ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
The diagnosis of asthma is based on recurrent episodes of cough, wheezing, dyspnea, or chest tightness, with various triggers, most commonly respiratory infections, exercise, aeroallergens, cold air, and irritants. At least 80% of children with asthma have an allergic predisposition.
Chronic airway inflammation, variable expiratory airflow limitation, and bronchial reactivity characterize the disease, but presentation is heterogeneous, and course over time, especially in children, is variable as well. The clinical course can be subtle for some children, but the risk of a severe, even life-threatening, asthma-related event is present.
Assessment of severity can be challenging particularly if comorbidities and adverse effects of chronic disease and medications are present. Hence assessment of control is helpful when treatment changes are being made.
The mainstay of asthma management involves targeting the inflammatory response and bronchoconstriction, avoidance of known triggers, identification of early warning signs, and creating an appropriate action plan. Regular assessment of response and control is necessary to prevent consequences of either poor disease control and medication side effects.
Due to the heterogeneity of asthma pathogenesis and still inadequate control found in some children with asthma-causing emergent health care utilization and school absences on regular controller therapy, add-on medications modulating specific immune responses can be helpful.
The Global Strategy for Asthma Management and Prevention 2014 (www.ginasthma.org) report offers a new definition of asthma as “a heterogeneous disease, usually characterized by chronic airway inflammation. It is defined by the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness, and cough that vary over time and in intensity, together with variable expiratory limitation.”
Asthma is the most common chronic disease of childhood, affecting 6.2 million children in the United States. While current prevalence rates for asthma had increased in the past decade, there has been an indication of a decrease in prevalence since 2011 (most recent estimate in children <18 years is 8.4%). At least half of persons with current asthma reported having had an asthma attack in the past year. Gender, race, and socioeconomic disparities in the prevalence of asthma exist: (1) More boys than girls are affected in childhood; (2) Higher percentage affected among black children compared to Hispanic and non-Hispanic white children; (3) Children belonging to poor families are more likely to be affected.
There is still a disproportionately higher health care utilization for asthma among children compared to adults affected by this disease. Asthma accounts for almost 50% of the emergency department visits and a third of the hospitalizations in children less than 18 years old. The emergency department visit rate due to asthma was the highest for children aged 0–4 years (20.8 visits per 100 persons with asthma). Children aged 0–17 years had a higher ED visit rate compared with adults (10.7 compared with 7.0 per 100 persons with asthma). Annual asthma hospitalizations rates were similar between children and adults. Still almost 140,000 children were hospitalized for asthma in 1 year. Hospitalizations and emergency department or urgent ambulatory or office visits, all indicators of asthma severity, impose significant costs to the health care system and to families, caretakers, schools, and parents’ employers. About half of children with asthma report one or more asthma-related missed school days. Indirect costs primarily from loss of productivity due to school/work absences are harder to measure, yet considerable, and are estimated to be three times the direct costs. Asthma remains a potentially life-threatening disease for children; among children, the population-based rate of asthma deaths per million was 2.8 in 2009, and the at-risk based rate of asthma deaths per 10,000 children with asthma was 0.3. Similar to disparities in prevalence, morbidity and mortality rates for asthma are higher among minority and inner city populations. The reasons for this are unclear but may be related to a combination of more severe disease, poor access to health care, lack of asthma education, delay in use of appropriate controller therapy, and environmental factors (eg, irritants including smoke and air pollutants, and perennial allergen exposure).
Up to 80% of children with asthma develop symptoms before their fifth birthday. Atopy (personal or familial) is the strongest identifiable predisposing factor. Sensitization to inhalant allergens increases over time and is found in the majority of children with asthma. The principal allergens associated with asthma are perennial aeroallergens such as dust mite, animal dander, cockroach, and Alternaria (a soil mold). Rarely, foods may provoke isolated asthma symptoms.
About 40% of infants and young children who have wheezing with viral infections in the first few years of life will have continuing asthma through childhood. Viral infections (eg, respiratory syncytial virus [RSV], rhinovirus, parainfluenza and influenza viruses, metapneumovirus) are associated with wheezing episodes in young children. RSV may be the predominant pathogen of wheezing infants in the emergency room setting, but rhinovirus can be detected in the majority of older wheezing children. It is uncertain if these viruses contribute to the development of chronic asthma, independent of atopy. Severe RSV bronchiolitis in infancy has been linked to asthma and allergy in childhood. Although speculative, individuals with lower airways vulnerability to common respiratory viral pathogens may be at risk for persistent asthma.
In addition to atopy and infections being associated with the development of asthma, observational studies have also demonstrated an increased risk of asthma attributed to acetaminophen exposure during prenatal periods, infancy, childhood, and even adulthood. Acetaminophen is the most commonly used antipyretic medication for children in the United States. There is evidence from secondary analyses suggesting that acetaminophen exposure increases the risk for subsequent asthma exacerbations or wheeze compared to ibuprofen; and that a dose-dependent elevated risk of asthma symptoms could be found.
There are several mechanisms which have been proposed: acetaminophen interfering with glutathione (a tripeptide antioxidant that is involved in free radical scavenging and xenobiotic detoxification) pathway and impairing respiratory antioxidant defenses; presence of genetic polymorphisms in the glutathione pathway that are associated with increased susceptibility to asthma; and acetaminophen causing a switch to a TH2 from a TH1 response. However, a recent double-blinded placebo controlled trial study comparing acetaminophen and ibuprofen used for fever or pain in preschool-aged children with persistent asthma did not show increased asthma worsening with use of either drug.
Exposure to tobacco smoke is also a risk factor and a trigger for asthma. Other triggers include exercise, cold air, pollutants, strong chemical odors, and rapid changes in barometric pressure. Aspirin sensitivity is uncommon in children. There are data suggesting that microbiome may also play a role in the development of asthma and allergy. Psychological factors may precipitate asthma exacerbations and place the patient at high risk from the disease.
Pathologic features of asthma include shedding of airway epithelium, edema, mucus plug formation, mast cell activation, and collagen deposition beneath the basement membrane. The inflammatory cell infiltrate includes eosinophils, lymphocytes, and neutrophils, especially in fatal asthma exacerbations. Airway inflammation contributes to airway hyperresponsiveness, airflow limitation, and disease chronicity. Persistent airway inflammation can lead to airway wall remodeling and irreversible changes.
The diagnosis of asthma in children, especially among preschool aged, is based largely on clinical judgment and an assessment of symptoms, activity limitation, and quality of life. For example, if a child with asthma refrains from participating in physical activities so as not to trigger asthma symptoms, their asthma would be inadequately controlled but not detected by the standard questions.
Wheezing is the most characteristic sign of asthma, although some children may have recurrent cough and shortness of breath. Complaints may include “chest congestion,” prolonged cough, exercise intolerance, dyspnea, and recurrent bronchitis or pneumonia. Chest auscultation during forced expiration may reveal prolongation of the expiratory phase and wheezing. As the obstruction becomes more severe, wheezes become more high-pitched and breath sounds diminished. With severe obstruction, wheezes may not be heard because of poor air movement. Flaring of nostrils, intercostal and suprasternal retractions, and use of accessory muscles of respiration are signs of severe obstruction. Cyanosis of the lips and nail beds may be seen with underlying hypoxia. Tachycardia and pulsus paradoxus also occur. Agitation and lethargy may be signs of impending respiratory failure.
Bronchial hyperresponsiveness, reversible airflow limitation, and airway inflammation are key features of asthma. Documentation of all these components is not always necessary, unless the presentation is rather atypical.
Bronchial hyperresponsiveness to nonspecific stimuli is a hallmark of asthma. These stimuli include inhaled pharmacologic agents such as histamine, methacholine, and mannitol, as well as physical stimuli such as exercise and cold air. Mannitol (Aridol) bronchoprovocation has been approved by the U.S. Food and Drug Administration (FDA) and is simpler and easier to administer in the office. It is available as a dry powder inhalation kit and takes less time to complete. Unlike methacholine and histamine challenges and similar to exercise challenge, it is considered an indirect challenge, that is, it simulates airway responses to specific physiologic situations, by creating an osmotic effect within the airway that subsequently leads to an inflammatory response. Airways may exhibit hyperresponsiveness or twitchiness even when baseline pulmonary function tests are normal. Giving increasing concentrations of a bronchoconstrictive agent to induce a decrease in lung function (usually a 20% drop in forced expiratory volume in 1 second [FEV1] for histamine and methacholine and a 15% reduction for mannitol) and doing an exercise challenge are ways to determine airway responsiveness. Hyperresponsiveness in normal children younger than age 5 years is greater than in older children. Bronchoprovocation challenges are not always available in a clinical setting but they help to establish a diagnosis of asthma when the history, examination, and pulmonary function tests are not definitive.
