Asthma in the 21st Century: New Research Advances

Asthma in the 21st Century: New Research Advances provides an overview on asthma, with discussions on its heterogeneity, risk factors and their interrelations, and e-health in an aging world based on current research knowledge. The book covers heterogeneity of the disease beyond severe asthma, new risk factors, new diagnoses with climate change, a focus on chemical exposures at home, e-health and links with aging, and notable advances in key areas such as diet and microbiota, the genetics of asthma, and the asthma versus COPD debate.

Worldwide, the total number of asthma sufferers is estimated to be ~270 million with an additional 100 million expected to develop asthma by 2025, and asthma is the most common chronic disease among children. There are a number of clinical books available on asthma, but none with much discussion on current scientific findings and new disease understanding. Yet, the concept of asthma has evolved quickly in the past 5–10 years, with many clinicians struggling to keep up with new scientific findings.

• Offers an overall view of asthma and addresses notable advances in key areas such as diet and the microbiota, the genetics of asthma, and asthma-COPD overlap syndrome
• Covers hot topics such as heterogeneity of asthma beyond severe asthma, new risk factors, more common complications with climate change, a focus on chemical exposures at home, e-health, and links with frailty in an aging world
• Provides a deep understanding of a multifactorial, complex, and heterogeneous chronic inflammatory disease known as asthma

• Language: English
• Publisher: Academic Press
• Release date: Sep 8, 2022
• ISBN: 9780323854207

Book preview

Chapter 1

Asthma: From one disease to endotypes

Rachel Nadifa, Marine Savouréa,b

a Université Paris‐Saclay, UVSQ, Univ. Paris‐Sud, Inserm, Equipe d’Epidémiologie Respiratoire Intégrative, CESP, Villejuif, France,

b French Environment and Energy Management Agency, Angers, France

1.1 Introduction

Asthma is–with the Chronic Obstructive Pulmonary Disease (COPD)–the most common chronic respiratory disease of the airways and other structures of the lung [1]: it affects ∼273 million people worldwide [2,3], and is the most common chronic disease among children [4].

Asthma is a disease manifesting with clinical symptoms of wheezing, shortness of breath, tightness, and cough. Asthma is also a heterogeneous disease with key aspects coming from the variability of the severity and expression of the symptoms from one person to another and over a lifetime [5]. Throughout history, the concept of asthma has hugely evolved and become increasingly complex from a singular disease to phenotypes then to endotypes. Asthma encompasses numerous and various observable characteristics called phenotypes that may vary, persist, remit or relapse. A better understanding of these phenotypes, in particular, their specific clinical presentation would enhance our understanding and management of the disease [6]. However, the study of these phenotypes alone does not offer insight into the underlying pathophysiology of the disease. Despite a similar clinical picture, distinct underlying etiologies for asthma may confer divergent natural histories and treatment responses. In 2018, the Lancet Commission recommended deconstructing asthma into component parts before planning treatment, focusing in particular on treatable traits/characteristics [7]. Identifying treatable traits/characteristics with specific clinical or molecular characteristics that could be targeted with treatment will help to understand which asthma subtype–also called endotype–a patient has and how it should be treated. Thus, there has been a recent impetus to decipher underlying asthma pathobiological mechanisms/endotypes through molecular and omics techniques, due to the advent of precision medicine strategies for the treatment of asthma. Over the last decade, studies mainly focused on patients with severe asthma who do not fully respond to currently available medications [8–10], and several clustering approaches have been used to identify asthma endotypes. However, identifying relevant asthma endotypes is a challenging issue and there is still an unmet need to identify and characterize distinct asthma endotypes beyond type 2 (T2) asthma and beyond severe asthma [11,12].

This chapter describes the history of the word asthma over time and the evolution of asthma from one disease to endotypes. It introduces the current epidemiology of asthma and describes childhood and adult asthma phenotypes and endotypes.

1.2 History of asthma

The word asthma comes to us from the Greek word ἄσθμα, ásthma, through the Latin language. It means a short-drawn breath, panting, or labored breathing. For a long time, asthma was considered and treated more as a symptom than as a condition.

