Pediatric asthma: Principles and treatment

Abstract

Approximately one-half of children with asthma present with symptoms before 3 years of age. The typical history describes recurrent episodes of wheezing and/or cough triggered by a viral upper respiratory infection (URI), activity, or changes in weather. When symptoms occur after a viral URI, children with asthma often take longer than the usual week to fully recover from their respiratory symptoms. Wheezing and coughing during exercise or during laughing or crying, and episodes triggered in the absence of infection suggest asthma. A trial of bronchodilator medication should show symptomatic improvement. The goal of asthma therapy is to keep children "symptom free" by preventing chronic symptoms, maintaining lung function, and allowing for normal daily activities. Avoidance of triggers identified by a history, such as second-hand cigarette smoke exposure, and allergens identified by skin-prick testing can significantly reduce symptoms. According to the 2007 National Asthma Education and Prevention Program (NAEPP) report, if impairment symptoms are present for >2 days/week or 2 nights/month, then the disease process is characterized as persistent, and, in all age groups, inhaled corticosteroids (ICS) are recommended as the preferred daily controller therapy. Montelukast is approved for children ages ≥ 12 months and is often used for its ease of daily oral dosing. Long-acting β-2 adrenergic agonists should only be used in combination with an ICS. For more-severe or difficult-to-control phenotypes, biologic therapy has been developed, which targets the type of inflammation present.

Asthma is the most common chronic disease of childhood, and approximately one-half of children with asthma present with symptoms before 3 years of age. However, nonasthmatic wheezing and cough are also common in pediatrics and frequently create a diagnostic challenge to the practitioner. To diagnose asthma in a child, one must be familiar with a differential diagnosis for wheezing and episodic cough, as listed in Table 1. The history is of utmost importance in the diagnosis of childhood asthma. The typical history describes recurrent episodes of wheezing and/or cough triggered by a viral upper respiratory infection (URI), activity, or changes in weather.

Table 1.

Differential diagnoses of asthma in children

Infants
Bronchiolitis
Pneumonia, pertussis
Gastroesophageal reflux
Bronchopulmonary dysplasia
Cystic fibrosis
Aspiration, with feeding or swallowing disorder
Congenital cardiac disease
Congenital airway defects
Subglottic stenosis (also previous intubation)
Laryngotracheomalacia
Laryngeal web
Vascular ring, other extrinsic airway compression
Tracheoesophageal fistula
Bronchopulmonary defects
Immunodeficiency syndromes
Ciliary dyskinesia syndromes
Toddlers
Viral airway infection, bronchiolitis, croup
Pneumonia, pertussis
Gastroesophageal reflux
Aspiration, foreign body
Cystic fibrosis
Epiglottitis
Anaphylaxis
Immunodeficiency syndromes
Ciliary dyskinesia syndromes
Older children (also consider toddlers' diagnoses)
Gastroesophageal reflux
Sinusitis
Other infectious processes, including pertussis and croup
Pneumonia, including Mycoplasma pneumoniae
Anaphylaxis
Tuberculosis
Adolescents
Sinusitis
Gastroesophageal reflux
Pneumonia, including M. pneumoniae
Vocal cord dysfunction
Habit or psychogenic cough
Tuberculosis
Human immunodeficiency virus
Anaphylaxis
Tumor, compressing airway
Toxic inhalation

When symptoms follow a viral URI, children with asthma often take longer than the usual week to recover fully from their respiratory symptoms. Wheezing and coughing during laughing or crying, and episodes triggered in the absence of infection suggest asthma. A trial of bronchodilator medication should show symptomatic improvement. Asking about previous emergency department visits, hospitalizations, or systemic steroid courses often reveals the frequency and severity of these episodes. A history of secondhand smoke exposure, gastroesophageal reflux, or sinusitis may identify the primary cause of respiratory symptoms, but, frequently, these also are triggers of underlying asthma. A personal or immediate family history of atopic disease, such as allergic rhinitis, food allergy, or eczema, increases the likelihood that a child will have persistent wheezing, especially if symptoms present in the first year of life.

A complete physical examination should be performed to rule out diseases that mimic asthma. The presence of persistent focal findings on repeated examinations should not be attributed solely to asthma and deserves further investigation. Between asthma exacerbations, physical examination findings may be normal or may reveal increased chest anterior-posterior diameter, prolongation of the expiratory phase of the respiratory cycle, or decreased air entry. When acutely symptomatic, the child may not be hypoxic but is usually tachypneic, with symmetric bilateral expiratory wheezing. Physical signs of overt respiratory distress are often less prominent in older children and teens compared with infants and younger children.

