Chest X-ray does not change the clinical approach and therapeutic decision in acute asthma crisis, being able to indicate, in the case of SpO
2 92% or fever, pathologies such as pneumonia, atelectasis or pneumothorax. Chest X-ray can help exclude some differential diagnoses, such as respiratory infections, foreign body inhalation or congenital diseases (cardiac, lobar emphysema)
[27][21]. Airway narrowing can also be assessed using CT imaging, single-photon emission computed tomography (SPECT), positron emission tomography (PET), magnetic resonance imaging (MRI) and optical coherence tomography (OCT), a new technique that involves the examination of the airways at the time of bronchoscopy and provides insight into the structure of their walls and the mechanical properties with an impact on their narrowing
[28][22].
5. Treatment
For a correct orientation regarding therapy and monitoring, asthma can be subdivided into type 2 (high) and non-type 2 (low) endotypes based on their underlying inflammatory pathways
[9][5].
Medications used to control background symptoms and asthma exacerbations in adolescent patients include inhaled corticosteroids (ICSs), short-acting inhaled bronchodilators (SABAs), long-acting β2-adrenergic receptor agonists (LABAs), long-acting muscarinic receptor antagonists, leukotriene receptors (LTRAs) and, for more serious forms of the disease, specific monoclonal antibodies (IgE (Omalizumab), IL-5 (Mepolizumab, Reslizumab, Benralizumab) and IL-4/IL-13 (Dupilumab))
[5,9,30][1][5][23]. Monoclonal antibodies have the clinical effect of increasing FEV
1 and quality of life, along with decreasing the need for inhaled corticosteroids and hospitalization. It should also be mentioned that Omalizumab can be administered after the age of 6 years, while Mepolizumab, Benralizumab and Dupilumab can be given after 12 years, and Reslizumab after 18 years
[31,32][24][25].
Currently, the treatment of the adolescent patient with asthma comprises two stages: the initial treatment, instituted at the first evaluation of the patient, and the subsequent treatment guided by the evolution of the disease. The first treatment regimen is chosen according to the presence and frequency of day/night symptoms, the limitation of physical activity and the risk of exacerbations. Afterwards, it is based on the patient’s response to the administered treatment plan, asthma being classified as controlled, partially controlled or uncontrolled
[33][26]. The choice of their optimal way of administration is made depending on the clinical form of asthma.
Depending on the type of asthma, there are various biomarkers used to evaluate the adherence to therapy, essentially for adolescent monitoring. For type 2-high asthma, potential biomarkers could be serum allergen-specific IgE (SIgE), fractional exhaled nitric oxide (FeNO), the blood eosinophile count, sputum, bronchoalveolar lavage (BAL) or a bronchial biopsy, as well as some cytokines (IL-4, IL-5 and IL-13) or some cytokines specific to the innate immune system (IL-25, IL-33 and TSLP). In contrast, the diagnosis for type 2-low asthma is more challenging.
Comorbidities that affect asthma control can include rhinosinusitis, obesity, gastroesophageal reflux disease, obstructive apnea, psychological disorders as well as medications (angiotensin-converting receptor blockers—ACE-, B-blockers, aspirin and other NSAIDs)
[31][24].
Being one of the basic drugs both in the treatment of acute asthma exacerbations and in the long term, systemic or inhaled corticosteroids must be carefully evaluated in terms of the risk/benefit ratio, their over-administration being burdened by increased mortality and adverse effects, such as osteopenia, osteoporosis, muscle atrophy and dyspepsia, impacts on the cardiovascular function, growth curve or visual acuity, the increased incidence of diabetes, obesity, infections and psychological manifestations (depression, anxiety, sleep disorders) as well as the suppression of the adrenal function, manifestations that partially overlap with the aspects related to the non-pharmacological management of patients, developed below. The harmful effects seem to be directly correlated with the frequency of use in the therapeutic scheme, their cumulative nature being still under research
[39][27].
The physiopathological stage targeted by corticotherapy is represented by the production of pro-inflammatory mediators, the stimulation of chemotaxis, adhesion molecules and the antigen–receptor interaction, a stage that it mitigates through its anti-inflammatory role exercised through transrepression. At the molecular level, it notes the reduction in eosinophilia, the increase in mRNA degradation, the synthesis of anti-inflammatory proteins and the reduction in vascular permeability with the consequent reduction in liquid extravasation and the stopping of the remodeling process
[39,41][27][28].
