Not all children who wheeze have asthma. Most children younger than 3 years who wheeze are not predisposed to asthma. Only 30% of infants who wheeze go on to develop asthma. Reactive airway disease has a large differential diagnosis and must not be confused with asthma.
To establish the diagnosis of asthma, certain criteria should be met[1] :
At least 5 years of age
Episodic symptoms of airflow obstruction or airway hyperresponsiveness
Reversible airflow obstruction of at least 10% of predicted forced expiratory volume in one second (FEV1) after use of short-acting beta2-agonist
Alternative diagnoses have been excluded
On June 25, 2009, The American Thoracic Society and the European Respiratory Society jointly released new official standards on asthma evaluation for clinical trials and practice.[2]
Numerous environmental stimuli induce an allergen-antibody interaction, causing a release of mediators that create airway inflammation. Airway inflammation is the primary factor responsible for smooth muscle hyperresponsiveness, edema, and increased mucous production. A complex interaction occurs between inflammatory cells and airway epithelium. Mast cells, eosinophils and lymphocytes secrete mediators include histamine, tryptase, heparin, leukotrienes, platelet-activating factor, cytokines, interleukins, and tumor necrosis factor and create an environment toxic to respiratory epithelial cells by causing edema, mucous secretion, bronchospasm and increased work of breathing.
Speculation exists that all infants are born with highly responsive airways. Increased immunoglobulin E (IgE) levels have been found in those younger than 2 years. A decrease in airway responsiveness may be associated with environmental allergens, viral respiratory diseases, and hereditary factors. In children younger than 3 years, the intrapulmonary airways are so small that any lower airway infection results in diminished airway function. Other anatomical factors, such as poor collateral ventilation, decreased elastic recoil pressure, and a partially developed diaphragm, may predispose the very young child to respiratory compromise.
Rhinovirus infections are an important contributor to asthma exacerbations in children. Hence, therapies against rhinovirus might reduce the risk of severe exacerbations.[3] Fever and bronchospasm are not associated with a more severe clinical course. In fact, fever as a response to infection may have a beneficial effect and can be seen as a good prognostic indicator.[4] Recently, it has been hypothesized that severe infection with Respiratory Syncytial Virus (RSV) may be a marker of a predisposing factor for asthma.[5]
There are several theories as to prevention of bronchospasm and asthma in children. The hygiene hypothesis suggests that early exposure to infections and allergens might protect children from developing asthma later in life because of improved immune system.[4]
Breastfeeding might protect children younger than 24 months of age against recurrent wheezing. The cytokine, TGF-B1, in human milk may have both suppression and enhancement functions in the immune reaction.
Exposure to maternal environmental tobacco smoke during pregnancy or the first year appears to predispose children to reactive airway disease.
Current research on the genetic basis for the pathogenesis of asthma may lead to new diagnostic and preventive treatments. The ADAM33 gene on the short arm of chromosome 20 is hypothesized as being important in the development and pathogenesis of asthma.
Pediatric asthma is a chronic, multifactorial, lower airway disease that affects 5-15% of children (2.7 million children in the United States alone). In the United States, approximately one half of all ED and clinic visits for asthma are children younger than 18 years. ED visits peak in the fall while school holidays disrupt the spread of infections resulting in a subsequent decrease in ED visits and hospitalizations. Status asthmaticus appears to be on the rise; several retrospective studies reflect an increase in hospital admissions, particularly in those younger than 4 years. Fewer hospital and ED visits occur in children using inhaled corticosteroid therapy.
Asthma prevalence appears to be increasing worldwide. Air pollutants may play a role in the prevalence increase. Higher prevalence occurs in poverty stricken urban areas where children are less likely to have routine doctor visits and access to the availability of medications.
A correlation may exist between high levels of exposure to cockroach allergen and the frequency of asthma-related health problems in inner-city children.[6] Homes in poverty areas were more likely to have high cockroach allergen levels. Asthma may develop in children from early exposure to cockroach allergen.[7] An association may exist between obesity and childhood asthma. Increased resistin, an adipokine produced by adipose tissue, may play a negative predictive role in asthma.[8]
An algorithm has been developed to determine the risk factors for developing persistent asthma symptoms among children younger than 3 years of age who had 4 or more episodes of wheezing during the previous year.[9] The Asthma Predictive Index included either (1) one of the following: parental history of asthma, a physician diagnosis of atopic dermatitis, or evidence of sensitization to aeroallergens; or (2) two of the following: evidence of sensitization to foods, ≥4% peripheral blood eosinophilia, or wheezing apart from colds.
International
Worldwide, the prevalence of asthma is increasing. Asthma is found to be more common in Western countries than in developing countries. Asthma is more prevalent in English-speaking countries. Prevalence increases as a developing country becomes more Westernized and urbanized.
Mortality/Morbidity
See the list below:
One third of all children younger than 18 years are significantly affected.
Reactive airway disease accounts for 13 million health care visits annually in the United States and 200,000 hospitalizations for which approximately $1.8 billion is spent annually.
Mortality rates are increasing despite new pharmacologist advances.
European Respiratory Society (ERS) and American Thoracic Society (ATS), created a task force to evaluate and provide management recommendations for severe or therapy-resistant asthma, recognized as a major unmet need. Severe asthma is defined as requiring treatment with high-dose inhaler plus a second controller and-or systemic corticosteroids to prevent it from becoming "uncontrolled" or that remains "uncontrolled" despite this therapy. Current research based on phenotyping (epidemiology, pathogenesis, pathobiology, structure and physiology) to allow better diagnosis and targeted treatment.[10]
Race
Reactive airway disease is more common in black and Hispanic children; hospitalization rates in African Americans are 4 times greater than in the white population. A correlation may exist between high levels of exposure to cockroach allergen and the frequency of asthma-related health problems in inner-city children.[6]
No correlation exists between education levels from a retrospective review.
