**9. Practical summary for diagnostic approach**

	- **a.** Family history: allergic pathology, respiratory or genetic pathology.
	- **b.** Own background: allergic comorbidity (eczema, allergies to milk proteins, etc.), recurrent infections
	- **c.** Symptomatology: for each one of the symptoms, it is necessary to specify the characteristics, age of onset, duration, severity, recurrence, association between them.
	- **d.** Environment: smoking, irritating substances, pets, rural area
	- **a.** In a symptomatic stage or during an interval
	- **b.** General inspection: development, nutrition, colour of skin and mucous membranes, acrocyanosis. If there is coughing: characteristics. Nasal or mouth breathing.
	- **c.** Thoracic inspection: circulation, retractions, respiratory rate, dyspnoea. Ausculta‐ tion: wheezing, rhonchus, crackles, localized or generalized, changing or not present when coughing. Localized hypophonia. Percussion: localized dullness.
	- **d.** Nasopharyngeal: nasal flaring, anterior or posterior rhinorrhea, appearance of mucus. Size and appearance of the tonsils: visible adenoids?

**a.** Complete blood count. ESR

The assessment of cough as a symptom, that in the case of asthma is often maintained between the crises of dyspnoea or wheezing, has some characteristics that can guide to others diagnosis not uncommon at preschool age, with symptoms that may be common to those of asthma, and therefore is mandatory to take them into account in order to conduct a correct differential

Congenital anomalies

—Vascular rings

—Laringo and tracheomalacias

Alpha-1-antitrypsin deficiency Hypersensitivity pneumonitis Pulmonary hemosiderosis Alveolar proteinosis Eosinophilic lung

**Dominant symptom: cough Pseudoasthmatic bronchial symptoms LESS common processes**

Mucoviscidosis (cystic pancreatic fibrosis)

Tumour or mediastinal adenopathy

**a.** Family history: allergic pathology, respiratory or genetic pathology.

**d.** Environment: smoking, irritating substances, pets, rural area

**b.** Own background: allergic comorbidity (eczema, allergies to milk proteins, etc.),

**c.** Symptomatology: for each one of the symptoms, it is necessary to specify the characteristics, age of onset, duration, severity, recurrence, association between them.

**b.** General inspection: development, nutrition, colour of skin and mucous membranes, acrocyanosis. If there is coughing: characteristics. Nasal or mouth breathing.

**c.** Thoracic inspection: circulation, retractions, respiratory rate, dyspnoea. Ausculta‐ tion: wheezing, rhonchus, crackles, localized or generalized, changing or not present

**d.** Nasopharyngeal: nasal flaring, anterior or posterior rhinorrhea, appearance of

when coughing. Localized hypophonia. Percussion: localized dullness.

mucus. Size and appearance of the tonsils: visible adenoids?

Immunodeficiencies Bronchiolitis Bronchitis obliterans Wheezy bronchitis

Tracheobronchial foreign body

Gastroesophageal reflux

**Table 4.** Most significant processes in the differential diagnosis.

**9. Practical summary for diagnostic approach**

**a.** In a symptomatic stage or during an interval

diagnosis (**Table 4**).

88 Asthma - From Childhood Asthma to ACOS Phenotypes

Whooping cough (pertussis) Primary ciliary dyskinesia Eosinophilic bronchitis

**1.** Medical history

**2.** Clinical examination

recurrent infections

**3.** Initial Investigations in all cases

Maxillary sinusitis Adenoids Rhinopharyngitis

	- **a.** Sweat test. Also required in the initial study, if symptoms are of an early onset, severe, with general deterioration or a family history of cystic fibrosis
	- **b.** Esophageal pH monitoring
	- **c.** Thoracis X-ray, front and profile: assessing abnormal masses, adenopathy, conden‐ sation, etc. Mediastinal swaying following the suspicion of a foreign body aspiration, especially in children under 3 years
	- **d.** Other imaging techniques based on radiological findings or presumed diagnosis: computed tomography, magnetic resonance, gammagraphy.
	- **e.** Serum antibodies against RSV, influenza, parainfluenza and other
	- **a.** Lung function study
	- **b.** Serum precipitin against actinomycetes
	- **c.** BAL: hemosiderophages (also in gastric contents), PAS+ protein, eosinophil
	- **d.** Alpha-1-antitrypsin serume
	- **e.** Bronchoscopy
	- **f.** Lung biopsy

#### **10. Treatment**

Although asthma treatment at any age is based on the same principles, the characteristics of the disease and the pathophysiology in pre-scholar children require adjusting each of the measures available to the peculiarities of the age.

