Pediatric Asthma: Questions and Answers

Abstract

Purpose of the Review:

Asthma although it is common in clinical practice and GINA guidelines are available for the management of the disease, an overview of the disease and current knowledge regarding literature is helpful. The management of more complicated asthma cases is based currently on the identification of different phenotypes and endotypes. Questions and answers regarding asthma are structured.

Methods:

A critical review of the relevant literature in PubMed.

Conclusion:

Asthma is a disease with a high prevalence, morbidity and mortality. New data in the literature based on the mechanisms of development of asthma lead on a more systematic approach and management of the disease to the already established practice. The definition, phenotypes and endotypes of asthma and relevant biomarkers, genetic predisposition and the role of the environment as well as prevention measures and treatment of asthma are discussed.

Definition

Asthma is an umbrella diagnosis with considerable heterogeneity emerging by different mechanisms, expressed by variable phenotypes and necessitating different treatment. The common pathway of asthma disease is inflammation of the respiratory tract and variable airflow obstruction. ¹ The diagnosis is based on clinical criteria including wheezing, breathlessness and tight chest and cough, while available tests (IgE, sIgE, spirometry, methacholine test) are only indicative of the disease supporting the background of inflammation and obstruction and in any case they only support the diagnosis of asthma. ² In the literature, many observations in adults are applied to children. ³

What Are the Asthma Phenotypes and Endotypes and Why It is Important to Identify Them?

The major differentiation of asthma phenotypes is on an atopic group with an allergic predisposition and on a non atopic or “intrinsic” group predominating in adults. However, additional parameters categorize asthma depending on age of onset, triggers, number of exacerbations, severity and treatment response. In research, in order to have common referral points, asthma is evaluated in accordance to the frequency of exacerbations, requirements for treatment in the Emergency Department or hospitalization, findings in spirometry and questionnaires associated with quality of life.

Asthma endotypes are the Th2_high and Th2_low meaning an endotype triggered by cytokines related to allergy such as IL-4,IL-5 and IL-13 and a distinct endotype with cytokines related to inflammation such as IL-6, or regulation of immune response such as IL-17. ³ In TH2_high endotypes include the early onset and late onset asthma, while the TH2_low asthma encompasses the aspirin exacerbated disease, disease of viral etiology, the obesity, and smoking and the pollution associated asthma. ⁴ Remodeling is related to severe asthma. ⁵

All these different phenotypes and endotypes identified currently with relevant specific biomarkers have a different natural course and they respond to different treatment. Thus, it is important to early identify the appropriate classification in order to individualize therapy and to have the optimal response results. Molecular investigation of sensitization in atopic asthma gives more information about co-sensitizations with pan-allergens or sensitization to allergens not currently included in conventional immunotherapy solutions. ⁶

Is Asthma Different in Adults and in Children and Are There Prediction Markers to Identify the Prone to the Asthma Cases? Which Are the Preventive Measures to Minimize Asthma Risk?

It is widely accepted that asthma is a chronic disease and physicians should amenably consider the diagnosis for young children. Thus, asthma phenotypes in childhood are distinct from adults including intermediate phenotypes with no confident approach to the asthma diagnosis. The widely accepted phenotypes to categorize children with wheezing in childhood with the arbitrary cutoff the age of 5 years are: episodic wheezers and multitrigger wheezers or children with transient wheezing, non-atopic wheezing, persistent wheezing, and severe wheezing with different natural course in the majority of cases.^7,8

Episodic or transient or non atopic wheezing expresses a phenotype named wheezy bronchitis which is used to describe children with episodes of wheeze triggered by viral infections. Rhinovirus and respiratory viral infections (RSV) are the most important. It is worth to mention that RSV triggers an IgE immune response. However, bronchoalveoral lavage detects a predominantly neutrophilic phenotype. ⁹ The specific phenotype is described also as post infectious asthma in the literature.

Overall, scientific trials conclude that 90% of non-atopic children will overcome their symptoms and they will attain normal lung function by puberty. Considering that non-atopic wheezers encompass the 1/3 of children at the age of 5 to 7 years, the number of children who do not progress into asthma is significant. ⁸

Who would be probable asthmatic children by adolescence could be relatively predicted. Children with multi-triggered wheezing, severe exacerbation attacks and atopic predisposition are most probably future asthmatics. ¹⁰ Atopic predisposition is well defined until the age of 5 years not only by the increased titers of IgE and the sensitizations to aeroallergens especially indoor allergens, but also with the development of other allergic conditions such as food allergy, atopic dermatitis, or/and allergic rhinitis demonstrating what is well-known as atopic march. ¹¹

Preventive indoor measures to dust mites, pets and mold could be beneficial to later lung function. ¹¹ Early identification of predisposing factors (age, gender, IgE, cationic protein, significant sensitization, other allergic co morbidities, hen’s egg and peanut sensitization) could modify the environment and the treatment of these children as a preventing measure for the development of asthma. ⁷

The main points to consider are personal history instead of family history, frequency and severity of exacerbations and sensitizations with those to dust mites and not to seasonal allergens as the most important. ¹² However, preventive measures mentioned in the literature as most efficient is not the avoidance of allergens per se, but the limitation of contributing environmental factors including tobacco smoke, type of bedding, indoor and outdoor air pollutants, psychosocial factors, and bioaerosols containing microbial breakdown products or allergens. ¹³

Which Biomarkers Are Used for Identification of Asthma Phenotypes and Endotypes?