Sex
The male-to-female ratio is 1.5:1.
Age
The peak prevalence of asthma is in those aged 6-11 years.
Initiation of symptoms (More than a few days decreases the chance of quick reversal in the ED because of prolonged inflammation and mucous plug formation)
Upper respiratory infection (URI) symptoms, fever, and production of phlegm
Precipitating factors
Use of an bronchodilator inhaler; how often it was used in the past 24-48 hours prior to the ED visit; how often it was used over the past week or month
How many inhalers were used in the past month
How many puffs are being administered with each use and if the inhaler is being used with a spacer
Compliance with use of corticosteroid inhaler (Ask if it was used daily despite any symptoms of wheezing)
Date of last ED visit; how severe the current episode is compared with previous episodes[12]
Date of the last hospital admission
Number of admissions in the past year; number of intensive care unit admissions
History of intubation and how long ago it was
Recent use of oral steroids
Factors that usually initiate symptoms
Whether this is a typical episode
Presence of any underlying cardiac, GI, or immunologic diseases
Other current medications
Exposure to tobacco smoke and allergens (ie, cat dander)
Ability to tolerate fluids
Recent mental status changes
Baseline peak expiratory flow rate (PEFR)
History of atopic dermatitis or other allergic skin conditions[13]
Dry cough or wheezing that is often worse at night
Infection -Respiratory syncytial virus (RSV) most commonly isolated from infants and preschool-aged children; Mycoplasma pneumoniae most commonly isolated from school-aged children
Tobacco smoke
Pet dander, cockroach and dust mite allergen
Molds
Pollen
Exercise
Weather changes
Stress
Drugs
A precipitant of bronchiolitis is respiratory infection, usually due to RSV.
Gastroesophageal fistula
Mediastinal mass (external compression of the airway)
A complete blood count (CBC) may be indicated for a suspected viral infection (lymphocytosis, leukopenia), parasitic infection (eosinophilia), or hemosiderosis.
An arterial blood gas (ABG) determination should be performed for any patient in status asthmaticus to check for hypoxia, hypercarbia, or acidosis; alternatively, a venous blood gas measurement can be used to assess for hypercarbia and acidosis and combined with pulse oximetry monitoring.
An assessment of electrolyte levels may reveal hypokalemia in patients who are using albuterol.
Although theophylline is prescribed less frequently, a theophylline level is useful for those on the drug.
All chronically wheezing infants and children with chronic asthma should have a sweat chloride test for cystic fibrosis at a subsequent primary care provider (PCP) visit or during inpatient evaluation.
A tuberculosis skin test may be indicated if significant risk factors exist.
Spirometry (decreased forced expiratory volume in one second [FEV1])
Bedside spirometry is the primary procedure for children with RAD who are older than 5 years.
Patients with decreased FEV1 require further evaluation and treatment.
A barium swallow may be indicated to determine any esophageal, pulmonary, or vascular pathology, particularly a tracheoesophageal fistula.
Bronchoscopy (rarely indicated) (see Table 1 below)
Peak expiratory flow (PEF) is the most common form of pulmonary function test monitoring. Record the best of 3 attempts. Possible life-threatening asthma exacerbation with PEF predicted of less than 30%; severe exacerbation, with less than 50%; and moderate exacerbation, with less than 80%.
Ultimately, best treatment for reactive airway disease is to prevent an exacerbation from occurring. Knowing the provocative factors such as infection, exercise, nonadherence to medication, weather, allergens and irritants can aid in early treatment intervention.
Phenotyping patients with asthma to allow for better understanding of disease heterogeneity and facilitate individualization of patient management by grouping patients with common clinical features is recommended.[16, 17]
Identification of reliable biomarkers can help in future therapeutic strategies in addition to determining the most effective drug for the right patient phenotype.[18]
A five-fold increase of regularly used inhaled glucocorticoids at the start of worsening symptoms known as the yellow zone has not shown to prevent severe exacerbations.[19] However, quadrupling the dose may be beneficial for adolescents and adults.[20]
Telemedicine, a rapidly growing trend in healthcare, can be used for controlling reactive airway symptoms and reduce the number of emergency room visits by improving adherence to therapy.[21] Symptoms and spirometry readings can be communicated through telephone, web-based systems and phone apps. Novel technologies such as a digital stethoscope and high resolution cameras can be used to gather information.
Provide oxygen during transport, cardiorespiratory monitoring and pulse oximetry, beta-agonist nebulization, and intravenous access if the patient is in moderate-to-severe respiratory distress. Subcutaneous terbutaline or epinephrine may be considered if severe distress and very poor air movement are present.
Albuterol is recommended for the initial treatment of mild-to-moderate acute exacerbations of asthma, administered either by a metered-dose inhaler with spacer (with or without mask) or by a hand-held nebulizer.
Two to six puffs of albuterol via metered-dose inhaler with spacer or 0.15 mg/kg (2.5 mg minimum dose, 5 mg maximum dose) via hand-held nebulizer every 20 minutes for up to 3 doses is recommended.
Severe exacerbations (PEF < 50% and/or oxygen saturation < 92% on room air) or exacerbations refractory to first-line treatment
Nebulized ipratropium bromide and short-acting beta-agonists, every 20 minutes for up to 3 treatments, are recommended for the treatment of children (250 mcg/dose) and adolescents (500 mcg/dose) with severe exacerbations.
Supplemental oxygen (by nasal cannula or mask, whichever is better tolerated) to maintain an oxygen saturation >92% is recommended during the delivery of short-acting beta-agonists and anticholinergics in patients with severe exacerbations.
Oral dexamethasone 0.6 mg/kg/dose (first-line treatment) or oral prednisolone 2 mg/kg/dose (second-line treatment) may be administered if early response to bronchodilators, otherwise parenteral steroids (dexamethasone or methylprednisolone) should be given.
