Admixture mapping of severe asthma exacerbations in Hispanic/Latino children and youth.

BACKGROUND: In the USA, genetically admixed populations have the highest asthma prevalence and severe asthma exacerbations rates. This could be explained not only by environmental factors but also by genetic variants that exert ethnic-specific effects. However, no admixture mapping has been performed for severe asthma exacerbations. OBJECTIVE: We sought to identify genetic variants associated with severe asthma exacerbations in Hispanic/Latino subgroups by means of admixture mapping analyses and fine mapping, and to assess their transferability to other populations and potential functional roles. METHODS: We performed an admixture mapping in 1124 Puerto Rican and 625 Mexican American children with asthma. Fine-mapping of the significant peaks was performed via allelic testing of common and rare variants. We performed replication across Hispanic/Latino subgroups, and the transferability to non-Hispanic/Latino populations was assessed in 1001 African Americans, 1250 Singaporeans and 941 Europeans with asthma. The effects of the variants on gene expression and DNA methylation from whole blood were also evaluated in participants with asthma and in silico with data obtained through public databases. RESULTS: Genomewide significant associations of Indigenous American ancestry with severe asthma exacerbations were found at 5q32 in Mexican Americans as well as at 13q13-q13.2 and 3p13 in Puerto Ricans. The single nucleotide polymorphism (SNP) rs1144986 (C5orf46) showed consistent effects for severe asthma exacerbations across Hispanic/Latino subgroups, but it was not validated in non-Hispanics/Latinos. This SNP was associated with DPYSL3 DNA methylation and SCGB3A2 gene expression levels. CONCLUSIONS: Admixture mapping study of asthma exacerbations revealed a novel locus that exhibited Hispanic/Latino-specific effects and regulated DPYSL3 and SCGB3A2.

Multi-ancestry genome-wide association study of asthma exacerbations.

BACKGROUND: Asthma exacerbations are a serious public health concern due to high healthcare resource utilization, work/school productivity loss, impact on quality of life, and risk of mortality. The genetic basis of asthma exacerbations has been studied in several populations, but no prior study has performed a multi-ancestry meta-analysis of genome-wide association studies (meta-GWAS) for this trait. We aimed to identify common genetic loci associated with asthma exacerbations across diverse populations and to assess their functional role in regulating DNA methylation and gene expression. METHODS: A meta-GWAS of asthma exacerbations in 4989 Europeans, 2181 Hispanics/Latinos, 1250 Singaporean Chinese, and 972 African Americans analyzed 9.6 million genetic variants. Suggestively associated variants (p ≤ 5 × 10-5 ) were assessed for replication in 36,477 European and 1078 non-European asthma patients. Functional effects on DNA methylation were assessed in 595 Hispanic/Latino and African American asthma patients and in publicly available databases. The effect on gene expression was evaluated in silico. RESULTS: One hundred and twenty-six independent variants were suggestively associated with asthma exacerbations in the discovery phase. Two variants independently replicated: rs12091010 located at vascular cell adhesion molecule-1/exostosin like glycosyltransferase-2 (VCAM1/EXTL2) (discovery: odds ratio (ORT allele ) = 0.82, p = 9.05 × 10-6 and replication: ORT allele  = 0.89, p = 5.35 × 10-3 ) and rs943126 from pantothenate kinase 1 (PANK1) (discovery: ORC allele  = 0.85, p = 3.10 × 10-5 and replication: ORC allele  = 0.89, p = 1.30 × 10-2 ). Both variants regulate gene expression of genes where they locate and DNA methylation levels of nearby genes in whole blood. CONCLUSIONS: This multi-ancestry study revealed novel suggestive regulatory loci for asthma exacerbations located in genomic regions participating in inflammation and host defense.

Alveolar nitric oxide and its role in pediatric asthma control assessment.

