Pediatric Pulmonology

Aims of the studyRoutinely collected health data are increasingly used for research, however important history items may be incomplete in medical records. We assessed clinical documentation of exercise-induced respiratory symptoms (EIS) by treating physicians and compared with parent-reported EIS for the same children. MethodsWe analysed data from the Swiss Paediatric Airway Cohort (SPAC), a multicentre observational study of children treated in Swiss outpatient pulmonology clinics. We included children 6 to 17 years of age who were referred to a paediatric pulmonologist for evaluation of EIS. Features of EIS recorded by physicians were extracted from outpatient clinical letters transmitted to the referring physician, while parent-reported EIS data were collected from a standardized questionnaire completed at SPAC enrolment. We calculated agreement between physician-documented and parent-reported EIS characteristics using Cohens and Fleisss kappa. ResultsOf 1669 children participating in SPAC (2017-2019), 193 (12%) met the inclusion criteria, of whom 48% were girls. Physicians provided detailed information on EIS in 186 (96%) outpatient clinical letters. Documented characteristics included: type of physical activity triggering EIS (69%), localisation of EIS in chest or throat (48%), respiratory phase of EIS (45%), and timing of EIS during or after exercise (37%). Previous bronchodilator use (94%) and its effect on EIS (88%) were consistently documented by physicians. The clinical letters of children diagnosed with dysfunctional breathing more often contained detailed EIS characteristics than for children diagnosed with asthma. The agreement between physician-documented and parent-reported EIS was moderate for use of bronchodilators (k=0.53) and poor to fair for all other features (k=0.01-0.36). ConclusionThis study highlights that outpatient clinical letters may lack some details on EIS characteristics, information which parents could provide. A standardized and detailed method for documenting paediatric respiratory symptoms in the coordinated data infrastructure may enhance future analyses of routinely collected health data.

INTRODUCTIONBronchial asthma (BA) is a heterogeneous pulmonary disease with various phenotypes based on detection of multiple biomarkers. However, most of the biomarkers are still experimental and present limitations for clinical practice. OBJECTIVEThe purpose of this study was to investigate the relationship between the level of the available T2-inflammatory biomarkers in childhood with poor asthma control and features of asthma management. MATERIAL AND METHODSThe study comprised 100 patients aged 5-17 years (median age 13 years) with an established bronchial asthma diagnosis. The level of asthma control of each patient was assessed by the Asthma Control Test (ACT and C-ACT) and the Composite Asthma Severity Index (CASI). T2-inflammatory biomarkers of the mucous membranes of the respiratory tract include total immunoglobulin E (IgE total) levels, peripheral blood eosinophil levels, fractional exhaled nitric oxide (FeNO) and a nasal smear eosinophil count. A measure of association was determined by standard statistical methods for data analysis. RESULTSDespite the prescribed basic therapy, the majority of children do not achieve adequate asthma symptom control. This research revealed that 43% of patients had at least one or more elevated markers of T2-inflammation. High levels of IgE total, increased levels of blood eosinophils ([≥]400 cells/{micro}L), as well as high FeNO values ([≥] 20 ppb) prevail in children with partially controlled and uncontrolled asthma. The most significant biomarker of poor asthma control in children is the total serum IgE concentration [≥] 100 IU/ml. In addition, a significant positive correlation was found between peripheral blood eosinophil levels and the ACT/C-ACT scores (r=0.287, p=0.0039). CONCLUSIONAllergic asthma in children is typically associated with Th2-lymphocytes predominance and eosinophilic airway inflammation. T2-inflammatory biomarkers may be useful in assessing airway inflammation activity and asthma-control assessment in children.

