Severe Asthma and Biological Therapies: Now and the Future.

Recognition of phenotypic variability in pediatric asthma allows for a more personalized therapeutic approach. Knowledge of the underlying pathophysiological and molecular mechanisms (endotypes) of corresponding biomarkers and new treatments enables this strategy to progress. Biologic therapies for children with severe asthma are becoming more relevant in this sense. The T2 phenotype is the most prevalent in childhood and adolescence, and non-T2 phenotypes are usually rare. This document aims to review the mechanism of action, efficacy, and potential predictive and monitoring biomarkers of biological drugs, focusing on the pediatric population. The drugs currently available are omalizumab, mepolizumab, benralizumab, dupilumab, and 1ezepelumab, with some differences in administrative approval prescription criteria between the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Previously, we described the characteristics of severe asthma in children and its diagnostic and therapeutic management.

Human genetics influences microbiome composition involved in asthma exacerbations despite inhaled corticosteroid treatment.

BACKGROUND: The upper-airway microbiome is involved in asthma exacerbations despite inhaled corticosteroid (ICS) treatment. Although human genetics regulates microbiome composition, its influence on asthma-related airway bacteria remains unknown. OBJECTIVE: We sought to identify genes and biological pathways regulating airway-microbiome traits involved in asthma exacerbations and ICS response. METHODS: Saliva, nasal, and pharyngeal samples from 257 European patients with asthma were analyzed. The association of 6,296,951 genetic variants with exacerbation-related microbiome traits despite ICS treatment was tested through microbiome genome-wide association studies. Variants with 1 × 10-4 

Epigenome-Wide Association Studies of the Fractional Exhaled Nitric Oxide and Bronchodilator Drug Response in Moderate-to-Severe Pediatric Asthma.

Asthma is the most prevalent pediatric chronic disease. Bronchodilator drug response (BDR) and fractional exhaled nitric oxide (FeNO) are clinical biomarkers of asthma. Although DNA methylation (DNAm) contributes to asthma pathogenesis, the influence of DNAm on BDR and FeNO is scarcely investigated. This study aims to identify DNAm markers in whole blood associated either with BDR or FeNO in pediatric asthma. We analyzed 121 samples from children with moderate-to-severe asthma. The association of genome-wide DNAm with BDR and FeNO has been assessed using regression models, adjusting for age, sex, ancestry, and tissue heterogeneity. Cross-tissue validation was assessed in 50 nasal samples. Differentially methylated regions (DMRs) and enrichment in traits and biological pathways were assessed. A false discovery rate (FDR) < 0.1 and a genome-wide significance threshold of p < 9 × 10-8 were used to control for false-positive results. The CpG cg12835256 (PLA2G12A) was genome-wide associated with FeNO in blood samples (coefficient= -0.015, p = 2.53 × 10-9) and nominally associated in nasal samples (coefficient = -0.015, p = 0.045). Additionally, three CpGs were suggestively associated with BDR (FDR < 0.1). We identified 12 and four DMRs associated with FeNO and BDR (FDR < 0.05), respectively. An enrichment in allergic and inflammatory processes, smoking, and aging was observed. We reported novel associations of DNAm markers associated with BDR and FeNO enriched in asthma-related processes.

Classifying asthma control using salivary and fecal bacterial microbiome in children with moderate-to-severe asthma.