BACKGROUND: Nitric oxide can be measured at multiple flow rates to determine proximal (maximum airway nitric oxide flux; JawNO) and distal inflammation (alveolar nitric oxide concentration; CANO). The main aim was to study the association among symptoms, lung function, proximal (maximum airway nitric oxide flux) and distal (alveolar nitric oxide concentration) airway inflammation in asthmatic children treated and not treated with inhaled glucocorticoids. METHODS: A cross-sectional study with prospective data collection was carried out in a consecutive sample of girls and boys aged between 6 and 16 years with a medical diagnosis of asthma. Maximum airway nitric oxide flux and alveolar nitric oxide concentration were calculated according to the two-compartment model. In asthmatic patients, the asthma control questionnaire (CAN) was completed and forced spirometry was performed. In controls, differences between the sexes in alveolar nitric oxide concentration and maximum airway nitric oxide flux and their correlation with height were studied. The correlation among the fraction of exhaled NO at 50 ml/s (FENO50), CANO, JawNO, forced expiratory volume in 1 second (FEV1) and the CAN questionnaire was measured and the degree of agreement regarding asthma control assessment was studied using Cohen's kappa. RESULTS: We studied 162 children; 49 healthy (group 1), 23 asthmatic participants without treatment (group 2) and 80 asthmatic patients treated with inhaled corticosteroids (group 3). CANO (ppb) was 2.2 (0.1-4.5), 3 (0.2-9.2) and 2.45 (0.1-24), respectively. JawNO (pl/s) was 516 (98.3-1470), 2356.67 (120-6110) and 1426 (156-11805), respectively. There was a strong association (r=0.97) between FENO50 and JawNO and the degree of agreement was very good in group 2 and was good in group 3. There was no agreement or only slight agreement between the measures used to monitor asthma control (FEV1, CAN questionnaire, CANO and JawNO). CONCLUSIONS: The results for CANO and JawNO in controls were similar to those found in other reports. There was no agreement or only slight agreement among the three measure instruments analyzed to assess asthma control. In our sample, no additional information was provided by CANO and JawNO.

Young infants with recurrent wheezing and positive asthma predictive index have higher levels of exhaled nitric oxide.

OBJECTIVE: The aim of this post hoc analysis was to establish the relationship between FE(NO) levels and the asthma predictive index (API) among infants with recurrent wheezing. METHODS: Infants with recurrent wheezing (three or more episodes) were recruited consecutively and online FE(NO) tests at tidal breathing with multiple breaths were performed. RESULTS: Twenty-seven (84%) out of 32 infants (median age of 12 months) who met the inclusion criteria for this post hoc analysis, successfully performed the FE(NO) determinations. Eighteen (66%) infants were classified with positive stringent API. FE(NO) levels were significantly higher among patients with positive API than those with negative (median [IQR] of 12.3 [14.8] ppb vs. 4.1 [7.9] ppb, respectively, p = .016). Furthermore, FE(NO) and positive API had a significant correlation (Spearman's rho, ρ = 0.4741, p = .0125). After logistic regression analysis including FE(NO) levels, gender, age, and use of controller therapy, FE(NO) was the only variable that was marginally related to API (OR = 1.12, 95% CI: 0.99-1.27, p = .07). CONCLUSION: Infants with recurrent wheezing who had a positive stringent API already had higher FE(NO) levels than those with a negative API. This finding needs to be corroborated in a larger prospective study.

Alpha-1 antitrypsin deficiency and Pi*S and Pi*Z SERPINA1 variants are associated with asthma exacerbations.

INTRODUCTION AND OBJECTIVES: Asthma is a chronic inflammatory disease of the airways. Asthma patients may experience potentially life-threatening episodic flare-ups, known as exacerbations, which may significantly contribute to the asthma burden. The Pi*S and Pi*Z variants of the SERPINA1 gene, which usually involve alpha-1 antitrypsin (AAT) deficiency, had previously been associated with asthma. The link between AAT deficiency and asthma might be represented by the elastase/antielastase imbalance. However, their role in asthma exacerbations remains unknown. Our objective was to assess whether SERPINA1 genetic variants and reduced AAT protein levels are associated with asthma exacerbations. MATERIALS AND METHODS: In the discovery analysis, SERPINA1 Pi*S and Pi*Z variants and serum AAT levels were analyzed in 369 subjects from La Palma (Canary Islands, Spain). As replication, genomic data from two studies focused on 525 Spaniards and publicly available data from UK Biobank, FinnGen, and GWAS Catalog (Open Targets Genetics) were analyzed. The associations between SERPINA1 Pi*S and Pi*Z variants and AAT deficiency with asthma exacerbations were analyzed with logistic regression models, including age, sex, and genotype principal components as covariates. RESULTS: In the discovery, a significant association with asthma exacerbations was found for both Pi*S (odds ratio [OR]=2.38, 95% confidence interval [CI]= 1.40-4.04, p-value=0.001) and Pi*Z (OR=3.49, 95%CI=1.55-7.85, p-value=0.003)Likewise, AAT deficiency was associated with a higher risk for asthma exacerbations (OR=5.18, 95%CI=1.58-16.92, p-value=0.007) as well as AAT protein levels (OR= 0.72, 95%CI=0.57-0.91, p-value=0.005). The Pi*Z association with exacerbations was replicated in samples from Spaniards with two generations of Canary Islander origin (OR=3.79, p-value=0.028), and a significant association with asthma hospitalizations was found in the Finnish population (OR=1.12, p-value=0.007). CONCLUSIONS: AAT deficiency could be a potential therapeutic target for asthma exacerbations in specific populations.

