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.

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.

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.

Experience in patch testing: A 6-year retrospective review from a single academic allergy practice.

BACKGROUND: Patch testing is the "gold standard" to identify culprit allergen(s) causing allergic contact dermatitis (ACD), but there are limited studies of patch testing from allergy practice settings. OBJECTIVE: We sought to explore patch test findings in a large academic allergy practice, including patch testing results, history of atopy, location of dermatitis, and referral source. We also wanted to determine whether patch testing using an extended panel, such as the North American screening series, compared with a limited series, such as the Thin-Layer Rapid-Use Epicutaneous (T.R.U.E.) Test, increased the sensitivity. METHODS: A retrospective chart review was conducted of patients referred for patch testing over a 6-year period. RESULTS: A total of 585 patients (mean age 48.7 years, 71.6 % female) underwent patch testing over the 6-year period, of which 369 (63%) had a positive test. Of those who tested positive, 202 (55%) reported a history of atopy. The extremities were the most commonly involved site, followed by the head/neck and trunk. The 5 most common positive allergens were nickel sulfate, gold sodium thiosulfate, methylchloroisothiazolinone, thimerosal, and bacitracin. Three hundred fourteen (53.6%) patients were positive to at least 1 allergen on TRUE testing. Extended screening series identified an additional 10.8% of patients with positive tests who were negative to T.R.U.E. test allergens. CONCLUSION: Patch testing is a valuable diagnostic tool for the practicing allergist and provides early identification of culprit allergens in ACD. Performing an extended screening series such as the North American Contact Dermatitis Group (NACDG) or supplemental panel of allergens increased sensitivity when compared with a limited series.

Immunologic characterization of patients with chronic mucocutaneous candidiasis disease.

Even if initial immunologic screen is normal, a high index of suspicion for immunodeficiency should guide the evaluation and management of patients with recurrent episodes of mucocutaneous candidiasis. Although rare, a diagnosis of chronic mucocutaneous disease should always be considered in order to improve their outcome.

Asthma pathogenesis, diagnosis, and management in the elderly.

BACKGROUND: Due to the aging population, there is an increase in the number of elderly patients with asthma. Although signs and symptoms are similar to those in younger patients, diagnosis can be challenging due to presence of coexisting conditions in this population. OBJECTIVES: The purpose of this review was to highlight the challenges with regards to diagnosis, management, the high rates of medical costs and mortality in elderly asthmatics. METHODS AND RESULTS: Scientific literature regarding asthma in the elderly population was reviewed. When compared to younger patients, elderly asthmatics have different drug responses, higher rates of bronchial hyper reactivity, more severe phenotype, and lower prevalence of atopy. In addition, there are issues with the adverse effects of asthma medications, use of proper inhaler technique and compliance. CONCLUSION: There is an unmet need for research in elderly patients with asthma, specifically to facilitate diagnosis, and to investigate therapeutic strategies to improve quality of life in this population.

The effect of omalizumab on small airway inflammation as measured by exhaled nitric oxide in moderate-to-severe asthmatic patients.

Measurement of fractional nitric oxide concentration in exhaled breath (FENO) is a simple, noninvasive method to evaluate eosinophilic airway inflammation. Nitric oxide (NO) arising from peripheral small airways/alveoli (alveolar NO concentration [CalvNO]) can be estimated using multiple flow rates and a two-compartment model of the airways and alveoli. Omalizumab, a monoclonal anti-IgE antibody, is approved for the treatment of allergic asthma and also has been shown to decrease FENO levels. This study investigates the effects of omalizumab, when added to an inhaled corticosteroid (ICS) ± long-acting beta-adrenergic agonist (LABA) treatment, on peripheral small airway/alveolar inflammation reflected by FENO measurements at higher flow rates. We hypothesized that compared with placebo, omalizumab would decrease CalvNO levels in asthmatic patients on ICS ± LABA. Forty-two patients with moderate-to-severe asthma were randomly assigned 2:1 to either omalizumab (n = 29) or placebo treatment (n = 13) for 16 weeks. Selection criteria included moderate-to-severe asthmatic patients on an ICS ± LABA, positive skin test to one or more perennial allergen, screening FENO of >13 ppb, and a baseline IgE of 30-700 IU/mL. FENO measured at multiple flow rates was used to calculate CalvNO over the course of 16 weeks. FENO levels decrease with increasing flow rates (p < 0.05 repeated measures ANOVA) but no differences between the placebo and treatment groups in overall CalvNO levels or in the changes of CalvNO with time were found. Omalizumab did not lower the CalvNO, which could have been caused by the initial low CalvNO in this asthmatic population. The model used may not be completely sufficient and/or sensitive enough to detect small changes in CalvNO.

Effects of low-dose fluticasone propionate/salmeterol combination therapy on exhaled nitric oxide and nitrite/nitrate in breath condensates from patients with mild persistent asthma.

OBJECTIVE: The long-acting ß2-agonist salmeterol in combination with the corticosteroid fluticasone propionate is used in clinical practice for the treatment of mild persistent asthma. Although the effect of fluticasone propionate alone in asthmatic patients is well documented, the effect of fluticasone propionate/salmeterol (FSC) combination therapy on airway inflammation and airway hyperresponsiveness (AHR) is not well characterized. Thus, we evaluated AHR, exhaled nitric oxide (FE(NO)), and nitrite and nitrate in exhaled breath condensates (EBCs) from mild persistent asthmatic patients treated with a low-dose FSC (100/50). METHODS: In this open label study, 18 mild persistent, steroid-naïve asthmatics (age, 22-62 years, forced expiratory volume in 1 s (FEV(1)) > 70% predicted, provocative dose resulting in 20% reduction (PD(20)) < 10 mg/mL) were treated with FSC 100/50 for 4 weeks. PD(20) to methacholine, FEV(1), FE(NO), and EBC nitrite and nitrate was measured before and after treatment. RESULTS: After 4 weeks of therapy with FSC 100/50, FE(NO) decreased from 74 ppb (SD = 37) to 34 ppb (SD = 15) (p < .001). FEV(1) (% predicted) increased from 89.4 (SD = 10.7) to 93.3 (SD = 9.5) (p < .01). The PD(20) for methacholine increased from 3.0 (±3.2) to 10.3 (±8.4) mg/mL (p < .01) in 3 of 18 patients reaching the maximum allowable dose (25 mg/mL). FE(NO) correlated with the log of the methacholine dose. There was no statistically significant change in EBC nitrite and nitrate before and after treatment. CONCLUSIONS: Treatment of mild persistent, steroid-naïve asthmatics with low-dose combination therapy is effective in rapidly reducing airway inflammation and AHR. Our results suggest different metabolic origins for nitrite, nitrate, and FE(NO) in this group of patients.