**3. Predisposing factors, risk factors and triggers**

Prevention of diseases is one of the challenges that medicine faces, therefore knowing the risk factors for each of the processes we aim to prevent is essential to carry out effective measures to achieve the proposed objectives. The best known risk factors and triggers that lead to allergic diseases, especially asthma and related bronchopaties, are as follows.

#### **3.1. Atopy: genetic bases**

**1. Introduction**

72 Asthma - From Childhood Asthma to ACOS Phenotypes

**2. Epidemiology**

tracheobronchial mucus glands.

circumstances in the bronchial mucosa.

breathing.

famous expression 'all that wheezes is not asthma'.

Episodes of breathlessness or wheezing are common in preschool children primarily in the first 2 years, being estimated that 50% of infants have episodes of this nature, and their causes are needed to be known. The insufficient development of the immune system opens up to fre‐ quent viral infections, but other factors can contribute, such as the home environment, partic‐ ularly if the mother is a smoker. Given the importance of genetic predisposition, family history of allergic diseases and asthma in particular is always is to be known, taking into account the

Some anatomical and physiological characteristics of the infant and young child's airways predispose to the development of processes that lead to the narrowing or bronchial obstruc‐ tion, manifested by common symptoms, such as coughing, dyspnoea and noisy or wheezing

The *narrower airway calibre* is a basic fact, which contributes to the obstruction due to the inflammation of the mucosa, the smooth muscle constriction or the increased secretion of

Infant *physiological increase of vagal tone*, which continues during the first years of life, as Montgomery and Tepper [18] demonstrated by methacholine inhalation, is known. Patholog‐ ically, bronchial hyperresponsiveness (BHR) is a key element in the pathogenesis of asthma. Having certain anomalies in the protein chain of the beta-receptors of the smooth muscle, such as the substitution of glycine for arginine at position 16 and glutamate for glutamine at position 27, is a characteristic of individuals with atopic predisposition. But in non-predisposed subjects, BHR is usually secondary to the inflammatory reaction that occurs in various

Regarding bronchopulmonary infectious pathology, it is the well-known *immaturity of the immune system*, which in some children continues for several years (infant transient immuno‐

It is not always easy to establish the true diagnosis of asthma in early life, as the evolution of symptoms over the years will confirm the diagnosis by excluding other possible causes of dyspnoea or wheezing, supported by immuno-allergological and respiratory function studies. In line with these concepts, Martinez et al. [16] distinguish the different phenotypes of the bronchospastic pathology in preschool children, identifying asthma and transient bronchitis (wheezy bronchitis) that encompass various processes suffered by a group of children who, after preschool age, do not show no broncholability, all a consequence of the predisposing factors cited above. However, it is not always easy to determine the phenotype of a particular patient, and in the course of time, as they evolve, the criteria may even have to be modified. Hence, the need to pay attention to the characteristics of the symptoms and their evolution, in addition to a number of circumstances, such as the suffering from other allergic processes by

deficiency), facilitating the development of bronchial inflammation processes.

The hereditary component in allergic diseases is well known, being asthma the most important, so that in approximately 70–80% of patients, close family members with the same or other allergy-related pathologies are identified. Allergic (atopic) predisposition is polygenic, that is there are several genes that support polymorphisms, which prompt the abnormal response of the organism to allergens.

In infants and pre-schooler children, the diagnosis of asthma is based on demonstrating the causality of allergic symptoms, and BHR, which is an essential condition for the diagnosis of the disease at any age. Polymorphisms in genes that lead to variants of the β2-adrenergic receptor in the bronchial smooth muscle are the basis for congenital BHR (primary BHR), which may be also due to the harmful influence of certain exogenous factors such as when smoker women do not drop the habit during pregnancy, thereby harming the normal devel‐ opment of the lung. The existence of congenital BHR is the first precursor of asthma in young children. Moreover, also in these early years, BHR may worsen or appear by the inhalation of pollutants present at home or in the exterior, being this cause of BHR (acquired BHR) the most prominent at later ages.

In children with wheezy bronchitis (transient), such family circumstances are not given, but the causes are different, such as pulmonary immaturity, viral infections or environmental pollution (micro-habitat).

#### **3.2. Foetal immunity and atopy: intrauterine sensitization**

The influence of the mother in the transmission of atopic predisposition is greater than the father's, possibly because of the intimate connection between the former and the foetus. Pregnancy maintenance requires an immune environment with predominance of activity of Th2 lymphocytes, which prevents the rejection of the foetus. Thus, the foetus develops in an environment in which cytokines from that lymphocyte subclass, especially interleukin (IL)-4, IL-10 and IL-5, are predominant, increased if the pregnant woman is atopic, suffering or not from any allergic disease. Although IL-13 is a cytokine of the Th2 group, it has been observed that it is produced to a lesser extent in foetuses and neonates at risk of atopic disease, which could be related to the immaturity of the development of the activity of T cells [27]. Along the same lines, low production of IFN-γ by mononuclear cells could be related, thereby reducing the suppression of Th2 activity, defect that is maintained for at least the first 2 years of life [24].

