Biomarkers in asthma, potential for therapeutic intervention.

Asthma is a heterogeneous disease characterized by multiple phenotypes with varying risk factors and therapeutic responses. This Commentary describes research on biomarkers for T2-"high" and T2-"low" inflammation, a hallmark of the disease. Patients with asthma who exhibit an increase in airway T2 inflammation are classified as having T2-high asthma. In this endotype, Type 2 cytokines interleukins (IL)-4, IL-5, and IL-13, plus other inflammatory mediators, lead to increased eosinophilic inflammation and elevated fractional exhaled nitric oxide (FeNO). In contrast, T2-low asthma has no clear definition. Biomarkers are considered valuable tools as they can help identify various phenotypes and endotypes, as well as treatment response to standard treatment or potential therapeutic targets, particularly for biologics. As our knowledge of phenotypes and endotypes expands, biologics are increasingly integrated into treatment strategies for severe asthma. These treatments block specific inflammatory pathways or single mediators. While single or composite biomarkers may help to identify subsets of patients who might benefit from these treatments, only a few inflammatory biomarkers have been validated for clinical application. One example is sputum eosinophilia, a particularly useful biomarker, as it may suggest corticosteroid responsiveness or reflect non-compliance to inhaled corticosteroids. As knowledge develops, a meaningful goal would be to provide individualized care to patients with asthma.

Development of a core outcome set for therapeutic studies in eosinophilic esophagitis (COREOS).

BACKGROUND: End points used to determine treatment efficacy in eosinophilic esophagitis (EoE) have evolved over time. With multiple novel therapies in development for EoE, harmonization of outcomes measures will facilitate evidence synthesis and appraisal when comparing different treatments. OBJECTIVE: We sought to develop a core outcome set (COS) for controlled and observational studies of pharmacologic and diet interventions in adult and pediatric patients with EoE. METHODS: Candidate outcomes were generated from systematic literature reviews and patient engagement interviews and surveys. Consensus was established using an iterative Delphi process, with items voted on using a 9-point Likert scale and with feedback from other participants to allow score refinement. Consensus meetings were held to ratify the outcome domains of importance and the core outcome measures. Stakeholders were recruited internationally and included adult and pediatric gastroenterologists, allergists, dieticians, pathologists, psychologists, researchers, and methodologists. RESULTS: The COS consists of 4 outcome domains for controlled and observational studies: histopathology, endoscopy, patient-reported symptoms, and EoE-specific quality of life. A total of 69 stakeholders (response rate 95.8%) prioritized 42 outcomes in a 2-round Delphi process, and the final ratification meeting generated consensus on 33 outcome measures. These included measurement of the peak eosinophil count, Eosinophilic Esophagitis Histology Scoring System, Eosinophilic Esophagitis Endoscopic Reference Score, and patient-reported measures of dysphagia and quality of life. CONCLUSIONS: This interdisciplinary collaboration involving global stakeholders has produced a COS that can be applied to adult and pediatric studies of pharmacologic and diet therapies for EoE and will facilitate meaningful treatment comparisons and improve the quality of data synthesis.

A compendium and review of pediatric pulmonary function testing assessment opportunities for asthma.

OBJECTIVE: Standard spirograms are widely used in the respiratory disease management community to help diagnosis asthma and provide longitudinal information. Surprisingly, basic information obtained on the spirogram, beyond the FEV1 and change in FEV1 after bronchodilator is underutilized. We reviewed information on pulmonary function and bronchodilator response in children since 2016. We present here a discussion of other element of the standard spirogram that can be used for pediatric asthma management.Methods: Medline search of pulmonary function, children, adolescents, bronchodilator reversibility, small airway disease, small airway function, asthma, airflow limitation, bronchodilator response. Studies since 2016 that provide information on normal or asthmatic children bronchodilator response, and/or small airway or pulmonary function values after albuterol. RESULTS: Limited data has been published on FEV1 bronchodilator response in children since 2016. Other parameters of the pulmonary function test in children have had recent documentation. CONCLUSIONS: New data on FEV1 bronchodilator response in normal children is limited since 2016. However, other details of pulmonary function interpretation in asthmatic children has had considerable attention, and are reviewed here.

Role of innate lymphoid cells in allergic diseases.

