Clinical approaches towards asthma and chronic obstructive pulmonary disease based on the heterogeneity of disease pathogenesis

Asthma and chronic obstructive pulmonary disease (COPD) are each heterogeneous disease classifications that include several clinical and pathophysiological phenotypes. This heterogeneity complicates characterization of each disease and, in some cases, hinders the selection of appropriate treatment. Therefore, in recent years, emphasis has been placed on improving our understanding of the various phenotypes of asthma and of COPD and identifying biomarkers for each phenotype. Likewise, the concept of the endotype has been gaining acceptance; an endotype is a disease subtype that is defined by unique or distinctive functional or pathophysiological mechanisms. Endotypes of asthma or COPD may be primarily characterized by increased susceptibility to type 2 inflammation, increased susceptibility to viral infections, bacterial colonization or impaired lung development. The ‘Dutch hypothesis’ is as follows: gene variants underlying particular endotypes interact with detrimental environmental stimuli (e.g. smoking, viral infection and air pollution) and contribute to the ultimate development of asthma, COPD or both. Novel approaches that involve multidimensional assessment should facilitate identification and management of the components that generate this heterogeneity. Ultimately, patients with chronic inflammatory lung diseases may be treated based on these endotypes as determined by the respective biomarkers that correspond to individual endotypes instead of on disease labels such as asthma, COPD or even asthma–COPD overlap syndrome (ACOS).     

Current and future biomarkers in allergic asthma

Diagnosis early in life, sensitization, asthma endotypes, monitoring of disease and treatment progression are key motivations for the exploration of biomarkers for allergic rhinitis and allergic asthma. The number of genes related to allergic rhinitis and allergic asthma increases steadily; however, prognostic genes have not yet entered clinical application. We hypothesize that the combination of multiple genes may generate biomarkers with prognostic potential. The current review attempts to group more than 161 different potential biomarkers involved in respiratory inflammation to pave the way for future classifiers. The potential biomarkers are categorized into either epithelial or infiltrate‐derived or mixed origin, epithelial biomarkers. Furthermore, surface markers were grouped into cell‐type‐specific categories. The current literature provides multiple biomarkers for potential asthma endotypes that are related to T‐cell phenotypes such as Th1, Th2, Th9, Th17, Th22 and Tregs and their lead cytokines. Eosinophilic and neutrophilic asthma endotypes are also classified by epithelium‐derived CCL‐26 and osteopontin, respectively. There are currently about 20 epithelium‐derived biomarkers exclusively derived from epithelium, which are likely to innovate biomarker panels as they are easy to sample. This article systematically reviews and categorizes genes and collects current evidence that may promote these biomarkers to become part of allergic rhinitis or allergic asthma classifiers with high prognostic value.     

Untangling asthma phenotypes and endotypes

Asthma phenotypes have been developed to address the complexities of the disease. However, owing to a lack of longitudinal studies, little is known about the onset as well as the stability of phenotypes. Distinguishing phenotypes with regard to the severity or duration of the disease is essential. A phenotype covers the clinically relevant properties of the disease, but does not show the direct relationship to disease etiology and pathophysiology. Different pathogenetic mechanisms might cause similar asthma symptoms and might be operant in a certain phenotype. These putative mechanisms are addressed by the term 'endotype'. Classification of asthma based on endotypes provides advantages for epidemiological, genetic, and drug-related studies. A successful definition of endotypes should link key pathogenic mechanisms with the asthma phenotype. Thus, the identification of corresponding molecular biomarkers for individual pathogenic mechanism underlying phenotypes or subgroups within a phenotype is important. Whether newly defined asthma endotypes predict the individual course of asthma has to be validated in longitudinal studies. The accurate endotyping reflects natural history of asthma and should help to predict treatment response. Thus, understanding asthma endotypes might be useful in clinical practice.     

