Asthma Treatment Response Research Articles

Impact of Dupilumab on Skin Surface Lipid-RNA Profile in Severe Asthmatic Patients.

The analysis of skin surface lipid-RNAs (SSL-RNAs) provides a non-invasive method for understanding the molecular pathology of atopic dermatitis (AD), but its relevance to asthma remains uncertain. Although dupilumab, a biologic drug approved for both asthma and AD, has shown efficacy in improving symptoms for both conditions, its impact on SSL-RNAs is unclear. This study aimed to investigate the impact of dupilumab treatment on SSL-RNA profiles in patients with severe asthma. An SSL-RNA analysis was performed before and after administering dupilumab to asthma patients requiring this intervention. Skin samples were collected non-invasively from patients before and after one year of dupilumab treatment. Although 26 patients were enrolled, an SSL-RNA analysis was feasible in only 7 due to collection challenges. After dupilumab treatment, improvements were observed in asthma symptoms, exacerbation rates, and lung function parameters. Serum levels of total IgE and periostin decreased. The SSL-RNA analysis revealed the differential expression of 218 genes, indicating significant down-regulation of immune responses, particularly those associated with type 2 inflammation, suggesting potential improvement in epithelial barrier function. Dupilumab treatment may not only impact type 2 inflammation but also facilitate the normalization of the skin. Further studies are necessary to fully explore the potential of SSL-RNA analysis as a non-invasive biomarker for evaluating treatment response in asthma.

Precision care in the treatment of pediatric asthma.

Precision medicine in pediatric asthma involves identification of asthma phenotypes, genetic markers, biomarkers, and biologics that target specific pathways. This review includes a discussion of the efficacy of currently approved biologics for pediatric asthma and most recent advances in biomarker/phenotype identification and genetic associations that affect asthma care. Biologics targeting type-2 mediated pathways have shown success in the treatment of moderate to severe asthma in pediatric and adult patients. In comparative studies, dupilumab, an interleukin-4 (IL-4) alpha receptor inhibitor, and mepolizumab, an IL-5 inhibitor, have shown more improvement in asthma exacerbation rates and lung function compared to other biologics such as tezepelumab, omalizumab and benralizumab. Other methods used to categorize asthma treatment response have been investigated and include use of biomarkers such as fractional exhaled nitric oxide (FeNO). Genomic studies are also emerging in precision care for pediatric asthma. An understanding of underlying immunologic and genetic mechanisms affecting the development of asthma in pediatric patients has resulted in the production of numerous targeted therapies that have led to improvement in lung function and reduced exacerbation burden.

Recent miRNA Research in Asthma.

The study of microRNA in asthma has revealed a vibrant new level of gene regulation underlying asthma pathology. Several miRNAs have been shown to be important in asthma, influencing various biological mechanisms which lead to asthma pathology and symptoms. In addition, miRNAs have been proposed as biomarkers of asthma affection status, asthma severity, and asthma treatment response. We review all recent asthma-miRNA work, while also presenting comprehensive tables of all miRNA results related to asthma. We here reviewed 63 recent studies published reporting asthma and miRNA research, and an additional 14 reviews of the same. We summarized the information for both adult and childhood asthma, as well as research on miRNAs in asthma-COPD overlap syndrome (ACOs), and virus-induced asthma exacerbations. We attempted to present a comprehensive collection of recently published asthma-associated miRNAs as well as tables of all published asthma-related miRNA results.

Age-Related Clinical Characteristics, Inflammatory Features, Phenotypes, and Treatment Response in Asthma

