Pediatric Asthma 

Updated: Jan 08, 2019
Author: Girish D Sharma, MD, FCCP, FAAP; Chief Editor: Kenan Haver, MD 

Overview

Practice Essentials

Asthma, which occurs in adult and pediatric patients, is a chronic inflammatory disorder of the airways characterized by an obstruction of airflow. Among children and adolescents aged 5-17 years, asthma accounts for a loss of 10 million school days annually and costs caretakers $726.1 million per year because of work absence.[1]

Signs and symptoms

History

The clinician should establish whether the patient has any of the following symptoms:

  • Wheezing: A musical, high-pitched whistling sound produced by airflow turbulence is one of the most common symptoms of asthma. The wheezing is usually during exhalation.

  • Cough: Usually, the cough is nonproductive and nonparoxysmal; coughing may be present with wheezing

  • Cough at night or with exercise: Coughing may be the only symptom of asthma, especially in cases of exercise-induced or nocturnal asthma; children with nocturnal asthma tend to cough after midnight, during the early hours of morning

  • Shortness of breath

  • Chest tightness: A history of tightness or pain in the chest may be present with or without other symptoms of asthma, especially in exercise-induced or nocturnal asthma

Sputum production

In an acute episode of asthma, symptoms vary according to the episode’s severity. Infants and young children suffering a severe episode display the following characteristics:

  • Breathless during rest

  • Not interested in feeding

  • Sit upright

  • Talk in words (not sentences)

  • Usually agitated

With imminent respiratory arrest, the child displays the aforementioned symptoms and is also drowsy and confused. However, adolescents may not have these symptoms until they are in frank respiratory failure.

Physical examination

Findings during a severe episode include the following:

  • Respiratory rate is often greater than 30 breaths per minute

  • Accessory muscles of respiration are usually used

  • Suprasternal retractions are commonly present

  • The heart rate is greater than 120 beats per minute

  • Loud biphasic (expiratory and inspiratory) wheezing can be heard

  • Pulsus paradoxus is often present (20-40 mm Hg)

  • Oxyhemoglobin saturation with room air is less than 91%

Findings in status asthmaticus with imminent respiratory arrest include the following:

  • Paradoxical thoracoabdominal movement occurs

  • Wheezing may be absent (in patients with the most severe airway obstruction)

  • Severe hypoxemia may manifest as bradycardia

  • Pulsus paradoxus may disappear: This finding suggests respiratory muscle fatigue

See Clinical Presentation for more detail.

Diagnosis

Tests used in the diagnosis of asthma include the following:

  • Pulmonary function tests: Spirometry and plethysmography

  • Exercise challenge: Involves baseline spirometry followed by exercise on a treadmill or bicycle to a heart rate greater than 60% of the predicted maximum, with monitoring of the electrocardiogram and oxyhemoglobin saturation

  • Fraction of exhaled nitric oxide (FeNO) testing: Noninvasive marker of airway inflammation

  • Radiography: Reveals hyperinflation and increased bronchial markings; radiography may also show evidence of parenchymal disease, atelectasis, pneumonia, congenital anomaly, or a foreign body

  • Allergy testing: Can identify allergic factors that may significantly contribute to asthma

  • Histologic evaluation of the airways: Typically reveal infiltration with inflammatory cells, narrowing of airway lumina, bronchial and bronchiolar epithelial denudation, and mucus plugs

See Workup for more detail.

Management

Guidelines from the National Asthma Education and Prevention Program emphasize the following components of asthma care[2] :

  • Assessment and monitoring: In order to assess asthma control and adjust therapy, impairment and risk must be assessed; 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: Self-management education should focus on teaching patients the importance of recognizing their own level of control and signs of progressively worsening asthma symptoms; educational strategies should also focus on environmental control and avoidance strategies, as well as on medication use and adherence (eg, correct inhaler techniques and use of other devices)

  • Control of environmental factors and comorbid conditions

  • Pharmacologic treatment

  • Pharmacologic treatment

Pharmacologic asthma management includes the use of agents for control and agents for relief. Control agents include the following:

  • Inhaled corticosteroids

  • Inhaled cromolyn or nedocromil

  • Long-acting bronchodilators

  • Theophylline

  • Leukotriene modifiers

  • Anti-immunoglobulin E (IgE) antibodies (omalizumab)

  • Interleukin inhibitors (eg, mepolizumab, benralizumab, dupilumab)

Relief medications include the following:

  • Short-acting bronchodilators

  • Systemic corticosteroids

  • Ipratropium

See Treatment and Medication for more detail.

Background

Asthma is a chronic inflammatory disorder of the airways characterized by an obstruction of airflow, which may be completely or partially reversed with or without specific therapy. Airway inflammation is the result of interactions between various cells, cellular elements, and cytokines. In susceptible individuals, airway inflammation may cause recurrent or persistent bronchospasm, which causes symptoms that include wheezing, breathlessness, chest tightness, and cough, particularly at night (early morning hours) or after exercise.

Airway inflammation is associated with airway hyperreactivity or bronchial hyperresponsiveness (BHR), which is defined as the inherent tendency of the airways to narrow in response to various stimuli (eg, environmental allergens and irritants).[3]

Asthma affects an estimated 300 million individuals worldwide (see Epidemiology). The prevalence of asthma is increasing, especially in children. Annually, the World Health Organization (WHO) has estimated that 15 million disability-adjusted life-years are lost and 250,000 asthma deaths are reported worldwide.[4] Approximately 500,000 annual hospitalizations (34.6% in individuals aged 18 y or younger) are due to asthma. In the United States, asthma prevalence, having increased from 1980 to 1996, showed a plateau at 9.1% of children (6.7 million) in 2007.[5]

The cost of illness related to asthma is around $6.2 billion. Each year, an estimated 1.81 million people (47.8% in individuals aged 18 y or younger) require treatment in the emergency department. Among children and adolescents aged 5-17 years, asthma accounts for a loss of 10 million school days and costs caretakers $726.1 million because of work absence.[1]

Guidelines from the National Asthma Education and Prevention Program provide recommendations on the diagnosis and treatment of pediatric asthma (see Clinical Presentation, Workup, and Treatment and Management).

Pathophysiology

Interactions between environmental and genetic factors result in airway inflammation, which limits airflow and leads to functional and structural changes in the airways in the form of bronchospasm, mucosal edema, and mucus plugs.

Airway obstruction causes increased resistance to airflow and decreased expiratory flow rates. These changes lead to a decreased ability to expel air and may result in hyperinflation. The resulting overdistention helps maintain airway patency, thereby improving expiratory flow; however, it also alters pulmonary mechanics and increases the work of breathing.

Hyperinflation compensates for the airflow obstruction, but this compensation is limited when the tidal volume approaches the volume of the pulmonary dead space; the result is alveolar hypoventilation. Uneven changes in airflow resistance, the resulting uneven distribution of air, and alterations in circulation from increased intra-alveolar pressure due to hyperinflation all lead to ventilation-perfusion mismatch.

Vasoconstriction due to alveolar hypoxia also contributes to this mismatch. Vasoconstriction is also considered an adaptive response to ventilation/perfusion mismatch.

In the early stages, when ventilation-perfusion mismatch results in hypoxia, hypercarbia is prevented by the ready diffusion of carbon dioxide across alveolar capillary membranes. Thus, patients with asthma who are in the early stages of an acute episode have hypoxemia in the absence of carbon dioxide retention. Hyperventilation triggered by the hypoxic drive also causes a decrease in PaCO2. An increase in alveolar ventilation in the early stages of an acute exacerbation prevents hypercarbia.

With worsening obstruction and increasing ventilation-perfusion mismatch, carbon dioxide retention occurs. In the early stages of an acute episode, respiratory alkalosis results from hyperventilation. Later, the increased work of breathing, increased oxygen consumption, and increased cardiac output result in metabolic acidosis. Respiratory failure leads to respiratory acidosis. Fatigue is also a potential contributor to respiratory acidosis.

Role of inflammation

Chronic inflammation of the airways is associated with increased BHR, which leads to bronchospasm and typical symptoms of wheezing, shortness of breath, and coughing after exposure to allergens, environmental irritants, viruses, cold air, or exercise. In some patients with chronic asthma, airflow limitation may be only partially reversible because of airway remodeling (hypertrophy and hyperplasia of smooth muscle, angiogenesis, and subepithelial fibrosis) that occurs with chronic untreated disease.