1.2.1 From antiquity to the 19th century

The history of the word asthma is described in detail by Roger Ellul-Micallef in the first chapter of volume 1 of the book ASTHMA published in 1997 [13]. To briefly summarize this long history, let's start with Ebell who identified in the Ebers papyrus from Ancient Egyptians (c. 1550 Before Christ (B.C.)) a list of remedies to treat cough, wheezing, and expectorations [14]. Later, Hippocrates (460–377 B.C.) suggested that asthma could be an inherited condition [15]. According to Elluf-Micallef, the best account of the condition in ancient times is that of Aretaeus (2nd century After Christ (A.C.)), a Greek physician who classified asthma as a disease [16]. Among other works of importance, Paulus Aegineta (625–690 A.C.), a Byzantine doctor who owed a lot of his predecessors including Galen, transmitted the knowledge on asthma through his seven books of Medicine [17].

Then, from the 7th century, the knowledge of asthma from the Hellenistic culture were preserved through Arabic writings. Abù-Ali al-Husayn ibn-Abd-Allãh ibn-Sinã, known as Avicenne, and Abù-Imrãn Mùsã ibn Ubayd-Allah ibn-Maymùn, known as Maimonides are among the best following Arabic writers. In his treatise on asthma [18], Maimonides pointed out that asthma should be treated according to its various causes, and recommended to Saladin to move from the humid air of Alexandria to the dry one of Cairo for better health for his son suffering from asthma. He advised the patients on hygiene, recommended medicines, and the best diet to follow, an echo of the modern recommendations for asthma treatment. This knowledge was translated into Latin and, from around the 11th century, have influenced Medieval medicines, especially those of the Europe of the Middle Ages.

No evolution of asthma seems to be of interest until the 19th century [13] when the French clinician René Laennec helped to clarify the nature and diagnosis of asthma by using the stethoscope he invented. He was convinced that bronchospasm is an essential characteristic of asthma, a hypothesis that was later confirmed experimentally. The 19th century also brings up the work of Charles Turner Thackrah who gave a list of occupations associated with asthma [19], and Henry Hyde Salter who—before the concept of allergy–pointed out that animal and vegetable emanations could precipitate an asthmatic attack [20]. Let's note that at the end of the 19th century and the beginning of the 20th century, by using the microscope, the Charcot-Leyden crystals, the eosinophils, and the mast cells will be identified in the induced sputum from asthmatic patients [13].

1.2.2 The modern ERA: From the 20th century to the present time

During the 20th century, advances in asthma knowledge came from the development of sciences, in particular in the area of medicine. The main advances were the description of the allergic component of asthma, the introduction of the term atopy to describe a hypersensitivity to allergens that are dependent on heredity, and last but not least, the discovery of the sensitized agent that mediates such hypersensitivity as the fifth immunoglobulin (Ig) class–IgE–at the end of 60s (see [13,21] and section 2.3 for more details).

The recognition of the allergic component of asthma further led to a large number of researches on the identification of allergic triggers including pollen grains, fungal spore, house-dust mite, chemicals, and drugs. Extensive works on the measurement of hyper-responsiveness were done, and one reported the fall in vital capacity in asthmatics after exposure to aerosolized pollen extracts. The role of eosinophils in asthma was also highlighted. At the same time, modern drug therapy was born (Chapter 1 vol. 1 and Chapter 11 vol. 2 of ASTHMA [13] for more details), and according to Ellul-Micallef, the first publication on an improvement of lung function in asthmatics following glucocorticoids administration appeared in 1974. The evolution of the concept of asthma is summarized in Fig. 1.1 on next page.

Fig. 1.1 Evolution of asthma concept from ancient history to nowadays.

Currently, the studies on phenotypes and endotypes of asthma are in the same line as the past objectives which aimed to better understand the asthma disease and better manage it. Before exploring the phenotyping and endotyping era of asthma, and to better addressing it, the clinical and epidemiological aspects of asthma are presented in the next section.

1.3 Clinical and epidemiological aspects of asthma

"How to define asthma?" is a key question to understanding the epidemiology, pathophysiology, and etiology of asthma. However, a consensus on the definition of asthma is a real challenge [22], especially in epidemiology.

