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The traditional healthcare model is focused on diseases (medicine and natural science) and does not acknowledge patients' resources and abilities to be experts in their own life based on their lived experiences. Improving healthcare safety, quality and coordination, as well as quality of life, are important aims in the care of patients with chronic conditions. Person-centred care needs to ensure that people's values and preferences guide clinical decisions. This paper reviews current knowledge to develop (i) digital care pathways for rhinitis and asthma multimorbidity and (ii) digitally-enabled person-centred care (1). It combines all relevant research evidence, including the so-called real-world evidence, with the ultimate goal to develop digitally-enabled, patient-centred care. The paper includes (i) Allergic Rhinitis and its Impact on Asthma (ARIA), a two-decade journey, (ii) Grading of Recommendations, Assessment, Development and Evaluation (GRADE), the evidence-based model of guidelines in airway diseases, (iii) mHealth impact on airway diseases, (iv) from guidelines to digital care pathways, (v) embedding Planetary Health, (vi) novel classification of rhinitis and asthma, (vi) embedding real-life data with population-based studies, (vii) the ARIA-EAACI strategy for the management of airway diseases using digital biomarkers, (viii) Artificial Intelligence, (ix) the development of digitally-enabled ARIA Person-Centred Care and (x) the political agenda. The ultimate goal is to propose ARIA 2024 guidelines centred around the patient in order to make them more applicable and sustainable.
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Recommendations for or against the use of interventions need to consider both desirable and undesirable effects as well as patients' values and preferences (V&P). In the decision-making context, patients' V&P represent the relative importance people place on the outcomes resulting from a decision. Therefore, the balance between desirable and undesirable effects from an intervention should depend not only on the difference between benefits and harms but also on the value that patients place on them. V&P are therefore one of the criteria to be considered when formulating guideline recommendations in the Evidence-to-Decision framework developed by the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) Working Group. Patients' V&P may be quantified through utilities, which can be elicited using direct methods (e.g., standard gamble or time trade-off) or indirect methods (using validated instruments to measure health-related quality of life, such as EQ-5D). The GRADE approach recommends conducting systematic reviews to summarise all the available evidence and assess the degree of certainty on V&P. In this article, we discuss the importance of considering patients' V&P and provide examples of how they are considered in the 2024 person-centred Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines.
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Mast cell activation syndrome (MCAS) is a term applied to several clinical entities that have gained increased attention from patients and medical providers. Although several descriptive publications about MCAS exist, there are many gaps in knowledge, resulting in confusion about this clinical syndrome. Whether MCAS is a primary syndrome or exists as a constellation of symptoms in the context of known inflammatory, allergic, or clonal disorders associated with systemic mast cell activation is not well understood. More importantly, the underlying mechanisms and pathways that lead to mast cell activation in MCAS patients remain to be elucidated. Here we summarize the known literature, identify gaps in knowledge, and highlight research needs. Covered topics include contextualization of MCAS and MCAS-like endotypes and related diagnostic evaluations; mechanistic research; management of typical and refractory symptoms; and MCAS-specific education for patients and health care providers.
