COBRAPed cohort: Do sensitization patterns differentiate children with severe asthma from those with a milder disease?

BACKGROUND: It is unclear whether sensitization patterns differentiate children with severe recurrent wheeze (SRW)/severe asthma (SA) from those with non-severe recurrent wheeze (NSRW)/non-severe asthma (NSA). Our objective was to determine whether sensitization patterns can discriminate between children from the French COBRAPed cohort with NSRW/NSA and those with SRW/SA. METHODS: IgE to 112 components (c-sIgE) (ImmunoCAP® ISAC) were analyzed in 125 preschools (3-6 years) and 170 school-age children (7-12 years). Supervised analyses and clustering methods were applied to identify patterns of sensitization among children with positive c-sIgE. RESULTS: We observed c-sIgE sensitization in 51% of preschool and 75% of school-age children. Sensitization to house dust mite (HDM) components was more frequent among NSRW than SRW (53% vs. 24%, p < .01). Sensitization to non-specific lipid transfer protein (nsLTP) components was more frequent among SA than NSA (16% vs. 4%, p < .01) and associated with an FEV1/FVC < -1.64 z-score. Among sensitized children, seven clusters with varying patterns were identified. The two broader clusters identified in each age group were characterized by "few sensitizations, mainly to HDM." One cluster (n = 4) with "multiple sensitizations, mainly to grass pollen, HDM, PR-10, and nsLTP" was associated with SA in school-age children. CONCLUSIONS: Although children with wheeze/asthma display frequent occurrences and high levels of sensitization, sensitization patterns did not provide strong signals to discriminate children with severe disease from those with milder disease. These results suggest that the severity of wheeze/asthma may depend on both IgE- and non-IgE-mediated mechanisms.

Small airway dysfunction is an independent dimension of wheezing disease in preschool children.

BACKGROUND: Whether small airway dysfunction (SAD), which is prevalent in asthma, helps to characterize wheezing phenotypes is undetermined. The objective was to assess whether SAD parameters obtained from impedance measurement and asthma probability are linked. METHODS: One hundred and thirty-nine preschool children (mean age 4.7 years, 68% boys) suffering from recurrent wheezing underwent impulse oscillometry that allowed calculating peripheral resistance and compliance of the respiratory system (markers of SAD) using the extended RIC model (central and peripheral resistance, inertance, and peripheral compliance). Children were classified using the probability-based approach of GINA guidelines (few, some, and most having asthma). A principal component analysis (PCA) that determined the dimensions of wheezing disease evaluated the links between SAD and asthma probability. RESULTS: Forty-seven children belonged to the few, 28 to the some, and 64 to the most having asthma groups. Whereas their anthropometrics and measured parameters were similar, the most having asthma group exhibited the lowest mean value of airway inertance after bronchodilator probably due to airway inhomogeneities. PCA characterized four independent dimensions including a peripheral resistance (constituted by baseline peripheral compliance, Frs, R5Hz, R5-20Hz, X5Hz, and AX), a central resistance (baseline central resistance, R20Hz), anthropometrics (age and height), and asthma probability (wheezing patterns and therapeutic steps). Thus, PCA showed that the SAD markers were independent from clinical dimensions and were unable to differentiate wheezing phenotypes. CONCLUSIONS: Lung function parameters obtained from impulse oscillometry and asthma probability were belonging to independent dimensions of the wheezing disease.

Determinants of blood eosinophilia in moderate and severe asthmatic patients during childhood: Evidence from the severe asthma molecular phenotype (SAMP) cohort.

BACKGROUND: Asthma is a heterogeneous disease in which the interaction between genetic and environmental factors plays a major role. The significance of blood eosinophil is unclear. The aim of the study was to determine the significance of blood eosinophil count in moderate-to-severe asthmatic children of preschool age and school age. METHODS: This was a prospective cross-sectional study performed from 2011 to 2015 including children from the severe asthma molecular phenotype (SAMP) cohort at Trousseau Hospital (Paris, France). We included children with severe and moderate asthma, or severe and moderate recurrent wheeze, aged from 1 to 15 years at the time of exploration. RESULTS: We analyzed data from 402 children: 248 of preschool age and 154 of school age. Blood eosinophil count third quartile thresholds were 322 and 600 cells/µL for the preschool- and school-age groups, respectively. In multivariate analysis, a blood eosinophil count over this threshold was associated with elevated total IgE (OR = 5.33, P < .01), multiple hospitalizations for asthma attacks (OR = 4.96, P = .03), and a maternal history of asthma (OR = 4.91, P = .01) in preschool children; and with staphylococcal toxin-specific IgE (OR = 2.75, P = .03) in children of school age. Random forest analysis reinforced these results. CONCLUSION: High blood eosinophil count is linked to both atopic features and control of asthma with different parameters associated with these features depending on age.

