Staphylococcal Sensitization: A Correlate of Type 2-High Inflammation in Children With Severe Asthma.

BACKGROUND: Sensitization to Staphylococcus aureus enterotoxin (SE) has been identified to be a risk factor for asthma, but its determinants remain unclear. OBJECTIVE: To determine the significance of SE sensitization in children with moderate to severe asthma. METHODS: This was an observational cross-sectional analysis performed from 2011 to 2015 including children from the prospective Severe Asthma Molecular Phenotype cohort: school-age children with severe and moderate asthma or preschool-age children with severe and moderate recurrent wheeze. We evaluated sensitization to four SEs (Staphylococcus enterotoxin A, Staphylococcus enterotoxin B, Staphylococcus enterotoxin C, and toxic shock staphylococcic toxin). RESULTS: We analyzed data from 377 children: 233 of preschool age and 144 of school age. Among them, 26 (11.2%) and 59 (41.0%) children, respectively, had sensitization to at least one SE. The burden of sensitization was higher in older children in terms of both specific IgE levels and the number of sensitizations. In multivariable analysis, SE sensitization was associated with elevated total IgE in both populations (odds ratio [OR] = 9.35, P = .01; and OR = 8.06, P < .01), and with bronchoalveolar lavage eosinophilia in both preschool and school-age children (OR = 3.95, P = .03; and OR = 4.11, P = .03, respectively). Classification and regression trees showed an association of SE sensitization with age and with total IgE in the entire population, and with total IgE, bronchoalveolar lavage eosinophilia, and blood eosinophilia in school-age children. CONCLUSIONS: Staphylococcal enterotoxin sensitization was correlated with type 2-high inflammation (eosinophilic inflammation and elevated total IgE count) in this population of moderate to severe asthmatic children.

Maintenance of Asthma Control in Adolescents with Severe Asthma After Transitioning to a Specialist Adult Centre: A French Cohort Experience.

Background: The prevalence of severe asthma in adolescents is estimated at 6.7%. Transition to adult health services is a vulnerable period for adolescents where there is a risk of poor treatment adherence and loss to follow-up. Purpose: This retrospective study evaluated the maintenance of asthma control in young severe asthmatics, 6 months and 1 year after transition to a specialist adult centre. Methods: Patients with severe asthma treated in a paediatric pulmonology centre in the Île-de-France and referred at least 6 months previously to an adult service were included. Asthma control was evaluated by measuring the ACT score and respiratory function. Patients were asked to answer an on-line questionnaire about their experiences during transition. Results: Fifty-four adolescents with severe asthma underwent transition to the adult service between 2014 and 2021. Thirteen patients (25%) were lost to follow-up after an average of 22.4 months of follow-up. Three-quarters (73%) of patients had well controlled asthma with an ACT score ≥20 during transition and the majority were able to maintain good control and respiratory function (>60% FEV1 >80%) during follow-up in adult pulmonology. Among the patients that answered the questionnaire, 64.8% were satisfied with the transition process. Conclusion: Asthma control and respiratory function were maintained 6 months and 1 year after transition to the adult centre in the majority of patients. Most patients were satisfied with the transition process, but several improvements can be proposed, including early discussion of the medical plan and the implementation of procedures to reduce loss to follow-up.

Omalizumab Effectiveness in Severe Allergic Asthma with Multiple Allergic Comorbidities: A Post-Hoc Analysis of the STELLAIR Study.

