Phenotypes and Endotypes in Asthma.

Asthma is a broadly encompassing diagnosis of airway inflammation with significant variability in presentation and response. Advances in molecular techniques and imaging have unraveled the delicate mechanistic tapestry responsible for the underlying inflammatory pathways in asthma. The elucidation of biomarkers and cellular components specific to these inflammatory pathways allowed for the categorization of asthma from generic phenotypes to more specific mechanistic endotypes, with two prominent subgroups emerging based on the level of Type 2 inflammation present - T2 high and T2 low (or non-T2). Sophisticated modeling and cluster analyses using a combination of clinical, physiologic, and biomarker parameters have permitted the identification of subendotypes within the broader T2 umbrella. This mechanistic-driven classification schema for asthma has dramatically altered the landscape of asthma management with the discovery and approval of targeted biologic therapies and has ushered in a new era of personalized precision medicine in asthma.

What has been learned by cytokine targeting of asthma?

Airway inflammation in asthma involves complex, interactive, and redundant cascades mediated by an array of proinflammatory cytokines, including a type 2 (T2) pattern of injury. T2 inflammation is characterized by elevations in absolute peripheral or sputum eosinophil counts and levels of IgE (total and allergen-specific) and fractional exhaled nitric oxide, which serve as biomarkers for the presence of this type of inflammation. T2 inflammation is mediated by key "downstream" cytokines, particularly IL-4, IL-5, and IL-13, which act at the effector cell level, as well as upstream cytokines, or "alarmins," such as thymic stromal lymphopoietin, IL-25, and IL-33 generated by epithelial cells. The relevance of these pathways has led to the development of biologic therapies targeting these T2 cytokines, which have not only resulted in modifying these biomarker signatures for inflammation but have also reduced the disease burden associated with asthma exacerbations, systemic corticosteroid use, and lung function compromises. This review will summarize experiences with anticytokine biologics to highlight which specific asthma outcomes they affect and how these effects reflect inflammatory pathways modified by biologics and may relate to pathophysiologic features of asthma.

Omalizumab for treatment of idiopathic angioedema.

BACKGROUND: Omalizumab has been found to improve outcomes in patients with chronic spontaneous urticaria (CSU). Idiopathic angioedema (IAE) is increasingly being recognized as a condition with similar underlying mechanisms as CSU and a form of CSU. We hypothesized that add-on therapy with omalizumab would benefit patients with uncontrolled IAE. OBJECTIVE: To study the safety and efficacy of omalizumab for the treatment of IAE in adults. METHODS: We conducted a randomized, placebo-controlled trial to study the efficacy of omalizumab in adults with 2 or more episodes of angioedema (AE) in the past 6 months for which no clinical or laboratory cause of AE could be found. A total of 10 patients were randomized on a 1:1 basis to receive omalizumab 300 mg subcutaneously or placebo every 4 weeks for 24 weeks with a 12-week follow-up period. The primary endpoint was the change in the Angioedema Activity Score. Secondary endpoints included the Angioedema Quality of Life Questionnaire, the Visual Analogue Scale, and the number of angioedema episodes per month. RESULTS: We observed improvement in the Angioedema Activity Score (-2.93 ln odds; 95% confidence interval [CI], -4.84 to -1.02; P = .003), Visual Analogue Scale (-3.49 ln odds; 95% CI, -6.58 to -0.40; P = .03), Angioedema Quality of Life Questionnaire (-9.43 score; 95% CI, -17.63 to -1.24; P = .03), and number of angioedema episodes per month (-1.93 ln count; 95% CI, -3.23 to -0.63; P = .005) in patients who received omalizumab vs placebo. CONCLUSION: This study provides preliminary prospective evidence that omalizumab improves outcomes in patients with IAE. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02966314. CLINICALTRIALS: gov URL:https://clinicaltrials.gov/ct2/show/NCT02966314?term=omalizumab&cond=Angioedema&draw=2&rank=1.

How to compare the efficacy of biologic agents in asthma.

OBJECTIVE: The use of biologics in severe asthma has made substantial strides in disease management and fostered a personalized medicine approach; however, how, when, and which biologic to choose are unresolved issues, which form the focus of this review. DATA SOURCES: The data sources were published literature, including current guidelines, available through PubMed searches and online resources. STUDY SELECTIONS: Studies and randomized controlled trials pertaining to the use of biologics in various phenotypes and/or endotypes of asthma and comparative analyses between biologics in asthma were included. RESULTS: Inflammatory constructs in asthma are complex and translate differentially into clinical practice for both disease severity and treatment responsiveness. The utilization of biologics, which target selected components of inflammation, has begun to dramatically improve the course of management for many patients with severe asthma. A retuning of our approach into selecting appropriate patient cohorts or phenotypes for studies and selection of clinically relevant outcomes, which are reflected by existing and novel emerging biomarkers, is enabling a paradigm shift in asthma management. Comparing the efficacy of the available biologics for asthma is challenging as no direct head-to-head studies are available, and indirect comparisons to this query provide varying results. CONCLUSION: Significant progress has been achieved in the management of severe asthma with treatment of target-specific biologics. Sophisticated algorithms and trial designs, using a combination of available biomarker profiles and clinical characteristics to stratify patient populations into more precise subphenotypes and endotypes to guide our choice of a biologic or therapy, are critically needed but currently not formulated.