1.3.1 Clinical aspects of asthma

The Global Initiative for Asthma (GINA) aims to improve the diagnosis, management, and prevention of asthma by providing an up-to-date evidence-based strategy and tools, and practical resources for clinicians worldwide. According to the latest report of GINA [23], asthma is a heterogeneous disease, usually characterized by chronic airway inflammation. It is defined by the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness, and cough that vary over time and in intensity, together with variable expiratory airflow. Variable expiratory airflow limitation means that expiratory lung function varies over time and in magnitude, to a greater extent than in healthy populations. In asthma, lung function may vary between completely normal and severely obstructed in the same patient, and poorly controlled asthma is associated with greater variability in lung function than well-controlled asthma.

According to GINA, Lung function testing should be carried out by well-trained operators with well-maintained and regularly calibrated equipment. Forced expiratory volume in 1 second (FEV1) from spirometry is more reliable than peak expiratory flow (PEF). If PEF is used, the same meter should be used each time, as measurements may differ from meter to meter by up to 20%. A reduced FEV1 may be found with many other lung diseases (or poor spirometric technique), but a reduced ratio of FEV1 to forced vital capacity (FEV1/FVC), compared with the lower limit of normal, indicates expiratory airflow limitation. Many spirometers now include multiethnic age-specific predicted values. In clinical practice, once an obstructive defect has been confirmed, variation in airflow limitation is generally assessed from variation in FEV1 or PEF. Variability refers to improvement and/or deterioration in symptoms and lung function. Excessive variability may be identified over the course of one day (diurnal variability), from day to day, from a visit to visit, seasonally, or from a reversibility test. Reversibility (also called responsiveness) generally refers to rapid improvements in FEV1 (or PEF), measured within minutes after inhalation of a rapid-acting bronchodilator such as 200–400 mcg salbutamol, or more sustained improvement over days or weeks after the introduction of effective controller treatment such as Inhaled Corticosteroids (ICS). The variations over time and in the intensity of symptoms and airflow limitation are often triggered by factors such as exercise, allergen or irritant exposure, change in weather, or viral respiratory infections. Symptoms and airflow limitation may resolve spontaneously or in response to medication, and may sometimes be absent for weeks or months at a time. On the other hand, patients can experience episodic flare-ups (exacerbations) of asthma that may be life-threatening and carry a significant burden on patients and the community. Asthma is usually associated with airway hyper-responsiveness to direct or indirect stimuli, and chronic airway inflammation. These features usually persist, even when symptoms are absent or lung function is normal but may normalize with treatment.

The paper by Reddel et al. [24] summarizes in detail the key recommendations from GINA 2021 and covers the diagnosis of asthma according to age, the establishment of personalized assess-treat-review cycles, the comprehensive care of asthma including treatment of modifiable risk factors and comorbidities, the treatment with ICS-containing therapy, the treatment of children less than 5 years old, the phases of stepping up and down to control symptoms or prevent exacerbations, and the written of a personalized asthma action plan for each patient, tailored to his/her health literacy, so he/she knows how to recognize and respond to worsening asthma. The main key changes relate to the clarification of the definition of severe asthma, the revision of the treatment recommendations for adults and children, the recommendation for primary prevention in children, and updated advice for managing asthma during the Corona Virus Disease 2019 (COVID-19) pandemic [25]. One part of the GINA report is also devoted to the diagnosis and initial treatment of patients with features of both asthma and COPD. Indeed, distinguishing asthma from COPD can be difficult, and both diseases can be viewed as distinct or components of a continuum, Chapter 9 of the book faces this question.

By addressing the comprehensive care of asthma including treatment of modifiable risk factors and comorbidities such as rhinitis or obesity, occupational asthma, specific populations/settings or periods of life such as adolescents or elderly, asthma during pregnancy in low-resource settings, and recommendations for primary prevention of asthma in children, the GINA report fits with some epidemiological aspects of asthma.

1.3.2 Epidemiological aspects of asthma

As previously said, asthma affects ∼273 million people worldwide [2] and is the most common chronic disease among children [4]. The prevalence rates of asthma vary over life, and among others, according to gender (see Chapter 4 for details), incomes and countries. Indeed, according to the 2017 Global Burden of diseases, the global prevalence rate of asthma ranged from 2.06% (95% CI 1.80%–2.35%) in South Africa to 12.1% (10.4%–13.9%) in Tonga [3].

