Drug hypersensitivity in children: a retrospective analysis of 101 pharmacovigilance reports.

Our objective was to describe and discuss management of recent cases of drug hypersensitivity in children reported in a pharmacovigilance center. Two pediatric allergy units conducted a collaborative retrospective analysis of 101 adverse drug reactions reported to a regional pharmacovigilance center between January 2016 and July 2019. Time lapse between hypersensitivity reaction onset and allergy consultation varied from 1 month to 12 years. Sixty-two patients (61.4%) presented with immediate reactions, 11 (10.9%) with non-immediate reactions, and 28 (27.7%) had reactions impossible to classify through medical interview. Overall, 92 children (91%) were explored for simultaneously administered drugs. All 113 prick tests were negative, and 2 were uncertain. Among 108 intradermal tests, 2 were positive to penicillin and to an iodinated contrast medium, 105 were negative, and 1 was uncertain. Overall, 129 drug provocation tests were proposed. Nine provocation tests among 80 were positive (11.25%): 6 to penicillin, 1 to sulfonamide antibiotics, and 2 to non-steroidal anti-inflammatory drugs; the remaining 71 were negative. No severe reaction was observed during these tests. Finally, drug allergy was only retained in 11 reported cases (10.9%).Conclusion: These pharmacovigilance reports show the difficulty in defining drug allergy in children only by anamnesis, and that explorations, particularly provocation tests, should take place at a reasonable time lapse after drug hypersensitivity reaction onset. What is Known: • True drug allergy is rarely observed in children. • Absence of full workup leads to falsely labeling children as "allergic." What is New: • Short time lapse between hypersensitivity onset and consultation improves classification of pediatric allergy. • Timely allergy consultations are essential, and tests are useful to confirm or exclude pediatric allergy.

Pru p 7 sensitization is a predominant cause of severe, cypress pollen-associated peach allergy.

BACKGROUND: Peach is a common elicitor of food allergic reactions. Peach-induced immediate reactions may occur as benign pollen-food syndromes, usually due to birch pollen-related PR-10 cross-reactivity in temperate climates, and as potentially severe primary food allergies, predominantly related to nsLTP Pru p 3 in Mediterranean regions. The newly described peach allergen Pru p 7 has gained recent attention as a potential peach allergy severity marker. Sensitization to Pru p 7 and its allergenic homologues of the gibberellin-regulated protein family occurs in areas with high Cupressaceae tree pollen exposure. OBJECTIVE: We sought to investigate the distribution, clinical characteristics and molecular associations of Pru p 7 sensitization among subjects with suspected peach allergy in different regions of France. METHODS: Subjects with suspected peach allergy (n = 316) were included. Diagnostic work-up was performed according to current guidelines, including open food challenge when required. IgE antibody measurements and competition experiments were performed using the ImmunoCAP assay platform. RESULTS: Sensitization to Pru p 7 was present in 171 (54%) of all subjects in the study and in 123 of 198 (62%) diagnosed as peach allergic, more than half of whom were sensitized to no other peach allergen. Frequency and magnitude of Pru p 7 sensitization were associated with the presence of peach allergy, the clinical severity of peach-induced allergic reactions and the level of cypress pollen exposure. Cypress pollen extract completely outcompeted IgE binding to Pru p 7. Pru p 7 was extremely potent in basophil activation tests. CONCLUSION AND CLINICAL RELEVANCE: A subtype of Cupressaceae pollinosis, characterized by Pru p 7 sensitization, can be an underlying cause of severe peach allergy.

Use of epinephrine in emergency department depends on anaphylaxis severity in children.