Emerging evidence suggests that aging affects asthma outcomes, but the mechanism remains largely unexplored. To explore age-related clinical, inflammatory characteristics, phenotypes and treatment response in asthma. This study was a prospective cohort study of asthmatic patients with a 12-month follow-up period in a real-word setting. Clinical, inflammatory and phenotypic characteristics, future risk of exacerbations, and treatment response were assessed across different ages (young: 18-39 years; middle-aged: 40-64 years; elderly: ≥ 65 years). In comparison with young (n = 106) and middle-aged (n = 179) asthmatics, elderly asthmatics (n = 55) had worse airway obstruction, more comorbidities including COPD and diabetes, less atopy, lower levels of IgE and FENO, and were more likely to have late onset and fixed airflow obstruction asthma, and reduced risk of having Type 2 profile asthma. Levels of IFN-γ, IL-17A and IL-8 in induced sputum were significantly increased in elderly asthmatic patients (all P < 0.05). Path analysis indicated that age directly and significantly led to future exacerbations in asthma, partially mediated by an upregulation of airway IFN-γ. Moreover, elderly patients with asthma had reduced treatment response (improvement in FEV1 ≥ 12% or 200 mL, and reduction in Borg sores ≥ 1) (adjusted OR [aOR] = 0.11, 95% CI = [0.02, 0.52], and aOR = 0.12, 95% CI = [0.03, 0.49], respectively). This study supports that asthma in the elderly represents a specific phenotype and indicates that aging can influence asthma in terms of clinical, inflammatory characteristics, exacerbations, and treatment response.

P067 DUPILUMAB LEADS TO CLINICAL ASTHMA REMISSION INDICATIVE OF COMPREHENSIVE IMPROVEMENT IN PATIENTS WITH ASTHMA

Asthma treatment response is ascertained by improvement in ≥1 key asthma outcome (exacerbations/symptom control/lung function). This post hoc analysis of QUEST (NCT02414854) patients assessed dupilumab’s effect using a multicomponent endpoint representing clinical asthma remission.

Asthma treatment response to inhaled corticosteroids is associated with variants in VEGFA gene.

• Variants in VEGFA gene are associated with asthma treatment response to ICS . • Carriers of C allele in variant rs2146323 appear to respond better to ICS treatment. • Atopic status influences response to ICS treatment.

Dupilumab Treatment Leads to Clinical Asthma Remission in Patients With Uncontrolled Moderate-to-Severe Asthma With Type 2 Inflammation

Asthma treatment response is ascertained by improvement in ≥1 key asthma outcome (exacerbations/symptom control/lung function). This post hoc analysis of LIBERTY ASTHMA QUEST (NCT02414854) assessed dupilumab effect in patients with uncontrolled, moderate-to-severe asthma using a multicomponent endpoint representing various dimensions of clinical asthma remission.

Precision Medicine in Childhood Asthma: Omic Studies of Treatment Response.

Asthma is a heterogeneous and multifactorial respiratory disease with an important impact on childhood. Difficult-to-treat asthma is not uncommon among children, and it causes a high burden to the patient, caregivers, and society. This review aims to summarize the recent findings on pediatric asthma treatment response revealed by different omic approaches conducted in 2018–2019. A total of 13 studies were performed during this period to assess the role of genomics, epigenomics, transcriptomics, metabolomics, and the microbiome in the response to short-acting beta agonists, inhaled corticosteroids, and leukotriene receptor antagonists. These studies have identified novel associations of genetic markers, epigenetic modifications, metabolites, bacteria, and molecular mechanisms involved in asthma treatment response. This knowledge will allow us establishing molecular biomarkers that could be integrated with clinical information to improve the management of children with asthma.

Pharmacogenetics of Pediatric Asthma: Current Perspectives.

Asthma is a chronic respiratory disease that affects 339 million people worldwide and has a considerable impact on the pediatric population. Asthma symptoms can be controlled by pharmacological treatment. However, some patients do not respond to therapy and continue suffering from symptoms, which impair the quality of life of patients and limit their daily activity. Genetic variation has been shown to have a role in treatment response. The aim of this review is to update the main findings described in pharmacogenetic studies of pediatric asthma published from January 1, 2018 to December 31, 2019. During this period, the response to short-acting beta-agonists and inhaled corticosteroids in childhood asthma has been evaluated by eleven candidate-gene studies, one meta-analysis of a candidate gene, and six pharmacogenomic studies. The findings have allowed validating the association of genes previously related to asthma treatment response (ADRB2, GSDMB, FCER2, VEGFA, SPAT2SL, ASB3, and COL2A1), and identifying novel associations (PRKG1, DNAH5, IL1RL1, CRISPLD2, MMP9, APOBEC3B-APOBEC3C, EDDM3B, and BBS9). However, some results are not consistent across studies, highlighting the need to conduct larger studies in diverse populations with more homogeneous definitions of treatment response. Once stronger evidence was established, genetic variants will have the potential to be applied in clinical practice as biomarkers of treatment response enhancing asthma management and improving the quality of life of asthma patients.

