Diagnosis and Management of Chronic Pediatric Asthma

DIAGNOSIS AND MANAGEMENT OF CHRONIC PEDIATRIC ASTHMA

A Summary and Literature Review

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A. Guidelines for Classification and Management of Pediatric Asthma

B. Asthma Med Delivery

C. Safety and Efficacy of Asthma Controllers

D. Additional Medication Regimens

A. GUIDELINES FOR ASTHMA CLASSIFICATION AND MANAGEMENT

Background

· Recent guidelines recommend that health care providers should classify asthma severity OR control at both acute asthma visits and at preventive health visits

o Commonly cited guidelines include the 2007 NHLBI Guidelines for Pediatric Asthma Diagnosis and Management (for kids 0-4, 5-12 and >12), and GINA (Global Initiative for Asthma) 2016 (adults and kids > 5)

o Classification is based on symptom frequency and severity, as well as impairment and risk (of severe exacerbation)

o Medical management should be INITIATED or MODIFIED (stepped up or down) based on classification

· SEVERITY: For children who are not currently on long-term controller medication

o Severity classifications include intermittent, mild persistent, moderate persistent or severe persistent

o “Mild intermittent” no longer exists, as pts with intermittent asthma represent 1/3 of asthma deaths

· CONTROL: For children who are currently taking a long-term controller medication

o Control classifications include well-controlled, not well-controlled and poorly controlled

· Assessment of impairment and risk includes

o Impairment of normal function: frequency of day/night symptoms, SABA use, activity restriction, and FEV1/FVC ratio (in children >4)

o Risk of severe exacerbation: hospitalizations, # of exacerbations requiring oral corticosteroids in last year

· This approach to assessment of severity and control can also be boiled down to a “Rule of 2’s”:

The Rule of 2’s: A quick and easy method for recognizing persistent or not well-controlled asthma

1. 2 or more daytime /exercise symptoms or SABA use/week or

2. 2 or more nighttime awakenings/month or

3. 2 or more systemic corticosteroid courses or hospitalizations in last year

= PERSISTENT OR NOT WELL-CONTROLLED ASTHMA

***Summary tables for the NHLBI classification of asthma severity and control (Figures 11 and 12 on page 40-41 of the EPR3) are reprinted at the end of this handout. From http://www.nhlbi.nih.gov/guidelines/asthma/asthsumm.htm***

Recommendations: Guidelines for Asthma Classification and Management

1. Current guidelines recommend assessing severity or control at each visit, and initiating or stepping up controller medication based on classification

Ø For children with persistent asthma are not on controller medication: initiate inhaled corticosteroids

Ø For children not well/poorly controlled on current regimen: increase to next step of management

2. Increasing evidence and expert consensus supports the initiation of chronic disease assessment and management strategies in the ED/urgent care clinic for children with asthma.

3. Options for controller medications in kids include inhaled corticosteroids (ICS), ICS/long-acting beta-agonist (LABA) combinations, and leukotriene modifiers (see below for additional discussion)

Ø Inhaled corticosteroids (ICS)

§ Recommended as the preferred preventative treatment for persistent asthma of all severities

Ø Long-acting beta-agonists (salmeterol, formoterol)

§ Should always be used in combination with an ICS

§ Generally recommended as first-line controller in adults and kids > 12 with moderate persistent asthma or asthma not well-controlled on low-dose ICS

§ In younger kids, use LABA as an adjunct to ICS only in patients who have failed therapy with adequate doses of ICS alone (see below for more details)

Ø Leukotriene modifiers (montelukast, zafirlukast)

§ Recommended as a second-line alternative to ICS alone for mild persistent asthma

§ Second-line adjunct to ICS for moderate persistent/poorly controlled on ICS alone (LABA preferred)

4. Provide a symptom-based action plan for acute and chronic symptoms to all pediatric patients

5. Refer to follow up care within 1-4 weeks

***Summary recommendations for management of pediatric asthma, and recommended doses of commonly used controller medications are at the end of this handout and available at http://www.nhlbi.nih.gov/guidelines/asthma/asthsumm.htm ***

B. ASTHMA MED DELIVERY

1. WHICH PEDIATRIC ASTHMA PATIENTS NEED A NEBULIZER?

Background:

· Inhaled short-acting beta-agonists (SABA’s) may be given via metered-dose-inhaler (MDI) or nebulizer

· Oral albuterol syrup should not be used for pediatric asthma

· Nebulizers

o Usually used to deliver albuterol in the ED/urgent care setting

o Also commonly prescribed for home use for young children

o May be perceived by physicians and families as more effective

· MDI with valved holding chamber (VHC)

o Allows infant/child to use MDI by holding aerosolized medication suspended inside tube, with one-way valve

o Advantages over nebulizer include rapid delivery and portability: can be used for exacerbations away from home

Evidence:

· Multiple RCT’s have concluded that equivalent doses of albuterol delivered by correctly used MDI/VHC, are just as effective (or more effective) than nebulized albuterol, even in the acute setting

o Efficacy established in young infants and children, even during exacerbations of moderate severity

o Cost-effectiveness is institution-dependent, depends on availability of meds, equipment

