Non-immediate-reading skin tests and prolonged challenges in non-immediate hypersensitivity to beta-lactams in children.

BACKGROUND: A minority of children reporting non-immediate reactions to beta-lactams (BLs) are allergic. Allergy workup usually includes late-reading (48-72 hours) skin tests (ST) and short (1-3 days) drug provocation tests (DPT), regardless of the chronology of the index reaction. The sensitivity of hyper-late-reading (≥6-7 days) ST and of prolonged DPT for the diagnosis of non-immediate hypersensitivity to BLs is yet to be determined. OBJECTIVES: To establish the diagnostic values of late-reading ST and hyper-late-reading ST and of prolonged DPT in children reporting non-immediate reactions to BLs. METHODS: Prospective assessment of children reporting non-immediate reactions to BLs with late- and additional hyper-late-reading intradermal (ID) and patch tests, and if negative, with prolonged DPT. RESULTS: Five hundred and fifty children reporting reactions to a single or several BLs (674 suspected BLs) were included. Non-immediate hypersensitivity to BLs was diagnosed in 63 children (11.5%), reporting 66 reactions (9.8%), based on responses in ST (n = 17, 25.8%: 5 to ID, 8 to patch tests, and 4 to both tests), DPT (n = 43, 65.2%), and clinical history (n = 6, 9.1%), including 3/9 children with severe cutaneous adverse reactions. Skin test positivity was observed after the 6-7th day in 14/17 children, and DPT positivity after a median time of 3 days. No severe reaction was observed after ST or during prolonged DPT. CONCLUSION: Additional hyper-late-reading of ST enhanced their positivity. However, their overall sensitivity remained weak, especially in non-severe cases. Prolonged DPT are safe and may improve the performance of DPT in the diagnosis of non-immediate hypersensitivity to BLs.

[Mild asthma in children: new data and a revival of interest]. / Asthme léger de l'enfant : données nouvelles et regain d'intérêt.

According to the Global Initiative for Asthma (GINA) classification, mild asthma includes intermittent and mild persistent asthma. It represents more than 75% of asthmatic children. The symptoms and functional impact are well described. Mild asthma can lead to severe exacerbations. Progression to more severe disease may occur. Consequently, it is important to diagnose mild asthma, to initiate the appropriate treatment early, and to identify the risk factors for aggravation. Nevertheless, mild asthma is under-diagnosed and under-treated. Bronchial inflammation and remodeling are observed in mild asthma. A daily low-dose of inhaled corticosteroids is the reference treatment for mild persistent asthma. Intermittent inhaled corticosteroids cannot be recommended in children with mild persistent asthma.

[Allergic march in children, from rhinitis to asthma: management, indication of immunotherapy]. / Marche allergique chez l'enfant, de la rhinite à l'asthme : prise en charge, place de la désensibilisation.

Allergic rhinitis (AR) is a common IgE dependent disorder. AR is maybe one of the steps of the allergic march, which starts with atopic dermatitis and food allergy and includes atopic asthma. AR and asthma are frequently associated. AR is frequently under-diagnosed and undertreated although it affects quality of life and school performance. Management of AR depends on its severity and will associate environmental control (best guided by environmental investigation and skin testing of specific IgE antibodies), pharmacotherapy (with antihistamines and intranasal corticosteroids as first line drugs). At present allergen immunotherapy is considered in patients with severe AR, insufficiently controlled by pharmacotherapy and who demonstrate specific IgE antibodies to relevant allergens. Sublingual immunotherapy is well tolerated. Only immunotherapy with the right allergens has the potential to alter the natural history of the allergic march, by preventing the development of new allergen sensitizations and reducing the risk for the subsequent development of asthma. This fact might extend the indications of specific allergen immunotherapy. Patients (and parents) education is of utmost importance in the management of allergic disorders.

Allergy to betalactam antibiotics in children: results of a 20-year study based on clinical history, skin and challenge tests.