Overall, these measures aim primarily to combat the cause of the disease, that is *etiological* treatment based, in one part on environmental measures (reduction of household allergens and reducing environmental pollutants) and on the other in desensitization by immunother‐ apy. The *pathogenic* treatment is based on fighting the bronchial inflammation, trying to prevent or eliminate it, being chromones, anti-leukotrienes and corticoids the appropriate medications, and finally, the *symptomatic* treatment with short-acting bronchodilators, mainly β2-agonists.

#### **10.1. Etiological: specific immunotherapy**

Immunotherapy is the only therapeutic procedure, for its widely proven effectiveness, which decreases the sensitivity (desensitization or hyposensitization) to the responsible allergens, in which its mechanisms of action are essential to prevent further sensitization, as is well known (in short, the Th1/Th2 balance).

WHO supports the term 'allergy vaccine' and considers this as the only treatment that can alter the natural course of allergic diseases and also prevent the development of asthma in patients with allergic rhinitis.

Although the age to initiate immunotherapy has been questioned, multiple studies and the own experience show the need for an early start, from the third year of age, provided that the requirements set out in **Table 5** are met.

Recent and extensive literature reviews conclude that it is a serious need to consider the start of immunotherapy in children under 5 years of age that fulfil the required conditions ([7, 8])


— In case of asthma:

— mild to moderate intensity


Exceptionally provocation with allergen will be used

	- —Early onset

**Table 5.** Premises for immunotherapy for optimal results in paediatrics.

Some of the few problems that can cause subcutaneous immunotherapy could be avoided if administered by sublingual channels, which is virtually risk-free. A problem in young children is the difficulty of successfully administering the pharmaceutical preparation, keeping it under their tongue for the right time, which is likely to be simplified with the most recent preparation in tablets or in atomiser (spray) (WAO).

#### **10.2. Pathogenic: antiinflammatories**

#### *Chromones*

apy. The *pathogenic* treatment is based on fighting the bronchial inflammation, trying to prevent or eliminate it, being chromones, anti-leukotrienes and corticoids the appropriate medications, and finally, the *symptomatic* treatment with short-acting bronchodilators, mainly β2-agonists.

Immunotherapy is the only therapeutic procedure, for its widely proven effectiveness, which decreases the sensitivity (desensitization or hyposensitization) to the responsible allergens, in which its mechanisms of action are essential to prevent further sensitization, as is well known

WHO supports the term 'allergy vaccine' and considers this as the only treatment that can alter the natural course of allergic diseases and also prevent the development of asthma in patients

Although the age to initiate immunotherapy has been questioned, multiple studies and the own experience show the need for an early start, from the third year of age, provided that the

Recent and extensive literature reviews conclude that it is a serious need to consider the start of immunotherapy in children under 5 years of age that fulfil the required conditions ([7, 8])

Some of the few problems that can cause subcutaneous immunotherapy could be avoided if administered by sublingual channels, which is virtually risk-free. A problem in young children is the difficulty of successfully administering the pharmaceutical preparation, keeping it under

— respiratory function within normal limits: parameters not <70% of those foreseen — Accurate allergologic diagnosis, skin tests and serum specific IgE are sufficient

— Minimum period of 3 years, and at least 1 year without onset of symptoms

**Table 5.** Premises for immunotherapy for optimal results in paediatrics.

**10.1. Etiological: specific immunotherapy**

90 Asthma - From Childhood Asthma to ACOS Phenotypes

requirements set out in **Table 5** are met.