Traditional pulmonary function testing is difficult to perform in young children and is generally not recommended in children < 5 years of age. However, other tests may prove useful when evaluating respiratory disease. At least one baseline chest radiograph should be performed to rule out a structural abnormality. Additional studies may be ordered to rule out different diagnoses or factors that are complicating asthma, such as gastroesophageal reflux, microaspiration, sinusitis, cystic fibrosis, sickle cell disease, tuberculosis, or immunodeficiency. As discussed in this issue, skin-prick testing to environmental allergens documents the presence of sensitization and may guide environmental control measures in children who are atopic. After the age of 5 years, traditional pulmonary function testing may be helpful to document airway resistance, flow volume loops, and lung volumes. Methacholine challenge may be helpful to document airway responsiveness but is not specific for asthma alone.

The goal of asthma therapy is to keep children "symptom free" by preventing chronic symptoms, maintaining lung function, and allowing for normal daily activities. Avoidance of triggers and allergens identified by a history and confirmed as clinically relevant by skin-prick testing or serum-specific immunoglobulin E (IgE) testing can significantly reduce symptoms and should be addressed at each physician encounter. In 2007, the National Asthma Education and Prevention Program published updated clinical practice guidelines for the medical treatment of asthma, with a focus on impairment and risk as the two key domains of severity and control of asthma.¹ These guidelines are likely to be updated in the near future. The guidelines currently address children in three groups separated by age: 0–4 years, 5–11 years, and ≥12 years.¹

In the assessment of severity, if impairment symptoms are present for >2 days/week or 2 nights/month, the disease process is characterized as persistent, and, in all age groups, inhaled corticosteroid (ICS) are recommended as the preferred daily controller therapy. The addition of a risk assessment provides recommendations for therapy in children who may be at higher risk for exacerbation but have low levels of impairment between exacerbations. Recommendations in this case include considering daily long-term therapy initiation, especially in children ages 0–4 years with risk factors for persistent asthma (i.e., parental asthma, physiciandiagnosed atopic dermatitis, aeroallergen or food sensitization, peripheral eosinophilia or wheezing apart from colds) and four or more episodes of wheezing in the past year that lasted > 1 day.

Similarly, children ages 0–4 years with two exacerbations that require oral corticosteroids in the past 6 months and children ages 5–11 years or youth ≥ 12 years of age with two or more exacerbations that required corticosteroids in the past year would meet risk criteria to start or step up long-term controller therapy. The use of ICS and short-acting β-agonist (SABA) therapy as needed only during times of illness has been shown to decrease exacerbations and the need for oral corticosteroids in children < 5 years of age with a history of recurrent wheezing compared with SABA alone.² In younger children (ages 1–4 years) with a history of recurrent wheezing and a positive modified asthma predictive index, the results of studies from the Childhood Asthma Research and Education Network indicate that, in this group, there was no therapeutic advantage between low-dose daily ICS compared with intermittent high-dose therapy and no differences in linear growth.³

The type and dosing of medication therapy for asthma is determined by the initial assessment of asthma severity and ongoing categorization of control. Low-dose ICS is the preferred medication for treatment of mild persistent disease in all age groups. Alternative medications include cromolyn and leukotriene receptor antagonists (montelukast); however, cromolyn is less efficacious than ICS, and montelukast occasionally may have associated neuropsychiatric adverse effects. Theophylline is included as an alternative agent in children > 5 years of age but requires close monitoring for potential toxicity and has minimal anti-inflammatory effects.

For patients with moderate persistent disease, it is preferred to start with a medium dose of ICS in children ≤ 4 years. However, for moderate persistent disease in children ages 5–11 years, it is equally acceptable to use low-dose ICS in combination with either montelukast or a long-acting 32 β-agonist (LABA) or to start the patient on a medium dose of ICS. In the National Asthma Education and Prevention Program guidelines,¹ in children ≥ 12 years of age, the addition of an LABA to low-dose ICS is preferred over the addition of montelukast. In 2003, a black box warning was applied to LABAs due to their possible contribution to asthma-related deaths; however, the U.S. Food and Drug Administration removed this warning from combination ICS-LABA therapies in December 2017 when safety trials did not support this increased risk.⁴ The black box warning remains on noncombination LABA products, and it is well accepted that LABAs should not be used as a monotherapy (i.e., should only be used in conjunction with ICS) and should not be used in patients with adequate asthma control on a low-to-medium dose of ICS.

For youths ≥ 12 years with uncontrolled, severe disease, the addition of a long-acting muscarinic antagonist (LAMA) to an ICS reduces asthma exacerbations and improves lung function, whereas, the addition to an ICS-LABA improves lung function and asthma control.² In addition, measuring serum biomarkers, e.g., total IgE and absolute eosinophil count, allow for determining whether patients are eligible for phenotypetargeted therapies to treat severe or difficult-to-control disease. Omalizumab, an anti-IgE monoclonal antibody is approved for moderate-severe asthma in children ≥ 6 years with aeroallergen sensitization.⁵

Mepolizumab, an anti-interleukin (IL) 5 monoclonal antibody, or benralizumab, an anti-IL-5 receptor monoclonal antibody, could be considered as add-on therapy in youths ≥ 6 years with asthma and with peripheral eosinophilia.⁵ The monoclonal antibody dupilumab targets IL-4 and IL-13 by binding a shared receptor subunit. This medication is approved as add-on therapy in youths ages ≥ 12 years with moderate-severe asthma and has been shown to reduce exacerbations and improve FEV1 in the first second of expiration.⁵ There are ongoing studies that continue to evaluate the efficacy and safety of these and other biologic agents in the pediatric population. The antiIgE and anti-IL-5 agents have been incorporated into the 2017 Global Initiative for Asthma guidelines⁵ for children with severe allergic or eosinophilic asthma as part of maintenance therapy.