BACKGROUND: Immunoglobulin (Ig) E-mediated pathophysiological mechanisms are common in allergic diseases including severe allergic asthma (SAA). The anti-IgE monoclonal antibody omalizumab may be particularly beneficial for patients with SAA and multiple allergic comorbidities (AC) including perennial/seasonal rhinitis, conjunctivitis, atopic dermatitis (AD), and food allergy. METHODS: We conducted a post-hoc analysis of the patients from the STELLAIR study (n=872, 149 minors and 723 adults). The patients were classified based on the presence of multiple AC (≥3 AC or <3 AC) or AD as assessed by questionnaire. Response to omalizumab was assessed after 4-6 months (T4-6) and after 12 months (T12). Asthma response at T4-6 was based on global evaluation of treatment effectiveness, reduction of ≥40% in annual exacerbation rate, and a combination of both. Asthma response at T12 was based on change in yearly exacerbation and hospitalization rates. AC improvement at T12 was based on patient perception. RESULTS: Patients with ≥3 AC demonstrated a higher combined response to omalizumab (74.7% vs 58.3%) at T4-6 and had reduced yearly exacerbation and hospitalization rates (88.9% vs 77.4% and -94.0% vs -70.5%, respectively). Patients with ≥3 AC were more likely to show an improvement in their AC (85.3% vs 51.9%) at T12. Results were similar in minors and adults. The presence of AD was associated with greater omalizumab effectiveness at T4-6 and a greater AC improvement at T12. Improvement of AD and food allergies at T12 were 73.2% and 38.7%, respectively, in the population overall. CONCLUSION: This post-hoc analysis of the STELLAIR study shows that omalizumab is beneficial for all SAA patients and especially for patients with multiple AC or AD. In patients with ≥3 AC, omalizumab also improved AC outcomes.

Mediterranean diet and lung function, sensitization, and asthma at school age: The PARIS cohort.

BACKGROUND: The Mediterranean diet (MD) has known health benefits, but its specific impact on allergy development is unclear. As part of the PARIS birth cohort follow-up, we aimed to investigate the adherence of 8-year-old children to the MD and its association with allergic/respiratory morbidity at school age. METHODS: Diet was assessed using a food frequency questionnaire completed by the parents. Adherence to the MD was assessed based on two scores: the KIDMED index and the Mediterranean Diet Score (MDS). Current allergic diseases (asthma, rhinitis, eczema), lung function indices (FEV1 and FVC), FeNO and specific IgE levels were determined during a health check-up at 8 years. Associations between levels of adherence to the MD and respiratory/allergic morbidity were studied using multivariable logistic and linear regression models adjusted for potential confounders. RESULTS: A total of 975 children were included in the present study, 35.6% with low adherence to the MD, 55.7% with moderate adherence and 8.7% with high adherence according to the KIDMED index. High family socioeconomic status, any breastfeeding at 6 months and consumption of organic food were associated with higher adherence to the MD. Compared with low adherence, high adherence was associated with lower risk of asthma and sensitization at 8 years, as well as higher FEV1 and FVC. CONCLUSION: This study suggests a protective effect of high adherence to the MD on allergic and respiratory morbidity at school age. These results need to be confirmed by further longitudinal analyses. A healthy diet may prevent allergic and respiratory morbidity in school-aged children.

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.

Association between lung function of school age children and short-term exposure to air pollution and pollen: the PARIS cohort.

BACKGROUND: Daily levels of ambient air pollution and pollen may affect lung function but have rarely been studied together. We investigated short-term exposure to pollen and air pollution in relation to lung function in school-age children from a French population-based birth cohort. METHODS: This study included 1063 children from the PARIS (Pollution and Asthma Risk: an Infant Study) cohort whose lung function and FeNO measurements were performed at age 8 years old. Exposure data were collected up to 4 days before testing. We estimated daily total pollen concentration, daily allergenic risk indices for nine pollen taxa, as well as daily concentrations of three air pollutants (particulate matter less than 10 µm (PM10), nitrogen dioxide (NO2), ozone (O3)). Children with similar pollen and air pollution exposure were grouped using multidimensional longitudinal cluster analysis. Associations between clusters of pollen and air pollution exposure and respiratory indices (FEV1, FVC, FeNO) were studied using multivariable linear and logistic regression models adjusted for potential confounders. RESULTS: Four clusters of exposure were identified: no pollen and low air pollution (Cluster 1), grass pollen (Cluster 2), PM10 (Cluster 3) and birch/plane-tree pollen with high total pollen count (Cluster 4). Compared with children in Cluster 1, children in Cluster 2 had significantly lower FEV1 and FVC levels, and children from Cluster 3 had higher FeNO levels. For FEV1 and FVC, the associations appeared stronger in children with current asthma. Additional analysis suggested a joint effect of grass pollen and air pollution on lung function. CONCLUSION: Daily ambient chemical and biological air quality could adversely influence lung function in children.