Exceptionally provocation with allergen will be used

— Prescription and control by a allergy and paediatrics expert

— Extract quality: purity, standardization, coadjutants — Correct therapeutic regimen monitoring: dose, intervals

— Right choice of allergen/s to be included

(in short, the Th1/Th2 balance).

with allergic rhinitis.

**— Correct clinical diagnosis**

— mild to moderate intensity

— Periodical clinical controls

—Early onset

— In case of asthma:

Under this description, cromolyn sodium and nedocromil are included. Both act by blocking the chloride channels of the membrane in the cells involved in the allergic reaction, especially mast cells and eosinophils, but also epithelial and nerve cells. On the activation of chloride channels depends the crossing of Ca ions into the cell, required for the activation thereof to occur. When these cells are stimulated (allergens, non-specific agents), there is a release of mediators (mast cells) and the commencement of the elements involved in the allergic reaction. When idle, chloride channels are closed and this is what is achieved with chromones, the blocking of the channels, thereby preventing activation of the cells that would lead to the allergic reaction. For this reason, we must consider that chromones act more like preventive agents of inflammation than anti-inflammatories.

Although currently they are less used as inflammation preventives, cromolyn could be indicated in preschool age, before asthma reaches a significant degree of severity, that is in mild intermittent or persistent asthma and in moderate asthma, in which case an inhaled corticoid or salbutamol could be added.

#### *Anti-leukotrienes*

These are medications that block the action of cysteinyl leukotrienes that might prevent the onset of one of the most important mechanisms involved in the production of the inflammatory reaction of the bronchial mucosa. They specifically avoid the activity of those on specific receptors localized in bronchial smooth muscle and in bronchoalveolar blood vessels. This is intended to prevent the development of inflammation in the initial period of obstructive bronchial disorders and also contribute to avoid the swelling to persist or increase, once present when asthma has been clinically established.

Knowledge of the receptors of the leukotrienes is a key for the intended purpose. Pharmaco‐ logical studies have determined that cysteinyl leukotrienes activate at least two types of receptors, named CysLT1 and CysLT2, being the first found in the bronchial muscle and the second in the pulmonary venous system. Depending on the consequences of the activation of these receptors by the corresponding leukotriene, the antagonists used therapeutically will produce diverse positive effects, even more prominent in children than in adults. On one hand, they achieved a discrete bronchodilation resulting as a consequence of counteracting the prolonged constrictor effect of leukotrienes.

In short, anti-leukotrienes behave more like inflammation preventives than as anti-inflamma‐ tories, an activity that is better performed by inhaled corticoids, and therefore, both treatments can be used simultaneously.

Of the preparations available (pranlukast, zafirlukast and montelukast), only the latter is indicated in children under 5 years of age, available in chewable tablets and granules. Since the permanence of the inflammatory reaction in all probability depends on the recurrence of episodes of dyspnoea and their intensity, montelukast may prevent the progression of the process in milder cases without resorting to inhaled corticoids. The advantage of oral admin‐ istration and the single daily dose make this drug of easy acceptance and secure compliance. In asthma of moderate or severe intensity, it will be necessary to combine the treatment with inhaled corticoids.

Several studies confirm the efficacy of the treatment with montelukast in children between 2 and 5 years of age even reducing the number of episodes caused by viral infections (5). Respiratory function improves from the early days of treatment, even in children under 2 years of age as a result of the reduction of the inflammation.

#### *Corticoids*

Physiologically, corticoids activate the cytoplasmic receptors that most cells have; the same which corticoids administered therapeutically act upon, with a power that depends on the affinity of each product with these receptors, entering into competition with the natural hormone. They are known to inhibit various cytokines, especially ILs (IL-1, IL-2, IL-3, IL-4, IL5, IL-6 and IL-13), tumour necrosis factor alpha (TNF-α) and the colony stimulating factor in granulocytes and macrophages (GM-CSF), while increasing the IFN-γ and IL-12, that is they reduce the action of Th2 leukocytes, and consequently, the number of basophils, eosinophils and mast cells in bronchial epithelium is reduced. The risk of any side effects resides on the fact that only between 10 and 40% of the drug administered by inhalation reach the bronchi, depending on the inhalation system. The rest of the substance remains in the mouth and is swallowed, getting into the general circulation via the gastrointestinal tract. They are mostly metabolized in the liver, being removed, but another part remains in the bloodstream, reaching the lung, where they produce the same effect as corticoids administered by other means. At the same time, part of the fraction that reached the lung by inhalation passes into the blood‐ stream, following the same path as the ingested portion. Some of these drawbacks are avoided with ciclesonide, with little oral bioavailability (only 10% of the active molecule is generated in the oropharynx), so that the pharmacotherapy is mainly dependent on deposit and pulmo‐ nary absorption.