New insights in the pathogenesis of asthma suggest that lymphocytes play a role. Airway inflammation in asthma may represent a loss of normal balance between two "opposing" populations of T helper (Th) lymphocytes. Two types of Th lymphocytes have been characterized: Th1 and Th2. Th1 cells produce interleukin (IL)-2 and interferon-α (IFN-α), which are critical in cellular defense mechanisms in response to infection. Th2, in contrast, generates a family of cytokines (interleukin-4 [IL-4], IL-5, IL-6, IL-9, and IL-13) that can mediate allergic inflammation.

The hygiene hypothesis

The current "hygiene hypothesis" of asthma illustrates how this cytokine imbalance may explain some of the dramatic increases in asthma prevalence in Westernized countries.[6] This hypothesis is based on the concept that the immune system of the newborn is skewed toward Th2 cytokine generation (mediators of allergic inflammation). Over time, environmental stimuli such as infections activate Th1 responses and bring the Th1/Th2 relationship to an appropriate balance.

Evidence suggests that the prevalence of asthma is reduced in children who experience the following events:

  • Certain infections (Mycobacterium tuberculosis, measles, or hepatitis A)

  • Rural living

  • Exposure to other children (eg, presence of older siblings and early enrollment in childcare

  • Less frequent use of antibiotics, including in the first week of life[7]

  • Early introduction of fish in the diet[7]

Furthermore, the absence of these lifestyle events is associated with the persistence of a Th2 cytokine pattern.

Under these conditions, the genetic background of the child, with a cytokine imbalance toward Th2, sets the stage to promote the production of immunoglobulin E (IgE) antibody to key environmental antigens (eg, dust mites, cockroaches, Alternaria, and possibly cats). Therefore, a gene-by-environment interaction occurs in which the susceptible host is exposed to environmental factors that are capable of generating IgE, and sensitization occurs.

A reciprocal interaction is apparent between the two subpopulations, in which Th1 cytokines can inhibit Th2 generation and vice versa. Allergic inflammation may be the result of an excessive expression of Th2 cytokines. Alternatively, recent studies have suggested the possibility that the loss of normal immune balance arises from a cytokine dysregulation in which Th1 activity in asthma is diminished.[8]

Results of two recently reported cross sectional studies of children growing up on farms in Central Europe who were exposed to greater variety of environmental microorganisms showed an inverse relationship between microbial exposure and the probability of asthma.[9]

Genetic factors

Some studies highlight the importance of genotypes in contributing to asthma susceptibility and allergic sensitization, as well as response to specific asthma treatments.[10, 11, 12, 13]

Through the use of cluster analysis, the Severe Asthma Research Program of the National Heart, Lung, and Blood Institute identified 5 phenotypes of asthma.[14] Cluster 1 patients have early-onset atopic asthma with normal lung function treated with two or fewer controller medications and minimal health care utilization. Cluster 2 patients have early-onset atopic asthma and preserved lung function but increased medication requirements (29% on three or more medications) and health care utilization.

Cluster 3 comprises mostly older obese women with late-onset nonatopic asthma, moderate reductions in pulmonary function, and frequent oral corticosteroid use to manage exacerbations. Cluster 4 and cluster 5 patients have severe airflow obstruction with bronchodilator responsiveness but differ in to their ability to attain normal lung function, age of asthma onset, atopic status, and use of oral corticosteroids.[14]

A recently reported meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations identified 5 susceptibility loci. Four were on previously reported loci on 17q21 and a new asthma susceptibility locus at PYHIN1, which is specific to the African American population.[15]

An Australian study identified 2 new loci with genome-wide significant association with asthma risk: rs4129267 in IL6R and rs7130588 on band 11q13.5. The IL6R association supports the hypothesis that cytokine dysregulation affects asthma risk, hence a specific antagonist to IL6R may help. The results for the 11q13.5 locus suggest its association with allergic sensitization and subsequent development of asthma.[16]

Other factors

A study that examined whether the lipid profile is associated with concurrent asthma concluded that the blood lipid profile is associated with asthma, airway obstruction, bronchial responsiveness, and aeroallergen sensitization in 7-year-old children. Caution must be applied before saying that asthma might be a systemic disorder. First, we don't know if the children with the elevated LDL  levels were more likely exposed to higher doses of inhaled, or systemic corticosteroids. The authors did find that those with worse lung function had higher LDL levels. However, it could also be that those children exercised less, a potential cause of obesity and abnormal lipid levels. The BMI was also not reported.[17, 18]

A 2012 study reported a significant association between lung function deficit and bronchial responsiveness in the neonatal period with development of asthma by age seven years.[19]

Lemanske et al reported that wheezing illnesses caused by rhinovirus infection during infancy were the strongest predictor of wheezing in the third year of life.[20]

In a study of preschool children with asthma, Guilbert et al found that 2 years of inhaled corticosteroid therapy did not change the asthma symptoms or lung function during a third, treatment-free year. This suggests that no disease-modifying effect of inhaled corticosteroids is present after the treatment is discontinued.[21]

In a study of children in the Cincinnati area, Reponen et al found that a high Environmental Relative Moldiness Index (ERMI)[22] at age 1 year made asthma at age 7 years more likely. The ERMI did not predict specific mold allergies at age 7 years. Air conditioning made asthma less likely. An elevated ERMI at age 7 years had no correlation with current asthma. Seeing or smelling mold in a home inspection at age 1 year did not correlate with the ERMI or with the development of asthma. They also found that black race, having a parent with asthma, and house dust allergy was predictive of a greater likelihood of asthma.[23]

A recent study from Australia reported that obesity is a determinant of asthma control independent of inflammation, lung function, and airway hyperresponsiveness.[24] A similar association between increased risk of worse asthma control and obesity was reported in a recent retrospective study of 32,321 children aged 5-17 years.[25]

A significant inverse relationship between serum vitamin D levels and patient IgE levels, steroid requirements, and in vitro responsiveness to corticosteroids in children has been reported.[26]

Parental cigarette smoking has been shown to increase the likelihood of asthma. This is more true for maternal smoking, though the authors of one study did not correct for primary caretakers. The more cigarettes the mother smoked, the greater the risk of asthma.[27]

A randomized clinical trial by Sheehan et al evaluated the association in children between frequent acetaminophen use and asthma-related complications. The study found that among young children with mild persistent asthma, as-needed use of acetaminophen was not shown to be associated with a higher incidence of asthma exacerbations or worse asthma control than was as-needed use of ibuprofen.[28, 29]

Etiology

In most cases of asthma in children, multiple triggers or precipitants are recognized, and the patterns of reactivity may change with age. Treatment can also change the pattern. Wheeze is common with respiratory syncytial virus (RSV) bronchiolitis and recurrent wheeze may persist up to 3-5 years. However, RSV is unlikely the sole explanation for the development of atopic asthma later in life. On the other hand, infection with human rhinovirus that requires hospitalization has been associated with future development of asthma (age 6 y).

Respiratory infections

Most commonly, these are viral infections. In some patients, fungi (eg, allergic bronchopulmonary aspergillosis), bacteria (eg, Mycoplasma, pertussis), or parasites may be responsible. Most infants and young children who continue to have a persistent wheeze and asthma have high immunoglobulin E (IgE) production and eosinophilic immune responses (in the airways and in circulation) at the time of the first viral upper respiratory tract infection (URTI). They also have early IgE-mediated responses to local aeroallergens.

Allergens and irritants

In patients with asthma, 2 types of bronchoconstrictor responses to allergens are recognized: early and late. Early asthmatic responses occur via IgE-induced mediator release from mast cells within minutes of exposure and last for 20-30 minutes.

Late asthmatic responses occur 4-12 hours after antigen exposure and result in more severe symptoms that can last for hours and contribute to the duration and severity of the disease. Inflammatory cell infiltration and inflammatory mediators play a role in the late asthmatic response. Allergens can be foods, household inhalants (eg, animal allergens, molds, fungi, roach allergens, dust mites), or seasonal outdoor allergens (eg, mold spores, pollens, grass, trees).

Tobacco smoke, cold air, chemicals, perfumes, paint odors, hair sprays, air pollutants, and ozone can initiate BHR by inducing inflammation.

Other factors

Asthma attacks can be related to changes in atmospheric temperature, barometric pressure, and the quality of air (eg, humidity, allergen and irritant content). In some individuals, emotional upsets clearly aggravate asthma.