The National Asthma Education and Prevention Program Expert Panel Report 3 (NAEPP3) reinforces the use of spirometry over peak expiratory flow rate (PEFR) measurements in the evaluation of airflow limitation in asthma. This can be measured by reduction in FEV1 and FEV1/FVC (forced vital capacity) values compared to reference or predicted values. By itself, it is not adequate in establishing a diagnosis, but it can be an important parameter to monitor asthma activity and treatment response. In children, FEV1 may be normal, despite frequent symptoms. Spirometric measures of airflow limitation can be associated with symptom severity, likelihood of exacerbation, hospitalization, or respiratory compromise. Regular monitoring of prebronchodilator (and ideally postbronchodilator) FEV1 can be used to track lung growth patterns over time. During acute asthma exacerbations, FEV1 is diminished and the flow-volume curve shows a “scooping out” of the distal portion of the expiratory portion of the loop (Figure 38–1).
Representative flow-volume loops in persons with normal lung function, asthma, and vocal cord dysfunction.
In addition to the importance placed on documentation of airflow limitation at any time during the diagnostic process, the GINA global strategy 2014 also puts an emphasis on documenting excessive variability in lung function. This can be gleaned from any of the following:
Bronchodilator reversibility: increase in FEV1 > 12% predicted
Excessive variability in twice daily peak flow readings over 2 weeks: average daily diurnal PEF variability > 13% ([Day’s highest PEF minus day’s lowest PEF]/mean of day’s highest and lowest), averaged over 1 week
Significant increase in lung function after 4 weeks of anti-inflammatory treatment (FEV1 > 12% and 200 mL (or PEF > 20%)
(+) Exercise challenge test: fall in FEV1 > 12% predicted or PEF > 15%
(+) Bronchoprovocation challenge test
Excessive variation in lung function between visits: variation in FEV1 of 12% or PEF > 15%
PEFR monitoring can be a simple and reproducible tool to assess asthma activity in children with moderate or severe asthma, a history of severe exacerbations, or poor perception of airflow limitation or worsening condition. Significant changes in PEFR may occur before symptoms become evident. In more severe cases, PEFR monitoring enables earlier recognition of suboptimal asthma control.
Lung function assessment using body box plethysmography to determine lung volume measurements can also be informative. The residual volume, functional residual capacity, and total lung capacity are usually increased, while the vital capacity is decreased. Reversal or significant improvement of these abnormalities in response to inhaled bronchodilator therapy or with anti-inflammatory therapy can be observed.
Infant pulmonary function can be measured in sedated children with compression techniques. The forced oscillation technique can be used to measure airway resistance even in younger children.
Hypoxemia is present early with a normal or low PCO2 level and respiratory alkalosis. Hypoxemia may be aggravated during treatment with a β2-agonist due to ventilation-perfusion mismatch. Oxygen saturation less than 91% is indicative of significant obstruction. Respiratory acidosis and increasing CO2 tension may ensue with further airflow obstruction and signal impending respiratory failure. Hypercapnia is usually not seen until the FEV1 falls below 20% of predicted value. Metabolic acidosis has also been noted in combination with respiratory acidosis in children with severe asthma and indicates imminent respiratory failure. PaO2 less than 60 mm Hg despite oxygen therapy and PaCO2 over 60 mm Hg and rising more than 5 mm Hg/h are relative indications for mechanical ventilation in a child in status asthmaticus.
Pulsus paradoxus may be present with moderate or severe asthma exacerbation. In moderate asthma exacerbation in a child, this may be between 10 and 25 mm Hg, and in severe asthma exacerbation between 20 and 40 mm Hg. Absence of pulsus paradoxus in a child with severe asthma exacerbation may signal respiratory muscle fatigue.
Clumps of eosinophils on sputum smear and blood eosinophilia are frequent findings. Their presence tends to reflect disease activity and does not necessarily mean that allergic factors are involved. Leukocytosis is common in acute severe asthma without evidence of bacterial infection and may be more pronounced after epinephrine administration. Hematocrit can be elevated with dehydration during prolonged exacerbations or in severe chronic disease. Noninvasive measures of airway inflammation include exhaled nitric oxide concentrations, serum eosinophil cationic protein levels, and induced sputum. Each test has its strengths and weaknesses.
Evaluation of asthma usually does not need chest radiographs (posteroanterior and lateral views) since they often appear normal, although subtle and nonspecific findings of hyperinflation (flattening of the diaphragms), peribronchial thickening, prominence of the pulmonary arteries, and areas of patchy atelectasis may be present. Atelectasis may be misinterpreted as the infiltrates of pneumonia. Some lung abnormalities, such as bronchiectasis, which may point to a different diagnosis implicating an asthma masquerader, such as cystic fibrosis, allergic bronchopulmonary mycoses (aspergillosis), ciliary dyskinesias, or immune deficiencies, can be better appreciated with high-resolution, thin-section chest computed tomography (HRCT) scans. It is primarily useful clinically in ruling out certain diagnoses in patients with difficult to manage asthma but radiation exposure should be considered when ordering HRCT.
Allergy testing is discussed in the section General Measures under Treatment, Chronic Asthma.
Diseases that may be mistaken for asthma are often related to the patient’s age (Table 38–1). Congenital abnormalities must be excluded in infants and young children. Asthma can be confused with croup, acute bronchiolitis, pneumonia, and pertussis. Immunodeficiency may be associated with cough and wheezing. Foreign bodies in the airway may cause dyspnea or wheezing of sudden onset, and on auscultation, wheezing may be unilateral. Asymmetry of the lungs secondary to air trapping may be seen on a chest radiograph, especially with forced expiration. Cystic fibrosis can be associated with or mistaken for asthma.
Table 38–1.Differential diagnosis of asthma in infants and children. ||Download (.pdf) Table 38–1. Differential diagnosis of asthma in infants and children.
Airway stenosis or web
Enlarged lymph nodes
Vocal cord dysfunction
Vocal cord dysfunction is an important masquerader of asthma, although the two can coexist. It is characterized by the paradoxic closure of the vocal cords that can result in dyspnea and wheezing. Diagnosis is made by direct visualization of the vocal cords. In normal individuals, the vocal cords abduct during inspiration and may adduct slightly during expiration. Asthmatic patients may have narrowing of the glottis during expiration as a physiologic adaptation to airway obstruction. In contrast, patients with isolated vocal cord dysfunction typically show adduction of the anterior two-thirds of their vocal cords during inspiration, with a small diamond-shaped aperture posteriorly. Because this abnormal vocal cord pattern may be intermittently present, a normal examination does not exclude the diagnosis. Bronchial challenges using exercise or methacholine can precipitate symptoms of vocal cord dysfunction. The flow-volume loop may provide additional clues to the diagnosis of vocal cord dysfunction. Truncation of the inspiratory portion can be demonstrated in most patients during an acute episode, and some patients continue to show this pattern even when they are asymptomatic (see Figure 38–1). Children with vocal cord dysfunction, especially adolescents, tend to be overly competitive, primarily in athletics and scholastics. A psychiatric consultation may help define underlying psychological issues and provide appropriate therapy. Treatment of isolated vocal cord dysfunction includes education regarding the condition and appropriate breathing exercises. Hypnosis, biofeedback, and psychotherapy have been effective for some patients.
Conditions That May Increase Asthma Severity
Chronic hyperplastic sinusitis is frequently found in association with asthma. Upper airway inflammation has been shown to contribute to the pathogenesis of asthma, and asthma may improve after treatment of sinusitis. However, sinus surgery is usually not indicated for initial treatment of chronic mucosal disease associated with allergy. In older children, rarely, hyperplastic sinusitis and polyposis and severe refractory asthma can be associated with aspirin sensitivity, known as aspirin-exacerbated respiratory disease (AERD).
A significant correlation has been observed between nocturnal asthma and gastroesophageal reflux. Patients may not complain of burning epigastric pain or have other reflux symptoms—cough may be the only sign. For patients with poorly controlled asthma, particularly with a nocturnal component, investigation for gastroesophageal reflux may be warranted even in the absence of suggestive symptoms.
Population studies have demonstrated associations between obesity and asthma. Obesity has been linked not only to the development of asthma but also with asthma control and severity. What contributes to these associations or to what extent inflammation or physiologic impairment relates to both obesity and asthma is less established. It becomes difficult to determine if a child’s trouble breathing is a result of obesity itself, its comorbidities (eg, gastroesophageal reflux or obstructive sleep apnea), and/or asthma. A management approach targeting weight reduction in obese children is encouraged to improve asthma control or its assessment.