The most prominent undesirable effects are the hypothalamic–pituitary–adrenal (HPA) axis suppression and growth retardation that, although it seems to be compensated in years not affecting final adult height, it must be considered in order not to fall into the usual trend of increasing doses when the desired effects are not achieved. Prolonged treatments or higher doses may result from severe hypoglycemia to cushingoid features. In children, it is rare that osteoporosis occurs. Depression of immunity caused by corticoids may increase the risk of infections. Other less important effects are of cutaneous nature, such as oral thrush or skin atrophy, less common in children.

A weighting between dose/guideline/efficacy/duration of therapy/adverse effects should be established. Effective maximum doses of inhaled corticoids in children have been established, which is 400 μg/day for beclomethasone dipropionate and budesonide, and 200 μg/day for fluticasone propionate. Despite the better tolerance with ciclesonide, only studies from 4 years of age have been published, with a maximum dose of 160 μg/day. Higher doses of any of them do not improve results and increase the risk of side effects. The daily dose is usually divided into two intakes, but can be simplified without losing efficiency, administering once the total daily dose in the morning, as the physiological hormone production would be reduced if taken at night. In mild-moderate asthma, there is an increased permeability of the airways, and therefore, the drug penetrates with greater ease making the most of the administered dose, hence the recommendation to use lower doses in milder cases.

The oral or intravenous administration of corticoids is reserved for asthma crises of medium or severe intensity, either at home or in hospital. The dose of 1–2 mg/kg/day of prednisone, prednisolone or methylprednisolone should not be prolonged for more than 5 days, but if more time is required, it should be progressively reduced.

Although inhaled corticoids may show a symptomatic improvement, in the long term, the course of the disease does not seem to change; therefore, the duration of the treatment will depend on the results and even a diagnostic review should be considered.

#### **10.3. Symptomatic: bronchodilators**

#### *Beta 2-agonists*

Of the preparations available (pranlukast, zafirlukast and montelukast), only the latter is indicated in children under 5 years of age, available in chewable tablets and granules. Since the permanence of the inflammatory reaction in all probability depends on the recurrence of episodes of dyspnoea and their intensity, montelukast may prevent the progression of the process in milder cases without resorting to inhaled corticoids. The advantage of oral admin‐ istration and the single daily dose make this drug of easy acceptance and secure compliance. In asthma of moderate or severe intensity, it will be necessary to combine the treatment with

Several studies confirm the efficacy of the treatment with montelukast in children between 2 and 5 years of age even reducing the number of episodes caused by viral infections (5). Respiratory function improves from the early days of treatment, even in children under 2 years

Physiologically, corticoids activate the cytoplasmic receptors that most cells have; the same which corticoids administered therapeutically act upon, with a power that depends on the affinity of each product with these receptors, entering into competition with the natural hormone. They are known to inhibit various cytokines, especially ILs (IL-1, IL-2, IL-3, IL-4, IL5, IL-6 and IL-13), tumour necrosis factor alpha (TNF-α) and the colony stimulating factor in granulocytes and macrophages (GM-CSF), while increasing the IFN-γ and IL-12, that is they reduce the action of Th2 leukocytes, and consequently, the number of basophils, eosinophils and mast cells in bronchial epithelium is reduced. The risk of any side effects resides on the fact that only between 10 and 40% of the drug administered by inhalation reach the bronchi, depending on the inhalation system. The rest of the substance remains in the mouth and is swallowed, getting into the general circulation via the gastrointestinal tract. They are mostly metabolized in the liver, being removed, but another part remains in the bloodstream, reaching the lung, where they produce the same effect as corticoids administered by other means. At the same time, part of the fraction that reached the lung by inhalation passes into the blood‐ stream, following the same path as the ingested portion. Some of these drawbacks are avoided with ciclesonide, with little oral bioavailability (only 10% of the active molecule is generated in the oropharynx), so that the pharmacotherapy is mainly dependent on deposit and pulmo‐