Spirometry In Classification and Management of Childhood Asthma

Asthma is the most common chronic illness of childhood. Measurement of lung function provides a better view in diagnosis and management of asthma. Considering scarcity of literature and usefulness of spirometry, this study done to assess role of spirometry on childhood asthma. Prospective study was conducted on children (n=52, age 6 to 12 years) attending asthma clinic in P.D.U. Medical College and Civil Hospital, Rajkot over a period of 2 years (oct-2016 to sep-2018). Diagnosis and management of asthma was done clinically and by spirometry according to GINA – 2015 guidelines. Spirometry is done for minimum 3 times with gap of 3 month each. High positive correlation between clinical and spirometry diagnosis with milder form of asthma. While severe form of asthma is more likely to under diagnosed and under treated (Intermittent, mild persistent and moderate persistent asthma positive correlation 71.5%, 77.3% and 32% respectively). Improvement in FEV1 and FEF25-75 values observes on subsequent spirometry ((FEV1)1 to (FEV1)2 p value=0.000, (FEV1)1 to (FEV1)3 p value=0.001, (FEF25-75)1 to (FEF25-75)2 p value=0.000, (FEF25-75)1 to (FEF25-75)3 p value=0.00). Significant decrease in amount of drug (inhalation steroid – budesonide, mcg/day) required (spirometry-1 mean 357.69, spirometry-2 mean 350.00, spirommetry-3 mean 273.07, p value=0.009). Spirometry is to be done in all children at the time of initial diagnosis of asthma and then once or twice every year. FEV1 and FEF25-75 is important tool for monitoring and assessing treatment response in asthma. Spirometry based treatment implementation leads to better asthma control, optimum dose adjustment.

P101 FAMILIAL SUCCESS IN ALLERGEN DESENSITIZATION

Allergic rhinitis (AR) is a widely prevalent immunoglobulin E-mediated inflammatory nasal condition resulting from re-exposure to an allergen in a sensitized individual. The genetic associations behind AR and other allergic conditions have been studied. However, familial success with AR therapies, specifically allergen desensitization through subcutaneous immunotherapy (SCIT), has never been reported in the literature. Pharmocogenetics has been gradually applied to link heritable genetic variants with drug responses, such as intergenic region variants APOBEC3B and APOBEC3C and β2-adrenergic receptor and glycoprotein ADAM33 polymorphisms as predictive biomarkers for biologic treatment response in asthma. We provide the first reported survey of familial success with SCIT.

Pharmacogenetic Factors Affecting Asthma Treatment Response. Potential Implications for Drug Therapy.

Asthma is a frequent disease, mainly characterized by airway inflammation, in which drug therapy is crucial in its management. The potential of pharmacogenomics testing in asthma therapy has been, to date, little explored. In this review, we discuss pharmacogenetic factors affecting asthma treatment, both related to drugs used as controller medications for regular maintenance, such as inhaled corticosteroids, anti-leukotriene agents, long-acting beta-agonists, and the new biologic agents used to treat severe persistent asthma. In addition, we discuss current pharmacogenomics knowledge for rescue medications provided to all patients for as-needed relief, such as short-acting beta-agonists. Evidence for genetic variations as a factor related to drugs response has been provided for the following genes and groups of drugs: Inhaled corticosteroids: FCER2; anti-leukotriene agents: ABCC1, and LTC4S; beta-agonists: ADRB2. However, the following genes require further studies confirming or rejecting association with the response to asthma therapy: ADCY9, ALOX5, ARG1, ARG2, CRHR1, CRHR2, CYP3A4, CYP3A5, CYSLTR1, CYSLTR2, GLCCI1, IL4RA, LTA4H, ORMDL3, SLCO2B1, SPATS2L, STIP1, T, TBX21, THRA, THRB, and VEGFA. Although only a minority of these genes are, at present, listed as associated with drugs used in asthma therapy, in the Clinical Pharmacogenomics Implementation Consortium gene-drug pair list, this review reveals that sufficient evidence to start testing the potential of clinical pharmacogenomics in asthma therapy already exists. This evidence supports the inclusion in pilot pharmacogenetics tests of at least four genes. Hopefully these tests, if proven useful, will increase the efficiency and the safety of asthma therapy.