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Mastocitos , Mastocitosis , Humanos , Mastocitos/inmunología , Mastocitosis/diagnóstico , Mastocitosis/inmunología , Síndrome , AnimalesAsunto(s)
Antialérgicos , Anticuerpos Antiidiotipos , Anticuerpos Monoclonales Humanizados , Hipersensibilidad a los Alimentos , Omalizumab , Humanos , Antialérgicos/uso terapéutico , Anticuerpos Antiidiotipos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Hipersensibilidad a los Alimentos/tratamiento farmacológico , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Omalizumab/uso terapéutico , AdultoRESUMEN
BACKGROUND: Cockroach allergy contributes to morbidity among urban children with asthma. Few trials address the effect of subcutaneous immunotherapy (SCIT) with cockroach allergen among these at-risk children. OBJECTIVES: We sought to determine whether nasal allergen challenge (NAC) responses to cockroach allergen would improve following 1 year of SCIT. METHODS: Urban children with asthma, who were cockroach-sensitized and reactive on NAC, participated in a year-long randomized double-blind placebo-controlled SCIT trial using German cockroach extract. The primary endpoint was the change in mean Total Nasal Symptom Score (TNSS) during NAC after 12 months of SCIT. Changes in nasal transcriptomic responses during NAC, skin prick test wheal size, serum allergen-specific antibody production, and T-cell responses to cockroach allergen were assessed. RESULTS: Changes in mean NAC TNSS did not differ between SCIT-assigned (n = 28) versus placebo-assigned (n = 29) participants (P = .63). Nasal transcriptomic responses correlated with TNSS, but a treatment effect was not observed. Cockroach serum-specific IgE decreased to a similar extent in both groups, while decreased cockroach skin prick test wheal size was greater among SCIT participants (P = .04). A 200-fold increase in cockroach serum-specific IgG4 was observed among subjects receiving SCIT (P < .001) but was unchanged in the placebo group. T-cell IL-4 responses following cockroach allergen stimulation decreased to a greater extent among SCIT versus placebo (P = .002), while no effect was observed for IL-10 or IFN-γ. CONCLUSIONS: A year of SCIT failed to alter NAC TNSS and nasal transcriptome responses to cockroach allergen challenge despite systemic effects on allergen-specific skin tests, induction of serum-specific IgG4 serum production and down-modulation of allergen-stimulated T-cell responses.
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The Human Epidemiology and Response to SARS-CoV-2 (HEROS) is a prospective multi-city 6-month incidence study which was conducted from May 2020-February 2021. The objectives were to identify risk factors for SARS-CoV-2 infection and household transmission among children and people with asthma and allergic diseases, and to use the host nasal transcriptome sampled longitudinally to understand infection risk and sequelae at the molecular level. To overcome challenges of clinical study implementation due to the coronavirus pandemic, this surveillance study used direct-to-participant methods to remotely enroll and prospectively follow eligible children who are participants in other NIH-funded pediatric research studies and their household members. Households participated in weekly surveys and biweekly nasal sampling regardless of symptoms. The aim of this report is to widely share the methods and study instruments and to describe the rationale, design, execution, logistics and characteristics of a large, observational, household-based, remote cohort study of SARS-CoV-2 infection and transmission in households with children. The study enrolled a total of 5,598 individuals, including 1,913 principal participants (children), 1,913 primary caregivers, 729 secondary caregivers and 1,043 other household children. This study was successfully implemented without necessitating any in-person research visits and provides an approach for rapid execution of clinical research.
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BACKGROUND: Introducing peanut products early can prevent peanut allergy (PA). The "Addendum guidelines for the prevention of PA in the United States" (PPA guidelines) recommend early introduction of peanut products to low and moderate risk infants and evaluation prior to starting peanut products for infants at high risk for PA (those with severe eczema and/or egg allergy). Rapid adoption of guidelines could aid in lowering the prevalence of PA. The Intervention to Reduce Early (Peanut) Allergy in Children (iREACH) trial was designed to promote PPA guideline adherence by pediatric clinicians. METHODS: A two-arm, cluster-randomized, controlled clinical trial was designed to measure the effectiveness of an intervention that included clinician education and accompanying clinical decision support tools integrated in electronic health records (EHR) versus standard care. Randomization was at the practice level (n = 30). Primary aims evaluated over an 18-month trial period assess adherence to the PPA guidelines using EHR documentation at 4- and 6-month well-child care visits aided by natural language processing. A secondary aim will evaluate the effectiveness in decreasing the incidence of PA by age 2.5 years using EHR documentation and caregiver surveys. The unit of observation for evaluations are individual children with clustering at the practice level. CONCLUSION: Application of this intervention has the potential to inform the development of strategies to speed implementation of PPA guidelines.
