Preface

The clinical expression of asthma in its many phenotypes and endotypes is based on multiple and diversified pathogenic mechanisms. Although in the inflammatory process there may be a predominance of some cell lines with very peculiar biological characteristics, there is always a complex and intricate participation of all the elements of the adaptive and innate immune system. Likewise all the resident and structural cells present in the bronchi are active vectors in the chronic inflammation, as are the contiguous extracellular matrix proteins.

Successive genome-wide association studies have proven the polygenic profile of asthma by identifying the complex and extensive networks of critical cellular mediators engaged in local bronchial mucosa as well as regional and systemic inflammation. In this context, a profound knowledge of cell biology is crucial, because it can allow to define a specific pathophysiological way for each clinical phenotype/endotype that may guide to a personalized therapy.

Even though much of the research is currently directed towards new biologics aimed at severe asthma patients, fortunately in clinical practice the overwhelming majority of asthmatics have more favorable treatment options. However, like other chronic inflammatory disorders deficient control is very common in clinical practice, also allying difficulties in adhesion and compliance to a long-lasting treatment plan.

This book exhaustively and didactically covers the biological expression of numerous cells and mediators involved in bronchial inflammation. The authors provide robust information identifying the diversity and complexity of the interrelationships between the different players, drawing attention to critical mechanisms in asthma.

These reviews show the impossibility of standardizing the therapeutic plan for asthma due mainly to the heterogeneity of pathophysiological mechanisms corresponding to different clinical profiles. Asthma, although prevalent in all age groups, is a diverse condition. While in most patients the currently available treatments (different anti-inflammatory drugs and bronchodilators) can help control asthma, they have no effect on other pathways of chronic inflammation, namely those leading to structural changes and remodeling. It is clear that the available biological treatments and others currently in pharmacological trials are clearly insufficient to effectively halt and control inflammation.

This update on the biological aspects of cells and mediators involved in asthma will hopefully open up new lines of research that may lead to new therapeutic approaches to optimize the control of inflammation and other symptoms as well as lung function and patient quality of life. Furthermore, this book highlights the use of new diagnostic procedures in order to identify different asthma biomarkers with high specificity and sensitivity for each predominant pathophysiological

mechanism involved. The information contained herein allows for the creation of personalized and effective treatment for asthmatic patients.

> **Celso Pereira, MD, PhD** Clinical Immunology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal

> > **1**

**Chapter 1**

**Abstract**

**1. Introduction**

Biomarkers

*Joy N. Eze and Samuel N. Uwaezuoke*

Childhood and Adult Asthma:

Phenotype- and Endotype-Based

The concept of asthma has changed from that of a single disease entity to that of a heterogeneous disease comprising several phenotypes linked to specific endotypes. Recently, significant progress has been made in disease classification into phenotypes and biologically distinct variants (endotypes). Classification of patients into endotypes has led to precision medicine in which specific biomarkers and appropriate individualized treatments have now been identified. Despite the ongoing classification of disease endotypes, the presence or absence of a T-helper 2 (Th2) molecular signature has resulted in the association of asthma endotypes with phenotypes so as to establish responders and non-responders to inhaled corticosteroid therapy. More importantly, biologic therapies predicated on disease endotypes may in future constitute a paradigm shift from the traditional pharmacologic treatments and lead to better prognosis in moderate-to-severe forms of the disease (in which they are presently used). This book chapter aims to discuss the current

concepts on asthma classification and biomarker-based diagnosis.

sible for their failure have now been documented.

**Keywords:** asthma, biomarkers, endotypes, heterogeneous disease, phenotypes

Asthma represents one of the major childhood noncommunicable respiratory diseases worldwide [1]. Asthma is now seen as a complex heterogeneous disease with variable natural history, severity, comorbidities, and therapeutic response. The disease is thus defined in several ways. For instance, asthma is defined as an airway disorder with underlying chronic inflammation characterized by hyper-responsive airway, which results in nonspecific symptoms like recurrent wheezing, breathlessness, nocturnal or early morning cough, and chest tightness. The symptoms tend to change over time and intensity, in conjunction with variable airflow limitation [2]. The disease also represents a syndrome with several phenotypes (the observable physical characteristics from the gene–environment interactions) and endotypes [3]. Research within the last decade has sought to better understand the heterogeneous nature of asthma. Disease heterogeneity particularly manifests in the clinical features, as well as the type and degree of airway inflammation and remodeling. Thus, there is now a paradigm shift in the concept of asthma as a single disease entity to that of a complex cluster of disease phenotypes [4]. Various subtypes of inflammation and complex immunoregulatory pathways and the factors respon-

#### **Chapter 1**

## Childhood and Adult Asthma: Phenotype- and Endotype-Based Biomarkers

*Joy N. Eze and Samuel N. Uwaezuoke*

#### **Abstract**

The concept of asthma has changed from that of a single disease entity to that of a heterogeneous disease comprising several phenotypes linked to specific endotypes. Recently, significant progress has been made in disease classification into phenotypes and biologically distinct variants (endotypes). Classification of patients into endotypes has led to precision medicine in which specific biomarkers and appropriate individualized treatments have now been identified. Despite the ongoing classification of disease endotypes, the presence or absence of a T-helper 2 (Th2) molecular signature has resulted in the association of asthma endotypes with phenotypes so as to establish responders and non-responders to inhaled corticosteroid therapy. More importantly, biologic therapies predicated on disease endotypes may in future constitute a paradigm shift from the traditional pharmacologic treatments and lead to better prognosis in moderate-to-severe forms of the disease (in which they are presently used). This book chapter aims to discuss the current concepts on asthma classification and biomarker-based diagnosis.

**Keywords:** asthma, biomarkers, endotypes, heterogeneous disease, phenotypes

#### **1. Introduction**

Asthma represents one of the major childhood noncommunicable respiratory diseases worldwide [1]. Asthma is now seen as a complex heterogeneous disease with variable natural history, severity, comorbidities, and therapeutic response. The disease is thus defined in several ways. For instance, asthma is defined as an airway disorder with underlying chronic inflammation characterized by hyper-responsive airway, which results in nonspecific symptoms like recurrent wheezing, breathlessness, nocturnal or early morning cough, and chest tightness. The symptoms tend to change over time and intensity, in conjunction with variable airflow limitation [2]. The disease also represents a syndrome with several phenotypes (the observable physical characteristics from the gene–environment interactions) and endotypes [3]. Research within the last decade has sought to better understand the heterogeneous nature of asthma. Disease heterogeneity particularly manifests in the clinical features, as well as the type and degree of airway inflammation and remodeling. Thus, there is now a paradigm shift in the concept of asthma as a single disease entity to that of a complex cluster of disease phenotypes [4]. Various subtypes of inflammation and complex immunoregulatory pathways and the factors responsible for their failure have now been documented.

