Asthma phenotyping and endotyping

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Asthma phenotyping and endotyping is a novel approach to asthma classification inspired by precision medicine. It seeks to separate the clinical presentations or clusters of signs and symptoms of asthma, known as asthma phenotypes , from their underlying etiologies or causes, known as asthma endotypes. [1] [2] [3]

Contents

Asthma endotyping is useful in predicting which patients will benefit from inhaled corticosteroids or targeted therapy using specific biologics, while phenotyping can help predict disease outcomes. Numerous asthma phenotypes and endotypes have been proposed, though not all have been validated or widely accepted. [1] [2] [3]

Asthma endotypes

Asthma is now recognised as a heterogenous condition by the Global Initiative for Asthma (GINA), [4] and as an umbrella term encompassing multiple different diseases by many scientists. [1] [3] This is because multiple different pathological processes amenable to different therapies and with different long-term prognoses and complications are at play in asthma. [1]

Asthma phenotypes

Asthma phenotypes are not fixed; a person's inflammatory phenotype may change over the course of a single day. Thus, basing asthma treatment plans on a single sputum eosinophil measurement may be misleading. It is not known to what extent asthma phenotypes can change in the long term. [3]

GINA presently recognises 5 asthma phenotypes: allergic asthma, non-allergic asthma, adult-onset asthma, asthma with persistent airflow limitation, and asthma with obesity. [4]

Type 2 inflammation-based endotyping

GINA currently recognises 2 asthma endotypes based on the degree of type 2 inflammation in the airways: type 2-high (T2-high) and type 2-low (T2-low) asthma. [3] [4]

Type 2-high asthma

GINA defines T2-high asthma as the presence of one or more of the following signs in a patient taking high-dose inhaled corticosteroids: [4]

Type 2 inflammation is produced by eosinophils in the lungs in response to various alarmins, including interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP), which themselves are produced in response to triggers such as allergens, irritants, and respiratory infections. [4] [5]

T2-high asthma phenotypes range in severity from mild to severe. [1] Severe type 2-high asthma is amenable to multiple targeted biologics, including anti-IL5R, anti-IL4, anti-IL13, and anti-TSLP antibodies. [4] [5]

Early-onset atopic asthma

Early-onset atopic asthma is the most common phenotype of asthma in childhood, called intrinsic asthma in the earlier intrinsic/extrinsic classification. Patients with early-onset atopic asthma frequently have a family history of atopy, and are sensitised to common allergens. This phenotype usually responds well to inhaled corticosteroids, and is only rarely severe, with most cases exhibiting mild disease. [1] [5]

Atopy, reduced lung function, and respiratory infections in infants with wheeze are risk factors for asthma persistence into adulthood, and a lower lung function and greater magnitude of atopy at this age is associated with more severe disease. [5]

Severe atopic asthma is also additionally amenable to anti-immunoglubulin E (IgE) therapy. [4] This type of targeted therapy reduces the concentration of IgEs, which normally bind to allergens and cause the release of mast cell mediators and alarmins, promoting type 2 airway inflammation and bronchoconstriction. [6]

Late-onset eosinophilic asthma

Late-onset eosinophilic asthma, previously called extrinsic asthma, presents in adults with no diagnosed atopy. However, late-onset asthma may frequently be allergic. Many patients still have elevated IgE levels, [7] may test positive against a broader panel of known allergens than is normally tested for in specific IgE testing and prick tests, [8] and frequently have comorbid allergic rhinitis and atopic dermatitis. [7]

This phenotype is frequently severe, resulting in relatively rapid lung function decline, [7] and unresponsive to inhaled corticosteroids; good asthma control may not be achieved even with high doses, instead requiring biologic treatment. [1]

Aspirin-exacerbated respiratory disease

It is estimated that around 5-15% of asthmatics experience bronchoconstriction after taking aspirin or other NSAIDs. [9] Aspirin sensitivity frequently presents with a late onset of severe asthma, and chronic rhinosinusitis with nasal polyps. This syndrome is termed aspirin-exacerbated respiratory disease (AERD). AERD is considered to be a sub-phenotype of late-onset eosinophilic asthma. [1] [7]