The risk factors for death from asthma include psychological and sociological factors. They are probably related to the consequences of illness denial, poor coping or self-management skills, as well as to nonadherence with prescribed therapy. Recent studies have shown that less than 50% of inhaled asthma medications are taken as prescribed and that compliance does not improve with increasing severity of illness. Moreover, children requiring hospitalization for asthma, or their caregivers, have often failed to institute appropriate home treatment.
With acute asthma, complications are primarily related to hypoxemia and acidosis and can include generalized seizures. Pneumomediastinum or pneumothorax can be a complication in status asthmaticus. With chronic asthma, recent studies point to airway wall remodeling and loss of pulmonary function with persistent airway inflammation. Childhood asthma independent of any corticosteroid therapy has been shown to be associated with delayed maturation and slowing of prepubertal growth velocity.
The NAEPP EPR3 and the GINA global strategy offer slightly different management approaches. GINA has been updated yearly based on new studies, with the most recent one from 2016 is cited in this chapter. Both guideline approaches include an assessment and regular monitoring of disease activity, education and partnership to improve the child’s and his/her family’s knowledge and skills for self-management, identification and management of triggers and conditions that may worsen asthma, and appropriate medications selected to address the patient’s needs. The objective of asthma management is the attainment of the best possible asthma control.
The NAEPP EPR3 stepwise approach is based on an assessment of severity and control. An assessment of asthma severity (ie, the intrinsic intensity of disease) is generally most accurate in patients not receiving controller therapy. Hence, assessing asthma severity directs the level of initial therapy. For those already on treatment, asthma severity can be classified according to the level of medication requirement to maintain adequate asthma control. The two general categories are intermittent and persistent asthma, the latter further subdivided into mild, moderate, and severe (Table 38–2). In contrast, asthma control refers to the degree to which symptoms, ongoing functional impairments, and risk of adverse events are minimized and goals of therapy are met. Assessment of asthma control should be done at every visit as this is important in adjusting therapy. It is categorized as “well controlled,” “not well controlled,” and “very poorly controlled” (Table 38–3). Responsiveness to therapy is the ease with which asthma control is attained by treatment. It can also encompass monitoring for adverse effects related to medication use.
Table 38–2.Assessing severity and initiating treatment for patients who are not currently taking long-term control medications. ||Download (.pdf) Table 38–2. Assessing severity and initiating treatment for patients who are not currently taking long-term control medications.
|Components of Severity ||Classification of Asthma Severity |
|Intermittent ||Persistent |
|Mild ||Moderate ||Severe |
|Impairment ||Daytime symptoms ||≤ 2 days/wk ||> 2 days/wk but not daily ||Daily ||Throughout the day |
| ||Nighttime awakenings || || || || |
| ||Age 0–4 y ||0 ||1–2 ×/mo ||3–4 ×/mo ||> 1 ×/wk |
| ||Age ≥ 5 y ||≤ 2 ×/mo ||3–4 ×/mo ||> 1 ×/wk but not nightly ||Often 7 ×/wk |
| ||SABA use for symptoms (not prevention of EIB) ||≤ 2 days/wk ||> 2 days/wk but not daily, and not more than 1 × on any day ||Daily ||Several times per day |
| ||Interference with normal activity ||None ||Minor limitation ||Some limitation ||Extremely limited |
| ||Lung function || || || || |
| ||FEV1% predicted ||Normal FEV1 between exacerbations || || || |
| ||Age ≥ 5 y ||> 80% predicted ||≥ 80% predicted ||60%–80% predicted ||< 60% predicted |
| ||FEV1/FVC ratio || || || || |
|Normal FEV1/FVC: 8–19 y, ||Age 5–11 y ||> 85% ||> 80% ||75%–80% ||< 75% |
|85% 20–39 y, 80% ||Age ≥ 12 y ||Normal ||Normal ||Reduced 5% ||Reduced > 5% |
|Risk ||Exacerbations requiring systemic corticosteroids || || || || |
| ||Age 0–4 y ||0–1/y (see Notes) ||≥ 2 exacerbations in 6 mo requiring systemic corticosteroids OR ≥ 4 wheezing episodes/year lasting > 1 day and risk factors for persistent asthma |
| ||Age ≥ 5 y ||0–1/y (see Notes) ||≥ 2/y (see Notes) |
| || ||Consider severity and interval since last exacerbation. Frequency and severity may fluctuate over time for patients in any severity category. Relative annual risk of exacerbations may be related to FEV1. |
|Recommended step for initiating therapy ||Step 1 ||Step 2 ||Age 0–4 y |
| || || ||Step 3 ||Step 3 |
| || || ||Age 5–11 y |
| || || ||Step 3, medium-dose ICS option ||Step 3, medium-dose ICS option, OR step 4 |
| || || ||Age ≥ 12 y |
| || || ||Step 3 ||Step 4 or 5 |
| || || ||Consider a short course of systemic corticosteroids |
| ||In 2–6 wk, evaluate level of asthma control that is achieved and adjust therapy accordingly. If no clear benefit is observed within 4–6 wk, consider adjusting therapy or alternative diagnoses. |
Table 38–3.Assessing asthma control and adjusting therapy in children. ||Download (.pdf) Table 38–3. Assessing asthma control and adjusting therapy in children.
|Components of Control ||Classification of Asthma Control |
|Well Controlled ||Not Well Controlled ||Very Poorly Controlled |
|Impairment ||Symptoms ||≤ 2 days/wk but not more than once on each day ||> 2 days/wk or multiple times on ≤ 2 days/wk ||Throughout the day |
| ||Nighttime awakenings || || || |
| ||Age 0–4 y ||≤ 1 × /mo ||> 1 × /mo ||> 1 × /wk |
| ||Age 5–11 y ||≤ 1 × /mo ||≥ 2 × /mo ||≥ 2 × /wk |
| ||Age ≥ 12 y ||≤ 2 × /mo ||1–3 × /wk ||≥ 4 × /wk |
| ||SABA use for symptoms (not EIB pretreatment) ||≤ 2 days/wk ||> 2 days/wk ||Several times per day |
| ||Interference with normal activity ||None ||Some limitation ||Extremely limited |
| ||Lung function || || || |
| ||Age 5–11 y || || || |
| ||FEV1% predicted or peak flow ||> 80% predicted or personal best ||60%–80% predicted or personal best ||< 60% predicted or personal best |
| ||FEV1/FVC ||> 80% ||75%–80% ||< 75% |
| ||Age ≥ 12 y || || || |
| ||FEV1% predicted or peak flow ||> 80% predicted or personal best ||60%–80% predicted or personal best ||< 60% predicted or personal best |
| ||Validated questionnaires || || || |
| ||Age ≥ 12 y || || || |
| ||ATAQ ||0 ||1–2 ||3–4 |
| ||ACQ ||≤ 0.75a ||≥ 1.5 ||N/A |
| ||ACT ||≥ 20 ||16–19 ||≤ 15 |
|Risk ||Exacerbations requiring systemic corticosteroids || || || |
| ||Age 0–4 y ||0–1 y ||2–3/y ||> 3/y |
| ||Age ≥ 5 y ||0–1 y ||≥ 2/y (see Notes) || |
| ||Consider severity and interval since last exacerbation. |
| ||Treatment-related adverse effects. ||Medication side effects can vary in intensity from none to very troublesome and worrisome. The level of intensity does not correlate to specific levels of control but should be considered in the overall assessment of risk. |
| ||Reduction in lung growth or progressive loss of lung function. ||Evaluation requires long-term follow-up care. |
|Recommended action for treatment. || || |
Step up (1 step).
Reevaluate in 2–6 wk.
If no clear benefit in 4–6 wk, consider alternative diagnoses or adjusting therapy.
For side effects, consider alternative options.
Consider short course of oral corticosteroids.
Step up (1–2 steps).
Reevaluate in 2 wk.
If no clear benefit in 4–6 wk, consider alternative diagnoses or adjusting therapy.
For side effects, consider alternative options.