Studies based on skin and challenge tests have shown that 12-60% of children with suspected betalactam hypersensitivity were allergic to betalactams. Responses in skin and challenge tests were studied in 1865 children with suspected betalactam allergy (i) to confirm or rule out the suspected diagnosis; (ii) to evaluate diagnostic value of immediate and non-immediate responses in skin and challenge tests; (iii) to determine frequency of betalactam allergy in those children, and (iv) to determine potential risk factors for betalactam allergy. The work-up was completed in 1431 children, of whom 227 (15.9%) were diagnosed allergic to betalactams. Betalactam hypersensitivity was diagnosed in 50 of the 162 (30.9%) children reporting immediate reactions and in 177 of the 1087 (16.7%) children reporting non-immediate reactions (p<0.001). The likelihood of betalactam hypersensitivity was also significantly higher in children reporting anaphylaxis, serum sickness-like reactions, and (potentially) severe skin reactions such as acute generalized exanthematic pustulosis, Stevens-Johnson syndrome, and drug reaction with systemic symptoms than in other children (p<0.001). Skin tests diagnosed 86% of immediate and 31.6% of non-immediate sensitizations. Cross-reactivity and/or cosensitization among betalactams was diagnosed in 76% and 14.7% of the children with immediate and non-immediate hypersensitivity, respectively. The number of children diagnosed allergic to betalactams decreased with time between the reaction and the work-up, probably because the majority of children with severe and worrying reactions were referred for allergological work-up more promptly than the other children. Sex, age, and atopy were not risk factors for betalactam hypersensitivity. In conclusion, we confirm in numerous children that (i) only a few children with suspected betalactam hypersensitivity are allergic to betalactams; (ii) the likelihood of betalactam allergy increases with earliness and/or severity of the reactions; (iii) although non-immediate-reading skin tests (intradermal and patch tests) may diagnose non-immediate sensitizations in children with non-immediate reactions to betalactams (maculopapular rashes and potentially severe skin reactions especially), the diagnostic value of non-immediate-reading skin tests is far lower than the diagnostic value of immediate-reading skin tests, most non-immediate sensitizations to betalactams being diagnosed by means of challenge tests; (iv) cross-reactivity and/or cosensitizations among betalactams are much more frequent in children reporting immediate and/or anaphylactic reactions than in the other children; (v) age, sex and personal atopy are not significant risk factors for betalactam hypersensitivity; and (vi) the number of children with diagnosed allergy to betalactams (of the immediate-type hypersensitivity especially) decreases with time between the reaction and allergological work-up. Finally, based on our experience, we also propose a practical diagnostic approach in children with suspected betalactam hypersensitivity.

Anaphylaxis to the 23-valent pneumococcal vaccine: a second explored case by means of immediate-reading skin tests with pneumococcal vaccines.

Anaphylaxis to pneumococcal vaccines is rare. In the only one child with anaphylaxis to a first injection of the 23-valent pneumococcal vaccine that has been explored, skin tests and specific IgE determination diagnosed immediate-type hypersensitivity to pneumococcal antigens. We report the case of a child who tolerated three injections of the 7-valent pneumococcal vaccine, but experienced anaphylaxis to a fourth injection of the 23-valent vaccine. Immediate responses in skin tests diagnosed immediate-type hypersensitivity to the two vaccines. Immunizations with the 7-valent pneumococcal vaccine may induce IgE-dependent sensitization to pneumococcal antigens, responsible for anaphylaxis to subsequent injections of pneumococcal vaccines.

17q21 variants modify the association between early respiratory infections and asthma.

Single nucleotide polymorphisms (SNPs) at chromosome 17q21 confer an increased risk of early-onset asthma. The objective was to study whether 17q21 SNPs modify associations between early respiratory infections and asthma. Association analysis was conducted in 499 children (268 with asthma, median age 11 yrs) from the Epidemiological Study on the Genetics and Environment of Asthma (EGEA). The 12-yr follow-up data were used to assess persistent or remittent asthma in young adulthood. Respiratory infection before 2 yrs of age was assessed retrospectively. For the 12 17q21 SNPs studied, the odds ratios (OR) for association between infection and early-onset asthma (age at onset

Oral food challenge in children: an expert review.