The Genomics and Metagenomics of Asthma Severity (GEMAS) Study: Rationale and Design.

Asthma exacerbations are a major contributor to the global disease burden, but no significant predictive biomarkers are known. The Genomics and Metagenomics of Asthma Severity (GEMAS) study aims to assess the role of genomics and the microbiome in severe asthma exacerbations. Here, we present the design of GEMAS and the characteristics of patients recruited from March 2018 to March 2020. Different biological samples and demographic and clinical variables were collected from asthma patients recruited by allergy and pulmonary medicine units in several hospitals from Spain. Cases and controls were defined by the presence/absence of severe asthma exacerbations in the past year (oral corticosteroid use, emergency room visits, and/or asthma-related hospitalizations). A total of 137 cases and 120 controls were recruited. After stratifying by recruitment location (i.e., Canary Islands and Basque Country), cases and controls did not differ for most demographic and clinical variables (p > 0.05). However, cases showed a higher proportion of characteristics inherent to asthma exacerbations (impaired lung function, severe disease, uncontrolled asthma, gastroesophageal reflux, and use of asthma medications) compared to controls (p < 0.05). Similar results were found after stratification by recruitment unit. Thereby, asthma patients enrolled in GEMAS are balanced for potential confounders and have clinical characteristics that support the phenotype definition. GEMAS will improve the knowledge of potential biomarkers of asthma exacerbations.

Small Airway Dysfunction in Children With Controlled Asthma. / Disfunción de la pequeña vía aérea en niños con asma controlada.

INTRODUCTION: Asthma is characterized by chronic inflammation of the central and distal airways. The aim of this study was to assess the small airway (SA) of children with moderate-severe asthma with normal FEV1. METHODS: This was an open-label, prospective, observational, cross-sectional study with consecutive inclusion of patients with moderate-severe asthma, receiving standard clinical treatment, with normal baseline FEV1. We determined multiflow FEno (CAno), oscillatory resistance and reactance (R5-R20, X5), forced spirometry (FEV1, FEF25-75), total body plethysmography (RV/TLC) and bronchodilation test. SA involvement was defined as: CAno>4.5 ppb, R5-R20>0.147kPa/L/s, X5<-0.18kPa/L, FEF25-75<-1.65 z-score, RV/TLC>33%. Poor asthma control was defined as ≤ 19 points on the ACT questionnaire or ≤ 20 on the c-ACT. RESULTS: In a cohort of 100 cases, 76 had moderate asthma and 24 had severe asthma; 71 children were classified as poorly controlled and 29 were well-controlled. In total, 77.78% of the group with all the correct determinations (n=72) showed ≥ 1 altered SA parameter and 48.61% ≥ 2 parameters. There were no differences between well-controlled or poorly controlled cases. CONCLUSIONS: Children with moderate-severe asthma, with normal FEV1, show a phenotype of dysfunctional SA. In our series, the evaluation of SA using the techniques described above did not provide information on disease control.

Isolated pulmonary interstitial glycogenosis associated with alveolar growth abnormalities: A long-term follow-up study.

INTRODUCTION: Pulmonary interstitial glycogenosis (PIG) is a rare infant interstitial lung disease characterized by an increase in the number of interstitial mesenchymal cells, presenting as enhanced cytoplasmic glycogen, and is considered to represent the expression of an underlying lung development disorder. METHODS: This study describes the clinical, radiological, and functional characteristics and long-term outcomes (median 12 years) of nine infants diagnosed with isolated PIG associated with alveolar simplification in the absence of other diseases. RESULTS: All patients presented with tachypnea. Additionally, seven patients had breathing difficulties and hypoxemia. Abnormalities in chest-computerized tomography (CT) with a pattern of ground-glass opacity, septal thickening, and air trapping were observed in all individuals, with images suggesting abnormal alveolar growth (parenchymal bands and architectural distortion). All lung biopsies showed alveolar simplification associated with an increased number of interstitial cells, which appeared as accumulated cytoplasmic glycogen. In the follow-up, all patients were asymptomatic. The respiratory function test was normal in only two patients. Five children showed an obstructive pattern, and two children showed a restrictive pattern. Chest-CT, performed after an average of 6.5 years since the initial investigation, revealed a partial improvement of the ground-glass opacity pattern; however, relevant alterations persisted. CONCLUSION: Although the patients with PIG in the absence of other associated pathologies had a good clinical outcome, significant radiographic alterations and sequelae in lung function were still observed after a median follow-up of 12 years, suggesting that PIG is a marker of some other persistent abnormalities in lung growth, which have effects beyond the symptomatic period.