The NAEPP EPR3 classification of either asthma severity or control is based on the domains of current impairment and risk, recognizing that these domains may respond differently to treatment. The level of asthma severity or control is established upon the most severe component of impairment or risk. Generally, the assessment of impairment is symptom based, except for the use of lung function for school-aged children and youths. Impairment includes an assessment of the patient’s recent symptom frequency and intensity and functional limitations (ie, daytime symptoms, nighttime awakenings, need for short-acting β2-agonists for quick relief, work or school days missed, ability to engage in normal or desired activities, and quality-of-life assessments) and airflow compromise preferably using spirometry. Numerous validated instruments and questionnaires for assessing health-related quality of life and asthma control have been developed. The Asthma Control Test (ACT, www.asthmacontrol.com), the Asthma Control Questionnaire (ACQ, www.qoltech.co.uk/Asthma1.htm), and the Asthma Therapy Assessment Questionnaire (ATAQ, www.ataqinstrument.com) for children 12 years of age and older, and the Childhood ACT for children 4–11 years of age are examples of self-administered questionnaires that have been developed with the objective of addressing multiple aspects of asthma control such as frequency of daytime and nocturnal symptoms, use of reliever medications, functional status, missed school or work, and so on. A five-item caregiver-administered instrument, the Test for Respiratory and Asthma Control in Kids (TRACK), has been validated as a tool to assess both impairment and risk presented in the NAEPP Expert Panel Report 3 (EPR3) guidelines in young children with recurrent wheezing or respiratory symptoms consistent with asthma.
“Risk” refers to an evaluation of the patient’s likelihood of developing asthma exacerbations, reduced lung growth in children (or progressive decline in lung function in adults), or risk of untoward effects from medications. The GINA 2014 strategy also cites risk factors for poor asthma outcomes (ie, exacerbations, fixed airflow limitation, and medication side effects). Potentially modifiable risk factors for exacerbations include uncontrolled asthma symptoms; excessive short-acting beta-agonist use (> 1 200-dose canister/month); inadequate or lack of inhaled corticosteroid; poor adherence; incorrect inhaler technique; low FEV1, especially if less than 60% predicted; major psychological or socioeconomic problems; presence of smoking or allergen exposure; having comorbidities (obesity, rhinosinusitis, confirmed food allergy); sputum or blood eosinophilia; and pregnancy. Considered major independent risk factors for flare-ups are history of intubation or ICU admission for asthma; and ≥1 severe exacerbation in last 12 months. Risk factors for developing fixed airflow limitation are lack of inhaled corticosteroid treatment; exposures to tobacco smoke, noxious chemicals, occupational exposures; low initial FEV1; and chronic mucus hypersecretion, sputum or blood eosinophilia. Frequent oral corticosteroid use, long-term high dose and/or potent inhaled corticosteroid, and intake of P450 inhibitors are risk factors for systemic medication side effects; while high-dose or potent inhaled corticosteroid and poor inhaler technique are also risk factors for local side effects.
Education is important and partnership with the child’s family is a key component in the management to improve adherence and outcomes. The patient and family must understand the role of asthma triggers, the importance of disease activity even without obvious symptoms, how to use objective measures to gauge disease activity, and the importance of airway inflammation—and they must learn to recognize the warning signs of worsening asthma, allowing for early intervention. A stepwise care plan should be developed for all patients with asthma. Providing asthma action plans is currently a requirement that is tracked by many hospitals and others to document that educational instruction for chronic disease management has been given. Asthma action plans should be provided to school personnel and all those who care for children with asthma.
Because the degree of airflow limitation is poorly perceived by many patients, peak flow meters can aid in the assessment of airflow obstruction and day-to-day disease activity. Peak flow rates may provide early warning of worsening asthma. They are also helpful in monitoring the effects of medication changes. Spacer devices optimize delivery of medication from metered-dose inhalers (MDIs) to the lungs and, with inhaled steroids, minimize side effects. Large-volume spacers are preferred. Poor understanding by patients and families of proper device use can lead to inadequate delivery and treatment with inhaled medications, especially inhaled controllers. Short instructive videos for device use can be provided to educate families and other caregivers (http://www.thechildrenshospital.org/conditions/lung/asthmavideos.aspx).
Patients should avoid exposure to tobacco smoke and allergens to which they are sensitized, exertion outdoors when levels of air pollution are high, β-blockers, and sulfite-containing foods. Patients with persistent asthma should be given the inactivated influenza vaccine yearly unless they have a contraindication.
For patients with persistent asthma, the clinician should use the patient’s history to assess sensitivity to seasonal allergens and Alternaria mold and in vitro testing (either by skin or blood test) to assess sensitivity to perennial indoor allergens, to assess the significance of positive tests in the context of the patient’s history, and to identify relevant allergen exposures. For dust mite–allergic children, important environmental control measures include encasing the pillow and mattress in an allergen-impermeable cover and washing the sheets and blankets on the patient’s bed weekly in hot water. Other measures include keeping indoor humidity below 50%, minimizing the number of stuffed toys, and washing such toys weekly in hot water. Children allergic to furred animals or feathers should avoid indoor exposure to pets, especially for prolonged periods of time. If removal of the pet is not possible, the animal should be kept out of the bedroom with the door closed. Carpeting and upholstered furniture should be removed. While a high-efficiency particle-arresting filter unit in the bedroom may reduce allergen levels, symptoms may persist if the pet remains indoors. For cockroach-allergic children, control measures need to be instituted when infestation is present in the home. Poison baits, boric acid, and traps are preferred to chemical agents, which can be irritating if inhaled by asthmatic individuals. Indoor molds are especially prominent in humid or damp environments. Measures to control dampness or fungal growth in the home may be of benefit. Patients can reduce exposure to outdoor allergens by staying in an air-conditioned environment. Allergen immunotherapy may be useful for implicated aeroallergens that cannot be avoided. However, it should be administered only in facilities staffed and equipped to treat life-threatening reactions.
Patients should be treated for rhinitis, sinusitis, or gastroesophageal reflux, if present. Treatment of upper respiratory tract symptoms is an integral part of asthma management. Intranasal corticosteroids are recommended to treat chronic rhinosinusitis in patients with persistent asthma because they reduce lower airway hyperresponsiveness and asthma symptoms. Intranasal cromolyn reduces asthma symptoms during the ragweed season but less so than intranasal corticosteroids. Treatment of rhinosinusitis includes medical measures to promote drainage and the use of antibiotics for acute bacterial infections (see Chapter 18). Medical management of gastroesophageal reflux includes avoiding eating or drinking 2 hours before bedtime, elevating the head of the bed with 6- to 8-in blocks, and using appropriate pharmacologic therapy.
A revised stepwise approach to pharmacologic therapy, broken down by age categories, is recommended in the NAEPP EPR3 (http://www.nhlbi.nih.gov) (Table 38–4). This approach is based on the concepts of asthma severity and asthma control. A separate set of recommendations for younger children is provided given the lack of tools which can be used to assess lung function and quality of life otherwise available for older children. Treatment recommendations for older children and adults are better supported by stronger evidence from available clinical trials, whereas those for younger children have been extrapolated from studies in older children and adults.
Table 38–4.Stepwise approach for managing asthma in children. ||Download (.pdf) Table 38–4. Stepwise approach for managing asthma in children.
| ||Intermittenta ||Persistent Asthma: Daily Medication |
| || || || || || || |
High-dose ICS + either LABA or LTRA AND oral corticosteroid
| || || || || || |
High-dose ICS + either LABA or LTRA
| || || || || |
Medium-dose ICS + either LABA or LTRA
| || || || |
| || || |
Cromolyn or montelukast
| || |
|Age 0–4 y |
|Age 5–11 y || |
Alternative Cromolyn, LTRA, nedocromil, or theophylline
EITHER Low-dose ICS + either LABA, LTRA, or theophylline OR medium-dose ICS
Medium-dose ICS + LABA
Alternative Medium-dose ICS + either LTRA or theophylline
High-dose ICS + LABA
Alternative High-dose ICS + either LTRA or theophylline
High-dose ICS + LABA AND oral corticosteroid Alternative
High-dose ICS + either LTRA or theophylline AND oral corticosteroid
Step down if possible (and asthma is well controlled at least 3 mo)
Step up if needed (first check inhaler technique, adherence, environmental control, and comorbid condition)
|Age ≥ 12 y || |
Alternative Cromolyn, LTRA, nedocromil, or theophylline
Low-dose ICS + LABA OR medium-dose ICS
Low-dose ICS + either LTRA, theophylline, or zileuton
Medium-dose ICS + LABA
Alternative Medium-dose ICS + either LTRA or theophylline or zileuton
High-dose ICS + LABA AND consider omalizumab for patients with allergies
High-dose ICS + LABA + oral corticosteroid AND consider omalizumab for patients with allergies
Each step: Patient education, environmental control, and management of comorbidities.
Age ≥ 5 y: Steps 2–4: Consider subcutaneous allergen immunotherapy for patients who have allergic asthma.
Quick-Relief Medication for All Patients
SABA as needed for symptoms. Intensity of treatment depends on severity of symptoms: up to three treatments at 20-min intervals as needed. Short course of oral systemic corticosteroids may be needed.