Background: Over the past decade, there has been increasing interest and research into understanding the type 2 immune responses by the epithelium-derived cytokines interleukin (IL) 33, IL-25, and thymic stromal lymphopoietin. Innate lymphoid cells (ILC) are a unique family of effector immune cells that functionally resemble T cells but lack clonal distributed antigen receptors. Group 2 ILCs, ILC2s, are known for their capability to secrete proallergic cytokines, including IL-5 and IL-13. ILC2s are enriched at mucosal barriers in lung, gut, and skin, and their activation has been associated with a variety of allergic disorders. Objective: To study the role of ILC2 in different allergic disorders, including allergic rhinitis, asthma, atopic dermatitis, and food allergies. Methods: A MEDLINE search was performed for articles that reported on ILC2 in allergic disorders, including allergic rhinitis, asthma, atopic dermatitis, and food allergies. Results: A review of the literature revealed an important role of ILC2 in various allergic disorders. Conclusion: Identification of ILC2s in patients with allergic rhinitis, asthma, and atopic dermatitis indicates that these cells may represent a new therapeutic target. In this review, we discussed the current understanding of ILC2 biology and its function and regulation in various allergic diseases.

A literature review of the evidence that a 12% improvement in FEV1 is an appropriate cut-off for children.

INTRODUCTION: A well-performed spirometry, using a change in forced expiratory volume in one second (FEV(1)) after albuterol, is commonly used to support the likelihood of an asthma diagnosis. The current standard, accepted by the 2007 National Heart Lung and Blood Institute Asthma Expert Panel Report-3 (EPR-3) guidelines, is a 12% improvement in the FEV(1) after a bronchodilator. OBJECTIVE: We sought to determine whether existing studies support or refute using a 12% improvement as a significant change in FEV(1) in children and adolescents. DATA SOURCES: We reviewed the literature of children and adolescents using Medline searches to discover pertinent population studies and comparative studies that included FEV(1) measurements. RESULT: The majority of the discovered studies suggest a less stringent improvement in FEV(1) in children might be applicable. CONCLUSION: Supported by the published literature, we suggest an alternative interpretive strategy of expressing the results of a spirometry measurement when a diagnosis of asthma in a child is being considered using a bronchodilator response.

Twin and family studies reveal strong environmental and weaker genetic cues explaining heritability of eosinophilic esophagitis.

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic antigen-driven allergic inflammatory disease, likely involving the interplay of genetic and environmental factors, yet their respective contributions to heritability are unknown. OBJECTIVE: To quantify the risk associated with genes and environment on familial clustering of EoE. METHODS: Family history was obtained from a hospital-based cohort of 914 EoE probands (n = 2192 first-degree "Nuclear-Family" relatives) and an international registry of monozygotic and dizygotic twins/triplets (n = 63 EoE "Twins" probands). Frequencies, recurrence risk ratios (RRRs), heritability, and twin concordance were estimated. Environmental exposures were preliminarily examined. RESULTS: Analysis of the Nuclear-Family-based cohort revealed that the rate of EoE, in first-degree relatives of a proband, was 1.8% (unadjusted) and 2.3% (sex-adjusted). RRRs ranged from 10 to 64, depending on the family relationship, and were higher in brothers (64.0; P = .04), fathers (42.9; P = .004), and males (50.7; P < .001) than in sisters, mothers, and females, respectively. The risk of EoE for other siblings was 2.4%. In the Nuclear-Family cohort, combined gene and common environment heritability was 72.0% ± 2.7% (P < .001). In the Twins cohort, genetic heritability was 14.5% ± 4.0% (P < .001), and common family environment contributed 81.0% ± 4% (P < .001) to phenotypic variance. Probandwise concordance in monozygotic co-twins was 57.9% ± 9.5% compared with 36.4% ± 9.3% in dizygotic co-twins (P = .11). Greater birth weight difference between twins (P = .01), breast-feeding (P = .15), and fall birth season (P = .02) were associated with twin discordance in disease status. CONCLUSIONS: EoE RRRs are increased 10- to 64-fold compared with the general population. EoE in relatives is 1.8% to 2.4%, depending on relationship and sex. Nuclear-Family heritability appeared to be high (72.0%). However, the Twins cohort analysis revealed a powerful role for common environment (81.0%) compared with additive genetic heritability (14.5%).