Exercise can trigger an early asthmatic response. Mechanisms underlying exercise-induced asthmatic response remain somewhat uncertain. Heat and water loss from the airways can increase the osmolarity of the fluid lining the airways and result in mediator release. Cooling of the airways results in congestion and dilatation of bronchial vessels. During the rewarming phase after exercise, the changes are magnified because the ambient air breathed during recovery is warm rather than cool.

The presence of acid in the distal esophagus, mediated via vagal or other neural reflexes, can significantly increase airway resistance and airway reactivity. Inflammatory conditions of the upper airways (eg, allergic rhinitis, sinusitis, or chronic and persistent infections) must be treated before asthmatic symptoms can be completely controlled.

Multiple factors have been proposed to explain nocturnal asthma. Circadian variation in lung function and inflammatory mediator release in the circulation and airways (including parenchyma) have been demonstrated. Other factors, such as allergen exposure and posture-related irritation of airways (eg, gastroesophageal reflux, sinusitis), can also play a role. In some cases, abnormalities in CNS control of the respiratory drive may be present, particularly in patients with a defective hypoxic drive and obstructive sleep apnea.

Children exposed to higher maternal stress during the pre- and postnatal period were reported to be at higher risk for wheeze. This was only true in non-atopic mothers.[30]

A 2012 Danish study reported an association between maternal obesity (BMI ≥35 and gestational weight gain ≥25 kg) during pregnancy with increased risk of asthma and wheezing in the offspring.[31]

Results of a prospective birth cohort study of 568 pregnant women and their offspring showed that postnatal bisphenol A (BPA) exposure in the first years of a child's life is associated with significantly increased risk for wheeze and asthma. Feeding bottles, sippy cups, or other containers designed for infants may contain it. The study also found, however, that fetal exposure to BPA during the third trimester of pregnancy was inversely associated with risk for wheeze in offspring at age 5 years.[32, 33]

Epidemiology

Approximately 34.1 million people in the United States have been diagnosed with asthma in their lifetime. According to the most recent US Centers for Disease Control and Prevention (CDC) Asthma Surveillance Survey, the prevalence of current asthma during 2001-2003 prevalence is estimated at 6.7% in adults and 8.5% in children, and the burden of asthma increased more than 75% from 1980-1999.[34, 35]

Asthma accounts for more school absences and more hospitalizations than any other chronic illness. In most children's hospitals in the United States, it is the most common diagnosis at admission.

Worldwide, 130 million people have asthma. The prevalence is 8-10 times higher in developed countries (eg, United States, Great Britain, Australia, New Zealand) than in the developing countries. In developed countries, the prevalence is higher in low-income groups in urban areas and inner cities than in other groups.

A long-term study of a birth cohort on the Isle of Wight showed that maternal asthma and eczema were associated with asthma and eczema in their daughters, but not in their sons. Similarly, paternal asthma and eczema were associated with asthma and eczema in their sons, but not in their daughters.[36]

Race-, sex-, and age-related demographics

The prevalence of asthma is higher in minority groups (eg, blacks, Hispanics) than in other groups; however, findings from one study suggest that much of the recent increase in the prevalence is attributed to asthma in white children. Approximately 5-8% of all black children have asthma at some time. The prevalence in Hispanic children is reported to be as high as 15%. In blacks, the death rate is consistently higher than in whites.

Before puberty, the prevalence of asthma is 3 times higher in boys than in girls. During adolescence, the prevalence is equal among males and females. Adult-onset asthma is more common in women than in men.

In most children, asthma develops before age 5 years, and, in more than half, asthma develops before age 3 years.

Among infants, 20% have wheezing with only upper respiratory tract infections (URTIs), and 60% no longer have wheezing by age 6 years. As Martinez et al have pointed out, however, many of these children are "transient wheezers" whose symptoms subside during the preschool or early school years.[37, 38] They tend to have no allergies, although their lung function is often abnormal. These findings have led to the idea that they have small lungs.

Children in whom wheezing begins early in conjunction with allergies are more likely to have wheezing when they are aged 6-11 years. Similarly, children in whom wheezing begins after age 6 years often have allergies, and the wheezing is more likely to continue when they are aged 11 years.[20]

Prognosis

Of infants who wheeze with URTIs, 60% are asymptomatic by age 6 years. However, children who have asthma (recurrent symptoms continuing at age 6 y) have airway reactivity later in childhood. Some findings suggest a poor prognosis if asthma develops in children younger than 3 years, unless it occurs solely in association with viral infections.

Individuals who have asthma during childhood have significantly lower forced expiratory volume in 1 second (FEV1), higher airway reactivity, and more persistent bronchospastic symptoms than those with infection-associated wheezing.

Children with mild asthma who are asymptomatic between attacks are likely to improve and be symptom-free later in life.

Children with asthma appear to have less severe symptoms as they enter adolescence, but half of these children continue to have asthma. Asthma has a tendency to remit during puberty, with a somewhat earlier remission in girls. However, compared with men, women have more BHR.

In a prospective study of 484 Australian children, Tai and colleagues found that having severe asthma in childhood was associated with an almost 12-fold increased risk of having asthma at age 50.[39, 40] At age 50, remission of asthma had occurred in 64% of subjects with mild wheezy bronchitis/wheezy bronchitis at baseline, compared with 47% of those with asthma at baseline and 15% of those with severe asthma. In a multivariate analysis, factors that significantly predicted asthma at age 50 were severe childhood asthma (odds ratio [OR] 11.9), childhood hay fever (OR 2.0, and female sex (OR 2.0).[39, 40]

Mortality and morbidity associated with asthma

Globally, morbidity and mortality associated with asthma have increased over the last 2 decades. This increase is attributed to increasing urbanization. Despite advancements in the understanding of asthma and the development of new therapeutic strategies, the morbidity and mortality rates due to asthma definitely increased from 1980-1995.

In the United States, the mortality rate due to asthma has increased in all age, race, and sex strata. In the United States, the mortality rate due to asthma is more than 17 deaths per 1 million population (ie, 5000 deaths per year).

From 1975-1993, the number of deaths nearly doubled in people aged 5-14 years. In the northeastern and midwestern United States, the highest mortality rate has been among persons aged 5-34 years. According to the most recent report from the CDC and the National Center for Health Statistics, 187 children aged 0-17 years died from asthma, or 0.3 deaths per 100,000 children compared with 1.9 deaths per 100,000 adults aged 18 or older in the year 2002.[34]

Non-Hispanic blacks were the most likely to die from asthma and had an asthma death rate more than 200% higher than non-Hispanic whites and 160% higher than Hispanics.

Patient Education

Patient and parent education should include instructions on how to use medications and devices (eg, spacers, nebulizers, metered-dose inhalers [MDIs]). The patient's MDI technique should be assessed on every visit. Discuss the management plan, which includes instructions about the use of medications, precautions with drug and/or device usage, monitoring symptoms and their severity (peak flow meter reading), and identifying potential adverse effects and necessary actions.

Write and discuss in detail a rescue plan for an acute episode. This plan should include instructions for identifying signs of an acute attack, using rescue medications, monitoring, and contacting the asthma care team. Parents should understand that asthma is a chronic disorder with acute exacerbations; hence, continuity of management with active participation by the patient and/or parents and interaction with asthma care medical personnel is important. Emphasize the importance of adherence to treatment.

Incorporate the concept of expecting full control of symptoms, including nocturnal and exercise-induced symptoms, in the management plans and goals (for all but the most severely affected patients). Avoid unnecessary restrictions in the lifestyle of the child or family. Expect the child to participate in recreational activities and sports and to attend school as usual.

A systematic review by Coffman and colleagues suggested a benefit school-based asthma education. Their review included 25 studies in children aged 4-17 years.[41] In most of those studies, compared with usual care, school-based asthma education improved knowledge of asthma (7 of 10 studies), self-efficacy (6 of 8 studies), and self-management behaviors (7 of 8 studies). Fewer studies reported favorable effects on quality of life (4 of 8 studies), days of symptoms (5 of 11 studies), nights with symptoms (2 of 4 studies), and school absences (5 of 17 studies).[41]

For patient education information, see the Asthma Center, as well as Asthma, Asthma FAQs, Understanding Asthma Medications, Asthma in Children, and Asthma in School Children: Educational Slides.

 

Presentation

History

Guidelines from the National Asthma Education and Prevention Program, which were updated in 2007, highlight the importance of correctly diagnosing asthma.[2] To establish the diagnosis of asthma, the clinician must confirm the following:

  • Episodic symptoms of airflow obstruction are present

  • Airflow obstruction or symptoms are at least partially reversible

  • Alternative diagnoses are excluded

Thus, obtaining a good patient history is crucial when diagnosing asthma and excluding other causes.