· Expert consensus (the EPR-3) and evidence-based reviews (Osmond, 2004) all concur: MDI/VHC is as effective as nebulizer for mild or moderate asthma exacerbations

· MDI/VHC actually preferred by most parents for ease of use

Recommendations:

1. Use MDI/VHC whenever available for SABA delivery in children with mild-moderate asthma exacerbations

Ø This reinforces use for the parent, and may be cost-effective depending on setting

Ø Dosing: 8 puffs from MDI approximately equivalent to a 2.5 mg unit dose in nebulizer

1. Nebulizers may be appropriate in

Ø Infants or young children who have demonstrated difficulty using MDI for daily treatments, or

Ø Those with frequent severe exacerbations, or

Ø Those whose parents strongly prefer the use of the nebulizer

2. To dispense a nebulizer for a patient

Ø Write prescription for appropriate medication in nebulized form

Ø Write “nebulizer” as a “non-SFGH” prescribed medication and place the prescription in outpatient social worker box in 6M doctor’s room (Erika Flores or Alice Slaughter).

Ø Make sure that address and phone number on prescription are up to date

3. Dispense MDI and VHC, and teach age-appropriate VHC technique before discharge to ALL patients

2. SHOULD INHALED CORTICOSTEROIDS (ICS) BE STARTED DURING AN ACUTE EXACERBATION?

Background:

o Systemic corticosteroids (prednisone, dexamethasone, solumedrol) are the standard of care for acute exacerbations of asthma in children and adults

o Short courses (5-7 days) are typical, but inflammation/hyperresponsiveness after an exacerbation can last for months

o Studies have investigated whether ICS can be used instead of systemic CS during an acute exacerbation, or if iCS in addition to systemic CS after discharge reduces relapses.

Evidence: Initiation of ICS during Exacerbation

· A Cochrane review (Edmonds, 2012) primarily in adults concluded that ED patients receiving ICS in addition to systemic CS after ED discharge showed a trend towards fewer relapses, although the benefit was not quite statistically significant

· In adults with non-severe asthma, the same review found that high-dose ICS was non-inferior to short courses of PO steroids

· In a 2005 editorial in Annals of Internal Medicine, two authors reviewed the evidence regarding the role of the ED in management of chronic asthma in both adults and children (Singer, Rowe 2005) and agreed that initiation of ICS in the ED should be considered in patients with persistent asthma

Recommendations:

1. In patients with persistent asthma who are not currently on ICS, expert consensus supports the initiation of ICS in ED during an acute exacerbation

2. In patients without persistent asthma, evidence does not support the addition of ICS to appropriate courses of systemic CS for acute asthma exacerbations, although some patients may benefit.

C. SAFETY AND EFFICACY OF ASTHMA CONTROLLERS

1. INHALED CORTICOSTEROIDS (ICS)

Evidence:

· ICS are the preferred long-term control therapy in children of all ages and adults for both safety and efficacy

o Efficacy in toddlers and young infants with recurrent wheeze has also been established (Kaiser, 2016)

· Risk of adverse effects increase with dose and with prolonged use

o However, use of ICS for prolonged periods of time (eg: >1year) has LESS potential for adverse effects than repeated doses of systemic corticosteroids

· Linear growth:

o Overall, experts concur that the benefits of ICS outweigh the risks (i.e.: poorly controlled asthma more likely to result in growth impairment than appropriate use of ICS for asthma control)

o The impact of ICS on growth in long-term trials follows the following principles (Loke 2015, Wolfgram 2015, Zhang 2014, Pruteanu 2013)

§ Final adult height: growth velocity is impaired primarily in the first year of treatment, and results in a permanent but mild decrease in final adult height (~1cm, depending on factors below)

§ Age: younger children are impacted more than older children

§ Dose-dependent: greater impact on growth seen with higher equivalent doses

§ Steroid molecule/mode of delivery: ICS forms with higher bioavailability (smaller particle size, MDI delivery, beclomethasone vs fluticasone) result in greater growth velocity reduction

§ Estimates for 1st year growth impact of high daily doses of common pediatric ICS formulations:

· 1.5 cm with 400mcg/day of beclomethasone

· 1.0 cm with 200 mcg/day of budesonide

· 0.43 cm with 200 mcg/day of fluticasone

· Other adverse effects: high doses of ICS for prolonged periods, in combination with frequent systemic steroid doses, may result in subcapsular cataracts, or reduced bone density

o Regular eye exams and bone density recommended in these patients

· Ciclesonide: an ICS that is not systemically absorbed?

o Background

§ A “pro-drug”: it undergoes “on-site activation” in the lungs to form the active metabolite

· It has low oral bioavailability (<1%) and is rapidly cleared by hepatic metabolism

· Lower bioavailability should reduce local and systemic side effects such as thrush and growth impairment

o Efficacy:

§ Appears to be non-inferior to other commonly used ICS for children with mild, moderate or severe persistent asthma (Pederson, 2006; Gelfand 2006, von Berg 2007) although the equivalent doses for mild, moderate or severe persistent asthma have not been established