Revisiting Type 2‐high and Type 2‐low airway inflammation in asthma: current knowledge and therapeutic implications

Asthma is a complex respiratory disorder characterized by marked heterogeneity in individual patient disease triggers and response to therapy. Several asthma phenotypes have now been identified, each defined by a unique interaction between genetic and environmental factors, including inflammatory, clinical and trigger‐related phenotypes. Endotypes further describe the functional or pathophysiologic mechanisms underlying the patient's disease. type 2‐driven asthma is an emerging nomenclature for a common subtype of asthma and is characterized by the release of signature cytokines IL‐4, IL‐5 and IL‐13 from cells of both the innate and adaptive immune systems. A number of well‐recognized biomarkers have been linked to mechanisms involved in type 2 airway inflammation, including fractional exhaled nitric oxide, serum IgE, periostin, and blood and sputum eosinophils. These type 2 cytokines are targets for pharmaceutical intervention, and a number of therapeutic options are under clinical investigation for the management of patients with uncontrolled severe asthma. Anticipating and understanding the heterogeneity of asthma and subsequent improved characterization of different phenotypes and endotypes must guide the selection of treatment to meet individual patients’ needs.     

Clinical phenotypes in asthma during childhood

Asthma is a heterogeneous disease characterized by numerous phenotypes relating to age of onset, triggers, comorbidities, severity (assessed by multiple exacerbations, lung function pattern) and finally the inflammatory cells involved in the pathophysiologic pathway. These phenotypes can vary over time in relation to changes in the principal triggers involved in the aetiology of the disease. Nevertheless, in a patient with multiple allergies and early‐onset disease (defined as multiple sensitizations and allergic comorbidities), the prognosis of asthma is poor with a high risk of persistence and severity of the disease during childhood. Future research will focus on classifying phenotypes into groups based on pathophysiologic mechanisms (endotypes) and the biomarkers attached to these endotypes, which could predict prognosis and lead to targeted therapy. Currently, these biomarkers are related to inflammatory cells associated with the asthma endotype, essentially eosinophils and neutrophils (and related cytokines) attached to Th‐2 and non Th‐1 pathways, respectively. The most severe asthma (refractory asthma) is linked to neutrophil‐derived inflammation (frequently associated with female sex, obesity and possibly disorganized airway microbiota) encountered in very young children or teenagers. Severe asthma is also linked to or a marked eosinophil inflammatory process (frequently associated with multiple atopy and, more rarely, with non‐atopic hypereosinophilic asthma in children) and frequently encountered in teenagers. Severe phenotypes of asthma could also play a role in the origin of chronic obstructive pulmonary disease in adult life.     

Precision medicine in allergic disease—food allergy,drug allergy,and anaphylaxis—PRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy,Asthma and Immunology

This consensus document summarizes the current knowledge on the potential for precision medicine in food allergy, drug allergy, and anaphylaxis under the auspices of the PRACTALL collaboration platform. PRACTALL is a joint effort of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma and Immunology, which aims to synchronize the European and American approaches to allergy care. Precision medicine is an emerging approach for disease treatment based on disease endotypes, which are phenotypic subclasses associated with specific mechanisms underlying the disease. Although significant progress has been made in defining endotypes for asthma, definitions of endotypes for food and drug allergy or for anaphylaxis lag behind. Progress has been made in discovery of biomarkers to guide a precision medicine approach to treatment of food and drug allergy, but further validation and quantification of these biomarkers are needed to allow their translation into practice in the clinical management of allergic disease.     

