The Predictive Role of Biomarkers and Genetics in Childhood Asthma Exacerbations.
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ABSTRACT:
SUBMITTER: di Palmo E
PROVIDER: S-EPMC8124320 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundAsthma is a major public health problem that affects millions of children worldwide, and exacerbations account for most of its morbidity and costs. Primary-care providers lack efficient tools to identify children at high risk for exacerbations. We aimed to construct a clinical score to help providers to identify such children.MethodsOur main outcome was severe asthma exacerbation, which was defined as any hospitalization, urgent visit, or systemic steroid course for asthma in the previous year, in children. A clinical score, consisting of a checklist questionnaire made up of 17 yes-no questions regarding asthma symptoms, use of medications and health-care services, and history, was built and validated in a cross-sectional study of Costa Rican children with asthma. It was then evaluated using data from the Childhood Asthma Management Program (CAMP), a longitudinal trial cohort of North American children.ResultsCompared with children at average risk for an exacerbation in the Costa Rican validation set, the odds of an exacerbation among children in the low-risk (OR, 0.2; 95% CI, 0.1-0.4) and high-risk (OR, 5.4; 95% CI, 1.5-19.2) score categories were significantly reduced and increased, respectively. In CAMP, the hazard ratios for an exacerbation after 1-year follow-up in the low-risk and high-risk groups were 0.6 (95% CI, 0.5-0.7) and 1.9 (95% CI, 1.4-2.4), respectively, with similar results at 2 years.ConclusionsThe proposed Asthma Exacerbation Clinical Score is simple to use and effective at identifying children at high and low risk for asthma exacerbations. The tool can easily be used in primary-care settings.
| S-EPMC2972623 | biostudies-literature
Project description:INTRODUCTION:Effective home management of childhood asthma by caregivers requires education along with a written asthma action plan (AAP), which should outline clear instructions for treatment during exacerbations. However, a large number of asthma exacerbations continue to be managed in the emergency department (ED) and in hospitals, particularly in Canada. The objective of this study was to assess caregiver management of acute asthma at home following the 2015 Global Initiative for Asthma (GINA) guidelines and to identify factors that may be associated with deviations from these guidelines. METHODS:122 caregivers of children, aged 3-17 years, with physician diagnosed asthma, completed a paper-based questionnaire. Correct caregiver management (defined according to the GINA guidelines) of acute asthma as well as their use of an AAP were assessed. RESULTS:Out of all caregivers, 74.6% incorrectly treated their child's asthma exacerbation in a home setting. Among those who used an AAP, we observed significantly more ED visits (0.9 ± 1.2 versus 0.5 ± 0.9, p = 0.04) and hospitalizations (0.2 ± 0.4 versus 0.0 ± 0.0, p = 0.02) when compared to non-AAP users in the past 1 year. CONCLUSIONS:Caregivers of children with asthma in Canada may still lack skills for proper home management of asthma exacerbations. We found a higher number of ED visits and hospitalizations in those using an AAP compared to those who did not use an AAP. These data suggest that current AAPs may not be sufficient for home asthma management.
| S-EPMC6966973 | biostudies-literature
Project description:Childhood asthma represents a heterogeneous challenging disease, in particular in its severe forms. The identification of different asthma phenotypes has stimulated research in underlying molecular mechanisms, such as the endotypes, and paved the way to the search for related specific biomarkers, which may guide diagnosis, management, and predict response to treatment. A limited number of biomarkers are currently available in clinical practice in the pediatric population, mostly reflecting type 2-high airway inflammation. The identification of biomarkers of childhood asthma is an active area of research that holds a potential great clinical utility and may represent a step forward toward tailored management and therapy: the so-called Precision Medicine. The aim of the present review is to provide an updated overview of asthma endotyping, mostly focusing on novel noninvasive biomarkers in childhood asthma.
| S-EPMC6069590 | biostudies-other
Project description:BACKGROUND:Asthma exacerbations occur frequently despite the regular use of asthma-controller therapies, such as inhaled glucocorticoids. Clinicians commonly increase the doses of inhaled glucocorticoids at early signs of loss of asthma control. However, data on the safety and efficacy of this strategy in children are limited. METHODS:We studied 254 children, 5 to 11 years of age, who had mild-to-moderate persistent asthma and had had at least one asthma exacerbation treated with systemic glucocorticoids in the previous year. Children were treated for 48 weeks with maintenance low-dose inhaled glucocorticoids (fluticasone propionate at a dose of 44 ?g per inhalation, two inhalations twice daily) and were randomly assigned to either continue the same dose (low-dose group) or use a quintupled dose (high-dose group; fluticasone at a dose of 220 ?g per inhalation, two inhalations twice daily) for 7 days at the early signs of loss of asthma control ("yellow zone"). Treatment was provided in a double-blind fashion. The primary outcome was the rate of severe asthma exacerbations treated with systemic glucocorticoids. RESULTS:The rate of severe asthma exacerbations treated with systemic glucocorticoids did not differ significantly between groups (0.48 exacerbations per year in the high-dose group and 0.37 exacerbations per year in the low-dose group; relative rate, 1.3; 95% confidence interval, 0.8 to 2.1; P=0.30). The time to the first exacerbation, the rate of treatment failure, symptom scores, and albuterol use during yellow-zone episodes did not differ significantly between groups. The total glucocorticoid exposure was 16% higher in the high-dose group than in the low-dose group. The difference in linear growth between the high-dose group and the low-dose group was -0.23 cm per year (P=0.06). CONCLUSIONS:In children with mild-to-moderate persistent asthma treated with daily inhaled glucocorticoids, quintupling the dose at the early signs of loss of asthma control did not reduce the rate of severe asthma exacerbations or improve other asthma outcomes and may be associated with diminished linear growth. (Funded by the National Heart, Lung, and Blood Institute; STICS ClinicalTrials.gov number, NCT02066129 .).
