Pediatric Asthma

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).

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]}

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]}

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]

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 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.