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Hipersensibilidad al Huevo , Hipersensibilidad al Cacahuete , Niño , Preescolar , Humanos , Lactante , Arachis , Inmunoglobulina E , Hipersensibilidad al Cacahuete/epidemiología , Hipersensibilidad al Cacahuete/prevención & control , Estados UnidosRESUMEN
BACKGROUND: MUPPITS-2 was a randomized, placebo-controlled clinical trial that demonstrated mepolizumab (anti-IL-5) reduced exacerbations and blood and airway eosinophils in urban children with severe eosinophilic asthma. Despite this reduction in eosinophilia, exacerbation risk persisted in certain patients treated with mepolizumab. This raises the possibility that subpopulations of airway eosinophils exist that contribute to breakthrough exacerbations. OBJECTIVE: We aimed to determine the effect of mepolizumab on airway eosinophils in childhood asthma. METHODS: Sputum samples were obtained from 53 MUPPITS-2 participants. Airway eosinophils were characterized using mass cytometry and grouped into subpopulations using unsupervised clustering analyses of 38 surface and intracellular markers. Differences in frequency and immunophenotype of sputum eosinophil subpopulations were assessed based on treatment arm and frequency of exacerbations. RESULTS: Median sputum eosinophils were significantly lower among participants treated with mepolizumab compared with placebo (58% lower, 0.35% difference [95% CI 0.01, 0.74], P = .04). Clustering analysis identified 3 subpopulations of sputum eosinophils with varied expression of CD62L. CD62Lint and CD62Lhi eosinophils exhibited significantly elevated activation marker and eosinophil peroxidase expression, respectively. In mepolizumab-treated participants, CD62Lint and CD62Lhi eosinophils were more abundant in participants who experienced exacerbations than in those who did not (100% higher for CD62Lint, 0.04% difference [95% CI 0.0, 0.13], P = .04; 93% higher for CD62Lhi, 0.21% difference [95% CI 0.0, 0.77], P = .04). CONCLUSIONS: Children with eosinophilic asthma treated with mepolizumab had significantly lower sputum eosinophils. However, CD62Lint and CD62Lhi eosinophils were significantly elevated in children on mepolizumab who had exacerbations, suggesting that eosinophil subpopulations exist that contribute to exacerbations despite anti-IL-5 treatment.
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Antiasmáticos , Anticuerpos Monoclonales Humanizados , Asma , Eosinófilos , Esputo , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Eosinófilos/inmunología , Niño , Esputo/citología , Esputo/inmunología , Masculino , Femenino , Asma/tratamiento farmacológico , Asma/inmunología , Antiasmáticos/uso terapéutico , Adolescente , Interleucina-5 , Progresión de la EnfermedadRESUMEN
BACKGROUND: Food allergies are common and are associated with substantial morbidity; the only approved treatment is oral immunotherapy for peanut allergy. METHODS: In this trial, we assessed whether omalizumab, a monoclonal anti-IgE antibody, would be effective and safe as monotherapy in patients with multiple food allergies. Persons 1 to 55 years of age who were allergic to peanuts and at least two other trial-specified foods (cashew, milk, egg, walnut, wheat, and hazelnut) were screened. Inclusion required a reaction to a food challenge of 100 mg or less of peanut protein and 300 mg or less of the two other foods. Participants were randomly assigned, in a 2:1 ratio, to receive omalizumab or placebo administered subcutaneously (with the dose based on weight and IgE levels) every 2 to 4 weeks for 16 to 20 weeks, after which the challenges were repeated. The primary end point was ingestion of peanut protein in a single dose of 600 mg or more without dose-limiting symptoms. The three key secondary end points were the consumption of cashew, of milk, and of egg in single doses of at least 1000 mg each without dose-limiting symptoms. The first 60 participants (59 of whom were children or adolescents) who completed this first stage were enrolled in a 24-week open-label extension. RESULTS: Of the 462 persons who were screened, 180 underwent randomization. The analysis population consisted of the 177 children and adolescents (1 to 17 years of age). A total of 79 of the 118 participants (67%) receiving omalizumab met the primary end-point criteria, as compared with 4 of the 59 participants (7%) receiving placebo (P<0.001). Results for the key secondary end points were consistent with those of the primary end point (cashew, 41% vs. 3%; milk, 66% vs. 10%; egg, 67% vs. 0%; P<0.001 for all comparisons). Safety end points did not differ between the groups, aside from more injection-site reactions in the omalizumab group. CONCLUSIONS: In persons as young as 1 year of age with multiple food allergies, omalizumab treatment for 16 weeks was superior to placebo in increasing the reaction threshold for peanut and other common food allergens. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT03881696.).