BackgroundAsthma is a frequent comorbidity in children with sickle cell disease and has been associated with an increased risk of acute complications, particularly vaso-occlusive crises and acute chest syndrome. However, determinants of clinical severity among children with sickle cell disease and confirmed asthma remain poorly characterized, especially in tropical settings. This study aimed to identify factors associated with clinical severity in this population. MethodsWe conducted an observational study among children with sickle cell disease followed in French Guiana. The analysis was restricted to children with confirmed asthma. Clinical severity was defined as the occurrence of at least two hospitalizations during the 12 months preceding evaluation for vaso-occlusive crises and/or acute chest syndrome. Factors associated with severity were assessed using univariate and multivariate logistic regression analyses. ResultsA total of 138 children with sickle cell disease and confirmed asthma were included, of whom 49 (35.5%) presented a severe clinical form. In multivariate analysis, no variable was independently associated with clinical severity. However, a trend toward an increased risk of severe disease was observed among children living in rural areas (adjusted OR = 1.94; 95% CI: 0.77-4.86), while a trend toward a protective effect was observed for Strongyloides stercoralis infection (adjusted OR = 0.18; 95% CI: 0.02-1.51). Allergic sensitization, although frequent (64.5%), was not associated with clinical severity after adjustment (adjusted OR = 0.66; 95% CI: 0.31-1.44). ConclusionAmong children with sickle cell disease and confirmed asthma, more than one third experience severe clinical disease. Severity does not appear to be driven by allergy but may be influenced by environmental and contextual factors specific to tropical settings. These findings support a stratified approach to sickle cell-associated asthma to identify high-risk children and prevent avoidable acute complications.

ObjectiveThis systematic review aims to identify social risk factors that influence pediatric asthma exacerbations. MethodsCohort studies published between 2010 and 2020 were systematically searched on the OVID Medline, Embase, and PsycInfo databases. Using our established phased inclusion and exclusion criteria, studies that did not address a pediatric population, social risk factors, and asthma exacerbations were excluded. Out of a total of 707 initially retrieved articles, 3 prospective cohort and 6 retrospective cohort studies were included. ResultsUpon analysis of our retrieved studies, two overarching domains of social determinants, as defined by Healthy People 2030, were identified as major risk factors for pediatric asthma exacerbations: Social/Community Context and Neighborhood/Built Environment. Social/Community factors including African American race and inadequate caregiver perceptions were associated with increased risk for asthma exacerbations. Patients in high-risk neighborhoods, defined by lower levels of education, housing, and employment, had higher rates of emergency department readmissions and extended duration of stay. Additionally, a synergistic interaction between the two domains was found such that patients with public or no health insurance and residence in high-risk neighborhoods were associated with excess hospital utilization attributable to pediatric asthma exacerbations. ConclusionSocial risk factors play a significant role in influencing the frequency and severity of pediatric asthma exacerbations. 3-Question Summary BoxO_ST_ABS1. What is the current understanding of this subject?C_ST_ABSThe individual impact of social factors such as insurance, neighborhood, and ethnicity on pediatric asthma exacerbations has previously been explored. 2. What does this report add to the literature?This review systematically identifies the relative importance of individual sociodemographic factors and interactions between them. Race, neighborhood risk, insurance status, caregiver perceptions, and a synergistic interaction between health insurance status and neighborhood risk were found to be contributary. 3. What are the implications for public health practice?It is important for providers to educate patients on how their surroundings impact their respiratory health and advocate for increased healthcare access for at-risk populations.

Population-based studies of children presenting with dry night cough alone compared with those who also wheeze are few and inconclusive. Luftibus in the school is a population-based study of schoolchildren conducted between 2013-2016 in Zurich, Switzerland. We divided children into four mutually exclusive groups based on reported dry night cough ( cough) and wheeze and compared parent-reported symptoms, comorbidities and exposures using multinomial regression, FeNO using quantile regression, spirometry using linear regression and healthcare use and treatments using descriptive statistics. Among 3457 schoolchildren aged 6-17 years, 294 (9%) reported cough, 181 (5%) reported wheeze, 100 (3%) reported wheeze and cough and 2882 (83%) were asymptomatic. Adjusting for confounders in a multinomial regression, children with cough reported more frequent colds, rhinitis and snoring than asymptomatic children; children with wheeze or wheeze and cough more often reported hay fever, eczema and parental histories of asthma. FeNO and spirometry were similar among asymptomatic and children with cough, while children with wheeze or wheeze and cough had higher FeNO and evidence of bronchial obstruction. Children with cough used healthcare less often than those with wheeze, and they attended mainly primary care. Twenty-two children (7% of those with cough) reported a physician diagnosis of asthma and used inhalers. These had similar characteristics as children with wheeze. Our representative population-based study suggests only a small subgroup (7%) of schoolchildren reporting dry night cough without wheeze have features typical of asthma, yet the majority (93%) should be investigated for alternative aetiologies, particularly upper airway disease. Take home messageOur population-based study found children with night cough alone clearly differ from those with wheeze, suggesting different aetiologies and pathophysiology. Yet, a small subgroup (7%) has features of asthma and may benefit from specific work-up.