1.3.2.1 Asthma definitions in epidemiology

Various childhood and adult asthma definitions have been used in epidemiological studies [26]. Among children younger than 6 years old, asthma is difficult to diagnose, and asthma is often defined by wheezing episodes characterized by their start date (early or late infancy) and/or their duration (transient or persistent) [27,28]. Among children aged between 6 and 18 years, an overview of the operational definitions to diagnose asthma reported 60 different definitions from 122 cohort studies published between 1998 and 2008 [29]. Half of the cohorts used a definition based on a doctor's diagnosis of asthma with or without other symptoms or medication use whatever the reference period (ever-, last 12 months, or others); one-third used a definition which was a combination of symptoms, (doctor's) diagnosis of asthma and asthma medication use; 11% included bronchial hyper-responsiveness or spirometry in the definition and 8% of the studies used definition based on symptoms alone. The symptoms were cough (nocturnal or not), chest tightness, and/or whistling/wheezing/wheeze. A recent review confirms these results [30]. Similarly, among adults, several definitions of asthma exist, most of them based on standardized questionnaires.

In epidemiological studies on large populations, the questionnaire is the preferred tool to identify participants with asthma. In the 1990th, based on the International Union Against Tuberculosis and Lung Disease questionnaire [31], two standardized questionnaires devoted to asthma and asthma-like symptoms have been developed, one by the International Study of Asthma and Allergies in Childhood (ISAAC) for children [32], and one by the European Community Respiratory Health Survey (ECRHS) for adults [33].

The dichotomous measure (yes/no) is the most widely used definition in epidemiological studies to assess incidence or prevalence of asthma. In ISAAC and ECRHS, questions on wheezing were available. In ISAAC and ECRHS, the positive answer to "Have you ever had asthma? defined ever-asthma. The subsidiary positive answer to Was this confirmed by a doctor?" defined doctor/physician-diagnosed asthma. Even if a doctor/physician-diagnosed asthma is considered the most reliable and used definition, asthma remains underdiagnosed, and population-based studies reported that in pediatric and adult populations having current asthma, the prevalence of undiagnosed asthma varies between 20% and 73% [34].

To assess asthma activity/control through middle-term and short-term measures, current asthma and the asthma control test (ACT) are useful widely used tools. Current asthma is defined according to the status of the disease during the past 12 months. According to ECRHS II, a participant who reported a doctor/physician's diagnosis of asthma and who had respiratory symptoms (wheeze; nocturnal chest tightness; attack of breathlessness after activity, at rest, or at night; or asthma attack) or had used asthma medications in the previous 12 months was considered as having current asthma [35]. There are other definitions of current asthma that include the three domains of asthma attacks/symptoms and treatment differently, but the definition from ECRHS is the most widely used in epidemiological settings. The ACT is a tool based on a questionnaire with five items assessing asthma symptoms (daytime and nocturnal), use of rescue medications, and the effect of asthma on daily functioning during the last 4 weeks [36]. Each item includes five response options corresponding to a five-point rating scale. Responses for each of the five items are summed to yield a score ranging from five (poor control of asthma) to 25 (complete control of asthma).

Asthma is, however, like many other chronic diseases, not a true dichotomy, and a continuous measure of asthma–the asthma symptom score–has been proposed by Pekkanen et al. [37]. The original version of the score includes eight questions regarding five symptoms in the past 12 months, ever asthma, attacks of asthma, and asthma medication. Two years later, an updated version including only the questions on the five symptoms was proposed [38], showing almost the same internal consistency as the original one. Table 1.1 summarizes the main definitions of asthma discussed above.

Table 1.1

1.3.2.2 Respiratory symptoms and asthma prevalence rates

The ISAAC, the International Study of Wheezing in Infants (ISW), the ECRHS, and the World Health Survey (WHS) were the largest and widest sources of data worldwide to compare asthma prevalence rates between countries, ISAAC and WHS covering all the regions of the world. Furthermore, ISAAC (1996–1997 and 2002–2003) and ISW (2005 and 2012) had undertaken a second cross-sectional population survey. The recent review by Asher et al. [39] summarizes and discusses these data and the time trends in asthma prevalence.