§ Cochrane review (Kramer,2013) concluded that ciclesonide was non-inferior to budesonide/fluticasone, but quality of evidence was limited, with fewer side effects

o Safety:

§ Individual trials have shown less growth suppression and oral thrush (von Berg, 2007; Skoner, 2008; Skoner 2006, Manning 2009)

§ Cochrane review (Kramer, 2013) concluded that evidence was insufficient as long-term safety studies are lacking.

o Dosing: dosing for mild, moderate or severe persistent asthma has not been established*

§ Dosing range of 40-160mcg daily has been studied: titrate to lowest dose to achieve control

Recommendations: Safe use of ICS in pediatric asthma:

1. Use the lowest dose required to achieve control

2. Use the safest type of steroid available, especially at moderate or high daily doses

Ø Ciclesonide is not yet widely available, and studies are limited. Could consider in children who have very high concern for growth effects from ICS

Ø Formulation: Alvesco 80 or 160 mcg/puff (limited coverage by current insurance plans)

3. Always use ICS with valved holding chamber (VHC) or spacer

Ø VHC use improves efficacy and reduces local side effects

Ø Systemic absorption of most ICS occurs in the lung epithelium, not the GI tract. However, spacer use will reduce the dose needed for clinical efficacy

4. Consider adding LABA or alternative adjunctive therapy to low/mod ICS (when appropriate) to avoid high dose ICS

5. Height should be monitored in all pre-pubertal children on long-term ICS, especially at moderate or high doses.

2. LONG-ACTING BETA-AGONISTS (LABA’S)

Available forms of long-acting beta-agonists/ICS combinations =

1. Advair (fluticasone 100/250/500+ salmeterol 50/puff in diskus, or 115/230/21 in MDI*)

2. Symbicort (budesonide 80 or 160+formoterol 4.5/puff in MDI)

3. Dulera (mometasone 100 or 200 + formoterol 5mcg/puff in MDI)

Evidence:

· Safety: Studies suggesting increased risk of severe asthma exacerbations (from the SMART study and others) resulted in a black box warning by FDA on all preparations containing LABA (May, 2006)

o SMART study (Nelson, 2006):

§ Large clinical trial including mostly pts on salmeterol ALONE for asthma control, showed increase risk of asthma related death (13/13,176 vs 3/13,179)

§ The study did not include any children < 12

§ The majority of pts were NOT on ICS in combination with LABA

o Recent meta-analyses (Salpeter, 2006; Rodrigo 2009) showed smaller but still statistically significant increase in asthma-related deaths in children and in patients taking ICS along with LABA

o Peters (2016): randomized >12,000 pts > 12 to get ICS vs ICS/formoterol and were unable to show a statistically significant increase in asthma-related deaths (although the only 2 which occurred were in the ICS/LABA group)

· Efficacy:

o Previous studies (Lemanske 2010; Gappa 2009) and a Cochrane review (Ducharme, 2010) have supported the overall superior efficacy of adding LABA to ICS for asthma control in kids

§ Decreased symptoms, decreased use of rescue meds and improved lung function to a GREATER degree than increasing dose of ICS (or adding montelukast)

o However, a recent meta-analysis in kids (Chauhan 2015) failed to show improved symptom control or reduction in exacerbations with addition of LABA to low-dose ICS (compared to low-dose or higher dose ICS)

§ LABA+ICS did result in decreased use of rescue SABA, and improved measures of lung function

§ There was a trend towards increased hospitalization in children receiving LABA+ICS

§ Children on low-dose ICS+LABA had less growth suppression than those on higher-dose ICS

Recommendations: Safe Use of ICS/LABA in Pediatric Asthma

1. LABA’s should NEVER be used as monotherapy or for treatment of acute symptoms – always use in combination with ICS

2. In select patients, adding LABA to ICS may benefit patients poorly controlled on ICS alone.

3. Children <5:

Ø LABA’s are not approved for children <5

Ø Although not approved, may consider only in children poorly controlled on medium/high dose ICS

4. Children 5-12 years:

Ø ICS/LABA is preferred step-up therapy for poor control on moderate dose ICS

Ø Consider for poor control on low-dose ICS (as alternative to mod dose ICS), if growth suppression a concern

5. Children ≥12 years:

Ø ICS/LABA is preferred initial therapy for severe persistent, or step-up therapy for poor control on low or moderate dose ICS

Ø Acceptable alternative to medium dose ICS alone in mod persistent or poor control on low dose ICS

6. For all children, re-assess frequently, and step-down to ICS alone after 3-6 months of good control

7. Dosing

Ø Daily use should not exceed 100mcg salmeterol (50mcg for <5) or 10mcg formoterol (5mcg for kids < 5)

Ø *Low/mod/high dosing has not been established for kids < 12

3. LEUKOTRIENE RECEPTOR ANTAGONISTS (LTRA)

Background:

· LTRA’s are a class of oral medications that oppose the action of leukotrienes, specifically at the cysLT1 receptor (located on respiratory epithelium, leads to bronchospasm, vascular permeability and edema)