Caution: Use of SABA > 2 days/wk for symptom relief (not prevention of EIB) generally indicates inadequate control and the need to step up treatment.
For ages 0–4 y: With viral respiratory infection: SABA q4-6h up to 24 h (longer with physician consult). Consider short course of systemic corticosteroids if exacerbation is severe or patient has history of previous severe exacerbations.
The choice of initial therapy is based on assessment of asthma severity. For patients who are already on controller therapy, treatment can be adjusted based on assessment of asthma control and responsiveness to therapy. The goals of therapy are to reduce the components of both impairment (eg, preventing chronic and troublesome symptoms, allowing infrequent need of quick-relief medications, maintaining “normal” lung function, maintaining normal activity levels including physical activity and school attendance, meeting families’ expectations and satisfaction with asthma care) and risk (eg, preventing recurrent exacerbations, reduced lung growth, and medication adverse effects).
The stepwise approach is meant to assist, not replace, the clinical decision making required to meet individual patient needs.
In the absence of persistent symptoms, the new clinical guidelines recommend considering initiation of long-term controller therapy for infants and younger children who have risk factors for asthma (ie, modified asthma predictive index: parental history of asthma, physician-diagnosed atopic dermatitis, or sensitization to aeroallergens or two of the following: wheezing apart from colds, sensitization to foods, or peripheral eosinophilia) and four or more episodes of wheezing over the past year that lasted longer than 1 day and affected sleep or two or more exacerbations in 6 months requiring systemic corticosteroids.
Inhaled corticosteroids, either as monotherapy or in combination with adjunctive therapy, are preferred treatment for all levels of persistent asthma.
Along with medium-dose inhaled corticosteroids, combination therapy with inhaled corticosteroids plus any of the following adjunctive therapies—long-acting inhaled β2-agonists (LABAs), leukotriene modifying agents, cromones, and theophylline—is recommended as step 3 treatment for moderate persistent asthma, or as step-up therapy for uncontrolled persistent asthma for school-aged children and youths. In children aged 0–4 years, medium-dose inhaled corticosteroids as monotherapy remain the step 3 therapy, and combination therapy to be initiated only as a step 4 treatment. A rescue course of systemic corticosteroids may be necessary at any step.
The GINA global strategy has a different and maybe simplified set of recommending options for initiation of controller therapy (Table 38–5). In their stepwise approach (Table 38–6), emphasis on maximizing benefit from available medications, inhaler technique, and adherence before step-up treatment is pursued.
Asthma medications are classified as long-term controller medications and quick-relief medications. The former includes anti-inflammatory agents, leukotriene modifiers, long-acting bronchodilators (LABAs and long-acting antimuscarinic agents [LAMAs]), and biologics (omalizumab and mepolizumab). Although LABAs (salmeterol, formoterol) are β-agonists, they are considered to be daily controller medications, but unlike the other asthma controller medications with primarily anti-inflammatory properties, LABAs cannot be administered as monotherapy. Bronchial thermoplasty is also an option which can be considered for some adult patients with severe asthma.
Inhaled corticosteroids are the most potent inhaled anti-inflammatory agents currently available. Although recommended as daily controller therapy, recent studies have shown their efficacy even for intermittent use for rescue or at the onset of acute respiratory illnesses. Different inhaled corticosteroids are not equivalent on a per puff or microgram basis (Table 38–7). Early intervention with inhaled corticosteroids can improve asthma control and prevent exacerbations during treatment, but they do not prevent the development of persistent asthma nor do they alter its natural history. Long-term inhaled corticosteroids may be associated with early slowing of growth velocity in children, and although this can impact the final adult height by a minimum degree, it is not a cumulative effect. Possible risks from inhaled corticosteroids need to be weighed against the risks from undertreated asthma. The adverse effects from inhaled corticosteroids are generally dose and duration dependent, so that greater risks for systemic adverse effects are expected with high doses. The various inhaled corticosteroids are delivered in different devices such as MDI (beclomethasone, ciclesonide, fluticasone propionate, flunisolide, mometasone, and triamcinolone), dry powder inhaler (DPI) (fluticasone propionate [Diskus], fluticasone furoate [Ellipta], budesonide [Flexhaler], and mometasone [Twisthaler]), and nebulized aerosol suspensions (budesonide respules). Inhaled medications delivered in MDI now use the more ozone-friendly hydrofluoroalkane (HFA) propellant, which has replaced chlorofluorocarbons (CFC). See instructions for different device use at the following URL: http://www.thechildrenshospital.org/conditions/lung/asthmavideos.aspx.
Table 38–5.Recommended options for initial controller treatment in adults and adolescents. ||Download (.pdf) Table 38–5. Recommended options for initial controller treatment in adults and adolescents.
|Presenting symptoms ||Preferred initial controller |
|Asthma symptoms or need for SABA < 2 ×/mo; no waking due to asthma in last month; and no risk factors for exacerbations, including no exacerbations in the last year ||Step 1: No controller |
|Infrequent asthma symptoms, but the patient has ≥ 1 risk factors for exacerbations; eg, low lung function, or exacerbation requiring OCS in the last year, or has ever been in ICU for asthma ||Step 2: Low-dose ICS |
|Asthma symptoms or need for SABA between twice a month and twice a week, or patient wakes ≥1 a month ||Step 2: Low-dose ICS |
|Asthma symptoms or need for SABA more than twice a week ||Step 2: Low-dose ICS; alternative options (LTRA or theophylline) |
|Troublesome asthma symptoms most days; or waking due to asthma ≥ 1 a week, especially if any risk factors exist ||Step 3: Medium-/high-dose ICS or Low-dose ICS/LABAa |
|Initial asthma presentation is with severely uncontrolled asthma, or with an acute exacerbation || |
Short course of oral CS AND Start regular controller treatment; options are:
High-dose ICS OR moderate-dose ICS/LABA
Table 38–6.GINA stepwise approach to control symptoms and minimize future risk. ||Download (.pdf) Table 38–6. GINA stepwise approach to control symptoms and minimize future risk.
| || || || || || |
Refer for add-on treatment, eg, tiotropium, omalizumab, mepolizumab
| || || || || |
| || || || |
*Children 6–11 y: Medium-dose ICS
| || |
| || || |
| || || |
|Preferred Controller Choice ||STEP 1 || || || || |
|Other controller options ||Consider low-dose ICS ||LTRA or low-dose theophylline ||Medium/High dose ICS or Low-dose ICS+LTRA (or +theophylline for adolescents and adults) ||Add tiotropium (for ≥ 12 y and for patients with a history of exacerbations) or use high dose ICS+LTRA (or +theophylline for adolescents and adults) ||Add low-dose OCS |
|Reliever ||As needed SABA ||As needed SABA (all children) or Low-dose ICS/formoterol |
|REMEMBER TO… || |
Provide guided self-management education (self-monitoring+written action plan+regular review)
Treat modifiable risk factors and comorbidities eg, smoking, obesity, and anxiety
Advise about nonpharmacologic therapies and strategies, eg, physical activity, weight loss, avoidance of sensitizers where appropriate
Consider stepping up if…uncontrolled symptoms, exacerbations or risks, but check diagnosis, inhaler technique, and adherence first
Consider stepping down if…symptoms controlled for 3 months + low risk for exacerbations. Ceasing ICS is not advised.
