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Management of Asthma in Children: Chronic Asthma – Preventing Asthma Exacerbations

Medications used in children to control asthma symptoms and to prevent exacerbations include inhaled corticosteroids (ICSs), leukotriene receptor antagonists (LTRAs) (or leukotriene modifiers in the older children), long-acting beta2-agonists (LABAs), theophylline, and cromolyn. No daily medications are needed for mild intermittent asthma, whereas mild to severe persistent asthma requires one or more controller medications. A low-dose ICS via a nebulizer or MDI with a holding chamber and with or without a face mask or dry powdered inhaler (DPI) for mild persistent asthma is preferred. Alternatives include cromolyn via nebulization or MDI with a holding chamber, LTRA, nedocromil, or sustained-release theophylline targeting serum concentrations at 5 to 15 µg/mL. For moderate persistent asthma, the preferred regimen includes a low-dose inhaled corticosteroid (ICS) and LABA or a medium-dose ICS alone. Alternatively, a low-dose ICS and an LTRA or, if cost is a concern, theophylline may be prescribed. Patients with inadequately controlled moderate persistent asthma who are taking low doses of an ICS may need to have a LABA added or their dosage of ICS increased. Alternatively, but not preferably, an LTRA or theophylline can be added to low to medium doses of inhaled corticosteroid (ICS) to avoid side effects from a higher dosage of ICS. If the child suffers from recurring severe exacerbations, the preferred treatment is a medium-dose ICS and LABA. A medium-dose ICS and LTRA or theophylline is a viable alternative. Combination therapy is generally preferred over increasing the dose of ICS, except in children younger than 4, in whom medium doses of inhaled corticosteroid (ICS) are effective in treating moderate and severe asthma.

Inhaled Corticosteroids

According to the NAEPP guidelines, inhaled corticosteroid (ICS) is the preferred therapy for maintaining long-term control by improving airway responsiveness, and the current trend is to prescribe an ICS before other traditional medications, such as cromolyn. ICS improves and sustains increases in pulmonary function and reduces symptomatology. The recommended dose of inhaled corticosteroid (ICS) depends on the classification of asthma, while the mode of delivery depends on the child’s age and maturity level. (see TABLE 3).If the child is 2 or younger, a nebulizer with a mask is preferred, whereas an metered dose inhaler (MDI) with a spacer/holding chamber with nebulization as needed is preferred in 3- to 5-year-olds. Children who are 5 or younger with mild persistent asthma should receive a low-dose ICS via a nebulizer (as young as 1 year), dry powdered inhaler (DPI) (as young as 4, but also depends on specific product), or an MDI with a spacer/holding chamber with or without a mask (as young as 12 months). Older children can use an MDI with a spacer/holding chamber with or without a mask or a DPI. Adolescents may opt to use an metered dose inhaler (MDI) without a spacer/holding chamber.

Table 3. Usual Pediatric Dosages for Selected Asthma Medications for Chronic Therapy
Medications Low Daily Dose Medium Daily Dose High Daily Dose
Beclomethasone HFA 40 or 80 µg/puff 84-336 µg 336-672 µg > 672 µg
Budesonide DPI 200 µg/inhalation 200-400 µg 400-800 µg > 800 µg
Budesonide inhalation suspension 0.5 mg 1 mg 2 mg
Fluticasone MDI 44, 110, 220 µg/puff 88-176 µg 176-440 µg > 440 µg
Fluticasone DPI 50, 100, 250 µg/inhalation 100-200 µg 200-400 µg > 400 µg
DPI: dry powdered inhaler; MDI: metered dose inhaler.

Fluticasone is available as a DPI (Flovent Diskus) approved by the FDA for children 4 and older and as an MDI (Flovent HFA) for children 12 months and older. Budesonide is available as a DPI (Pulmicort Turbuhaler) for children 6 and older and a nebulized solution (Pulmicort Respules) for children ages 1 to 8. Beclomethasone MDI (QVAR) is another inhaled corticosteroid (ICS), as is Advair Diskus, which combines fluticasone and salmeterol. Selection of an MDI, DPI, or nebulized solution is based on patient cooperation.

Oral inhaled corticosteroids are generally well tolerated by children. Most concerns about inhaled corticosteroid (ICS) as a class involve their effect on a child’s growth velocity, bone mineral density, and adrenal suppression. One long-term evaluation of the adverse effects of ICS in children ages 5 to 12 demonstrated a small risk of delayed growth. Agertoft and Pedersen showed that 95% of children diagnosed with asthma at a mean age of 3.4 years who received an average daily dose of 412 µg (1.35 g cumulative dose) of inhaled budesonide for an average of nine years (range, 3 to 13 years) reached their target adult height despite initial growth retardation. A cross-sectional evaluation of 5- to 12-year-old children with mild-moderate persistent asthma for four to seven years demonstrated normal height achievement. Severe persistent asthma, however, may have a negative effect on adult height. More common side effects are oral thrush and dysphonia, which are both minimized with the proper use of a spacer with the metered dose inhaler (MDI) and mouth rinsing. A six-week course of inhaled corticosteroid (ICS) is the minimum time span to determine its efficacy.

