Diagnosing and Management of Asthma in Children Four years

and Younger

Khaled Saad MD Pediatric Pulmonary Unit

Objectives

• To better understand how to differentiate between infants who wheeze and go on to develop asthma and those who wheeze but do not go on to have asthma.

• To discuss management strategies for treating children with a high risk of developing asthma.

• To discuss possible prevention therapies for asthma in children five years old or younger.

Asthma is the most common chronic lower respiratory disease in childhood throughout world.

Papadopoulos et al. International consensus on (ICON) pediatric asthma.

Allergy 67 (2012) 976–997.

What is Asthma? • Disease of chronic

inflammatory disorder of the airways

• Characterized by • Airway inflammation • Airflow obstruction • Airway

hyperresponsiveness

http://health.allrefer.com/health/asthma-normal-versus-asthmatic-bronchiole.html

Cookson W. Nature 1999; 402S: B5-11

Definition of Asthma

A chronic inflammatory disorder of the airways

Many cells and cellular elements play a role

Chronic inflammation is associated with airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing

Widespread, variable, and often reversible airflow limitation

Asthma Prevalence and Mor tality

Source: Masoli M et al. Allergy 2004

Stages of Asthma

In the maintenance phase a balance between the different

environmental exposures ultimately determines outcome.

Gelfand E W .Proc Am Thorac Soc (6 ) 278–282,2009

Symptoms of Asthma

Symptoms of Asthma

• Cough • Wheeze • Shortness of

breath • Chest tightness • Retractions

A Lot Going On Beneath The Surface

Airway inflammation

Airflow obstruction

Bronchial hyperresponsiveness

Symptoms

What Causes Asthma? • Asthma is a complex trait

• Heritable and environmental factors contribute to its pathogenesis. Viral infections appears have an expanding role as well.

• Onset appears early in life and severity remains constant

• Multiple interacting genes • At least 20 distinct chromosomal regions with

linkage to asthma and asthma related traits have been identified: Chromosome 5q , ADAM33 , PHF11

Potential Risk Factors

• Host factors • Genetic predisposition • Atopy • Airway

hyperresponsiveness • Gender • Race/Ethnicity

• Environmental factors • Indoor allergens • Outdoor allergens • Occupational sensitizer

• Environmental factors (cont) • Tobacco smoke • Air pollution • Respiratory infections • Socioeconomic status • Family size • Diet and drugs • Obesity

Masoli M, et al. The Global Burden of Asthma: Executive Summary of the GINA Dissemination Committee Report. Allergy 2004; 59: 469-78.

Diagnosing Asthma-Not Easy

• Clinical diagnosis supported by the certain historical, physical and laboratory findings • History of episodic symptoms of airflow

obstruction (e.g.. breathlessness, wheezing, and COUGH)-response to therapy!

• Physical: wheeze, hyperinflation • Laboratory: spirometry

• Exclude other possibilities

Differential Diagnosis Wheezing • Asthma • Congenital Anomalies with airway impingement: Vascular

rings, tracheobronchial obstruction, mediastinal mass • Bronchopulmonary dysplasia • Cystic fibrosis • Gastroesophageal reflux • Aspiration • Foreign Body Aspiration • Heart Failure • Sinusitis and allergic rhinitis • Bronchiolitis • Pertussis • Tuberculosis • Immune system Disorders

Wheezing in Infants 1. Group 1: Low Lung function: children

improve within a few years and "outgrow" their asthma

2. Group 2: Non-Atopic, viral-induced asthma: also outgrow asthma after a somewhat longer period of time (non atopic wheezing).

3. Group 3: Atopic Asthma: in contrast, children who will go on to develop persistent wheezing beyond infancy and early childhood usually have a family history of asthma and allergies and present with allergic symptoms very early in life (atopy-associated asthma).