Allergic Rhinitis and its Impact on Asthma (ARIA) Phase 4 (2018): Change management in allergic rhinitis and asthma multimorbidity using mobile technology.

Allergic Rhinitis and its Impact on Asthma (ARIA) has evolved from a guideline by using the best approach to integrated care pathways using mobile technology in patients with allergic rhinitis (AR) and asthma multimorbidity. The proposed next phase of ARIA is change management, with the aim of providing an active and healthy life to patients with rhinitis and to those with asthma multimorbidity across the lifecycle irrespective of their sex or socioeconomic status to reduce health and social inequities incurred by the disease. ARIA has followed the 8-step model of Kotter to assess and implement the effect of rhinitis on asthma multimorbidity and to propose multimorbid guidelines. A second change management strategy is proposed by ARIA Phase 4 to increase self-medication and shared decision making in rhinitis and asthma multimorbidity. An innovation of ARIA has been the development and validation of information technology evidence-based tools (Mobile Airways Sentinel Network [MASK]) that can inform patient decisions on the basis of a self-care plan proposed by the health care professional.

New perspectives of childhood asthma treatment with biologics.

Asthma is no longer considered as a single disease but rather as a syndrome corresponding to different entities and pathophysiologic pathways. A targeted strategy is part of personalized medicine which aims to better define each patient's phenotype and endotype so as to prescribe the most suitable treatment at an individual level. Omalizumab and, more recently, mepolizumab are the first biologics approved for children (6-18 years). Omalizumab is now widely used to treat severe allergic asthma in children and is highly effective for asthma exacerbations and asthma control with a good safety profile. Moreover, several other drugs-lebrikizumab, dupilumab, tezepelumab, mepolizumab, reslizumab, benralizumab-are used or are being studied in both teenagers and adults and could benefit younger children in the near future. We hypothesize that defining the asthma phenotype/endotype regarding the type and intensity of inflammation, association with allergic or non-allergic comorbidities, and airway remodeling should contribute to the choice of a specific biologic. Pediatric specificities have to be addressed and validated by studies in children. Long-term effectiveness and particularly the impact on the natural history of asthma should also be investigated. Severe asthma in children is a complex disease, and patients have to be referred to a specialized pediatric asthma center to confirm diagnosis and initiate the best treatment strategy which could include biologics while taking into account their high cost.

Unsupervised trajectories of respiratory/allergic symptoms throughout childhood in the PARIS cohort.

BACKGROUND: Natural course and co-occurrence of asthma, eczema, and allergic rhinitis through childhood are still not fully documented. We aim to identify and characterize profiles based on the time course, severity, and apparent triggers of respiratory/allergy symptoms in school-aged children. METHODS: Data on occurrence, severity, and triggers of asthma, rhinitis, and dermatitis symptoms were collected annually during the follow-up of the PARIS birth cohort. Children with similar symptom trajectories until 8-9 years were grouped into profiles using multidimensional (all symptoms considered simultaneously) cluster analysis. Associations between profiles and different health outcomes were analyzed using logistic or linear regression models. RESULTS: Six distinct symptomatic profiles were identified. A profile was defined by persistent dermatitis symptoms, associated with sensitization to food and aeroallergens. Two profiles were characterized by wheezing: one with early transient wheezing and the other with persistent wheezing related to doctor-diagnosed asthma, airway obstruction, and perennial aeroallergen sensitization. Three profiles were characterized by rhinitis symptoms: one non-allergic and two allergic, either with persistent rhinitis symptoms related to allergic multimorbidity and sensitization to perennial aeroallergens, or with late-onset symptoms, related to both pollen and perennial aeroallergens sensitization as well as low lung function. CONCLUSION: This study brings further insights into the developmental profiles of respiratory/allergic outcomes from birth to school age. The identified profiles clearly differed regarding objective features such as diagnosed morbidity, sensitization, or lung function measurements, thus highlighting their biologic and clinical relevance. Allergic rhinitis profiles deserve particular attention, since they were likely to be involved in multimorbidity patterns.

RSV-hRV co-infection is a risk factor for recurrent bronchial obstruction and early sensitization 3 years after bronchiolitis.