#### **2. Asthma phenotypes and endotypes: A snapshot**

An endotype is a subtype of a disease recognized by a characteristic pathophysiologic mechanism, whereas a disease phenotype refers to any identifiable characteristic without any evidence of a mechanism [5]. Recent advances in asthma management have tried to group patients by a plethora of possible phenotypic features including age of onset, presence of atopy, airway inflammation and severity of airway obstruction, and the need for drugs. On the basis of the diverse cellular and molecular mechanisms, several phenotypes are currently recognized [6]. Using sputum cytological examination, there is now a classification of the major inflammatory phenotypes into eosinophilic, neutrophilic, mixed-complex inflammation, and pauci-granulocytic phenotypes [7]. Other recognizable phenotypes include early-onset mild allergic asthma, late-onset asthma associated with obesity, and severe nonatopic asthma with frequent exacerbations [8]. Experts from the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma, and Immunology produced the PRACTALL (Practical Allergy) consensus report which proposed the use of parameters such as clinical features, biomarkers, pulmonary physiology, genetics, histopathology, therapeutic response, and epidemiology for characterizing disease endotypes [9]. The consensus of opinion was that each endotype should meet at least five of these seven criteria [9].

#### **3. Phenotype- and endotype-based biomarkers**

Biomarkers are unique parameters linked to disease endotypes which are estimated for the evaluation of any biologic or pathogenic processes, including responses to therapeutic interventions [5]. Their use has made it possible for novel diagnostic tools and targeted therapies to be developed.

#### **3.1 Phenotype-based inflammatory biomarkers**

Several biomarkers are now veritable sources of information with respect to disease phenotypes and therapeutic responses. The major examples are described as follows:

#### *3.1.1 Inflammatory cells*

Marked blood eosinophilia has been linked to a severe form of late-onset asthma. In fact, blood or sputum eosinophilia is an indicator of Th2-type inflammation in the lungs, while sputum eosinophilia is associated with exacerbations [10, 11] and airway remodeling in asthma [12, 13]. The actions of T-helper 2 (Th2) cells are believed to trigger the stimulation of eosinophilic infiltration into the airways. Eosinophils are made to evolve from an inactive state to a state of increased hyper-responsiveness by priming agents such as these cytokines, interleukin (IL)-3, IL-4, IL-5, and IL-13 [8], and granulocyte-monocyte colony-stimulating factor (GM-CSF) [14]. IL-4 and IL-13 upregulate vascular adhesion molecules and facilitate the migration of eosinophils into tissue sites of inflammation, while IL-5 facilitates differentiation, survival, and chemotaxis of eosinophils [8, 13, 14].

#### *3.1.2 Proteins*

While Th2 cytokines can be assayed from bronchial washings, the approach may not be practicable. Proteins emanating from the bronchus which are linked to Th2 airway inflammation are used as surrogate markers for disease phenotype and endotype. Three genes upregulated by Th2 cytokines (IL-13) have been identified, namely,

**3**

*3.2.1 Allergic asthma*

*Childhood and Adult Asthma: Phenotype- and Endotype-Based Biomarkers*

POSTN, which encodes periostin; CLCA1, which encodes calcium-activated chloride channel regulator 1; and SERPINB2, which encodes serpin peptidase inhibitor, clade B (ovalbumin), member 2 (serpinB2, also known as plasminogen activator inhibitor-2) [13]. Increased levels of these proteins correlate with higher amount of bronchial tissue IL-13 and IL-5 messenger RNA and elevated number of eosinophils and mast cells. Blood levels of periostin have been studied as a surrogate marker for airway eosinophilia and as a method for predicting response to pharmacologic IL-13 blockade with lebrikizumab and anti-IL-13 antibody. The findings of these proteins in subjects with high Th2 also correlate with better response to ICS therapy than Th2-low group. Thus, identification of these proteins is predictive of corticosteroid-responsive asthma.

There is a high differential expression of microRNAs (miRNAs) in the airway epithelium of subjects with asthma as compared with healthy controls [15]. MicroRNAs have been identified as regulators of key biologic processes in epithelial cells such as cell proliferation, cell differentiation, and cell death [16, 17]. Woodruff

There is a moderate correlation between exhaled nitric oxide and bronchial or blood eosinophilia in asthmatics. The enzyme nitric oxide (NO) synthase that produces NO is under direct regulation of IL-13, which is a Th2 cytokine. Elevated FeNO level reflects increased IL-13 activity [22] and indicates the presence of Th2 phenotype. The FeNO is a consistent predictor of a potential steroid responsiveness more than other indices (spirometry, airway hyper-responsiveness to methacholine,

This is a form of persistent asthma which commences in the pediatric-age period. Sensitization to allergens and allergic rhinitis are prominent features. Inhalation of a specific allergen is a stimulus for the acute constriction of bronchial

et al. conducted in vitro experimentation with bronchial epithelial cells and observed that IL-13 had obvious effects on bronchial epithelial miRNA expression and that several of these changes underscored the differences between asthma and health that were seen in humans [13]. Subsequent work focused on constant in vivo and in vitro suppression of four members of the miR-34/449 family (miR-34c-5p, miR- 34c-5p, miR-449a, and miR-449b-5p) in asthma and by IL-13, respectively. These data lend credence to the possible biological role of the miR-34/449 family in airway epithelial cells. It is uncertain whether the potential regulation of miRNAs, or others by IL-13, can be an indicator of a high-Th2 asthma endotype. However, miRNAs possess a relatively distinct characteristic which may qualify them as potential biomarkers. In other words, miRNAs can assume forms in extracellular fluids which are resistant to breakdown by RNases and thus can be estimated in sputum, bronchoalveolar lavage fluid, and blood using PCR, microarrays, and sequencing methods [13]. The following proteins, miR-181a, miR- 146a, and miR-146b, are expressed in spleen CD41 T lymphocytes and probably function as proinflammatory agents in an animal model of asthma [18, 19]. Specifically, there was downregulation of miR-375 in IL-13 transgenic mice and its repression in human bronchial (and esophageal) epithelial cells by IL-13 [20]. In addition, miRNA let-7 possesses a complex but proinflammatory activity in an animal model of the disease [21].

*DOI: http://dx.doi.org/10.5772/intechopen.86006*

*3.1.3 Epithelial microRNAs*

*3.1.4 Exhaled nitric oxide (FeNO)*

bronchodilator response, peak flow variation, etc.) [23].

**3.2 Asthma endotypes and associated biomarkers**

#### *Childhood and Adult Asthma: Phenotype- and Endotype-Based Biomarkers DOI: http://dx.doi.org/10.5772/intechopen.86006*

POSTN, which encodes periostin; CLCA1, which encodes calcium-activated chloride channel regulator 1; and SERPINB2, which encodes serpin peptidase inhibitor, clade B (ovalbumin), member 2 (serpinB2, also known as plasminogen activator inhibitor-2) [13]. Increased levels of these proteins correlate with higher amount of bronchial tissue IL-13 and IL-5 messenger RNA and elevated number of eosinophils and mast cells. Blood levels of periostin have been studied as a surrogate marker for airway eosinophilia and as a method for predicting response to pharmacologic IL-13 blockade with lebrikizumab and anti-IL-13 antibody. The findings of these proteins in subjects with high Th2 also correlate with better response to ICS therapy than Th2-low group. Thus, identification of these proteins is predictive of corticosteroid-responsive asthma.

