Pediatric Asthma Treatment & Management

The National Asthma Education and Prevention Program guidelines highlight the importance of treating impairment and risk domains of asthma. ^[2] The goals for therapy are as follows:

• Control asthma by reducing impairment through prevention of chronic and troublesome symptoms (eg, coughing or breathlessness in the daytime, in the night, or after exertion)

• Reduce the need for a short-acting beta2-agonist (SABA) for quick relief of symptoms (not including prevention of exercise-induced bronchospasm)

• Maintain near-normal pulmonary function

• Maintain normal activity levels (including exercise and other physical activity and attendance at work or school)

• Satisfy patients' and families' expectations for asthma care

Reduction in risk can be achieved by preventing recurrent exacerbations of asthma and minimizing the need for emergency room visits and hospitalizations, and preventing progressive loss of lung function. For children, preventing reduced lung growth and providing optimal pharmacotherapy with minimal or no adverse effects is important.

When a patient has major allergies to dietary products, avoidance of particular foods may help. In the absence of specific food allergies, dietary changes are not necessary. Unless compelling evidence for a specific allergy exists, milk products do not have to be avoided.

The goal of long-term therapy is to prevent acute exacerbations. The patient should avoid exposure to environmental allergens and irritants that are identified during the evaluation.

The current guidelines emphasize 4 important components of asthma care, as follows ^[2] :

• Assessment and monitoring

• Education

• Control of environmental factors and comorbid conditions

• Pharmacologic treatment

Assessment and monitoring

Once the patient's condition is classified and therapy has been initiated, continual assessment is important for disease control. Asthma control is defined as "the degree to which the manifestations of asthma are minimized by therapeutic intervention and the goals of therapy are met." ^[2] Asthma can be classified as well controlled, not well controlled, or very poorly controlled; classification criteria vary by patient age (view PDF).

In order to assess asthma control and adjust therapy, impairment and risk must be assessed. Assessment of impairment focuses on the frequency and intensity of symptoms and the functional limitations associated with these symptoms. Risk assessment focuses on the likelihood of asthma exacerbations, adverse effects from medications, and the likelihood of the progression of lung function decline; spirometry should be measured every 1-2 years, or more frequently for uncontrolled asthma.

Because asthma varies over time, follow-up every 2-6 weeks is initially necessary (when gaining control of the disease) and then every 1-6 months thereafter.

Education

Patient education continues to be important in all areas of medicine and is particularly important in asthma. Self-management education should focus on teaching patients the importance of recognizing their own their level of control and signs of progressively worsening asthma symptoms.

Both peak flow monitoring and symptom monitoring have been shown to be equally effective; however, peak flow monitoring may be more helpful in cases in which patients have a history of difficulty in perceiving symptoms, a history of severe exacerbations, or moderate-to-severe asthma.

Educational strategies should also focus on environmental control and avoidance strategies and medication use and adherence (eg, correct inhaler techniques and use of other devices).

Using a variety of methods to reinforce educational messages is crucial in patient understanding. Providing written asthma action plans in partnership with the patient (making sure to review the differences between long-term control and quick-relief medications), education through the involvement of other members of the healthcare team (eg, nurses, pharmacists, physicians), and education at all points of care (eg, clinics, hospitals, schools) are examples of various educational tools that are available and valuable for good patient adherence and understanding.

Control of environmental factors and comorbid conditions

As mentioned above, environmental exposures and irritants can play a strong role in symptom exacerbations. Therefore, in patients who have persistent asthma, the use of skin testing or in vitro testing to assess sensitivity to perennial indoor allergens is important. Once the offending allergens are identified, counsel patients on avoidance from these exposures. In addition, education to avoid tobacco smoke (both first-hand and second-hand exposure) is important for patients with asthma.