Table 38–7.Estimated comparative inhaled corticosteroid doses. ||Download (.pdf) Table 38–7. Estimated comparative inhaled corticosteroid doses.
|Drug ||Low Daily Dose ||Medium Daily Dose ||High Daily Dose |
|0–4 y ||5–11 y ||≥ 12 y ||0–4 y ||5–11 y ||≥ 12 y ||0–4 y ||5–11 y ||≥ 12 y |
|Beclomethasone HFA, 40 or 80 mcg/puff ||NA ||80–160 mcg ||80–240 mcg ||NA ||> 160–320 mcg ||> 240–480 mcg ||NA ||> 320 mcg ||> 480 mcg |
|Budesonide DPI 90, 80, or 200 mcg/inhalation ||NA ||180–400 mcg ||180–600 mcg ||NA ||> 400–800 mcg ||> 600–1200 mcg ||NA ||> 800 mcg ||> 1200 mcg |
|Budesonide inhaled suspension for nebulization, 0.25-, 0.5-, and 1.0-mg dose ||0.25–0.5 mg ||0.5 mg ||NA ||> 0.5–1.0 mg ||1.0 mg ||NA ||> 1.0 mg ||2.0 mg ||NA |
|Flunisolide, 250 mcg/puff ||NA ||500–750 mcg ||500–1000 mcg ||NA ||1000–1250 mcg ||> 1000–2000 mcg ||NA ||> 1250 mcg ||> 2000 mcg |
|Flunisolide HFA, 80 mcg/puff ||NA ||160 mcg ||320 mcg ||NA ||320 mcg ||> 320–640 mcg ||NA ||≥ 640 mcg ||> 640 mcg |
|Fluticasone HFA/MDI, 44, 110, or 220 mcg/puff ||176 mcg ||88–176 mcg ||88–264 mcg ||> 176–352 mcg ||> 176–352 mcg ||> 264–440 mcg ||> 352 mcg ||> 352 mcg ||> 440 mcg |
|Fluticasone DPI, 50, 100, or 250 mcg/inhalation ||NA ||100–200 mcg ||100–300 mcg ||NA ||> 200–400 mcg ||> 300–500 mcg ||NA ||> 400 mcg ||> 500 mcg |
|Mometasone DPI, 220 mcg/inhalation ||NA ||NA ||220 mcg ||NA ||NA ||440 mcg ||NA ||NA ||> 440 mcg |
|Triamcinolone acetonide, 75 mcg/puff ||NA ||300–600 mcg ||300–750 mcg ||NA ||> 600–900 mcg ||> 750–1500 mcg ||NA ||> 900 mcg ||> 1500 mcg |
Only inhaled corticosteroids have been shown to be effective in long-term clinical studies for infants. Nebulized budesonide is approved for children as young as 12 months. The suspension (available in quantities of 0.25 mg/2 mL, 0.5 mg/2 mL, and 1.0 mg/2 mL) is usually administered either once or twice daily in divided doses. For effective drug delivery, it is critical that the child has a mask secured on the face for the entire treatment, as blowing it in the face is not effective and yet a common practice by parents. Notably, this drug should not be given by ultrasonic nebulizer. Limited data suggest that inhaled corticosteroids may be effective even in very young children when delivered by MDI with a spacer and mask. Low daily dose in mcg (defined as a dose that has not been associated with adverse effects in trials that evaluated safety measures) for various inhaled corticosteroids for children 5 years and younger is as follows: beclomethasone dipropionate (HFA) 100 mcg; budesonide pMDI+spacer 200 mcg; budesonide nebulized 500 mcg; fluticasone propionate (HFA) 100 mcg; and ciclesonide 160 mcg.
Fewer data are available with nedocromil, although data from the Childhood Asthma Management Program study showed that an inhaled corticosteroid was superior to nedocromil with respect to several efficacy parameters, including rate of hospitalization, symptom-free days, need for albuterol rescue, and longer time to treatment with prednisone, when each was compared to a placebo.
Theophylline is rarely used. Sustained-release theophylline, an alternative long-term control medication for older children, may have particular risks of adverse effects in infants, who frequently have febrile illnesses that increase theophylline concentrations. Hence, if theophylline is used, it requires monitoring of serum concentration to prevent numerous dose-related acute toxicities.
For school-aged children whose asthma is uncontrolled on low-dose inhaled corticosteroid (ie, requiring step 3 guidelines therapy), majority are likely to respond to a step-up combination therapy with a long-acting β2-agonist bronchodilator (eg, salmeterol and formoterol), although some respond best either to an increased dose of inhaled corticosteroid or to an addition of a leukotriene receptor antagonist. LABAs should not be used for treatment of acute symptoms, nor should they be used without any inhaled corticosteroid therapy, even if the patient feels better. Salmeterol is available as an inhalation powder (one inhalation twice daily for patients aged 4 years and older). It is also available combined with fluticasone (50 mcg salmeterol with 100, 250, or 500 mcg fluticasone in a DPI or 21 mcg salmeterol with 45, 115, or 230 mcg fluticasone in an MDI). For children 12 years and older, one inhalation DPI or two inhalations MDI can be taken twice daily. (Note: The 100/50 fluticasone/salmeterol combination is approved in children aged 4 and older.) Salmeterol can also be used 30 minutes before exercise (but not in addition to regularly used LABAs). Formoterol has a more rapid onset of action and is available singly either as a DPI (Aerolizer, 12 mcg) or a nebulized solution approved only for COPD (Perforomist); or combined with an inhaled steroid (formoterol fumarate, either 4.5 mcg with budesonide [80 or 160 mcg] or 5 mcg with mometasone [100 or 200 mcg], in an MDI). Formoterol DPI is approved for use in children 5 years and older, one inhalation (12 mcg) twice daily, while the combination product is approved for children 6 years and older, two inhalations twice daily. For long-term control, formoterol should be used in combination with an anti-inflammatory agent. It can be used for exercise-induced bronchospasm in patients 5 years and older, one inhalation at least 15 minutes before exercise (but not in addition to regularly used LABAs). An even longer acting LABA, vilanterol, with a 24-hour activity, combined with fluticasone furoate (Breo) is approved for asthma in patients 18 years and older. Of note, FDA has requested the manufacturers of Advair Diskus and HFA (salmeterol and fluticasone), Serevent Diskus (salmeterol xinafoate), Foradil Aerolizer (formoterol fumarate), Symbicort HFA, and Brovana (arformoterol tartrate inhalation solution, a LABA approved for chronic obstructive pulmonary disease) to update their product information warning sections regarding an increase in severe asthma episodes associated with these agents. This action is in response to data showing an increased number of asthma-related deaths in patients receiving LABA therapy in addition to their usual asthma care as compared with patients not receiving LABAs. This notice is also intended to reinforce the appropriate use of LABAs in the management of asthma. Specifically, LABA products should not be initiated as first-line asthma therapy, used with worsening wheezing, or used for acute control of bronchospasm. No data are available regarding safety concerns in patients using these products for exercise-induced bronchoconstriction. Additional information, including copies of the Patient and Healthcare Professional information sheets, can be found at: http://www.fda.gov/cder/drug/infopage/LABA/default.htm. In 2010, the FDA requested the four manufacturers of LABAs to conduct a prospective trial to evaluate whether a LABA added to an inhaled corticosteroid would be noninferior to an inhaled corticosteroid alone with regard to the risk of serious asthma related event (hospitalization, endotracheal intubation, or death). One study focused on the safety of LABAs in children 4–11 years of age, found that there was no excess risk of serious asthma related event associated with fluticasone propionate-salmeterol combination compared to fluticasone alone. Similar findings were found in two other trials which enrolled adults and adolescents, that LABAs in fixed-dose combination with an inhaled corticosteroid was associated with the risk of serious asthma-related event comparable to the risk with the inhaled corticosteroid alone.
Montelukast and zafirlukast are leukotriene-receptor antagonists available in oral formulations. Montelukast is given once daily and has been approved for treatment of chronic asthma in children aged 1 year and older, as an alternative step 2 monotherapy and add-on therapy for steps 3–6. It is also indicated for seasonal allergic rhinitis in patients 2 years and older, and for perennial allergic rhinitis in patients 6 months and older. To date, no drug interactions have been noted. The dosage is 4 mg for children 1–5 years (oral granules are available for children aged 12–23 months), 5 mg for children aged 6–14 years, and 10 mg for those aged 15 years and older. The drug is given without regard to mealtimes, preferably in the evening. Zafirlukast is approved for patients aged 5 years and older. The dose is 10 mg twice daily for those 5–11 years and 20 mg twice daily for those 12 years and older. It should be taken 1 hour before or 2 hours after meals. Zileuton is a 5-lipoxygenase inhibitor indicated for chronic treatment in children 12 years of age and older, available in regular 600 mg dose tablet four times a day or extended release 600 mg dose tablet, 2 tablets twice a day. Patients need to have hepatic transaminase levels evaluated at initiation of therapy, then once a month for the first 3 months, every 2–3 months for the remainder of the first year, and periodically thereafter if receiving long-term zileuton therapy. Rare cases of Churg-Strauss syndrome have been reported in adult patients with severe asthma whose steroid dosage was being tapered during concomitant treatment with leukotriene-receptor antagonists (as well as inhaled corticosteroids), but no causal link has been established. Both zafirlukast and zileuton are microsomal P-450 enzyme inhibitors that can inhibit the metabolism of drugs such as warfarin and theophylline. The FDA has requested that manufacturers include a precaution in the drug prescribing information (drug labeling) regarding neuropsychiatric events (agitation, aggression, anxiousness, dream abnormalities and hallucinations, depression, insomnia, irritability, restlessness, suicidal thinking and behavior, and tremor) based on postmarket reports of patients taking leukotriene-modifying agents. Of note, in a study of children with mild to moderate persistent asthma that looked at whether responses to an inhaled corticosteroid and a leukotriene-receptor antagonist were concordant for individuals or whether asthmatic patients who did not respond to one medication responded to the other, responses to fluticasone and montelukast were found to vary considerably. Children with low pulmonary function or high levels of markers associated with allergic inflammation responded better to the inhaled corticosteroid.