BACKGROUND: Uncontrolled asthma can lead to severe exacerbations and reduced quality of life. Research has shown that the microbiome may be linked with asthma characteristics; however, its association with asthma control has not been explored. We aimed to investigate whether the gastrointestinal microbiome can be used to discriminate between uncontrolled and controlled asthma in children. METHODS: 143 and 103 feces samples were obtained from 143 children with moderate-to-severe asthma aged 6 to 17 years from the SysPharmPediA study. Patients were classified as controlled or uncontrolled asthmatics, and their microbiome at species level was compared using global (alpha/beta) diversity, conventional differential abundance analysis (DAA, analysis of compositions of microbiomes with bias correction), and machine learning [Recursive Ensemble Feature Selection (REFS)]. RESULTS: Global diversity and DAA did not find significant differences between controlled and uncontrolled pediatric asthmatics. REFS detected a set of taxa, including Haemophilus and Veillonella, differentiating uncontrolled and controlled asthma with an average classification accuracy of 81% (saliva) and 86% (feces). These taxa showed enrichment in taxa previously associated with inflammatory diseases for both sampling compartments, and with COPD for the saliva samples. CONCLUSION: Controlled and uncontrolled children with asthma can be differentiated based on their gastrointestinal microbiome using machine learning, specifically REFS. Our results show an association between asthma control and the gastrointestinal microbiome. This suggests that the gastrointestinal microbiome may be a potential biomarker for treatment responsiveness and thereby help to improve asthma control in children.

Medication use in uncontrolled pediatric asthma: Results from the SysPharmPediA study.

BACKGROUND: Uncontrolled pediatric asthma has a large impact on patients and their caregivers. More insight into determinants of uncontrolled asthma is needed. We aim to compare treatment regimens, inhaler techniques, medication adherence and other characteristics of children with controlled and uncontrolled asthma in the: Systems Pharmacology approach to uncontrolled Paediatric Asthma (SysPharmPediA) study. MATERIAL AND METHODS: 145 children with moderate to severe doctor-diagnosed asthma (91 uncontrolled and 54 controlled) aged 6-17 years were enrolled in this multicountry, (Germany, Slovenia, Spain, and the Netherlands) observational, case-control study. The definition of uncontrolled asthma was based on asthma symptoms and/or exacerbations in the past year. Patient-reported adherence and clinician-reported medication use were assessed, as well as lung function and inhalation technique. A logistic regression model was fitted to assess determinants of uncontrolled pediatric asthma. RESULTS: Children in higher asthma treatment steps had a higher risk of uncontrolled asthma (OR (95%CI): 3.30 (1.56-7.19)). The risk of uncontrolled asthma was associated with a larger change in FEV1% predicted post and pre-salbutamol (OR (95%CI): 1.08 (1.02-1.15)). Adherence and inhaler techniques were not associated with risk of uncontrolled asthma in this population. CONCLUSION: This study showed that children with uncontrolled moderate-to-severe asthma were treated in higher treatment steps compared to their controlled peers, but still showed a higher reversibility response to salbutamol. Self-reported adherence and inhaler technique scores did not differ between controlled and uncontrolled asthmatic children. Other determinants, such as environmental factors and differences in biological profiles, may influence the risk of uncontrolled asthma in this moderate to severe asthmatic population.

The upper-airway microbiome as a biomarker of asthma exacerbations despite inhaled corticosteroid treatment.

BACKGROUND: The response to inhaled corticosteroids (ICS) in asthma is affected by the interplay of several factors. Among these, the role of the upper-airway microbiome has been scarcely investigated. We aimed to evaluate the association between the salivary, pharyngeal, and nasal microbiome with asthma exacerbations despite receipt of ICS. METHODS: Samples from 250 asthma patients from the Genomics and Metagenomics of Asthma Severity (GEMAS) study treated with ICS were analyzed. Control/case subjects were defined by the absence/presence of asthma exacerbations in the past 6 months despite being treated with ICS. The bacterial microbiota was profiled by sequencing the V3-V4 region of the 16S rRNA gene. Differences between groups were assessed by PERMANOVA and regression models adjusted for potential confounders. A false discovery rate (FDR) of 5% was used to correct for multiple comparisons. Classification models of asthma exacerbations despite ICS treatment were built with machine learning approaches based on clinical, genetic, and microbiome data. RESULTS: In nasal and saliva samples, case subjects had lower bacterial diversity (Richness, Shannon, and Faith indices) than control subjects (.007 ≤ P ≤ .037). Asthma exacerbations accounted for 8% to 9% of the interindividual variation of the salivary and nasal microbiomes (.003 ≤ P ≤ .046). Three, 4, and 11 bacterial genera from the salivary, pharyngeal, and nasal microbiomes were differentially abundant between groups (4.09 × 10-12 ≤ FDR ≤ 0.047). Integrating clinical, genetic, and microbiome data showed good discrimination for the development of asthma exacerbations despite receipt of ICS (AUCtraining: 0.82 and AUCvalidation: 0.77). CONCLUSION: The diversity and composition of the upper-airway microbiome are associated with asthma exacerbations despite ICS treatment. The salivary microbiome has a potential application as a biomarker of asthma exacerbations despite receipt of ICS.