A key distinguishing feature of AERD is a dysregulated arachidonic acid metabolism and prostaglandin E2 (and prostaglandin E2 receptor) deficiency, leading to excess production of bronchoconstricting leukotrienes, such as leukotriene D4, and immune cell activation, together causing respiratory symptoms. Bronchospasm due to aspirin is thought to occur because aspirin's inhibition of cyclooxygenase shifts arachidonic acid metabolism even more towards bronchoconstrictive leukotriene synthesis. [1] [9]

Allergic bronchopulmonary aspergillosis

Allergic bronchopulmonary aspergillosis (ABPA) is a respiratory disease caused by a hypersensitivity reaction to Aspergillus fumigatus mold that has germinated and persists in the lower airways. While ABPA can also be frequently present in cystic fibrosis patients, most ABPA patients seem to be asthmatics. [10] In asthmatics, ABPA may be regarded as a T2-high asthma phenotype. [11]

Sensitisation to Aspergillus fumigatus may be present in up to 20% of asthmatic children, [10] and it is considered a precursor to ABPA. ABPA itself is estimated to affect 12.9% of adult asthmatics. [12]

Cough variant asthma

Cough variant asthma (CVA), asthma where the only symptom is cough responsive to bronchodilator therapy, may be a T2-high asthma phenotype. CVA may be a precursor stage of other T2-high asthma phenotypes, as 30% of CVA patients are estimated to develop the classical asthma phenotype of wheeze and dyspnea. However, long-term inhaled corticosteroid treatment can reduce the risk of CVA developing into asthma with wheeze and dyspnea. [13] [14]

This classification of CVA has thus far not been widely accepted. Also, recent evidence suggests that other inflammatory endotypes rather than just the T2-high endotype may be seen in CVA. Thus, the classification of CVA as T2-high asthma is uncertain. [15]

Type 2-low asthma

T2-low asthma is rare compared to T2-high asthma, but is often severe and refractory to inhaled corticosteroids. [1] There is a lack of targeted therapies to treat severe T2-low asthma, [1] [3] with the exception of anti-TSLP therapy, which is indicated for severe asthma regardless of etiology. [4] Detectable type 1 airway inflammation may or may not be present in T2-low asthma. Sputum neutrophil counts may or may not be elevated. [4] [3]

Asthma with obesity

Asthma with obesity, insulin resistance, vitamin D deficiency, or metabolic syndrome is now recognised as a distinct T2-low phenotype of severe asthma refractory to inhaled corticosteroids. Obesity is a known risk factor for asthma development and exacerbation. Though a causal link has not been established, multiple reasons for this association have been proposed. [16] [17]

Firstly, obesity mechanically impairs lung function and promotes airway hyperresponsiveness, a hallmark of asthma. Gastroesophageal reflux disease (GERD) is a common comorbidity in both obesity and asthma and has been shown to reduce asthma control. [16] [17]

Adipose tissue releases pro-inflammatory mediators such as C-reactive protein (CRP), tumour necrosis factor (TNF)-α, transforming growth factor (TGF)-β, and IL-6. These mediators may contribute to type 1 inflammation in the lungs. Losing weight, such as via bariatric surgery, can improve asthma control and reduce CRP levels in the blood, a marker of systemic inflammation. [16] This adipocytic inflammation can propagate inflammatory responses in other organs via the circulatory system, including the airways, which may cause bronchoconstriction and airway hyperresponsiveness. Consequently, inflammatory cytokines can be detected in the lungs of asthmatics with obesity even without antigenic challenge. [17]

TGF-β has also been linked to airway remodelling, a potential complication of asthma resulting in reduced lung function and irreversible airway obstruction. [18]

Inflammatory granulocyte-based endotyping

More recently, another endotyping strategy has been proposed with a focus on inflammatory granulocytic involvement in asthma, yielding 4 endotypes: eosinophilic, neutrophilic, mixed-granulocytic, and paucigranulocytic asthma. [3]

Asthma endotyping based on inflammatory granulocytic involvement. [19]
Sputum cellsNeutrophils
Cell countsElevatedNot elevated
EosinophilsElevatedmixed-granulocytic asthma