Familial Success in Allergen Desensitization.

IntroductionAllergic rhinitis (AR) is a widely prevalent immunoglobulin E-mediated inflammatory nasal condition resulting from reexposure to an allergen in a sensitized individual. The genetic associations behind AR and other allergic conditions have been studied. However, familial success with AR therapies, specifically allergen desensitization through subcutaneous immunotherapy (SCIT), has never been reported in the literature. Pharmocogenetics has been gradually applied to link heritable genetic variants with drug responses, such as intergenic region variants APOBEC3B and APOBEC3C and β2-adrenergic receptor and glycoprotein ADAM33 polymorphisms as predictive biomarkers for biologic treatment response in asthma. We provide the first reported survey of familial success with SCIT.MethodsWe administered a month-long, institutional review board-approved (20190493) questionnaire to 200 adult patients receiving SCIT in a suburban allergy/immunology practice. The anonymous survey inquired about demographics, target allergens for their SCIT, current symptom improvement on SCIT, and family history of allergies and SCIT management.ResultsTwenty-six percent (52 of 200, 26%) SCIT patients reported familial success with the same allergy treatment modality. AR diagnosis and symptom improvement from SCIT was similar among previous/same (18 of 52, 38%; 26 of 52, 54%) and subsequent (10 of 52, 21%; 19 of 52, 40%) generations of family members. A combination of seasonal and perennial allergies was most prevalent (81%) among this population.ConclusionIn a subpopulation of SCIT patients, there appears to be a familial success rate with this allergen desensitization treatment. This is the first reported pharmocogenetic evidence of assessing hereditary influence on effective AR therapy. Understanding pharmacogenetic associations involved with SCIT may improve allergists’ recommendations for this treatment option.

Differential connectivity of gene regulatory networks distinguishes corticosteroid response in asthma

Variations in drug response between individuals have prevented us from achieving high drug efficacy in treating many complex diseases, including asthma. Genetics plays an important role in accounting for such interindividual variations in drug response. However, systematic approaches for addressing how genetic factors and their regulators determine variations in drug response in asthma treatment are lacking. We sought to identify key transcriptional regulators of corticosteroid response in asthma using a novel systems biology approach. We used Passing Attributes between Networks for Data Assimilations (PANDA) to construct the gene regulatory networks associated with good responders and poor responders to inhaled corticosteroids based on a subset of 145 white children with asthma who participated in the Childhood Asthma Management Cohort. PANDA uses gene expression profiles and published relationships among genes, transcription factors (TFs), and proteins to construct the directed networks of TFs and genes. We assessed the differential connectivity between the gene regulatory network of good responders versus that of poor responders. When compared with poor responders, the network of good responders has differential connectivity and distinct ontologies (eg, proapoptosis enriched in network of good responders and antiapoptosis enriched in network of poor responders). Many of the key hubs identified in conjunction with clinical response are also cellular response hubs. Functional validation demonstrated abrogation of differences in corticosteroid-treated cell viability following siRNA knockdown of 2TFs and differential downstream expression between good responders and poor responders. We have identified and validated multiple TFs influencing asthma treatment response. Our results show that differential connectivity analysis can provide new insights into the heterogeneity of drug treatment effects.

Genetic variation in uncontrolled childhood asthma despite ICS treatment.