Emergence of pollen food allergy syndrome in asthmatic children in Paris.

BACKGROUND: Over the last few decades, the level of pollen from birch and homologous trees has increased in parts of Europe. Sensitization to birch pollen allergens (principally Bet v 1) has been associated with food cross-reactivity called pollen food allergy syndrome (PFAS). OBJECTIVE: To evaluate changes in allergic diseases due to IgE sensitization over 25 years in asthmatic children. METHODS: This was a cross-sectional retrospective study conducted in Paris. We analyzed two cohorts of asthmatic children with similar characteristics explored between 1993-1999 (old cohort = OC) and 2012-2018 (recent cohort = RC). RESULTS: 121 children were in the OC and 120 in the RC. An increase in sensitization to tree pollens was found especially for birch pollen, which was 11.6% in the OC and 31% in the RC (P = .0002). Allergic rhinitis prevalence was significantly higher in the RC than in the OC (96% vs 52%, respectively, P < .0001). IgE-mediated food allergy increased from 6% to 16% in the OC and RC, respectively, (P = .01) mainly due to PFAS. In the RC, a higher mean Bet v 1-specific IgE level was observed in children with PFAS compared to children without (105.7 KU/L ± 17.8 and 48.9 kU/L ± 15.7, respectively, P < .05). CONCLUSION: Allergic rhinitis and food allergy with tree pollen sensitization have increased in Paris over 25 years mainly due to PFAS. Environmental factors could be responsible for these modifications as described in the literature.

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.

Infant feeding clusters are associated with respiratory health and allergy at school age in the PARIS birth cohort.

BACKGROUND: As infant feeding may influence allergy development, we aimed to identify groups of infants based on feeding practices and to examine their associations with respiratory health/allergy at 8 years in the PARIS birth cohort. METHODS: Data on breastfeeding, consumption of infant formula (regular, pre-/probiotics, partially hydrolysed with hypoallergenic label [pHF-HA], extensively hydrolysed [eHF], soya) and solid food introduction were collected using repeated questionnaires at 1, 3, 6, 9 and 12 months. Infants with similar feeding practices over the first year of life were grouped using multidimensional longitudinal cluster analysis. Respiratory/allergic morbidity was studied at 8 years as symptoms, doctor's diagnoses (asthma, hay fever, eczema, food allergy), and measurement of lung function, FeNO and specific IgE. Associations between feeding-related clusters and respiratory/allergic morbidity were investigated using multivariable logistic and linear regression models adjusted for potential confounders including early respiratory/allergic outcomes and parental history of allergy. RESULTS: Five clusters were identified among 3446 infants: Cluster 1 (45%) mainly fed with regular formula, Cluster 2 (27%) exclusively breastfed during the first 3 months, and three other clusters consuming different types of formula (pre-/probiotics for Cluster 3 [17%], pHF-HA for Cluster 4 [7%], eHF/soya for Cluster 5 [4%]). Compared to Cluster 1, children from Cluster 2 tended to have a lower risk of asthma and children from Cluster 4 had a significant lower lung function (FEV1 , FVC), higher FeNO and higher risk of sensitization at 8 years. CONCLUSION: Early pHF-HA use was negatively associated with objective measures of respiratory/allergic morbidity at school age, while children breastfed for at least 3 months seem protected against asthma at 8 years old.

Influence of Moderate Hyperbilirubinemia on Cardiorespiratory Control in Preterm Lambs.