Diagnosing Asthma in Young Children – Asthma Predictive Index

• > 4 episodes/yr of wheezing lasting more than 1 day affecting sleep in a child with one MAJOR or two MINOR criteria

• Major criteria • Parent with asthma • Physician diagnosed

atopic dermatitis • Minor criteria

• Physician diagnosed allergic rhinitis

• Eosinophilia (>4%) • Wheezing apart from

colds Adapted from Castro-Rodriquez JA, et al. AJRCCM 2000; 162: 1403

Asthma Diagnosis Made

• Identify precipitating factors (pets, mold) • Identify comorbid conditions that may

aggravate asthma (GERD, allergies etc) • Assess the patient/families knowledge and

self management skills • Classify asthma severity using the

Guidelines .

Classifying Asthma Severity in Children 0-5 Years of Age

• Break down into intermittent, mild, moderate, or severe persistent asthma depending on symptoms of impairment and risk

• Once classified, use the 6 steps depending on the severity to obtain asthma control with the lowest amount of medication

• Controller medications (inhaled steroids) should be considered if >4 exacerbations/year, 2 episodes of oral steroids in 6 months, or use of SABA’s (salbutamol) more then twice a week

Asthma Classification of severity

Clinical features before treatment

Symptoms Night-time symptoms PEF

STEP 4 Severe persistent

STEP 3 Moderate persistent

STEP 2 Mild persistent

STEP 1 Intermittent

Continuous Limited physical activity

Daily Use β2-agonist daily Attacks affect activity

>1 time a week but <1 time a day

<1 time a week

Asymptomatic and normal PEF between attacks

Frequent

>1 time a week

>2 times a month

<2 times a month

<60% predicted Variability >30%

>60% - <80% predicted Variability >30%

>80% predicted Variability 20-30%

>80% predicted Variability <20%

GINA Guidelines Prof.Ashraf Hatem

The stepwise approach to asthma treatment in childhood aims at disease control.

Steps of Therapy 0-5 Years • Step 1: intermittent- use SABA • Step 2: mild persistent-use low dose ICS OR

montelukast OR cromolyn alternatives • Step 3: moderate persistent: moderate dose of

ICS • Step 4: moderate persistent: moderate dose of

ICS and add either montelukast or LABA • Step 5: severe persistent: high dose ICS and

montelukast or LABA • Step 6: severe persistent: high dose ICS and

montelukast or LABA plus oral steroids • Consult asthma specialist if step 3 or higher

(consider at step 2)

Maintaining Control • Monitor carefully- every 6 months if stable,

more often if not • If stable after 3 months, try to reduce therapy

(usually by 25-50%) • Inhaled steroids are safe even in the young at

mild to moderate doses with only a slight decrease in growth velocity. Higher doses have been shown to affect growth, cause cataracts and reduce bone density

• Response to therapy is very important in this age group!

Inhaled Corticosteroid • Preferred treatment alone or in combination

for all persistent categories of asthma • Safe when use is monitored • Reduces asthma symptoms, bronchial

hyperreactivity, exacerbations and hospitalizations, need for rescue medications

• Improves lung function, quality of life • May prevent airway remodeling…Probably

no longer true

Role of ICS in Asthma • Trials show that among children with asthma (or at risk for

asthma), controller therapy with ICS is efficacious in controlling asthma symptoms

• However, ICS, do not change the natural clinical course of the disease.

• PEAK trial 285 children aged 2 to 3 years at high risk for asthma were randomized to therapy with either an ICS (fluticasone, 88 μg twice daily for 2 years) or placebo

• Results showed significantly better clinical outcomes and lung function outcomes in children treated with fluticasone than in those treated with placebo

• However, clinical differences between groups rapidly disappeared a few weeks after discontinuation of regular treatments.