~3% of asthmatics

eosinophilic asthma

~42% of asthmatics

Not elevatedneutrophilic asthma

~16% of asthmatics

paucigranulocytic asthma

~40% of asthmatics

Other studies than the one conducted by University Asthma Clinic of Liege ascribed the above endotypes to different fractions of asthmatics. However, most studies have found paucigranulocytic asthma to be the most common inflammatory cellular phenotype followed by eosinophilic asthma, and mixed-granulocytic asthma to be the least common one. [3]

Paucigranulocytic asthma

In inflammatory granulocytic asthma endotyping, paucigranulocytic asthma (PGA) is an endotype wherein neither sputum eosinophil nor neutrophil counts are elevated. According to one hypothesis, these inflammatory granulocytes may have been depleted in past episodes of vigorous inflammation. [3]

Because the definition of PGA only relies on the absence of elevated sputum neutrophils and eosinophils, PGA may, according to GINA's definition, simultaneously be T2-high or T2-low in type 2 inflammation-based endotyping. This is because GINA's definition of T2-high asthma does not require elevated eosinophils so long as at least one T2-high asthma sign is present. [4]

As asthma has primarily been described as a chronic inflammatory disease, the pathogenesis of paucigranulocytic asthma has not yet been elucidated. While granulocytes are not elevated in sputum in PGA, macrophages and mast cells are. Additionally, mitochondrial and metabolic genes seem to be overexpressed in PGA, suggesting that mitochondrial or metabolic dysfunction may play a role. However, more research on PGA is needed. [3]

Most cases of PGA are mild, and PGA itself tends to be milder than other endotypes. [3]

Neutrophilic asthma

Neutrophilic asthma (NA) is an asthma endotype with elevated sputum neutrophils. Type 1 neutrophilic airway inflammation is associated with respiratory bacterial and fungal infections, resistance to corticosteroids, and severe asthma. [20] Smoking may shift the asthma endotype towards type 1 inflammation. [21]

Related Research Articles

<span class="mw-page-title-main">Asthma</span> Long-term inflammatory disease of the airways of the lungs

Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, coughing, chest tightness, and shortness of breath. These may occur a few times a day or a few times per week. Depending on the person, asthma symptoms may become worse at night or with exercise.

<span class="mw-page-title-main">Corticosteroid</span> Class of steroid hormones

Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involved in a wide range of physiological processes, including stress response, immune response, and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior.

<span class="mw-page-title-main">Cough</span> Sudden expulsion of air from the lungs as a reflex to clear irritants

A cough is a sudden expulsion of air through the large breathing passages which can help clear them of fluids, irritants, foreign particles and microbes. As a protective reflex, coughing can be repetitive with the cough reflex following three phases: an inhalation, a forced exhalation against a closed glottis, and a violent release of air from the lungs following opening of the glottis, usually accompanied by a distinctive sound.

<span class="mw-page-title-main">Sputum</span> Mucus that is coughed up from the lower airways

Sputum is mucus that is coughed up from the lower airways. In medicine, sputum samples are usually used for a naked eye examination, microbiological investigation of respiratory infections and cytological investigations of respiratory systems. It is crucial that the specimen does not include any mucoid material from the nose or oral cavity.

<span class="mw-page-title-main">Eosinophil</span> Variety of white blood cells

Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. Along with mast cells and basophils, they also control mechanisms associated with allergy and asthma. They are granulocytes that develop during hematopoiesis in the bone marrow before migrating into blood, after which they are terminally differentiated and do not multiply. They form about 2 to 3% of white blood cells in the body.

<span class="mw-page-title-main">Rhinitis</span> Irritation and inflammation of the mucous membrane inside the nose

Rhinitis, also known as coryza, is irritation and inflammation of the mucous membrane inside the nose. Common symptoms are a stuffy nose, runny nose, sneezing, and post-nasal drip.

<span class="mw-page-title-main">Aspirin-exacerbated respiratory disease</span> Chronic inflammatory disease affecting the sinuses and lungs

Aspirin-exacerbated respiratory disease (AERD), also called NSAID-exacerbated respiratory disease (N-ERD) or historically aspirin-induced asthma and Samter's Triad, is a long-term disease defined by three simultaneous symptoms: asthma, chronic rhinosinusitis with nasal polyps, and intolerance of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). Compared to aspirin tolerant patients, AERD patients' asthma and nasal polyps are generally more severe. Reduction or loss of the ability to smell is extremely common, occurring in more than 90% of people with the disease. AERD most commonly begins in early- to mid-adulthood and has no known cure. While NSAID intolerance is a defining feature of AERD, avoidance of NSAIDs does not affect the onset, development or perennial nature of the disease.