The clinician should establish whether the patient has any of the following symptoms:

  • Wheezing

  • Cough

  • Cough at night

  • Cough during or after exercise

  • Shortness of breath

  • Chest tightness

  • Sputum production

The clinician should determine the pattern of symptoms, as follows:

  • Perennial, seasonal, or both

  • Continuous or intermittent

  • Daytime or nighttime

  • Onset and duration

The clinician should ask whether any of the following precipitate and/or aggravate symptoms:

  • Viral infections

  • Environmental allergens

  • Irritants (eg, smoke exposure, chemicals, vapors, dust)

  • Exercise

  • Emotions

  • Home environment (eg, carpets, pets, mold)

  • Stress

  • Drugs (eg, aspirin, beta blockers)

  • Foods

  • Changes in weather

The presence of other conditions that may affect asthma should be determined. Such conditions may include the following:

  • Thyroid disease

  • Pregnancy

  • Menses

  • Gastroesophageal reflux disease (GERD)

  • Sinusitis

  • Rhinitis

Questions about the development and treatment of the patient’s disease should touch on the following:

  • Age at onset and diagnosis

  • Progression of symptoms (better or worse)

  • Improvement with bronchodilators

  • Use of oral corticosteroids

The family history should include any history of asthma, allergy, sinusitis, rhinitis, eczema, or nasal polyps in close relatives, and the social history should cover factors that may contribute to nonadherence of asthma medications, as well as any illicit drug use.

The history of exacerbations should include the usual prodromal signs or symptoms, rapidity of onset, associated illnesses, number in the last year, and need for hospitalization. Symptoms of asthma may include wheezing, coughing, and chest tightness, among others. Patients with persistent asthmatic symptoms are more likely to experience severe asthma exacerbations.[42]

Wheezing

A musical, high-pitched, whistling sound produced by airflow turbulence is one of the most common symptoms. The wheezing usually occurs during exhalation.

In the mildest form, wheezing is only end expiratory. As severity increases, the wheeze lasts throughout expiration. In a more severe asthmatic episode, wheezing is also present during inspiration. During the most severe episodes, wheezing may be absent because of the severe limitation of airflow associated with airway narrowing and respiratory muscle fatigue.

Asthma can occur without wheezing when obstruction involves predominantly the small airways. Thus, wheezing is not necessary for the diagnosis of asthma. Furthermore, wheezing can be associated with other causes of airway obstruction, such as cystic fibrosis and heart failure.

Patients with vocal cord dysfunction have a predominantly inspiratory monophonic wheeze/sound (different from the polyphonic wheeze in asthma), which is heard best over the laryngeal area in the neck. Patients with bronchomalacia and tracheomalacia also have a monophonic wheeze.

In exercise-induced or nocturnal asthma, wheezing may be present after exercise or during the night, respectively.

Coughing and chest tightness

Cough may be the only symptom of asthma, especially in cases of exercise-induced or nocturnal asthma. Usually, the cough is nonproductive and nonparoxysmal. In addition, coughing may be present with wheezing. Children with nocturnal asthma tend to cough after midnight, during the early hours of morning. A history of tightness or pain in the chest may be present with or without other symptoms of asthma, especially in exercise-induced or nocturnal asthma.

Other nonspecific symptoms

Infants or young children may have a history of recurrent bronchitis, bronchiolitis, or pneumonia; a persistent cough with colds; and/or recurrent croup or chest rattling. Most children with chronic or recurrent bronchitis have asthma. Asthma is the most common underlying diagnosis in children with recurrent pneumonia. Older children may have a history of chest tightness and/or recurrent chest congestion.

In an acute episode, symptoms vary according to the severity of the episode. During a mild episode, patients may be breathless after physical activity such as walking. They can talk in sentences and lie down, and they may be agitated. During a moderate-to-severe episode, patients are breathless while talking. Infants have feeding difficulties and a softer, shorter cry.

During a severe episode, patients are breathless during rest, are not interested in feeding, sit upright, talk in words (not sentences), and are usually agitated. With imminent respiratory arrest (in addition to the aforementioned symptoms), the child is drowsy and confused. However, adolescents may not have these symptoms until they are in frank respiratory failure.

Physical Examination

The clinical picture of pediatric asthma varies. Symptoms may be associated with upper respiratory infections (URTIs), nocturnal or exercise-induced asthmatic symptoms, and status asthmaticus.

Status asthmaticus, or an acute severe asthmatic episode that is resistant to appropriate outpatient therapy, is a medical emergency that requires aggressive inpatient management. This may include admission to an ICU for the treatment of hypoxia, hypercarbia, and dehydration and possibly for assisted ventilation because of respiratory failure.

Physical findings vary with the absence or presence of an acute episode and its severity.

Findings in the absence of an acute episode

The physical findings between acute episodes vary with the severity of the asthma. During an outpatient visit, a patient with mild asthma may have normal findings on physical examination. Patients with more severe asthma are likely to have signs of chronic respiratory distress and chronic hyperinflation.

Signs of atopy or allergic rhinitis, such as conjunctival congestion and inflammation, ocular shiners, a transverse crease on the nose due to constant rubbing associated with allergic rhinitis, and pale violaceous nasal mucosa due to allergic rhinitis, may be present.

The anteroposterior diameter of the chest may be increased because of hyperinflation. Hyperinflation may also cause an abdominal breathing pattern.

Lung examination may reveal prolongation of the expiratory phase, expiratory wheezing, coarse crackles, or unequal breath sounds. In a child who is not sick, forced exhalation may reveal expiratory wheeze. Forced exhalation can be obtained by asking the child to blow hard (like blowing imaginary birthday candles) or, in the case of toddlers or infants, pushing on the abdomen may be used to cause forced exhalation. Clubbing of the fingers is not a feature of straightforward asthma and indicates a need for more extensive evaluation and work-up to exclude other conditions, such as cystic fibrosis.

Findings during an acute episode

Physical examination during an acute episode may reveal different findings in mild, moderately severe, and severe episodes and in status asthmaticus with often imminent respiratory arrest.

Findings during a mild episode include the following:

  • Increased respiratory rate

  • Accessory muscles of respiration are not used

  • The heart rate is less than 100 beats per minute

  • Pulsus paradoxus is not present

  • Auscultation of chest reveals moderate wheezing, which is often end expiratory

  • Oxyhemoglobin saturation with room air is greater than 95%

Findings during a moderately severe episode include the following:

  • Increased respiratory rate

  • Accessory muscles of respiration typically are used

  • Suprasternal retractions are present

  • The heart rate is 100-120 beats per minute

  • Loud expiratory wheezing can be heard

  • Pulsus paradoxus may be present (10-20 mm Hg)

  • Oxyhemoglobin saturation with room air is 91-95%

Findings during a severe episode include the following:

  • The respiratory rate is often greater than 30 breaths per minute

  • Accessory muscles of respiration are usually used

  • Suprasternal retractions are commonly present

  • The heart rate is greater than 120 beats per minute

  • Loud biphasic (expiratory and inspiratory) wheezing can be heard

  • Pulsus paradoxus is often present (20-40 mm Hg)

  • Oxyhemoglobin saturation with room air is less than 91%.

Findings in status asthmaticus with often imminent respiratory arrest include the following:

  • Paradoxical thoracoabdominal movement

  • Wheezing may be absent (in patients with the most severe airway obstruction)

  • Severe hypoxemia may manifest as bradycardia

  • Pulsus paradoxus may disappear; this finding suggests respiratory muscle fatigue

Staging

Asthma severity is defined as "the intensity of the disease process" prior to the initiation of therapy. Defining asthma severity helps in determining the initiation of therapy in a patient who is not on any controller medications.[2]

The severity of asthma is classified as intermittent, mild persistent, moderate persistent, or severe persistent. This classification is based on the impairment and risk related to disease, which is measured by the following:

  • Frequency and severity of symptoms, including nocturnal symptoms

  • Characteristics of acute episodes

  • Pulmonary function

  • Exacerbations

Features of these categories have been divided into 3 charts to reflect classification in different age groups (0-4 y, 5-11 y, and 12 y and older), according to the 2007 National Asthma Education and Prevention Program guidelines.[2]

An important point to remember is that the presence of one severe feature is sufficient to diagnose severe persistent asthma. In addition, the characteristics in this classification system are general and may overlap because asthma severity varies widely. In addition, a patient’s classification may change over time .