Genetic variation may partly explain asthma treatment response heterogeneity. We aimed to identify common and rare genetic variants associated with asthma that was not well controlled despite inhaled corticosteroid (ICS) treatment. Data of 110 children was collected in the Children Asthma Therapy Optimal trial. Associations of genetic variation with measures of lung function (FEV1%pred), airway hyperresponsiveness (AHR) to methacholine (Mch PD20) and treatment response outcomes were analyzed using the exome chip. The 17q12-21 locus (containing ORMDL3 and GSMDB) previously associated with childhood asthma was investigated separately. Single-nucleotide polymorphisms (SNPs) in the 17q12-21 locus were found nominally associated with the outcomes. The strongest association in this region was found for rs72821893 in KRT25 with FEV1%pred (P=3.75*10(-5)), Mch PD20 (P=0.00095) and Mch PD20-based treatment outcome (P=0.006). No novel single SNPs or burden tests were significantly associated with the outcomes. The 17q12-21 region was associated with FEV1%pred and AHR, and additionally with ICS treatment response.

Reaching Beyond Disparity: Safely Improving Asthma Control in the At-Risk African-American Population

In the United States, substantial racial disparities exist in asthma prevalence, etiology, morbidity and mortality, particularly between African Americans and white Americans. African-American patients with asthma have inadequate access to appropriate healthcare, insufficient asthma management guidance from their physicians and poor adherence to asthma medications-all factors that may contribute to disproportionate morbidity. Historically, African Americans have been under-represented in clinical asthma studies, and a paucity of data exists surrounding asthma treatment response. One controversial study from 2006 suggests an increased safety risk with the use of long-acting beta2-adrenergic agonists (LABAs) in African Americans. More recently, several studies have evaluated the use of LABAs in combination with an ICS in African-American populations. This article reviews the existing data on asthma treatment outcomes, with particular emphasis on the recently published short- and long-term studies of ICS/LABA products conducted in African-American populations with moderate-to-severe asthma. Overall, evidence suggests that if African-American patients with asthma are provided with access to well-trained physicians, appropriate asthma management and effective medications, existing disparities in asthma control between African-American and white populations may be overcome.

Asthma Treatment Outcome in Children Is Associated with Vascular Endothelial Growth Factor A (VEGFA) Polymorphisms

Asthma is a common chronic disease characterized by airway inflammation and structural remodeling. Vascular endothelial growth factor (VEGF), a major regulator of angiogenesis, is elevated in asthma patients. VEGF contributes to airway responsiveness and remodeling. It has been shown that treatment of asthma patients decreases VEGF levels, and inhibition of VEGF diminishes asthma symptoms in mice. Therefore, polymorphisms in the vascular endothelial growth factor A (VEGFA) gene might be associated with asthma treatment response. This study enrolled 131 children with asthma treated with different therapies - specifically, the inhaled corticosteroid (ICS) fluticasone propionate or the leukotriene receptor antagonist (LTRA) montelukast. We performed an association analysis between improvement of lung function - assessed by measurement of the percentage of the predicted forced expiratory volume in 1 second (%predicted FEV(1)), the ratio between the FEV(1) and the forced vital capacity (FEV(1)/FVC) after 6 and 12 months of treatment, and asthma control after 12 months of treatment - and two polymorphisms, rs2146323 and rs833058, in the VEGFA gene. Polymorphism rs2146323 A>C in VEGFA was associated with response to ICS therapy. Asthma patients with the AA genotype had a greater improvement in the %predicted FEV(1) than those with the AC or CC genotype (p = 0.018). Conversely, the AA genotype in rs2146323 was associated with uncontrolled asthma in patients regularly receiving LTRA therapy (p = 0.020) and a worse FEV(1)/FVC ratio in patients who episodically used LTRA therapy (p = 0.044). Furthermore, polymorphism rs833058 C>T was associated with treatment response to episodically used LTRA therapy. A subgroup of patients with the TT genotype had an improvement in the %predicted FEV(1), compared with no improvement in patients with the CT or CC genotype (p = 0.029). Our results showed that treatment response to commonly used asthma therapies (ICS or LTRA) is associated with polymorphisms rs2146323 and rs833058 in VEGFA. With additional replication of this preliminary study, our findings could contribute to the development of individualized asthma therapy.

