to the European Union Health Strategy and will add value to existing public health knowledge by: 1) proposing a common framework of care pathways for chronic respiratory diseases, which will facilitate comparability and trans-national initiatives; 2) informing cost-effective policy development, strengthening in particular those on smoking and environmental exposure; 3) aiding risk stratification in chronic disease patients, using a common strategy; 4) having a significant impact on the health of citizens in the short term (reduction of morbidity, improvement of education in children and of work in adults) and in the long-term (healthy ageing); 5) proposing a common simulation tool to assist physicians; and 6) ultimately reducing the healthcare burden (emergency visits, avoidable hospitalisations, disability and costs) while improving quality of life. In the longer term, the incidence of disease may be reduced by innovative prevention strategies. AIRWAYSICPs was initiated by Area 5 of the Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing. All stakeholders are involved (health and social care, patients, and policy makers).

Clinical relevance is associated with allergen-specific wheal size in skin prick testing.

BACKGROUND: Within a large prospective study, the Global Asthma and Allergy European Network (GA(2) LEN) has collected skin prick test (SPT) data throughout Europe to make recommendations for SPT in clinical settings. OBJECTIVE: To improve clinical interpretation of SPT results for inhalant allergens by providing quantitative decision points. METHODS: The GA(2) LEN SPT study with 3068 valid data sets was used to investigate the relationship between SPT results and patient-reported clinical relevance for each of the 18 inhalant allergens as well as SPT wheal size and physician-diagnosed allergy (rhinitis, asthma, atopic dermatitis, food allergy). The effects of age, gender, and geographical area on SPT results were assessed. For each allergen, the wheal size in mm with an 80% positive predictive value (PPV) for being clinically relevant was calculated. RESULTS: Depending on the allergen, from 40% (blatella) to 87-89% (grass, mites) of the positive SPT reactions (wheal size ≥ 3 mm) were associated with patient-reported clinical symptoms when exposed to the respective allergen. The risk of allergic symptoms increased significantly with larger wheal sizes for 17 of the 18 allergens tested. Children with positive SPT reactions had a smaller risk of sensitizations being clinically relevant compared with adults. The 80% PPV varied from 3 to 10 mm depending on the allergen. CONCLUSION: These 'reading keys' for 18 inhalant allergens can help interpret SPT results with respect to their clinical significance. A SPT form with the standard allergens including mm decision points for each allergen is offered for clinical use.

The minimally important difference in the Rhinoconjunctivitis Total Symptom Score in grass-pollen-induced allergic rhinoconjunctivitis.

BACKGROUND: The minimally important difference (MID) has been defined as the smallest improvement considered worthwhile by a patient. The MID has not been estimated for the Rhinoconjunctivitis Total Symptom Score (RTSS). METHODS: In a prospective multicentre study, patients consulting for grass-pollen-induced allergic rhinitis (AR) recorded a 15-point global rating of change scale (GRCS) score and the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) score on a weekly basis and the individual symptom scores comprising the RTSS on a daily basis over two consecutive weeks. The MID in the RTSS was determined with anchor-based methods (using the GRCS and the RQLQ) and a distribution-based method [based on the RTSS' standard deviation (SD)]. RESULTS: The study population comprised 806 patients (253 children, 250 adolescents and 303 adults). During the first week of the study, the mean ± SD RTSSs for these age groups were 6.5 ± 3.3, 6.8 ± 3.4 and 7.0 ± 3.4, respectively. For an improvement of 2 points in the GRCS or 0.5 points in the RQLQ score, the regression analysis yielded MIDs in the RTSS of 1.24 ± 0.17 and 1.12 ± 0.14 in children, 1.33 ± 0.14 and 1.20 ± 0.13 in adolescents and 1.13 ± 0.14 and 0.89 ± 0.12 in adults, respectively. When applying distribution-based methods, the MID ranged from 1.09 to 1.13 (based on 0.33 SDs of the first-week RTSS) and from 1.22 to 1.40 (based on 0.5 SDs of the difference in RTSSs between the first and second weeks). CONCLUSION: The MID in the RTSS was consistently estimated as 1.1-1.3 (and could conceivably be rounded to 1) in patients with grass-pollen-induced AR.

Visual analogue scale in patients treated for allergic rhinitis: an observational prospective study in primary care: asthma and rhinitis.