Acute severe asthma, also known as status asthmaticus, is an acute exacerbation of asthma that does not respond to standard treatments of bronchodilators (inhalers) and corticosteroids. Asthma is caused by multiple genes, some having protective effect, with each gene having its own tendency to be influenced by the environment although a genetic link leading to acute severe asthma is still unknown. Symptoms include chest tightness, rapidly progressive dyspnea, dry cough, use of accessory respiratory muscles, fast and/or labored breathing, and extreme wheezing. It is a life-threatening episode of airway obstruction and is considered a medical emergency. Complications include cardiac and/or respiratory arrest. The increasing prevalence of atopy and asthma remains unexplained but may be due to infection with respiratory viruses.

<span class="mw-page-title-main">Interleukin 13</span> Protein and coding gene in humans

Interleukin 13 (IL-13) is a protein that in humans is encoded by the IL13 gene. IL-13 was first cloned in 1993 and is located on chromosome 5q31.1 with a length of 1.4kb. It has a mass of 13 kDa and folds into 4 alpha helical bundles. The secondary structural features of IL-13 are similar to that of Interleukin 4 (IL-4); however it only has 25% sequence identity to IL-4 and is capable of IL-4 independent signaling. IL-13 is a cytokine secreted by T helper type 2 (Th2) cells, CD4 cells, natural killer T cell, mast cells, basophils, eosinophils and nuocytes. Interleukin-13 is a central regulator in IgE synthesis, goblet cell hyperplasia, mucus hypersecretion, airway hyperresponsiveness, fibrosis and chitinase up-regulation. It is a mediator of allergic inflammation and different diseases including asthma.

<span class="mw-page-title-main">Allergic bronchopulmonary aspergillosis</span> Medical condition

Allergic bronchopulmonary aspergillosis (ABPA) is a condition characterised by an exaggerated response of the immune system to the fungus Aspergillus. It occurs most often in people with asthma or cystic fibrosis. Aspergillus spores are ubiquitous in soil and are commonly found in the sputum of healthy individuals. A. fumigatus is responsible for a spectrum of lung diseases known as aspergilloses.

Pitrakinra is a 15-kDa human recombinant protein of wild-type human interleukin-4 (IL-4). It is an IL-4 and IL-13 antagonist that has been studied in a phase IIb clinical trial for the treatment of asthma. Two point mutations on pitrakinra confer its ability to block signaling of IL-4 and interleukin-13 (IL-13) by preventing assembly of IL-4 receptor alpha (IL-4Rα) with either IL-2Rγ or IL-13Rα. Upregulation of Th2 cytokines, including IL-4 and IL-13, is thought to be critical for the allergic inflammation associated with atopic diseases such as asthma and eczema. The targets of pitrakinra action are inflammatory cells and structural cells that express IL-4Rα. The drug has been applied both as a subcutaneous injection and as an inhalation, but the latter formulation proved to be more effective.

<span class="mw-page-title-main">Exhaled nitric oxide</span> Breath test for respiratory inflammation

In medicine, exhaled nitric oxide (eNO) can be measured in a breath test for asthma and other respiratory conditions characterized by airway inflammation. Nitric oxide (NO) is a gaseous molecule produced by certain cell types in an inflammatory response. The fraction of exhaled NO (FENO) is a promising biomarker for the diagnosis, follow-up and as a guide to therapy in adults and children with asthma. The breath test has recently become available in many well-equipped hospitals in developed countries, although its exact role remains unclear.

<span class="mw-page-title-main">Pathophysiology of asthma</span> Medical condition

Asthma is a common pulmonary condition defined by chronic inflammation of respiratory tubes, tightening of respiratory smooth muscle, and episodes of bronchoconstriction. The Centers for Disease Control and Prevention estimate that 1 in 11 children and 1 in 12 adults have asthma in the United States of America. According to the World Health Organization, asthma affects 235 million people worldwide. There are two major categories of asthma: allergic and non-allergic. The focus of this article will be allergic asthma. In both cases, bronchoconstriction is prominent.