Lastly, comorbid conditions that may affect asthma must be diagnosed and appropriately managed. These include the following:

• Bronchopulmonary aspergillosis

• Gastroesophageal reflux disease (GERD)

• Obesity

• Obstructive sleep apnea

• Rhinitis

• Sinusitis

• Depression

• Stress

• Low vitamin D levels

Based upon reports of an inverse correlation between low vitamin D levels and asthma control, vitamin D supplementation in children might enhance corticosteroid responses, control atopy, and improve asthma control. ^[26] In a long-term study of children with asthma, those with Vitamin D deficiency or insufficiency responded less well to adequate doses of inhaled corticosteroids. ^[46]

A recent clinical trial of lansoprazole in children with poorly controlled asthma without gastroesophageal symptoms showed no improvement in symptoms or lung function, but was associated with increased adverse effects. ^[47]

Inactivated influenza vaccine is indicated for all children with asthma older than 6 months unless specifically contraindicated.

Pharmacologic treatment

Pharmacologic management includes the use of agents for control and agents for relief. Control agents include inhaled corticosteroids, inhaled cromolyn or nedocromil, long-acting bronchodilators, theophylline, leukotriene modifiers, and more recent strategies such as the use of the anti-immunoglobulin E (IgE) antibody (omalizumab) or IL-5 monoclonal antibodies (mepolizumab, benralizumab), or IL-4 receptor alpha monoclonal antibody (dupilumab) Relief medications include short-acting bronchodilators, systemic corticosteroids, and ipratropium.

For all but the most severely affected patients, the ultimate goal is to prevent symptoms, minimize morbidity from acute episodes, and prevent functional and psychological morbidity to provide a healthy (or near healthy) lifestyle appropriate to the age of child.

A stepwise approach to pharmacologic therapy is recommended to gain and maintain control of asthma in both the impairment and risk domains. The type, amount, and scheduling of medication is dictated by asthma severity (for initiating therapy) and the level of asthma control (for adjusting therapy). Step-down therapy is essential to identify the minimum medication necessary to maintain control. See table below.

When children are well controlled, it is reasonable to try to reduce their therapy. Whether on relatively high-dose inhaled steroids, or a combination of steroid/long-acting beta2-agonist, it is best to try to continue to control them on a lower dose, or on less medication. Reducing inhaled steroids and/or eliminating the long-acting beta2-agonist could result in a deterioration in asthma control. When such steps are taken, it is critical to see those children frequently, monitoring their history, physical examination and spirometry. ^[48]

For pharmacotherapy, children with asthma are divided into 3 groups based on age: 0-4 y, 5-11 y, 12 y and older.

For all patients, quick-relief medications include rapid-acting beta2-agonists as needed for symptoms. The intensity of treatment depends on the severity of symptoms. If rapid-acting beta2-agonists are used more than 2 days a week for symptom relief (not including use of rapid-acting beta2-agonists for prevention of exercise induce symptoms), stepping up treatment may be considered. See the stepwise approach to asthma medications in Table 1, below.

Table 1. Stepwise Approach to Asthma Medications (Open Table in a new window)

In the Salmeterol Multicenter Asthma Research Trial (SMART), salmeterol use in asthma patients, particularly African Americans, was associated with a small but significantly increased risk of serious asthma-related events. ^[49] This trial was a large, double-blind, randomized, placebo-controlled, safety trial in which salmeterol 42 mcg twice daily or placebo was added to usual asthma therapy for 28 weeks.

The study was halted following interim analysis of 26,355 participants because patients exposed to salmeterol (n = 13,176) were found to experience a higher rate of fatal asthma events compared with individuals receiving placebo (n = 13,179); the rates were 0.1% and 0.02%, respectively. This resulted in an estimated 8 excess deaths per 10,000 patients treated with salmeterol.

In the post-hoc subgroup analysis, the relative risks of asthma-related deaths were similar among whites and blacks, although the corresponding estimated excess deaths per 10,000 patients exposed to salmeterol were higher among blacks than whites.

A meta-analysis by Salpeter et al found that LABAs increased the risk for asthma-related intubations and deaths by 2-fold, even when used in a controlled fashion with concomitant inhaled corticosteroids. However, the absolute number of adverse events remained small. ^[50] The large pooled trial included 36,588 patients, most of them adults.