Management of status asthmaticus
Management of status asthmaticus includes continuous inhaled beta-agonist of 0.5 mg/kg/h, nebulized ipratropium, IV dexamethasone 0.6 mg/kg, and intravenous magnesium 25-40 mg/kg (given over 20 min as a single dose up to a maximum of 2 g) concurrently for the child in severe respiratory distress. Consideration for IM or SC epinephrine or terbutaline. IV hydration is recommended in severe asthmatic requiring admission. Patient should be kept NPO in case of respiratory failure and need for intubation.
Frequent evaluation of the patient's cardiorespiratory status is imperative. Pulse oximetry and noninvasive end-tidal CO2 monitoring are ideal. Serial blood gas measurements may be necessary if the patient remains critically ill. If a child fails to improve with these interventions, admission to an ED observation area, inpatient unit, or pediatric critical care unit should be initiated. Continued failure to respond with mental status changes is an ominous finding and suggests rising pCO2. Consider noninvasive positive pressure ventilation (PPV) (eg, continuous positive airway pressure [CPAP] 3-5 cm H2 O, intermittent positive airway pressure [IPAP] 10-18 cm H2 O) prior to rapid sequence intubation. BiPAP utilization in acute pediatric asthma exacerbations for patients 20 kg or less is safe and may improve clinical outcomes.[22] Consider the increased risk of pneumothorax if intubated. Optimize ventilator settings.
Avoid intubation if possible.
Consider all other measures first (eg, bilevel positive airway pressure, continuous beta-agonist, helium-oxygen mixture [heliox]).
For rapid sequence intubation, use ketamine for sedation/dissociative state, 1 mg/kg IV (provides 15 min anesthesia and may provide further bronchodilation for up to 30 min) then paralysis with succinylcholine, 2 mg/kg IV preceded by atropine 0.02 mg/kg in the pediatric patient (older adolescent: 1-1.5 mg/kg IV without atropine) may be used. For more information, see Tracheal Intubation, Medications.
Tube size = (age/4) + 4
Avoid nasal intubation. Oral intubation allows for a larger tube size and easier access for suctioning and bronchoscopy.
Albuterol
Aerosolized albuterol, a short acting beta2-agonist (SABA), relieves bronchospasm.
Although studies suggest that delivery of albuterol by metered dose inhaler (MDI) with spacer is equally as effective as nebulization in children as young as 2 years, nebulization is recommended for those younger than 6 years or those with severe asthma or poor air movement. Infants and small children need doses of MDI equivalent to those used by adults because of decreased retention time of the drug in the lung, because of their inability to hold their breath, and because the size of the airway limits delivery of medication.
The use of chlorofluorocarbon (CFC) inhalers is being phased out to protect the ozone layer. A decreased ozone layer may lead to health and environmental problems. No difference exists in efficacy between CFC and non-CFC inhalers.
Continuous albuterol nebulization may reduce the need for endotracheal intubation in status asthmaticus.
Levalbuterol, the single isomer, may result in higher patient discharge rates from the ED or hospital and hence may be more cost-effective than the traditional, racemic albuterol given.
Ipratropium: The combination of a beta-adrenergic agonist and ipratropium improves FEV1 more effectively than either agent used alone. Other anticholinergics, such as glycopyrrolate, also may be nebulized. Tiotropium bromide, a long-acting muscarinic antagonist, improved lung function, reduced the need for short acting beta-agonist and moderately reduced the risk of a severe exacerbation in severe asthmatics taking high dose inhaled corticosteroids and long acting beta-agonist.[10]
Oral steroids given early during ED treatment reduce hospital admission rates.
Dexamethasone (given as an oral dose or parenteral dose) is the preferred steroid because of longer duration of action and the need for only one additional dose (0.6 mg/kg) to be given 1 or 2 days later.
The dosages for prednisone and prednisolone both are 2 mg/kg/dose. Prednisone, in tablet form, is given to older children or adolescents. Prednisolone can be given orally (Prelone), or methylprednisolone (Solu-Medrol) may be given parenterally.
Nebulized corticosteroids could prove useful in the ED setting. Further studies are pending.
Long-term use of inhaled steroids may have a deleterious effect on lung and organ development during the first 3 years of life.
Inhaled albuterol has largely replaced an oral beta2-agonist because of increased effectiveness and safety.
In one study, use of inhaled beta2-agonist was shown to be safe and effective in children younger than 2 years.[23] The patient selection represents the most common acuity of patients younger than age 2 years (with a significant number of subjects younger than age 1). Ninety micrograms of albuterol every 20 minutes (total 4 treatments in 1 h) was successful in restoring normal breathing in most subjects, with a few subjects requiring 1-2 more treatments. Most patients also received corticosteroids per established protocol.
All patients in this study had continuous cardiac monitoring, and no significant cardiac events were reported. Patients ill enough to require more closely spaced "rescue" dosing, or early administration of epinephrine, terbutaline, or intubation, were deleted from this study.[23]
Theophylline has no role in the acute setting. It may be considered for outpatient treatment in patients with poor compliance with inhaled beta-agonist and for patients with nocturnal asthma exacerbation.
Magnesium at 40 mg/kg IV may provide a "therapeutic bridge." Studies remain in conflict regarding magnesium's effectiveness.
European Respiratory Society (ERS) and American Thoracic Society (ATS) 2014 Guidelines recommend against routine use of macrolide therapy.[10]
Asthma management is shown in the illustration below.
View Image
Stepwise approach for managing asthma in children 0 to 4 years of age. National Institutes of Health. National Heart, Lung, and Blood Institute. Natio....