#### *3.1.3 Epithelial microRNAs*

*Asthma - Biological Evidences*

**2. Asthma phenotypes and endotypes: A snapshot**

**3. Phenotype- and endotype-based biomarkers**

diagnostic tools and targeted therapies to be developed.

**3.1 Phenotype-based inflammatory biomarkers**

*3.1.1 Inflammatory cells*

An endotype is a subtype of a disease recognized by a characteristic pathophysiologic mechanism, whereas a disease phenotype refers to any identifiable characteristic without any evidence of a mechanism [5]. Recent advances in asthma management have tried to group patients by a plethora of possible phenotypic features including age of onset, presence of atopy, airway inflammation and severity of airway obstruction, and the need for drugs. On the basis of the diverse cellular and molecular mechanisms, several phenotypes are currently recognized [6]. Using sputum cytological examination, there is now a classification of the major inflammatory phenotypes into eosinophilic, neutrophilic, mixed-complex inflammation, and pauci-granulocytic phenotypes [7]. Other recognizable phenotypes include early-onset mild allergic asthma, late-onset asthma associated with obesity, and severe nonatopic asthma with frequent exacerbations [8]. Experts from the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma, and Immunology produced the PRACTALL (Practical Allergy) consensus report which proposed the use of parameters such as clinical features, biomarkers, pulmonary physiology, genetics, histopathology, therapeutic response, and epidemiology for characterizing disease endotypes [9]. The consensus of opinion was that each endotype should meet at least five of these seven criteria [9].

Biomarkers are unique parameters linked to disease endotypes which are estimated for the evaluation of any biologic or pathogenic processes, including responses to therapeutic interventions [5]. Their use has made it possible for novel

Marked blood eosinophilia has been linked to a severe form of late-onset asthma. In fact, blood or sputum eosinophilia is an indicator of Th2-type inflammation in the lungs, while sputum eosinophilia is associated with exacerbations [10, 11] and airway remodeling in asthma [12, 13]. The actions of T-helper 2 (Th2) cells are believed to trigger the stimulation of eosinophilic infiltration into the airways. Eosinophils are made to evolve from an inactive state to a state of increased hyper-responsiveness by priming agents such as these cytokines, interleukin (IL)-3, IL-4, IL-5, and IL-13 [8], and granulocyte-monocyte colony-stimulating factor (GM-CSF) [14]. IL-4 and IL-13 upregulate vascular adhesion molecules and facilitate the migration of eosinophils into tissue sites of inflammation, while IL-5 facilitates differentiation, survival, and chemotaxis of eosinophils [8, 13, 14].

While Th2 cytokines can be assayed from bronchial washings, the approach may not be practicable. Proteins emanating from the bronchus which are linked to Th2 airway inflammation are used as surrogate markers for disease phenotype and endotype. Three genes upregulated by Th2 cytokines (IL-13) have been identified, namely,

Several biomarkers are now veritable sources of information with respect to disease phenotypes and therapeutic responses. The major examples are described as follows:

**2**

*3.1.2 Proteins*

There is a high differential expression of microRNAs (miRNAs) in the airway epithelium of subjects with asthma as compared with healthy controls [15]. MicroRNAs have been identified as regulators of key biologic processes in epithelial cells such as cell proliferation, cell differentiation, and cell death [16, 17]. Woodruff et al. conducted in vitro experimentation with bronchial epithelial cells and observed that IL-13 had obvious effects on bronchial epithelial miRNA expression and that several of these changes underscored the differences between asthma and health that were seen in humans [13]. Subsequent work focused on constant in vivo and in vitro suppression of four members of the miR-34/449 family (miR-34c-5p, miR- 34c-5p, miR-449a, and miR-449b-5p) in asthma and by IL-13, respectively. These data lend credence to the possible biological role of the miR-34/449 family in airway epithelial cells. It is uncertain whether the potential regulation of miRNAs, or others by IL-13, can be an indicator of a high-Th2 asthma endotype. However, miRNAs possess a relatively distinct characteristic which may qualify them as potential biomarkers. In other words, miRNAs can assume forms in extracellular fluids which are resistant to breakdown by RNases and thus can be estimated in sputum, bronchoalveolar lavage fluid, and blood using PCR, microarrays, and sequencing methods [13]. The following proteins, miR-181a, miR- 146a, and miR-146b, are expressed in spleen CD41 T lymphocytes and probably function as proinflammatory agents in an animal model of asthma [18, 19]. Specifically, there was downregulation of miR-375 in IL-13 transgenic mice and its repression in human bronchial (and esophageal) epithelial cells by IL-13 [20]. In addition, miRNA let-7 possesses a complex but proinflammatory activity in an animal model of the disease [21].

#### *3.1.4 Exhaled nitric oxide (FeNO)*

There is a moderate correlation between exhaled nitric oxide and bronchial or blood eosinophilia in asthmatics. The enzyme nitric oxide (NO) synthase that produces NO is under direct regulation of IL-13, which is a Th2 cytokine. Elevated FeNO level reflects increased IL-13 activity [22] and indicates the presence of Th2 phenotype. The FeNO is a consistent predictor of a potential steroid responsiveness more than other indices (spirometry, airway hyper-responsiveness to methacholine, bronchodilator response, peak flow variation, etc.) [23].

#### **3.2 Asthma endotypes and associated biomarkers**

#### *3.2.1 Allergic asthma*

This is a form of persistent asthma which commences in the pediatric-age period. Sensitization to allergens and allergic rhinitis are prominent features. Inhalation of a specific allergen is a stimulus for the acute constriction of bronchial smooth muscles and subsequent infiltration of inflammatory cells, usually followed by a late asthmatic presentation [9]. This condition is believed to be sustained by a Th2-dominant inflammation. Airway eosinophilia is a common feature, and the disease comprises a wide spectrum of disease severities and therapeutic responses. The explorations of IL-4/IL-13 pathway modifiers and the effectiveness of omalizumab in severe allergic asthma underscore the role of IgE and Th2 cells/cytokines in this endotype. Children with asthma predictive indices (API) are susceptible to developing asthma and may or may not include the classic"allergic asthma endotype." The API include presentation with recurrent wheezing episodes (more than three episodes in the first 3 years of life) and at least one of the three major criteria (personal atopic dermatitis, parental asthma, or sensitization to an aeroallergen) or two of the three minor criteria (peripheral eosinophils >4%, wheezing unrelated to the common cold, or sensitization to a food allergen) [24, 25]. Patients who fulfilled these criteria at 3 years of age are clearly at increased risk of manifesting with active asthma symptoms at 6 years of age [9, 25].