Guilbert et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma, N Engl J Med 354 (2006), pp. 1985–1997

FDA Approved Therapies

• ICS budesonide nebulizer solution (1-8 years) • ICS fluticasone DPI (4 years of age and older) • LABA and LABA/ICS combination DPI and MDI

(4 years of age and older) • Montelukast chewables (2-4 years), granules

(down to 1 year of age) • Cromolyn sodium nebulizer (2 years and older)

Reliever Medications

Rapid-acting inhaled β2-agonists Systemic glucocorticosteroids Anticholinergics Theophylline Short-acting oral β2-agonists

Controller Medications

Inhaled glucocorticosteroids Leukotriene modifiers Long-acting inhaled β2-agonists in combination

with inhaled glucocorticosteroids Systemic glucocorticosteroids Theophylline Cromones Anti-IgE

Estimate Comparative Daily Dosages for Inhaled Glucocorticosteroids by Age

Drug Low Daily Dose (µg) Medium Daily Dose (µg) High Daily Dose (µg) > 5 y Age < 5 y > 5 y Age < 5 y > 5 y Age < 5 y

Beclomethasone 200-500 100-200 >500-1000 >200-400

>1000 >400

Budesonide

200-600 100-200

600-1000 >200-400 >1000 >400

Budesonide-Neb Inhalation Suspension

250-500 500-1000 >1000

Ciclesonide 80 – 160 80-160 >160-320 >160-320 >320-1280 >320

Flunisolide 500-1000 500-750 >1000-2000 >750-1250 >2000 >1250

Fluticasone 100-250 100-200 >250-500 >200-500 >500 >500

Mometasone furoate 200-400 100-200 > 400-800 >200-400 >800-1200 >400

Triamcinolone acetonide 400-1000 400-800 >1000-2000 >800-1200 >2000 >1200

Medications used for acute relief of symptoms

• Relievers’ are used for the acute, within minutes, relief of asthma symptoms, through bronchodilation.

• Use of inhaled short-acting β2 adrenergic agonists (SABA), most commonly

salbutamol, as first-line reliever therapy is unanimously promoted for children of all ages (Evidence A).

• They are typically given on an ‘as needed’ basis, although frequent or prolonged use may indicate

the need to initiate or increase anti-inflammatory medication.

• Compared to other relievers, SABA have a quicker and greater effect on airway smooth muscle, while their safety profile is favorable; a dose-dependent,

self-limiting tremor and tachycardia are the most common side effects.

• Oral SABA are generally discouraged. • Anticholinergic agents, mainly ipratropium,

are second-line relievers, but are less effective than SABA.

Medications used for long-term asthma control

Inhaled corticosteroids (ICS)

The use of ICS as daily controller medications in persistent asthma is ubiquitously supported, as there is robust evidence that therapeutic doses of ICS improve symptoms and lung function, decrease need for additional medication, and reduce rate of asthma exacerbations and asthma-induced hospital admissionsin children of all ages .

Barnes PJ. N Engl J Med 1995;332:868–875.

Inhaled steroid (ICS) dose equivalence

Leukotriene receptor antagonists (LTRA).

Among leukotriene modifiers, montelukast is available worldwide; zafirlukast is mentioned only in NAEPP and pranlukast only in Japanese Guideline for Childhood Asthma, 2008 (JGCA).

Leukotriene receptor antagonists (LTRA).

They are generally less efficacious than ICS in clinical trials, although in some cases noninferiority has bee shown . Price et al. N Engl J Med 2011;364:1695–1707. Garcia Garcia et al. Pediatrics 2005;116:360–369.

Leukotriene receptor antagonists (LTRA).

Furthermore, there is evidence suggesting particular effectiveness of montelukast in exercise-induced asthma, possibly superior to other treatments . Stelmach et al. J Allergy Clin Immunol 2008;121:383–389

Leukotriene receptor antagonists (LTRA).

• In most guidelines they are recommended as second choice after low-dose ICS, or occasionally as ‘alternative first-line treatment’ (AAMH, PRACTALL), for the initial step of chronic treatment.

• In the context of the next treatment steps, they are also effective as add-on medications, but less so in comparison with LABA .

Ram et al. Cochrane Database Syst Rev 2005: CD003137.

Leukotriene receptor antagonists (LTRA).

PRACTALL also suggests that LTRA may be particularly useful when the patient has concomitant rhinitis.

Long-acting β2 adrenergic agonists (LABA)

• LABA, including salmeterol and formoterol, have long-lasting bronchodilator action.

• All documents agree that LABA should only be prescribed in combination with ICS and are therefore relevant as add on treatment.