Phenotypes and endotypes in eosinophilic esophagitis

ObjectiveTo improve understanding of the heterogeneous presentation of eosinophilic esophagitis (EoE), and its different potential phenotypes and endotypes.Data SourcesWe reviewed studies addressing EoE genetics, risks, natural history, treatment, phenotype, or endotype to assess data relating to differences in the presentation of EoE in children and adults. This review was restricted to articles in the English language.Study SelectionsData source abstracts, pertinent articles, and book chapters meeting the objectives were critically reviewed.ResultsData to support differing phenotypes and endotypes in EoE are emerging, but findings are based on multiple studies and therefore sometimes incomparable. Like other atopic disorders EoE is a complex disease with diverse clinical presentations (phenotypes) based on response to therapy, natural history, and association with atopic comorbidities. Different pathogenetic mechanisms (endotypes) may drive the multiple phenotypes. T Helper type 2 inflammation, epithelial barrier defects, enhanced fibrosis, and association with rare monogenetic diseases are the most described endotypes in EoE.ConclusionEosinophilic esophagitis is an atopic disorder that is increasing in prevalence and can be difficult to treat. Better understanding of phenotypes and endotypes in EoE may enable future care to be individualized more effectively, resulting in shorter time to remission and fewer endoscopies.     

Diagnosis and management of NSAID‐Exacerbated Respiratory Disease (N‐ERD)—a EAACI position paper

NSAID‐exacerbated respiratory disease (N‐ERD) is a chronic eosinophilic, inflammatory disorder of the respiratory tract occurring in patients with asthma and/or chronic rhinosinusitis with nasal polyps (CRSwNP), symptoms of which are exacerbated by NSAIDs, including aspirin. Despite some progress in understanding of the pathophysiology of the syndrome, which affects 1/10 of patients with asthma and rhinosinusitis, it remains a diagnostic and therapeutic challenge. In order to provide evidence‐based recommendations for the diagnosis and management of N‐ERD, a panel of international experts was called by the EAACI Asthma Section. The document summarizes current knowledge on the pathophysiology and clinical presentation of N‐ERD pointing at significant heterogeneity of this syndrome. Critically evaluating the usefulness of diagnostic tools available, the paper offers practical algorithm for the diagnosis of N‐ERD. Recommendations for the most effective management of a patient with N‐ERD stressing the potential high morbidity and severity of the underlying asthma and rhinosinusitis are discussed and proposed. Newly described sub‐phenotypes and emerging sub‐endotypes of N‐ERD are potentially relevant for new and more specific (eg, biological) treatment modalities. Finally, the document defines major gaps in our knowledge on N‐ERD and unmet needs, which should be addressed in the future.     

Inflammatory biomarkers for asthma endotyping and consequent personalized therapy

Introduction: We argue that asthma be considered a syndrome caused by multiple inflammatory pathogenic processes. Bronchial hyperresponsiveness, reversible airflow limitation, and chronic airway inflammation characterize asthma pathophysiology. Personalized Medicine, i.e. a tailored management approach, is appropriate for asthma management and is based on the identification of discrete phenotypes and endotypes. Biomarkers can help define phenotypes and endotypes. Several biomarkers have been described in asthma, but most of them are not commonly available or still need external validation.

Areas covered: This review presents useful pragmatic biomarkers available in daily clinical practice for assessing airway inflammation in asthmatic patients.

Expert commentary: Eosinophil counts and serum allergen-specific IgE assessments are the most reliable biomarkers. Lung function, mainly concerning FEF_25-75, and nasal cytology may be envisaged as ancillary biomarkers in asthma management. In conclusion, biomarkers have a clinical relevance in asthma in identifying asthma endotypes to direct personalized therapy.     

Biomarkers for diagnosis and prediction of therapy responses in allergic diseases and asthma

Modern health care requires a proactive and individualized response to diseases, combining precision diagnosis and personalized treatment. Accordingly, the approach to patients with allergic diseases encompasses novel developments in the area of personalized medicine, disease phenotyping and endotyping, and the development and application of reliable biomarkers. A detailed clinical history and physical examination followed by the detection of IgE immunoreactivity against specific allergens still represents the state of the art. However, nowadays, further emphasis focuses on the optimization of diagnostic and therapeutic standards and a large number of studies have been investigating the biomarkers of allergic diseases, including asthma, atopic dermatitis, allergic rhinitis, food allergy, urticaria and anaphylaxis. Various biomarkers have been developed by omics technologies, some of which lead to a better classification of distinct phenotypes or endotypes. The introduction of biologicals to clinical practice increases the need for biomarkers for patient selection, prediction of outcomes and monitoring, to allow for an adequate choice of the duration of these costly and long-lasting therapies. Escalating healthcare costs together with questions about the efficacy of the current management of allergic diseases require further development of a biomarker-driven approach. Here, we review biomarkers in diagnosis and treatment of asthma, atopic dermatitis, allergic rhinitis, viral infections, chronic rhinosinusitis, food allergy, drug hypersensitivity and allergen immunotherapy with a special emphasis on specific IgE, the microbiome and the epithelial barrier. In addition, EAACI guidelines on biologicals are discussed within the perspective of biomarkers.     

Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome

It is increasingly clear that asthma is a complex disease made up of number of disease variants with different underlying pathophysiologies. Limited knowledge of the mechanisms of these disease subgroups is possibly the greatest obstacle in understanding the causes of asthma and improving treatment and can explain the failure to identify consistent genetic and environmental correlations to asthma. Here we describe a hypothesis whereby the asthma syndrome is divided into distinct disease entities with specific mechanisms, which we have called "asthma endotypes." An "endotype" is proposed to be a subtype of a condition defined by a distinct pathophysiological mechanism. Criteria for defining asthma endotypes on the basis of their phenotypes and putative pathophysiology are suggested. Using these criteria, we identify several proposed asthma endotypes and propose how these new definitions can be used in clinical study design and drug development to target existing and novel therapies to patients most likely to benefit. This PRACTALL (PRACtical ALLergy) consensus report was produced by experts from the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology.     

Use of endotypes,phenotypes, and inflammatory markers to guide treatment decisions in chronic rhinosinusitis

ObjectiveWith the advent of new treatment options for Chronic Rhinosinusitis (CRS) comes the ability for physicians to provide more individualized patient care. Physicians are now tasked with identifying who may be the best candidate for a particular therapy. In this review, existing biomarkers and potentially new methods that could guide treatment choices in CRS patients will be discussed.Data SourcesPublished literature obtained through PubMed searches.Study SelectionStudies relevant to inflammatory endotypes, phenotypes, and biomarkers in CRS were included.ResultsCurrently, there are no clinically validated tools that determine the best therapeutic modality for CRS patients with or without nasal polyps (CRSwNP or CRSsNP). Patients with CRS can be classified into three endotypes based on the presence of type 1, type 2, or type 3 inflammation. CRS endotypes can be influenced by age and geographic location. Clinical application however may be limited since endotyping current requires basic research laboratory support. Clinical symptoms may also predict inflammatory endotypes with smell loss being indicative of type 2 inflammation. Numbers of tissue and/or peripheral eosinophils as well as levels of IgE may predict disease severity in CRSwNP but not necessarily treatment responses. Unique clinical phenotypes or biomarkers are especially lacking that predict type 1 or type 3 inflammation in CRSwNP or type 1, type 2, or type 3 inflammation in CRSsNP.ConclusionWhile significant progress has been made in characterizing endotypes, phenotypes, and biomarkers in CRS, additional studies are needed to determine if and how these factors could assist physicians in providing more individualized clinical care.     

Minimal persistent inflammation, an emerging concept in the nature and treatment of allergic rhinitis: the possible role of leukotrienes.

OBJECTIVE: To review the emerging concept of minimal persistent inflammation in allergic rhinitis and its implications for therapy. DATA SOURCES: Relevant clinical studies in the English language were reviewed. STUDY SELECTION: Material was taken from academic/scholarly journals. RESULTS: Accumulating evidence suggests that allergic rhinitis is a chronic inflammatory disease instead of a disease of acute symptoms. An approach to the therapy for allergic rhinitis should consider that even when symptoms are absent, a minimal level of persistent inflammation may persist. To prevent unexpected exacerbations, the treatment strategy may need to include managing subclinical persistent inflammation. Therapeutic options addressing the major inflammatory elements in allergic rhinitis, including eosinophils, the cysteinyl leukotrienes, and histamine, must be evaluated as management strategies that can achieve effective control. Traditional medications include intranasal corticosteroids, antihistamines, and immunotherapy. Recently, a leukotriene receptor antagonist has been approved for major rhinitis symptoms (congestion, rhinorrhea, sneezing, and pruritus), suggesting a new option for the treatment of allergic rhinitis. CONCLUSIONS: Because of the possible presence of a minimal persistent inflammation during rhinitis patients' asymptomatic periods, it is important to consider a prophylactic approach to treating allergic rhinitis to prevent or reduce exacerbations during an acute increase in allergen. In light of the advances in the understanding of the pathogenesis of allergic rhinitis, agents must be considered based on their safety, efficacy, and ability to deal with underlying inflammation as well as symptom relief.     