#### *3.2.2 Allergic bronchopulmonary mycosis (ABPM)*

This condition develops in adults with asthma or in adult/pediatric patients with cystic fibrosis [26]. It is characterized by hypersensitivity reaction to airway colonization by molds, especially *Aspergillus fumigatus* [9, 26]. The main histological feature of ABPM is allergic (eosinophilic) mucin-harboring hyphae in the bronchi, as the induction of the formation of eosinophilic extracellular DNA cell death (ETosis) by viable fungi remains vital [26]. Clinically, ABPM is characterized by episodic bronchial obstruction and mucoid impaction, peripheral blood eosinophilia, elevated serum IgE levels, IgE and IgG antibodies specific for fungi, and typical radiographic findings [9, 26]. A mixed picture of neutrophilic and eosinophilic airway inflammation has also been described [9]. This endotype is characterized by severe bronchial asthma with recurrent exacerbations and progressive lung damage but may respond to systemic glucocorticoids, antifungal agents, and the anti-IgE monoclonal antibody (mAb), omalizumab [9, 26]. Patients develop bronchiectasis and fixed airflow obstruction over time. Early-onset ABPM may be a sequela of the allergic asthma endotype or cystic fibrosis [9].

#### *3.2.3 Aspirin-sensitive asthma (ASA)*

It almost always appears in adulthood and has a distinct clinical presentation, presenting after the intake of a nonsteroidal anti-inflammatory drug (NSAID) [9, 27]. Severe and prolonged airway obstruction is characteristically associated with chronic/severe rhinosinusitis and nasal polyps (aspirin-exacerbated respiratory disease), peripheral blood eosinophilia, and raised urinary leukotrienes at baseline and post-aspirin challenge. Pathophysiologically, ASA has been linked to increased elaboration of cysteinyl leukotriene and increased expression of leukotriene C4 synthase. Cysteinyl leukotriene receptor antagonists and leukotriene C4 synthesis inhibitors ameliorate ASA symptoms although these medications do not protect the patient from NSAID adverse effects [28].

A subgroup of individuals with late-onset asthma in adulthood fulfills the criteria for a distinctive asthma endotype. They constitute about 20% of patients grouped as having refractory asthma and exhibit a typical pattern of severe exacerbations which are circumvented by systemic corticosteroid but not ICS, as well as hyper-eosinophilia in the blood (>1000/mm3 ) and sputum (>10%) [29]. These patients also have a lower prevalence of atopy than the "allergic asthma" endotype [9]. Moreover, the degrees of bronchodilator responsiveness and nonspecific airway hyper-responsiveness may be

**5**

**Table 1.**

*Culled from [9].*

*Childhood and Adult Asthma: Phenotype- and Endotype-Based Biomarkers*

IL-5 therapy may also be effective in this endotype [30, 31].

less than those in the "allergic asthma" endotype. Studies have suggested that anti-

It is defined as episodes of asthma symptoms and/or wheeze closely associated with strenuous skiing-related exercise and concomitant airway hyper-responsiveness. An extremely cold, dry climate promotes the evolution of this type of asthma in comparison with warmer, more humid conditions [32, 33]. Cross-country skiers' asthma is rarely associated with allergic sensitization but is characterized by airway inflammation dominated by elevated numbers of lymphocytes, macrophages, and neutrophils but rarely eosinophils. Lymphoid aggregates in the form of bronchusassociated lymphoid tissue in the mucosa, as well as evidence of airway remodeling with thickening of the reticuloepithelial membrane can be identified in broncho-

Amateur endurance runners had an elevated number of bronchial epithelial cells and apoptosis of bronchial cells in induced sputum evolving through repeated halfmarathon races, in addition to increased serum levels of CC16 and raised supernatant interleukin (IL)-8 levels in induced sputum [34]. Furthermore, urinary levels of CC16 are increased following exercise [35, 36]. Increased expression as measured by polymerase chain reaction (PCR) of the gel-forming mucin, MUC5AC, in induced sputum and levels of supernatant cysteinyl leukotrienes and higher ratio of cysteinyl leukotrienes to prostaglandins have been reported. This endotype is resistant to ICS therapy, but its symptoms often improve with a drop in intensity of training.

Endotypes: allergic asthma (adult)\*, aspirin-sensitive asthma, severe late-onset hyper-

Endotypes: allergic asthma (adult)\*, aspirin-sensitive asthma\*, late-onset hyper-eosinophilic asthma, API-positive preschool wheezers\*, ABPM\*, viral-exacerbated asthma, premenstrual

Endotypes: airflow obstruction caused by obesity, severe steroid-dependent asthma, severe

Endotypes: cross-country skiers' asthma, other forms of elite-athlete asthma, allergic

Endotypes: aspirin-sensitive asthma\*, infection-induced asthma, severe late-onset hyper-

Endotypes: noneosinophilic (neutrophilic) asthma, steroid-insensitive eosinophilic asthma,

**\****NB: asthma phenotypes can be present in more than 1 endotypes and endotypes can contain more than 1 phenotype.*

*DOI: http://dx.doi.org/10.5772/intechopen.86006*

*3.2.4 Cross-country skiers' asthma*

Phenotype Eosinophilic asthma

Phenotype Exacerbation-prone asthma

asthma Phenotype Obesity-related asthma

Phenotype Exercise-induced asthma

eosinophilic asthma\*

Phenotype Poorly steroid-responsive asthma

*Proposed relationship between asthma phenotypes and endotypes.*

Phenotype Adult-onset asthma

Phenotype Fixed airflow limitation

eosinophilic asthma\*, ABPM\*

late-onset hyper-eosinophilic asthma\*

asthma, API-positive preschool wheezers\*

Endotypes: noneosinophilic (neutrophilic) asthma

airflow obstruction caused by obesity

scopic studies.

less than those in the "allergic asthma" endotype. Studies have suggested that anti-IL-5 therapy may also be effective in this endotype [30, 31].

#### *3.2.4 Cross-country skiers' asthma*

*Asthma - Biological Evidences*

asthma symptoms at 6 years of age [9, 25].

*3.2.2 Allergic bronchopulmonary mycosis (ABPM)*

allergic asthma endotype or cystic fibrosis [9].

protect the patient from NSAID adverse effects [28].

*3.2.3 Aspirin-sensitive asthma (ASA)*

smooth muscles and subsequent infiltration of inflammatory cells, usually followed by a late asthmatic presentation [9]. This condition is believed to be sustained by a Th2-dominant inflammation. Airway eosinophilia is a common feature, and the disease comprises a wide spectrum of disease severities and therapeutic responses. The explorations of IL-4/IL-13 pathway modifiers and the effectiveness of omalizumab in severe allergic asthma underscore the role of IgE and Th2 cells/cytokines in this endotype. Children with asthma predictive indices (API) are susceptible to developing asthma and may or may not include the classic"allergic asthma endotype." The API include presentation with recurrent wheezing episodes (more than three episodes in the first 3 years of life) and at least one of the three major criteria (personal atopic dermatitis, parental asthma, or sensitization to an aeroallergen) or two of the three minor criteria (peripheral eosinophils >4%, wheezing unrelated to the common cold, or sensitization to a food allergen) [24, 25]. Patients who fulfilled these criteria at 3 years of age are clearly at increased risk of manifesting with active