Among children, data from the ISAAC phase 1 (1994–1995) involved over 700,000 adolescents and children from 156 centers and 56 countries, 91 centers for the 6–7 years old age group and 155 centers for the 13–14 years old age group [40]. Among the 6–7 years old age group, for the positive answer to the question on current wheezing (CW), there was a fivefold difference in prevalence between countries (4.1%–32.1%), with the lowest rates in India, Indonesia, Iran, and Malaysia and highest rates in Australia, Brazil, Costa Rica, New Zealand, and Panama. Among the 13–14 years old group, for the positive answer to the question on CW, there was a very wide range of prevalence, up to 15-fold differences between countries, ranging from 2.1% to 4.4% in Albania, China, Greece, Georgia, Indonesia, Romania, and Russia, to 29.1% to 32.2% in Australia, New Zealand, Republic of Ireland and the United Kingdom (UK). The Worldwide time trends in the prevalence of symptoms of asthma from ISAAC phase one to three were published in 2006 [41]: in the 6–7 years old age-group, the prevalence of asthma symptoms changed by 1 standard error (SE) or more in most centers (59%). Of the 39 centers with changes, prevalence increased in 25 and decreased in 14, and increases occurred more often than decreases for all levels of mean prevalence. In the 13–14 years old age-group, the prevalence of asthma symptoms changed by one SE or more in most centers (77%). Of the 82 centers with changes, about equal numbers showed an increase [42] and a decrease [40] in prevalence. For lower mean prevalence values, more centers showed increases in the prevalence of 1 SE or more, but for centers with higher mean prevalence, decreases in prevalence of one SE or more were more common. As noted by Asher et al. [39], time trends between ISAAC phases 1–3 show increases in asthma symptom prevalence in the most populous parts of the world where prevalence was previously low (Africa, Latin America, and parts of Asia), indicating that the global burden of asthma is continuing to rise.

Using a methodology partially based on that employed in the ISAAC, the ISW included in 2005 30,093 children aged 12–15 months from 17 centers in Latin America (LA) and Europe (EU) [42]. In the whole sample, 45.2% of infants wheezed at least once during their first year of life; 16.7% of them had their first episode of wheezing during the first 3 months of life, 20.3% had recurrent wheezing (RW), and 8.5% reported physician-diagnosed asthma. There was a very wide range of prevalence of RW, with up to 15-fold differences between countries from LA, ranging from 2.3% in Mexico to 36.3% in Brazil, while in the EU centers it ranged from 12.1% to 18.6% (Spain centers). Seven years later, three centers, two in Brazil and one in Chile, were able to give data on time trends [43], and observed decreases in the mean prevalence of RW and in wheezing during the first 3 months of life, the results being significant only in one center. These three centers also observed an increase in the mean prevalence of physician-diagnosed asthma from 13.3% to 21.8%, the results being significant in Curitiba and Sao Paulo.

Recently, using the same methods as ISAAC phase 3, the Global Asthma Network (GAN) Phase 1 study produced comparable estimates of the prevalence and severity of asthma symptoms in 119,795 school-aged children over nearly 3 decades (1993–2020) from 27 centers in 14 countries in the Africa and Eastern Mediterranean, America, Europe, and South-East Asia and Western Pacific regions [4]. About one in 10 individuals of both the 6–7 years old and the 13–14 years old age groups had CW, of whom almost half had severe symptoms. Most centers showed a change in prevalence of two SE or more between ISAAC Phase 3 to GAN Phase 1. Over the 27-year period, adolescents showed a significant decrease in percentage point prevalence per decade in severe asthma symptoms (–0.37) and an increase in ever having asthma (+1.25) and in night cough (+4.25) which was also found in children (+3.21). The prevalence of CW decreased in low-income countries (–1.37 in children and –1.67 in adolescents) and increased in lower-middle-income countries (+1.99 in children and +1.69 in adolescents), but it was stable in upper-middle-income and high-income countries.

Among adults, the ECRHS I (1991–1993) recruited 137,619 participants aged 20–44 years in 48 centers from 22 countries mostly in Europe including five non-European countries: Algeria, Australia, India, New Zealand, and the United States of America (USA) [33,44]. An eight-fold geographical variation in the prevalence of wheeze (from 4.1% to 32%), and a six-fold geographical variation in the prevalence of current asthma (2.1% to 11.9%) were found: the prevalence of respiratory symptoms and asthma was found to be high in Australia, New Zealand, USA, Ireland, and the UK and low in Iceland, parts of Spain, Germany, Italy, Algeria, and India. At ECRHS II (1998–2003), in the same individuals, increases in reported asthma attacks and use of asthma medication were observed, but there was no corresponding change in the prevalence of CW, chest tightness, or waking with breathlessness or with cough [45]. Over the 20-year period (ECRHS III, 2010–2013), decreases in the prevalence of CW and wheeze in the absence of a cold fell were observed (net change in prevalence −2.4% and −1.5% respectively). There was no change in the prevalence of CW with breathlessness, but there was a net increase in the prevalence of asthma attacks, in current use of treatments for asthma, and in self-reported diagnosed-asthma (+ 0.6%, + 3.6%, and +3.5% respectively) [46]. As stated by Asher et al. [39], the three phases done in the same individuals over time make ECRHS a longitudinal study less suited than repeated cross-sectional studies for examining time trends in population asthma prevalence.