To assess risk factors of recurrent bronchial obstruction and allergic sensitization 3 years after an episode of acute bronchiolitis, whether after ambulatory care treatment or hospitalization. A monocentric prospective longitudinal study including infants aged under 1 year with acute bronchiolitis was performed, with clinical (severity score), biological (serum Krebs von den Lungen 6 antigen), and viral (14 virus by naso-pharyngeal suction detection) assessments. Follow-up included a quaterly telephone interview, and a final clinical examination at 3 years. Biological markers of atopy were also measured in peripheral blood, including specific IgEs towards aero- and food allergens. Complete data were available for 154 children. 46.8% of them had recurrent wheezing (RW). No difference was found according to initial severity, care at home or in the hospital, respiratory virus involved, or existence of co-infection. A familial history of atopy was identified as a risk factor for recurrent bronchial obstruction (60% for RW infants versus 39%, P = 0.02), as living in an apartment (35% versus 15%, P = 0.002). 18.6% of the infants were sensitized, with 48.1% of them sensitized to aeroallergens and 81.5% to food allergens. Multivariate analysis confirmed that a familial history of atopy (P = 0.02) and initial co-infection RSV-hRV (P = 0.02) were correlated with the risk of sensitization to aeroallergens at 3 years. Familial history of atopy and RSV-hRV co-infection are risk factors for recurrent bronchial obstruction and sensitization.

Predicting the severity of acute bronchiolitis in infants: should we use a clinical score or a biomarker?

Krebs von den Lungen 6 antigen (KL-6) has been shown to be a useful biomarker of the severity of Respiratory syncytial virus bronchiolitis. To assess the correlation between the clinical severity of acute bronchiolitis, serum KL-6, and the causative viruses, 222 infants with acute bronchiolitis presenting at the Pediatric Emergency Department of Estaing University Hospital, Clermont-Ferrand, France, were prospectively enrolled from October 2011 to May 2012. Disease severity was assessed with a score calculated from oxygen saturation, respiratory rate, and respiratory effort. A nasopharyngeal aspirate was collected to screen for a panel of 20 respiratory viruses. Serum was assessed and compared with a control group of 38 bronchiolitis-free infants. No significant difference in KL-6 levels was found between the children with bronchiolitis (mean 231 IU/mL ± 106) and those without (230 IU/mL ± 102), or between children who were hospitalized or not, or between the types of virus. No correlation was found between serum KL-6 levels and the disease severity score. The absence of Human Rhinovirus was a predictive factor for hospitalization (OR 3.4 [1.4-7.9]; P = 0.006). Older age and a higher oxygen saturation were protective factors (OR 0.65[0.55-0.77]; P < 0.0001 and OR 0.67 [0.54-0.85] P < 0.001, respectively). These results suggest that in infants presenting with bronchiolitis for the first time, clinical outcome depends more on the adaptive capacities of the host than on epithelial dysfunction intensity. Many of the features of bronchiolitis are affected by underlying disease and by treatment.

Natural history of allergic sensitization in infants with early-onset atopic dermatitis: results from ORCA Study.

BACKGROUND: Early-onset atopic dermatitis (AD) is a particular phenotype that may convey a risk of developing multiple sensitizations to allergens but little is known about the pathway of sensitization. The aims of this study were to describe the natural history of sensitization to allergens for this phenotype and to identify the most predictive marker associated with the risk of developing sensitization to inhaled allergens in a well-selected cohort of infants with AD. METHODS: Infants with active AD were enrolled and prospectively explored for biological markers of atopy every year until the age of 6 yr. Allergic sensitization was defined as the presence of positive specific IgEs to allergens and multiple sensitizations as being sensitized to ≥2 allergens. Elevated blood eosinophilia was defined as an eosinophil blood count ≥470 eosinophils/mm(3) and elevated total IgE as a serum IgE level ≥45 kU/l. RESULTS: Two hundred and twenty-nine infants were included. Elevated blood eosinophilia was observed at baseline in 60 children (26.2%) and elevated total IgE in 85 (37.1%). When elevated at baseline, eosinophilia and IgE levels remained significantly higher during the follow-up period. Sensitization to food allergens decreased from 58% to 34%, whereas sensitization to inhaled allergens increased over time from 17% to 67%. Initial multiple sensitizations to food allergens were the most predictive factor for the risk of developing sensitization to inhaled allergens at 6 yr (OR 3.72 [1.68-8.30] p < 0.001). CONCLUSIONS: In the early-onset AD phenotype, multiple sensitization to food allergens conveys a higher risk of sensitization to inhaled allergens than single sensitization.

Features of children with critical asthma hospitalized in a pediatric intensive care unit: Results from the ICU-3A study.

