Asthma: an international perspective

Dr Paul D. Robinson MBChB, MRCPCH, FRACP, PhD

Staff Specialist, Department of Respiratory Medicine The Children’s Hospital Westmead

Paediatric Medical Association Allergy Section conference (BLFa)

Skovde, 21st September 2017

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Overview of talk

•  Reminder of what asthma is •  Evolution of asthma

–  When does preschool wheeze become asthma? Risk factors?

–  Importance of early appropriate treatment •  Step wise approach to management •  Ongoing concerns about mortality

–  Steps being taken to address

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Definition of Asthma “ A condition of obstructive lung disease, characterized by hyper-

reactivity of the airways to a variety of stimuli, and a high degree of reversibility, either spontaneously or as a result of treatment”

•  Wheeze, shortness of breath, chest tightness and/or cough:

•  More than 1 symptom •  That vary over time (worse at night) •  That vary in intensity

•  Variable expiratory airflow limitation •  Non specific and allergenic triggers •  Associated with AHR and chronic airway

inflammation

GINA 2017; BTS 2016

Based on consensus No gold standard for asthma diagnosis ?functional definition of a syndrome

Silverman et al 1997 Lancet 2006

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Asthma pathology: Cardinal features

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Bronchodilator responsiveness

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Asthma Epidemiology •  334 million have asthma globally

•  250,000 premature deaths attributed to asthma

•  Total cost $56billion US, 20billion Euro (Eur)

•  Highest prevalence of childhood asthma = Australia, NZ, UK

•  Recent wheeze = 25% of children

•  Doctor Diagnosed asthma = 33% of children (by age 8 - 11 yrs)

•  Prevalence finally stabilised in childhood

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Asthma pathogenesis Risk of asthma is age dependent

Jackson et al Annals ATS 2014

The majority of asthma begins in the preschool years

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*TEWz,TransientEarlyWheeze;‡VIWz,Viral-InducedWheeze(or†WARI,Wheeze-AssociatedRespiratoryInfecAon)

Early life wheezing phenotypes

ALSPAC study: Henderson et al Thorax 2008

PIAMA study: Savenije et al JACI 2011

Tuscon study

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Risk Factors Risk Factors •  Family history asthma / atopy

–  CDHR3 (Enables RV-C binding and replication)

–  17q21 Genotype (TT, interaction with RV)

•  Maternal smoking (in utero) •  Early infection

–  colonization with Streptococcus –  Febrile illness –  RV LRTI especially

•  Sensitisation

Protective Factors •  Non asthmatic parents

•  Large family (3 or more siblings)

•  Living on a farm with livestock

•  Length of Breast feeding (e.g. > 4-6 mths)

•  Endotoxin exposure

•  Aboriginal (indigenous lifestyle)

Teo et al, Cell Host Microbe 2015 Bochkov et al Proc Nat Acad Sci USA 2015 Caliskan M et al. NEJM 2013

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Seasonal pattern of early life wheezing

Mostly Episodic – completely well in between •  Virus infections (espec RV, RSV, Paraflu)

imp •  Some have multi-trigger wheeze

(symptoms outside of viral respiratory infections)

Brand et al, ERJ 2008 Bisgaard et al, AJRCCM 2005 Jackson DJ et al AJRCCM 2008

RV wheeze & Asthma •  Year 1 OR 2.7 •  Year 2 OR 6.5 •  Year 3 OR 31.7

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When does histology start to look like asthma?

