Asthma is a chronic inflammatory disorder of the airways that causes recurrent wheezing, breathlessness, chest tightness and coughing. It is the most common chronic lower respiratory disease in children. This document discusses differentiating transient wheezing from asthma in young children, managing high-risk children, and prevention therapies. It also covers diagnosing and classifying asthma severity, recommended treatment steps based on severity including inhaled corticosteroids and reliever medications, and FDA-approved treatment options for children ages 4 and under.

1. Diagnosing and Management of
Asthma in Children Four years
and Younger
Khaled SaadMD
Pediatric Pulmonary Unit

2. 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.

3. 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.

4. 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

5. 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

6. Asthma Prevalence and Mortality
Source: Masoli M et al. Allergy 2004

7. 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

8. Symptoms of Asthma

9. Symptoms of Asthma
• Cough
• Wheeze
• Shortness of
breath
• Chest tightness
• Retractions

10. A Lot Going On Beneath The Surface
Airway
inflammation
Airflow
obstruction
Bronchial
hyperresponsiveness
Symptoms

11. 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

12. 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.

13. 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

14. 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

15. 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).

16. 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

17. 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 .

18. 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

19. 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

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

21. 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)

22. 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!

23. 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

24. 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

25. 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)

26. Reliever Medications
 Rapid-acting inhaled β2-agonists
 Systemic glucocorticosteroids
 Anticholinergics
 Theophylline
 Short-acting oral β2-agonists

27. Controller Medications
 Inhaled glucocorticosteroids
 Leukotriene modifiers
 Long-acting inhaled β2-agonists in combination
with inhaled glucocorticosteroids
 Systemic glucocorticosteroids
 Theophylline
 Cromones
 Anti-IgE

28. 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

29. Medications used for acute relief of symptoms

30. • 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).

31. • 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.

32. • Oral SABA are generally discouraged.
• Anticholinergic agents, mainly ipratropium,
are second-line relievers, but are less
effective than SABA.

33. Medications used for long-term asthma
control

34. 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.

35. Inhaled steroid (ICS) dose equivalence

36. 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).

37. 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.

38. 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

39. 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.

40. Leukotriene receptor antagonists (LTRA).
PRACTALL also suggests that LTRA may
be particularly useful when the patient has
concomitant rhinitis.

41. 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.

42. 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.

43. 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.

44. 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 .

45. 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

46. 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

47. 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.

48. Strategies for asthma pharmacotherapy

49. • 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).

50. • 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).

51. • 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.

52. • Oral corticosteroids are kept as the last
resort, for very severe patients (Step 5).
• GINA includes omalizumab here.

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

54. • 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.

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

57. Assessment of exacerbation severity

58. Because of their pleiotropic anti-
inflammatory activity, initiation of ICS
therapy generally constitutes the first step of
regular treatment
(Evidence A).

59. 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

60. 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.