Oral food challenges are indicated for the diagnosis of food allergy and the double-blind, placebo-controlled oral food challenge is considered the gold standard diagnostic method in children with suspected food allergy. This practice parameter for oral food challenges in children was prepared by a workgroup at the request of the French Society for Allergology and Clinical Immunology (SFAIC) and the French Paediatric Society for Allergology and Pulmonology (SP2A). We aimed to develop practical guidelines for oral food challenges in children for the diagnosis of suspected food allergy or the evaluation of food tolerance. We also considered the safety measures to be implemented during testing and management of the potentially serious allergic reactions that may arise during the test. The strength of the recommendations was established, using the GRADE evidence-based approach. We considered four issues: (1) the selection of children for oral food challenges (indications and contraindications); (2) the procedure used (material, where the test should be carried out, technique and management of reactions); (3) interpretation of the test and (4) consequences of the test.

[Exercise alveolar hypoventilation in long-term survivors of bronchopulmonary dysplasia]. / Hypoventilation alvéolaire à l'exercice chez des enfants avec dysplasie bronchopulmonaire.

BACKGROUND: We aimed to confirm that children who have survived bronchopulmonary dysplasia (BPD) display lower ventilation during exercise than healthy children, and to determine whether alveolar hypoventilation associated with exercise-induced hypoxemia occurred in these children. METHODS: Twenty children with BPD (birth weight 1441+/-523 g [mean +/- SD], gestational age 31+2.3 weeks), aged 7 to 14 years, and 18 matched healthy children, born at term, performed resting pulmonary function and cardiopulmonary incremental exercise tests. Arterialized capillary blood gases were measured at rest and at maximal exercise in the BPD group. RESULTS: The BPD group showed moderate expiratory airflow limitation and hyperinflation. Maximal oxygen uptake and ventilatory threshold were similar in the two groups. The BPD group displayed ventilatory limitation on exercise, with greater use of the ventilatory reserve (p<0.01), lower maximal ventilation (p<0.01), tidal volume (p=0.01). Changes in ventilation (p<0.0001) and tidal volume (p=0.003) during exercise were significantly smaller in the BPD group than in controls, at similar submaximal workloads. At peak exercise, we observed hypoxemia in 12 BPD children (60%). In the subgroup with hypoxemia, a significant increase in PaCO2 (p=0.01) was measured at peak exercise, showing alveolar hypoventilation sustained by the lower tidal volume. CONCLUSIONS: Despite normal maximal aerobic performance, BPD children showed ventilatory limitation on exercise, frequently with hypoxemia and alveolar hypoventilation. Despite an improvement in their pulmonary condition, continued follow-up by cardiopulmonary exercise testing, is strongly recommended.

Airway remodeling is correlated with obstruction in children with severe asthma.

BACKGROUND: Severe asthma may involve an irreversible obstructive pattern, and structural changes in bronchial airways are believed to play a key role in this context. The aim of the present study was to compare airway remodeling in severe asthmatic children with or without obstructive pattern. METHODS: Two groups of children with severe asthma and persistent symptoms, 5-14 years old were included, 15 with persistent obstructive pattern (group O) and 10 without obstructive pattern (group N). Persistent obstructive pattern was defined as a forced expiratory volume in 1 s (FEV(1)) less than 80% of the predicted value after a course of systemic corticosteroids and no significant improvement after bronchodilator. We examined bronchial biopsies by pathological and immunochemical methods and quantified airway smooth muscle (ASM) and mucus gland areas, reticular basement membrane (RBM) thickening, distance between ASM and RBM, muscle light chain kinase (MLCK) expression and number of vessels (CD31 expression). RESULTS: Surface area of ASM (P = 0.009), MLCK expression (P = 0.03) and number of vessels (P = 0.0008) were increased in group O compared with group N. Distance of RBM-ASM was shorter in group O (P = 0.007). FEV(1) negatively correlated with ASM area (r = -0.6; P = 0.002), MLCK expression (r = -0.45; P = 0.02) and CD31 expression (r = -0.7; P = 0.0003), and positively correlated with the distance of RBM-ASM (r = 0.5; P = 0.007). CONCLUSIONS: Structural abnormalities of airway remodeling are present in children with severe asthma. Only an increase in surface area of ASM and the density of the vascular network are more pronounced in children with persistent obstructive pattern, while RBM thickening is similar. These results are concordant with longitudinal studies which emphasize the precocity of bronchial obstruction.