The US Food and Drug Administration (FDA) has reviewed the data and the issues and has determined that the benefits of LABAs in improving asthma symptoms outweigh the potential risks when LABAs are used appropriately with an asthma controller medication in patients who need the addition of LABAs. The FDA recommends the following measures for improving the safe use of these drugs ^[51] :

• LABAs should be used long-term only in patients whose asthma cannot be adequately controlled on inhaled steroids

• LABAs should be used for the shortest duration of time required to achieve control of asthma symptoms and discontinued, if possible, once asthma control is achieved; patients should then be switched to an asthma controller medication

• Pediatric and adolescent patients who require the addition of a LABA to an inhaled corticosteroid should use a combination product containing both an inhaled corticosteroid and a LABA to ensure compliance with both medications

Concerns about the safety of long-acting beta2-agonists and resultant drug safety communications create a question as to the course of treatment if asthma is not controlled by inhaled corticosteroids. ^[51] A study by Lemanske et al addressed this question and concluded that addition of long-acting beta2-agonist was more likely to provide the best response than either inhaled corticosteroids or leukotriene-receptor antagonists. ^[52] Asthma therapy should be regularly monitored and adjusted accordingly.

The CHASE (ChildHood Asthma Safety and Efficacy) international clinical trial further evaluated the combination of inhaled corticosteroids plus long-acting beta2 agonists. Orally inhaled budesonide/formoterol (Symbicort) 80/4.5 mcg with orally inhaled budesonide 80 mcg in pediatric patients with asthma aged 6-12 years who were symptomatic on low-dose inhaled corticosteroids. A statistically significant improvement in lung function (FEV1 at 1 h postdose) was observed with the children randomized to budesonide/formoterol (n=92) compared with budesonide alone (n=95) (p ≤0.005). ^[53]

A systematic review of 18 placebo-controlled clinical trials evaluating monotherapy with inhaled corticosteroids supports their safety and efficacy in children with asthma. ^[54] In addition, the data provide new evidence linking inhaled corticosteroids use in children with asthma to improved asthma control. A recent study to assess the effectiveness of an inhaled corticosteroid used as rescue treatment recommends that children with mild persistent asthma should not be treated with rescue albuterol alone and the most effective treatment to prevent exacerbations is daily inhaled corticosteroids. This study suggests that inhaled corticosteroids as rescue medication with albuterol might be an effective step down strategy for children as it is more effective at reducing exacerbations than is use of rescue albuterol alone. ^[55] .

Due to concern about oral corticosteroid overuse, Farber et al conducted a study that reported that of the 69,056 children with asthma reported in the Texas Children’s Health Plan database from 2011-2015, 42.1% to 44.2% were prescribed oral corticosteroid more than once. Repeated prescriptions of oral corticosteroids were more common in children younger than 5 years and 81%-83% of children prescribed oral corticosteroids did not have other signs of poor asthma control (excessive β-agonist refills, emergency department visits, or hospitalizations for asthma). ^{[56, 57]}

A recent Cochrane review concluded that more research is needed to assess the effectiveness of increased inhaled corticosteroid doses at the onset of asthma exacerbation. ^[58]

In children, long-term use of high-dose steroids (systemic or inhaled) may lead to adverse effects, including growth failure. Recent data from the Childhood Asthma Management Program (CAMP) study and results of the long-term use of inhaled steroids (budesonide) suggest that the long-term use of inhaled steroids has no sustained adverse effect on growth in children. ^{[59, 60]}

A review by Rodrigo et al looked at 8 studies of omalizumab in children with moderate to severe asthma and elevated IgE levels. ^[61] Children treated with omalizumab were more significantly able to reduce their use of rescue inhalers and their inhaled and/or oral steroid dose than patients in the placebo group. Although no significant differences in pulmonary function were observed, patients receiving omalizumab had fewer exacerbations than the children receiving placebo. These studies lasted a year or less and did not reveal any significant adverse effects of the omalizumab.

A randomized trial of omalizumab for asthma in inner-city children showed improved asthma control, elimination of seasonal peaks in asthmatic exacerbations, and reduced need for other medications for asthma control. ^[62]

Another study, by Deschildre et al, indicated that adding omalizumab to maintenance therapy can improve asthma control in children with severe, uncontrolled allergic asthma. In a study of 104 such children, Deschildre and colleagues found that adding omalizumab increased the rate of good asthma control from 0% to 53% and reduced exacerbation and hospitalization rates by 72% and 88.5%, respectively. By 1-year follow-up, FEV1 (forced expiratory volume in 1 second) had improved in the study's patients by 4.9%, and inhaled corticosteroid dose had decreased by 30%. ^{[63, 64]}

Additional monoclonal antibodies have been approved for children, but unlike omalizumab, they target various interleukin (IL) subtypes. Monoclonal antibodies approved for severe asthma that target IL-5 include mepolizumab and benralizumab. Dupilumab inhibits IL-4 receptor alpha, and thereby blocks IL-4 and IL-13 signaling.