Genome-wide Association Identifies the T Gene as a Novel Asthma Pharmacogenetic Locus

To date, most studies aimed at discovering genetic factors influencing treatment response in asthma have focused on biologic candidate genes. Genome-wide association studies (GWAS) can rapidly identify novel pharmacogenetic loci. To investigate if GWAS can identify novel pharmacogenetic loci in asthma. Using phenotypic and GWAS genotype data available through the NHLBI-funded Single-nucleotide polymorphism Health association-Asthma Resource Project, we analyzed differences in FEV(1) in response to inhaled corticosteroids in 418 white subjects with asthma. Of the 444,088 single nucleotide polymorphisms (SNPs) analyzed, the lowest 50 SNPs by P value were genotyped in an independent clinical trial population of 407 subjects with asthma. The lowest P value for the GWAS analysis was 2.09 × 10(-6). Of the 47 SNPs successfully genotyped in the replication population, three were associated under the same genetic model in the same direction, including two of the top four SNPs ranked by P value. Combined P values for these SNPs were 1.06 × 10(-5) for rs3127412 and 6.13 × 10(-6) for rs6456042. Although these two were not located within a gene, they were tightly correlated with three variants mapping to potentially functional regions within the T gene. After genotyping, each T gene variant was also associated with lung function response to inhaled corticosteroids in each of the trials associated with rs3127412 and rs6456042 in the initial GWAS analysis. On average, there was a twofold to threefold difference in FEV(1) response for those subjects homozygous for the wild-type versus mutant alleles for each T gene SNP. Genome-wide association has identified the T gene as a novel pharmacogenetic locus for inhaled corticosteroid response in asthma.

The pharmacogenetics and pharmacogenomics of asthma therapy

Despite the availability of several classes of asthma medications and their overall effectiveness, a significant portion of patients fail to respond to these therapeutic agents. Evidence suggests that genetic factors may partly mediate the heterogeneity in asthma treatment response. This review discusses important findings in asthma pharmacogenetic and pharmacogenomic studies conducted to date, examines limitations of these studies and, finally, proposes future research directions in this field. The focus will be on the three major classes of asthma medications: β-adrenergic receptor agonists, inhaled corticosteroids and leukotriene modifiers. Although many studies are limited by small sample sizes and replication of the findings is needed, several candidate genes have been identified. High-throughput technologies are also allowing for large-scale genetic investigations. Thus, the future is promising for a personalized treatment of asthma, which will improve therapeutic outcomes, minimize side effects and lead to a more cost-effective care.

Assessment of inhaled corticosteroid treatment response in asthma using hypertonic histamine challenge‐induced cough

Bronchial provocation tests may be utilised to monitor the efficacy of the corticosteroid treatment. Unfortunately, these measurements necessitate good patient cooperation during the spirometry. Coughing during such tests is related to the degree of the bronchoconstriction and occurs involuntarily, i.e. independent of patient cooperation. This study aimed to evaluate the utility of a hypertonic histamine challenge-induced cough in assessing the efficacy of inhaled corticosteroid treatment. A total of 16 steroid-naïve asthmatics and 10 non-asthmatic, symptomatic controls received 800-microg beclomethasone (Beclomet Easyhaler(R), Orion Ltd., Orion Pharma, Helsinki, Finland) via powder inhaler per day for 8 weeks. Videoed inhalation challenge with hypertonic histamine solution was performed before and after the treatment. Symptom questionnaire was completed before both challenges. The airway responsiveness to hypertonic histamine was expressed as the cumulative number of coughs divided by the final histamine concentration administered [coughs/concentration ratio (CCR)] and as the provocative concentration of histamine to induce a 20% fall in FEV(1)(PC(20)). CCR [geometric mean; 95% confidence interval (CI)] of the asthmatic subjects decreased from 494 (209-1168) to 73.6 (29.8-182) coughs per mg/mL (P = 0.002). Their PC(20) levels were 1.31 (1.07-1.60) and 1.91 (1.33-2.74) mg/mL over the treatment period (P = 0.01). The symptom frequency also decreased significantly in the asthmatics (P = 0.039). There were no significant changes in PC(20) level, in CCR level or in symptom frequency in non-asthmatic subjects during the treatment. Hypertonic histamine challenge-induced cough and PC(20) are sensitive measures in assessing the treatment effect in asthma. The cough response may be especially useful in subjects who cannot perform spirometry reliably.