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Antialérgicos , Desensibilización Inmunológica , Hipersensibilidad a los Alimentos , Omalizumab , Adolescente , Niño , Humanos , Lactante , Alérgenos/efectos adversos , Arachis/efectos adversos , Desensibilización Inmunológica/métodos , Hipersensibilidad a los Alimentos/diagnóstico , Hipersensibilidad a los Alimentos/tratamiento farmacológico , Hipersensibilidad a los Alimentos/inmunología , Hipersensibilidad a los Alimentos/terapia , Omalizumab/efectos adversos , Omalizumab/uso terapéutico , Hipersensibilidad al Cacahuete/tratamiento farmacológico , Hipersensibilidad al Cacahuete/inmunología , Hipersensibilidad al Cacahuete/terapia , Antialérgicos/administración & dosificación , Antialérgicos/uso terapéutico , Preescolar , Adulto Joven , Adulto , Persona de Mediana EdadRESUMEN
BACKGROUND: Five distinct respiratory phenotypes based on latent classes of longitudinal patterns of wheezing, allergic sensitization. and pulmonary function measured in urban children from ages from 0 to 7 years have previously been described. OBJECTIVE: Our aim was to determine whether distinct respiratory phenotypes are associated with early-life upper respiratory microbiota development and environmental microbial exposures. METHODS: Microbiota profiling was performed using 16S ribosomal RNA-based sequencing of nasal samples collected at age 12 months (n = 120) or age 36 months (n = 142) and paired house dust samples collected at 3 months (12-month, n = 73; 36-month, n = 90) from all 4 centers in the Urban Environment and Childhood Asthma (URECA) cohort. RESULTS: In these high-risk urban children, nasal microbiota increased in diversity between ages 12 and 36 months (ß = 2.04; P = .006). Age-related changes in microbiota evenness differed significantly by respiratory phenotypes (interaction P = .0007), increasing most in the transient wheeze group. At age 12 months, respiratory illness (R2 = 0.055; P = .0001) and dominant bacterial genus (R2 = 0.59; P = .0001) explained variance in nasal microbiota composition, and enrichment of Moraxella and Haemophilus members was associated with both transient and high-wheeze respiratory phenotypes. By age 36 months, nasal microbiota was significantly associated with respiratory phenotypes (R2 = 0.019; P = .0376), and Moraxella-dominated microbiota was associated specifically with atopy-associated phenotypes. Analysis of paired house dust and nasal samples indicated that 12 month olds with low wheeze and atopy incidence exhibited the largest number of shared bacterial taxa with their environment. CONCLUSION: Nasal microbiota development over the course of early childhood and composition at age 3 years are associated with longitudinal respiratory phenotypes. These data provide evidence supporting an early-life window of airway microbiota development that is influenced by environmental microbial exposures in infancy and associates with wheeze- and atopy-associated respiratory phenotypes through age 7 years.
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Microbiota , Fenotipo , Ruidos Respiratorios , Población Urbana , Humanos , Lactante , Preescolar , Masculino , Femenino , Estudios Longitudinales , Asma/microbiología , Asma/epidemiología , Polvo/análisis , Polvo/inmunología , Exposición a Riesgos Ambientales , Nariz/microbiología , ARN Ribosómico 16S/genética , NiñoRESUMEN
Studies of asthma and allergy are generating increasing volumes of omics data for analysis and interpretation. The National Institute of Allergy and Infectious Diseases (NIAID) assembled a workshop comprising investigators studying asthma and allergic diseases using omics approaches, omics investigators from outside the field, and NIAID medical and scientific officers to discuss the following areas in asthma and allergy research: genomics, epigenomics, transcriptomics, microbiomics, metabolomics, proteomics, lipidomics, integrative omics, systems biology, and causal inference. Current states of the art, present challenges, novel and emerging strategies, and priorities for progress were presented and discussed for each area. This workshop report summarizes the major points and conclusions from this NIAID workshop. As a group, the investigators underscored the imperatives for rigorous analytic frameworks, integration of different omics data types, cross-disciplinary interaction, strategies for overcoming current limitations, and the overarching goal to improve scientific understanding and care of asthma and allergic diseases.