Saglani et al, AJRCCM 2005 A = reversible obstruction B = irreversible obstruction C = normal lung function D = school age asthma

Saglani et al, AJRCCM 2007

RBM thickness correlates with eosinophilic inflammation

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Impact of sensitisation

Jackson DJ et al. AJRCCM, 2008 Rubner et al. JACI 2017

Sensitization Leads to Viral Wheeze (the reverse does not appear to be true) Jackson et al. AJRCCM 2012

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Innate Immunity and Asthma Risk Amish vs Hutterite

•  Amish prevalence of asthma 4 x lower (5 vs 21%) –  allergic sensitisation 5x lower (7 vs. 33%) –  endotoxin levels in Amish house dust 6.8x higher

•  Differences in WBCs

•  Intranasal (inhaled) dust in mice –  Amish dust inhibits AHR and eosinophilia –  Hutterite dust didn’t

Stein et al NEJM 2016

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Potential unifying hypothesis

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Prevention: Bacterial extract •  ORBEX trial

–  36 month parallel arm, double-blind, placebo controlled trial

–  6-18 months old, at increased risk for asthma

–  Year 1-2 = Broncho-Vaxom® or placebo for 10 days per month for 2 yrs.

–  Year 3 = 12 month observation period

–  Time to occurrence of the first WLRI episode off study drug

De Benedetto Multi Resp Med 2013

ClinicalTrials.gov Identifier: NCT02148796 Oral Bacterial Extract for the Prevention of Wheezing Lower Respiratory Tract Illness (ORBEX)

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Importance of Appropriate early treatment: Lung function deficit established by 6 years

Morgan et al, AJRCCM 2005 ALSPAC study: Henderson et al Thorax 2008

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These trajectories persist its downhill from there…

Sears et al, NEJM 2003

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Low lung function leads to increased mortality

Vasquez et al AJRCCM 2017 Letter by Andy Bush and author reply

Tucson study Used 1st lung function available between 21-35 years

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Patterns of Asthma Infrequent Intermittent

Frequent Intermittent

Persistent Mild Moderate Severe

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Management of Preschool wheeze

•  Challenging age range where asthma diagnosis often unclear –  ≈1/3 of preschoolers intermittently wheeze

•  Predominantly viral triggers •  Classification of episodic wheezing and multitrigger

wheeze recently introduced Brand et al. ERJ 2008 –  Not fixed within the preschool years –  Progression/Resolution not definite beyond the preschool

years

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OCS only if hospitalised!

Brand et al ERJ 2014

“The decision to start any controller therapy is most strongly determined by the pattern, frequency and severity of symptoms”

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Don’t forget the other causes of wheeze

Bush et al. BMJ 2014

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Management of Preschool wheeze

•  Early Rx with ICS does not affect progression –  2/52 ICS (BUD 400mcg) with exacerbations for 3yrs from 1st

exacerbation Bisgaard et al. NEJM 2006 •  Mothers with doctor diagnosed asthma

–  Continuous 200mcg FLU for 2yrs from age 2-3yrs, then 1yr observation Guilbert et al. NEJM 2006

•  Positive asthma predictive index •  Negative growth effect (0.7cm)

•  Same picture in childhood asthma –  Follow up at 5 years after CAMP study Strunk et al. J Pediatr. 2009

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ICS: Disease modifying? •  411 infants (maternal asthma) •  294 budesonide vs placebo

•  n=285, 2-3 years •  Fluticasone vs placebo

Guilbert et al NEJM 2006

Better during treatment, so = effective

Bisgaard et al NEJM 2006

2 week course budesonide (400 µg/d) or placebo, initiated after 3 day episode of wheezing 3 year study

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Adapted from Barns et al. Am J Respir Crit Care Med 1998;157:S1-53.

ICS- How much?

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Impact of Long-Term ICS on Growth?

•  Impact on final adult height Kelly et al NEJM 2012 –  Mean (±SD) age 24.9±2.7

yrs –  Mean (95% CI) adult height

1.2 (1.9 to 0.5) lower in budesonide vs. placebo group (p=0.001)

CAMP study authors, NEJM 2000 Also shown by Doull et al AJRCCM 1995

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Impact can be seen in early life…

Guilbert et al NEJM 2006

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Efficacy of ICS: Metanalysis Need for OCS Symptom free days

Ducharme et al Lancet 2014

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Across more than one metanalysis.. Persistent asthma subgroup, preventing exacerbations

Kaiser SV et al. Pediatrics 2016

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Different picture in Viral-induced wheeze