INTRODUCTION: Despite improvements in long-term asthma treatment, an increasing number of children are being hospitalized in pediatric intensive care units (PICU) for asthma. The main objective of this study was to describe a recent cohort of children hospitalized in PICU for asthma to identify risk factors associated with a need for respiratory support, and multiple PICU stays. METHODS: We conducted a retrospective cohort study in three PICUs in Paris (intensive care units 3A Study), using medical files of children hospitalized for asthma between February 2019 and October 2020. Need for respiratory support was defined by the need for high-flow nasal cannula or mechanical ventilation (MV) (either noninvasive [NIV] or invasive [IMV]). RESULTS: During the study period, 252 stays corresponding to 234 patients were analyzed. MV was required in 17.5% of stays, for significantly younger patients (2.37 vs. 4.18 years, p = 0.002). On multivariate analysis, a higher risk of progression to a need for respiratory support was found for children requiring magnesium sulfate or oxygen therapy ≥6 L/mn before PICU admission (RR 4.48; CI95% [1.85-10.89]; p = 0.001, and RR 2.86; CI95% [1.13-7.22]; p = 0.03, respectively), and those with atelectasis detected on chest radiography (RR 3.38; CI95% [1.43-8.00]; p < 0.01). Multiple PICU stays were associated with greater social deprivation (RR for French Deprivation Index 1.25; CI95% [1.03-1.51]; p = 0.03). CONCLUSION: Children experiencing social deprivation are at greater risk of multiple PICU stays for severe asthma. After transfer to PICU, children with chest radiograph detected atelectasis on admission are at higher risk of needing respiratory support.

Objectives for algorithmic decision-making systems in childhood asthma: Perspectives of children, parents, and physicians.

Objectives: To identify with children, parents and physicians the objectives to be used as parameters for algorithmic decision-making systems (ADMSs) adapting treatments in childhood asthma. Methods: We first conducted a qualitative study based on semi-structured interviews to explore the objectives that children aged 8-17 years, their parents, and their physicians seek to achieve when taking/giving/prescribing a treatment for asthma. Following the grounded theory approach, each interview was independently coded by two researchers; reconciled codes were used to assess code frequency, categories were defined, and the main objectives identified. We then conducted a quantitative study based on questionnaires using these objectives to determine how children/parents/physicians ranked these objectives and whether their responses were aligned. Results: We interviewed 71 participants (31 children, 30 parents and 10 physicians) in the qualitative study and identified seven objectives associated with treatment uptake and five objectives associated with treatment modalities. We included 291 participants (137 children, 137 parents, and 17 physicians) in the quantitative study. We found little correlation between child, parent, and physician scores for each of the objectives. Each child's asthma history influenced the choice of scores assigned to each objective by the child, parents, and physician. Conclusion: The identified objectives are quantifiable and relevant to the management of asthma in the short and long term. They can therefore be incorporated as parameters for future ADMS. Shared decision-making seems essential to achieve consensus among children, parents, and physicians when choosing the weight to assign to each of these objectives.

Serum S100B determination in the management of pediatric mild traumatic brain injury.

BACKGROUND: The place of serum S100B measurement in mild traumatic brain injury (mTBI) management is still controversial. Our prospective study aimed to evaluate its utility in the largest child cohort described to date. METHODS: Children younger than 16 years presenting at a pediatric emergency department within 3 h after TBI were enrolled prospectively for blood sampling to determine serum S100B concentrations. The following information was collected: TBI severity determined by using the Masters classification [1: minimal or Glasgow Coma Scale (GCS) 15, 2: mild or GCS 13-15, and 3: severe or GCS <13]; whether hospitalized or not; good or bad clinical evolution (CE); whether cranial computed tomography (CCT) was prescribed; and related presence (CCT+) or absence (CCT-) of lesions. RESULTS: For the 446 children enrolled, the median concentrations of S100B were 0.21, 0.31, and 0.44 µg/L in Masters groups 1, 2, and 3, respectively, with a statistically significant difference between these groups (P < 0.05). In Masters group 2, 65 CCT scans were carried out. Measurement of S100B identified patients as CCT+ with 100% (95% CI 85-100) sensitivity and 33% (95% CI 20-50) specificity. Of the 424 children scored Masters 1 or 2, 21 presented "bad CE." S100B identified bad CE patients with 100% (95% CI 84-100) sensitivity and 36% (95% CI 31-41) specificity. Of the 242 children hospitalized, 81 presented an S100B concentration within the reference interval. CONCLUSIONS: Serum S100B determination during the first 3 h of management of children with mTBI has the potential to reduce the number of CCT scans, thereby avoiding unnecessary irradiation, and to save hospitalization costs.

A simple tool to identify infants at high risk of mild to severe childhood asthma: the persistent asthma predictive score.