Disfunción de la pequeña vía aérea en niños con asma controlada / Small Airway Dysfunction in Children With Controlled Asthma

Introducción: El asma se caracteriza por una inflamación crónica de las vías respiratorias centrales y distales. El objetivo de este estudio ha sido evaluar la vía aérea pequeña (VAP) en niños con asma moderada y/o grave con FEV1 normal. Métodos: Estudio abierto, prospectivo, observacional y transversal con inclusión consecutiva de casos con asma moderada o grave, bajo tratamiento clínico habitual con FEV1 basal normal. Se ha determinado la FEno a flujos múltiples (CAno), resistencias y reactancia oscilatorias (R5-R20, X5), espirometría forzada (FEV1, FEF25-75), pletismografía corporal total (RV/TLC) y prueba de broncodilatación. La afectación de la VAP se definió por: Cano > 4,5 ppb, R5-R20 > 0,147kPa/L/s, X5 <-0,18kPa/L, FEF25-75 < -1,65 z-score, RV/TL > 33%. El mal control de asma se definió por ≤ 19 puntos en el cuestionario ACT o ≤ 20 en c-ACT. Resultados: Cohorte de 100 casos, 76 con asma moderada y 24 con asma grave, 71 niños clasificados como mal controlados y 29 bien controlados. El 77,78% del grupo con todas las determinaciones correctas (n =7 2) mostró ≥ 1 parámetro alterado de VAP y el 48,61% ≥ 2 parámetros. No hubo diferencias entre los casos bien y mal controlados. Conclusiones: Los niños con asma moderada y grave, con el FEV1 preservado, muestran un fenotipo de VAP disfuncionante. En nuestra muestra, la evaluación de la VAP mediante las técnicas descritas, no aporta información sobre el control habitual de la enfermedad

Introduction: Asthma is characterized by chronic inflammation of the central and distal airways. The aim of this study was to assess the small airway (SA) of children with moderate-severe asthma with normal FEV1. Methods: This was an open-label, prospective, observational, cross-sectional study with consecutive inclusion of patients with moderate-severe asthma, receiving standard clinical treatment, with normal baseline FEV1. We determined multiflow FEno (CAno), oscillatory resistance and reactance (R5-R20, X5), forced spirometry (FEV1, FEF25-75), total body plethysmography (RV/TLC) and bronchodilation test. SA involvement was defined as: Cano > 4.5 ppb, R5-R20 > 0.147kPa/L/s, X5< -0.18kPa/L, FEF25-75 < -1.65 z-score, RV/TLC > 33%. Poor asthma control was defined as ≤ 19 points on the ACT questionnaire or ≤ 20 on the c-ACT. Results: In a cohort of 100 cases, 76 had moderate asthma and 24 had severe asthma; 71 children were classified as poorly controlled and 29 were well-controlled. In total, 77.78% of the group with all the correct determinations (n=72) showed ≥ 1 altered SA parameter and 48.61% ≥ 2 parameters. There were no differences between well-controlled or poorly controlled cases. Conclusions: Children with moderate-severe asthma, with normal FEV1, show a phenotype of dysfunctional SA. In our series, the evaluation of SA using the techniques described above did not provide information on disease control

[Differences in airway resistances in children measured by plethysmography with and without closure of the occluder]. / Concordancia en niños entre las resistencias de la vía aérea medidas mediante pletismografía con y sin cierre del oclusor.