First of all, an escalation on the choice of biomarkers to measure is prudent and cost-effective. In every day practice, the identification of the atopic profile (TH2 endotype) by simply measuring the number of eosinophils, total IgE and measurement of specific IgE to allergens by skin prick tests or ELISA methods is the first step.

However, it is important to measure other biomarkers when more sophisticated treatments such as Immunotherapy or biologic treatments are investigated. More specifically, eosinophilic inflammation is measured additionally by airway infiltration with eosinophils detected in the sputum (cutoff point = 3%) or by endoscopic lavage or measurement of exhaled FeNo (cut off > 50 in adults and >35 ppb in children). Measuring blood periostin is a reliable index of lung remodeling in TH2_high endotype of asthma. Urinary LTE4 is a highly sensitive marker to detect aspirin exacerbating asthma, while measurement of neutrophils in sputum or lavage (>40%-60%) or the detection of paucigranulocytic profile is associated with TH2 _low endotype. INF-γ and IL-17 are cytokines important in neutrophil recruitment and they are indicative of TH2_low endotype, which depicts the most severe and uncontrolled phenotype of asthma. An IL-6, IL-17, and IL-22 high levels are associated with obesity asthma, while measurement of metalloproteinase 9, when possible, and is associated with the remodeling process of the TH2_low endotype. ⁶

What Other Tests Are Considered Appropriate for the Diagnosis and Follow Up of Asthma Cases?

Spirometry with bronchodilator reversibility ≥20% is a reliable testing to detect obstruction before and after the initiation of treatment. In cases with intermittent not identifiable symptoms, methacholine challenge testing could clarify obscure cases. Since spirometry could be reliable in children older than 6 years old due to adherence reasons, impulse oscillometry could be applied with caution in younger children. ³

How Important is the Genetic Predisposition in Asthma? Which is the Role of Atopic Predisposition?

Asthma is considered a multifactorial disease and Genome Wide Association studies have unraveled many genes responsible for inflammation and smooth muscle development of the lungs in early age. Local innate immune maturation in the lungs contributes considerably in the development of disease. Since the genes have not changed the last 50 years, but the increase on the prevalence of asthma is 200% unfold, it seems that environmental factors have an important role. ¹¹

In Atopic Asthma, Which Are the Most Frequent Sensitizations Predisposing to Severe Asthma?

Sensitization to indoor allergens including dust mites, pets and molds is associated with perennial and more severe symptoms that manifest early in life (<3 years). Sensitizations to Der p1 and Der p2 are predictive of asthma at school age and specifically Der p1 and Der p23 with asthma severity. Sensitization to cat (Fel d1) and dog (Can f1) are associated also with increased risk for the progress of chronic wheezing to severe asthma. Fungal allergy is detected in 7% to 20% of the asthma population, 35% to 75% of cases of severe asthma and 54% to 91% of life threatening cases of asthma, especially sensitizations to Aspergillus, Altenaria, or Cladosporium accordingly. Sensitizations to grasses and the flowering of plants is associated with short term seasonal symptoms, while sensitizations to weeds is responsible for long term seasonal symptoms, most of them during early spring to autumn with symptoms varying depending on the concentration of pollens in the air.^7,10 Polysensitization is common and over 50% of patients with a respiratory allergy are sensitized to 2 or more allergens. However, identifying the relevant allergens responsible for the symptoms is within the action plan of an allergic investigation. ¹²

Which is the Role of Environment?

The most important environmental identifiers for asthma are pollutants and virus infections. Outdoor pollution, for example living close to motorways, increased use of indoor irritants as detergents or colognes; they increase oxidative stress and the relative damage in the lung epithelium. In the same way, tobacco smoke is an important determinant of indoors pollution with similar mechanisms. Although, large families, living in the country and exposure to low potential microbial parts including endotoxin are considered protective for the development of allergic disease, it seems more accurate to suppose that the age of exposure, the load of virus and bacteria and their virulence potential as well as host factors including genetic predisposition and the maturity of the innate and the specific B and T cell response determine the response of the individual to insults. ¹⁴ The overuse of antibiotics, sterile environment and limited exposure to natural environment as well nutritional factors including breastfeeding, fast foods and highly processed foods full in unsaturated fats, ω-3, and vitamins contribute to a balanced or defective immune response. ¹⁵ The above consist the well known Hygiene Hypothesis.

Is There a Need for Treatment of Asthma With Antibiotics?