CD11b immunophenotyping identifies inflammatory profiles in the mouse and human lungs

The development of easily accessible tools for human immunophenotyping to classify patients into discrete disease endotypes is advancing personalized therapy. However, no systematic approach has been developed for the study of inflammatory lung diseases with often complex and highly heterogeneous disease etiologies. We have devised an internally standardized flow cytometry approach that can identify parallel inflammatory alveolar macrophage phenotypes in both the mouse and human lungs. In mice, lung innate immune cell alterations during endotoxin challenge, influenza virus infection, and in two genetic models of chronic obstructive lung disease could be segregated based on the presence or absence of CD11b alveolar macrophage upregulation and lung eosinophilia. Additionally, heightened alveolar macrophage CD11b expression was a novel feature of acute lung exacerbations in the SHIP-1^−/− model of chronic obstructive lung disease, and anti-CD11b antibody administration selectively blocked inflammatory CD11b^pos but not homeostatic CD11b^neg alveolar macrophages in vivo. The identification of analogous profiles in respiratory disease patients highlights this approach as a translational avenue for lung disease endotyping and suggests that heterogeneous innate immune cell phenotypes are an underappreciated component of the human lung disease microenvironment.     

Asthma in children

Asthma is the most common chronic disease in childhood characterized by chronic bronchial inflammation of variable intensity accompanied by spontaneous or drug reversible airflow obstruction. The onset of asthma, clinical presentation and response to therapy are influenced by numerous genetic and environmental factors. Asthma in childhood is characterized by its heterogeneity in terms of possible etiology, degree of inflammation and airway obstruction, lung function as well as the natural course of disease that may persist and continue to adulthood. Protective factors linked to early life experiences have also been delineated which may impact the development of asthma. Pathophysiological mechanisms of allergic reaction as an excessive inflammation driven by T-helper-2 (Th2) immunity, offer poor understanding of the heterogeneity of clinical disease. A recently introduced approach defines asthma as a syndrome that comprises of several subtypes or endotypes based on entirely novel pathways to disease. Timely diagnosis and adequate treatment are necessary to prevent irreversible airway remodeling and consequent decrease in pulmonary function.     

Characterizing wheeze phenotypes to identify endotypes of childhood asthma,and the implications for future management

It is now a commonly held view that asthma is not a single disease, but rather a set of heterogeneous diseases sharing common symptoms. One of the major challenges in treating asthma is understanding these different asthma phenotypes and their underlying biological mechanisms. This review gives an epidemiological perspective of our current understanding of the different phenotypes that develop from birth to childhood that come under the umbrella term ‘asthma’. The review focuses mainly on publications from longitudinal birth cohort studies where the natural history of asthma symptoms is observed over time in the whole population. Identifying distinct pathophysiological mechanisms for these different phenotypes will potentially elucidate different asthma endotypes, ultimately leading to more effective treatment and management strategies.     