Sensitization to food allergens or pneumoallergens may occur already during pregnancy, as the foetus can produce IgE from the 11th week of gestation, even IgE specific to antigens, as has been shown to occur against parasites (helminths, filaria) in some countries.

What is yet to be clarified is the route by which the allergens that have passed to the mother by inhalation or digestion are brought into contact with the foetus for the immune stimulation that promotes IgE production to occur.

What it is also to be elucidated is the relationship that may exist between the degree of maternal exposure to allergens and the possibility that the foetus becomes sensitized. It does not seem that an environment rich in pneumoallergens cause a greater number of foetuses affected or that the diet of pregnant woman devoid of the most allergenic foods reduce the number of sensitivities.

#### **3.3. Risk factors**

#### *Lung development*

Regardless of atopic predisposition, various circumstances constitute an added risk for the early onset of asthma, which can also promote the development of wheezing transient bronchitis. Some of these facts can act on the lung during foetal life affecting both the devel‐ opment and maturation of the immune system, but also after birth, especially in the first year of life.

Lung development can be affected by certain circumstances. Prolonged stress of the mother can affect the imbalance of Th1/Th2 activity, due to the excessive production of cortisone that occurs in this emotional condition, since the hormone exerts its immunomodulatory activity in favour of Th2 activity [11]. Similarly, some incidents during pregnancy can affect the development of the lung, such as uterine bleeding, placental insufficiency or other processes that alter the physiology of the uterus favouring premature birth and a consequent low birth weight. Also, prolonged malnutrition of the pregnant mother is detrimental to the overall development of the foetus and particularly of the lung, increasing the risk for prematurity in which many of these pregnancies end.

#### *Smoking during pregnancy and lactation*

In children with wheezy bronchitis (transient), such family circumstances are not given, but the causes are different, such as pulmonary immaturity, viral infections or environmental

The influence of the mother in the transmission of atopic predisposition is greater than the father's, possibly because of the intimate connection between the former and the foetus. Pregnancy maintenance requires an immune environment with predominance of activity of Th2 lymphocytes, which prevents the rejection of the foetus. Thus, the foetus develops in an environment in which cytokines from that lymphocyte subclass, especially interleukin (IL)-4, IL-10 and IL-5, are predominant, increased if the pregnant woman is atopic, suffering or not from any allergic disease. Although IL-13 is a cytokine of the Th2 group, it has been observed that it is produced to a lesser extent in foetuses and neonates at risk of atopic disease, which could be related to the immaturity of the development of the activity of T cells [27]. Along the same lines, low production of IFN-γ by mononuclear cells could be related, thereby reducing the suppression of Th2 activity, defect that is maintained for at least the first 2 years of life [24].

Sensitization to food allergens or pneumoallergens may occur already during pregnancy, as the foetus can produce IgE from the 11th week of gestation, even IgE specific to antigens, as

What is yet to be clarified is the route by which the allergens that have passed to the mother by inhalation or digestion are brought into contact with the foetus for the immune stimulation

What it is also to be elucidated is the relationship that may exist between the degree of maternal exposure to allergens and the possibility that the foetus becomes sensitized. It does not seem that an environment rich in pneumoallergens cause a greater number of foetuses affected or that the diet of pregnant woman devoid of the most allergenic foods reduce the number of

Regardless of atopic predisposition, various circumstances constitute an added risk for the early onset of asthma, which can also promote the development of wheezing transient bronchitis. Some of these facts can act on the lung during foetal life affecting both the devel‐ opment and maturation of the immune system, but also after birth, especially in the first year

Lung development can be affected by certain circumstances. Prolonged stress of the mother can affect the imbalance of Th1/Th2 activity, due to the excessive production of cortisone that occurs in this emotional condition, since the hormone exerts its immunomodulatory activity in favour of Th2 activity [11]. Similarly, some incidents during pregnancy can affect the

has been shown to occur against parasites (helminths, filaria) in some countries.

pollution (micro-habitat).

74 Asthma - From Childhood Asthma to ACOS Phenotypes

that promotes IgE production to occur.

sensitivities.

**3.3. Risk factors**

*Lung development*

of life.

**3.2. Foetal immunity and atopy: intrauterine sensitization**

Among the risk factors that affect lung development in both its structure and mechanisms of immune defence, the greatest interest is focused on the smoking habits of the mother during pregnancy and the first year of life, including also other smokers in the vicinity of the newborn and infant.