Development of Lung Function in Preterm Infants During the First Two Years of Life.

INTRODUCTION: It remains unclear if prematurity itself can influence post delivery lung development and particularly, the bronchial size. AIM: To assess lung function during the first two years of life in healthy preterm infants and compare the measurements to those obtained in healthy term infants during the same time period. METHODS: This observational longitudinal study assessed lung function in 74 preterm (30+0 to 35+6 weeks' gestational age) and 76 healthy term control infants who were recruited between 2011 and 2013. Measurements of tidal breathing, passive respiratory mechanics, tidal and raised volume forced expirations (V'maxFRC and FEF25-75, respectively) were undertaken following administration of oral chloral hydrate sedation according to ATS/ERS recommendations at 6- and 18-months corrected age. RESULTS: Lung function measurements were obtained from the preterm infants and full term controls initially at 6 months of age. Preterm infants had lower absolute and adjusted values (for gestational age, postnatal age, sex, body size, and confounding factors) for respiratory compliance and V'maxFRC. At 18 months corrected postnatal age, similar measurements were repeated in 57 preterm infants and 61 term controls. A catch-up in tidal volume, respiratory mechanics parameters, FEV0.5 and forced expiratory flows was seen in preterm infants. CONCLUSION: When compared with term controls, the lower forced expiratory flows observed in the healthy preterm group at 6 months was no longer evident at 18 months corrected age, suggesting a catch-up growth of airway function.

Development of Lung Function in Preterm Infants During the First Two Years of Life / Desarrollo de la función pulmonar en lactantes pretérmino durante los 2 primeros años de vida

Introduction: It remains unclear if prematurity itself can influence post delivery lung development and particularly, the bronchial size.AimTo assess lung function during the first two years of life in healthy preterm infants and compare the measurements to those obtained in healthy term infants during the same time period.MethodsThis observational longitudinal study assessed lung function in 74 preterm (30+0 to 35+6 weeks’ gestational age) and 76 healthy term control infants who were recruited between 2011 and 2013. Measurements of tidal breathing, passive respiratory mechanics, tidal and raised volume forced expirations (V’maxFRC and FEF25–75, respectively) were undertaken following administration of oral chloral hydrate sedation according to ATS/ERS recommendations at 6- and 18-months corrected age.ResultsLung function measurements were obtained from the preterm infants and full term controls initially at 6 months of age. Preterm infants had lower absolute and adjusted values (for gestational age, postnatal age, sex, body size, and confounding factors) for respiratory compliance and V’maxFRC. At 18 months corrected postnatal age, similar measurements were repeated in 57 preterm infants and 61 term controls. A catch-up in tidal volume, respiratory mechanics parameters, FEV0.5 and forced expiratory flows was seen in preterm infants.ConclusionWhen compared with term controls, the lower forced expiratory flows observed in the healthy preterm group at 6 months was no longer evident at 18 months corrected age, suggesting a catch-up growth of airway function. (AU)