Children with persistent asthma who remain uncontrolled on inhaled corticosteroid monotherapy are more likely to respond to a combination treatment of an inhaled corticosteroid and a LABA; however, there are children who can respond best to a higher dose of inhaled corticosteroid, or even a low-dose inhaled corticosteroid plus montelukast. It has not been definitely determined what clinical features would be helpful in selecting the most appropriate medication for any one patient.
The long-acting antimuscarinic agent, tiotropium (Spiriva respimat [1.25 mcg] has now been approved as once daily maintenance treatment for asthma in patients 12 years and older), as an add-on therapy to inhaled corticosteroids. GINA 2016 recommends tiotropium by mist inhaler as an add-on Step 4 and Step 5 treatment for adolescents and adults with a history of exacerbations. Tiotropium by mist inhaler (particularly at 5 mcg daily dose) improves lung function and time to severe exacerbation. There is a recently published data demonstrating improved lung function with add on tiotropium in children 6–11 years of age with severe uncontrolled asthma.
Anti-IgE (omalizumab) is a recombinant DNA-derived humanized IgG1 monoclonal antibody that selectively binds to human IgE. It inhibits the binding of IgE to the high-affinity IgE receptor (FcεRI) on the surface of mast cells and basophils. Reduction in surface-bound IgE on FcεRI-bearing cells limits the degree of release of mediators of the allergic response. Treatment with omalizumab also reduces the number of FcεRI receptors on basophils in atopic patients. Omalizumab is now indicated for children as young as 6 years with moderate to severe persistent asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen with total serum IgE of 30–1300 IU/mL for children 6–11 years (30–700 IU/mL for adolescents), and whose symptoms are inadequately controlled with medium- to high-dose inhaled corticosteroids. Omalizumab has been shown to decrease the incidence of asthma exacerbations and improve asthma control. Dosing is based on the patient’s weight and serum IgE level and is given subcutaneously every 2–4 weeks. The FDA has ordered a black box warning to the label because of new reports of serious and life-threatening anaphylactic reactions (bronchospasm, hypotension, syncope, urticaria, and angioedema of the throat or tongue) in patients after treatment with omalizumab (Xolair). Based on pre-marketing clinical trials in patients with asthma, anaphylaxis occurred with 0.1% of patients; in postmarketing spontaneous reports based on an estimated exposure of about 57,300 patients from June 2003 through December 2006, the frequency of anaphylaxis attributed to Xolair use was estimated to be at least 0.2% of patients. From a case control study, patients with a history of anaphylaxis from whatever cause considered at increased risk of anaphylaxis with Xolair, compared to those with no prior history of anaphylaxis. Although these reactions occurred within 2 hours of receiving a omalizumab subcutaneous injection, they also included reports of serious delayed reactions 2–24 hours or even longer after receiving the injections. Anaphylaxis occurred after any dose of omalizumab (including the first dose), even in patients with no allergic reaction to previous doses. Omalizumab-treated patients should be observed in the facility for an extended period after the drug is given, and medical providers who administer the injection should be prepared to manage life-threatening anaphylactic reactions. Patients who receive omalizumab should be fully informed about the signs and symptoms of anaphylaxis, their chance of developing delayed anaphylaxis following each injection, and how to treat it, including the use of autoinjectable epinephrine. Malignancy (eg, breast, non-melanoma skin, prostate, melanoma, and parotid, etc.) was observed in 20 of 4127 (0.5%) Xolair-treated patients compared with 5 of 2236 (0.2%) control patients in clinical studies of adults and adolescents with asthma and other allergies. A more recent observational study of 5007 Xolair-treated and 2829 non-Xolair-treated patients with moderate to severe persistent allergic asthma followed for up to 5 years showed similar incidence rates (per/1000 patient years) of primary malignancies among Xolair-treated (12.3) and non-Xolair-treated patients (13.0).
New biologics or immunomodulators directed against specific type 2 helper T-cell cytokines have been studied to target the inflammatory component of asthma. The US FDA has recommended approval of both anti-IL-5 antibodies—mepolizumab (Nucala, monoclonal antibody IgG1K, administered 100 mg subcutaneously every 4 weeks) for patients 12 years and older; and reslizumab (Cinquil™, monoclonal antibody IgG4K, given 3 mg/kg intravenously monthly) for adult patients aged 18 years and older. Benralizumab, humanized monoclonal antibody directed against the alpha subunit of the IL-5 receptor, was recently FDA approved (subcutaneous injection 30 mg every 4 weeks for the first 3 doses, then 30 mg every 8 weeks thereafter) for add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype as well. These drugs are targeted biologic therapy for the treatment of poorly controlled asthma in patients with elevated blood eosinophils, shown to be effective at reducing exacerbations and improving lung function and symptom control.
Immunotherapy (discussed in more detail in section Immunotherapy) can be considered for children 5 years and older with allergic asthma who require steps 2, 3, and 4 of therapy.
Continual monitoring is necessary to ensure that control of asthma is achieved and sustained. Once control is established, gradual reduction in therapy is appropriate and may help determine the minimum amount of medication necessary to maintain control. Regular follow-up visits with the clinician are important to assess the degree of control and consider appropriate adjustments in therapy. At each step, patients should be instructed to avoid or control exposure to allergens, irritants, or other factors that contribute to asthma severity.
Referral to an asthma specialist for consultation or comanagement is recommended if there are difficulties in achieving or maintaining control. For children younger than age 5 years, referral is recommended for moderate persistent asthma or if the patient requires step 3 or 4 care and should be considered if the patient requires step 2 care. For children 5 years and older, consultation with a specialist is recommended if the patient requires step 4 care or higher and should be considered at step 3. Referral is also recommended if allergen immunotherapy or a biologic is being considered.
Quick-relief medications include short-acting inhaled β2-agonists (SABAs) such as albuterol, levalbuterol, pirbuterol, or terbutaline. Albuterol can be given by nebulizer, 0.05 mg/kg (with a minimal dose of 0.63 mg and a maximum of 5 mg) in 2–3 mL saline (although it is also available in a 2.5 mg/3 mL single vial or 5 mg/mL concentrated solution) or by MDI (90 mcg/actuation) or by breath-actuated DPI (Respiclick). It is better to use SABAs as needed rather than on a regular basis. Increasing use, including more than one canister per month, may signify inadequate asthma control and the need to step up or revise controller therapy. Levalbuterol, the (R)-enantiomer of racemic albuterol, is available in solution for nebulization in patients aged 6–11 years, 0.31 mg every 8 hours, and in patients 12 years and older, 0.63–1.25 mg every 8 hours. It has recently become available in an HFA formulation for children 4 years and older, two inhalations (90 mcg) every 4–6 hours as needed. Anticholinergic agents such as ipratropium, 1–3 puffs or 0.25–0.5 mg by nebulizer every 6 hours, may provide additive benefit when used together with an inhaled SABA. Systemic corticosteroids such as prednisone, prednisolone, and methylprednisolone can be given in a dosage of 1–2 mg/kg, usually up to 60 mg/day in single or divided doses for 3–10 days. There is no evidence that tapering the dose following a “burst” prevents relapse.
3. Exercise-induced bronchospasm
Exercise-induced bronchospasm should be anticipated in all asthma patients. It typically occurs during or minutes after vigorous activity, reaches its peak 5–10 minutes after stopping the activity, and usually resolves over the next 20–30 minutes. Participation in physical activity should be encouraged in children with asthma, although the choice of activity may need to be modified based on the severity of illness, presence of other triggers such as cold air, and, rarely, confounding factors such as osteoporosis. Poor endurance or exercise-induced bronchospasm can be an indication of poorly controlled persistent asthma. If symptoms occur during usual play activities, either initiation of or a step-up in long-term therapy is warranted. However, for those with exercise-induced bronchospasm as the only manifestation of asthma despite otherwise being “well-controlled,” treatment immediately prior to vigorous activity or exercise is usually effective. SABAs, leukotriene receptor antagonists, cromolyn, or nedocromil can be used before exercise. The combination of a SABA with either cromolyn or nedocromil is more effective than either drug alone. Salmeterol and formoterol may block exercise-induced bronchospasm for up to 12 hours (as discussed earlier). However, decreased duration of protection against exercise-induced bronchospasm can be expected with regular use. Montelukast may be effective up to 24 hours. An extended warm-up period may induce a refractory state, allowing patients to exercise without a need for repeat medications.