BACKGROUND: Allergic rhinitis (AR) severity is evaluated using scores such as Rhinoconjunctivitis Quality-of-Life Questionnaire (RQLQ) and total symptom score (TSS). However, a simple assessment is needed to enable physicians to evaluate the severity of the AR and the efficacy of the treatment. OBJECTIVE: The main objective was to validate visual analogue scale (VAS) as a simple quantitative tool to assess the burden of AR in primary care. METHODS: The study was multi-centre prospective observational conducted in patients consulting general practitioners for symptomatic rhinitis. VAS, RQLQ and TSS6 were assessed at the consultation day and 14 days later, and changes were analysed using paired test. Correlations between VAS, RQLQ and TSS6 were assessed. Cut-off levels for VAS, which discriminate significant from insignificant changes, were established using Receiver Operating Characteristic curves. RESULTS: A total of 990 patients were included in the study. According to allergic rhinitis and its impact on asthma classification, mild intermittent rhinitis was diagnosed in 20% patients, mild persistent in 17%, moderate/severe intermittent in 15% and moderate/severe persistent in 48%, at the consultation day. At day-14, rhinitis symptoms and QoL improved significantly in almost all patients. Impairment incurred by AR and assessed with VAS improved also. The established cut-off variation of 23 mm for VAS was associated with a cut-off variation of 0.5 for RQLQ. Sensitivity analysis with RQLQ and TSS6 scales confirmed the aptitude of the cut-off value (23 mm) to discriminate changes in symptoms and QoL. CONCLUSION AND CLINICAL RELEVANCE: The VAS can detect with high sensitivity the variations of symptoms and QoL in patients with AR.

Understanding the molecular sensitization for Cypress pollen and peach in the Languedoc-Roussillon area.

BACKGROUND: Cypress allergy is a typical winter pollinosis and the most frequent one in the South of France. Main symptoms are rhinitis, conjunctivitis, and asthma. Peach allergy is common too in Southern Europe. Allergic cross-reactions between cypress and peach have been reported, including an oral allergy syndrome. We wanted to investigate whether a cross-reactive allergen between cypress and peach might be responsible for the observed clinical association. METHODS: We analyzed 127 patients included over a 3-month period, outside the pollen season, and we dosed specific IgE levels, for selected, individual allergens. RESULTS: Patients sensitized to peach were mainly positive for the peach-nonspecific lipid-transfer protein. CONCLUSIONS: Profilins or thaumatins could not explain the observed clinical association between cypress and peach.

Allergic Rhinitis and its Impact on Asthma (ARIA): achievements in 10 years and future needs.

Allergic rhinitis (AR) and asthma represent global health problems for all age groups. Asthma and rhinitis frequently coexist in the same subjects. Allergic Rhinitis and its Impact on Asthma (ARIA) was initiated during a World Health Organization workshop in 1999 (published in 2001). ARIA has reclassified AR as mild/moderate-severe and intermittent/persistent. This classification closely reflects patients' needs and underlines the close relationship between rhinitis and asthma. Patients, clinicians, and other health care professionals are confronted with various treatment choices for the management of AR. This contributes to considerable variation in clinical practice, and worldwide, patients, clinicians, and other health care professionals are faced with uncertainty about the relative merits and downsides of the various treatment options. In its 2010 Revision, ARIA developed clinical practice guidelines for the management of AR and asthma comorbidities based on the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) system. ARIA is disseminated and implemented in more than 50 countries of the world. Ten years after the publication of the ARIA World Health Organization workshop report, it is important to make a summary of its achievements and identify the still unmet clinical, research, and implementation needs to strengthen the 2011 European Union Priority on allergy and asthma in children.

Results of drug hypersensitivity evaluations in a large group of children and adults.

BACKGROUND: Proven IgE or T-cell mediated drug hypersensitivity reactions (DHRs) seem less common in children compared with adults. However, this has never been proved by data. OBJECTIVE: To determine and compare proven DHR prevalence in children and adults. METHODS: Using the DAHD (Drug Allergy and Hypersensitivity Database) cohort, children with proven DHRs were compared with adults. The international EAACI-ENDA recommendations were followed. Patients were divided into four groups: index reaction and test during childhood (C/C), index reaction at childhood and test at adulthood (C/A), index reactions at childhood and adulthood and test at adulthood (CA/A), index reaction and test at adulthood (A/A). RESULTS: A total of 3275 patients (67.9% female), comprising a total of 4370 patient-episodes, were evaluated (74.5% belonged to the A/A group). Prevalence of positive tests was 15.2% (95%CI, 14.1-16.2) for all tested classes, 10.6% (8.3-13.0) for C/C, 10.6% (7.5-13.6) for C/A, 22.1% (12.8-31.3) for CA/A and 16.5% (15.2-17.8) for A/A. The prevalence was lower in group C/C compared with groups A/A (P < 0.0001) and CA/A (P = 0.003). It was also lower in group C/A compared with the two latter groups (respectively P = 0.003 and P = 0.005). Significant differences were found for maculopapular exanthemas only, and not for urticaria/angiœdema and anaphylaxis. The difference was mainly observed with ß-lactams and not for NSAIDs. CONCLUSION AND CLINICAL RELEVANCE: Suspicions of DHRs are less likely to be confirmed in children.