In the WHS, among 178,215 adults aged 18–45 years from 70 countries, the prevalence of asthma was based on responses to questions relating to self-reported doctor-diagnosed asthma, clinical/treated asthma, and CW. This study showed that there were wide variations in the prevalence of wheezing and asthma regardless of overall national income, the global prevalence rates were 4.3% for doctor-diagnosed asthma, 4.6% for clinical/treated asthma, and 8.6% for wheezing, varying by as much as 21-fold across countries regardless of overall national income.

In summary, epidemiological studies in large populations worldwide showed wide variability in the prevalence rates of respiratory symptoms and asthma. Recent available data showed that trends in prevalence and severity of asthma symptoms over the past three decades varied by age group, country income, region, and center among school-age children. The interpretation of these patterns is complex because a wide range of risk factors exists and environmental changes are at play. Unmet needs for time trend data among adults and elderly remain.

1.3.3 From one disease to phenotypes

Slowly, from the second half of the 20th century to the beginning of the 21st one, a general consensus has emerged to admit that, in children as in adults, asthma is unlikely to be a single disease entity [47]. The works on the allergic component of asthma by Chandler Walker [48] and Francis Rackemann [49] in 1917–1918, introducing the intrinsic or extrinsic asthma–based on the positive or negative skin-test responses–may be considered as the starting point. Then, further major observations made the concept of asthma evolve to the notion of phenotypes [50]: not all the patients had asthma with an allergic component, the corticosteroid therapy did not work on all patients either among children or adults, research on mouse models of asthma identified the crucial type 2(T2)/T helper cell type 2(Th2) pathway cytokines but the biological approaches to treat asthma failed to improve the control of asthma in some patients that remained refractory or difficult-to-treat, and some patients had less or more severe asthma. A working classification of asthma was proposed by Francis M Rackemann in 1947, based on the intrinsic/extrinsic feature of asthma and on the age of onset ([51], Fig. 1.1).

1.4 Asthma phenotypes

According to Merriam-Webster's medical dictionary, a phenotype is defined as the observable characteristics or traits of an organism that are produced by the interaction of the genotype and the environment [52]. To date, asthma encompasses numerous and various phenotypes that may overlap, and Elisabeth Bel [53] and Sally Wenzel [5] were the first to propose a summary of these phenotypes in 2004 and 2006 respectively. Since then, asthma phenotypes were periodically reviewed and summarized [50,54–58]. Some of the latter references include a graphical summary [50,54,56], and one is a systematic review [58].

Many classifications of asthma phenotypes could be described: we decided to start the present section with a description of the phenotypes according to the age of onset whatever the period of life, then respectively in childhood and adulthood. Both in children and in adults, asthma may be associated with multimorbidities and lack of response to therapy, both being actors of its severity, thus no section was specifically devoted to severe asthma. Inflammatory phenotypes of asthma were one of the first phenotypes to be described [5], and as Chapter 2 is devoted to them, this section will not be developed here. The definition of these phenotypes is based on the predominant cell type involved in airway inflammation that is, eosinophils and neutrophils, which makes the border between inflammatory phenotype and endotype blurred.

Fig. 1.2 summarizes the various asthma phenotypes that have consistently emerged from conventional or data-driven approaches in childhood or adulthood.

Fig. 1.2 Asthma phenotypes according to age of onset, inflammation, and severity.