This condition develops in adults with asthma or in adult/pediatric patients with cystic fibrosis [26]. It is characterized by hypersensitivity reaction to airway colonization by molds, especially *Aspergillus fumigatus* [9, 26]. The main histological feature of ABPM is allergic (eosinophilic) mucin-harboring hyphae in the bronchi, as the induction of the formation of eosinophilic extracellular DNA cell death (ETosis) by viable fungi remains vital [26]. Clinically, ABPM is characterized by episodic bronchial obstruction and mucoid impaction, peripheral blood eosinophilia, elevated serum IgE levels, IgE and IgG antibodies specific for fungi, and typical radiographic findings [9, 26]. A mixed picture of neutrophilic and eosinophilic airway inflammation has also been described [9]. This endotype is characterized by severe bronchial asthma with recurrent exacerbations and progressive lung damage but may respond to systemic glucocorticoids, antifungal agents, and the anti-IgE monoclonal antibody (mAb), omalizumab [9, 26]. Patients develop bronchiectasis and fixed airflow obstruction over time. Early-onset ABPM may be a sequela of the

It almost always appears in adulthood and has a distinct clinical presentation, presenting after the intake of a nonsteroidal anti-inflammatory drug (NSAID) [9, 27]. Severe and prolonged airway obstruction is characteristically associated with chronic/severe rhinosinusitis and nasal polyps (aspirin-exacerbated respiratory disease), peripheral blood eosinophilia, and raised urinary leukotrienes at baseline and post-aspirin challenge. Pathophysiologically, ASA has been linked to increased elaboration of cysteinyl leukotriene and increased expression of leukotriene C4 synthase. Cysteinyl leukotriene receptor antagonists and leukotriene C4 synthesis inhibitors ameliorate ASA symptoms although these medications do not

A subgroup of individuals with late-onset asthma in adulthood fulfills the criteria for a distinctive asthma endotype. They constitute about 20% of patients grouped as having refractory asthma and exhibit a typical pattern of severe exacerbations which are circumvented by systemic corticosteroid but not ICS, as well as hyper-eosinophilia

prevalence of atopy than the "allergic asthma" endotype [9]. Moreover, the degrees of bronchodilator responsiveness and nonspecific airway hyper-responsiveness may be

) and sputum (>10%) [29]. These patients also have a lower

**4**

in the blood (>1000/mm3

It is defined as episodes of asthma symptoms and/or wheeze closely associated with strenuous skiing-related exercise and concomitant airway hyper-responsiveness. An extremely cold, dry climate promotes the evolution of this type of asthma in comparison with warmer, more humid conditions [32, 33]. Cross-country skiers' asthma is rarely associated with allergic sensitization but is characterized by airway inflammation dominated by elevated numbers of lymphocytes, macrophages, and neutrophils but rarely eosinophils. Lymphoid aggregates in the form of bronchusassociated lymphoid tissue in the mucosa, as well as evidence of airway remodeling with thickening of the reticuloepithelial membrane can be identified in bronchoscopic studies.

Amateur endurance runners had an elevated number of bronchial epithelial cells and apoptosis of bronchial cells in induced sputum evolving through repeated halfmarathon races, in addition to increased serum levels of CC16 and raised supernatant interleukin (IL)-8 levels in induced sputum [34]. Furthermore, urinary levels of CC16 are increased following exercise [35, 36]. Increased expression as measured by polymerase chain reaction (PCR) of the gel-forming mucin, MUC5AC, in induced sputum and levels of supernatant cysteinyl leukotrienes and higher ratio of cysteinyl leukotrienes to prostaglandins have been reported. This endotype is resistant to ICS therapy, but its symptoms often improve with a drop in intensity of training.


#### **Table 1.**

*Proposed relationship between asthma phenotypes and endotypes.*


#### **Table 2.**

*Biomarkers associated with some endotypes.*

Obviously, the pathophysiologic mechanisms underlying the various asthma phenotypes and endotypes are diverse. Thus, the biomarkers of these phenotypes and endotypes are different but may be interwoven since phenotypes may be linked with more than one endotype and vice versa. **Table 1** shows the possible relationship between asthma phenotypes and endotypes, while **Table 2** shows some of the biomarkers associated with disease endotypes.

#### **4. Conclusion**

The pathogenic concept of asthma in childhood and adulthood is changing. Its current concept is that of a heterogeneous and genetically complex disease with several phenotypes presenting with distinct clinical features which are linked to endotypes with different underlying mechanisms and characteristic therapeutic responses. More importantly, the categorization of endotypes in childhood asthma is still evolving as disease classification has now been able to associate phenotypes with endotypes based on airway and serum biomarkers. Better still, there is a potential nexus between disease phenotypes and endotypes or biomarkers, as well as some potential personalized therapeutic options. In the future, endotypes may be used together with specific biomarkers to predict responses to targeted treatments.

**7**

**Author details**

provided the original work is properly cited.

Joy N. Eze1,2 and Samuel N. Uwaezuoke1,2\*

1 College of Medicine, University of Nigeria, Enugu, Nigeria

\*Address all correspondence to: samuel.uwaezuoke@unn.edu.ng

2 University of Nigeria Teaching Hospital, Enugu, Nigeria

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*Childhood and Adult Asthma: Phenotype- and Endotype-Based Biomarkers*

*DOI: http://dx.doi.org/10.5772/intechopen.86006*

*Childhood and Adult Asthma: Phenotype- and Endotype-Based Biomarkers DOI: http://dx.doi.org/10.5772/intechopen.86006*

#### **Author details**

*Asthma - Biological Evidences*

wheezers

(ABPM)

**Table 2.**

**4. Conclusion**

Asthma predictive index preschool

Allergic bronchopulmonary mycosis

*Biomarkers associated with some endotypes.*

biomarkers associated with disease endotypes.

**Endotypes Biomarkers**

Allergic asthma (adults) Positive SPT, elevated IgE/elevated FeNO

Aspirin-sensitive asthma Blood eosinophilia, increased urinary LTEs

*SPT, skin prick test; FeNO, fractional exhaled nitric oxide; IgE, immunoglobulin E; LTEs, leukotrienes.*

Cross-country skiers' asthma FeNO normal, normal blood eosinophil count, increased urinary LTEs

Obviously, the pathophysiologic mechanisms underlying the various asthma phenotypes and endotypes are diverse. Thus, the biomarkers of these phenotypes and endotypes are different but may be interwoven since phenotypes may be linked with more than one endotype and vice versa. **Table 1** shows the possible relationship between asthma phenotypes and endotypes, while **Table 2** shows some of the

The pathogenic concept of asthma in childhood and adulthood is changing. Its current concept is that of a heterogeneous and genetically complex disease with several phenotypes presenting with distinct clinical features which are linked to endotypes with different underlying mechanisms and characteristic therapeutic responses. More importantly, the categorization of endotypes in childhood asthma is still evolving as disease classification has now been able to associate phenotypes with endotypes based on airway and serum biomarkers. Better still, there is a potential nexus between disease phenotypes and endotypes or biomarkers, as well as some potential personalized therapeutic options. In the future, endotypes may be used together with specific biomarkers to predict responses to targeted treatments.