Allergic rhinitis in children with asthma: a questionnaire-based study.

BACKGROUND: Allergic rhinitis (AR) and asthma frequently coexist but has rarely been evaluated in children. OBJECTIVE: This prospective study aimed to estimate the prevalence of AR in asthmatic children, and ascertain whether AR is a risk factor for the severity of asthma. METHODS: The questionnaire, modified from the adult form of the score for allergic rhinitis (SFAR), was completed by 404 asthmatic children aged 3-18 years seen in the outpatient clinic between June 2005 and July 2007. Each item was assigned a number of points with a final score ranging from 0 to 17. AR and asthma were classified according to ARIA and GINA 2004 recommendations, respectively. RESULTS: AR was diagnosed in 237 patients (58.7%). It was intermittent in 57.8% of the patients and persistent in 42.2%. A total score >or=9 was discriminant for AR (sensitivity=91.1%, specificity=95.2%, positive predictive value=96.4%, negative predictive value=88.3%, Youden's Index=0.86). The proportion of children having mild or moderate-to-severe asthma was independent of the presence of AR, 61.6% of moderate-to-severe asthmatic children and 55.4% of intermittent and mild asthmatic children having AR. CONCLUSION: AR and asthma are frequently associated (58.7%). The SFAR adapted for children seems to be a simple and a reliable tool to detect AR in asthmatic children.

Identification of a new natural Ara h 6 isoform and of its proteolytic product as major allergens in peanut.

Numerous food allergens of plant origin belong to the 2S albumin family, including peanut Ara h 2. In addition to Ara h 2, several other conglutins related to 2S albumins are present in peanut seeds. We evaluated the allergenicity of different peanut conglutins as compared with Ara h 2. Several conglutins were isolated from the kernel, i.e. Ara h 2, a new isoform of Ara h 6 and its derived product, which is likely to be naturally formed during seed processing. Enzyme allergosorbent tests performed on sera of peanut allergic patients showed that more than 94% of 47 analyzed patients had positive IgE responses to Ara h 6 isoform and to its degradation product. Skin prick tests with the new isoform of Ara h 6 led to a positive response in seven out of the eight tested patients. Both enzyme allergosorbent tests and skin prick tests showed that the reactivity of Ara h 6 was similar to, or even higher than, that of Ara h 2, suggesting that the present isoform of Ara h 6 is as allergenic as Ara h 2. In addition the IgE response to the plant processed (i.e., hydrolyzed) Ara h 6 new isoform is equivalent to the IgE response to the native isoform. The IgE immunoreactivity is mostly abrogated by chemical reduction and denaturation of Ara h 6 isoforms, which underlined the importance of tertiary structure in Ara h 6 immunoreactivity. These results, and particularly the high correlation between anti-Ara h 2 and anti-Ara h 6 IgE responses, emphasise the major role of 2S albumins in peanut allergenicity.

Incidence rate and factors related to post-bronchoalveolar lavage fever in children.