Hyperbilirubinemia (HB) is responsible for neonatal jaundice in 60% of term newborns and 90% of preterm infants. Neonatal HB can induce neurological damage (acute HB encephalopathy) and has been associated with persistent apneas. The objective of the present study was to investigate the immediate and delayed effects of moderate, clinically-relevant HB on cardiorespiratory control in preterm lambs. Two groups of five preterm lambs, namely control and HB, were studied. At day five of life, moderate HB (150-250 µmol/L) was induced and maintained during 17 h in the HB group while control lambs received a placebo solution. Six hours after HB onset, 7-h polysomnographic recordings with electrocardiogram (ECG) and respiratory (RESP) signals were performed to assess the immediate effects of HB on heart rate variability (HRV), respiratory rate variability (RRV), and cardiorespiratory interrelations. Identical recordings were repeated 72 h after HB induction to examine the delayed effects of HB on HRV, RRV and cardiorespiratory interrelations. Our results demonstrate a higher HRV and vagal activity immediately after induction of moderate HB. Meanwhile, a decrease in respiratory rate with an increase in both long- and short-term RRV was also noted, as well as a higher amplitude of the respiratory sinus arrhythmia and cardiorespiratory coupling. Seventy-two hours later, the alterations in HRV, RRV, and cardiorespiratory interrelations were attenuated, although a number of them were still present, suggesting a lasting influence of HB on the basal control of the cardiorespiratory system. Our results pave the way for studies in human preterms to assess the relevance of monitoring HRV, RRV, and cardiorespiratory interrelations to detect the acute neurological effects of HB and consequently adapt the treatment of neonatal jaundice.

The IL-4 rs2070874 polymorphism may be associated with the severity of recurrent viral-induced wheeze.

BACKGROUND: Childhood recurrent wheezing and consequently asthma corresponds to various phenotypes. Our aim was to link genetic variants of asthma candidate genes to the phenotypes of early onset wheezing. STUDY DESIGN: We included very young consecutive children presenting with recurrent wheezing who had been evaluated for the severity of wheezing, associated atopic comorbidities, and tested for biomarkers of atopy and inflammation. All were genotyped for 16 single nucleotide polymorphisms (SNPs) linked with asthma or atopy. An unsupervised hierarchical bottom-up method was used for clustering the phenotypes and a multinomial logistic regression was performed for each individual SNP. RESULTS: We replicated the three phenotypes previously described Trousseau Asthma Program in 317 children aged 21.5 ± 7.9 months: cluster 1 (nonatopic uncontrolled severe wheeze), n = 207, a severe viral-induced wheeze, cluster 2 (atopic multiple trigger wheeze), n = 61, with multiple allergic comorbidities, and cluster 3 (episodic viral wheeze), n = 49, a mild viral-induced wheeze. The TT-genotype of the IL-4 rs2070874 polymorphism was significantly associated with the nonatopic uncontrolled severe wheeze compared to the episodic viral wheeze (OR 7.9; CI95% [2.5-25.3]; P = 0.001). CONCLUSION: Association between the TT-genotype of IL-4 rs2070874 polymorphism and a severe phenotype of viral-induced wheeze further underlines the role IL-4 plays in the inflammation pathway leading to viral respiratory infections.

Why and how to explore respiratory allergies in asthmatic patients? / Pourquoi et comment explorer les allergies respiratoires chez l'asthmatique ?

Respiratory allergy is commonly associated with asthma, and affects the short and long-term prognosis of asthma. Its research is an integral part of the evaluation of the asthmatic patient and should be systematic. It can be detected by a multi-allergenic test which must be completed by a careful examination and a complete allergenic assessment in case of positivity. The diagnosis of a respiratory allergy is crucial for long-term management because it may require the implementation of environmental measures, specific allergenic immunotherapy or biotherapy.

L'allergie respiratoire est fréquemment associée à l'asthme dont elle aggrave le pronostic à court et long terme. Elle fait partie intégrante de l'évaluation du patient asthmatique et doit être systématiquement recherchée. Elle peut être dépistée par un test multiallergénique qui doit être complété par un interrogatoire soigneux et un bilan allergologique complet en cas de positivité. Le diagnostic d'une allergie respiratoire est déterminant pour la prise en charge au long cours car elle peut permettre la mise en place de mesures environnementales, d'une immunothérapie allergénique spécifique ou d'une biothérapie.

