At present, there is no cure for asthma, and treatment typically involves therapies that prevent or reduce asthma symptoms, without modifying the underlying disease. A "disease-modifying" treatment ...can be classed as able to address the pathogenesis of a disease, preventing progression or leading to a long-term reduction in symptoms. Such therapies have been investigated and approved in other indications,
rheumatoid arthritis and immunoglobulin E-mediated allergic disease. Asthma's heterogeneous nature has made the discovery of similar therapies in asthma more difficult, although novel therapies (
biologics) may have the potential to exhibit disease-modifying properties. To investigate the disease-modifying potential of a treatment, study design considerations can be made, including: appropriate end-point selection, length of trial, age of study population (key differences between adults/children in physiology, pathology and drug metabolism) and comorbidities in the patient population. Potential future focus areas for disease-modifying treatments in asthma include early assessments (
to detect patterns of remodelling) and interventions for patients genetically susceptible to asthma, interventions to prevent virally induced asthma and therapies to promote a healthy microbiome. This review explores the pathophysiology of asthma, the disease-modifying potential of current asthma therapies and the direction future research may take to achieve full disease remission or prevention.
Background Previous studies have identified asthma phenotypes based on small numbers of clinical, physiologic, or inflammatory characteristics. However, no studies have used a wide range of variables ...using machine learning approaches. Objectives We sought to identify subphenotypes of asthma by using blood, bronchoscopic, exhaled nitric oxide, and clinical data from the Severe Asthma Research Program with unsupervised clustering and then characterize them by using supervised learning approaches. Methods Unsupervised clustering approaches were applied to 112 clinical, physiologic, and inflammatory variables from 378 subjects. Variable selection and supervised learning techniques were used to select relevant and nonredundant variables and address their predictive values, as well as the predictive value of the full variable set. Results Ten variable clusters and 6 subject clusters were identified, which differed and overlapped with previous clusters. Patients with traditionally defined severe asthma were distributed through subject clusters 3 to 6. Cluster 4 identified patients with early-onset allergic asthma with low lung function and eosinophilic inflammation. Patients with later-onset, mostly severe asthma with nasal polyps and eosinophilia characterized cluster 5. Cluster 6 asthmatic patients manifested persistent inflammation in blood and bronchoalveolar lavage fluid and exacerbations despite high systemic corticosteroid use and side effects. Age of asthma onset, quality of life, symptoms, medications, and health care use were some of the 51 nonredundant variables distinguishing subject clusters. These 51 variables classified test cases with 88% accuracy compared with 93% accuracy with all 112 variables. Conclusion The unsupervised machine learning approaches used here provide unique insights into disease, confirming other approaches while revealing novel additional phenotypes.
Busse discusses the Aspirin-exacerbated respiratory disease (AERD) which is a unique phenotype of asthma with nasal polyps and characterized by sensitivity to aspirin and nonsteroidal ...antiinflammatory drugs (NSAIDs). A hallmark feature of AERD is dysregulated function of the 5-lipoxygenase pathway, which leads to overproduction of cysteinyl leukotrienes (LTs) by mast cells (MCs) after exposure to cyclooxygenase inhibitors. Although the mechanisms of AERD are not fully established, T. M. Laidlaw and J. A. Boyce have identified dysregulated MC activation as a pivotal component of NS AID-sensitive asthma. a. In AERD, NSAIDs inhibit cyclooxygenase, shifting 5-lipoxygenase metabolism to generate excessive cysteinyl LTs and large quantities of prostaglandin D2 (PGD2) from MCs, thereby causing acute airflow obstruction. A biomarker for dysregulated MC function in AERD is elevated urinary excretion of cysteinyl LT metabolites.
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.
Despite the availability of effective inhaled therapies, many patients with asthma have poor asthma control. Uncontrolled asthma presents a significant burden on the patient and society, and, for ...many, remains largely preventable. There are numerous reasons why a patient may remain uncontrolled despite access to therapies, including incorrect inhaler technique, poor adherence to treatment, oversight of triggers and suboptimal medical care. Shared decision-making, good patient-clinician communication, supported self-management, multidisciplinary patient education, new technology and risk stratification may all provide solutions to this major unmet need in asthma. Novel treatments such as biologics could benefit patients' lives, while the investigations into biomarkers, non-Type 2 asthma, treatable traits and disease modification give an exciting glimpse into the future of asthma care.
Asthma exacerbations are major factors in asthma morbidity and also have long-term consequences.
Asthma is characterized by an accelerated and progressive loss of lung function. Recent evidence has ...pointed to the frequency of exacerbations as being a significant contributor to a loss of lung function in asthma.