Patients with asthma of any level of severity may have mild, moderate, or severe exacerbations.

Some patients with intermittent asthma have severe and life-threatening exacerbations separated by episodes with almost normal lung function and minimal symptoms; however, they are likely to have other evidence of increased BHR (eg, on exercise or challenge testing) due to ongoing inflammation.

 

DDx

Diagnostic Considerations

Problems to be considered include the following:

  • Tracheobronchomalacia

  • Hyperventilation syndrome

  • Vocal cord dysfunction

  • Pulmonary edema

  • Collagen vascular disease

  • Reactive airway disease

Differential Diagnoses

 

Workup

Approach Considerations

According to the National Asthma Education and Prevention Program guidelines, spirometry is an essential objective measure for establishing the diagnosis of asthma. Additional studies are not routinely necessary, but they may be useful when the clinician is considering alternative diagnoses.[2] Eosinophil counts and IgE levels may be useful when allergic factors are suspected.

Bronchial provocation tests may be performed to diagnose bronchial hyperresponsiveness (BHR). These tests are performed in specialized laboratories by specially trained personnel to document airway hyperresponsiveness to substances (eg, methacholine, histamine). Increasing doses of provocation agents are given, and FEV1 is measured. The endpoint is a 20% decrease in FEV1 (PC 20 ).

For more information, see the Medscape Reference topic Peak Flow Rate Measurement.

Pulmonary Function Tests

Results of pulmonary function testing are not reliable in patients younger than 5 years. In young children (3-6 y) and older children who are unable to perform the conventional spirometry maneuver, newer techniques, such as measurement of airway resistance using impulse oscillometry system, are used. Measurement of airway resistance before and after a dose of inhaled bronchodilator may help to diagnose bronchodilator-responsive airway obstruction.

Spirometry

In a typical case, an obstructive defect is present in the form of normal forced vital capacity (FVC), reduced forced expiratory volume in 1 second (FEV1), and reduced forced expiratory flow more than 25-75% of the FVC (FEF 25-75). The flow-volume loop can be concave. Documentation of reversibility of airway obstruction after bronchodilator therapy is central to the definition of asthma. FEF 25-75 is a sensitive indicator of obstruction and may be the only abnormality in a child with mild disease.

In an outpatient or office setting, measurement of the peak flow rate by using a peak flow meter can provide useful information about obstruction in the large airways. Take care to ensure maximum patient effort. However, a normal peak flow rate does not necessarily mean a lack of airway obstruction.

Plethysmography

Patients with chronic persistent asthma may have hyperinflation, as evidenced by an increased total lung capacity (TLC) at plethysmography. Increased residual volume (RV) and functional residual capacity (FRC) with normal TLC suggests air trapping. Airway resistance is increased when significant obstruction is present.

Exercise Challenge

In a patient with a history of exercise-induced symptoms (eg, cough, wheeze, chest tightness or pain), the diagnosis of asthma can be confirmed with the exercise challenge. In a patient of appropriate age (usually >6 y), the procedure involves baseline spirometry followed by exercise on a treadmill or bicycle to a heart rate greater than 60% of the predicted maximum, with monitoring of the electrocardiogram and oxyhemoglobin saturation.

The patient should be breathing cold, dry air during the exercise to increase the yield of the study. Spirographic findings and the peak expiratory flow (PEF) rate (PEFR) are determined immediately after the exercise period and at 3 minutes, 5 minutes, 10 minutes, 15 minutes, and 20 minutes after the first measurement. The maximal decrease in lung function is calculated by using the lowest postexercise and highest pre-exercise values. The reversibility of airway obstruction can be assessed by administering aerosolized bronchodilators.

Methacholine challenge

The degree of airway responsiveness can be assessed by methacholine challenge testing.[43] Methacholine causes bronchoconstriction via muscarinic acetylcholine receptor M3, and the resultant decrease in FEV1 is recorded by spirometry. The test can help to confirm the diagnosis of asthma in a patient with history of asthma but normal spirometry findings.

During the test, the patient inhales increasing concentrations of methacholine aerosol via a nebulizer; spirometry is performed before and after each dose. A positive response is a 20% fall in FEV1. The corresponding concentration of methacholine (mg/mL) is called PC 20 . A PC 20 of greater than 16 mg/mL indicates normal bronchial responsiveness. PC 20 values of 4-16 mg/mL, 1-4 mg/mL, and < 1 mg/mL indicate borderline, mild, and moderate-to-severe bronchial hyperresponsiveness, respectively.

Methacholine challenge testing is more useful in excluding a diagnosis of asthma than in establishing one because its negative predictive power is greater than its positive predictive power.[43] Other agents (ie, histamine, mannitol) are also used for bronchoprovocation.

Fraction of Exhaled Nitric Oxide Testing

Measuring the fraction of exhaled nitric oxide (FeNO) has proved useful as a noninvasive marker of airway inflammation, in order to guide adjustment of the dose of inhaled corticosteroids. In one study involving home monitoring of FeNO and symptom scores, the 2 correlated. Further, in some patients, the FeNO rose before significant exacerbations of the asthma[44] ; thus, although studies of FeNO in large groups have either shown it to be helpful or not, it may be a useful method of evaluating therapy in individual patients. Due to the high cost of equipment, FeNO measurement is used primarily as a research tool at present.

Measuring the level of interleukin-5 in exhaled breath condensate is a possible way of titrating asthma progress, according to one study. In a longitudinal study of 40 asthmatic children aged 6-16 years, asthma control score and level of interleukin-5 were significant predictors of an asthma exacerbation.[45]

Radiography and CT Scan

Include chest radiography in the initial workup if the asthma does not respond to therapy as expected. In addition to typical findings of hyperinflation and increased bronchial markings, a chest radiograph may reveal evidence of parenchymal disease, atelectasis, pneumonia, congenital anomaly, or a foreign body.

In a patient with an acute asthmatic episode that responds poorly to therapy, a chest radiograph helps in the diagnosis of complications such as pneumothorax or pneumomediastinum. Consider using sinus radiography and CT scanning to rule out sinusitis.

For more information, see the Medscape Reference topic Imaging in Asthma.

Allergy Testing

Allergy testing can be used to identify allergic factors that may significantly contribute to the asthma. Once identified, environmental factors (eg, dust mites, cockroaches, molds, animal dander) and outdoor factors (eg, pollen, grass, trees, molds) may be controlled or avoided to reduce asthmatic symptoms.

Allergens for skin testing are selected on the basis of suspected or known allergens identified from a detailed environmental history. Antihistamines can suppress the skin test results and should be discontinued for an appropriate period (according to the particular agent’s duration of action) before allergy testing. Topical or systemic corticosteroids do not affect the skin reaction.

Histologic Findings

Asthma is an inflammatory disease characterized by the recruitment of inflammatory cells, vascular congestion, increased vascular permeability, increased tissue volume, and the presence of an exudate. Eosinophilic infiltration, a universal finding, is considered a major marker of the inflammatory activity of the disease.

Histologic evaluations of the airways in a typical patient reveal infiltration with inflammatory cells, narrowing of airway lumina, bronchial and bronchiolar epithelial denudation, and mucus plugs. Additionally, a patient with severe asthma may have a markedly thickened basement membrane and airway remodeling in the form of subepithelial fibrosis and smooth muscle hypertrophy or hyperplasia.

 

Treatment

Approach Considerations

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.

Components of Asthma Care

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)

Intermittent Asthma

Persistent Asthma: Daily Medication

Age

Step 1

Step 2

Step 3

Step 4

Step 5

Step 6

< 5 y

Rapid-acting beta2-agonist prn

Low-dose inhaled corticosteroid (ICS)

Medium-dose ICS

Medium-dose ICS plus either long-acting beta2-agonist (LABA) or montelukast

High-dose ICS plus either LABA or montelukast

High-dose ICS plus either LABA or montelukast; Oral systemic corticosteroid

Alternate regimen: cromolyn or montelukast

5-11 y

Rapid-acting beta2-agonist prn

Low-dose ICS

Either low-dose ICS plus either LABA, LTRA, or theophylline OR Medium-dose

Medium-dose ICS plus LABA

High-dose ICS plus LABA

High-dose ICS plus LABA plus oral systemic corticosteroid

Alternate regimen: cromolyn, leukotriene receptor antagonist (LTRA), or theophylline

Alternate regimen: medium-dose ICS plus either LTRA or theophylline

Alternate regimen: high-dose ICS plus either LABA or theophylline

Alternate regimen: high-dose ICS plus LRTA or theophylline plus systemic corticosteroid

12 y or older

Rapid-acting beta2-agonist as needed

Low-dose ICS

Low-dose ICS plus LABA OR Medium-dose ICS

Medium-dose ICS plus LABA

High-dose ICS plus LABA (and consider omalizumab for patients with allergies)

High-dose ICS plus either LABA plus oral corticosteroid (and consider omalizumab for patients with allergies)

Alternate regimen: cromolyn, LTRA, or theophylline

Alternate regimen: low-dose ICS plus either LTRA, theophylline, or zileuton

Alternate regimen: medium-dose ICS plus either LTRA, theophylline, or zileuton

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 of Status Asthmaticus

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.