Biologic Therapy and Asthma.

Although airway inflammation is an intrinsic and key feature of asthma, this response varies in its intensity and translation to clinical characteristics and responsiveness to treatment. The observations that clinical heterogeneity is an important aspect of asthma and a feature that likely dictates and determines responses to treatment in severe asthma, patient responsiveness to medication is incomplete, and risks for exacerbation are increased. The development of biologics, which target selected and specific components of inflammation, has been a promising advance to achieve asthma control in patients with severe disease. This article reviews the current biologics available and under development and how their use has affected asthma and which subpopulations appear to benefit the greatest.

Immunotherapy for house dust mite sensitivity: where are the knowledge gaps?

House dust mites (HDMs) are found in the environments where human habitation exists. Their density is dependent on environmental relative humidity; therefore, higher populations are present in areas of the world with higher humidity levels, e.g., coastal areas and tropics. To date, 24 HDM allergens have been identified. Many of these represent digestive enzymes since HDM feces are the major source of allergen exposure. IgE- medicated sensitization to HDM allergens is an important factor in the pathogenesis of allergic diseases since it is the most common aeroallergen detected by skin testing or in vitro IgE assays. Sensitization to HDM allergens often occurs early in life and appears to play an important role in the progression from allergic rhinitis to asthma (the so-called Allergic March) in children. HDM sensitization is also associated with asthma across all age groups. Efforts to control environmental exposure to HDM allergens have often proven to be unsuccessful. While medications can improve symptoms, only immunotherapy currently provides disease-modifying effects in allergic rhinitis and asthma. Several systemic reviews and meta-analysis indicate that both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) are effective in the treatment of allergic rhinitis and asthma for HDM sensitivity. In this report, we review recent studies and the evidence for the use of HDM SCIT and SLIT. Fundamental gaps in knowledge are identified which could lead to improved approaches to HDM allergy.

Relevance of allergy in adult asthma.

Recent studies on asthma have demonstrated multiple phenotypes, based on the clinical characteristics of the disease. With the current interest in personalized medicine, the question arises whether the presence of allergic sensitization has any relevance for these phenotypes and the management of asthma. This review will examine the current knowledge of asthma phenotypes and the impact of atopy on asthma diagnosis and severity in adults. In addition, this review will address whether therapies targeted at the atopic axis help improve asthma outcomes, including lung function indices and exacerbations.

Glucocorticoid-induced osteoporosis: an update on effects and management.

Glucocorticoids remain a cornerstone of guideline-based management of persistent asthma and allergic diseases. Glucocorticoid-induced osteoporosis (GIO) is the most common iatrogenic cause of secondary osteoporosis and an issue of concern for physicians treating patients with inhaled or oral glucocorticoids either continuously or intermittently. Patients with GIO experience fragility fractures at better dual-energy x-ray absorptiometry T-scores than those with postmenopausal or age-related osteoporosis. This might be explained, at least in part, by the effects of glucocorticoids not only on osteoclasts but also on osteoblasts and osteocytes. Effective options to detect and manage GIO exist, and a management algorithm has been published by the American College of Rheumatology to provide treatment guidance for clinicians. This review will summarize GIO epidemiology and pathophysiology and assess the role of inhaled and oral glucocorticoids in asthmatic adults and children, with particular emphasis on the effect of such therapies on bone health. Lastly, we will review the American College of Rheumatology GIO guidelines and discuss diagnostic and therapeutic strategies to mitigate the risk of GIO and fragility fractures.

Retrospective analysis of the efficacy of omalizumab in chronic refractory urticaria.

Omalizumab has been shown to be effective in chronic urticaria (CU) patients in numerous reports. However, it remains unknown whether there are specific phenotypes of CU that are more responsive to omalizumab therapy. We sought to identify CU phenotypes responsive to treatment with omalizumab by characterizing patients and their response patterns. A retrospective chart review analysis of refractory CU patients unresponsive to high-dose H1-blockers and immunomodulators and subsequently treated with omalizumab at the University of Wisconsin Allergy Clinic was performed with particular focus on their autoimmune characteristics, response to therapy, and dosing parameters. We analyzed 19 refractory CU patients (16 patients failed or had toxic side effects to immunomodulators) treated with omalizumab with an overall response rate of 89% (17/19). Of these 19 patients, 9 patients (47%) had a complete response, 8 patients (42%) had a partial response, and 2 patients (11%) had no response. In comparing the response patterns to omalizumab, we found no statistically significant differences among "autoimmune positive" versus "autoimmune negative" patients. No statistically significant differences in responses were observed when comparing demographic parameters including age, gender, IgE levels, or dosing regimen. Our study shows that omalizumab has robust efficacy in refractory CU patients regardless of their autoimmune status, age, gender, IgE levels, or dosing protocol.

The role of autoimmune testing in chronic idiopathic urticaria.