1.4.1 Phenotypes according to the age of onset of asthma

Asthma is a disease that can occur in childhood or in adulthood and the age of onset first define these asthma phenotypes. Childhood asthma differs from adulthood asthma by some characteristics but both also share common ones. Indeed, characteristics of asthma such as the allergic component, the multimorbidities, and the severity are different according to gender through various ages [59]. It is well-established that childhood asthma is frequently associated with allergy, while adulthood asthma is commonly associated with diabetes, osteoporosis, metabolic syndrome, cardiovascular diseases, anxiety, and depression [26]. Risk factors of asthma phenotypes may be common or different from childhood to adulthood and Chapters 3 to 8 of the book address this issue. Lastly, both in children and in adults, asthma may be associated with obesity, be difficult-to-treat, and be less or more severe.

1.4.1.1 Phenotypes in childhood

Based on both conventional and data-driven findings from children cohorts [60–62], various asthma phenotypes in childhood have been proposed depending on the time of onset (early/preschool i.e.,<6 years or late/school age), the frequency of the wheeze (transient or persistent), the triggers (episodic viral wheeze or multiple-trigger wheeze) and the allergic expression of the disease. Among children, the work by Fernando Martinez was one of the first to define sub-phenotypes of childhood asthma according to early or late, and transient or persistent wheezing [27], differences in serum IgE concentration and response to skin prick test (SPT) to aeroallergens being observed between groups. The stability of these phenotypes depended on the allergic expression of the disease, and on the time of onset, the phenotype labeled nonallergic and with episodic viral wheeze tended to resolve by late childhood. The severity of the disease is associated with the frequency of the wheezing episodes, the allergic status, the association with other allergic comorbidities [63] or with obesity [64], and the predominance of the type of inflammation–eosinophilic, neutrophilic, or paucigranulocytic–but with controversial results according to the studies regarding inflammation.

1.4.1.2 Phenotypes in adulthood

From childhood to adulthood, the number and heterogeneity of asthma phenotypes increase. Among adults, asthma may also appear early or late (elderly,> 65 years), and may be induced by environmental or occupational exposures, aspirin or exercise, be related to menses, or overlap with COPD later in adulthood. In the last decade, the identification of asthma phenotypes in adults has evolved from conventional to data-driven method approaches. In 2021, a systematic review of asthma phenotypes derived by data-driven methods was published [58], including 68 studies and showing a lack of consistency in the choice of the statistical method and variables, and in the identified phenotypes. The variables covered the personal, functional, clinical, allergic/atopic, inflammatory, medication, healthcare use, and behavioral domains. The number of phenotypes per study ranged from two to eight, a majority of studies identifying between three and five phenotypes, half of the studies have evaluated the consistency of the phenotypes over time. Some phenotypes identified were in line with those previously described by conventional methods [50,54,65]. The phenotypes were characterized by allergy/atopy in 45 studies, by gender in 31 studies, by lung function/airflow obstruction in 30 studies, by early-onset/late-onset in 29 studies, by mild-to-moderate/severe in 27 studies, by symptoms/exacerbation/treatment in 26 studies, by the type of inflammation T2/Th2 or noneosinophilic/eosinophilic/paucigranulocytic in 20 studies, by Body Mass Index (BMI)/obesity in 19 studies, by smoking status in 16 studies, by asthma control in 10 studies, by comorbidities/rhinitis in four studies, by aspirin sensitivity/intolerance in four studies and by healthcare use in four studies, the results depending on the variables included in the clustering analyses. Overall, the most frequent phenotypes were related to allergy/atopy, gender (female), and severe asthma. None of the 68 studies investigated exercise-induced asthma previously described by Wenzel [5,54], one study investigated phenotypes of occupational asthma [66], and five studies asthma/COPD overlap phenotypes [67–71]. Some studies have identified phenotypes based on characteristics never studied before: one by using quantitative computed tomography-based structural and functional variables extracted from scans [72], one based on common beliefs and attitudes toward asthma and its management [73], one based on asthma control, attitude towards the disease, and compliance with treatment [74], and one among asthmatics with depressive symptoms [75]. A phenotype characterized by old age asthmatics was identified in 6 studies [76–81], with less atopy as a characteristic observed consistently across studies. Only one study has identified asthma phenotypes in elderly that differed from each other's by asthma duration, BMI, allergic sensitization, depression score, comorbidities, and severe asthma [82]. Lastly, one study identified asthma phenotypes based on 15 biomarkers from routine blood tests [83], making this study intermediate between the identification of phenotypes and