Consultations

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.

Long-Term Monitoring

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]

Surgical Care

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]

 

Medication

Medication Summary

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

In December 2018, FDA approved ProAir Digihaler (albuterol), the first digital and mobile-connected inhaler. The built-in sensors detects when the device is used and measures the strength of the user’s inhalation. The inhaler sends the user’s data to its mobile app companion and their healthcare provider.[84]

Bronchodilators, Beta2-Agonists

Class Summary

These agents are used to treat bronchospasm in acute asthmatic episodes, and used to prevent bronchospasm associated with exercise-induced asthma or nocturnal asthma. Several studies have suggested that short-acting beta2-agonists such as albuterol may produce adverse outcomes (eg, decreased peak flow or increased risk of exacerbations) in patients homozygous for arginine (Arg/Arg) at the 16th amino acid position of beta-adrenergic receptor gene compared with patients homozygous for glycine (Gly-Gly). Similar findings are reported for long-acting beta2-agonists, such as salmeterol.

Albuterol (AccuNeb, Proventil HFA, Ventolin HFA, ProAir HFA, ProAir RespiClick, ProAir Digihaler)

This beta2-agonist is the most commonly used bronchodilator that is available in multiple forms (eg, solution for nebulization, MDI, PO solution). This is most commonly used in rescue therapy for acute asthmatic symptoms. Used as needed. Prolonged use may be associated with tachyphylaxis due to beta2-receptor downregulation and receptor hyposensitivity.

Nonracemic Form of the Beta2-Agonist Albuterol

Class Summary

This nonracemic form of albuterol offers a significant reduction in the adverse effects associated with racemic albuterol (eg, muscle tremors, tachycardia, hyperglycemia, hypokalemia).

Levalbuterol (Xopenex, Xopenex HFA)

Nonracemic form of albuterol, levalbuterol (R isomer) is effective in smaller doses and is reported to have fewer adverse effects (eg, tachycardia, hyperglycemia, hypokalemia). The dose may be doubled in acute severe episodes when even a slight increase in the bronchodilator response may make a big difference in the management strategy (eg, in avoiding patient ventilation). It is available as an MDI (45 mcg per actuation) or solution for nebulized inhalation.

Long-Acting Beta2-Agonists

Class Summary

Long-acting bronchodilators (LABA) are not used for the treatment of acute bronchospasm. They are used for the preventive treatment of nocturnal asthma or exercise-induced asthmatic symptoms, for example.

Salmeterol is the only single-agent LABA available in the United States that is approved for asthma. Salmeterol and formoterol are available as combination products with inhaled corticosteroids that are approved for asthma in the United States (Advair, Symbicort, Dulera).

LABA may increase the chance of severe asthma episodes and death when those episodes occur. Most cases have occurred in patients with severe and/or acutely deteriorating asthma; they have also occurred in a few patients with less severe asthma.

LABAs are not considered first-line medications to treat asthma. LABAs should not be used as isolated medications and should be added to the asthma treatment plan only if other medicines do not control asthma, including the use of low- or medium-dose corticosteroids. If used as isolated medication, LABAs should be prescribed by a subspecialist (ie, pulmonologist, allergist).

Salmeterol (Serevent)

This long-acting preparation of a beta2-agonist is used primarily to treat nocturnal or exercise-induced symptoms. It has no anti-inflammatory action and is not indicated in the treatment of acute bronchospastic episodes. It may be used as an adjunct to inhaled corticosteroids to reduce the potential adverse effects of the steroids. The medication is delivered via a Diskus DPI.

Inhaled Corticosteroids

Class Summary

Steroids are the most potent anti-inflammatory agents. Inhaled forms are topically active, poorly absorbed, and least likely to cause adverse effects. They are used for long-term control of symptoms and for the suppression, control, and reversal of inflammation. Inhaled forms reduce the need for systemic corticosteroids.

Inhaled steroids block late asthmatic response to allergens; reduce airway hyperresponsiveness; inhibit cytokine production, adhesion protein activation, and inflammatory cell migration and activation; and reverse beta2-receptor downregulation and subsensitivity (in acute asthmatic episodes with LABA use).

Ciclesonide (Alvesco)

Ciclesonide is an aerosol inhaled corticosteroid indicated for maintenance treatment of asthma as prophylactic therapy in adult and adolescent patients aged 12 y and older. Not indicated for relief of acute bronchospasm.

Corticosteroids have wide range of effects on multiple cell types (eg, mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (eg, histamines, eicosanoids, leukotrienes, cytokines) involved in inflammation.

Individual patients experience variable time to onset and degree of symptom relief. Maximum benefit may not be achieved for 4 wk or longer after initiation of therapy.

After asthma stability is achieved, it is best to titrate to lowest effective dosage to reduce the possibility of adverse effects. For patients who do not adequately respond to the starting dose after 4 wk of therapy, higher doses may provide additional asthma control.

Beclomethasone (QVAR Redihaler)

Beclomethasone inhibits bronchoconstriction mechanisms; causes direct smooth muscle relaxation; and may decrease the number and activity of inflammatory cells, which, in turn, decreases airway hyperresponsiveness. It is available as 40 mcg/actuation or 80 mcg/actuation.

Fluticasone (Flovent Diskus, Flovent HFA)

Fluticasone has extremely potent vasoconstrictive and anti-inflammatory activity. It has a weak hypothalamic-pituitary adrenocortical axis inhibitory potency when applied topically. It is available as an MDI aerosolized product (HFA) or DPI (Diskus).

Fluticasone furoate inhaled (Arnuity Ellipta)

Synthetic trifluorinated corticosteroid that elicits anti-inflammatory activity. Has low oral bioavailability owing to extensive first-pass metabolism that is desirable to minimize systemic exposure. Exhibits high binding affinity for human glucocorticoid receptor (~1.7 times higher than fluticasone propionate). It is indicated for once-daily maintenance treatment of asthma as prophylactic therapy in children aged ≥5 years.

Budesonide inhaled (Pulmicort Flexhaler or Respules)

Budesonide has extremely potent vasoconstrictive and anti-inflammatory activity. It has a weak hypothalamic-pituitary adrenocortical axis inhibitory potency when applied topically. It is available as a DPI in 90 mcg/actuation (delivers about 80 mcg/actuation) or 180 mcg/actuation (delivers about 160 mcg/actuation). A nebulized susp (ie, Respules) is also available for young children.

Mometasone furoate inhalation powder (Asmanex Twisthaler)

Mometasone is a corticosteroid for inhalation. It is indicated for asthma as prophylactic therapy.

Systemic Corticosteroids

Class Summary

These agents are used for short courses (3-10 d) to gain prompt control of inadequately controlled acute asthmatic episodes. They are also used for long-term prevention of symptoms in severe persistent asthma as well as for suppression, control, and reversal of inflammation. Frequent and repetitive use of beta2-agonists has been associated with beta2-receptor subsensitivity and downregulation; these processes are reversed with corticosteroids.

Higher-dose corticosteroids have no advantage in severe asthma exacerbations, and intravenous administration has no advantage over oral therapy, provided that GI transit time or absorption is not impaired. The usual regimen is to continue frequent multiple daily dosing until the FEV1 or peak expiratory flow (PEF) is 50% of the predicted or personal best values; then, the dose is changed to twice daily. This usually occurs within 48 hours.

Prednisone (Deltasone, Orasone) and prednisolone (Pediapred, Prelone, Orapred)

An immunosuppressant for the treatment of autoimmune disorders, prednisone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear neutrophil (PMN) activity.