Introducción: Todavía no está claro si la prematuridad por sí sola puede tener influencia en el desarrollo pulmonar tras el parto y, en particular, en el tamaño bronquial.ObjetivoValorar la función pulmonar durante los 2 primeros años de vida en lactantes pretérmino sanos y comparar las medidas con las obtenidas en lactantes nacidos a término sanos durante el mismo periodo de tiempo.MétodosEste ensayo longitudinal observacional valoró la función pulmonar en 74 lactantes pretérmino (30+0 a 35+6 semanas de edad gestacional) y 76 lactantes nacidos a término sanos como controles, que se seleccionaron entre 2011 y 2013. Se llevaron a cabo las mediciones de la respiración corriente, la mecánica respiratoria pasiva, los flujos espiratorios forzados a volumen corriente y con insuflación previa (V’maxFRC y FEF25-75, respectivamente) tras la sedación con hidrato de cloral siguiendo las recomendaciones de las ATS/ERS a la edad corregida de 6 y 18 meses.ResultadosInicialmente se obtuvieron las medidas de función pulmonar de los lactantes pretérmino y los controles a término a los 6 meses de edad. Los lactantes pretérmino presentaron unos valores absolutos y ajustados (a la edad gestacional, la edad posnatal, el sexo, el tamaño corporal y los factores de confusión) menores para la distensibilidad pulmonar y la V’maxFRC. A los 18 meses de edad posnatal corregida, se repitieron las mismas mediciones en 57 lactantes pretérmino y 61 controles a término. Se observó una recuperación del volumen corriente, los parámetros de mecánica respiratoria, el FEV0,5 y los flujos espiratorios forzados en los lactantes pretérmino.ConclusiónEn comparación con los controles a término, los flujos espiratorios forzados más bajos observados en el grupo de pretérminos sanos a los 6 meses no se observaron a los 18 meses de edad corregida, lo que evidencia un crecimiento de recuperación de la función de la vía respiratoria. (AU)

A System Pharmacology Multi-Omics Approach toward Uncontrolled Pediatric Asthma.

There is a clinical need to identify children with poor asthma control as early as possible, to optimize treatment and/or to find therapeutic alternatives. Here, we present the "Systems Pharmacology Approach to Uncontrolled Pediatric Asthma" (SysPharmPediA) study, which aims to establish a pediatric cohort of moderate-to-severe uncontrolled and controlled patients with asthma, to investigate pathophysiological mechanisms underlying uncontrolled moderate-to-severe asthma in children on maintenance treatment, using a multi-omics systems medicine approach. In this multicenter observational case-control study, moderate-to-severe asthmatic children (age; 6-17 years) were included from four European countries (Netherlands, Germany, Spain, and Slovenia). Subjects were classified based on asthma control and number of exacerbations. Demographics, current and past patient/family history, and clinical characteristics were collected. In addition, systems-wide omics layers, including epi(genomics), transcriptomics, microbiome, proteomics, and metabolomics were evaluated from multiple samples. In all, 145 children were included in this cohort, 91 with uncontrolled (median age = 12 years, 43% females) and 54 with controlled asthma (median age = 11.7 years, 37% females). The two groups did not show statistically significant differences in age, sex, and body mass index z-score distribution. Comprehensive information and diverse noninvasive biosampling procedures for various omics analyses will provide the opportunity to delineate underlying pathophysiological mechanisms of moderate-to-severe uncontrolled pediatric asthma. This eventually might reveal novel biomarkers, which could potentially be used for noninvasive personalized diagnostics and/or treatment.

Streptococcus pneumoniae, an unusual cause of early-onset neonatal sepsis and necrotizing pneumonia.

Vertically transmitted sepsis due to Streptococcus pneumoniae has a low incidence, and vaginal colonization among pregnant women is exceptional. Necrotizing pneumonia is uncommon in immunocompetent term neonates, and the prognosis is uncertain. At present, systematic screening does not seem warranted in pregnant women. Therefore, aggressive treatment of neonates remains the best treatment.

New reference ranges for interpreting forced expiratory manoeuvres in infants and implications for clinical interpretation: a multicentre collaboration.