Atopic Dermatitis is More than Skin Deep: A Commentary on Atopic Dermatitis and Review of Pertinent Publications from Children 2019-2021.

The journal Children has a significant publication record on the topic of Atopic Dermatitis (AD) the past four years [...].

Persistent Hyper IgA as a Marker of Immune Deficiency: A Case Report.

An elevated IgA level obtained in a 10-year-old male a year after an episode of pneumococcal sepsis led to the discovery of a broad-based IgG-specific antibody deficiency syndrome. The specifics of the case and pertinent literature are presented, including a discussion of the hyper-IgD syndrome. An elevated IgA, greater than two standard deviations above the expected age range should prompt a complete workup for selective antibody deficiency syndrome and adds an additional associated marker of an indolent hyper-IgD syndrome in a different clinical circumstance, although the lack of antibody response to vaccines is atypical of the hyper-IgD syndrome.

Small Airway Disease in Pediatric Asthma: the Who, What, When, Where, Why, and How to Remediate. A Review and Commentary.

Asthma affects all portions of the airways. Small airways, however, comprise a substantial component of the conducting lung air flow. In asthma, inflammatory processes can affect the whole respiratory tract, from central to peripheral/small airways. The emphasis in adult and pediatric respiratory disease clinics is to focus on large airway obstruction and reversibility. This information, although valuable, underemphasizes a large portion of the conduction airway of asthmatics. Standard descriptions of asthma management focus on a multiple medication approaches. We particularly focused on the management of asthma in the international guidelines for the Global Initiative for Asthma (GINA). Overall, however, minimal attention is placed on the small airway pool in asthma medical management. We took the opportunity to thoroughly review and present specific data from the adult asthma literature which supported the concept that small airway abnormalities may play a role in the pathogenesis and clinical expression of asthma. Based on the conclusions of the adult asthma literature, we here present a thorough review of the literature as it relates to small airway disease in children with asthma. We used, collectively, individual data sources of data to expand the information available from standard diagnostic techniques, especially spirometry, in the evaluation of small airway disease. As the pharmacological approaches to moderate to severe asthma are advancing rapidly into the realm of biologics, we sought to present potential pharmacological options for small airway dysfunction in pediatrics prior to biological modifier intervention.

An a Priori Approach to Small Airway Dysfunction in Pediatric Asthmatics.

Small airway dysfunction remains a stepchild in the pediatric asthma care pathway. In brief, elements of the pulmonary function test (PFT) concerning smaller airway data remain less utilized. To further the value of the standard PFT we underwent a prospective Proof of Concept (POC) project, utilizing the outpatient performance of PFT tests in children 6-18 years during a 15-month period. The goal of the study was to determine if a priori the PFT represented a small airway disease pattern or not. Only the pulmonary function was used to make that distinction. Children 6-18 years with asthma who completed a PFT had their PFT as being characterized with or without a small airway dysfunction (SAD) designation, coded in the electronic medical record as an a priori decision using the code J98.4 (other disorders of lung) as a marker for electronic medical records retrieval. Subsequently, the results were analyzed between a group of 136 children designated (a priori) as having no small airway dysfunction in comparison to 91 children a priori designated as having small airway dysfunction. The a priori designation groups were post hoc compared for large and smaller airway function differences. Both large and smaller airway dysfunction were highly significantly different between the 2 groups, based solely on the initial division of the total group based on the decision the PFT represented a small airway pattern. We concluded the baseline pulmonary function test used in the evaluation of pediatric asthma has readily identifiable information regarding the presence of small airway dysfunction, and we characterized what was unique on the PFT based on that SAD classification.

Hypersensitivity Reactions: An Everyday Occurrence in Pediatric Allergy Clinics.

The explanation of hypersensitivity reactions has long relied on the classification of Gell and Coombs, originally proposed in the 1960s. However, their concepts were predated by other authors by at least 50 years. A 21st century pediatric allergy clinic provides multiple examples of these basic concepts on a daily basis. We review classic and less classic examples of the original criteria, highlight where current disease pathophysiology does not always fit the original model, and provide updated language for common and uncommon immunologically driven hypersensitivity diseases.

Fifty Years of Chronic Rhinosinusitis in Children: The Accepted, the Unknown, and Thoughts for the Future.