The most prominent undesirable effects are the hypothalamic–pituitary–adrenal (HPA) axis suppression and growth retardation that, although it seems to be compensated in years not affecting final adult height, it must be considered in order not to fall into the usual trend of increasing doses when the desired effects are not achieved. Prolonged treatments or higher doses may result from severe hypoglycemia to cushingoid features. In children, it is rare that osteoporosis occurs. Depression of immunity caused by corticoids may increase the risk of infections. Other less important effects are of cutaneous nature, such as oral thrush or skin

A weighting between dose/guideline/efficacy/duration of therapy/adverse effects should be established. Effective maximum doses of inhaled corticoids in children have been established,

inhaled corticoids.

*Corticoids*

nary absorption.

atrophy, less common in children.

of age as a result of the reduction of the inflammation.

92 Asthma - From Childhood Asthma to ACOS Phenotypes

The indication of short-acting β2-agonists (salbutamol, terbutaline) is the bronchospasm crisis, whatever its intensity. The most appropriate route of administration is inhalation, achieving improvement in a few minutes, in the case of acute asthma attacks. Continued inhalation is indicated for the inpatient treatment of severe crisis. Other routes of administration are subcutaneous and, above all, continuous intravenous to which we must turn in severe crisis. The oral route may be useful in mild cases or after achieving a significant improvement with the inhaler.

In preschool children, the most common is the metered-dose inhaler (MDI) with a spacer or with a nebulizer when it is necessary to continuously administer the drug. Otherwise, the efficacy appears to be similar with both inhalation systems. Powdered formula, for which there are different systems (turbuhaler, diskhaler, accuhaler), is less useful at this age, because a greater degree of collaboration is required.

#### *Anticholinergics*

*Ipratropium bromide*, is a derivative of atropine, which does not produce the side effects of atropine. Because of its low lipid solubility, it hardly passes biological membranes and produces an effect almost exclusively in the bronchial tree, when administered by inhalation. The recommended dose for all ages is 0.04 mg three or four times daily. The greatest benefits are achieved in asthma attacks triggered by non-specific agents, which may act via vagal.

The bronchodilator action is more deferred with this product, but it remains longer than with the β2-mimetic, and in some cases might be administered simultaneously, for which there are even preparations with formoterol or salbutamol and ipratropium bromide, although it is preferable to dispense them separately.

### **11. Therapeutic schemes**

#### **11.1. Treatment of crises**

The therapeutic approach in episodes of respiratory difficulty should be preceded by a reflection on the different diagnostic possibilities, since various acute processes may manifest common and sometimes confusing symptoms, needing different treatments, care and control. The severity of the case will be visible by observation and by assessing dyspnoea, intercostal, subcostal or supraclavicular retractions, colouring and sensory. The assessment of breath sounds that can be discernible by auscultation is essential for diagnosis as it can indicate the location of the process (trachea, central or peripheral bronchi, alveoli), if bronchospasm, condensation or atelectasis are present, which can be deduced from the presence or prevalence of wheezing, stridor, crackles or coarse crackles, decreased murmur, among other respiratory noises. Other causes of severe respiratory distress that may resemble an asthma attack, should also be considered, especially the frequent aspiration of a foreign body, which requires radiological confirmation, and bronchiolitis, both of a sudden onset and which can also occur in children that already suffer from asthma. Once it is concluded that it is a bronchospasm crisis, its severity will be assessed and of this assessment will depend the therapeutic activities:



 to get better. After follow the evolution every 1–4–6 h Aminophylline: continuous infusion (monitor serum) Ipratropium bromide: every 6 h Hydrocortisone repeated every 6 h, or Methylprednisolone ev: 1–2 mg/kg/day (spread in 4 doses) If there is no improvement or worse: Admission to Intensive Care Unit: Protocol status asthmaticus *Leaving the hospital:* Salbutamol or terbutaline inhaled or oral, to a week Methylprednisolone oral, decreasing doses, depending on the dose and previously administered treatment days