There are no doubts about the relationship between smoking and respiratory disease of the small child, with an increase in the prevalence among children of school age. Nevertheless, it is difficult to prove whether the functional changes are already initiated in the foetus or if this occurs later during lactation. Gilliland et al. [9] found decreased respiratory function (FEF25– 75) in children whose mothers smoked during pregnancy, but not after birth, suggesting that the injuries already started in the foetus.

Modern methods to assess respiratory function allow the study of BHR already in the first months of life, having shown a slight but real increase in the children of smoking mothers. Regarding immunity, several studies in cord blood appear to show that tobacco produces some changes in the immune response of the foetus, having found higher levels of IgE and a significant production of Th2 cytokines (IL-13, IL-5mRNA, IL-6), after *in vitro* stimulation of lymphocytes with allergens (ovalbumin, mite).

#### *Environmental chemical pollutants*

Various common contaminants at home may act as irritants that can cause or increase bronchial reactivity or produce an inflammatory condition of the airways. This may precipitate both sensitization to environmental allergens and be the cause of respiratory symptoms of varying intensity, from irritative cough to wheezing bronchitis. The most common environmental pollutants have a variable influence, in logical dependency on the concentration of chemicals, ventilation, housing characteristics and location (urban, suburban, rural).

It seems less likely that the outside environmental irritants may cause the same problems in young children, perhaps because the degree of exposure is lower than in later ages. However, in big cities or in the vicinity of industrial areas, pollution can be a serious risk, from which only small infants that spend little time outdoors will be protected.

#### **3.4. Trigger factors**

#### *Early sensitization*

As already mentioned, sensitization to allergens seems possible already during foetal life, although the onset of symptoms of asthma may take some time, depending on the degree of exposure and environmental conditions in addition to the genetic load. But it is after birth when the child is more exposed to common domestic allergens, being mites the most common (*Dermatophagoides pteronyssinus* and *Dermatophagoides farinae*), but sensitization and subse‐ quent development of allergic symptoms in the respiratory tract are associated with atopic predisposition, concentration of allergens and allergenic potency of each of them, and their ability to release the antigens when the particles are deposited on the wet surface of the mucosa, as well as the involvement of adjuvants, as are the aforementioned pollutants or the intercur‐ rent respiratory infections.

#### *Viral infections*

Respiratory tract infections caused by viruses are responsible for a high percentage of bron‐ chospasm in young children, for which their characteristic tendency for allergic symptoms in their in upper respiratory tract or even crises of wheezing and/or dyspnoea had already been revealed. But also in non-atopic children, RSV mainly can cause lesions of the bronchial mucosa that facilitate contact with allergens, causing sensitization to them, with a simultaneous increase in broncholability. Also in not-predisposed children, RSV infections and other viruses trigger wheezing crisis or broncho-obstruction, as a pathogenic base for transient or wheezy bronchitis. The cause of these disorders lies in diverse mechanisms, dependent some on the injury of the mucosal epithelium and others on the activation of the cells involved in the immune–allergic response (**Table 1**).

RSV belongs to the *Pneumovirus* genus of the *Paramyxoviridae* family. Through a protein (G), the virus attaches to the surface of target cells, resulting in the fusion of the lipids of the cell membrane by another protein (F), which facilitates the insertion of RNA into the invaded cell. The G protein promotes a Th2 response, whereas the F protein stimulates the production cytokines in Th1 lymphocytes. In connection with the predominance of one or other protein, it has been established the existence of two types of RSV, A and B, whose variety may depend on the different clinical manifestations [13].

The metapneumovirus is responsible for 10–15% of the respiratory infections in children, with the same clinical impact than the VRS, with which shares a certain genotypic and epidemio‐ logical similarity. They also belong to the *Paramyxoviridae* family and are genetically similar to the pneumovirus of the avian flu.

The influenza virus A and B, and parainfluenza 1, 2 and 3 are less aggressive but also cause obstructive crisis in atopic and non-atopic children, because they cause desquamation of trachea–larynx–bronchial epithelial cells and bronchial submucosal oedema with infiltration of neutrophils and mononuclear cells, lesions that are reversible within 6 weeks [3].

Moreover, it is possible that in healthy children, RSV infection may be the cause of asthma to be developed later, but is more likely to result in the wheezing bronchitis process that will persist for some time. It is shown that, after severe infection, deterioration of the lung function occurs with increased bronchial reactivity to methacholine or histamine and to physical exercise, as well as the existence of specific IgE antibodies against the virus, which decreases over time, which could be related to the transience of broncho-obstructive crises.

