1. THE WHEEZY INFANT: WILL HE BECOME AN ASTHMATIC CHILD?
Gábor Uhereczky and Éva Gács
Heim Pál Children’s Hospital Budapest 1

2. DEPARTMENT OF PULMONOLGY
Heim Pál
Children’s Hospital
Budapest, Hungary
First , let me show our hospital , this our building, and departement
DEPARTMENT OF PULMONOLGY

3. PRESCHOOL WHEEZE AND LATER ASTHMA
EPIDEMIOLOGY
PRESCHOOL WHEEZE AND LATER ASTHMA
 Wheeze - a very common childhood symptom
 1 in 3 will have an episode of wheezing before their 3rd birthday
 Less than 50% will be asthmatic later on

4. CHILDHOOD ONSET ASTHMA PHENOTYPES WENCZEL SE LANCET 2006: 368: 804-13.44
CHILDHOOD ONSET ASTHMA PHENOTYPES WENCZEL SE LANCET 2006: 368:

5. CLINICAL HETEROGENEITY OF PRESCHOOL WHEEZING Preschool wheeze syndrome
Symptom onset
<3 yr, yr, >6 yr
Symptom pattern
Viral / Persistent
Preschool wheeze syndrome
Lung function
Airway hyperreactivity
Atopy
Family history 5

6. 66
Rising # of publications on phenotypes Wheeze & phenotype & child, not genetics (N=335)
After a Pubmed search using the keywords:
Phenotypes
Asthma or wheeze &
Child or Paediatric But excluding “genetics”
This is what I found
And you immediately see that my first hopes were decieved
It shows on the x-axis the year of publication, from 1980 to 2009 and on the y axis the annual number of publications.
Although papers dealing with phenotypes in conjunction with childhood asthma were almost inexistent for many decades,
You see a steep increase during the past 10 years, with currently 40 to 50 publications appearing each year.
So I had to print them out and read them all. These are the results:
4 reviews focusing on asthma phenotypes
10 papers comparing risk factors between established phenotypes, 4 comparing prognosis and x comparing pathophysiology
Only 4 were methodological papers, trying to answer the questions of this talk.
Kuehni: asthma phenotypes, ERS 2009

7. GINA 2006*: WHEEZING PHENOTYPES
*Yearly updated guideline for diagnosis and management of asthma
Transient early wheezing
Non atopic (viral)
wheezing
Good for epidemiological studies, not helpful in everyday clinical practice a b
Persistens atopic
wheezing d c
F. Martinez: The Tuscon Children Asthma Study from 1995

8. Preschool wheezing phenotypes
ERS Task Force definitions
„Definition, assesment and treatment of wheezing disorders in preschool children: an evidence-based approach.” Brand P et al ERJ 2008;32:
Temporal pattern of wheeze
Definition
Episodic (viral) wheeze
EVW
Wheeze at discrete times
Often with evidence of viral cold
NO symptoms in between episodes
Multiple-trigger wheeze
MTW
Wheeze with discrete exacerbations
AND symptoms between episodes
Maintenance treatment is indicated Stop it when not effective!
Limitations:
- these phenotypes are not stable: 80% of children switched phenotype over a two year period of time
- the severity is out of consideration

9. Who will become asthmatic?
EVW – episodic viral wheezer
MTW – multi trigger wheezer
Who will become asthmatic? 9

10. Looking for pathological changes in preschool wheeze
Inflammation
Structural changes in the airway wall
Systemic
Airway lumen (BAL)
Airway wall
(mucosal inflammation in biopsy)
Exhaled NO
Airway remodelling

11. but increased inflammation in interval wheezers
Similar tissue eosinophilic inflammation in viral wheezers and non-wheezing controls
but increased inflammation in interval wheezers
Median age 29 months
Regardless of atopic status
Saglani MD Thesis 2006
Interval whezer = MTW after 2008

12. Similar RBM thickness in viral wheezers and non-wheezing controls,
increased RBM thickness in interval wheezers
Median age 29 months
Regardless of atopic status
Saglani MD Thesis 2006
Interval whezer = MTW after 2008