Severe late-onset hyper-eosinophilic asthma Peripheral blood eosinophilia

>4% eosinophil in blood (minor), aeroallergen-specific IgE

Blood eosinophilia, markedly elevated IgE and specific IgE

**6**

Joy N. Eze1,2 and Samuel N. Uwaezuoke1,2\*

1 College of Medicine, University of Nigeria, Enugu, Nigeria

2 University of Nigeria Teaching Hospital, Enugu, Nigeria

\*Address all correspondence to: samuel.uwaezuoke@unn.edu.ng

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[2] Bateman ED, Hurd SS, Barnes PJ, et al. Global strategy for asthma management and prevention: GINA executive summary. The European Respiratory Journal. 2008;**31**(1):143-178. DOI: 10.1183/09031936.00138707

[3] Lockey RF. Asthma phenotypes: An approach to the diagnosis and treatment of asthma. The Journal of Allergy and Clinical Immunology. 2014;**2**(6): 682-685. DOI: 10.1016/j.jaip.2014.09.008

[4] Bierbaum S, Heinzmann A. The genetics of bronchial asthma in children. Respiratory Medicine. 2007;**101**:1369-1375. DOI: 10.1016/j. rmed.2007.01.018

[5] Agache I, Akdis CA. Endotypes of allergic diseases and asthma: An important step in building blocks for the future of precision medicine. Allergology International. 2016;**65**: 243-252. DOI: 10.1016/j.alit.2016.04.011

[6] Papi A, Brightling C, Pedersen SE, Reddel HK. Asthma. Lancet. 2018;**391**(10122):783-800. DOI: 10.1016/ S0140-6736(17)33311-1

[7] Simpson JL, Scott R, Boyle MJ, Gibson PG. Inflammatory subtypes in asthma: Assessment and identification using induced sputum. Respirology. 2006;**11**(1):54-61. DOI: 10.1111/j.1440-1843.2006.00784.x

[8] Corren J. Asthma phenotype and endotypes: An evolving paradigm for classification. Discovery Medicine. 2013;**15**(83):243-249

[9] Lötvall J, Akdis CA, Bacharier LB, et al. Asthma endotypes: A new approach to classification of disease entities within the asthma syndrome. The Journal of Allergy and Clinical Immunology. 2011;**127**(2):355-360. DOI: 10.1016/j.jaci.2010.11.037

[10] Casciano J, Krishnan JA, Small MB, et al. Burden of asthma with elevated blood eosinophil levels. BMC Pulmonary Medicine. 2016;**16**(1):100. DOI: 10.1186/s12890-016-0263-8

[11] Casciano J, Krishnan J, Dotiwala Z, Li C, Sun SX. Clinical and economic burden of elevated blood eosinophils in patients with and without uncontrolled asthma. Journal of Managed Care & Specialty Pharmacy. 2017;**23**(1):85-91. DOI: 10.18553/jmcp.2017.23.1.85

[12] Bergeron C, Tulic MK, Hamid Q. Airway remodeling in asthma: From bench side to clinical practice. Canadian Respiratory Journal. 2010;**17**(4):e85-e94. DOI: 10.1155/2010/318029

[13] Woodruff PG. Subtypes of asthma defined by epithelial cell expression of messenger RNA and MicroRNA. Annals of the American Thoracic Society. 2013;**10**(Suppl):S186-S189. DOI: 10.1513/AnnalsATS.201303-070AW

[14] George L, Brightling CE. Eosinophilic airway inflammation: Role in asthma and chronic obstructive pulmonary disease. Therapeutic Advances in Chronic Disease. 2016;**7**(1):34-51. DOI: 10.1177/2040622315609251

[15] Solberg OD, Ostrin EJ, Love MI, et al. Airway epithelial miRNA expression is altered in asthma. American Journal of Respiratory and Critical Care Medicine. 2012;**186**(10):965-974. DOI: 10.1164/ rccm.201201-0027OC

[16] Corney DC, Flesken-Nikitin A, Godwin AK, Wang W, Nikitin AY.

**9**

*Childhood and Adult Asthma: Phenotype- and Endotype-Based Biomarkers*

[23] Cowan DC, Cowan JO, Palmay R, Williamson A, Taylor R. Effects of steroid therapy on inflammatory cell subtypes in asthma. Thorax. 2010;**65**(5):384-390. DOI: 10.1136/

[24] Castro-Rodríguez JA, Holberg CJ, Wright AL, Martinez FD. A clinical index to define risk of asthma in young children with recurrent wheezing. American Journal of Respiratory and Critical Care Medicine. 2000;**162**: 1403-1406. DOI: doi.org/10.1164/

[25] Castro-Rodriguez JA, Santiago P. The asthma predictive index: A very useful tool for predicting asthma in young children. The Journal of Allergy and Clinical Immunology.

[26] Asano K, Kamei K, Hebisawa A. Allergic bronchopulmonary mycosis—Pathophysiology, histology, diagnosis, and treatment. Asia Pacific Allergy. 2018;**8**(3):e24. DOI: 10.5415/

[27] Morwood K, Gillis D, Smith W, Kette F. Aspirin-sensitive asthma. Internal Medicine Journal. 2005;**35**(4):240-246. DOI: doi.

org/10.1111/j.1445-5994.2004.00801.x

[28] Dahlén B, Nizankowska E, Szczeklik A, et al. Benefits from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirinintolerant asthmatics. American

Journal of Respiratory and Critical Care Medicine. 1998;**157**(4 Pt 1):1187-1194. DOI: 10.1164/ajrccm.157.4.9707089

[29] Haldar P, Pavord ID, Shaw DE, et al. Cluster analysis and clinical asthma phenotypes. American Journal of Respiratory and Critical Care Medicine.

thx.2009.126722

ajrccm.162.4.9912111

2010;**126**:212-216

apallergy.2018.8.e24

2008;**178**(3):218-224

[30] Nair P, Pizzichini MMM,

Kjarsgaard M, et al. Mepolizumab for

*DOI: http://dx.doi.org/10.5772/intechopen.86006*

MicroRNA-34b and MicroRNA-34c are targets of p53 and cooperate in control of cell proliferation and adhesion-independent growth. Cancer Research. 2007;**67**(18):8433-8438. DOI: 10.1158/0008-5472.CAN-07-1585

[17] Liu X, Nelson A, Wang X, et al. MicroRNA-146a modulates human bronchial epithelial cell survival in response to the cytokineinduced apoptosis. Biochemical and Biophysical Research Communications. 2009;**380**(1):177-182. DOI: 10.1016/j.

[18] Simpson LJ, Patel S, Bhakta NR, et al. A miRNA upregulated in asthma airway T cells promotes T H 2 cytokine production HHS public access. Nature Immunology. 2014;**15**(12):1162-1170.