BACKGROUND: Recurrent wheezing in infants is a recognized risk factor for the development of childhood asthma. We sought to develop an easy-to-use persistent asthma predictive score (PAPS) in a population of young recurrent wheezers. METHODS: We retrospectively studied clinical and biological data of infants under 2 years of age presenting recurrent wheezing and evaluated current asthma at 6 years of age using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. Multivariate analysis was performed to select predictive variables to generate a PAPS. The score was then tested on another cohort for independent validation. RESULTS: Two hundred infants were included in the cohort used to create the PAPS, and 227 in the validation cohort. In the first population, 47% of the children had developed asthma at 6 years of age, including 33% with mild to severe persistent asthma. Three parameters independently predicted persistent asthma: family history of asthma, personal atopic dermatitis, and multiple allergen sensitizations. Based on these variables, the PAPS showed 42% sensitivity, 90% specificity, 67% positive predictive value, and 76% negative predictive value for the prediction of persistent asthma. It was able to discriminate future persistent asthmatic from nonfuture persistent asthmatic children, with an accuracy of 74% in the initial population and 67% in the validation population. CONCLUSIONS: The PAPS, based on three easy-to-obtain variables, could help the physician in clinical practice to identify infants at high risk for persistent childhood asthma, and thus better evaluate the need for secondary preventive measures.

Rhinovirus Infection and Familial Atopy Predict Persistent Asthma and Sensitisation 7 Years after a First Episode of Acute Bronchiolitis in Infancy.

BACKGROUND: We set out to assess the risk factors for asthma outcome in a cohort of infants who experienced their first episode of acute bronchiolitis. METHODS: A cohort of 222 infants who were included during a first episode of acute bronchiolitis was prospectively followed. Herein, we present the results of their assessments (symptom history, skin prick tests, specific IgE assay, respiratory function tests) at age seven. RESULTS: Of the 68/222 (30.6%) children assessed at age seven, 15 (22.05%) presented with asthma and were mainly males (p = 0.033), 14 (20%) had respiratory allergies, 17 (25%) presented atopic dermatitis and none had a food allergy. Family history of atopy was associated with asthma and sensitisation to aeroallergens at age seven (p = 0.003, p = 0.007). Rhinovirus (hRV) infection and rhinovirus/respiratory syncytial virus (RSV) co-infection were significantly associated with asthma at age seven (p = 0.035, p = 0.04), but not with the initial severity of bronchiolitis. Eosinophil counts at ages three and seven were significantly higher in the asthmatics (p = 0.01, p = 0.046). CONCLUSION: Any infant, especially male, presenting a first episode of acute bronchiolitis due to hRV with a family history of atopy should be closely monitored via follow-up due to a higher risk for asthma at school age.

Two Different Composite Markers Predict Severity and Threshold Dose in Peanut Allergy.

BACKGROUND: Safe and cost-effective biological surrogate markers to evaluate the severity and threshold dose of peanut allergy (PA) reactions during an oral food challenge (OFC) are lacking. OBJECTIVE: To evaluate biological markers associated with the severity and threshold dose of an allergic reaction during an OFC in a population of children with PA. METHODS: Demographic and biological parameters of children with peanut OFC and basophil activation test (BAT) results were collected. Patients were stratified into 2 severity groups (mild-to-moderate and severe) and 2 cumulative threshold dose groups: low (LCTG) ≤100 mg crushed peanut and high >100 mg. RESULTS: Among the 68 children included, there was a 96% concordance between the OFC and BAT result for the diagnosis of PA. Of the 56 children with a positive OFC and BAT to peanut (median age: 8.8 years), the severity of an allergic reaction and the cumulative threshold dose were not correlated (P = .24). Higher Ara h 2-specific IgE and FcεRI-positive control values were both associated with severe reactions to peanut. Combining these 2 markers led to a 92% sensitivity (84%-97%) and an 82% specificity (71%-89%) for severe reactions in all subjects. For children in the LCTG, a 4-variable composite marker, including age, normalized basophil sensitivity (EC50), and FcεRI- and fMLP-positive control values, resulted in a 97% sensitivity (89%-99%) and 61% specificity (49%-71%). CONCLUSION: Distinct composite markers including BAT allergen-specific and non-allergen-specific parameters appear to be associated with severity and cumulative threshold dose in children with PA.

Childhood-onset severe hypereosinophilic asthma: efficacy of benralizumab.

Severe hypereosinophilic asthma in children is extremely rare. This letter adds to the existing literature by providing long-term follow-up, and is the first report of the marked efficacy of benralizumab after failure of other biologic treatments. https://bit.ly/2G7Tc2k.