BACKGROUND: There have been several studies that have measured airway resistances using plethysmography without closing the occluder. OBJECTIVE: To investigate the differences between the total resistances (sRaw(TOT)) and the specific resistances (sRaw) with the same technique (plethysmography) but different methodology (with and without closure of the occluder) in child subjects. MATERIAL AND METHODS: An observational and cross-sectional study of a consecutive sample of children between 6 and 14 years old who were seen at the Childhood Pneumology clinics from 15th January to 15th February 2009. Determination of sRaw(TOT), sRaw and specific conductance (sGaw) using plethysmography (MasterLab V5.1, Viasys, Wuerzburg, Germany) without closing the occluder. The same determinations were then performed with the occluder closed. The qualitative variables were: sex, diagnosis and treatment, and the quantitative variables: age, weight, height, sRaw(TOT), sRaw, sGaw and respiratory rate with and without closing the occluder. The results were analysed for association and concordance between sRaw(TOT), sRaw and sGaw with and without closure of the occluder using paired Student t test, Bland-Altman method and a scatter plot. RESULTS: Thirty-six cases were included and all (100%) the tests were performed successfully. The mean age was 9.91+/-2.37 years. There were no differences between sRawTOT, sRaw or sGaw with and without closure of the occluder. Neither were there any differences between the regression of the means obtained for sRaw(TOT), sRaw and sGaw with and without closure of the occluder. CONCLUSIONS: There is good agreement between the sRaw(TOT) y sRaw obtained by plethysmography with and without closure of the occluder.

Concordancia en niños entre las resistencias de la vía aérea medidas mediante pletismografía con y sin cierre del oclusor / Differences in Airway Resistances in Children Measured by Plethysmography With and Without Closure of the Occluder

AntecedentesDiversos investigadores han estudiado las resistencias de la vía aérea mediante pletismografía sin cierre del oclusor.ObjetivoComprobar la concordancia entre las resistencias totales (sRawTOT) y las resistencias específicas (sRaw) con la misma técnica (pletismografía) y diferente metodología (con y sin cierre del oclusor) en niños colaboradores.Material y MétodosEstudio observacional y transversal de una muestra consecutiva de niños entre 6 y 14 años que acudieron a consultas de Neumología Infantil, desde el 15 de enero hasta el 15 de febrero de 2009. Determinación de sRawTOT, sRaw y conductancia específica (sGaw) mediante pletismografía (MasterLab V5.1, Viasys®, Wuerzburg, Alemania) sin cierre del oclusor. En todos se realizaron a continuación las mismas determinaciones con cierre del oclusor. Variables cualitativas: sexo, diagnóstico y tratamiento, y variables cuantitativas: edad, peso, talla, sRawTOT, sRaw, sGaw y FRcon y sin cierre del oclusor. Análisis de la asociación y concordancia entre sRawTOT, sRaw y sGaw con y sin cierre del oclusor mediante t de Student pareada, método Bland-Altman y diagrama de puntos (Scatter plot).ResultadosSe incluyeron 36 casos. El 100% realizó las pruebas con éxito. Edad media: 9,91±2,37 años. No hubo diferencias entre sRawTOT, sRaw ni sGaw con y sin cierre del oclusor. Tampoco hubo diferencias entre la regresión de las medias obtenidas de sRawTOT, sRaw y sGaw con y sin cierre del oclusor, respecto a la diferencia de las mismas.ConclusionesExiste una buena concordancia entre sRawTOT y sRaw obtenidas por pletismografía con y sin cierre del oclusor(AU)

BackgroundThere have been several studies that have measured airway resistances using plethysmography without closing the occluderObjectiveTo investigate the differences between the total resistances (sRawTOT) and the specific resistances (sRaw) with the same technique (plethysmography) but different methodology (with and without closure of the occluder) in child subjects.Material and MethodsAn observational and cross-sectional study of a consecutive sample of children between 6 and 14 years old who were seen at the Childhood Pneumology clinics from 15th January to 15th February 2009. Determination of sRawTOT, sRaw and specific conductance (sGaw) using plethysmography (MasterLab V5.1, Viasys®, Wuerzburg, Germany) without closing the occluder. The same determinations were then performed with the occluder closed. The qualitative variables were: sex, diagnosis and treatment, and the quantitative variables: age, weight, height, sRawTOT, sRaw, sGaw and respiratory rate with and without closing the occluder. The results were analysed for association and concordance between sRawTOT, sRaw and sGaw with and without closure of the occluder using paired Student t test, Bland-Altman method and a scatter plot.ResultsThirty-six cases were included and all (100%) the tests were performed successfully. The mean age was 9.91±2.37 years. There were no differences between sRawTOT, sRaw or sGaw with and without closure of the occluder. Neither were there any differences between the regression of the means obtained for sRawTOT, sRaw and sGaw with and without closure of the occluder.ConclusionsThere is good agreement between the sRawTOT y sRaw obtained by plethysmography with and without closure of the occluder(AU)