[19] Liu Y, Chen Z, Xu K, et al. Next generation sequencing for miRNA profile of spleen CD4 + T cells in the murine model of acute asthma. Epigenomics. 2018;**10**(8):1071-1083. DOI: doi.org/10.2217/epi-2018-0043

[20] Lu TX, Lim E-J, Wen T, et al. MiR-375 is down-regulated in epithelial cells after IL-13 stimulation and regulates an IL-13 induced epithelial transcriptome. Mucosal Immunology. 2012;**5**(4): 388-396. DOI: 10.1038/mi.2012.16

[21] Polikepahad S, Knight JM, Naghavi AO, et al. Proinflammatory role for let-7 MicroRNAs in experimental asthma. The Journal of Biological Chemistry. 2010;**285**(39):30139-30149. DOI:

[22] Chibana K, Trudeau JB. Mustovitch, et al. IL-13 induced increases in nitrite levels are primarily driven by increases in inducible nitric oxide synthase as compared with effects on arginases in human primary bronchial epithelial cells. Clinical and Experimental Allergy. 2008;**38**(6):936-946. DOI: 10.1111/j.1365-2222.2008.02969.x

10.1074/jbc.M110.145698

bbrc.2009.01.066

DOI: 10.1038/ni.3026

*Childhood and Adult Asthma: Phenotype- and Endotype-Based Biomarkers DOI: http://dx.doi.org/10.5772/intechopen.86006*

MicroRNA-34b and MicroRNA-34c are targets of p53 and cooperate in control of cell proliferation and adhesion-independent growth. Cancer Research. 2007;**67**(18):8433-8438. DOI: 10.1158/0008-5472.CAN-07-1585

[17] Liu X, Nelson A, Wang X, et al. MicroRNA-146a modulates human bronchial epithelial cell survival in response to the cytokineinduced apoptosis. Biochemical and Biophysical Research Communications. 2009;**380**(1):177-182. DOI: 10.1016/j. bbrc.2009.01.066

[18] Simpson LJ, Patel S, Bhakta NR, et al. A miRNA upregulated in asthma airway T cells promotes T H 2 cytokine production HHS public access. Nature Immunology. 2014;**15**(12):1162-1170. DOI: 10.1038/ni.3026

[19] Liu Y, Chen Z, Xu K, et al. Next generation sequencing for miRNA profile of spleen CD4 + T cells in the murine model of acute asthma. Epigenomics. 2018;**10**(8):1071-1083. DOI: doi.org/10.2217/epi-2018-0043

[20] Lu TX, Lim E-J, Wen T, et al. MiR-375 is down-regulated in epithelial cells after IL-13 stimulation and regulates an IL-13 induced epithelial transcriptome. Mucosal Immunology. 2012;**5**(4): 388-396. DOI: 10.1038/mi.2012.16

[21] Polikepahad S, Knight JM, Naghavi AO, et al. Proinflammatory role for let-7 MicroRNAs in experimental asthma. The Journal of Biological Chemistry. 2010;**285**(39):30139-30149. DOI: 10.1074/jbc.M110.145698

[22] Chibana K, Trudeau JB. Mustovitch, et al. IL-13 induced increases in nitrite levels are primarily driven by increases in inducible nitric oxide synthase as compared with effects on arginases in human primary bronchial epithelial cells. Clinical and Experimental Allergy. 2008;**38**(6):936-946. DOI: 10.1111/j.1365-2222.2008.02969.x

[23] Cowan DC, Cowan JO, Palmay R, Williamson A, Taylor R. Effects of steroid therapy on inflammatory cell subtypes in asthma. Thorax. 2010;**65**(5):384-390. DOI: 10.1136/ thx.2009.126722

[24] Castro-Rodríguez JA, Holberg CJ, Wright AL, Martinez FD. A clinical index to define risk of asthma in young children with recurrent wheezing. American Journal of Respiratory and Critical Care Medicine. 2000;**162**: 1403-1406. DOI: doi.org/10.1164/ ajrccm.162.4.9912111

[25] Castro-Rodriguez JA, Santiago P. The asthma predictive index: A very useful tool for predicting asthma in young children. The Journal of Allergy and Clinical Immunology. 2010;**126**:212-216

[26] Asano K, Kamei K, Hebisawa A. Allergic bronchopulmonary mycosis—Pathophysiology, histology, diagnosis, and treatment. Asia Pacific Allergy. 2018;**8**(3):e24. DOI: 10.5415/ apallergy.2018.8.e24

[27] Morwood K, Gillis D, Smith W, Kette F. Aspirin-sensitive asthma. Internal Medicine Journal. 2005;**35**(4):240-246. DOI: doi. org/10.1111/j.1445-5994.2004.00801.x

[28] Dahlén B, Nizankowska E, Szczeklik A, et al. Benefits from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirinintolerant asthmatics. American Journal of Respiratory and Critical Care Medicine. 1998;**157**(4 Pt 1):1187-1194. DOI: 10.1164/ajrccm.157.4.9707089

[29] Haldar P, Pavord ID, Shaw DE, et al. Cluster analysis and clinical asthma phenotypes. American Journal of Respiratory and Critical Care Medicine. 2008;**178**(3):218-224

[30] Nair P, Pizzichini MMM, Kjarsgaard M, et al. Mepolizumab for

**8**

*Asthma - Biological Evidences*

[1] Asher I, Pearce N. Global burden of asthma among children. The International Journal of Tuberculosis and Lung Disease. 2014;**18**(11): 1269-1278. DOI: 10.5588/ijtld.14.0170

approach to classification of disease entities within the asthma syndrome. The Journal of Allergy and Clinical Immunology. 2011;**127**(2):355-360. DOI:

[10] Casciano J, Krishnan JA, Small MB, et al. Burden of asthma with elevated blood eosinophil levels. BMC Pulmonary Medicine. 2016;**16**(1):100. DOI: 10.1186/s12890-016-0263-8

[11] Casciano J, Krishnan J, Dotiwala Z, Li C, Sun SX. Clinical and economic burden of elevated blood eosinophils in patients with and without uncontrolled asthma. Journal of Managed Care & Specialty Pharmacy. 2017;**23**(1):85-91. DOI: 10.18553/jmcp.2017.23.1.85

[12] Bergeron C, Tulic MK, Hamid Q. Airway remodeling in asthma: From bench side to clinical practice. Canadian Respiratory Journal. 2010;**17**(4):e85-e94.

[13] Woodruff PG. Subtypes of asthma defined by epithelial cell expression of messenger RNA and MicroRNA. Annals of the American Thoracic Society. 2013;**10**(Suppl):S186-S189. DOI: 10.1513/AnnalsATS.201303-070AW

DOI: 10.1155/2010/318029

[14] George L, Brightling CE. Eosinophilic airway inflammation:

Role in asthma and chronic obstructive pulmonary disease. Therapeutic Advances in Chronic Disease. 2016;**7**(1):34-51. DOI: 10.1177/2040622315609251

[15] Solberg OD, Ostrin EJ, Love MI, et al. Airway epithelial miRNA expression is altered in asthma. American Journal of Respiratory and Critical Care Medicine.