Despite multiple recommendations, intramuscular epinephrine is poorly prescribed in emergency department receiving pediatric anaphylaxis. To evaluate the role of severity symptoms on this use, we included all admissions for a diagnosis linked to possible allergy in the two pediatric emergency departments of our institution between January 2010 and December 2015. Selection and analysis were restricted to children under 18 years fulfilling Sampson's criteria for anaphylaxis. We retrospectively ranked these admissions with the Ring and Messmer anaphylaxis severity score and compared the use of epinephrine according to this classification. Among 422,483 admissions, 204 (0.05%) fulfilled the anaphylaxis criteria (170 (83.3%) grade II anaphylaxis, and 34 (16.7%) grade III; mean age 7.9 years). Previous allergy, anaphylaxis, and asthma were found in respectively 60.8%, 36.8%, and 35.1%. Food allergy was the main suspected causal trigger. Epinephrine was used in 32.7% (n = 65/199), before admission (11.4% (n = 23/201)) or in the emergency department (22.2% (n = 45/202)). Epinephrine was more frequently prescribed in grade III than in grade II anaphylaxis (84.8% vs 22.3%, p < 0.001; OR = 19.05 [7.05-54.10]). Upon discharge, epinephrine auto-injectors prescription and allergy referral were rare (31.7% and 44.2%).Conclusion: Pediatricians intuitively adapt their epinephrine use to the severity of the anaphylaxis and contribute to epinephrine underuse in pediatric anaphylaxis. What is known: • Intramuscular epinephrine is the recommended treatment for pediatric anaphylaxis. However, most of the European and North-American studies show a low prescription rate of epinephrine in both prehospital and pediatric emergency department management. • Reasons for such a low prescription rate are unknown. What is new: • This study confirms that intramuscular epinephrine is poorly prescribed in pediatric anaphylaxis (about one case among 10 before admission and one among 5 in pediatric emergency departments). • Despite recommendations, pediatricians intuitively adapt their prescription to the clinical severity of anaphylaxis, with a fourfold increase prescription in grade III compared to grade II anaphylaxis. This medical behavior ascertainment may be in part explained by the delay between the ED admission/management and the anaphylactic episode onset.

Vibrating-mesh nebulizer maintenance by CF patients: Results from a French survey.

PURPOSE OF THE STUDY: Vibrating-mesh nebulizers are widely used at home for cystic fibrosis (CF) treatment, with a therapeutic efficiency closely linked to the mesh performance. This national study looks at the maintenance at home by CF patients and their families of the mesh of the eFlow®rapid nebulizer. Ninety-two patients from 34 French CF centers, treated at home with inhaled drugs delivered with a vibrating-mesh nebulizer, answered to a phone standardized questionnaire specifying the different techniques of maintenance of the nebulizer. PRINCIPAL RESULTS: Patients were aged from 2 to 68 years (58.7% of children). They inhaled a mean of 1.8 nebulizations per day. Maintenance was assumed by patients in 36% of the cases. All steps of the theoretical maintenance of a nebulizer were respected in 66% of the cases. The mesh was not cleaned in 45.6%, not disinfected or not thermically disinfected in 32.5%, and not rinsed after chemical disinfection in 45.5% of the case. Only 49% of the patients knew the role of the MeshCare® system in the mesh maintenance, and only 39% had already used it when the nebulization duration reached 10 min. CONCLUSIONS: Efforts about education, particularly for the maintenance of the mesh, are needed for CF patients using a vibrating-mesh nebulizer at home.

Early Halt of a Randomized Controlled Study with 3% Hypertonic Saline in Acute Bronchiolitis.

BACKGROUND: Albeit not recommended because of contradictory results, nebulized 3% hypertonic saline is widely used for treating acute viral bronchiolitis. Whether clinical differences may be attributed to the type of nebulizer used has never been studied. OBJECTIVES: By modifying the amount of salt deposited into the airways, the nebulizer characteristics might influence clinical response. METHODS: A prospective, randomized, controlled trial included infants hospitalized in a French university hospital for a first episode of bronchiolitis. Each child received 6 nebulizations of 3% hypertonic saline during 48 h delivered with 1 of the 3 following nebulizers: 2 jet nebulizers delivering large or small particles, with a low aerosol output, and 1 mesh nebulizer delivering small particles, with a high aerosol output. The primary endpoint was the difference in the Wang score at 48 h. RESULTS: Only 61 children of 168 were recruited before stopping this study because of severe adverse events (n = 4) or parental requests for discontinuation due to discomfort to their child during nebulization (n = 2). One minor adverse event was noted in 91.8% (n = 56/61) of children. A high aerosol output induced 75% of the severe adverse events; it was significantly associated with the nebulization-induced cough between 24 and 48 h (p = 0.036). Decreases in Wang scores were not significantly different between the groups at 48 h, 9 recoveries out of 10 being obtained with small particles. CONCLUSION: No beneficial effects and possibly severe adverse events are observed with 3% hypertonic saline in the treatment of bronchiolitis.

Possible alternative strategies to implement basophil activation testing in multicentric studies.