IntroductionAsthma poses a diagnostic challenge due to its intermittent symptoms and variable airflow obstruction. Diagnostic assessments such as spirometry and bronchodilator response are frequently non-diagnostic, necessitating confirmatory bronchial provocation testing. Biomarkers of type-2 inflammation --exhaled nitric oxide (FeNO) and blood eosinophil counts (BEC)-- are useful in asthma, but their diagnostic values in children and in combination (FeNO+BEC) are unclear. This systematic review will evaluate the diagnostic accuracy of FeNO alone or in combination with BEC in paediatric and adult asthma. Methods and AnalysisThis protocol is reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols. The review will include studies of any design on the diagnostic accuracy of FeNO with or without BEC in asthma compared to the reference standards bronchodilator response and provocation testing in patients [≥] 5 years old selected from MEDLINE, Embase, and Cochrane CENTRAL databases. Screening, study selection, and data extraction will be independently performed by two reviewers. Risk of bias will be assessed using QUADAS-2 and QUADAS-C. Meta-analysis will be carried out by pooling the sensitivity and specificity of FeNO alone or in combination with BEC in a bivariate random effects model allowing the generation of summarised operating characteristic curves and summary points. Further analysis utilising a multiple thresholds model will enable the computation of diagnostic thresholds for FeNO. Ethics and DisseminationNo patient data will be stored without prior approval from ethics committee. The findings will be submitted in a peer-reviewed publication. RegistrationPROSPERO CRD42023489738 SOCIAL MEDIA MESSAGEDiagnosing asthma is challenging. Spirometry and bronchodilator reversibility are often non-diagnostic, calling for provocation testing. Our systematic review will explore complementary approaches using FeNO with and without the blood eosinophil count.

BackgroundClinical practice guidelines for asthma diagnosis are rarely evaluated in real-life practice. Within the Swiss Paediatric Airway Cohort (SPAC), we initiated the SPAC-asthma project to develop a standardised diagnostic approach for school-aged asthma, based on the algorithm recommended by the European Respiratory Society (ERS) guideline. Here, we report the development and feasibility of this approach after implementation across multiple paediatric pulmonology clinics. MethodWe used a modified Delphi process with paediatric pulmonologists from participating clinics to tailor the ERS algorithm for feasible implementation in children aged 5-17 years with suspected asthma. Key adaptations included selection of initial tests, criteria for further testing, test cutoffs, the role of medication trial and follow-up procedures. One year after implementation, we evaluated adherence to the adapted approach at four clinics and explored the reasons for any deviations. ResultsThe final SPAC-asthma approach included spirometry, fractional exhaled nitric oxide and allergy testing as initial tests, followed by either bronchodilator reversibility testing, bronchial challenge test or medication trial. Overall adherence after one year was 77% (182/236 patients). Deviations were due to practice-related (e.g., different criteria for bronchial obstruction), patient-related (e.g., inability to perform spirometry), and logistical reasons (e.g., scheduling difficulties). ConclusionThe diagnostic approach was well implemented, but the observed deviations highlighted the need for flexibility when applying guidelines in real-world settings. As a next step, we will assess whether implementing the ERS asthma guidelines in school-aged children improves diagnostic accuracy. Take home messageWe tested a standardised ERS guideline-based approach to diagnose school-age asthma across Swiss paediatric pulmonology clinics. After expert adaptation and a year, adherence was good and we identified areas to improve guideline implementation.