Several recommendations exist regarding management of acute loss of asthma control. An SABA should be initiated at two to four puffs every 4–6 hours in combination with recommended controller therapy. For patients controlled with a low-to-medium dose of ICS, there have been previous recommendations for quadrupling the daily ICS dose for acute loss of asthma control; however, results of a recent study suggested no improved outcomes and possible growth effects with short-term quintupling of the ICS dose.^6,7 Although there have been investigations into the use of patient-directed, dynamic step-up dosing with ICSLABA during times of acute loss of asthma control, in the United States, ICS-LABA therapy is not approved as both maintenance and reliever.⁶

In children, asthma education should include the regular reinforcement of proper delivery-device technique. For metered-dose inhalers, this must include a valved holding chamber to ensure consistent medication delivery to the airways. Dry powder inhaler devices do not require a valved holding chamber, but instruction on proper technique is equally important and may not be appropriate for children unable to participate in spirometry.

Many parents are hesitant to administer inhaled steroids for fear of adverse effects. Poor adherence to controller therapy is one of the largest barriers to consistent asthma care; therefore, physicians must take the time to address the benefit-to-risk ratio of ICS with the family. To date, the only significant ICS adverse effect identified in children is an initial decrease in growth velocity, which results in an ∼1 cm difference in height from peers after 1–2 years of treatment with budesonide 400 µg/day, a difference that, on long-term follow-up, was shown to be persistent into adulthood.⁸

These differences may be more pronounced in prepubertal children. Studies in even younger age groups performed over 2 years show similar effects on shortterm growth, although effects on long-term growth with dosing in the first years of life are not yet known.⁹ After discontinuation of the ICS, younger children may exhibit adequate catch-up growth; however, results of one study indicated that this degree of catch-up growth was not evident over 2 years of follow-up in children 2 years of age and who weighed < 17 kg.¹⁰

There may be mild, clinically insignificant effects of ICS on bone mineral density in children; however, physicians and health-care professionals should be attentive to additional risk factors for diminished bone mineral density that a child might have because the addition of a high-dose ICS may then have an additive, clinically significant effect.¹¹ Epidemiologic evaluations of cataract incidence have not been conclusive in finding an increased risk with ICS use alone. Despite these potential adverse effects, parents should understand that poor asthma control may lead to severe and potentially life-threatening exacerbations and more frequent systemic steroid use, which can also suppress growth with additional unwanted adverse effects.

Parents frequently ask, "Will my child outgrow asthma?" Most children who wheeze in infancy will not have persistent wheezing in later childhood. Known risk factors for persistent wheezing include smoke exposure, a family history of asthma or atopy, and a personal history of atopic inflammation (such as allergic rhinitis, eczema, or increased eosinophil counts). The subset of children who have persistent wheezing have normal initial infant pulmonary functions but will show decreased FEV1 in the first second of expiration compared with peers by 6 years of age. Longitudinal data also reveal that decreased pulmonary function in middle childhood may persist into adult life and may be correlated with severity. Therefore, early disease severity may correlate with a decreased chance of quiescent asthma, or "outgrowing asthma," later in life.

IMMUNOLOGY

• Bronchoalveolar lavage (BAL) fluid from children with wheezing has increased numbers of lymphocytes, polymorphonuclear cells, macrophages, and monocytes compared with normal controls. Leukotriene B4 (LTB₄), leukotriene C4 (LTC₄), and Prostaglandin E2 (PGE₂) also are increased.¹²

• Asthma can be phenotyped by the type of airway inflammation present (i.e., neutrophilic, eosinophilic, etc.), and this may increasingly inform the therapeutic approach.⁵

CLINICAL PEARLS

• Childhood wheezing and cough are common and do not always represent asthma.

• The physician and health-care professional should be familiar with an age-appropriate differential diagnosis of asthma and what history and physical examination markers predict a risk for persistent wheezing.

• Inhaled corticosteroids are preferred first-line controller therapy in childhood persistent asthma. The consistent adverse effect shown in children is a decrease in growth velocity, which does not seem to be progressive but may be persistent. More data are needed to evaluate the long-term safety profile of inhaled steroids in preschool children.

• Asthma trigger avoidance, medication compliance, and medication administration technique should be reviewed at interval physician encounters. Valved holding chambers should be used with metered-dose inhaler medicines in children.