Delivery devices and best route of administration

In pediatric asthma, inhaled treatment is the cornerstone of asthma management. Inhaler devices currently used to deliver inhaled corticosteroids (ICSs) fall into the following 4 categories:

• Pressurized metered dose inhaler (pMDI) - Propellant used to dispense steroid when canister is pressed manually

• Dry powder inhaler (DPI) - Does not require hand-breath coordination to operate

• Breath-actuated pMDI - Propellant used to dispense steroid when patient inhales

• Nebulized solution devices

Go to Use of Metered Dose Inhalers, Spacers, and Nebulizers for complete information on this topic.

In pediatric patients, the inhaler device must be chosen on the basis of age, cost, safety, convenience, and efficacy of drug delivery. ^[4]

Based on current research, the preferred device for children younger than 4 years is a pMDI with a valved holding chamber and age-appropriate mask. Children aged 4-6 years should use a pMDI plus a valved holding chamber. Lastly, children older than 6 years can use either a pMDI, a DPI, or a breath-actuated pMDI. For all 3 groups, a nebulizer with a valved holding chamber (and mask in children younger than 4 y) is recommended as alternate therapy. ^[4]

Valved holding chambers are important. The addition of a valved holding chamber can increase the amount of drug reaching the lungs to 20%. The use of a valved holding chamber helps reduce the amount of drug particles deposited in the oropharynx, thereby helping to reduce systemic and local effects from oral and gastrointestinal absorption.

A Cochrane review on the use of valved holding chambers versus nebulizers for inhaled steroids found no evidence that nebulizers are better than valved holding chamber. ^[65] Nebulizers are expensive, inconvenient to use, require longer time for administration, require maintenance, and have been shown to have imprecise dosing.

Newer devices are showing greater efficacy. For MDIs, chlorofluorocarbon (CFC) propellants (implicated in ozone depletion) have been phased out in favor of the hydrofluoroalkane-134a (HFA) propellant. Surprisingly, the HFA component is more environmentally friendly and has proven to be more effective, due to its smaller aerosol particle size, which results in better drug delivery. MDIs with HFA propellant have better deposition of drug in the small airways and greater efficacy at equivalent doses compared with CFC-MDIs.

Treatment goals for acute severe asthmatic episodes (status asthmaticus) are as follows:

• Correction of significant hypoxemia with supplemental oxygen; in severe cases, alveolar hypoventilation requires mechanically assisted ventilation

• Rapid reversal of airflow obstruction with repeated or continuous administration of an inhaled beta2-agonist; early administration of systemic corticosteroids (eg, oral prednisone or intravenous methylprednisolone) is suggested in children with asthma that fails to respond promptly and completely to inhaled beta2-agonists

• Reduction in the likelihood of recurrence of severe airflow obstruction by intensifying therapy: Often, a short course of systemic corticosteroids is helpful

Achieving these goals requires close monitoring by means of serial clinical assessment and measurement of lung function (in patients of appropriate ages) to quantify the severity of airflow obstruction and its response to treatment. Improvement in FEV₁ after 30 minutes of treatment is significantly correlated with a broad range of indices of the severity of asthmatic exacerbations, and repeated measurement of airflow in the emergency department can help reduce unnecessary admissions.

The use of the peak flow rate or FEV₁ values, patient's history, current symptoms, and physical findings to guide treatment decisions is helpful in achieving the aforementioned goals. When using the peak expiratory flow (PEF) expressed as a percentage of the patient's best value, the effect of irreversible airflow obstruction should be considered. For example, in a patient whose best peak flow rate is 160 L/min, a decrease of 40% represents severe and potentially life-threatening obstruction.