BackgroundWheezing and asthma exacerbations are leading causes of pediatric hospital admissions. Predicting which children will experience persistent exacerbations remains challenging. Prior research has identified immune endotypes in the nasal epithelium of children with acute asthma and wheezing, characterized by varying balances of interferons and inflammatory markers. Notably, children exhibiting low interferon responses coupled with high inflammation are at an increased risk for recurrent respiratory exacerbations. ObjectiveThis study aims to determine if blood-based gene network biomarkers can detect immune endotypes in children presenting with acute wheeze and asthma, potentially serving as predictive tools for future exacerbations. MethodsWe conducted gene expression analysis using microarrays of peripheral blood mononuclear cell (PBMC) samples from pediatric patients who presented to hospital for acute wheeze and asthma. Personal network inference was employed to discern gene expression patterns, facilitating the classification of patients into distinct immune endotypes. ResultsThree immune endotypes were identified. One endotype, characterized by low interferon responses and elevated expression of both innate and adaptive immune pathways, was significantly associated with an increased risk of subsequent hospital respiratory presentations and a persistent pattern of respiratory exacerbations over time. ConclusionPBMC-based personal gene network biomarkers can effectively identify immune endotypes correlating with clinical outcomes in pediatric asthma. The high-risk endotype represents a potential treatable trait in acute wheezing episodes. Therapeutic strategies aimed at enhancing interferon responses and/or reducing inflammation may benefit this subgroup. Clinical ImplicationsWe have identified a potential treatable trait of paediatric asthma and wheezing. Classifying children based on their immune profiles may enable tailored management strategies aligned with their future exacerbation risk. Capsule SummaryPersonal gene network biomarkers effectively identifies immune endotypes correlating with clinical outcomes in pediatric asthma. The high-risk endotype, marked by low interferon responses and high innate and adaptive inflammation represents a potential treatable trait in acute wheezing episodes.

BackgroundIt is well established that there are different asthma phenotypes, but whereas determinants of atopic asthma are well studied, little is known about non-atopic asthma. We compared risk factors for atopy, atopic asthma (AA) in atopics, and non-atopic asthma (NAA) in non-atopics, in children in a wide variety of countries. MethodsUsing four studies, across 23 countries, we assessed asthma status and atopy (skin prick tests) for children aged 6-17, plus risk factors from housing, heating, pets, family, diet, and air-quality categories. Using mixed effects logistic regression models we assessed risk factors over 4 pathways: Pathway 1: non-atopic non-asthma to NAA; Pathway 2: non-atopic non-asthma to atopy (no asthma); Pathway 3: atopic non-asthma to AA; Pathway 4: non-atopic non-asthma to AA. We compared the log odds of risk factors between pathways using Pearsons correlation coefficient. ResultsOur final sample of 32741 children comprised 67% with neither atopy nor asthma, 15% with atopy but without asthma, 8% with AA and 10% with NAA. Risk factors were similar between Pathway 1 and Pathway 3 (Pearsons correlation = 0.81, 95% confidence interval = [0.68, 0.94]). In contrast, risk factors differed between Pathway 2 and Pathway 3 (-0.06, [-0.29, 0.17]). DiscussionThese findings indicate that although atopy increases the risk of asthma, the risk factors for subsequently developing asthma are generally the same in those with and without atopy. This raises important questions about the role of atopy in asthma, particularly whether it is an inherent part of the aetiological process or is coincidental. Key messagesO_ST_ABSWhat is already known on this topicC_ST_ABSIt is well established that there are different phenotypes of asthma but little is known about risk factors for non-atopic asthma. What this study addsUsing a novel approach, we found that lifestyle and environmental risk factors for developing asthma are generally similar in atopic children and non-atopic children but the risk factors for atopy are quite different. How this study might affect research, practice or policyOur findings suggest that atopy and asthma may be coincidental in a large proportion of children who are defined as having atopic asthma. This has important implications for our understanding of the causes and mechanisms of different asthma phenotypes, and therefore prevention and treatment of asthma.

ObjectiveTo examine whether the use of gas stoves in the home is associated with increased asthma severity among children and adolescents ages 0-17 in the US. MethodsUsing the 2020 CDC Asthma Call-Back Survey for children, the association between gas stove usage and childhood asthma symptoms, asthma attack or episode, and emergency department visit for asthma was assessed. With a cross-sectional study design, bivariate analyses and multivariable logistic regression were conducted. Survey weights were used in the analyses for US population-based estimates. ResultsChildren who live in a household that uses gas for cooking or has a gas stove had 1.133 (95% CI: 0.48, 2.68)) times the odds of having an asthma attack or episode within the past 12 months, 9.141 (95% CI: 1.99, 42.06) times the odds of having visited the emergency department or urgent care within the past 12 months, and 1.739 (95% CI: 1.02, 2.95) times the odds of recent symptoms of asthma compared to children who live in a household that does not use gas for cooking or does not have a gas stove, controlling for all confounders. There is an association between the usage of gas stoves and asthma symptoms, asthma attacks/episodes, and ED visits among asthmatic children. Reducing the exposure of gas stove usage should be a consideration in regards to existing and future interventions to prevent childhood asthma and reduce exacerbation of underlying childhood asthma.