One study showed that the rate of return to the emergency department or admission to the hospital was decreased if the patient was discharged home with an inhaled corticosteroid.[24] Another study showed that 2 days of dexamethasone instead of 5 days of prednisone at the time of emergency department visit for asthma leads to a decreased number of emergency department visits and hospital admissions.[25]
Recent experimental biological approaches targeting specific asthmatic inflammatory pathways based on immuno-inflammatory phenotypes. Mepolizumab and reslizumab, anti-IL5 antibodies, used in severe asthmatics with persistent sputum eosinophilia have shown to decrease exacerbations and oral corticosteroid use.[10]
PROSE (Preventative Omalizumab or Step-Up Therapy for Fall Exacerbations) Trial
A 3-arm, randomized, double-blind, double placebo-controlled, multicenter clinical trial was conducted among inner-city asthmatic children aged 6 to 17 years with 1 or more recent exacerbations , comparing omalizumab or an inhaled steroid.
Study found that asthma exacerbations, that are most frequent during the fall season, can be reduced with a preventative strategy of treating high-risk group of allergic asthma subjects with omalizumab (Xolair) four to six weeks before the start of school and continuing it for the next four months. Omalizumab is thought to increase the release of an antiviral substance called interferon-alpha from certain immune cells thereby restoring immune protection against common cold viruses. Increasing inhaled steroid treatment levels above those determined to achieve control, offered little to no additional benefit in preventing exacerbations.[26]
Intermittent use of inhaled corticosteroids at the start of asthma exacerbations can decrease the need for future oral corticosteroids. [27]
Clinical Context:
Long-acting beta2-agonist. Not for emergent use since onset is 30 min or more. By relaxing the smooth muscles of the bronchioles in conditions associated with bronchitis, emphysema, asthma, or bronchiectasis, can relieve bronchospasms. Effect may also facilitate expectoration.
Adverse effects are more likely to occur when administered at high or more frequent doses than recommended. Available as a dry powder for inhalation in 50 mcg blister packs.
Clinical Context:
Beta-agonist for bronchospasm refractory to epinephrine. Relaxes bronchial smooth muscle by action on beta2-receptors with little effect on cardiac muscle contractility. May decrease mediator release from mast cells and basophils and inhibit airway microvascular leakage. MDI delivers 90 mcg/actuation.
Continuous therapy may reduce need for mechanical ventilation.
Clinical Context:
Used for treatment or prevention of bronchospasm. A selective beta2-agonist agent. Albuterol is a racemic mixture, while levalbuterol contains only the active R-enantiomer of albuterol. The S-enantiomer does not bind to beta2-receptors but may be responsible for some adverse effects of racemic albuterol, including bronchial hyperreactivity and reduced pulmonary function during prolonged use.
These agents relieve reversible bronchospasm by relaxing smooth muscles of the bronchi. Systemic beta-agonists allow systemic delivery of medication to the pulmonary system in medical conditions where bronchoconstriction may inhibit delivery of medication to desired site because of little to no air movement. Oral administration is less effective than inhaled beta-adrenergic agonists, and has therefore fallen into disfavor. Does not appear to alter admission.
Salmeterol is a highly selective, long-acting beta2-adrenergic agonist (LABA) with bronchodilatory activity. Salmeterol's benzene moiety resembles the structure of catecholamines, and occupies the active site of beta2-adrenergic receptor, while the long, lipophilic side chain of salmeterol, binds to the so-called exosite near the beta2-receptors. The binding at the exosite allows the active portion of the molecule to remain at the receptor site and continually engage and disengage with the receptor, therefore providing a long duration of action. This agent stimulates intracellular adenyl cyclase to catalyze the conversion of adenosine triphosphate to cyclic-3',5'-adenosine monophosphate (cAMP). Increased cAMP levels result in relaxation of bronchiolar smooth muscle, bronchodilation, and increased bronchial airflow. LABA may not decrease the episodes of asthma exacerbations and may even lead to increased hospitalizations. [28]
Clinical Context:
A quaternary ammonium anticholinergic bronchodilator acting at muscarinic receptors of the parasympathetic nervous system. Chemically related to atropine. Has antisecretory properties and, when applied locally, inhibits secretions from serous and seromucous glands lining the nasal mucosa.
Synergistic with beta2-agonists. Each actuation delivers 17 mcg. Solution for nebulization available as 0.02% (500 mcg/vial).
These agents provide bronchodilation at the cellular level. The exact mechanism is unknown (eg, alteration of intracellular calcium, inhibition of phosphodiesterase, and/or antagonism of prostaglandins). Routine addition to beta-agonist provides benefit in ED management. May be of benefit in impending respiratory failure.
Clinical Context:
Reduces airway resistance in bronchi with turbulent flow because of low density. Decreases the work of breathing, hence, delaying the onset of respiratory muscle fatigue, allowing other therapies to work.
Available in mixtures of 80:20 (helium:oxygen), 70:30, and 60:40.
Nonbarbiturate anesthetic/analgesic agent. An induction agent for airway management in patients with status asthmaticus and has a brief bronchodilatory effect.
Clinical Context:
Inhibits histamine release and slow-reacting substance of anaphylaxis from mast cell. MDI delivers 800 mcg/actuation. Solution for nebulization available as 20 mg/2 mL
Clinical Context:
Cysteinyl leukotriene-receptor antagonist. Inhibits aspirin-induced, cold air, and exercise-induced asthma. Not for use in acute episodes of asthma.
Clinical Context:
Has many pharmacologic benefits but significant adverse effects. Stabilizes cell and lysosomal membranes, increases surfactant synthesis, increases serum vitamin A concentration, inhibits prostaglandin and proinflammatory cytokines (eg, TNF-alpha, IL-6, IL-2, and IFN-gamma). The inhibition of chemotactic factors and factors that increase capillary permeability inhibits recruitment of inflammatory cells into affected areas. Suppresses lymphocyte proliferation through direct cytolysis and inhibits mitosis. Breaks down granulocyte aggregates, and improves pulmonary microcirculation. Has multiple glucocorticoid and mineralocorticoid effects.