UNLABELLED: The raised volume rapid thoracoabdominal compression (RVRTC) technique is commonly used to obtain full forced expiratory manoeuvres from infants, but reference equations derived from 'in-house' equipment have been shown to be inappropriate for current commercially available devices. AIM: To explore the impact of equipment differences on RVRTC outcomes, derive robust equipment-specific RVRTC reference ranges and investigate their potential clinical impact on data interpretation. METHOD: RVRTC data from healthy subjects using Jaeger BabyBody or the 'Respiratory Analysis Software Program, RASP' systems were collated from four centres internationally. Data were excluded if gestational age <37 weeks or birth weight <2.5 kg. Reference equations for RVRTC outcomes were constructed using the LMS (lambda-mu-sigma) method, and compared with published equations using data from newborn screened infants with cystic fibrosis (CF). RESULTS: RVRTC data from 429 healthy infants (50.3% boys; 88% white infants) on 639 occasions aged 4-118 weeks were available. When plotted against length, flows were significantly higher with RASP than Jaeger, requiring construction of separate equipment-specific regression equations. When comparing results derived from the new equations with those from widely used published equations based on different equipments, discrepancies in forced expiratory volumes and flows of up to 2.5 z-scores were observed, the magnitude of which increased with age. According to published equations, 25% of infants with CF fell below the 95% limits of normal for FEV0.5, compared with only 10% when using the new equations. CONCLUSIONS: Use of equipment-specific prediction equations for RVRTC outcomes will enhance interpretation of infant lung function results; particularly during longitudinal follow-up.

Patrones inflamatorios en niños asmáticos basados en la determinación de óxido nítrico alveolar / Inflammatory Patterns in Asthmatic Children Based on Alveolar Nitric Oxide Determination

Introducción: El óxido nítrico (NO) puede medirse a nivel proximal (flujo máximo NO en vía aérea [J'awNO]) y distal (concentración alveolar de NO [CANO]). Se han descrito 4 patrones inflamatorios en asmáticos, aunque su relevancia no ha sido bien establecida. El objetivo ha sido determinar el J'awNO y la CANO para establecer 4 categorías inflamatorias en asmáticos. Material y métodos: Estudio transversal de una muestra de niños sanos y asmáticos. Determinación de NO exhalado a flujos múltiples. De acuerdo con el modelo bicompartimental se obtuvieron la CANOy el J'awNO. En asmáticos se realizó cuestionario de control de asma (CAN) y espirometría forzada. Categorización de pacientes en tipo i (J'awNO y CANO normal), tipo ii (J'awNO elevado y CANO normal), tipo iii (J'awNO y CANO elevados) y tipo iv (J'awNO normal y CANO elevado). Estudio de correlación entre FENO,50, J'awNO y CANO mediante R de Spearman. Análisis de la varianza y comparaciones pareadas, mediante corrección post hoc de Bonferroni. Resultados: Se estudiaron 162 niños: 49 (32,23%) controles sanos y 103 (67,76%) asmáticos. Se excluyeron 10 niños, 4 (2.4%) porque las eterminaciones fueron incorrectas y 6 (3,7%) porque las determinaciones no siguieron el modelo lineal (valores de CANO negativos). En controles la FENO,50 (ppb) (mediana y rango) fue 11,5 (1,6-27,3), J'awNO (pl/s) 516 (98,3-1.470) y CANO(ppb) 2,2 (0,1-4,5). De los asmáticos, 44 (42,7%) se categorizaron en tipo i, 41 (39,8%) en tipo ii, 14 (13,5%%) en tipo iii y 4 (3,88%) en tipo iv. Buena correlación entre J'awNO y FENO,50(r = 0,97). No hubo asociación entre J'awNO y CANO. Disminución significativa de FEV1/FVC en tipo iii (media 79,8 ± 7,5). La morbilidad fue significativamente superior en tipos iii y iv. Conclusiones: Los valores de normalidad obtenidos son similares a los previamente publicados. Los asmáticos con CANO elevado presentaron mayor morbilidad. No hay correlación entre inflamación proximal y distal