The Basophil Activation Test (BAT) enables flow cytometry characterization of basophil reactivity against specific allergenic molecules. The focus now revolves around democratizing this tool, but, as blood sample stability could be challenging, after having developed a simplified approach, herein, we aimed to characterize two strategies for implementing BAT in multicentric studies: store and ship blood before or after sample processing. Fresh heparin- and EDTA-anticoagulated whole blood samples followed both BAT workflows: "collect, store, process & analyze" or "collect, process, store & analyze". Storage temperatures of 18-25 °C or 2-8 °C and preservation times from 0 to 7 days were considered. Interleukin-3 was also evaluated. With the "collect, store, process & analyze" workflow, heparin-anticoagulated blood and 18-25 °C storage were better than other conditions. While remaining possible, basophil activation exhibited a possible reactivity decay after 24 h. Under the conditions tested, interleukin-3 had no role in enhancing basophil reactivity after storage. Conversely, the "collect, process, store & analyze" workflow demonstrated that either heparin- or EDTA-anticoagulated blood can be processed and kept up to 7 days at 18-25 °C or 2-8 °C before being analyzed. Various strategies can be implemented to integrate BAT in multicentric studies. The "collect, store, process & analyze" workflow remains a simplified logistical approach, but depending on time required to ship from the clinical centers to the reference laboratories, it might not be applicable, or should be used with caution. The "collect, process, store & analyze" workflow may constitute a workflow improvement to provide significant flexibility without impact on basophil reactivity.

Streamlining basophil activation testing to enable assay miniaturization and automation of sample preparation.

BACKGROUND: Numerous studies have demonstrated the capabilities of the basophil activation test (BAT) but various parameters such as a lack of standardization and a time consuming and labor intensive workflow continue to hinder the field to fully leverage the capabilities of this technique. When pediatric patients have to be considered, an additional limitation is related to blood volume consumption. OBJECTIVES: This work aimed at developing and characterizing a simplified and standardized whole-blood based BAT prototype procedure and at further assessing the feasibility of automating and miniaturizing the developed assay into a 96 well plate format. METHODS: A dry and room temperature stable reagent technology was used to simplify and standardize BAT. Under optimized conditions, EDTA anticoagulated whole blood samples of non-allergic and allergic donors (<24 h old) together with calcium containing buffer were added to ready-to-use dry reagent tubes or 96 well plates (negative controls, positive controls and allergen tests) containing a 5 color compensation-free antibody panel (CD45-KrO/CD3-PC7/CRTH2-A647/CD203c-PE/CD63-PB). Upon mixing and incubation at 37 °C for 15 min, erythrocytes were lysed and samples were analyzed by flow cytometry without further washing steps. While it is important to precisely control the incubation time to minimize the assay variability, herein, a 15 min incubation time was chosen as it provides a suitable compromise for both the magnitude of basophil activation and the quality of the staining. A Biomek NXP robotic platform (Beckman Coulter) was used for automation and both CD203c and CD63 levels were monitored to characterize basophil reactivity. RESULTS: This streamlined BAT protocol is no-wash, compensation free and only requires 4 pipetting steps to be completed. The assessment of assay performance characteristics showed wide applicability, satisfactory repeatability and a high degree of standardization as demonstrated by very low intra-assay and inter-operator variabilities (CVs < 10%). Leveraging these technical foundations, it was then proven that this new BAT procedure can easily be transposed into the 96 well plate format, thereby benefiting from a miniaturized format and full automation capabilities. When considering 8 dilution points to characterize the ex vivo basophil reactivity of a given whole blood sample, we found that as little as 5 µL of blood per point could be used. CONCLUSIONS: A whole blood based and simplified procedure for BAT is proposed. It relies on a dry antibody formulation technology and requires only a few manual steps to be completed. This procedure can also be transposed in a 96 well plate format, fully automated and miniaturized, when sample volume reduction, throughput increase or unattended sample preparation is required.

A review of non-cystic fibrosis bronchiectasis in children with a focus on the role of long-term treatment with macrolides.

Bronchiectasis is a rare chronic airway disease arising from several respiratory and systemic diseases. The grade of evidence for specific treatment of childhood bronchiectasis unrelated to cystic fibrosis (CF) is low with very few randomized controlled trials. Treatment has been based mainly on evidence from studies in adults with non-cystic fibrosis bronchiectasis and patients with cystic fibrosis. Recently, long-term treatment with macrolides has been proposed. These molecules offer the advantage of anti-inflammatory and immunomodulatory properties in addition to their antibacterial properties. A total of three randomized double-blind placebo-controlled trials conducted in adults showed that macrolides taken for 6-12 months led to a significant reduction in exacerbation rates. Only one long-term, randomized double-blind placebo-controlled trial was conducted in the pediatric population. It showed that azithromycin administered weekly for up to 24 months reduced pulmonary exacerbations. Further randomized controlled studies are needed to determine the optimal dose and duration of treatment with macrolides. The clinical profile of children who would benefit from this treatment also needs to be determined.