*Medical surveillance:* 2–4days

even preparations with formoterol or salbutamol and ipratropium bromide, although it is

The therapeutic approach in episodes of respiratory difficulty should be preceded by a reflection on the different diagnostic possibilities, since various acute processes may manifest common and sometimes confusing symptoms, needing different treatments, care and control. The severity of the case will be visible by observation and by assessing dyspnoea, intercostal, subcostal or supraclavicular retractions, colouring and sensory. The assessment of breath sounds that can be discernible by auscultation is essential for diagnosis as it can indicate the location of the process (trachea, central or peripheral bronchi, alveoli), if bronchospasm, condensation or atelectasis are present, which can be deduced from the presence or prevalence of wheezing, stridor, crackles or coarse crackles, decreased murmur, among other respiratory noises. Other causes of severe respiratory distress that may resemble an asthma attack, should also be considered, especially the frequent aspiration of a foreign body, which requires radiological confirmation, and bronchiolitis, both of a sudden onset and which can also occur in children that already suffer from asthma. Once it is concluded that it is a bronchospasm crisis, its severity will be assessed and of this assessment will depend the therapeutic activities: **1.** Mild: β-mimetic inhaled: according to severity: 2 doses × 20 min, maximum 3 doses, or

**3.** In both situations, after the improvement, treatment with β-mimetic continue orally (±1

**4.** Grave whose intensity, more complex processing conditions outlined in **Table 6**.

every 4–6–8 h depending on severity; maximum 24–36 h.

**2.** Moderate: add oral corticosteroids: 1–2 mg/kg/day: 3–4 days

week) or mucolytic and expectorant, if required.

Aminophylline e.v.: 5 mg/kg in micro-drip (20 min) followed

 (Investigate whether there were received a dose above) Inhaled ipratropium bromide 0.25 mg (0.125 in infants)

Salbutamol: Continuous inhalation or every 30 min until

preferable to dispense them separately.

94 Asthma - From Childhood Asthma to ACOS Phenotypes

**11. Therapeutic schemes**

**11.1. Treatment of crises**

*Immediate:*

Controls: Symptomatology

*Monitoring*

Oxygen inhalation by flow of a β-mimetic:

 (Half dose in children under 1 year) Intravenous hydrocortisone 100 mg In more severe cases, adding:

continuous infusion of 1 mg/kg/h

 Salbutamol: 2.5–5 mg Terbutaline: 5–10 mg

Oximetry: to reach SaO2 > 92%

If no improvement in 15–30 min:

**Table 6.** Treatment of severe asthma attacks in children under 5 years of age (Abridged outline various guides).

#### **11.2. Maintenance treatment**

Pharmacological treatment mainly depends on the frequency and intensity of the symptoms, the severity of which is deduced for each single case (**Table 7**).

When symptoms occur sporadically (occasional episodic) unless there is a crisis, a treatment is not usually needed. When the frequency is higher (frequent episodic), it is recommended to start with montelukast, which will act as an inflammation preventive and if there is a failure to control the symptoms, a low-dose inhaled corticoid will be added.

If symptoms occur more frequently, with intermittent crises (moderate persistent), apart from montelukast, inhaled corticoids without exceeding the maximum recommended dose will be added. If control is not reached, cromolyn sodium nebulizer three times a day will often achieve satisfactory results. Once symptoms are controlled, continue with montelukast and inhaled corticoids.

From the third year of age, when the allergic causality of the process is certain and the re‐ sponsible allergen has been identified, immunotherapy is the fundamental etiological treat‐ ment, provided that the above criteria are met, following WHO recommendations.


**Table 7.** Classification of asthma in children under 6 years of age.
