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

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

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

CHILDHOOD ONSET ASTHMA PHENOTYPES WENCZEL SE LANCET 2006: 368: 804-13. 44 CHILDHOOD ONSET ASTHMA PHENOTYPES WENCZEL SE LANCET 2006: 368: 804-13.

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

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

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

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;32:1096-110 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

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

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

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

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

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

WHEN DOES ASTHMA START ? 14

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

WHEEZING BEFORE THE AGE OF 1 WHAT IS THE FUTURE?

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

ATOPY ?

 Atopy  Early senzitisation + Severe episodes Modified asthma predictive index (mAPI) 4 wheezing episodes and Early senzitisation + Severe episodes One major or 2 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

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

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

SEVERITY 22

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

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”.

EARLY PREVENTIVE THERAPY? 25 25

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

Steroids help symptoms and exacerbations, Preventive treatment with ICS in high risk children 2006: 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: 1985-97 27

SUMMARY 28

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

Thank You for Listening