The most effective strategy in managing asthma exacerbations involves early recognition of warning signs and early treatment. For patients with moderate or severe persistent asthma or a history of severe exacerbations, this should include a written action plan. The latter usually defines the patient’s green, yellow, and red zones based on symptoms (and PEFR for patients with poor symptom perception) with corresponding measures to take according to the state the patient is in. PEFR cut-off values are conventionally set as > 80% (green), 50%–80% (yellow), and < 50% (red) of the child’s personal best. Prompt communication with the clinician is indicated with severe symptoms or a drop in peak flow or with decreased response to SABAs. At such times, intensification of therapy may include a short course of oral corticosteroids. The child should be removed from exposure to any irritants or allergens that could be contributing to the exacerbation.
Early treatment of asthma exacerbations may prevent hospitalization and a life-threatening event. Initial treatment should be with a SABA such as albuterol or levalbuterol; 2–6 puffs from an MDI can be given every 20 minutes up to three times, or a single treatment can be given by nebulizer (0.05 mg/kg [minimum dose, 1.25 mg; maximum, 2.5 mg] of 0.5% solution of albuterol in 2–3 mL saline; or 0.075 mg/kg [minimum dose, 1.25 mg; maximum, 5 mg] of levalbuterol). If the response is good as assessed by sustained symptom relief or improvement in PEFR to over 80% of the patient’s best, the SABA can be continued every 3–4 hours for 24–48 hours. Patients should be advised to seek medical care once excessive doses of bronchodilator therapy are used or for prolonged periods (eg, > 12 puffs/day for > 24 hours). Doubling the dose of inhaled corticosteroids is not proven sufficient to prevent worsening of exacerbations; however, recent evidence indicates that quadrupling the inhaled corticosteroid dose at the early sign of deterioration might be effective. If the patient does not completely improve from the initial therapy or PEFR falls between 50% and 80% predicted or personal best, the SABA should be continued, an oral corticosteroid should be added, and the patient should contact the physician urgently. If the child experiences marked distress or if PEFR persists at 50% or less, the patient should repeat the SABA immediately and go to the emergency department or call 911 or another emergency number for assistance.
3. Management in the office or emergency department
Functional assessment of the patient includes obtaining objective measures of airflow limitation with PEFR or FEV1 and monitoring the patient’s response to treatment; however, very severe exacerbations and respiratory distress may prevent the execution of lung function measurements using maximal expiratory maneuver. Flow-volume loops should be obtained to differentiate upper and lower airway obstruction, especially in patients with atypical presentation. Other tests may include oxygen saturation and blood gases. Chest radiographs are not recommended routinely but should be considered to rule out pneumothorax, pneumomediastinum, pneumonia, or lobar atelectasis. If the initial FEV1 or PEFR is over 40%, initial treatment can be with a SABA by inhaler (albuterol, 4–8 puffs) or nebulizer (0.15 mg/kg of albuterol 0.5% solution; minimum dose, 2.5 mg), up to three doses in the first hour. Oxygen should be given to maintain oxygen saturation at greater than 90%. Oral corticosteroids (1–2 mg/kg/day in divided doses; maximum of 60 mg/day for children aged ≤ 12 years and 80 mg/day for those > 12 years) should be instituted if the patient responds poorly to therapy or if the patient has recently been on oral corticosteroids. Sensitivity to adrenergic drugs may improve after initiation of corticosteroids. For severe exacerbations or if the initial FEV1 or PEFR is under 40%, initial treatment should be with a high-dose SABA plus ipratropium bromide, 1.5–3 mL every 20 minutes for 3 doses (each 3 mL vial contains 0.5 mg ipratropium bromide and 2.5 mg albuterol), then as needed by nebulizer. Continuous albuterol nebulized treatments (0.5 mg/kg/h for small and 10–15 mg/h for older children) can be administered for evidence of persistent obstruction. Oxygen should be given to maintain oxygen saturation at greater than 90%, and systemic corticosteroids should be administered. For patients with severe exacerbation having no response to initial aerosolized therapy, or for those who cannot cooperate with or who resist inhalation therapy, adjunctive therapies such as intravenous magnesium sulfate (25–75 mg/kg up to 2 g in children) and heliox-driven albuterol nebulization should be considered. There is an ongoing trial evaluating the efficacy of magnesium nebulization in the emergency room in preventing a hospital admission for asthma in children. Epinephrine 1:1000 or terbutaline 1 mg/mL (both 0.01 mg/kg up to 0.3–0.5 mg) may be administered subcutaneously every 20 minutes for three doses; although the use of intravenous β2-agonists is still unproven. For impending or ongoing respiratory arrest, patients should be intubated and ventilated with 100% oxygen, given intravenous corticosteroids, and admitted to an intensive care unit (ICU). Potential indications for ICU admission also include any FEV1 or PEFR less than 25% of predicted that improves less than 10% after treatment or values that fluctuate widely. (See Asthma [life-threatening] in Chapter 14.) Further treatment is based on clinical response and objective laboratory findings. Hospitalization should be considered strongly for any patient with a history of respiratory failure.
For patients who do not respond to outpatient and emergency department treatment, admission to the hospital becomes necessary for more aggressive care and support. The decision to hospitalize should also be based on presence of risk factors for mortality from asthma, duration and severity of symptoms, severity of airflow limitation, course and severity of previous exacerbations, medication use at the time of the exacerbation, access to medical care, and home and psychosocial conditions. Fluids should be given at maintenance requirements unless the patient has poor oral intake secondary to respiratory distress or vomiting, because overhydration may contribute to pulmonary edema associated with high intrapleural pressures generated in severe asthma. Potassium requirements should be kept in mind because both corticosteroids and β2-agonists can cause potassium loss. Moisturized oxygen should be titrated by oximetry to maintain oxygen saturation above 90%. Inhaled β2-agonist should be continued by nebulization in single doses as needed or by continuous therapy, along with systemic corticosteroids (as discussed earlier). Ipratropium is no longer recommended during hospitalization. In addition, the role of methylxanthines in hospitalized children remains controversial. Antibiotics may be necessary to treat coexisting bacterial infection. Sedatives and anxiolytic agents are contraindicated in severely ill patients owing to their depressant effects on respiration. Chest physiotherapy is usually not recommended for acute exacerbations.
Criteria for discharging patients home from the office or emergency department should include a sustained response of at least 1 hour to bronchodilator therapy with FEV1 or PEFR greater than 70% of predicted or personal best and oxygen saturation greater than 90% in room air. Prior to discharge, the patient’s or caregiver’s ability to continue therapy and assess symptoms appropriately needs to be considered. Patients should be given an action plan for management of recurrent symptoms or exacerbations, and instructions about medications should be reviewed. The inhaled SABA and oral corticosteroids should be continued, the latter for 3–10 days. Finally, the patient or caregiver should be instructed about the follow-up visit, typically within 1 week. Hospitalized patients should receive more intensive education prior to discharge. Referral to an asthma specialist should be considered for all children with severe exacerbations or multiple emergency department visits or hospitalizations.
Since the 1970s, morbidity rates for asthma have increased, but mortality rates may have stabilized. Mortality statistics indicate that a high percentage of deaths have resulted from underrecognition of asthma severity and undertreatment, particularly in labile asthmatic patients and in asthmatic patients whose perception of pulmonary obstruction is poor. Long-term outcome studies suggest that children with mild symptoms generally outgrow their asthma, while patients with more severe symptoms, marked airway hyperresponsiveness, and a greater degree of atopy tend to have persistent disease. Data from an unselected birth cohort from New Zealand showed more than one in four children had wheezing that persisted from childhood to adulthood or that relapsed after remission. Recent evidence suggests that early intervention with anti-inflammatory therapy does not alter the development of persistent asthma, and it is also unclear if such intervention or environmental control measures influence the natural history of childhood asthma. Nonetheless, the pediatrician or primary care provider together with the asthma specialist has the responsibility to optimize control and, it is hoped, reduce the severity of asthma in children. Interventions that can have long-term effects such as halting progression or inducing remission are necessary to decrease the public health burden of this common condition.
Resources for health care providers, patients, and families include:
LM: Changing trends in asthma prevalence among children. Pediatrics 2016;137:2015–2354
Center for Disease Control and Prevention. National Center for Health Statistics. Health Data Interactive. Summary Health Statistics for U.S. Children: National Health Interview Survey, 2015. https://www.cdc.gov/nchs/fastats/asthma.htm
. Accessed January 16, 2018.