Mast cell tryptase changes with Aspergillus fumigatus - Host crosstalk in cystic fibrosis patients.

Pulmonary and systemic antifungal immunity influences quality of life and survival of people with cystic fibrosis. Aspergillus fumigatus (Af) induces specific IgG and IgE. Mast cells respond to IgE, IgG and direct interactions with Af. Mast cells are the source of the protease tryptase. We aimed at evaluating serum baseline tryptase as a potential biomarker of the Af-host interaction in cystic fibrosis patients. Serum baseline tryptase, IgE and IgG directed to Af extract and Af molecular allergens were measured in 76 cystic fibrosis patients. The main findings were (i) lower levels of serum baseline tryptase in patients displaying specific IgE to Af (p < 0.0001) and (ii) an association between tryptase levels and IgE or IgG responses to Af and ribotoxin (Asp f 1). These findings suggest that serum baseline tryptase is influenced by Af-host interactions and thus might be a marker for mast cell regulation and pulmonary immune defenses.

When Christmas decoration goes hand in hand with bronchial aspiration .

We report the case of a 14-month-old girl suffering from cough and wheeze around Christmas. She was treated with anti-asthmatic drugs with no success, and 3 weeks later a chest X-ray revealed a LED bulb in the left main bronchus. This LED bulb came from a Christmas light garland decorating the Christmas tree. We discuss the different Christmas objects that can be inhaled by young children, the challenge to diagnose bronchial inhalation during this winter period, and the emergence of new foreign bodies, such as LED bulbs, with a particularly aerodynamic shape.

Multivariate Analysis As a Support for Diagnostic Flowcharts in Allergic Bronchopulmonary Aspergillosis: A Proof-of-Concept Study.

Molecular-based allergy diagnosis yields multiple biomarker datasets. The classical diagnostic score for allergic bronchopulmonary aspergillosis (ABPA), a severe disease usually occurring in asthmatic patients and people with cystic fibrosis, comprises succinct immunological criteria formulated in 1977: total IgE, anti-Aspergillus fumigatus (Af) IgE, anti-Af "precipitins," and anti-Af IgG. Progress achieved over the last four decades led to multiple IgE and IgG(4) Af biomarkers available with quantitative, standardized, molecular-level reports. These newly available biomarkers have not been included in the current diagnostic criteria, either individually or in algorithms, despite persistent underdiagnosis of ABPA. Large numbers of individual biomarkers may hinder their use in clinical practice. Conversely, multivariate analysis using new tools may bring about a better chance of less diagnostic mistakes. We report here a proof-of-concept work consisting of a three-step multivariate analysis of Af IgE, IgG, and IgG4 biomarkers through a combination of principal component analysis, hierarchical ascendant classification, and classification and regression tree multivariate analysis. The resulting diagnostic algorithms might show the way for novel criteria and improved diagnostic efficiency in Af-sensitized patients at risk for ABPA.

Correction of CFTR function in nasal epithelial cells from cystic fibrosis patients predicts improvement of respiratory function by CFTR modulators.

Clinical studies with modulators of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein have demonstrated that functional restoration of the mutated CFTR can lead to substantial clinical benefit. However, studies have shown highly variable patient responses. The objective of this study was to determine a biomarker predictive of the clinical response. CFTR function was assessed in vivo via nasal potential difference (NPD) and in human nasal epithelial (HNE) cultures by the response to Forskolin/IBMX and the CFTR potentiator VX-770 in short-circuit-current (∆IscF/I+V) experiments. CFTR expression was evaluated by apical membrane fluorescence semi-quantification. Isc measurements discriminated CFTR function between controls, healthy heterozygotes, patients homozygous for the severe F508del mutation and patients with genotypes leading to absent or residual function. ∆IscF/I+V correlated with CFTR cellular apical expression and NPD measurements. The CFTR correctors lumacaftor and tezacaftor significantly increased the ∆IscF/I+V response to about 25% (SEM = 4.4) of the WT-CFTR level and the CFTR apical expression to about 22% (SEM = 4.6) of the WT-CFTR level in F508del/F508del HNE cells. The level of CFTR correction in HNE cultures significantly correlated with the FEV1 change at 6 months in 8 patients treated with CFTR modulators. We provide the first evidence that correction of CFTR function in HNE cell cultures can predict respiratory improvement by CFTR modulators.