Background Recent guidelines differ in how fractional exhaled nitric oxide (FeNO) is used to diagnose school-age asthma, either as one of several tests with a cut-off at 25 ppb or as a single rule-in test at 35 ppb. Evidence on its diagnostic performance and clinical utility in subgroups remain limited. Methods We analysed data from 1,979 school-age children in the Swiss Paediatric Airway Cohort referred for suspected asthma. We investigated FeNO performance with diagnosis by paediatric pulmonologists as reference standard using receiver operating characteristics curves, selected cut-offs and simulated predictive values across different prevalence. Subgroup analyses considered allergic sensitisation with allergic rhinitis and current inhaled corticosteroid (ICS) use. Results In the overall cohort (asthma diagnosis 70%), FeNO showed poor discrimination for asthma (AUC 0.66; 95% CI 0.64-0.68) with an optimal cut-off at 22 ppb. At 25 and 35 ppb, sensitivity was low (43%, 95% CI 40-46; 31%, 95% CI 29-34) and specificity moderate to high (84%, 95% CI 77-84; 90%, 95% CI 87-92). Positive predictive value at 35 ppb was 88% and was 57% when simulated at a prevalence of 30%. FeNO had no diagnostic value in non-sensitised children and lower performance in sensitised children with allergic rhinitis than in those without (AUC 0.59 vs 0.68). Current ICS use did not influence performance. Conclusion FeNO has limited diagnostic performance as a stand-alone test for school-age asthma, and underlying asthma prevalence and allergic characteristics should be considered in the interpretation.

BackgroundAsthma is a complex chronic inflammatory disease affecting approximately 339 million people worldwide. The ADAM33 gene, encoding a disintegrin and metalloproteinase, has emerged as a key susceptibility gene for asthma, with the rs2280091 (T1) polymorphism showing variable associations across different populations. This study represents the first genetic investigation of asthma in the Syrian population. MethodsA case-control study was conducted at Aleppo University Hospital from April to November 2019, including 100 participants (80 asthma patients and 20 healthy controls) aged 20-40 years. Asthma diagnosis was confirmed using spirometry and reversibility testing according to GINA guidelines. Genomic DNA was extracted from whole blood, and the rs2280091 polymorphism was genotyped using PCR-RFLP with NcoI restriction enzyme. Statistical analysis was performed using SPSS 25.0 with significance set at p[≤]0.05. ResultsThe study population showed balanced sex distribution (50% male, 50% female) with mean ages of 26.13 years (cases) and 29.65 years (controls). Genotype frequencies were: A/A (43.0%), A/G (45.0%), and G/G (12.0%), with allele frequencies of A=0.66 and G=0.34, conforming to Hardy-Weinberg equilibrium. While no significant association was found between genotype and asthma occurrence (p=0.871), the G/G genotype showed significant association with increased asthma severity (p=0.016). ANOVA analysis revealed significantly lower FEV1 values in G/G carriers compared to A/A and A/G genotypes (p=0.001). ConclusionsThe ADAM33 rs2280091 G/G genotype is significantly associated with increased asthma severity in the Syrian population, suggesting its potential utility as a genetic marker for severe asthma phenotypes. This finding contributes to understanding asthma genetics in Middle Eastern populations and supports the role of ADAM33 in airway remodeling processes.

BackgroundLongitudinal measurements of intra-breath respiratory impedance (Zrs) in preschool-aged children may be able to distinguish abnormal lung function trajectories in children with a history of wheezing compared to healthy ones. MethodsChildren from a prospective, longitudinal community-based cohort performed annual intra-breath oscillometry (IB-OSC) measurements from age 3-years to 7-years. IB-OSC was performed using a single 10 Hz sinusoid while clinically asymptomatic. Linear mixed-effects models were developed to explore the effects of wheezing phenotypes, growth, and sex on seven IB-OSC outcome variables over time: resistance at end-expiration (ReE), resistance at end-inspiration (ReI), the tidal change in resistance ({Delta}R=ReE-ReI), reactance at end-expiration (XeE), reactance at end-inspiration (XeI), the tidal change in reactance ({Delta}X=XeE-XeI), and {Delta}X normalised by tidal volume ({Delta}X/VT). ResultsEighty-five children produced 375 acceptable IB-OSC measurements. Subjects were classified into one of three wheeze groups: never (n=36), transient (n=35), or persistent (n=14). After adjusting for height, children with persistent wheezing, compared to those who never wheezed, had -0.669 hPa{middle dot}s{middle dot}L -1 XeE (95% confidence interval [CI] -1.102 to -0.237, p<0.01), -0.465 hPa{middle dot}s{middle dot}L -1 {Delta}X (95%CI -0.772 to -0.159, p<0.01) and +1.433 hPa{middle dot}s{middle dot}L -1 {Delta}X/VT (95%CI +0.492 to +2.374, p<0.01). Increasing subject height had a significant effect on all IB-OSC resistance and reactance variables when adjusted for the effect of preschool wheezing. ConclusionsIB-OSC is feasible for tracking lung function in preschool-aged children, and intra-breath reactance outcomes may allow abnormal lung function to be identified early in asymptomatic children with a history of persistent wheeze.