Moderate Hyperbilirubinemia Alters Neonatal Cardiorespiratory Control and Induces Inflammation in the Nucleus Tractus Solitarius.

Hyperbilirubinemia (HB) occurs in 90% of preterm newborns. Moderate HB can induce acute neurological disorders while severe HB has been linked to a higher incidence of apneas of prematurity. The present study aimed to test the hypothesis that even moderate HB disrupts cardiorespiratory control in preterm lambs. Two groups of preterm lambs (born 14 days prior to term), namely control (n = 6) and HB (n = 5), were studied. At day 5 of life, moderate HB (150-250 µmol/L) was induced during 17 h in the HB group after which cardiorespiratory control as well as laryngeal and pulmonary chemoreflexes were assessed during baseline recordings and during hypoxia. Recordings were repeated 72 h after HB induction, just before euthanasia. In addition, neuropathological studies were performed to investigate for cerebral bilirubin deposition as well as for signs of glial reactivity in brainstem structures involved in cardiorespiratory control. Results revealed that sustained and moderate HB: (i) decreased baseline respiratory rate and increased the time spent in apnea; (ii) blunted the cardiorespiratory inhibition normally observed during both laryngeal and pulmonary chemoreflexes; and (iii) increased heart rate in response to acute hypoxia. These acute physiological changes were concurrent with an activation of Alzheimer type II astrocytes throughout the brain, including the brainstem. Concomitantly, bilirubin deposits were observed in the leptomeninges, but not in brain parenchyma. While most cardiorespiratory alterations returned to normal 72 h after HB normalization, the expression of glial fibrillary acid protein (GFAP) and ionized calcium binding adaptor molecule 1 (Iba1) was still increased within the nucleus tractus solitarius. In conclusion, moderate and sustained HB in preterm lambs induced cardiorespiratory alterations, the latter of which were associated with neurohistopathological changes. These changes are indicative of an inflammatory response in the brainstem neuroanatomical substrates involved in cardiorespiratory control.

Effects of Moderate Hyperbilirubinemia on Nutritive Swallowing and Swallowing-Breathing Coordination in Preterm Lambs.

BACKGROUND: Hyperbilirubinemia (HB) occurs in 90% of preterm newborns. HB induces acute neurological disorders (somnolence, abnormal tone, feeding difficulties, auditory dysfunction) and alterations in respiratory control. These findings suggest brainstem neurotoxicity that could also affect swallowing centers. OBJECTIVE: To test the hypothesis that HB impairs nutritive swallowing (NS) and swallowing-breathing coordination. METHODS: Two groups of preterm lambs (born 14 days prior to term), namely control (n = 6) and HB (n = 5), were studied. On day 5 of life (D0), moderate HB (150-250 µmol/l) was induced during 17 h in the HB group. Swallowing was assessed via recording of pharyngeal pressure and respiration by respiratory inductance plethysmography and pulse oximetry. The effect of HB on NS was assessed during standardized bottle-feeding. A second recording was performed 48 h after recovery from HB (D3). RESULTS: Swallows were less frequent (p = 0.003) and of smaller volume (p = 0.01) in HB lambs while swallowing frequency was decreased (p = 0.004). These differences disappeared after HB normalization. Swallowing-breathing coordination was impaired in HB lambs, with a decrease in percent time with NS burst-related apneas/hypopneas at D0 and D3. Simultaneously, HB lambs tended to experience more severe desaturations (<80%) during bottle-feeding. Finally, following bottle-feeding, the respiratory rate was significantly lower, along with an increased apnea duration in HB lambs. CONCLUSIONS: Swallowing and swallowing-breathing coordination are altered by acute moderate HB in preterm lambs. Decreased efficiency at bottle-feeding is accompanied by continuation of breathing during swallow bursts, which may promote lung aspiration.