Readily absorbed via the GI tract and metabolized in the liver. Inactive metabolites are excreted via the kidneys. Lacks salt-retaining property of hydrocortisone.
Patients can be switched from an IV to PO regimen in a 1:1 ratio.
Clinical Context:
Glucocorticosteroid that occurs naturally and synthetically. Used for both acute and chronic asthma. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.
Loading or initial dose should be taken all at once in the am; may suppress natural cortisone production; hence, requires tapering the dose upon discontinuation.
As soon as the dose for relief is found, a maintenance dose may be established until the nonsteroidal drugs are effective; must always use a decreasing dose to avoid serious renal suppression.
In seasonal allergy a "booster" of prednisone may speed resolution of symptoms. Quite effective in "exhaustion" stage of seasonal allergy.
Clinical Context:
For treatment of inflammatory and allergic reactions. By reversing increased capillary permeability and suppressing PMN activity, may decrease inflammation. Allows reduction of ongoing airway inflammation. May increase responsiveness to beta2-agonists by increasing the number of beta2-adrenergic receptors. Prophylactic inhaled steroids in those diagnosed with asthma may impede airway remodeling, bronchial hyperreactivity, and future airway damage.
Systemic adverse effects rarely occur with inhaled corticosteroids. Systemic response time is the same in IV and PO.
Steroid use is recommended if minimal improvement occurs after first beta2-agonist treatment, the patient was recently discontinued from steroids, the patient reports a history of asthma symptoms for a few days before presentation, or URI-associated symptoms are present.
These agents have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli. Oral prednisone should never be substituted for an inhaled corticosteroid in children with a severe acute asthma exacerbation.
Frequent use of inhaled corticosteroid therapy is associated with less ED visits and less hospitalizations. Current research has not proven any long-term adverse effects with children receiving long-term inhaled corticosteroid.
Clinical Context:
If no response to H1 antagonist alone, coadministration with this H2 antagonist treats itching and flushing in anaphylaxis, pruritus, urticaria, and contact dermatitis.
Clinical Context:
Recombinant, DNA-derived, humanized IgG monoclonal antibody that binds selectively to human IgE on surface of mast cells and basophils. Reduces mediator release, which promotes allergic response. Indicated for moderate-to-severe persistent asthma in patients who react to perennial allergens in whom symptoms are not controlled by inhaled corticosteroids.
Clinical Context:
Mepolizumab is a humanized IgG1 kappa monoclonal antibody specific for interleukin-5 (IL-5). Mepolizumab binds to IL-5, and therefore stops IL-5 from binding to its receptor on the surface of eosinophils. It is indicated for add-on maintenance treatment of patients with severe asthma aged ≥12 y, and with an eosinophilic phenotype.
Clinical Context:
Two delivery mechanisms are available (ie, powder for inhalation [Diskus], metered-dose inhaler [MDI]). Diskus is available as a combination of salmeterol 50 mcg with fluticasone 100 mcg, 250 mcg, or 500 mcg. The MDI is available as 21 mcg salmeterol with fluticasone 45 mcg, 115 mcg, or 230 mcg.
The use of combination therapy with a long-acting beta2 agonist plus an inhaled corticosteroid as initial preventer treatment in children who are not already taking inhaled corticosteroids, is not supported by clinical trials. [29]
Clinical Context:
Available as powder for inhalation in 90 mcg/actuation (actuation delivers ~80 mcg) or 180 mcg/actuation (actuation delivers ~160 mcg). Also available as suspension for nebulized inhalation in 0.25-mg/2 mL, 0.5-mg/2 mL, and 1-mg/2 mL. Indicated for maintenance treatment of asthma and prophylactic therapy.
Receiving bronchodilators or inhaled corticosteroids: 80 mcg inhaled PO twice daily initially; may increase to 160 mcg twice daily Receiving Oral Corticosteroids: 80 mcg inhaled twice daily initially; may increase to 320 mcg twice daily
Clinical Context:
<5 years: Safety and efficacy not established
5-12 years: 40 mcg inhaled PO BID for patients with/without prior history of inhaled corticosteroid use; do not exceed 80 mcg inhaled BID
>12 years
No prior history of inhaled corticosteroid use: 40-80 mcg inhaled PO BID; do not exceed 320 mcg BID Prior history of inhaled corticosteroid use: 40-160 mcg inhaled PO BID; do not exceed 320 mcg BID
12 years (prior inhaled corticosteroid use): 88-220 mcg PO q12hr; not to exceed 440 mcg q12hr >12 years (prior PO corticosteroid use): 440 mcg PO q12hr; not to exceed 880 mcg q12hr
Inhaled powder
12 years (prior bronchodilator use): 100 mcg PO q12hr; not to exceed 500 mcg q12hr >12 years (prior inhaled corticosteroid use): 100-250 mcg PO q12hr; not to exceed 500 mcg q12hr >12 years (prior PO corticosteroid use): 500-1000 mcg PO q12hr; not to exceed 1000 mcg q12hr
Inhibits bronchoconstriction mechanisms, produces direct smooth muscle relaxation, may decrease number and activity of inflammatory cells, in turn decreasing airway hyperresponsiveness. Has extremely potent vasoconstrictive and anti-inflammatory activity. Alters level of inflammation in airways by inhibiting multiple types of inflammatory cells and decreasing production of cytokines and other mediators. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing capillary permeability.