BACKGROUND: The clinical implications of autoimmune testing in chronic idiopathic urticaria (CIU) are not well established. OBJECTIVE: To identify the association of autoimmune biomarkers in CIU with disease severity. METHODS: We retrospectively evaluated 195 patients with a diagnosis of CIU for the presence of antinuclear antibody (ANA), anti-thyroglobulin antibody (ATG), anti-thyroperoxidase antibody (ATPO), and Chronic Urticaria (CU) Index. The patients were categorized into controlled and refractory subgroups based on their response to antihistamines with or without a leukotriene receptor antagonist. RESULTS: The percentage of patients with a positive test for ANA (titer>1:160), ATG, ATPO, and CU Index were 29%, 6%, 26%, and 38%, respectively. Among those tested, the percentage of patients categorized as refractory was significantly higher in those with a positive CU index (80% vs 46%; P = .01) or a positive ANA titer (50% vs 30%; P = .04) than those with negative test results; however, a similar relationship was not observed for ATPO or ATG antibodies. Odds ratios of individual or combinations of autoimmune biomarkers in CIU were examined for associations with refractoriness to antihistamines with or without a leukotriene receptor antagonist. The CU Index alone has an odds ratio of 4.5 (P = .005), whereas the combination of ANA, ATG, and ATPO has an odds ratio of 3.1 (P = .01) and ANA alone has an odds ratio of 2.3 (P = .04) for correlating with a refractory outcome. CONCLUSION: Our data indicate the CU Index independently has the strongest correlation with disease severity followed by the combination of ANA, ATG, and ATPO and the ANA alone.

Allergen immunotherapy in allergic respiratory diseases: from mechanisms to meta-analyses.

Allergen-specific immunotherapy (SIT) involves the repeated administration of allergenic extracts to atopic individuals over a period of 3 to 5 years either subcutaneously (SCIT) or sublingually (SLIT) for the treatment of allergic respiratory diseases, including asthma and allergic rhinitis (AR). In studies, SCIT and SLIT have been shown to improve existing symptoms of asthma and AR and to also have the capability to cause disease-modifying changes of the underlying atopic condition so as to prevent new allergic sensitization as well as arrest progression of AR to asthma. Recent evidence suggests that immunotherapy brings about these effects through actions that use T-regulatory cells and blocking antibodies such as IgG(4) and IgA(2,) which can then result in an "immune deviation" from a T-helper (Th) 2 cell pattern to a Th1 cell pattern. Numerous meta-analyses and studies have been performed to evaluate the existing data among these studies, with the consensus recommendation favoring the use of immunotherapy because of its potential to modify existing diseases. Significant adverse reactions can occur with immunotherapy, including anaphylaxis and, very rarely, death. A primary factor in considering SIT is its potential to provide long-lasting effects that are able to be sustained well after its discontinuation. Given the significant burden these allergic diseases impose on the health-care system, SIT appears to be a cost-effective adjunctive treatment in modifying the existing disease state.

What effect does asthma treatment have on airway remodeling? Current perspectives.

Airway remodeling, or structural changes of the airway wall arising from injury and repair, plays an important role in the pathophysiology of asthma. Remodeling is characterized as structural changes involving the composition, content, and organization of many of the cellular and molecular constituents of the bronchial wall. These structural changes can include epithelial injury, subepithelial thickening/fibrosis, airway smooth muscle hyperplasia, goblet cell hypertrophy and hyperplasia, and angiogenesis. Historically, these changes are considered a consequence of long-standing airway inflammation. Recent infant and child studies, however, suggest that remodeling occurs in parallel with inflammation in asthmatic subjects. Despite advancements in the recognition of key cellular and molecular mechanisms involved in remodeling, there remains a paucity of information about which treatments or interactions are most likely to regulate these processes. Furthermore, it is unclear as to when is the best time to initiate treatments to modify remodeling, which components to target, and how best to monitor interventions on remodeling. Indeed, inhaled corticosteroids, which are generally considered to have limited influence on remodeling, have been shown to be beneficial in studies in which the dose and duration of treatment were increased and prolonged, respectively. Moreover, several studies have identified the need to identify novel asthma indices and phenotypes that correlate with remodeling and, as a consequence, might specifically respond to new therapies, such as anti-IgE, anti-IL-5, and anti-TNF-α mAbs. Our review will evaluate the development of remodeling in asthmatic subjects and the effects of treatment on these processes.

Role of allergen sensitization in older adults.

There is a common perception among physicians and patients that allergic diseases are not relevant in older adults. There is also recognition that innate and adaptive immune functions decline with aging. It is the function of a variety of immune cells in the form of allergic inflammation that is a hallmark of allergic diseases. In fact, there is a fairly consistent observation that measures of allergic sensitization, such as skin prick testing, specific IgE, or total IgE, decline with age. Nonetheless, the association between allergic sensitization and allergic diseases, particularly asthma and allergic rhinitis, remains robust in the older adult population. Consequently, an appropriate evaluation of allergic sensitivities is warranted and indicated in older asthma and rhinitis patients to provide optimal care for the individual and minimize any resultant morbidity and mortality.