13. Clinical preschool wheeze phenotypes seem pathologically distinct
Episodic viral wheeze (stable)
Multi-trigger wheeze (stable)
No eosinophylic inflammation
No elevation of exhaled nitric oxide
No remodelling
Pathologicially resemble non-wheezing controls
Increased inflammation
BAL: neutrophilic /eosinophilic
Biopsy: eosinophilic
Elevated exhaled nitric oxide
Airway remodelling present
Pathologically resemble “asthma”
Unfortunately, stable MTW and stable EVW are relatively uncommon
However 1 to 3-year- olds wih stable MTW are at much increased risk of asthma

14. WHEN DOES ASTHMA START ? 14

15. Pathology of asthma in preschool wheeze develops after 1 & 3 years
Infants (median age 1 year)
Preschool children (median age 3 years)
Confirmed wheeze
Controls 1 2 3 4
EG2 volume density (%)
p < 0.05 NS
1.25
1.00
0.75
Eosinophils (%)
0.50
0.25
0.00
Reversible airflow obstruction
Normal lung function
There is no eosinophylic infiltration and RBM thickness before 1 yr (even in atopics)
Confirmed wheeze
Controls
0.0
2.5
5.0
7.5
10.0
RBM (mm)
p < 0.01
Normal lung function
Reversible airflow obstruction
0.0
2.5
5.0
7.5
10.0 NS
RBM (mm)
Saglani et al AJRCCM 2005
Saglani et al AJRCCM 2007

16. WHEEZING BEFORE THE AGE OF 1 WHAT IS THE FUTURE?

17. Children under 1 yr should not be treated as asthmatics (with few exceptions)

18. ATOPY ?

19.  Atopy  Early senzitisation + Severe episodes
Modified asthma predictive index (mAPI) 4 wheezing episodes and
Early senzitisation + Severe episodes
One major or minor factors
 atopic parent
 atopic dermatitis
 senzitisation with
aero-allergens
 wheezing outside colds
 eozinofils >4%
 allergic rhinitis
Decreased lung function later in childhood
Manchester Asthma and Allergy Study Pediatr Allergy Immunol 2002 Custovits A: CIPP Congress Bruges 2014 
JA Castro-Rodrigez AJRCCM 2000, NHLBI Guidelines 2007 S Chang J Allergy Clin Immunol 2013 
Increased risk of asthma in school-age
But:
Symtoms can disappear later even in early senzitised children

20. Early viral infections in atopic children (API+) and asthma development later on 259 wheezy infants followed to 6 years of age
10 fold increased risk of asthma at school-age with early RV infection
Jackson et al AJRCCM 2008;178:667-72

21. Early viral infection and later asthma
Jackson et al AJRCCM 2008;178:667-72

22. SEVERITY 22

23. J Henderson: CIPP Congress Lisboa June 22-24. 2017.

24. Oswald H. Outcome of childhood asthma in mid-adult life BMJ 1994;309:95–96 Follow up from 1969
“The more severe the asthma during the infancy, the less probable it is that the symptoms will disappear in adult life”.

25. EARLY PREVENTIVE THERAPY?25 25

26. The goal of early treatment: to change the natural history of asthma
Does such a therapy exist? 26

27. Steroids help symptoms and exacerbations,
Preventive treatment with ICS in high risk children : Guilbert n:285, Murray n:206, Bisgaard n:294
Steroids help symptoms and exacerbations,
but are not disease modifying
No preventive effect
Guilbert NEJM 2006; 354: 27

28. SUMMARY 28

29. Who will become an asthmatic child from wheezy infants. And when
Who will become an asthmatic child from wheezy infants? And when? Answer in 2017: It is difficult to predict in individual cases
Increased risk: Symptoms between wheezing episodes (especially severe) Atopy and early sensitisation Early rhinovirus infection
Wheezy children under 1 yr should not be treated as asthmatics (with few exceptions)
When?
Pathology of asthma in preschool wheeze develops between the age of 1 and 3

30. Thank You for Listening