Long-acting β2 adrenergic agonists (LABA)

In older children and adults, ICS– LABA combinations have been shown to improve asthma outcomes to a better extent than higher doses of ICS . Woolcock et al. Am J Respir Crit Care Med 1996;153:1481–1488. Greening et al. Lancet 1994;344:219–224. Ducharme et al . Cochrane Database Syst Rev 2010:CD005533.

Long-acting β2 adrenergic agonists (LABA)

• In the absence of data of safety and efficacy in children younger than 5 years, it is probably better to be cautious, until such data are produced.

• For older children, it is clear that ICS+LABA are an important treatment option, preferable for at least a subpopulation of patients.

Lemanske et al. N Engl J Med 2010;362:975–985.

Theophylline

• Theophylline, the most used methylxanthine, has bronchodilatory properties and a mild anti-

inflammatory action. • It may be beneficial as add-on to ICS, however,

less than LABA (Evidence B). • It has a narrow therapeutic index requiring

monitoring of blood levels .

Theophylline

As a result, its role as controller medication is very limited and is only recommended as second-line treatment, where other options are unavailable . Weinberger et al. N Engl J Med 1996;334:1380–1388

Omalizumab • Omalizumab is indicated for children with

allergic asthma poorly controlled by other medications (Evidence B).

• It reduces symptoms and exacerbations and improves quality of life and to a lesser extent lung function

Walker et al. Cochrane Database Syst Rev 2006:CD003559. Finn et al. J Allergy Clin Immuno l2003;111:278–284. Rodrigo et al. Chest 2011;139:28–35. Kopp MV. Allergy 2011;66:792–797

Immunotherapy

Allergen-specific immunotherapy (SIT) involves

the administration of increasing doses of allergen extracts to induce persistent clinical tolerance in patients with allergen-induced symptoms.

Strategies for asthma pharmacotherapy

• Reliever medication should be used at any level of severity/control, if symptoms

appear/exacerbate . • At the mildest spectrum of the disease, no

controller medication is needed (step 0).

• The next step entails the use of one controller

medication (step 1). • If this is not enough, two medications, or a double dose of inhaled steroid, can be used

(step 2).

• In more difficult cases, increase of inhaled steroid dose, alone or in combination with additional medication is needed (step 3–4).

• In the first, LABA or LTRA (or exceptionally theophylline) are added to the medium-dose ICS, and in the second, the ICS dose is increased (NAEPP, AAMH). • Omalizumab is also considered at this step by NAEPP.

• Oral corticosteroids are kept as the last resort, for very severe patients (Step 5).

• GINA includes omalizumab here.

It should be noted that in low-income countries, an important obstacle to asthma management is the cost of medications.

• Stepping up or down should be evaluated at regular intervals, measured by level of control.

• Treatment adherence, exposure to triggers and alternative diagnoses should always be considered before stepping up.

There is considerable variation in the individual response to each medication, therefore, close monitoring and relevant adjustments are equally or even more important.

Assessment of exacerbation severity

Because of their pleiotropic anti-inflammatory activity, initiation of ICS therapy generally constitutes the first step of regular treatment

(Evidence A).

Asthma Prevention • There has been remarkable progress in

pharmacotherapy, education and environmental measures in treating asthma

• However, no single action has been demonstrated to decrease the risk of developing asthma

• Genetic and environmental influences-key! • Exposure to microbial products- Hygiene? • Low level of lung function present in preschoolers with

asthma • Prevention will depend on factors influencing the

development and progression of asthma

Next Steps • There is a need to develop therapeutic modalities that,

initiated even earlier in life and before the development of the first asthma-like symptoms, will prevent progression along the pathways to airway dysfunction.

• If a group of children with asthma in whom the disease is confirmed, early genetic and phenotypic markers are needed to target them for the development of specific therapies that will thwart that progression.

• It is essential to determine whether in children with mild persistent asthma, whether intermittent, symptom-triggered anti-inflammatory therapy might be as effective as daily continuous therapy with controller medications in decreasing exacerbations and improving quality of life.