Chronic sinusitis is an often-used term in both lay and medical circumstances. In children, it has significant but largely undefined healthcare costs. Chronic rhinosinusitis (CRS) in children has well demarcated time periods and symptoms, although the actual pathway from normal sinus to CRS is not well understood. There is reasonable consensus as to the standards for diagnosis, the selection of a first-round antibiotic, and length of treatment. However, no recent prospective studies of antibiotics are available. Areas of continued speculation include the following: the microbiome of pediatric CRS, the best use of standard imaging, alternative antibiotic selection, ancillary therapy, and treatment of refractory CRS. In addition, older adolescents can present with a more adult-oriented CRS with or without polyps, suggesting a broader spectrum of disease than is commonly recognized. An accounting of the accepted elements of pediatric rhinosinusitis, as well as areas for future research, is emphasized in this review and, where appropriate, suggestions for potential investigations are offered.

Prevalence of asthma among school children in Gaborone, Botswana.

BACKGROUND: Asthma prevalence is high (>10%) in developed countries and although data is still missing for most of Africa, rates are increasing in developing regions as they become more westernized. We investigated the prevalence of asthma in school children in Gaborone, Botswana. METHODS: This was a cross sectional descriptive study. ISAAC methodology was used. A representative proportionate size random sample of two age groups of children (13-14 year olds and 6-7 year olds) was consecutively enrolled from 10 schools. The schools were selected using a table of random numbers. A minimum sample size of 924 individuals (462 from each group) was adequate to achieve a precision of 3 % around our estimated prevalence of asthma of 10% with 95% confidence assuming a non-response rate of 20%. Data was collected using the validated International study of Asthma and Allergies in children (ISAAC) questionnaire. In accordance with the ISAAC criteria, Asthma was defined as wheezing in the previous 12 months. Data was captured in microsoft excel and analysed using SPSS version 23. RESULTS: The prevalence of asthma (wheezing in the previous 12 months) was 16.5% (194/1175). Among the 6-7 year olds, the prevalence of asthma (wheezing in the previous 12 months) was 15.9%, while among the 13-14 years olds it was 16.8 %. The prevalence school type was 22.3 % in private schools versus 14.5 % in public schools. More severe asthma was associated with older children, 13-14 years. The older children reported more limited speech due to wheezing (OR= 2.0, 95% CI =1.034, 3.9, p-value=0.043), ever had asthma (OR= 1.5, 95% CI=1.031, 2.3, p-value=0.034) and wheezing during exercise (OR=3.4, 95% CI= 2.5, 4.9, p-value= <0.001) compared to the younger children 6-7 years. Children from private schools had more wheezing symptoms. They were more likely to have ever wheezed (OR=2.2, .95% CI=1.7,2.9, p-value < 0.0001), wheezed in the previous twelve months (have asthma) (OR=1.7,95%CI=1.2,2.4, p-value = 0.001), ever had asthma (OR=2.4, 95% CI=1.7,3.5, p-value< 0.0001), and wheezed during exercise (OR=1.8, 95% CI=1.4,2.4, p-value < 0.0001). CONCLUSION: The prevalence of asthma amongst school children in Gaborone, Botswana is high with older children experiencing more severe symptoms of asthma.

Recurrent wheezing in infants and young children and bronchial hyperresponsiveness: a perspective.

Epidemiological studies report a 50% incidence of at least one wheezing episode in young children. If we can argue that 10% of children have asthma sometime during their pediatric years, it still leaves a significant percentage of children with an unexplained cause for their wheezing. Other recognized phenotypes of recurrent wheezing include young children exposed to excessive environmental tobacco smoke (ETS), while other infants wheeze recurrently following a significant episode of bronchiolitis. Bronchial hyperresponsiveness (BHR) is a universally recognized phenomenon of asthma, but its presence in young children with recurrent wheezing is not as well studied. Currently available studies demonstrates that BHR is also seen in young pediatric asthmatics, paralleling what is well recognized in adolescent or adult asthma. In those children with post-bronchiolitis wheezing, BHR appears to be present to a degree; while infants and young children exposed to ETS have increased BHR, as a group. If exaggerated BHR in recurrent wheezing children without asthma has the same inherent disadvantage as it does in asthmatic children, additional studies looking directly at this issue in a longitudinal fashion need to be designed. A hypothesis of BHR in non-asthmatic children is presented that could be studied prospectively.