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Asma , Hipersensibilidad , Estados Unidos , Humanos , National Institute of Allergy and Infectious Diseases (U.S.) , Hipersensibilidad/genética , Asma/etiología , Genómica , Proteómica , MetabolómicaAsunto(s)
Hipersensibilidad a los Alimentos , Hipersensibilidad al Cacahuete , Lactante , Humanos , Arachis , Hipersensibilidad al Cacahuete/diagnóstico , Hipersensibilidad al Cacahuete/epidemiología , Inmunoglobulina E , Alérgenos , Administración Oral , Hipersensibilidad a los Alimentos/diagnóstico , Hipersensibilidad a los Alimentos/epidemiologíaRESUMEN
BACKGROUND: Peanut introduction guidelines recommend that infants with severe eczema and/or egg allergy consume 6 g of peanut protein weekly to prevent peanut allergy. Rates of new peanut allergy after introduction and adherence remain under study. OBJECTIVE: To determine compliance with peanut introduction guidelines, rates of new peanut allergy, and reasons for discontinuation of peanut consumption in a cohort of high-risk infants. METHODS: A prospective cohort of 4- to 11-month-old high-risk infants (defined as moderate-severe eczema or non-peanut food allergy or a first-degree relative with peanut allergy) with no prior peanut exposure who were determined to not be peanut allergic were recommended to introduce 6 g of peanut protein weekly. Participants were followed to 30 months with 2 in-person visits and monthly questionnaires. RESULTS: Two hundred seventy-seven infants were followed. At last follow-up, 245 (88%) were consuming some peanut protein with median weekly consumption of 3 g (interquartile range: 1-5 g). New peanut allergy developed in 6 (2%), with 2 of those cases consistent with food protein-induced enterocolitis syndrome. Fear of reaction in another household member was the most common reason for peanut discontinuation. Reactions to peanut after introduction in the index infant occurred in <2% of peanut-allergic siblings and in 20% of peanut-allergic parents. CONCLUSION: We found low rates of new peanut allergy and generally low rates of peanut discontinuation after introduction in our high-risk cohort. However, families of high-risk infants require significant support with introduction, especially those with another peanut-allergic member.
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Eccema , Hipersensibilidad al Huevo , Hipersensibilidad a los Alimentos , Hipersensibilidad al Cacahuete , Lactante , Humanos , Hipersensibilidad al Cacahuete/epidemiología , Hipersensibilidad al Cacahuete/prevención & control , Estudios Prospectivos , Hipersensibilidad al Huevo/epidemiología , Arachis , Alérgenos , Hipersensibilidad a los Alimentos/prevención & controlRESUMEN
Background: Food allergy (FA) and atopic dermatitis (AD) are common conditions that often present in the first year of life. Identification of underlying mechanisms and environmental determinants of FA and AD is essential to develop and implement effective prevention and treatment strategies. Objectives: We sought to describe the design of the Systems Biology of Early Atopy (SunBEAm) birth cohort. Methods: Funded by the National Institute of Allergy and Infectious Diseases (NIAID) and administered through the Consortium for Food Allergy Research (CoFAR), SunBEAm is a US population-based, multicenter birth cohort that enrolls pregnant mothers, fathers, and their newborns and follows them to 3 years. Questionnaire and biosampling strategies were developed to apply a systems biology approach to identify environmental, immunologic, and multiomic determinants of AD, FA, and other allergic outcomes. Results: Enrollment is currently underway. On the basis of an estimated FA prevalence of 6%, the enrollment goal is 2500 infants. AD is defined on the basis of questionnaire and assessment, and FA is defined by an algorithm combining history and testing. Although any FA will be recorded, we focus on the diagnosis of egg, milk, and peanut at 5 months, adding wheat, soy, cashew, hazelnut, walnut, codfish, shrimp, and sesame starting at 12 months. Sampling includes blood, hair, stool, dust, water, tape strips, skin swabs, nasal secretions, nasal swabs, saliva, urine, functional aspects of the skin, and maternal breast milk and vaginal swabs. Conclusions: The SunBEAm birth cohort will provide a rich repository of data and specimens to interrogate mechanisms and determinants of early allergic outcomes, with an emphasis on FA, AD, and systems biology.