| S-EPMC5972517 | biostudies-literature
Project description:BACKGROUND:Research in transformed immortalized cell lines indicates the cadherin-related family member 3 (CDHR3) protein serves as a receptor for human rhinovirus (HRV)-C. Similar experiments indicate that the CDHR3 coding variant rs6967330 increases CDHR3 protein surface expression. OBJECTIVE:We sought to determine whether CDHR3 is necessary for HRV-C infection of primary airway epithelial cells (AECs) and to identify molecular mechanisms by which CDHR3 variants confer risk for asthma exacerbations. METHODS:CDHR3 function and influence on HRV-C infection were investigated by using single-cell transcriptomics, CRISPR-Cas9 gene knockout, and genotype-specific donor experiments performed in primary AECs. Nasal airway epithelium cis-expression quantitative trait locus (eQTL) analysis of CDHR3 was performed, followed by association testing for asthma hospitalization in minority children. RESULTS:CDHR3 lung expression is exclusive to ciliated AECs and associated with basal bodies during and after motile ciliogenesis. Knockout of CDHR3 in human AECs did not prevent ciliated cell differentiation but was associated with a decrease in transepithelial resistance and an 80% decrease in HRV-C infection of the mucociliary epithelium. AECs from subjects homozygous for the risk-associated rs6967330 single nucleotide polymorphism (SNP) exhibited greater HRV-C infection compared with cells homozygous for the nonrisk allele. AEC cis-eQTL analysis indicated that rs6967330 and other SNPs are eQTLs for CDHR3. Only the eQTL block containing the rs6967330 SNP showed a significant association with childhood asthma hospitalization. CONCLUSIONS:Genetic deletion and genotype-specific studies in primary AECs indicate CDHR3 is critical to HRV-C infection of ciliated cells. The rs6967330 SNP confers risk of severe childhood asthma exacerbations, likely through increasing HRV-C infection levels and protein surface localization.
| S-EPMC6766426 | biostudies-literature
Project description:BACKGROUND:Current US guidelines recommend the Asthma Control Test (ACT) for assessing disease control and selecting treatment. OBJECTIVE:The goal of this study was to prospectively assess the ACT and its component questions for their utility in predicting the risk of severe asthma exacerbations. METHODS:Individuals were participants in the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity, and those included in the current analysis had the following characteristics: age 18 years or more, physician-diagnosed asthma, and longitudinal care received at a large health system in southeastern Michigan. Study participants underwent a baseline evaluation, which included answering the ACT. A severe asthma exacerbation was defined as one requiring oral steroids, an emergency department visit, or inpatient admission. Receiver-operator characteristic curves were used to measure and compare the predictive utility of the ACT and its component questions for severe asthma exacerbations. RESULTS:Of 1180 participants, 354 (30.0%) experienced a severe asthma exacerbation within 6 months of their baseline evaluation. When compared with the individual questions that composed the ACT, the composite score was significantly better at predicting severe exacerbations with 1 exception; the composite ACT score and the question assessing rescue medication use were not significantly different (P = .580). Pharmacy-based records of metered-dose inhaler short-acting beta-agonist use and asthma severity were also not significantly different from the composite ACT score. CONCLUSIONS:Our study demonstrates that although the ACT is modestly predictive for exacerbations, the composite score may not be superior to assessing rescue medication use alone for predicting the risk of severe asthma exacerbations.