Follow-up of pediatric asthma patients may be conducted by phone or in person; may include physical examination and/or spirometry; and may be performed by a case manager, registered nurse, nurse practitioner, or physician. Follow-up is recommended:
Within 1 week of an asthma exacerbation
Within 4 weeks after initiation of therapy or any significant change in therapy, and every 2-4 weeks thereafter until control is obtained
Every 4-6 months to assess control for patients with persistent asthma
Assessment of severity and treatment plan
Assess the severity of the symptoms and effectiveness of treatment.[1]
Impairment:
Symptoms:
Mild - 2 days or more per week but not daily
Moderate - Daily
Severe - Throughout the day
Nighttime awakenings
Mild - 3-4 times per month
Moderate - More than 1 time per week but not nightly
Severe - Nightly (7 times a week)
Maintenance treatment (a recommended approach)
See the list below:
Mild - Low-dose inhaled corticosteroids
Moderate - Medium-dose inhaled corticosteroids and long-acting beta2-agonist
Severe - High-dose inhaled corticosteroids, long-acting beta2-agonist, and leukotriene modifier
Children aged 4-11 years with asthma who were treated with a fixed-dose combination of fluticasone and salmeterol had fewer serious asthma exacerbations and lower treatment costs than those who were given an inhaled corticosteroid and montelukast. In one study, risk was reduced by 96% of having an asthma-related inpatient hospital visit and a 56% lower risk of having an ED visit.[30, 31]
Best Add on Therapy Giving Effective Responses (BADGER), in phase III of clinical trials, compared how effectively the 3 different step-up treatments improved asthma control in 182 children aged 6-18 years. All participants had mild-to-moderate persistent asthma that was not controlled on low-dose inhaled corticosteroids. At the current stage of this ongoing study, adding a long-acting beta-agonist to inhaled corticosteroids was significantly more likely (1.5 times) to be the best step-up therapy compared to adding a leukotriene receptor antagonist to inhaled corticosteroids or to doubling inhaled corticosteroids.[32]
For patients 12 years and older with moderate-to-severe asthma, a combination of high-dose inhaler, long-acting beta2-agonist, and omalizumab, has shown significant reduction in the need for oral corticosteroids and has also improved lung function (FEV1).[33, 34]
Though not FDA approved for children aged 6 to younger than 12 years, reports of adding omalizumab to therapy in patients with moderate-to-severe asthma has shown promising results.[35]
Evaluating the Clinical Effectiveness and Long-Term Safety in Patients with Moderate to Severe Asthma (EXCELS) study is an ongoing observational study for patients 12 years and older using omalizumab (completion date, 2012.) In early observation, there may be an increase in ischemic heart disease; arrhythmias; cardiomyopathy and cardiac failure; pulmonary hypertension; cerebrovascular disorders; and embolic, thrombotic, and thrombophlebitic events with use of omalizumab and should be used with caution. Risk and benefits should be considered before starting omalizumab.[36]
Monitoring PEFR is an easily performed test that can be mastered for those as young as 3-4 years. PEFR monitoring is an important tool in asthma management that uses a zone system to optimize effectiveness of asthma control. Zone determination should also be based on symptom recognition.
Green zone (80-100% predicted or child's best) - Good control; no cough, wheeze, chest tightness, or shortness of breath
Yellow zone (50-80%) - Necessitates increased awareness and treatment; slight cough, wheeze, chest tightness, shortness of breath, mild chest congestion from cold or allergies; cannot perform all normal activities; waking up at night with cough
Red zone (< 50%) - Poor control, requires immediate intervention; persistent cough or wheeze, very short of breath; cannot do usual activities; waking up more than once a night with cough or wheeze, fast breathing, symptoms not getting better after 2 days in yellow zone
Spacer devices should be used in all children with asthma. They improve the deposition of drug into the lower airway, hence improving efficacy of medication.
Long-acting bronchodilators do not replace the need for routine preventers. Their slow onset means the short-acting dilators may still be required. However, long-acting bronchodilators combined with inhaled corticosteroids may provide better asthma control and compliance, hence decreasing the number of acute attacks.
SMART: Symbicort Maintenance and Relief Therapy, approved for use with a Turbuhaler device, can be used for maintenance and acute symptoms. With SMART, the need for rescue oral corticosteroids appears to be decreased. The combination budesonide/formoterol comes in a pressurized MDI in the United States but has not been approved for SMART (Turbuhaler device is not available in the United States).[37]
Little evidence is available to support or refute the use of alternative medicine such as acupuncture, osteopathic, chiropractic, physiotherapy, or respiratory therapeutic maneuvers.
There is no evidence that air ionizers improve asthma symptoms.[38]
A daily low-dose regimen of budesonide has not been shown to be superior to other treatments.[39]
Consider admission if the initial peak expiratory flow rate (PEFR) is less than 20-25% of predicted and posttreatment is less than 70% of predicted or if no improvement occurs after 4 hours.
If a child fails to improve within the first 2-3 hours of ED management, admission to an ED observation area, inpatient unit, or pediatric critical care unit is warranted.
If the patient is able to ambulate and tolerate fluids in the ED without distress, discharge may be considered.
Arrange for follow-up with the primary care provider within 24 hours.
The Children’s Asthma Care (CAC) measure set assesses whether pediatric patients admitted to hospitals with asthma exacerbation receive relievers (CAC-1) and systemic corticosteroids (CAC-2) during admission and whether they are discharged with a complete home management plan of care (CAC-3). A cross-sectional study using data for 30 US children’s hospitals found that CAC-1 and CAC-2 hospital compliance was high and that CAC-3 hospital compliance was moderate.[40] There was no significant association between CAC-3 hospital compliance and subsequent ED visits and asthma-related readmissions, suggesting that the CAC-3 measure needs further refinement to ensure evidence-based home management plans are being developed and conveyed to families in an effective manner.
Parents of asthmatic children should have at least 2 sets of inhalers (eg, one for school and one for home).
After an asthma exacerbation, the child may return to school when asymptomatic and the PEFR is within 20% of normal.
Reduction in allergen exposure results in reduction of asthma and rhinitis symptoms and medications needed.