<span class="mw-page-title-main">Eosinophilic bronchitis</span> Medical condition

Eosinophilic bronchitis (EB) is a type of airway inflammation due to excessive mast cell recruitment and activation in the superficial airways as opposed to the smooth muscles of the airways as seen in asthma. It often results in a chronic cough. Lung function tests are usually normal. Inhaled corticosteroids are often an effective treatment.

Chronic Mycoplasma pneumonia and Chlamydia pneumonia infections are associated with the onset and exacerbation of asthma. These microbial infections result in chronic lower airway inflammation, impaired mucociliary clearance, an increase in mucous production and eventually asthma. Furthermore, children who experience severe viral respiratory infections early in life have a high possibility of having asthma later in their childhood. These viral respiratory infections are mostly caused by respiratory syncytial virus (RSV) and human rhinovirus (HRV). Although RSV infections increase the risk of asthma in early childhood, the association between asthma and RSV decreases with increasing age. HRV on the other hand is an important cause of bronchiolitis and is strongly associated with asthma development. In children and adults with established asthma, viral upper respiratory tract infections (URIs), especially HRVs infections, can produce acute exacerbations of asthma. Thus, Chlamydia pneumoniae, Mycoplasma pneumoniae and human rhinoviruses are microbes that play a major role in non-atopic asthma.

Eoxins are proposed to be a family of proinflammatory eicosanoids. They are produced by human eosinophils, mast cells, the L1236 Reed–Sternberg cell line derived from Hodgkin's lymphoma, and certain other tissues. These cells produce the eoxins by initially metabolizing arachidonic acid, an omega-6 (ω-6) fatty acid, via any enzyme possessing 15-lipoxygenase activity. The product of this initial metabolic step, 15(S)-hydroperoxyeicosatetraenoic acid, is then converted to a series of eoxins by the same enzymes that metabolize the 5-lipoxygenase product of arachidonic acid metabolism, i.e. 5-Hydroperoxy-eicosatetraenoic acid to a series of leukotrienes. That is, the eoxins are 14,15-disubstituted analogs of the 5,6-disubstituted leukotrienes.

NSAIDhypersensitivity reactions encompass a broad range of allergic or allergic-like symptoms that occur within minutes to hours after ingesting aspirin or other NSAID nonsteroidal anti-inflammatory drugs. Hypersensitivity drug reactions differ from drug toxicity reactions in that drug toxicity reactions result from the pharmacological action of a drug, are dose-related, and can occur in any treated individual. Hypersensitivity reactions are idiosyncratic reactions to a drug. Although the term NSAID was introduced to signal a comparatively low risk of adverse effects, NSAIDs do evoke a broad range of hypersensitivity syndromes. These syndromes have recently been classified by the European Academy of Allergy and Clinical Immunology Task Force on NSAIDs Hypersensitivity.

<span class="mw-page-title-main">Asthma trigger</span> Factor that provokes symptoms of asthma

Asthma triggers are factors or stimuli that provoke the exacerbation of asthma symptoms or increase the degree of airflow disruption, which can lead to an asthma attack. An asthma attack is characterized by an obstruction of the airway, hypersecretion of mucus and bronchoconstriction due to the contraction of smooth muscles around the respiratory tract. Its symptoms include a wide range of manifestations such as breathlessness, coughing, a tight chest and wheezing.

Asthma-Chronic Obstructive Pulmonary Disease (COPD) Overlap (ACO), also known as Asthma-COPD Overlap Syndrome (ACOS) is a chronic inflammatory, obstructive airway disease in which features of both asthma and COPD predominate. Asthma and COPD were once thought of as distinct entities, however in some, there are clinical features of both asthma and COPD with significant overlap in pathophysiology and symptom profile. It is unclear whether ACO is a separate disease entity or a clinical subtype of asthma and COPD. The pathogenesis of ACO is poorly understood, but it is thought to involve both type 2 inflammation as well as type 1 inflammation. The incidence and prevalence of ACO are not well known. The risk factors for ACO are also incompletely understood, but tobacco smoke is known to be a major risk factor.

<span class="mw-page-title-main">Airway remodelling</span> Asthma complication

Airway remodelling, or airway remodeling, is a potential complication of certain endotypes (subtypes) of asthma. It is the sum of changes that occur in the airways of some asthmatic people compared to people without the disease.

References

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