BACKGROUND: Post-bronchoscopy and bronchoalveolar lavage (BAL) fever in children has been described by several authors. OBJECTIVES: This study aimed at assessing the occurrence of fever after these examinations and associated risk factors. METHODS: The study was performed in the Bronchoscopy Unit of Hôpital Necker-Enfants Malades, Paris, France, from June 2004 to July 2005. 148 children who underwent fiberoptic bronchoscopy and BAL, and remained in the Unit for 24 h, were included. RESULTS: 37.8% of the patients presented post-BAL fever. In the multivariate analysis of the selected factors (age, immunodeficiency, general or local anesthesia, mucosal biopsy, inflammation and suppuration at the moment of the examination, abnormal bronchoalveolar fluid cellularity and infection), only age <2 years and presence of infection remained associated with fever. CONCLUSIONS: The occurrence of fever is a frequent event in children who underwent BAL. In order to reduce post-BAL fever, antibiotic strategies should be devised based on prospective studies assessing identification of predictive air-way infection criteria and/or rapid bacteriological result analysis.

Pharmacoeconomic assessment of specific immunotherapy versus current symptomatic treatment for allergic rhinitis and asthma in France.

OBJECTIVES: The therapeutic benefit of specific immunotherapy (SIT) in allergic rhinitis and asthma has been endorsed by expert consensus. This study compared the cost/efficacy (C/E) of SIT with current symptomatic treatments (CST) for allergic rhinitis and asthma. METHODS: A C/E analysis was performed using a decision tree model. The decision tree and medical and economic hypotheses were defined by a panel of experts. The perspective adopted was that of the French Social Security. The costs and efficacy of SIT and CST were compared for dust-mite and pollen allergies, in adults and children. Direct medical costs included diagnosis and follow-up, consultations, CST and SIT. End-point economic criteria were cost per stabilised patient and cost per asthma case avoided. A sensitivity analysis was performed for each model. RESULTS: In adults, the incremental costs per asthma case avoided with injectable SIT were 393 Euro and 1327 Euro for dust-mite and pollen allergy, respectively, over a 6-year period. For sublingual SIT, the costs per asthma case avoided were 3158 Euro and 1708 Euro, respectively. In children, over a 7-year period, the incremental costs per asthma case avoided with injectable SIT were 583 Euro and 597 Euro for dust-mite and pollen allergy, respectively. For sublingual SIT the incremental costs were 3938 Euro and 824 Euro. CONCLUSION: Compared to CST, SIT is a cost-effective treatment in pollen and dust-mite-induced allergic rhinitis and asthma. Sublingual SIT is an attractive option in pollen-induced rhinitis, particularly in children. SIT appears to be an economically relevant strategy compared to CST.

[Environmental factors for asthma severity and allergy: results from the EGEA study]. / Facteurs environnementaux de l'asthme sévère et de l'allergie: résultats de l'étude EGEA.

INTRODUCTION: EGEA (Epidemiological study on the genetics and environment of asthma, bronchial hyperresponsiveness and atopy), a case control and family study including 2048 individuals, was initiated to look for environmental and genetic risk factors for asthma. A synthesis of the results obtained since 2002 on phenotypic and environmental aspects of asthma severity and allergy are presented in this article. METHODS AND RESULTS: The results support a role for hormonal factors in asthma severity and in various allergic markers of asthma. A greater body mass index was related to a more severe asthma in women with early menarche. Associations between markers of allergy (eosinophils, IgE and atopy) and hormonal dependent events in women (premenstrual asthma, menopause and oral contraceptive use) have been found. In asthmatics, exposure to agents known to be associated with occupational asthma, active and passive smoking were associated with an increased clinical asthma severity score. The study underlines the protective role of country living and exposure to pets in early life on allergy markers in adulthood, supporting the hygiene hypothesis. CONCLUSIONS: New hypothesis will be tested in the near future from the second stage of this survey.

[Allergic and pseudoallergic reactions to analgesics, antipyretics and non-steroidal anti-inflammatory drugs]. / Les réactions allergiques et pseudoallergiques aux antalgiques, antipyrétiques et anti-inflammatoires non stéroïdiens.