Asthma in adults and its association with chronic rhinosinusitis: the GA2LEN survey in Europe.

BACKGROUND: The prevalence of asthma and its association with chronic rhinosinusitis (CRS) have not been widely studied in population-based epidemiological surveys. METHODS: The Global Allergy and Asthma Network of Excellence (GA(2) LEN) conducted a postal questionnaire in representative samples of adults living in Europe to assess the presence of asthma and CRS defined by the European Position Paper on Rhinosinusitis and Nasal Polyps. The prevalence of self-reported current asthma by age group was determined. The association of asthma with CRS in each participating centre was assessed using logistic regression analyses, controlling for age, sex and smoking, and the effect estimates were combined using standard methods of meta-analysis. RESULTS: Over 52,000 adults aged 18-75 years and living in 19 centres in 12 countries took part. In most centres, and overall, the reported prevalence of asthma was lower in older adults (adjusted OR for 65-74 years compared with 15-24 years: 0.72; 95% CI: 0.63-0.81). In all centres, there was a strong association of asthma with CRS (adjusted OR: 3.47; 95% CI: 3.20-3.76) at all ages. The association with asthma was stronger in those reporting both CRS and allergic rhinitis (adjusted OR: 11.85; 95% CI: 10.57-13.17). CRS in the absence of nasal allergies was positively associated with late-onset asthma. CONCLUSION: Geographical variation in the prevalence of self-reported asthma was observed across Europe, but overall, self-reported asthma was more common in young adults, women and smokers. In all age groups, men and women, and irrespective of smoking behaviour, asthma was also associated with CRS.

Practical guide to skin prick tests in allergy to aeroallergens.

This pocket guide is the result of a consensus reached between members of the Global Allergy and Asthma European Network (GA(2) LEN) and Allergic Rhinitis and its Impact on Asthma (ARIA). The aim of the current pocket guide is to offer a comprehensive set of recommendations on the use of skin prick tests in allergic rhinitis-conjunctivitis and asthma in daily practice. This pocket guide is meant to give simple answers to the most frequent questions raised by practitioners in Europe, including 'practicing allergists', general practitioners and any other physicians with special interest in the management of allergic diseases. It is not a long or detailed scientific review of the topic. However, the recommendations in this pocket guide were compiled following an in-depth review of existing guidelines and publications, including the 1993 European Academy of Allergy and Clinical Immunology position paper, the 2001 ARIA document and the ARIA update 2008 (prepared in collaboration with GA(2) LEN). The recommendations cover skin test methodology and interpretation, allergen extracts to be used, as well as indications in a variety of settings including paediatrics and developing countries.

Severe chronic allergic (and related) diseases: a uniform approach--a MeDALL--GA2LEN--ARIA position paper.

Concepts of disease severity, activity, control and responsiveness to treatment are linked but different. Severity refers to the loss of function of the organs induced by the disease process or to the occurrence of severe acute exacerbations. Severity may vary over time and needs regular follow-up. Control is the degree to which therapy goals are currently met. These concepts have evolved over time for asthma in guidelines, task forces or consensus meetings. The aim of this paper is to generalize the approach of the uniform definition of severe asthma presented to WHO for chronic allergic and associated diseases (rhinitis, chronic rhinosinusitis, chronic urticaria and atopic dermatitis) in order to have a uniform definition of severity, control and risk, usable in most situations. It is based on the appropriate diagnosis, availability and accessibility of treatments, treatment responsiveness and associated factors such as comorbidities and risk factors. This uniform definition will allow a better definition of the phenotypes of severe allergic (and related) diseases for clinical practice, research (including epidemiology), public health purposes, education and the discovery of novel therapies.

Epidemiology of cypress pollen allergy in Montpellier.

BACKGROUND: Cupressaceae pollen allergy is a worldwide winter pollinosis. Exposure to cypress pollen has increased enormously during recent decades, and cypress pollen allergy has become a major health problem, especially in Mediterranean countries. OBJECTIVES: We aimed to evaluate the prevalence of cypress pollen sensitization and allergy in the Montpellier area and the symptoms presented by sensitized patients. METHODS: We included all 6185 consecutive patients who were referred to our center for any allergic disorder during a 36-month period. For each patient, we evaluated skin prick test results, allergy symptoms, pulmonary function test results, and the need for allergen immunotherapy. RESULTS: We found that 20.7% of patients were sensitized to cypress pollen and 46.4% presented symptoms during the pollen season. The main symptoms were rhinoconjunctivitis and asthma. Oral allergy syndrome to peach was detected in 4% of sensitized and symptomatic patients. Allergen immunotherapy was necessary to control symptoms in 57.9% of cases. CONCLUSIONS: Cypress pollen allergy is one of the leading causes of respiratory allergy in the Montpellier area. Symptoms are often severe and include pollen-induced asthma. Moreover,many patients need allergen immunotherapy in order to achieve better control of their symptoms.