In young children, a neutrophilic phenotype is related with a disease named bacterial bronchitis associated with asthma symptoms. The disease is associated with prolonged productive, purulent chronic cough not responding to rescue inhalers and steroids. It is caused by the infection of mucous membranes by bacteria such as Streptococcus pneumonia, Haemophilus influenza and Moraxella catarrhalis. These children respond to treatment with antibiotics for a long period. ¹⁶ Persistent Mycoplasma and Chlamydia infection should always be excluded due to their prolonged course and clinical presentation with low grade fever and dry cough. ¹⁶

Otherwise, antibiotic use in chronic wheezing has no position. In adults, the neutrophilic phenotype also does not respond to antibiotics, because it is a condition related with the production of proinflammatory cytokines and not infection. Macrolide use for the control of asthma is widely used in children not only because of its antimicrobial, but also due to its anti-inflammatory properties. However, metaanalysis of trials including 418 adults and children detected controversial results regarding its efficacy. ⁸

What is the Exercise Induced Asthma?

Asthma is exacerbated from exercise and cough triggered by exercise is a diagnostic symptom of asthma. However, a separate entity called exercise induced bronchoconstriction is a transient narrowing of lower airways after vigorous exercise frequently mentioned in elite athletes. Asthma symptoms are accompanied by findings in spirometry and a fall of FEV1 up to 10% to 15%. Cross country skiing, speed scatting, summer sports trigger the disease. The cause of this asthma phenotype is the severe dehydration and cooling of the airway surface followed by a reactive hyperemia in association with osmotic aberrations and release of mediators such as leucotrienes. Exudative fluid is extravagated from the cells causing narrowing of small bronchi and osmotic phenomena. ¹⁷ Moreover, hypersensitivity reactions such as urticaria, angioedema, asthma or anaphylaxis are related to exercise and consumption of certain foods within the last 2 to 3 hours. For example, consumption of fruits and vegetables and sensitization to lipid transfer proteins and rarely to profilins can be related with asthma symptoms. ¹⁴ These allergens are called pan allergens and exercise acts as a cofactor to induce hypersensitivity reactions. A similar condition is related to the consumption of wheat products and sensitization to ω5 gliadin. ¹⁸ These exercise-induced reactions are new recognized entities. ¹⁸ Aspirin exacerbated asthma is also another recognized entity induced by non-steroid antinflammatory drugs due to inhibition of COX1 and 2 enzymes and shift to the 5-LOX pathway and release of leukotrienes. ¹⁹

What is the Cornerstone of Treatment of Asthma?

Airway obstruction can be released by the so-called rescue treatment which includes short term and long term b-2 adrenergic drugs. However, as asthma is a non-infectious inflammation related disease, the cornerstone of treatment are steroids administrated in an inhaled form in order to avoid long term complications from these drugs. ²⁰

Step Up and Down Treatment, How Often Should be the Follow Up?

Asthma is a disease with chronic course with remissions and exacerbations related to extrinsic (eg, allergen load) and intrinsic factors (increased stress). Follow up is considered appropriate every 3 to 6 months depending on the control of symptoms and spirometry findings. Step up treatment is an add-on therapy with increase of the dose of current medications, especially steroids or with an additional medication of a different class. During remissions the opposite process is necessary. The aim of treatment is the control of asthma with less medication with emphasis to accomplish steroid free periods. ²¹

Asthma is a Contradiction to Immunotherapy (AIT) or Not? What Are the Results of AIT in Asthma?

Severe uncontrolled asthma is the most important contradiction for AIT associated with significant morbidity and mortality, while controlled severe asthma is a relative contradiction. Mild to moderate atopic asthma which is well controlled could be treated with AIT. Although randomized control studies show efficacy of treatment and they report a reduction of symptoms, exacerbations and hospitalization requirements, improvement of spirometry and steroid sparing effects, the heterogeneity of trials and meta-analyses results support controversial response and an obscure picture regarding efficacy. ¹⁴

However, AIT is indicative for treatment of both seasonal and perennial asthma in children. SLIT both pre- and co-seasonal AIT with grass pollen allergoid was proven efficient when it is applied for 3 years in regard to symptoms, use of rescue treatment and steroid sparing effect with improvement of symptoms 2 years after. ¹⁴ Regarding treatment of dust mite related disease, results are comparable regarding the route of administration (SCIT or SLIT), but evidence regarding the control of symptoms and long-term efficacy, although they show some benefit, they do not prove efficacy. ²²

When Allergic Rhinitis is Treated With Immunotherapy? Is a Reasonable Prevention Measure of Asthma?

Allergic rhinitis is considered a precursor of asthma and it is statistically associated with asthma. However, studies regarding the role of treating allergic rhinitis with AIT as a preventive measure for asthma are not well supported, especially as far as mild disease and disease caused by dust mites is concerned. ²³ An EACCI metaanalysis of trials for AIT for grass pollens, dust mites and Altenaria showed that prevention is evident and cost effective only in children with severe rhinitis. Additionally, AIT complications and duration of treatment are the cons of such intervention. ¹⁴ There are not currently available biomarkers for risk assessment of asthma in children suffering from allergic rhinitis. ²⁴ The younger age for initiating treatment has not also been established by studies. ²⁴

Conclusion

Asthma is an umbrella diagnosis disease with heterogeneity in phenotypes and endotypes. Recent advances in clarifying asthma are helpful for a better diagnosis and management of patients. Prevention measures and the role of the environment are discussed. Stepwise treatment with conservative drugs and modifying treatment is mentioned.