RationaleVitamin-D-binding-protein transports vitamin-D metabolites and regulates vitamin-D levels in circulation. Additionally, maternal vitamin-D levels during pregnancy plays an important role in lung development and childhood asthma occurrence. ObjectivesThis study analyzes the joint effect of maternal 25-hydroxyvitamin-D and vitamin-D-binding-protein on offspring asthma. Methods806 mother-child pairs who participated in the Vitamin D Antenatal Asthma Reduction Trial were included in this analysis. The primary outcome was offspring asthma by age 3. Maternal plasma vitamin-D-binding-protein levels were measured for 515 participants at 10-18 and 32-38 weeks of gestation. Logistic regression models estimated the relationships between maternal vitamin-D-binding-protein, total 25-hydroxyvitamin-D, and offspring asthma. In addition, offspring asthma was modeled as a function of estimated free 25-hydroxyvitamin-D. A bootstrap approach was used for robust confidence interval estimation. Measurements and Main ResultsMaternal vitamin-D-binding-protein levels generally increased as pregnancy progressed. A significant positive interaction effect between maternal vitamin-D-binding-protein and total 25-hydroxyvitamin-D on offspring asthma risk was observed for both the full cohort and the subset of mothers with asthma, suggesting that the protective effect of total 25-hydroxyvitamin-D increases with lower levels of vitamin-D-binding-protein. For mothers with asthma, estimated maternal free 25-hydroxyvitamin-D was found to have a significant protective effect against offspring asthma, surpassing the effects of vitamin-D-binding-protein or total 25-hydroxyvitamin-D individually. ConclusionsThese results highlight the interplay between vitamin-D metabolites during pregnancy and their protective effects for offspring asthma. These results also provide evidence for the free hormone hypothesis, which suggests that free vitamin-D is more biologically relevant than total vitamin-D.

BACKGROUNDVariation in genetic ancestry among admixed racial/ethnic groups may influence the fit of guideline-recommended spirometry reference equations, which rely on self-identified race/ethnicity. RESEARCH QUESTIONWhat is the influence of genetic ancestry on the fit of the guideline-recommended racial/ethnic-based spirometry reference equations in populations of genetically admixed children? STUDY DESIGN AND METHODSCross-sectional fit of guideline-recommended racial/ethnic-based spirometry reference equations was evaluated in control subjects from case-control studies of asthma. Anthropometry, blood samples, and spirometric measurements were obtained in 599 healthy admixed children, aged 8 to 21-years. Genetic ancestry was estimated using genome-wide genotype data. Equation fit was determined as a mean z-score between -0.5 and 0.5 and assessed in self-identified African American (N = 275) and Puerto Rican (N = 324) children using the distribution to determine cut points of genetic ancestry. RESULTSFor African American children, African American-derived equations fit for predicting FEV1 and FVC in those with an African ancestry above the median (81-100%), whereas composite equations for "other/mixed" populations fit for predicting FEV1 and FVC in those with an African ancestry below the median (31-81%). Among Puerto Rican children, White-derived equations fit for predicting FEV1, and the composite equations fit for predicting FVC for those with African ancestry above the median (21-88%). In contrast, in Puerto Rican children with African ancestry below the median (6-21%), only equations derived in Whites provide an adequate fit. INTERPRETATIONGuideline-recommended spirometry reference equations yielded biased estimates of lung function in admixed populations with high variation of African ancestry. Spirometry is due for reference equations that incorporate genetic ancestry, either for more precise application of the current equations or the derivation and utilization of new equations.