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BACKGROUND: Allergen immunotherapy (AIT) is a well-established disease-modifying therapy for allergic rhinitis, yet the fundamental mechanisms underlying its clinical effect remain inadequately understood. Gauging Response in Allergic Rhinitis to Sublingual and Subcutaneous Immunotherapy was a randomized, double-blind, placebo-controlled trial of individuals allergic to timothy grass who received 2 years of placebo (n = 30), subcutaneous immunotherapy (SCIT) (n = 27), or sublingual immunotherapy (SLIT) (n = 27) and were then followed for 1 additional year. OBJECTIVE: We used yearly biospecimens from the Gauging Response in Allergic Rhinitis to Sublingual and Subcutaneous Immunotherapy study to identify molecular mechanisms of response. METHODS: We used longitudinal transcriptomic profiling of nasal brush and PBMC samples after allergen provocation to uncover airway and systemic expression pathways mediating responsiveness to AIT. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01335139, EudraCT Number: 2010-023536-16. RESULTS: SCIT and SLIT demonstrated similar changes in gene module expression over time. In nasal samples, alterations included downregulation of pathways of mucus hypersecretion, leukocyte migration/activation, and endoplasmic reticulum stress (log2 fold changes -0.133 to -0.640, false discovery rates [FDRs] <0.05). We observed upregulation of modules related to epithelial development, junction formation, and lipid metabolism (log2 fold changes 0.104 to 0.393, FDRs <0.05). In PBMCs, modules related to cellular stress response and type 2 cytokine signaling were reduced by immunotherapy (log2 fold changes -0.611 to -0.828, FDRs <0.05). Expression of these modules was also significantly associated with both Total Nasal Symptom Score and peak nasal inspiratory flow, indicating important links between treatment, module expression, and allergen response. CONCLUSIONS: Our results identify specific molecular responses of the nasal airway impacting barrier function, leukocyte migration activation, and mucus secretion that are affected by both SCIT and SLIT, offering potential targets to guide novel strategies for AIT.
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Rinitis Alérgica , Inmunoterapia Sublingual , Humanos , Transcriptoma , Leucocitos Mononucleares , Polen , Alérgenos , Desensibilización Inmunológica/métodos , Inmunoterapia Sublingual/métodos , Phleum , Inyecciones Subcutáneas , Rinitis Alérgica/terapia , Rinitis Alérgica/tratamiento farmacológicoRESUMEN
This survey study examines changes in pediatric clinicians' knowledge of eczema identification and the 2017 Addendum Guidelines for the Prevention of Peanut Allergy after an educational intervention.