Introduction: Nitric oxide (NO) levels can be measured at proximal (maximum airway NO flux [J’awNO]) and distal (alveolar NO concentration [CANO]) levels. Four inflammatory patterns have been described in asthmatic individuals, although their relevance has not been well established. The objective was to determine J’awNO and CANO in order to establish four inflammatory categories in asthmatics. Material and methods: Cross-sectional study of a sample consisting of healthy and asthmatic children. Exhaled NO was determined at multiple flows. J’awNO and CANO were obtained according to the two-compartment model. The asthma control questionnaire (ACQ) and spirometry were administered to asthmatic children. Patients were categorized as type i (normal J’awNO and CANO), type ii (elevated J’awNO and normal CANO), type iii (elevated J’awNO and CANO) and type iv (normal J’awNO and elevated CANO). Correlation between FENO,50, J’awNO and CANO was analyzed using Spearman’s R Correlation Test. Analysis of variance and paired comparisons were performed using the Bonferroni correction. Results: One hundred sixty-two children were studied, of whom 49 (32.23%) were healthy controls and 103 (67.76%) asthmatics. In the control subjects, FENO,50 (ppb)(median and range) was 11.5 (1.6 to 27.3), J’awNO (pl/s) was 516 (98.3 to 1470) and CANO (ppb) was 2.2 (0.1 to 4.5). Forty-four (42.7%) of the asthmatic participants were categorized as type i, 41 (39.8%) as type ii, 14 (13.5%) as type iii and 4 (3.88%) as type iv. Good correlation was observed between J’awNO and FENO,50 (r = 0.97). There was no association between J’awNO and CANO. FEV1/FVC decreased significantly in type iii (mean 79.8 ± 7.5). Morbidity was significantly higher in types iii and iv. Conclusions: Normal values obtained are similar to those previously reported. Asthmatics with high CANO showed higher morbidity. No correlation was found between proximal and distal inflammation

Inflammatory patterns in asthmatic children based on alveolar nitric oxide determination.

INTRODUCTION: Nitric oxide (NO) levels can be measured at proximal (maximum airway NO flux [J'aw(NO)]) and distal (alveolar NO concentration [C(ANO)]) levels. Four inflammatory patterns have been described in asthmatic individuals, although their relevance has not been well established. The objective was to determine J'aw(NO) and C(ANO) in order to establish four inflammatory categories in asthmatics. MATERIAL AND METHODS: Cross-sectional study of a sample consisting of healthy and asthmatic children. Exhaled NO was determined at multiple flows. J'aw(NO) and C(ANO) were obtained according to the two-compartment model. The asthma control questionnaire (ACQ) and spirometry were administered to asthmatic children. Patients were categorized as type I (normal J'aw(NO) and C(ANO)), type II (elevated J'aw(NO) and normal C(ANO)), type III (elevated J'aw(NO) and C(ANO)) and type IV (normal J'aw(NO) and elevated C(ANO)). Correlation between FE(NO,50), J'aw(NO) and C(ANO) was analyzed using Spearman's R Correlation Test. Analysis of variance and paired comparisons were performed using the Bonferroni correction. RESULTS: One hundred sixty-two children were studied, of whom 49 (32.23%) were healthy controls and 103 (67.76%) asthmatics. In the control subjects, FE(NO,50) (ppb)(median and range) was 11.5 (1.6 to 27.3), J'aw(NO) (pl/s) was 516 (98.3 to 1470) and C(ANO) (ppb) was 2.2 (0.1 to 4.5). Forty-four (42.7%) of the asthmatic participants were categorized as type I, 41 (39.8%) as type II, 14 (13.5%) as type III and 4 (3.88%) as type IV. Good correlation was observed between J'aw(NO) and FE(NO,50) (r=0.97). There was no association between J'aw(NO) and C(ANO). FEV1/FVC decreased significantly in type III (mean 79.8±7.5). Morbidity was significantly higher in types III and IV. CONCLUSIONS: Normal values obtained are similar to those previously reported. Asthmatics with high C(ANO) showed higher morbidity. No correlation was found between proximal and distal inflammation.