Heterogeneity of lung disease associated with NK2 homeobox 1 mutations.

We retrospectively studied the clinical presentation, treatment modalities and outcome in 16 patients with heterozygous NKX2-1 mutation associated with chronic lung disease. Twelve different NKX2-1 mutations, including 4 novel mutations, were identified in the 16 patients. Nine patients presented with brain-lung-thyroid syndrome, 3 had neurological and lung symptoms and 4 had only pulmonary symptoms. Ten patients had neonatal respiratory distress, and 6 of them developed infiltrative lung disease (ILD). The other patients were diagnosed with ILD in childhood (n = 3) or in adulthood (n = 3). The median age at diagnosis was 36 months (IQ 3.5-95). Patient testing included HRCT (n = 13), BALF analysis (n = 6), lung biopsies (n = 3) and lung function tests (n = 6). Six patients required supplemental oxygen support with a median duration of 18 months (IQ 2.5-29). All symptomatic ILD patients (n = 12) benefited from a treatment consisting of steroids, azithromycin (n = 9), and/or hydroxychloroquine (n = 4). The median follow-up was 36 months (IQ 24-71.5). One patient died of respiratory failure at 18 months and another is waiting for lung transplantation. In summary, the initial diagnosis was based on clinical presentation and radiological features, but the presentation was heterogeneous. Definitive diagnosis required genetic analysis, which should be performed, even in absence of neurological or thyroid symptoms.

Bronchial epithelium in children: a key player in asthma.

Bronchial epithelium is a key element of the respiratory airways. It constitutes the interface between the environment and the host. It is a physical barrier with many chemical and immunological properties. The bronchial epithelium is abnormal in asthma, even in children. It represents a key component promoting airway inflammation and remodelling that can lead to chronic symptoms. In this review, we present an overview of bronchial epithelium and how to study it, with a specific focus on children. We report physical, chemical and immunological properties from ex vivo and in vitro studies. The responses to various deleterious agents, such as viruses or allergens, may lead to persistent abnormalities orchestrated by bronchial epithelial cells. As epithelium dysfunctions occur early in asthma, reprogramming the epithelium may represent an ambitious goal to induce asthma remission in children.

Aucun n'est recommandé et ne remplace la désobstruction rhino-pharyngée.

Use of inhaled treatments in acute viral bronchiolitis in infants. Inhaled therapies are widely used by practitioners for treating acute viral bronchiolitis. Therefore, their efficacy has a low level of proof that does not sustain their use. Even if they need to be better studied in atopic infants, beta-2 agonists have no effect, excepted side effects. Anticholinergic drugs are not recommended. Adrenaline, despite some positive effects, is not recommended too. Corticosteroids are not useful, both for treating the acute problem and for preventing a possible post-viral asthma. Ribavirine, an antiviral agent, is reserved to very precise indications. At last, hypertonic saline, which has given some hopes, nowadays cumulates negative studies, and is no longer recommended. At all, in 2016, any inhaled treatment is recommended for treating acute viral bronchiolitis in infants..

Place des traitements inhalés dans la bronchiolite aiguë du nourrisson. Les traitements inhalés sont largement proposés en pratique clinique en cas de bronchiolite aiguë du nourrisson. Cependant, les niveaux de preuve d'efficacité sont en défaveur de ces traitements. Même s'ils méritent d'être mieux étudiés chez l'enfant atopique, les bêta-2-agonistes ne semblent pas avoir d'autres effets que latéraux. Les anticholinergiques ne sont pas recommandés. L'adrénaline, même si quelques effets positifs sont notés, non plus. Les corticoïdes ne sont utiles ni en aigu ni en prévention d'un potentiel asthme viral. La ribavirine, agent antiviral, est réservée à des indications très ciblées. Le sérum salé hypertonique, après avoir été un espoir, accumule les études négatives et n'est pas non plus indiqué. Au total, en 2016, aucun traitement inhalé n'est recommandé dans la bronchiolite aiguë du nourrisson.

Toxocariasis: An unusual cause of pleural effusion.

Toxocara canis, one of the most frequent parasites worldwide, rarely triggers respiratory symptoms. We report the case of a 5-year-old girl hospitalized for a unilateral eosinophilic pleural effusion due to Toxocara canis. Besides the fact that she was living in a squat, no other medical condition was reported. There was no other site of infection caused by the parasite and she was successfully treated with albendazole. This case report is obviously unique as very few cases of pleural effusion due to Toxocara canis are reported in literature, all in adult patients.