Management_of_Asthma_in_Children:

Systemic Corticosteroids

There is a subgroup of patients who have debilitating, steroid-dependent asthma requiring larger than usual daily doses of oral corticosteroids, despite adherence to inhaled corticosteroid (ICS) and other adjunctive therapies. These patients seem to suffer from a more severe form of asthma earlier on for a longer duration and have a family history of asthma. It also appears to be more prevalent in blacks than in whites. Monitoring and treating adverse effects is important. For instance, patients can take calcium supplements to help prevent osteoporosis.

Cromolyn

Cromolyn sodium (Intal) is a safe and effective anti-inflammatory agent used for long-term control. However, the Expert Panel no longer recommends using cromolyn as first-line therapy because ICSs were found to be more effective. Instead, it is an alternative to ICSs for mild persistent asthma. Cromolyn is available as a nebulized solution appropriate for children age 5 and younger or as an metered dose inhaler (MDI) with a holding chamber for all children. Of note, cromolyn also is used commonly as prophylaxis prior to exercise or unavoidable exposure to known allergens.

Leukotriene Modifiers

Leukotriene modifiers are recommended by the Expert Panel as an alternative to inhaled corticosteroid (ICS) in mild persistent asthma in all ages and as adjunct therapy in patients with moderate persistent asthma because of their modest effect on lung function when used as monotherapy. Zileuton, a 5-lipoxygenase pathway inhibitor, is indicated in persons 12 and older, while zafirlukast and montelukast, both leukotriene receptor antagonists (LTRAs), are indicated for children as young as 7 and 2, respectively. Zafirlukast also requires twice-daily dosing and may be less favorable in young children, while montelukast is dosed once daily. In recent years, montelukast has become the more popular LTRA for children with asthma and is now also approved for allergic rhinitis. It is available as a powder for reconstitution and in tablets of 4, 5, and 10 mg (the 4- and 5-mg tablets are chewable).

Long-acting Beta2-Agonists

The Expert Panel prefers the addition of inhaled LABAs to high-dose ICSs for severe persistent asthma and to low-dose ICSs in moderate persistent asthma as daily medications in all ages. However, because it is uncertain whether long-acting beta2-agonists (LABAs) offer long-term bronchodilation, they should not be used as monotherapy except to prevent exercise-induced asthma. Dose-related side effects of LABAs include headache, tremors, and palpitations. Salmeterol (Serevent Diskus) is the LABA most commonly used in children age 4 and older. Formeterol (Foradil Aerolizer) joined the armamentarium in 2003 for maintenance of asthma and exercise-induced asthma in children age 5 and older, but experience of use is limited.

Theophylline

Theophylline is not prescribed commonly but serves as a viable alternative to increasing the dose of ICSs from low to medium when used in conjunction with a low-dose inhaled corticosteroid (ICS). Target serum concentrations should fall between 5 and 15 mg/mL at steady state.

Intravenous Immunoglobulin

Intravenous immunoglobulin (IVIg) use for steroid-dependent asthma is an off-label indication that has been explored, although its true glucocorticoid-sparing mechanism is unknown. Mazer and Gelfand reported an open trial in which eight children receiving monthly high-dose IVIg infusions had a threefold decrease in daily doses of corticosteroids, reduction in symptoms, improved lung function, and reduction in skin test reactivity. However, cessation of therapy did not sustain these benefits. Salmun et al examined a loading dose of 2 g/kg followed by 400 mg/kg IVIg or placebo every three weeks for nine months in patients ages 5 to 17 who required more than 2,000 mg (5.5 mg/day) of prednisone a year. The researchers found a statistically significant decrease of daily prednisone dose but no differences in lung function (p=.078).Despite the successful reduction of daily corticosteroid dose and hospital admissions after a 1 g/kg dose monthly for six months, lung function was not improved in a study of seven patients. Headache and nausea are common side effects, and IVIg should be avoided in patients with IgA deficiency due to a risk of anaphylactic reactions. Although promising, IVIg remains expensive, time-consuming to administer, and may transmit an undefined viral infection. Thus, larger and longer trials using IVIg in severe asthma would be helpful.

Omalizumab

Omalizumab (Xolair) is the first IgE antagonist used with inhaled corticosteroid (ICS) to prevent allergic asthma exacerbations in patients 12 and older. Only those with moderate to severe persistent asthma and “confirmed positive skin test or in vitro reactivity to perennial aeroallergens and are suboptimally controlled with ICS therapy” are candidates for omalizumab. It is dosed by pretreatment serum IgE levels and given subcutaneously every two to four weeks. A statement of medical necessity and preapproval by insurance companies is required for reimbursement. Serious adverse effects include malignancies and anaphylaxis; common adverse effects include local injection site reactions, viral infections, upper respiratory tract infections, headache, and pharyngitis.

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