Óxido nítrico exhalado e índice predictivo de asma en menores de dos años / Fraction of Exhaled Nitric Oxide and Asthma Predictive Index in Infants Less Than Two Years-Old

Introducción: La fracción exhalada del óxido nítrico (FENO) se considera marcador indirecto de la inflamacióneosinofílica de la vía aérea. En niños colaboradores la metodología habitual es mediante respiraciónúnica. La imposibilidad de realizarla en niños no colaboradores ha permitido desarrollar la técnica a respiracióncorriente on-line y off-line. El objetivo del estudio ha sido analizar la relación entre la FENO on-linea respiraciones múltiples y el índice predictivo de asma (IPA) en niños menores de dos años.Material y métodos: Estudio observacional y transversal en una muestra consecutiva de niños y niñas entredos meses y dos años de edad, durante un período de 4 meses. Se determinó la FENO postprandial onlinea respiración corriente con respiraciones múltiples y flujo espiratorio entre 40 y 60 ml/s, medianteanalizador de quimioluminiscencia estacionario (CLD 88 sp). Variables cuantitativas: edad, peso, IgE,eosinofilia, FENO, flujo espiratorio. Variables cualitativas: sexo, dermatitis atópica, rinitis alérgica, alergiaalimentaria y medicamentosa, antecedentes familiares de asma y atopia, diagnóstico y tratamiento. Seha analizado la asociación entre IPA y FENO mediante test exacto de Fisher y t de Student y el grado deacuerdo entre IPA y FENO mediante Kappa de Cohen. Se ha estudiado la relación entre eosinofilia, IgE,dermatitis atópica y FENO (test exacto de Fisher y t de Student).Resultados: Cohorte constituida por 38 pacientes. Realizaron las determinaciones con éxito 32 (84,21%)casos. Edad media 10,9±5,06 meses. Los casos con IPA positivo tenían valores de FENO significativamentesuperiores a los IPA negativos con grado de acuerdo entre IPA y FENO de 0,71.Conclusiones: Existe asociación significativa y un buen grado de acuerdo entre la FENO a respiracióncorriente online y el IPA(AU)

Introduction: The fraction of exhaled nitric oxide (FENO) is considered as an indirect marker of eosinophilicinflammation of the airway. In collaborating children the usual method is by a single breath. Theimpossibility of performing this in non-collaborating children has led to the development of the onlineand offline tidal breathing technique. The objective of the study has been to analyse the relationshipbetween the multiple breaths online FENO and the asthma predictive index (API) in children less than 2years-old.Material and methods: An observational and cross-sectional study on a consecutive sample of boys andgirls between 2 months and 2 years of age, over a period of 4 months. The post-prandial multiple breathsonline FENO and flow spirometry between 40 and 60 ml/s, using a stationary chemiluminescence analyser(CLD 88 sp). The quantitative variables were: age, weight, IgE, eosinophilia, FENO, flow spirometry. Thequalitative variables were: gender, atopic dermatitis, allergic rhinitis, food and medical allergies, familyhistory of asthma and atopy, diagnosis and treatment. The relationship between API and FENO was analysedusing the exact Fisher and Student t tests and the level of agreement between API and FENO usingCohen’s Kappa. The relationship between eosinophilia, IgE, atopic dermatitis and FENO was also studied(exact Fisher and Student t tests). Results: The cohort consisted of 38 patients. The determinations were successfully carried out on 32(84.21) of the cases. The mean age was 10.9±5.06 months. The cases with a positive API had significantlyhigher FENO values than those with a negative API, with a level of agreement between API and FENO of0.71.Conclusions: There is a significant relationship and a good level of agreement between the online tidalbreathing FENO and the API(AU)

[Exhaled nitric oxide in children: a noninvasive marker of airway inflammation]. / Oxido nítrico exhalado en niños: un indicador no invasivo de la inflamación de las vías aéreas.