Avoid outdoor exposure and/or physical activity during periods of high smog alerts in community.
Change home furnace filters, remove dust, change linen, and vacuum regularly to reduce potential triggers.
In humid climates, keep humidity below 50% by using a dehumidifier to keep mold from growing.
Fluctuations in humidity and temperature can cause exacerbation of asthma attacks up to 2 days later.[41]
Avoid second-hand tobacco smoke, a well-known trigger of asthma attacks in infants and children.
Pediatric Asthma Controller Trial (PACT)[42] compared the effectiveness of 3 regimens in achieving asthma control:
Fluticasone 100 mg twice daily (fluticasone monotherapy), fluticasone 100 mg/salmeterol 50 mg in the morning and salmeterol 50 mg in the evening (PACT combination), and montelukast 5 mg in the evening
The conclusions of the study were in favor of fluticasone monotherapy in treating children (>6 y) with mild-to-moderate persistent asthma.
Volunteers in the community can help as educators by providing home visits or in-school visits. Internet and MP3 players may help to engage adolescents in acquiring asthma knowledge.[43]
Annual influenza vaccination is recommended to prevent the complications from infection. The CDC's Advisory Committee on Immunization Practices (ACIP) and the American Academy of Pediatrics (AAP) recommend annual influenza vaccination for all persons aged at least 6 months.
In addition to the pneumococcal conjugate vaccine (PCV13) that is administered per schedule for healthy children, asthmatics should receive the 23-valent pneumonococcal polysaccharide vaccine (PPSV23) at least 8 weeks after they have completed immunization with PCV13.[44]
The trivalent inactive influenza vaccination administered intramuscularly is preferred over the live-attenuated vaccination administered intranasally.[45, 46]
Bronchial thermoplasty is a novel procedure approved by the FDA in 2010 for severe asthmatics (aged at least 18 years) who are not well controlled with medications. Ablation or radiofrequency is used to destroy the overgrowth of smooth muscle in the airway. The concept behind the treatment is that with less muscle, there is a decrease of the ability of the airways to constrict and narrow during a bronchospasm. The procedure is not without risk and does not cure asthma, but rather decreases the severity of asthmatic episodes.[47]
A new drug being tested is mepolizumab—a monoclonal antibody against interleukin 5—and is thought to inhibit eosinophilic airway inflammation. A multicenter, double-blind, placebo-controlled trial found mepolizumab to be effective and well-tolerated treatment that reduces the risk of asthma exacerbations in patients with eosinophilic asthma.[48]
FDA has approved tiotropium bromide Inhalation Spray for use in the treatment of asthma. It is approved by the FDA for the long-term, once-daily, maintenance treatment of asthma in patients 12 years of age and older. When used as an add-on treatment to inhaled corticosteroid maintenance therapy, a study has shown a significant reduction in severe asthma exacerbations. [49]
What is pediatric reactive airway disease and how is it differentiated from asthma?What is the pathophysiology of pediatric reactive airway disease?What is the prevalence of pediatric reactive airway disease in the US?What is the global prevalence of pediatric reactive airway disease?What is the mortality and morbidity associated with pediatric reactive airway disease?What are the racial predilections of pediatric reactive airway disease?What are the sexual predilections of pediatric reactive airway disease?Which age groups have the highest prevalence of pediatric reactive airway disease?What is the prognosis of pediatric reactive airway disease?What is the focus of the clinical history to evaluate pediatric reactive airway disease?Which physical findings are characteristic of pediatric reactive airway disease?What causes pediatric reactive airway disease?What are the differential diagnoses for Pediatric Reactive Airway Disease?What is the role of lab tests in the workup of pediatric reactive airway disease?What is the role of radiography in the workup of pediatric reactive airway disease?When is a sweat chloride test indicated in the workup of pediatric reactive airway disease?Which tests may be beneficial in the workup of pediatric reactive airway disease?What is the role of spirometry in the workup of pediatric reactive airway disease?What is the role of barium swallow and bronchoscopy in the workup of pediatric reactive airway disease?What is the role of PFT in the workup of pediatric reactive airway disease?How is pediatric reactive airway disease treated?What is included in the prehospital care of pediatric reactive airway disease?How is status asthmaticus treated in pediatric reactive airway disease?What is included in the ED care of mild-to-moderate exacerbations of pediatric reactive airway disease?What is included in the ED care of severe exacerbations of pediatric reactive airway disease?What is the role of intubation in the treatment of pediatric reactive airway disease?What is the role of albuterol in the treatment of pediatric reactive airway disease?What is the role of ipratropium in the treatment of pediatric reactive airway disease?What is the role of inhaled beta2-agonist in the treatment of pediatric reactive airway disease?Which medications should not be used in the ED treatment of pediatric reactive airway disease?What are the NIH guidelines on the stepwise approach to managing pediatric reactive airway disease and asthma?What may decrease rates of return to the emergency department for pediatric reactive airway disease?Which specialist consultations are beneficial to patients with pediatric reactive airway disease?How are exacerbations of pediatric reactive airway disease prevented?What is the goal of drug treatment for pediatric reactive airway disease?Which medications in the drug class Corticosteroids, Inhalants are used in the treatment of Pediatric Reactive Airway Disease?Which medications in the drug class Corticosteroids are used in the treatment of Pediatric Reactive Airway Disease?Which medications in the drug class Combination Inhaled Steroids/Long-Acting Beta2-Agonists are used in the treatment of Pediatric Reactive Airway Disease?Which medications in the drug class Monoclonal Antibody are used in the treatment of Pediatric Reactive Airway Disease?Which medications in the drug class H2 Receptor Antagonists are used in the treatment of Pediatric Reactive Airway Disease?Which medications in the drug class Corticosteroid are used in the treatment of Pediatric Reactive Airway Disease?Which medications in the drug class Leukotriene Inhibitors are used in the treatment of Pediatric Reactive Airway Disease?Which medications in the drug class Mast Cell Stabilizers are used in the treatment of Pediatric Reactive Airway Disease?Which medications in the drug class General Anesthetic are used in the treatment of Pediatric Reactive Airway Disease?Which medications in the drug class Gas Mixture are used in the treatment of Pediatric Reactive Airway Disease?Which medications in the drug class Magnesium Salt are used in the treatment of Pediatric Reactive Airway Disease?Which medications in the drug class Methylxanthines are used in the treatment of Pediatric Reactive Airway Disease?Which medications in the drug class Beta2-Adrenergic Agonist Agents, Injection are used in the treatment of Pediatric Reactive Airway Disease?Which medications in the drug class Anticholinergic Agents are used in the treatment of Pediatric Reactive Airway Disease?Which medications in the drug class Beta2-Adrenergic Agonist Agents, Inhaled are used in the treatment of Pediatric Reactive Airway Disease?What is included in long-term monitoring of pediatric reactive airway disease?How is severity and treatment effectiveness assessed in pediatric reactive airway disease?What is maintenance treatment for pediatric reactive airway disease?When is inpatient care indicated in the treatment of pediatric reactive airway disease?How is pediatric reactive airway disease prevented?What are regimens for achieving asthma control in the prevention of pediatric reactive airway disease?What are the possible complications of pediatric reactive airway disease?What is the prognosis of pediatric reactive disease?What is included in the patient education about pediatric reactive airway disease?