Respiratory exacerbations are a frequent cause of hospitalisation in children with severe neurodisability (ND). Direct aspiration of food/saliva, reflux aspiration of gastric contents or a combination of both is thought to be a common cause of respiratory symptoms and disease, particularly when this occurs silently. A number of aspiration biomarkers, including bile acids and pepsin, have been proposed, however, no gold-standard diagnostic tests are currently available. In children with severe ND at high risk of both direct and reflux aspiration, we analysed lower airway samples for saliva- and/or gastric-specific proteins with biomarker potential.

BackgroundFractional exhaled nitric oxide (FeNO) and peripheral eosinophils are important biomarkers of Type 2 inflammation in asthma. FeNO reflects airway inflammation, while eosinophil counts indicate systemic eosinophilic activity. Their combined utility in asthma management warrants further investigation. ObjectiveThis study aimed to assess and compare FeNO levels and peripheral eosinophils in asthmatic patients, examining their relationship with disease characteristics and bronchodilator responsiveness (BDR). MethodsA retrospective analysis of 101 adult asthmatic patients at King Abdulaziz University, Jeddah, was conducted. Patient data on FeNO, eosinophil counts, spirometry, and comorbidities were collected and analyzed using correlation and receiver operating characteristic (ROC) curve analysis. ResultsThe mean FeNO level was 68.9{+/-}61.3 ppb, and the mean eosinophil count was 310.5{+/-}344.2 cells/L. FeNO levels were significantly higher in patients with eosinophil counts [&ge;]300 cells/L (p=0.012) and correlated positively with BDR (r=0.38, p=0.001) but not with eosinophil counts (r=0.16, p=0.11) or asthma control test (ACT) scores. Eosinophil counts were significantly associated with moderate airway obstruction (p=0.041). FeNO showed a borderline ability to differentiate allergic rhinitis (p=0.059) but limited performance in identifying other comorbidities, such as chronic rhinosinusitis (p=0.17), GERD (p=0.87), and eczema/atopic dermatitis (p=0.11 and p=0.24, respectively). ConclusionFeNO and peripheral eosinophil counts are valuable complementary biomarkers for assessing type 2 inflammation in asthma and guiding treatment. However, their variability across clinical contexts underscores the need for integration with other assessments. These findings support a multidimensional approach to asthma management and call for further research to refine their clinical applications.

ObjectivesLongitudinal data is commonly acquired in asthma studies, to help assess asthma progression in patients, and to determine predictors of future outcomes, including asthma exacerbations and asthma control. Different methods exist for quantifying temporal behaviour in routinely collected diary variables to obtain meaningful predictive biomarkers of asthma outcomes. The aims of this systematic review were to evaluate the methods for extracting biomarkers from longitudinally collected diary data in asthma and investigate associations between the extracted measures and asthma patient reported outcomes (PROs). SettingA systematic review of MEDLINE, EMBASE, CINAHL and the Cochrane Library was conducted, using index terms relating to diary variables and asthma outcomes. Studies that focused on preschool children were excluded, to avoid confounding asthma with multi-factorial preschool wheeze. Study quality and risk of bias were assessed using the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) and the Prediction model Risk Of Bias ASessment Tool (PROBAST), respectively. ParticipantsAdults and/or children of school age ([&ge;]5 years old), with clinician-diagnosed asthma Primary outcomesAsthma PROs, namely asthma exacerbations, asthma control, asthma-related quality of life and asthma severity Results24 full-text articles met the inclusion criteria and were included in the review. Generally, higher levels of variability in the diary variables were associated with poorer outcomes, especially increased asthma exacerbation risk, and poor asthma control. There was increasing interest in nonparametric methods to quantify complex behaviour of diary variables (6/24). TRIPOD and PROBAST highlighted a lack of consistent reporting of model performance measures and potential for model bias. DiscussionRoutinely collected diary variables aid in generating asthma assessment tools, including surrogate endpoints, for clinical trials, and predictive biomarkers of adverse outcomes, warranting monitoring through remote sensors. Studies consistently lacked robust reporting of model performance. Future research should utilise diary variable-derived biomarkers. Article SummaryStrengths and limitations of this study O_LIThis is the first systematic review that explores the different methods applied to time series of diary variables, namely peak flow, reliever use, symptom scores and awakenings. C_LIO_LIThe scope of this review included multiple patient-reported outcomes, including asthma exacerbations, asthma control and asthma severity. C_LI Only one reviewer was involved in screening the titles and abstracts for inclusion into the systematic review.