Methylprednisolone (Solu-Medrol)

Methylprednisolone may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Dexamethasone (Baycadron, Dexamethasone Intensol)

Dexamethasone in the ED can provide equivalent relief to a 5-day course of prednisone—and without the adverse side effect of vomiting—for acute asthma flare-ups in children. Researchers performed a meta-analysis of 6 studies based in the ED and found that significantly fewer patients receiving dexamethasone vomited in the ED or at home after discharge compared with patients receiving oral prednisone or prednisolone. The data suggest that emergency physicians should consider single or 2-dose dexamethasone regimens over 5-day prednisone/prednisolone regimens for the treatment of acute asthma exacerbations.

Leukotriene Modifiers

Class Summary

Knowledge that leukotrienes cause bronchospasm, increased vascular permeability, mucosal edema, and inflammatory cell infiltration has led to the concept of modifying their action by using pharmacologic agents. These are either 5-lipoxygenase inhibitors or leukotriene-receptor antagonists.

Zafirlukast (Accolate)

Zafirlukast is a selective competitive inhibitor of LTD4 and LTE4 receptors.

Montelukast (Singulair)

The last agent introduced in its class, montelukast has the advantages that it is chewable, it has a once-a-day dosing, and it has no significant adverse effects.

Methylxanthines

Class Summary

These agents are used for long-term control and prevention of symptoms, especially nocturnal symptoms.

Theophylline (Theo-24, Theochron)

Theophylline is available in short-acting and long-acting formulations. Because of the need to monitor serum concentrations, this agent is used infrequently. The dose and frequency depend on the particular product selected.

Combination Inhaled Steroids/Long-Acting Beta2-Agonists

Class Summary

These combinations may decrease asthma exacerbations when inhaled short-acting beta2-agonists and corticosteroids have failed. Refer to previous discussion in the LABAs section regarding increased risk of severe asthma episodes and death with LABAs. In a recent study, use of combination therapy using fluticasone propionate and salmeterol prolonged time to first severe asthma exacerbation.[70]

Budesonide is an inhaled corticosteroid that alters level of inflammation in airways by inhibiting multiple types of inflammatory cells and decreasing production of cytokines and other mediators involved in the asthmatic response. Available as MDI in 2 strengths; each actuation delivers formoterol 4.5 mcg with either 80 mcg or 160 mcg.

Budesonide/formoterol (Symbicort)

Formoterol relieves bronchospasm by relaxing the smooth muscles of the bronchioles in conditions associated with asthma. Budesonide is an inhaled corticosteroid that alters the level of inflammation in airways by inhibiting multiple types of inflammatory cells and decreasing production of cytokines and other mediators involved in the asthmatic response. This combination is available as an MDI in 2 strengths; each actuation delivers formoterol 4.5-mcg with either 80-mcg or 160-mcg of budesonide. The 80/4.5 mcg strength is approved for use in children aged 6-12 y, whereas, either strength is approved for children aged ≥12 y.

Mometasone and formoterol (Dulera)

This is a combination corticosteroid and LABA metered-dose inhaler. Mometasone elicits local anti-inflammatory effects in the respiratory tract with minimal systemic absorption. Formoterol elicits bronchial smooth muscle relaxation.

This combination is indicated for prevention and maintenance of asthma symptoms in patients inadequately controlled with other asthma controller medications (eg, low-dose to medium-dose inhaled corticosteroids) or whose disease severity clearly warrants initiation of treatment with 2 maintenance therapies, including a LABA. Available in 2 strengths; each actuation delivers mometasone/formoterol 100 mcg/5 mcg or 200 mcg/5 mcg.

Salmeterol/fluticasone inhaled (Advair)

This is a combination corticosteroid and LABA metered-dose inhaler. Fluticasone inhibits bronchoconstriction mechanisms, produces direct smooth muscle relaxation, and may decrease number and activity of inflammatory cells, in turn decreasing airway hyper-responsiveness. It also has vasoconstrictive activity. Salmeterol relaxes the smooth muscles of the bronchioles in conditions associated with bronchitis, emphysema, asthma, or bronchiectasis and can relieve bronchospasms. Its effect may also facilitate expectoration. Adverse effects are more likely to occur when administered at high or more frequent doses than recommended. Two delivery mechanisms are available (ie, powder for inhalation [Diskus], metered-dose inhaler [MDI]). Diskus is available as a combination of salmeterol 50 mcg with fluticasone 100 mcg, 250 mcg, or 500 mcg. The MDI is available as 21 mcg salmeterol with fluticasone 45 mcg, 115 mcg, or 230 mcg.

Anticholinergic Agents

Class Summary

The long-acting anticholinergic agent, tiotropium, may be considered for long-term maintenance therapy, but not for acute treatment of asthma exacerbations.

Tiotropium (Spiriva Respimat)

Tiotropium is a long-acting antimuscarinic agent, often referred to as an anticholinergic. Inhibits M3-receptors at smooth muscle, leading to bronchodilation. It is indicated for long-term, once-daily, maintenance treatment of asthma in patients aged ≥6 years.

Ipratropium (Atrovent)

Chemically related to atropine, ipratropium has antisecretory properties and, when applied locally, inhibits secretions from serous and seromucous glands lining the nasal mucosa. The MDI delivers 17 mcg/actuation. Solution for inhalation contains 500 mcg/2.5 mL (ie, 0.02% solution for nebulization). It is not approved for asthma, but off-label use for acute exacerbations of asthma in addition to beta2-agonist therapy has been described in the literature. It is a short-acting anticholinergic agent with an onset of 15 minutes.

Monoclonal Antibodies, Anti-asthmatics

Class Summary

Monoclonal antibody effects vary depending on their receptor target. Omalizumab binds to IG-E on the surface of mast cells and basophils. It reduces release of these mediators that promote an allergic response. Mepolizumab and benralizumab inhibit IL-5 binding to eosinophils and results in reduced blood, tissue, and sputum eosinophil levels. Dupilumab inhibits IL-4 receptor alpha, and thereby blocks IL-4 and IL-13 signaling. This in turn reduces cytokine-induced inflammatory response.

Mepolizumab approval was based on 3 key phase 3 trials (DREAM, MENSA, and SIRIUS). Each trial demonstrated statistically significant improvement in decreasing asthma exacerbations and emergency department visits or hospitalization. Mean reduction in glucocorticoid use was 50% in the mepolizumab group, while also reducing the asthma exacerbation rate. Significant improvement in FEV1 was also observed compared with placebo.[71, 72, 73]

Benralizumab approval was based on results from the WINDWARD clinical trial program, including the Phase III exacerbation trials, SIROCCO and CALIMA, and the Phase III oral corticosteroid (OCS)-sparing trial, ZONDA.[74, 75, 76] Results for the 8-week benralizumab dosing regimen from these trials showed significantly reduced annual asthma exacerbation rate (AAER), improved FEV1, and a 75% median reduction in daily OCS use and discontinuation of OCS use in 52% of eligible patients compared with placebo.

Approval for dupilumab was based on the LIBERTY QUEST (n=1902) and VENTURE (n=210) phase 3 clinical trials. In the LIBERTY QUEST trial, patients with moderate-to-severe uncontrolled asthma were administered dupilumab add-on therapy to current maintenance therapy every 2 weeks or matched placebo. Those receiving a 200-mg dose demonstrated a 47.7% lower rate of annualized severe asthma exacerbations compared with placebo add-on (P < 0.001). The 300-mg dose showed a similar response.[82]

In the LIBERTY VENTURE trial, patients with oral corticosteroid-dependent severe asthma were administered dupilumab add-on therapy or matched placebo to current maintenance therapy every 2 weeks for 24 weeks or matched placebo. Corticosteroid doses were gradually decreased from week 4 to week 20 and then maintained for 4 weeks. Patients receiving dupilumab had a 70.1% greater corticosteroid dose reduction compared with 41.9% for placebo add-on (P < 0.001). Additionally, patients receiving dupilumab had a 59% (95% [CI], 37 to 74) lower rate of severe asthma exacerbations than those taking placebo add-on.[83]

Omalizumab (Xolair)

Omalizumab is a recombinant, DNA-derived, humanized IgG monoclonal antibody that binds selectively to human IgE on surface of mast cells and basophils. It reduces mediator release, which promotes allergic response. It is indicated for moderate-to-severe persistent asthma in patients aged 6 years or older who react to perennial allergens in whom symptoms are not controlled by inhaled corticosteroids.