This article is an academic review of the application in children of the measurement of fractional exhaled nitric oxide (FENO). We outline the joint American Thoracic Society/European Respiratory Society recommendations for online measurement of FENO in both cooperating children and children unable to cooperate, offline measurement with uncontrolled exhalation flow rate, offline measurement with controlled exhalation flow rate using a dynamic flow restrictor, and offline measurement during tidal breathing in children unable to cooperate. This is followed by a review of the normal range of values for single-breath online measurements obtained with a chemiluminescence FENO analyzer (geometric mean, 9.7 parts per billion [ppb]; upper limit of the 95% confidence interval, 25.2 ppb). FENO values above 17 ppb have a sensitivity of 81% and a specificity of 80% for predicting asthma of an eosinophilic phenotype. We discuss the response of FENO values to anti-inflammatory treatment and the use of this marker in the management of asthma. Results obtained with chemiluminescence and portable electrochemical analyzers are compared. The portable devices offer the possibility--in children over 5 years of age--of accurate and universal monitoring of exhaled nitric oxide concentrations, an emerging marker of eosinophilic inflammation in asthma that facilitates diagnosis, monitoring of disease progression, and assessment of response to therapy.

Óxido nítrico exhalado en niños: un indicador no invasivo de la inflamación de las vías aéreas / Exhaled nitric oxide in children: a noninvasive marker of airway inflammation

En este artículo se presenta una revisión académica sobre la aplicabilidad de la medida de la fracción exhalada de óxido nítrico (FENO) en niños. De acuerdo con las normas conjuntas de la American Thoracic Society/European Respiratory Society, se describen los métodos de medida on-line en niños colaboradores y no colaboradores, los registros off-line sin control de flujo de exhalación y con control de flujo de exhalación mediante restrictor de flujo dinámico, y el registro off-line a respiración corriente en niños no colaboradores. Se revisan los valores de normalidad, fundamentalmente con los analizadores de la FENO por quimioluminiscencia, mediante registro on-line de una única respiración (media geométrica: 9,7 ppb ­partes por mil millones­; límite superior del intervalo de confianza del 95%: 25,2 ppb). Los valores de la FENO superiores a 17 ppb aportan un 81% de sensibilidad y un 80% de especificidad para predecir asma de fenotipo eosinofílico. Se analiza la respuesta de la FENO al tratamiento antiinflamatorio y al seguimiento del asma. Por último, se comparan los resultados entre los analizadores por quimioluminiscencia y los electroquímicos, portátiles. Estos últimos ofrecen la posibilidad, en niños mayores de 5 años, de un seguimiento adecuado y universal del óxido nítrico exhalado como indicador emergente de la inflamación eosinofílica en la enfermedad asmática, de modo que facilitan el diagnóstico, el control evolutivo y el seguimiento terapéutico

We outline the joint American Thoracic Society/European Respiratory Society recommendations for online measurement of FENO in both cooperating children and children unable to cooperate, offline measurement with uncontrolled exhalation flow rate, offline measurement with controlled exhalation flow rate using a dynamic flow restrictor, and offline measurement during tidal breathing in children unable to cooperate. This is followed by a review of the normal range of values for single-breath online measurements obtained with a chemiluminescence FENO analyzer (geometric mean, 9.7 parts per billion [ppb]; upper limit of the 95% confidence interval, 25.2 ppb). FENO values above 17 ppb have a sensitivity of 81% and a specificity of 80% for predicting asthma of an eosinophilic phenotype. We discuss the response of FENO values to anti-inflammatory treatment and the use of this marker in the management of asthma. Results obtained with chemiluminescence and portable electrochemical analyzers are compared. The portable devices offer the possibility--in children over 5 years of age--of accurate and universal monitoring of exhaled nitric oxide concentrations, an emerging marker of eosinophilic inflammation in asthma that facilitates diagnosis, monitoring of disease progression, and assessment of response to therapy