A statement on cefazolin immediate hypersensitivity: data from a large database, and focus on the cross-reactivities.

BACKGROUND: More perioperative cefazolin use has resulted in an increased risk of cefazolin-associated reactions. OBJECTIVE: The aim of this article is to study immediate reactions to cefazolin and attempt to determine possible allergic cross-reactivity with other ß-lactams using data from the Drug Allergy and Hypersensitivity Database (DAHD). METHODS: All 25 cefazolin-associated reactions in the DAHD were reviewed. The cases identified were then investigated according to the European Network for Drug Allergy (ENDA) recommendations by skin testing and challenges. RESULTS: A total of 10 individuals with proven IgE-mediated cefazolin hypersensitivity were identified between January 1999 and July 2009. All the index reactions were compatible with an acute IgE-mediated process, six with anaphylaxis, two with systemic allergic reactions without hypotension, and two with urticaria/angioedema. Cefazolin skin tests were positive in seven individuals and cefazolin challenges were positive in three more individuals. In the eight cefazolin allergic patients who had challenges with other ß-lactams, there was no positive reaction noted. CONCLUSION AND CLINICAL RELEVANCE: In this cohort of patients with IgE-mediated reactions to cefazolin, a majority tolerated amoxicillin and several patients tolerated other cephalosporins. This implies that the R1 side-chain may play an essential role in IgE-mediated reactions to cefazolin. No clear rule to predict cross-reactivity with other ß-lactams could be determined. More research on IgE-mediated hypersensitivity to cefazolin and other cephalosporins is needed.

Evaluating the negative predictive value of provocation tests with nonsteroidal anti-inflammatory drugs.

BACKGROUND: The nonsteroidal anti-inflammatory drugs (NSAIDs) hypersensitivity work-up is based on clinical history, skin tests, and drug provocation tests. The negative predictive value (NPV) of the latter is not established. METHOD: A cohort study was conducted in the Allergy Department in Montpellier to evaluate the NPV of the provocation test with NSAIDs in patients with clinical presentation suggestive of hypersensitivity, and negatively tested. Patients were contacted at least 6 months after the work-up. Patients who took NSAID and reacted were proposed a new allergy work-up, which included a provocation test with the culprit drug. RESULTS: Among the 393 patients contacted, 279 (71.0%) were followed up. Two hundred and sixty (93.2%) patients had taken a NSAID at least once: 139 (53.5%) the same drug as the one tested and 215 (82.7%) an alternative (94, 33.7% taking both the tested NSAID and an alternative). Eight patients (3.1%) reported a reaction (five with the negatively tested NSAID and three with another NSAID). All the reactions occurred immediately after the first administration and were not severe. Among the five patients who reacted with the negatively tested NSAID, only three accepted a re-challenge, negative in two cases and positive in one, representing a NPV of 97.8% (95% CI: 95.4-100%). Three patients (3/215) reported a reaction when an alternative NSAID was taken, representing a NPV of 98.6% (95% CI: 97-100%). CONCLUSION: The NPV of NSAIDs drug provocation test is high. This should reassure physicians who might hesitate to prescribe NSAIDs, especially in patients with negative allergic work-ups.

The 2009-2010 H1N1 vaccination campaign for patients with egg allergy in a region of France.

We describe our experience of the influenza H1N1 vaccination in patients with egg allergy. All patients tolerated the vaccination in a simple or double dose protocol without any significant allergic reaction in this series.

Comparison of five techniques of skin prick tests used routinely in Europe.

BACKGROUND: Skin prick tests represent indispensable tools in allergy, even more than 30 years after their introduction in clinical practice. OBJECTIVES: Few recent European studies have focused on this topic and we thus wanted to compare the instruments most often used today. METHODS: Four instruments were investigated: the 23G intravenous (IV) needle, the ALK Lancet, the Stallergenes (STG) Prick Lancet and the Stallerpoint(®) (using two different methods). Sensitivity, reproducibility, and acceptability were evaluated. In 22 subjects, we calculated the sensitivity and reproducibility (both intra- and interpatient) of these methods by testing the positive control five times. In 50 subjects, we tested the single-blind acceptability of these same five techniques. RESULTS: In terms of sensitivity, the IV needle (100%) and metal lancets (96% for the ALK Lancet and 98% for the STG Prick Lancet) were superior (P < 0.01) to the two Stallerpoint(®) methods (20% and 57%). Intrapatient reproducibility was 16.2%, 14.6%, 15.0%, 97.1% and 18.1%, respectively. The instruments that were best tolerated by the patients were the IV needle and the two metal lancets. CONCLUSION: Metal needles and/or lancets are the tools of choice for skin prick testing.