The role of filaggrin in the atopic diathesis

Atopic dermatitis (AD) is an inflammatory disease characterized by pruritic skin lesions, immunodysregulation, disrupted epidermal barrier function and IgE‐mediated sensitization to food and environmental allergens. Identification of the aetiology of AD has become increasingly a priority, as it is clear that the disease burden exceeds AD alone, with many children suffering severe, multi‐system and occasionally life‐threatening allergic disease. Previous approaches to understanding AD have centred on mechanisms in the adaptive immune system, often with an emphasis on the Th1–Th2 paradigm. Recently, the conceptual focus has increasingly shifted to include a primary defect in the epithelial barrier as a threshold event in moderate‐to‐severe AD. Familial aggregation of the disease is well established through many family studies of AD, asthma and allergic rhinitis, suggesting a significant heritable component. The identification of loss‐of‐function mutations in the filaggrin (FLG) gene, whose product is a key structural protein in the outermost layer of the epidermis in up to 50% of patients with AD, provides a significant insight into explaining disease initiation and points to a complex secondary interplay of environmental and immunological sequelae once barrier disruption is established. The elucidation of the environmental, genetic and immunobiological modifiers of this structural molecule may also direct our understanding of the pathomechanisms and endotypes central to the atopic diathesis. The recent identification of a murine model for FLG‐AD, with the detection of a homozygous frame‐shift mutation in the Flg gene in flaky‐tail (ft/ft) mice, stands to rapidly accelerate our understanding of mechanisms and therapeutic intervention points in AD. Refining the molecular understanding of AD and its subtypes will allow for specific diagnostic, treatment and ultimately, preventative algorithms, and has opened an exciting new world of investigative challenges and collaborations. Cite this as: G. M. O'Regan and A. D. Irvine, Clinical & Experimental Allergy, 2010 (40) 965–972.     

Inflammatory endotypes in COPD

Chronic obstructive pulmonary disease (COPD) is a major global health problem that is poorly treated by current therapies as it has proved difficult to treat the underlying inflammation, which is largely corticosteroid‐resistant in most patients. Although rare genetic endotypes of COPD have been recognized, despite the clinical heterogeneity of COPD, it has proved difficult to identify distinct inflammatory endotypes. Most patients have increased neutrophils and macrophages in sputum, reflecting the increased secretion of neutrophil and monocyte chemotactic mediators in the lungs. However, some patients also have increased eosinophils in sputum and this may be reflected by increased blood eosinophils. Increased blood and sputum eosinophils are associated with more frequent exacerbations and predict a good response to corticosteroids in reducing and treating acute exacerbations. Eosinophilic COPD may represent an overlap with asthma but the mechanism of eosinophilia is uncertain as, although an increase in sputum IL‐5 has been detected, anti‐IL‐5 therapies are not effective in preventing exacerbations. More research is needed to link inflammatory endotypes to clinical manifestations and outcomes in COPD and in particular to predict response to precision medicines.     

The clinical heterogeneity of adult onset Still’s disease may underlie different pathogenic mechanisms. Implications for a personalised therapeutic management of these patients

Adult-onset Still’s disease (AOSD) is a rare inflammatory disease of unknown aetiology usually affecting young adults and manifesting with a clinical triad of spiking fever, arthritis, and evanescent cutaneous rash. AOSD may be considered a highly heterogeneous disease, despite a similar clinical presentation, the disease course may be completely different. Some patients may have a single episode of the disease whereas others may evolve toward a chronic course and experience life-threatening complications. On these bases, to dissect the clinical heterogeneity of this disease, four different subsets were identified combining the manifestations at the beginning with possible diverse outcomes over time. Each one of these derived subsets would be characterised by a prominent different clinical feature from others, thus proposing dissimilar underlying pathogenic mechanisms, at least partially. Consequently, a distinct management of AOSD may be suggested to appropriately tailor the therapeutic strategy to these patients, according to principles of the precision medicine. These findings would also provide the rationale to recognise a different genetic and molecular profile of patients with AOSD. Taking together these findings, the basis for a precision medicine approach may be suggested in AOSD, which would drive a tailored therapeutic approach in these patients. A better patient stratification may also help in arranging specific designed studies to improve the management of patients with AOSD. Behind these different clinical phenotypes, distinct endotypes of AOSD may be suggested, probably differing in pathogenesis, outcomes, and response to therapies.