BackgroundLung oscillometry is an emerging lung function test for assessing obstructive airway disease. Comparisons of oscillometry parameters and their bronchodilator responsiveness (BDR) between bronchial asthma and chronic obstructive pulmonary disease (COPD) patients are limited. Research QuestionDo oscillometry parameters and their BDR differ between stable asthma and COPD patients with similar severity of airflow obstruction? Study Design and MethodsWe included 467 consecutive adult patients with a clinical history of asthma (n=187) or COPD (n=280). Oscillometry, spirometry, and body plethysmography were performed before and after inhaling 400 g of salbutamol. Patients were stratified based on the severity of airflow obstruction in spirometry. The z scores of the oscillometry parameters were used for the comparison. The BDR of oscillometry parameters with other lung function parameters was also compared. ResultsThe average age of the study population was 54.9 years, and 76.4% were male. COPD patients were older, had a greater number of smokers, and had poorer lung function. The magnitude of oscillometry parameters worsened with increasing severity of airflow obstruction, regardless of the underlying disease. Asthma patients, particularly those with moderate and severe airway obstruction, had significantly higher R5 and R19 than COPD patients. The within- and whole-breath X5 of asthma were not different from those of COPD patients with similar severities of airflow obstruction. Expiratory flow limitation at tidal breaths ({Delta}X5 > 0.28 kPa/L/s) was observed in both asthma and COPD patients across all severities of airflow obstruction. The proportion of BDR in oscillometry was significantly lower than that in spirometry for both asthma (35.3% vs. 57.1%; p<0.01) and COPD patients (19.3% vs. 47.1%; p=0.02). InterpretationOscillometry parameters except for R5 and R19 did not differ between asthma and COPD patients with similar severities of airflow obstruction. Similar to spirometry, COPD patients had lower BDR in oscillometry than asthma patients. Take-home PointsO_ST_ABSStudy QuestionC_ST_ABSAre oscillometry parameters and their bronchodilator responsiveness different between bronchial asthma and COPD patients with similar severities of airflow obstruction? ResultsWe compared the FOT between 187 bronchial asthma and 280 COPD patients. Except for R5 and R19, the severity and distribution of high oscillometry parameters did not differ between asthma and COPD patients. InterpretationThe severity of oscillometry abnormalities is primarily determined by the severity of airflow obstruction, not the underlying disease.

BackgroundWe previously elucidated the fundamental pathophysiological features of various aetiologies of chronic cough, such as cough variant asthma, atopic cough, and sinobronchial syndrome. We also established a pathophysiological diagnostic procedure for aetiology identification. In this study, we aimed to disclose the aetiologies of chronic cough using the pathophysiological diagnostic procedure and to determine the outcomes of treatment administered on the basis of aetiology. Patients and MethodsWe retrospectively reviewed the medical records of patients with chronic cough who visited our cough specialty clinic from September 2013 to August 2018 and analyzed the pathophysiological diagnostic procedure-based aetiologies and corresponding treatments. The pathophysiological diagnostic procedure included the capsaicin cough test, methacholine cough test, bronchial reversibility test, bronchial responsiveness test, chest and sinus CT, and sputum examinations. ResultsInitially, 303 patients were selected, and 300 patients underwent the diagnostic procedure. Aetiologies of chronic cough were diagnosed in 297 patients (99.0%). In the other three patients (1.0%), all results of the diagnostic procedure were within normal limits; their aetiologies were evaluated using the therapeutic diagnostic procedure. Tweleve patients discontinued follow-up before completing treatment. Of the 291 remaining patients, cough resolved completely in 283 patients. The median time required for the complete resolution of cough was 5.0 weeks (95% CI 4.3[~]5.7 weeks). ConclusionsThe pathophysiological diagnostic procedure can lead to rapid and objective diagnosis of causes of chronic cough, which leads to superior treatment results compared to therapeutic diagnostic procedure. Trial registration numberUMIN ID: UMIN000018679 Key MessagesOur pathophysiological diagnostic procedure can lead to rapid and objective diagnosis of the aetiology of chronic cough, leading to superior treatment results compared to those of therapeutic diagnostic procedures.