More recently, rhinovirus, with its three subgroups A, B and C, has been identified as the main cause of respiratory infections which will later trigger half of asthma attacks in early childhood. The *in vitro* rhinovirus contact with blood mononuclear cell from adult asthmatics, compared to healthy subjects, demonstrates the production of IL-4 only in patients and less IFNy in these than in controls, with a IFNy(gamma interferon)/IL-4 ratio over three times lower in asthmat‐ ics, which shows that rhinoviruses directly induce the activity of Th2 cells, which does not rule out a greater responsibility of rhinoviruses in the pathogenesis of asthma.

#### *Bacterial infections*

exposure and environmental conditions in addition to the genetic load. But it is after birth when the child is more exposed to common domestic allergens, being mites the most common (*Dermatophagoides pteronyssinus* and *Dermatophagoides farinae*), but sensitization and subse‐ quent development of allergic symptoms in the respiratory tract are associated with atopic predisposition, concentration of allergens and allergenic potency of each of them, and their ability to release the antigens when the particles are deposited on the wet surface of the mucosa, as well as the involvement of adjuvants, as are the aforementioned pollutants or the intercur‐

Respiratory tract infections caused by viruses are responsible for a high percentage of bron‐ chospasm in young children, for which their characteristic tendency for allergic symptoms in their in upper respiratory tract or even crises of wheezing and/or dyspnoea had already been revealed. But also in non-atopic children, RSV mainly can cause lesions of the bronchial mucosa that facilitate contact with allergens, causing sensitization to them, with a simultaneous increase in broncholability. Also in not-predisposed children, RSV infections and other viruses trigger wheezing crisis or broncho-obstruction, as a pathogenic base for transient or wheezy bronchitis. The cause of these disorders lies in diverse mechanisms, dependent some on the injury of the mucosal epithelium and others on the activation of the cells involved in the

RSV belongs to the *Pneumovirus* genus of the *Paramyxoviridae* family. Through a protein (G), the virus attaches to the surface of target cells, resulting in the fusion of the lipids of the cell membrane by another protein (F), which facilitates the insertion of RNA into the invaded cell. The G protein promotes a Th2 response, whereas the F protein stimulates the production cytokines in Th1 lymphocytes. In connection with the predominance of one or other protein, it has been established the existence of two types of RSV, A and B, whose variety may depend

The metapneumovirus is responsible for 10–15% of the respiratory infections in children, with the same clinical impact than the VRS, with which shares a certain genotypic and epidemio‐ logical similarity. They also belong to the *Paramyxoviridae* family and are genetically similar to

The influenza virus A and B, and parainfluenza 1, 2 and 3 are less aggressive but also cause obstructive crisis in atopic and non-atopic children, because they cause desquamation of trachea–larynx–bronchial epithelial cells and bronchial submucosal oedema with infiltration

Moreover, it is possible that in healthy children, RSV infection may be the cause of asthma to be developed later, but is more likely to result in the wheezing bronchitis process that will persist for some time. It is shown that, after severe infection, deterioration of the lung function occurs with increased bronchial reactivity to methacholine or histamine and to physical exercise, as well as the existence of specific IgE antibodies against the virus, which decreases

of neutrophils and mononuclear cells, lesions that are reversible within 6 weeks [3].

over time, which could be related to the transience of broncho-obstructive crises.

rent respiratory infections.

76 Asthma - From Childhood Asthma to ACOS Phenotypes

immune–allergic response (**Table 1**).

on the different clinical manifestations [13].

the pneumovirus of the avian flu.

*Viral infections*

Unlike viruses, bacteria do not exercise such a harmful function. Some bacterial antigens have an immunomodulatory capacity and repeated infections are what promote the predominance of the activity of Th1 versus Th2 lymphocytes, preventing sensitization to allergens.

Although the protective action against sensitization to pneumoallergens and food in children under 2 years of age seems confirmed, there are studies that nuance the findings, as is the potential coadjuvant effect of endotoxins with sensitization to mites and perhaps other pneumoallergens.


**Table 1.** Mechanisms responsible for bronchobstructive crises caused by viruses.

Moreover, at very low concentrations (10 ng/ml), endotoxins are able to activate alveolar macrophages and promote bronchial inflammation, increasing bronchoreactivity both in asthmatic and healthy people; therefore, it is possible that in the severity of asthma, environ‐ mental endotoxin levels may have an outstanding role not only in adults but also from school age, causing especially wheezy bronchitis or non-atopic asthma (6,10).

Conversely, if the asthmatic has a bacterial infection with respiratory location, it is most likely that obstructive symptoms will be intensified by the action of bacterial enterotoxins that act as superantigens, which promote the mechanisms by which the inflammation of the respiratory mucosa is established.