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Eccema , Hipersensibilidad al Cacahuete , Humanos , Hipersensibilidad al Cacahuete/prevención & control , Pruebas Cutáneas , ConocimientoRESUMEN
BACKGROUND: Despite well-known susceptibilities to other respiratory viral infections, individuals with allergic asthma have shown reduced susceptibility to severe coronavirus disease 2019 (COVID-19). OBJECTIVE: We sought to identify mechanisms whereby type 2 inflammation in the airway protects against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by using bronchial airway epithelial cells (AECs) from aeroallergen-sensitized children with asthma and healthy nonsensitized children. METHODS: We measured SARS-CoV-2 replication and ACE2 protein and performed bulk and single-cell RNA sequencing of ex vivo infected AEC samples with SARS-CoV-2 infection and with or without IL-13 treatment. RESULTS: We observed that viral replication was lower in AECs from children with allergic asthma than those from in healthy nonsensitized children and that IL-13 treatment reduced viral replication only in children with allergic asthma and not in healthy children. Lower viral transcript levels were associated with a downregulation of functional pathways of the ciliated epithelium related to differentiation as well as cilia and axoneme production and function, rather than lower ACE2 expression or increases in goblet cells or mucus secretion pathways. Moreover, single-cell RNA sequencing identified specific subsets of relatively undifferentiated ciliated epithelium (which are common in allergic asthma and highly responsive to IL-13) that directly accounted for impaired viral replication. CONCLUSION: Our results identify a novel mechanism of innate protection against SARS-CoV-2 in allergic asthma that provides important molecular and clinical insights during the ongoing COVID-19 pandemic.
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Asma , COVID-19 , Niño , Humanos , SARS-CoV-2 , Interleucina-13 , Pandemias , Asma/epidemiología , Inflamación , Células Epiteliales/metabolismo , Epitelio/metabolismoRESUMEN
BACKGROUND: Asthma prevalence and severity have markedly increased with urbanisation, and children in low-income urban centres have among the greatest asthma morbidity. Outdoor air pollution has been associated with adverse respiratory effects in children with asthma. However, the mechanisms by which air pollution exposure exacerbates asthma, and how these mechanisms compare with exacerbations induced by respiratory viruses, are poorly understood. We aimed to investigate the associations between regional air pollutant concentrations, respiratory illnesses, lung function, and upper airway transcriptional signatures in children with asthma, with particular focus on asthma exacerbations occurring in the absence of respiratory virus. METHODS: We performed a retrospective analysis of data from the MUPPITS1 cohort and validated our findings in the ICATA cohort. The MUPPITS1 cohort recruited 208 children aged 6-17 years living in urban areas across nine US cities with exacerbation-prone asthma between Oct 7, 2015, and Oct 18, 2016, and monitored them during reported respiratory illnesses. The last MUPPITS1 study visit occurred on Jan 6, 2017. The ICATA cohort recruited 419 participants aged 6-20 years with persistent allergic asthma living in urban sites across eight US cities between Oct 23, 2006, and March 25, 2008, and the last study visit occurred on Dec 30, 2009. We included participants from the MUPPITS1 cohort who reported a respiratory illness at some point during the follow-up and participants from the ICATA cohort who had nasal samples collected during respiratory illness or at a scheduled visit. We used air quality index values and air pollutant concentrations for PM2·5, PM10, O3, NO2, SO2, CO, and Pb from the US Environmental Protection Agency spanning the years of both cohorts, and matched values and concentrations to each illness for each participant. We investigated the associations between regional air pollutant concentrations and respiratory illnesses and asthma exacerbations, pulmonary function, and upper airway transcriptional signatures by use of a combination of generalised additive models, case crossover analyses, and generalised linear mixed-effects models. FINDINGS: Of the 208 participants from the MUPPITS1 cohort and 419 participants from the ICATA cohort, 168 participants in the MUPPITS1 cohort (98 male participants and 70 female participants) and 189 participants in the ICATA cohort (115 male participants and 74 female participants) were included in our analysis. We identified that increased air quality index values, driven predominantly by increased PM2·5 and O3 concentrations, were significantly associated with asthma exacerbations and decreases in pulmonary function that occurred in the absence of a provoking viral infection. Moreover, individual pollutants were significantly associated with altered gene expression in coordinated inflammatory pathways, including PM2·5 with increased epithelial induction of tissue kallikreins, mucus hypersecretion, and barrier functions and O3 with increased type-2 inflammation. INTERPRETATION: Our findings suggest that air pollution is an important independent risk factor for asthma exacerbations in children living in urban areas and is potentially linked to exacerbations through specific inflammatory pathways in the airway. Further investigation of these potential mechanistic pathways could inform asthma prevention and management approaches. FUNDING: National Institutes of Health, National Institute of Allergy and Infectious Diseases.