Eric S Chin, MD, Consulting Staff, Department of Emergency Medicine, Kaiser Permanente Hospital, S San Francisco
Disclosure: Nothing to disclose.
Specialty Editors
Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
Grace M Young, MD, Associate Professor, Department of Pediatrics, University of Maryland Medical Center
Disclosure: Nothing to disclose.
Chief Editor
Kirsten A Bechtel, MD, Associate Professor of Pediatrics, Section of Pediatric Emergency Medicine, Yale University School of Medicine; Co-Director, Injury Free Coalition for Kids, Yale-New Haven Children's Hospital
Disclosure: Nothing to disclose.
Additional Contributors
Debra Slapper, MD, Physician, Southwest Washington Free Clinic System-Urgent Care; Former FEMA Physician and Military Contractor; Former Associate Professor, University of Miami, Leonard M Miller School of Medicine and University of South Florida Morsani College of Medicine
Disclosure: Nothing to disclose.
References
[Guideline] Expert panel commissioned by the National Asthma Education and Prevention Program (NAEPP) Coordinating Committee(CC), coordinated by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health. The Expert Panel Report 3 (EPR-3) Full Report 2007: Guidelines for the Diagnosis and Management of Asthma. August 28, 2007.
SJ Teach et al. Preseasonal treatment with either omalizumab or an inhaled corticosteroid boost to prevent fall asthma exacerbations. Journal of Allergy and Clinical Immunology. December 2015. Volume 136, Issue 6:1476–1485.
Ducharme FM, Ni Chroinin M, Greenstone I, Lasserson TJ. Addition of long-acting beta2-agonists to inhaled steroids versus higher dose inhaled steroids in adults and children with persistent asthma. Cochrane Database Syst Rev. APR 2010. Issue 4:
Stanford R, et al. Comparative clinical and economic outcomes in children with asthma initiating eitherfluticasone propionate plus salmeterol or inhaled corticosteroids plus montelukast. Ann Allergy Asthma Immunol. Nov 2009. 103(5):62.
Childhood Asthma Treatment: Not One-Size-Fits-All. National Heart, Lung, and Blood Institute (NHLBI). March 2,2010. Available at http://www.nih.gov/news/health/mar2010/nhlbi-02.htm
Early Communication about an Ongoing Safety Review of Omalizumab (marketed as Xolair). US Department of Health and Human Services/FDA. July 2009. Available at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm172218.htm
US Food and Drug Administration. Asthmatx, Inc. Alair Bronchial Thermoplasty System - P080032. 2010. Available at http://www.fda.gov/medicaldevices/productsandmedicalprocedures/deviceapprovalsandclearances/recently-approveddevices/ucm212594.htm
J. Bernstein et. al. Once-Daily Tiotropium Respimat Added-On to Inhaled Corticosteroids in a 1-Year Study in Adolescent Patients With Symptomatic Asthma Is Efficacious and Well Tolerated. Chest Journal. October 29, 2014. October 2014, Vol 146, No. 4_MeetingAbstracts:
Wolfram RW. Asthma. The Clinical Practice of Emergency Medicine. 2nd ed. 1997. 1093-96.
Zeffren BS, Windom HH, Bahna SL. Modern Treatment of Asthma in Children. Mosby Year Book; 1996. Vol 43: 423-68.
Stepwise approach for managing asthma in children 0 to 4 years of age. National Institutes of Health. National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the diagnosis and management of asthma. August 2007. NIH publication no. 07-4051. Available at: http://www.nhlbi.nih.gov/guidelines/asthma/index.htm. 3 Accessed December 30, 2007. PRN, As necessary.
Patient peak flow record.
This nomogram results from tests carried out by S. Godfrey, MD, and his colleagues on a sample of 382 healthy boys and girls aged 5-18 years. Each child blew 5 times into a standard Wright Peak Flow Meter, and the highest reading was accepted in each case. All measurements were completed within a 6-week period. The outer lines of the graph indicated that the results of 95% of the children fell within these boundaries.
Stepwise approach for managing asthma in children 0 to 4 years of age. National Institutes of Health. National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the diagnosis and management of asthma. August 2007. NIH publication no. 07-4051. Available at: http://www.nhlbi.nih.gov/guidelines/asthma/index.htm. 3 Accessed December 30, 2007. PRN, As necessary.
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