The effectiveness of corticosteroid therapy is influenced by the non-pharmacological conditions to which the patient is exposed, namely, the adherence to therapy and correct inhalation technique, continued exposure to allergenic stimuli in the environment (which can induce corticosteroid resistance mediated by IL-2 and IL-4), associated comorbidities as well as genetic variability (e.g., T-box 21 variants, Fc fragment of the IgE II receptor, histone deacetylase 1, dual-specificity phosphatase 1). Thus, a series of predictive factors of the response to corticotherapy have been outlined over time, which, in the pediatric population, are represented by the pulmonary function at the time of the initiation of therapy, inflammatory markers, the gene functionality or the degree of sensitization to allergens
[41][28].
Therapy based on systemic/inhaled corticosteroids has aroused the interest of researchers regarding the possibility of the similar use of magnesium in refractory bronchial asthma, and specifically moderate/severe bronchiolitis. However, no statistical results were observed to encourage this practice
[43,44][29][30].
Therefore, another therapeutic class used in the control of pediatric asthma is represented by muscarinic receptor agonists (anticholinergic). These exert influence through their action on the M1/M2/M3 receptors that modulate the neuronal and non-neuronal signals of acetylcholine, the tone of the respiratory muscles (reducing bronchoconstriction), the mucous secretion of the glands as well as inflammation or remodeling. With regard to the method of administration, one can opt for monotherapy or combined therapy with β-agonists (e.g., Tiotropium/Olodaterol, Aclidinium/Formoterol, Glicopyronium/Indacaterol), the combined preparation form, as well as the long-acting one, recording promising results in the control of asthmatic exacerbations in children over 2 years of age and of long-term symptoms. It is also worth mentioning the superiority of monotherapy with β2-agonists, compared to anticholinergics, when opting for this
[52,53,54][31][32][33].
Having as the main representatives Montelukast, Zafirlukast, Pranlukast or Zileuton, the asthma medications that act at the level of leukotriene receptors with the aim of suppressing production and antagonizing inflammation are divided, depending on the therapeutic target, into G protein-coupled receptor antagonists or inhibitors of 5-lipoxygenase, with action at the level of leukotrienes B4, C4, D4 and E4
[53][32]. Montelukast, a selective antagonist of the D4 receptor, has proven its effectiveness in bronchial asthma compared to placebos, its administration reducing the need for corticotherapy in controlled forms of asthma. Presenting a peak of action approximately two and a half hours post-administration and at a half-life of 3–4 h, the therapeutic dose in pediatrics is 4 mg/day (2–5 years)–5 mg/day (6–14 years), without the need for adjustment in cases of impaired renal or hepatic function (due to excretion mainly through the biliary tract, except in severe cases).
With relatively little therapeutic experience, partly due to the recent introduction in management protocols, biological agents target individual stages of the physio-pathological cascade, an aspect from which arises the need to study and know the phenotypic particularities of asthma in order to choose the appropriate preparation. The best-known biological agents are Omalizumab (which acts on IgE, reducing the immune response and, consequently, allergic symptoms), Dupilumab (which blocks the IL-4 and IL-13 pathways), Mepolizumab, Reslizumab and Benralizumab (which targets the IL-5 pathway, thus decreasing eosinophilic proliferation)
[53][32]. Antibiotics from the macrolide class (Azithromycin, Clarithromycin) can be added to their support, which, in addition to their anti-inflammatory and antimicrobial roles, have modulatory effects on adhesion molecules and the neutrophil function, and also have a prophylactic function in asthmatic exacerbations caused by respiratory infections with
Chlamydia or
Mycoplasma pneumoniae [65][34].
Summarizing the above, the differences from a therapeutic and pharmacological point of view between different age groups reside mainly in the therapeutic classes proven to be effective and safe among them. Thus, in early childhood, the main therapeutic modality is aimed at steroids. Other therapeutic strategies include short-acting inhaled bronchodilators (SABAs), long-acting β2-adrenergic receptor agonists (LABAs) and long-acting muscarinic receptor antagonists and leukotriene receptors (LTRAs). With advancing age, the current guidelines recommend the introduction of monoclonal antibodies to the therapeutic scheme. This introduction is performed successively, having as essential age steps the ages of 6 years (Omalizumab), 12 years (Mepolizumab, Benralizumab, Dupilumab) and 18 years (Reslizumab). At the opposite pole, the treatment of adults aims at the same broad lines; the difference lies not only in a greater variety of monoclonal antibodies that can not only be addressed in therapy, but also in the need to adjust doses according to comorbidities and chronic therapy associated with advanced age. From a pharmacological point of view, although the means of action of the substances are varied, they do not have different administration implications depending on age. The primary difference is the adaptation of the dose and combinations according to body weight/comorbidities/severity, as well as the knowledge of and strict adherence to the parameters of efficiency and safety (especially with regard to modern monoclonal antibody therapies) dictated by the current studies, with statistical relevance.