| S-EPMC5222777 | biostudies-literature
Project description:The Asthma Predictive Index (API) and persistent wheezing phenotypes are associated with childhood asthma, but previous studies have not assessed their ability to predict objectively confirmed asthma.To determine whether the University of Cincinnati API Index (ucAPI) and/or persistent wheezing at age 3 can accurately predict objectively confirmed asthma at age 7.Data from the Cincinnati Childhood Allergy and Air Pollution Study, a high-risk prospective birth cohort, was used. Asthma was defined as parent-reported or physician-diagnosed asthma objectively confirmed by a change in FEV1 of ?12% after bronchodilator or a positive methacholine challenge (PC20 ? 4 mg/mL); or as prior treatment with daily asthma controller medication(s). Multivariate logistic regression was used to investigate the relationship between confirmed asthma at age 7 and a positive ucAPI (adapted and modified from prior published API definitions) and persistent wheezing at age 3.At age 7, 103 of 589 children (17.5%) satisfied the criteria for asthma. Confirmed asthma at age 7 was significantly associated with a positive ucAPI (adjusted odds ratio [aOR] 13.3 [95% CI, 7.0-25.2]; P < .01) and the persistent wheezing phenotype (aOR 9.8 [95% CI, 4.9-19.5]; P < .01) at age 3. Allergic persistent wheezing was associated with a significantly higher risk of asthma (aOR 10.4 [95% CI, 4.1-26.0]; P < .01) than nonallergic persistent wheezing (aOR 5.4 [95% CI, 2.04-14.06]; P < .01).Both a positive ucAPI and persistent wheeze at age 3 were associated with objectively confirmed asthma at age 7; however, the highest risk was associated with ucAPI. These results demonstrate the ucAPI as a clinically useful tool for predicting future asthma in school-age children.
| S-EPMC4254628 | biostudies-literature
Project description:Rhinovirus (RV) is ubiquitous and typically causes only minor upper respiratory symptoms. However, especially in children and adolescent asthmatics, RV is responsible for most exacerbations. This ability of RV to drive exacerbations typically requires the concomitant presence of exposure to a bystander allergen. Susceptibility to RV-mediated exacerbations is also related to the genetic background of the host, which contributes to greater infectivity, more severe infections, altered immune responses, and to greater inflammation and loss of asthma control. Given these responses, there are several treatments available or being developed that should improve the control of exacerbations related to RV infection.
| S-EPMC6625523 | biostudies-literature
Project description:Asthma is a heterogeneous disease that results from the complex interaction between genetic factors and environmental exposures that occur at critical periods throughout life. It seems plausible to regard childhood-onset and adult-onset asthma as different entities, each with a different pathophysiology, trajectory, and outcome. This review provides an overview about the role of genetics and gene-environment interactions in these two conditions. Looking at the genetic overlap between childhood and adult onset disease gives one window into whether there is a correlation, as well as to mechanism. A second window is offered by the genetics of the relationship between each type of asthma and other phenotypes e.g., obesity, chronic obstructive pulmonary disease (COPD), atopy, vitamin D levels, and inflammatory and immune status; and third, the genetic-specific responses to the many environmental exposures that influence risk throughout life, and particularly those that occur during early-life development. These represent a large number of possible combinations of genetic and environmental factors, at least 150 known genetic loci vs. tobacco smoke, outdoor air pollutants, indoor exposures, farming environment, and microbial exposures. Considering time of asthma onset extends the two-dimensional problem of gene-environment interactions to a three-dimensional problem, since identified gene-environment interactions seldom replicate for childhood and adult asthma, which suggests that asthma susceptibility to environmental exposures may biologically differ from early life to adulthood as a result of different pathways and mechanisms of the disease.
| S-EPMC6918916 | biostudies-literature
Project description:BACKGROUND:Epigenetic modifications may have a role in asthma susceptibility. OBJECTIVE:To investigate whether epigenetic modification at birth of a CpG site necessary for the regulation of IL-2 transcription (IL-2 Site1) is associated with the development of asthma during childhood. METHODS:Methylation of IL-2 Site1 was assessed in cord blood from 303 children (225 with atopic mothers); as controls, we measured methylation of a site not important in the transcription of IL-2 (IL-2 Site7) and methylation of the LINE-1 repetitive element. Children were followed to the age of 8 years. Information on severe asthma exacerbations and hospital admissions was collected from child's primary care medical record. To account for potential confounding by bronchiolitis, we used exacerbations/hospitalizations after age 1 year as primary outcomes. RESULTS:There were 49 severe exacerbations amongst 33 children, and 22 hospital admissions amongst 11 children. The risk of asthma exacerbation increased 1.07-fold (95% CI 1.01-1.14, P = 0.03) and the risk of hospital admission increased 1.12-fold (95% CI 1.04-1.20, P = 0.002) for each one per cent increase in IL-2 Site1 methylation. Children who were admitted to hospital at any time-point had significantly higher IL-2 Site1 methylation than children not admitted to hospital (P = 0.007). There was a significant interaction between age at exacerbation (P = 0.03) or hospital admission (P = 0.02) and methylation, with the effect of methylation increasing with increasing age. Methylation of the control IL-2 Site7 or LINE-1 was not a significant predictor of asthma exacerbations/hospital admission, and we found no association between IL-2 Site1 methylation and hospital admissions for other reasons (0.99 [0.92-1.06]). Cord blood mononuclear cell phytohemagglutinin-stimulated lymphoproliferative responses decreased significantly with increasing IL-2 Site1 methylation (P < 0.001). CONCLUSIONS:Increasing methylation in cord blood of a functional CpG site in the IL-2 promoter is associated with increased likelihood of severe asthma exacerbations and hospital admissions for asthma/wheeze between ages of 2 and 8 years.
| S-EPMC6344940 | biostudies-literature