2012;**186**(10):965-974. DOI: 10.1164/

[16] Corney DC, Flesken-Nikitin A, Godwin AK, Wang W, Nikitin AY.

rccm.201201-0027OC

10.1016/j.jaci.2010.11.037

[2] Bateman ED, Hurd SS, Barnes PJ, et al. Global strategy for asthma management and prevention: GINA executive summary. The European Respiratory Journal. 2008;**31**(1):143-178.

DOI: 10.1183/09031936.00138707

[3] Lockey RF. Asthma phenotypes: An approach to the diagnosis and treatment of asthma. The Journal of Allergy and Clinical Immunology. 2014;**2**(6):

682-685. DOI: 10.1016/j.jaip.2014.09.008

[4] Bierbaum S, Heinzmann A. The genetics of bronchial asthma in children. Respiratory Medicine. 2007;**101**:1369-1375. DOI: 10.1016/j.

[5] Agache I, Akdis CA. Endotypes of allergic diseases and asthma: An important step in building blocks for the future of precision medicine. Allergology International. 2016;**65**: 243-252. DOI: 10.1016/j.alit.2016.04.011

[6] Papi A, Brightling C, Pedersen SE, Reddel HK. Asthma. Lancet. 2018;**391**(10122):783-800. DOI: 10.1016/

S0140-6736(17)33311-1

2013;**15**(83):243-249

[7] Simpson JL, Scott R, Boyle MJ, Gibson PG. Inflammatory subtypes in asthma: Assessment and identification using induced sputum. Respirology. 2006;**11**(1):54-61. DOI: 10.1111/j.1440-1843.2006.00784.x

[8] Corren J. Asthma phenotype and endotypes: An evolving paradigm for classification. Discovery Medicine.

[9] Lötvall J, Akdis CA, Bacharier LB, et al. Asthma endotypes: A new

rmed.2007.01.018

**References**

prednisone-dependent asthma with sputum eosinophilia. The New England Journal of Medicine. 2009;**360**(10): 985-993. DOI: 10.1056/NEJMoa0805435

[31] Nair P, O'Byrne PM. Measuring Eosinophils to make treatment decisions in asthma. Chest. 2016;**150**(3):485-487. DOI: doi.org/10.1016/j.chest.2016.07.009

[32] Carlsen KH. Mechanisms of asthma development in elite athletes. Breathe. 2012;**8**(4):279-284. DOI: 10.1183/20734735.009512

[33] Carlsen KH, Lødrup-Carlsen KC. Asthma and the Olympics. The Journal of Allergy and Clinical Immunology. 2016;**138**(2):409-410

[34] Chimenti L, Morici G, Paternò A, et al. Bronchial epithelial damage after a half-marathon in nonasthmatic amateur runners. American Journal of Physiology. Lung Cellular and Molecular Physiology. 2010;**298**:857-862. DOI: 10.1152/ajplung.00053.2010

[35] Bolger C, Tufvesson E, Anderson SD, et al. Effect of inspired air conditions on exercise-induced bronchoconstriction and urinary CC16 levels in athletes. Journal of Applied Physiology. 2011;**111**:1059-1065. DOI: 10.1152/japplphysiol.00113.2011

[36] Bolger C, Tufvesson E, Sue-Chu M, et al. Hyperpnoea-induced bronchoconstriction and urinary CC16 levels in athletes. Medicine and Science in Sports and Exercise. 2011;**43**(7):1207-1213. DOI: 10.1249/ MSS.0b013e31820750d8

**11**

**Chapter 2**

**Abstract**

spirometry.

**1. Introduction**

management of asthma.

Oscillometry

Clinical Applications of Impulse

Impulse oscillometry is a noninvasive procedure that can be performed within few minutes. The purpose of the procedure is to measure the resistance of the small and large airways, as well as the reactants of the airways. It is gradually gaining popularity in evaluating lung function, particularly in patients with asthma and COPD. In contrast to spirometry, the test performs measurement during tidal breathing. In other words, forced exhalation is not required. Other advantages include, but are not limited to, evaluating COPD patients' reversibility which is rarely noted on spirometry. IOS also is tool for chronic management of patients with asthma and COPD while on treatment. It can evaluate children with asthma even as young as 2 years old. Spirometry requires the child to cooperate and usually is of meaningful use beginning at the age of 5 years old. Other potential applications include early evaluation of transplant rejection, cystic fibrosis, and vocal cord disorder. In this chapter, we will explore the procedure itself, the settings, advantages and disadvantages, and comparative data with

The expert panel 3 of the National Asthma Education and Prevention Program defines asthma as "a common chronic disorder of the airways that is complex and characterized by variable and recurring symptoms, airflow obstruction, bronchial hyperresponsiveness, and an underlying inflammation. The interaction of these features of asthma determines the clinical manifestations and severity of asthma and the response to treatment." This definition allows for incorporation of the clinical, physiological, and pathological findings of asthma. Traditional spirometry, while the gold standard, can be unreliable in pediatric patients and is dependent on patient effort. Impulse oscillometry is a clinical tool that is independent of patient effort and allows for diagnosis and management of pediatric and adult patients with asthma. IOS can enhance the clinical evaluation for patients with asthma. IOS is a technique that measures airway impedance (resistance and reactance). IOS is a noninvasive technique that is beneficial either as a single modality or in combination with traditional spirometry for patients in the diagnosis and

*Constantine Saadeh and Nicole Davey-Ranasinghe*

**Keywords:** impulse oscillometry, spirometry, asthma, COPD

#### **Chapter 2**

*Asthma - Biological Evidences*

prednisone-dependent asthma with sputum eosinophilia. The New England Journal of Medicine. 2009;**360**(10): 985-993. DOI: 10.1056/NEJMoa0805435

[31] Nair P, O'Byrne PM. Measuring Eosinophils to make treatment decisions in asthma. Chest. 2016;**150**(3):485-487. DOI: doi.org/10.1016/j.chest.2016.07.009

[32] Carlsen KH. Mechanisms of asthma development in elite athletes. Breathe. 2012;**8**(4):279-284. DOI:

[33] Carlsen KH, Lødrup-Carlsen KC. Asthma and the Olympics. The Journal of Allergy and Clinical Immunology. 2016;**138**(2):409-410

[34] Chimenti L, Morici G, Paternò A, et al. Bronchial epithelial damage after a half-marathon in nonasthmatic amateur runners. American Journal of Physiology. Lung Cellular and Molecular Physiology. 2010;**298**:857-862. DOI:

[35] Bolger C, Tufvesson E, Anderson SD, et al. Effect of inspired air conditions on exercise-induced

bronchoconstriction and urinary CC16 levels in athletes. Journal of Applied Physiology. 2011;**111**:1059-1065. DOI: 10.1152/japplphysiol.00113.2011

[36] Bolger C, Tufvesson E, Sue-Chu M, et al. Hyperpnoea-induced bronchoconstriction and urinary CC16 levels in athletes. Medicine and Science in Sports and Exercise. 2011;**43**(7):1207-1213. DOI: 10.1249/

MSS.0b013e31820750d8

10.1152/ajplung.00053.2010

10.1183/20734735.009512

**10**