An Australian study by Vuillermin et al found that asthma severity decreased in school-aged children when parents initiated a short course of prednisolone for acute asthma. ^[66] Children who received parent-initiated prednisolone for episodes of asthma had lower daytime and nighttime asthma scores, reduced risk of health resource use, and reduced school absenteeism compared with children who received placebo.

Any patient with high-risk asthma should be referred to a specialist. The following may suggest high risk:

• History of sudden severe exacerbations

• History of prior intubation for asthma

• Admission to an ICU because of asthma

• Two or more hospitalizations for asthma in the past year

• Three or more emergency department visits for asthma in the past year

• Hospitalization or an emergency department visit for asthma within the past month

• Use of 2 or more canisters of inhaled short-acting beta2-agonists per month

• Current use of systemic corticosteroids or recent withdrawal from systemic corticosteroids

Referral to an asthma specialist for consultation or comanagement of the patient is also recommended if additional education is needed to improve adherence or if the patient requires step 4 care or higher (step 3 care or higher for children aged 0–4 y). Consider referral if a patient requires step 3 care (step 2 care for children aged 0–4 y) or if additional testing for the role of allergy is indicated. ^[2]

The choice between a pediatric pulmonologist and an allergist may depend on local availability and practices. A patient with frequent ICU admissions, previous intubation, and a history of complicating factors or comorbidity (eg, cystic fibrosis) should be referred to a pediatric pulmonologist. When allergies are thought to significantly contribute to the morbidity, an allergist may be helpful.

Consider consultation with an ear, nose, and throat (ENT) specialist for help in managing chronic rhinosinusitis. Consider consultation with a gastroenterologist for help in excluding and/or treating gastroesophageal reflux.

Regular follow-up visits are essential to ensure control and appropriate therapeutic adjustments. In general, patients should be assessed every 1-6 months. At every visit, adherence, environmental control, and comorbid conditions should be checked.

If patients have good control of their asthma for at least 3 months, treatment can be stepped down. However, the patient should be reassessed in 2-4 weeks to make sure that control is maintained with the new regimen. If patients require step 2 asthma medications or higher, consultation with an asthma specialist should be considered.

Outpatient visits should include the following:

• Interval history of asthmatic complaints, including history of acute episodes (eg, severity, measures and treatment taken, response to therapy)

• History of nocturnal symptoms

• History of symptoms with exercise, and exercise tolerance

• Review of medications, including use of rescue medications

• Review of home-monitoring data (eg, symptom diary, peak flow meter readings, daily treatments)

Patient evaluation should include the following:

• Assessment for signs of bronchospasm and complications

• Evaluation of associated conditions (eg, allergic rhinitis)

• Pulmonary function testing (in appropriate age group)

Address issues of treatment adherence and avoidance of environmental triggers and irritants.

Long-term asthma care pathways that incorporate the aforementioned factors can serve as roadmaps for ambulatory asthma care and help streamline outpatient care by different providers.

In the author's asthma clinic, a member of the asthma care team sits with each patient to review the written asthma care plan and to write and discuss in detail a rescue plan for acute episodes, which includes instructions about identifying signs of an acute episode, using rescue medications, monitoring, and contacting the asthma care team. These items are reviewed at each visit.

One study using directly observed administration of daily preventive asthma medications by a school nurse showed significantly improved symptoms among urban children with persistent asthma. ^[67]

In a study of 13,506 children with asthma who underwent adenotonsillectomy and 27,012 matched controls with asthma who did not undergo adenotonsillectomy, Bhattacharjee et al found that those who had the procedure showed significant improvement on several measures of asthma disease severity, including acute asthma exacerbations and acute status asthmaticus. ^{[68, 69]}

Compared to the year before the procedure, at 1-year postadenotonsillectomy follow-up, there was a 30.2% reduction in acute asthma exacerbations and a 37.9% reduction in acute status asthmaticus (P< 0.0001 for both). ^{[68, 69]} In addition, asthma-related emergency department visits were reduced by 25.6% and asthma-related hospitalizations by 35.8%. Patients who underwent the procedure also had significantly fewer refills of several asthma medications. In contrast, no significant reductions were observed in any of these outcomes among children who did not undergo adenotonsillectomy. ^{[68, 69]}