A consequence of asthma exacerbations is a greater loss of lung function. Airway inflammation is central to asthma severity and susceptibility for exacerbations. Evidence suggests that the increase in airway inflammation during an asthma exacerbation further compromised lung function. Treatment of severe asthma with Type (T)-2 directed biologics significantly prevents the frequency of exacerbations in severe asthma. Early indications also suggest that prevention of exacerbations by biologics may reduce a loss in lung function from exacerbations.
Asthma is a heterogeneous disease with multiple phenotypes that have variable risk factors and responses to therapeutics. Mild-to-moderate asthma often responds to traditional medications, whereas ...severe disease can be refractory to inhaled corticosteroids, long-acting β-agonists, and leukotriene receptor antagonists. There is robust research into the variable phenotypes of asthma. Biomarkers help define the specific pathophysiology of different asthma phenotypes and identify potential therapeutic targets. The following review will discuss the current use of biomarkers for the diagnosis of asthma, triaging the severity of a patient's disease, and the potential efficacy of treatments. This information can be used to define certain patient populations that are more likely to respond to inhaled corticosteroids or biologics. As knowledge of patient phenotypes and endotypes and biological agents to target specific classes of asthma emerge, the ability to provide personalized care to asthmatic patients will follow.
African Americans have higher rates of asthma prevalence, morbidity, and mortality in comparison with other racial groups. We sought to characterize endotypes of childhood asthma severity in African ...American patients in an inner-city pediatric asthma population. Baseline blood neutrophils, blood eosinophils, and 38 serum cytokine levels were measured in a sample of 235 asthmatic children (6-17 years) enrolled in the NIAID (National Institute of Allergy and Infectious Diseases)-sponsored Asthma Phenotypes in the Inner City (APIC) study (ICAC (Inner City Asthma Consortium)-19). Cytokines were quantified using a MILLIPLEX panel and analyzed on a Luminex analyzer. Patients were classified as Easy-to-Control or Difficult-to-Control based on the required dose of controller medications over one year of prospective management. A multivariate variable selection procedure was used to select cytokines associated with Difficult-to-Control versus Easy-to-Control asthma, adjusting for age, sex, blood eosinophils, and blood neutrophils. In inner-city African American children, 12 cytokines were significant predictors of Difficult-to-Control asthma (n = 235). CXCL-1, IL-5, IL-8, and IL-17A were positively associated with Difficult-to-Control asthma, while IL-4 and IL-13 were positively associated with Easy-to-Control asthma. Using likelihood ratio testing, it was observed that in addition to blood eosinophils and neutrophils, serum cytokines improved the fit of the model. In an inner-city pediatric population, serum cytokines significantly contributed to the definition of Difficult-to-Control asthma endotypes in African American children. Mixed responses characterized by TH2 (IL-5) and TH17-associated cytokines were associated with Difficult-to-Control asthma. Collectively, these data may contribute to risk stratification of Difficult-to-Control asthma in the African American population.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
...IL-17A is the focus of Östling et al1 and has an important and perhaps pivotal role in the pathophysiology of psoriasis, and therapies directed against IL-17A (eg, secukinumab and ixekizumab or ...IL-17RA) lead to dramatic control of psoriasis symptoms. ...in mouse models of chronic obstructive pulmonary disease, IL-17A contributes to airway neutrophilia and acute exacerbations.4 Furthermore, IL-17A potentiates the effects of other inflammatory mediators, such as TNF-α, by stabilizing target mRNA; TNF-α was included with IL-17A in the epithelial gene profile by Choy et al.9 Not to edit the findings of Östling et al, but it is important to note that their observations likely represent the actions of IL-17A but not all, or other, members of the IL-17 family. ...the IL-17A–high phenotype had greater airway neutrophilia both in sputum (63.7%) and bronchial submucosa biopsy specimens. ...Östling et al1 confirm an anticipated clinical phenotype of IL-17A severe asthma with distinct immunoinflammatory characteristics and, surprisingly, a link to the genetic pattern of psoriasis. ...correlating clinical phenotypic features to the genetic markers linked to IL-17A substantiates and validates the expected immunophenotype of IL-17A severe asthma (ie, neutrophilic airway inflammation). Because the IL-17 pathway is associated with severe asthma, why was there no clinical signal provided by blockage of IL-17RA with brodalumab in patients with moderate-to-severe asthma? At this time, the parallel between psoriasis and asthma might provide insights into the complexity of the IL-17A pathway and the pathobiological effects that follow its involvement. ...our interpretation of the findings of Östling et al1 should also follow the notations with psoriasis being an IL-17A–driven disease and prompt us to increase the precision of IL-17's role in asthma to the IL-17A family member.
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