Mepolizumab (Nucala)

Mepolizumab is a humanized IgG1 kappa monoclonal antibody specific for interleukin-5 (IL-5). Mepolizumab binds to IL-5, and therefore stops IL-5 from binding to its receptor on the surface of eosinophils. It is indicated for add-on maintenance treatment of patients with severe asthma aged 12 years or older, and with an eosinophilic phenotype.

Benralizumab (Fasenra)

Benralizumab is a humanized monoclonal antibody (IgG1/kappa-class) selective for the IL-5 alpha subunit of basophils and eosinophils. It is indicated for add-on maintenance treatment of severe asthma in patients aged 12 years or older who have an eosinophilic phenotype.

Dupilumab (Dupixent)

Inhibits IL-4 receptor alpha, and thereby blocks IL-4 and IL-13 signaling. This in turn reduces cytokine-induced inflammatory response. It is indicated as an add-on maintenance treatment for moderate-to-severe asthma in patients aged 12 years or older with eosinophilic phenotype or PO corticosteroid dependent asthma.

 

Questions & Answers

Overview

What is pediatric asthma?

Which symptoms help to establish a diagnosis of pediatric asthma?

What are the signs and symptoms of pediatric asthma?

Which physical findings are characteristic of severe episodes of pediatric asthma?

What are the physical findings indicative of status asthmaticus with imminent respiratory arrest in pediatric asthma?

Which tests are performed in the evaluation of pediatric asthma?

What are the National Asthma Education and Prevention Program guidelines for pediatric asthma care?

Which control medications are used in the management of pediatric asthma?

Which relief medications are used in the management of pediatric asthma?

What is pediatric asthma?

What is the prevalence of pediatric asthma?

What is the economic impact of pediatric asthma?

Which organization has published treatment guidelines for pediatric asthma?

What is the role of airway inflammation in the pathophysiology of pediatric asthma?

What is the pathogenesis of pediatric asthma?

What is the pathophysiology of the early stages of pediatric asthma?

What is the role of lymphocytes in the pathophysiology of pediatric asthma?

What is the hygiene hypothesis of the pathophysiology of pediatric asthma?

Which factors have been shown to reduce the prevalence of pediatric asthma?

What is the role of genetics in the pathogenesis of pediatric asthma?

Which loci have been identified as susceptible for asthma?

What is the role of the lipids in the pathogenesis of asthma?

Which early childhood factors may increase the risk for pediatric asthma?

What causes pediatric asthma?

What is the role of respiratory infections in the etiology of pediatric asthma?

What is the role of allergens and irritants in the etiology of pediatric asthma?

What triggers asthma attacks?

How does exercise trigger asthma attacks?

What significantly increase airway resistance and airway reactivity in the pathophysiology of pediatric asthma?

What causes nocturnal asthma?

What factors increase the risk for wheezing in pediatric asthma?

What is the prevalence of pediatric asthma?

What are the racial predilections for pediatric asthma?

How does the prevalence of pediatric asthma vary by sex?

In which age groups is pediatric asthma most prevalent?

What is the prognosis of pediatric asthma?

What is the mortality and morbidity associated with pediatric asthma?

What is included in patient education for pediatric asthma?

What are the benefits of patient education for pediatric asthma?

Presentation

What are the diagnostic criteria for pediatric asthma?

Which factors may precipitate or aggravate symptoms of pediatric asthma?

Which conditions may affect precipitate or aggravate asthma?

What should be the focus of history for pediatric asthma?

What should be included in the family history for pediatric asthma?

What should be included in the history of exacerbations of pediatric asthma?

How is wheezing characterized in pediatric asthma?

How is coughing characterized in pediatric asthma?

What are the nonspecific symptoms of pediatric asthma?

How does the clinical presentation of pediatric asthma vary?

Which physical findings suggest pediatric asthma in the absence of an acute episode?

During an acute episode of pediatric asthma, what will determine the physical findings?

What are the characteristic physical findings during a mild episode of pediatric asthma?

What are the characteristic physical findings during a mild moderately severe episode of pediatric asthma?

What are the characteristic physical findings during a severe episode of pediatric asthma?

What are the characteristic physical findings of status asthmaticus with imminent respiratory arrest?

How is asthma severity defined?

What should be considered when staging pediatric asthma?

DDX

Which conditions should be included in the differential diagnosis of pediatric asthma?

What are the differential diagnoses for Pediatric Asthma?

Workup

What are the diagnostic guidelines for pediatric asthma?

What is the accuracy of pulmonary function tests in the evaluation of pediatric asthma?

What is the role of spirometry in the diagnosis of pediatric asthma?

What is the role of plethysmography in the evaluation of pediatric asthma?

What is the role of exercise challenge testing in the evaluation of pediatric asthma?

What is the role of methacholine challenge testing in the evaluation of pediatric asthma?

What is the role of fraction of exhaled nitric oxide (FeNO) measurement in the evaluation of pediatric asthma?

What is the role of radiography in the evaluation of pediatric asthma?

What is the role of CT scanning in the evaluation of pediatric asthma?

What is the role of allergy testing in the evaluation of pediatric asthma?

Which histologic findings are characteristic of pediatric asthma?

Treatment

What are the goals of therapy for pediatric asthma?

How is the reduction in risk of pediatric asthma achieved?

Which dietary modifications may be beneficial in the treatment of pediatric asthma?

What is the goal of long-term therapy for pediatric asthma?

What are the components of asthma care?

What is included in the assessment and monitoring of pediatric asthma?

What is include in patient education for pediatric asthma?

Which environmental factors and comorbidities must be controlled as part of the management of pediatric asthma?

What is the role of vitamin D supplementation in the treatment of pediatric asthma?

What is the role of lansoprazole and inactivated influenza vaccine in the treatment of pediatric asthma?

What is included in pharmacologic management of pediatric asthma?

What is the goal of pharmacologic treatment of pediatric asthma?

What is the stepwise approach to pharmacologic therapy for pediatric asthma?

What is the role of salmeterol in the treatment of pediatric asthma?

What is the role of long-acting beta-agonists (LABAs) in the treatment of pediatric asthma?

What are safety concerns regarding the use of long-acting beta2-agonist in the treatment of pediatric asthma?

How frequently is pediatric asthma treated with oral corticosteroids?

What is the efficacy of increased inhaled corticosteroid doses at the onset of asthma exacerbation in children?

What are the adverse effects of long-term use of high-dose steroids for the treatment of pediatric asthma?

What inhaler devices are currently used to deliver inhaled corticosteroids (ICSs) for pediatric asthma?

What is the preferred device for delivery of medications in children younger than 4 years with pediatric asthma?

What is the role of valved holding chambers in the administration of medications for pediatric asthma?

What newer devices have been shown to be effective in the treatment of pediatric asthma?

What are the treatment goals for acute severe asthmatic episodes (status asthmaticus) in pediatric asthma?

Which tests can help guide treatment for acute severe asthmatic episodes (status asthmaticus) in pediatric asthma?

Which factors suggest high risk in pediatric asthma?

Which specialist consultations may be beneficial in the treatment of pediatric asthma?

What is included in long-term monitoring of pediatric asthma?

What should be included in outpatient care for pediatric asthma?

What should be included in the ongoing evaluation of pediatric asthma?

What is the efficacy of monitoring in pediatric asthma?

What is the role of surgery in the treatment of pediatric asthma?

Medications

Which medications are used in the treatment of pediatric asthma?

Which medications in the drug class Monoclonal Antibodies, Anti-asthmatics are used in the treatment of Pediatric Asthma?

Which medications in the drug class Anticholinergic Agents are used in the treatment of Pediatric Asthma?

Which medications in the drug class Combination Inhaled Steroids/Long-Acting Beta2-Agonists are used in the treatment of Pediatric Asthma?

Which medications in the drug class Methylxanthines are used in the treatment of Pediatric Asthma?

Which medications in the drug class Leukotriene Modifiers are used in the treatment of Pediatric Asthma?

Which medications in the drug class Systemic Corticosteroids are used in the treatment of Pediatric Asthma?

Which medications in the drug class Inhaled Corticosteroids are used in the treatment of Pediatric Asthma?

Which medications in the drug class Long-Acting Beta2-Agonists are used in the treatment of Pediatric Asthma?

Which medications in the drug class Nonracemic Form of the Beta2-Agonist Albuterol are used in the treatment of Pediatric Asthma?

Which medications in the drug class Bronchodilators, Beta2-Agonists are used in the treatment of Pediatric Asthma?