Antalgics, antipyretics and non-steroidal anti-inflammatory drugs (NSAIDs) are widely used, but suspected allergic reactions to these drugs are rare, especially in children. Most frequent reactions are cutaneous (urticaria, angioedema) and respiratory (rhinitis, asthma). Other reactions (anaphylaxis or anaphylactoid reactions, potentially harmful toxidermias) are rare. In a few patients, reactions may result from a specific (allergic) hypersensitivity (HS), with positive responses in prick and intradermal tests (anaphylaxis, immediate urticaria and/or angioedema) and in intradermal and patch tests (non-immediate reactions). However, most reactions result from a non-specific (non-allergic) HS (intolerance), with a frequent cross-reactivity between the various families of antalgics, antipyretics and NSAIDs, including acetaminophen (paracetamol). Based on a convincing clinical history and/or positive responses in challenge tests, intolerance to antalgics, antipyretics and NSAIDs has been diagnosed in 13 to 50% of the patients with allergic-like reactions to these drugs. Risk factors for HS to antalgics, antipyretics and NSAIDs are a personal atopy and age. In our experience, 50% of the children with allergic-like reactions to antipyretics, antalgics and NSAIDs were diagnosed intolerant to these drugs. Risk was high in children reporting reactions to NSAIDs (aspirin, ibuprofen) and lower in children reporting reactions to paracetamol. All the children intolerant to paracetamol were also intolerant to NSAIDs. In contrast, most children with NSAID intolerance were tolerant to paracetamol. A personal history of atopy and a mean age >or= 8 years were significant risk factors for intolerance to antalgics, antipyretics and NSAIDs.

Allergy to betalactam antibiotics in children: a prospective follow-up study in retreated children after negative responses in skin and challenge tests.

BACKGROUND: Up to 10% of the patients in whom suspected betalactam hypersensitivity (HS) has been excluded by skin and challenge tests report suspected allergic reactions during subsequent treatments with the same or very similar betalactams. It has been suggested that the reactions may result from a resensitization induced by the challenge performed at the time of the allergological work-up. However, most patients did not undergo a second allergological work-up, to determine if the reactions resulted from betalactam HS or not. OBJECTIVES: We aimed to determine if children diagnosed nonallergic to betalactams have tolerated subsequent treatments with the initially suspected and/or other betalactams, and, in case of a reaction, if the reaction resulted from betalactam HS. METHODS: We sent a questionnaire concerning the clinical history of their children to the parents of 256 children previously diagnosed nonallergic to betalactams. A second allergological work-up was performed in the children reporting suspected allergic reactions during subsequent treatments with the same and/or other betalactams. Skin tests were performed with the soluble form of the suspected (or very similar) betalactams and other betalactams from the same and other classes. Skin test responses were assessed at 15-20 min (immediate), 6-8 h (semi-late) and 48-72 h (late). Oral challenge (OC) was performed in children with negative skin tests, either at the hospital (immediate and accelerated reactions), or at home (delayed reactions). RESULTS: A response was obtained from 141 children (55.3%). Forty-eight (34%) of those children had not been treated with the betalactams for whom a diagnosis of allergy had been ruled out previously. Seven (7.5%) of the 93 children who had been treated again reported suspected allergic reactions. Skin tests and OC were performed in six of those children, and gave negative results in five children. In one child previously diagnosed nonallergic to amoxicillin associated with clavulanic acid, we diagnosed a delayed HS to clavulanic acid and a serum sickness-like disease to cefaclor. Thus, the frequency of reactions resulting from betalactam HS in children with negative skin and challenge tests is very low, and does not exceed 2.1% (2/93) if we consider that the child which refused a second allergological work-up is really allergic to betalactams. CONCLUSION: Our results in a very large number of children show that reactions presumed to result from betalactam HS are rare in children in whom the diagnosis of betalactam allergy has been ruled out previously. Moreover, they suggest that, as shown for the initial reactions, most of the reactions during subsequent treatments are rather a consequence of the infectious diseases for whom betalactams have been prescribed than a result of betalactam HS. Finally, they suggest that the risk of resensitization by OC is very low, and do not support the notion that skin testing should be repeated in children diagnosed nonallergic to betalactams.