Kaiser SV et al. Pediatrics 2016

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OCS: when to use? •  Metanalysis

–  11 studies (n = 1,733) - significant heterogeneity •  outpatient studies: higher hospitalization rate (RR: 2.15 [ 1.08-4.29]) •  ED studies: lower risk of hospitalization (RR: 0.58 [0.37-0.92]) •  inpatient studies: fewer additional OCS courses (RR: 0.57

[0.40-0.81])

•  Treatment with OCS in the ED or hospital may be beneficial in toddlers and preschoolers with frequent asthma/wheezing exacerbations

Castro-Rodriguez JA et al. Pediatr Pulmonol. 2016

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LTRA in Preschool wheeze: LTRI Stratification may be the key to improve outcomes

Intermittent use when unwell •  Leukotrienes elevated in urine if URTI + wheeze. •  RCT montelukast vs placebo •  2- 14 years for 7 days following

onset of viral illness

•  Results –  Reduced use of health care

resource: OR 0.65 (0.47-0.89) –  School absences reduced 37 % –  Parent time off work reduced by

33%

Intermittent use, Stratify by genes •  WAIT •  1358 1-5 year olds •  Prn LTRA, Stratify by genes •  Fewer OOH if genetically

susceptible and LTRA

Robertson et al AJRCCM 2007 Turner et al Lancet Resp Med 2014

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Neuropsychiatric side effects •  retrospective cohort study, age 1–17

years initiated on montelukast. •  nested cohort study, matched initiated

LTRA monotherapy/add on to children initiated on ICS monotherapy.

•  Non-leading parental interview for occurrence of any ADRs

•  N=106 LTRA participants –  median (IQR) age of 5 (3–8) years.

•  Incidence (95% CI) of drug cessation due to neuropsychiatric ADRs 16 (10–26)%

–  mostly occurring within 2 weeks. –  Most frequent = irritability, aggressiveness

and sleep disturbances. –  Relative risk of neuropsychiatric ADRs

associated with montelukast versus ICS was 12 (2–90).

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Increased awareness of side effects is important

•  Use LTRAs in part driven by c/o ICS side effects

•  106/223 completed the interview •  12% cessation rate LTRA if used

definitely/probably related to LTRA •  No reports of suicidal ideation

–  Only a few adolescents

•  Monitoring for neuropsychiatric ADRs should be integrated into existing asthma guidelines

•  Sufficiently common and potentially difficult to recognise in young children to require that parents be informed of these at the initiation of treatment.

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In summary

•  Increased understanding during early childhood –  Mechanisms for development for asthma –  Impact on initial school age lung function and later

adult outcomes •  Appropriate treatment may improve early school,

age lung function –  Stratification offers opportunity for further

improvement –  Awareness and discussion of potential side effects of

treatment

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Shift to symptom control (GINA, 2007)

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Step wise approach to Management

BTS guidelines 2016 National Asthma Handbook, Australia

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Paediatric asthma

WHO detailed mortality database February 2014 update

Australia

Sweden

High income

Low income

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Australian New South Wales Child Death Review Team annual report

•  increase in asthma deaths in children aged up to 17 years.

•  main identified risk factors –  low socioeconomic status –  poor follow-up care –  poor adherence to medication –  lack of written asthma action

plans –  exposure to tobacco smoke

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Deaths from childhood asthma, 2004–2013: what lessons can we learn? Van Asperen MJA 2015

•  20 children up to 17 years died from asthma in NSW –  60% deaths 10-17 years, 70% male –  Average 2 deaths/yr, however 50% in last 2 years ?cause

•  All had been diagnosed with asthma –  Most persistent asthma (80%) and atopic (90%)

•  35% history of food allergy (most confirmed on SPT) -  15% had history of anaphylaxis, prescribed or used Epipen

•  75% hospitalised in previous 5 years -  55% in year before death, 30% in past 3 months

•  All s/b GP for asthma, not regular f/u, 40% by specialist

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UK National Review of Asthma Deaths

•  46% deaths avoidable if patients better managed in the year before they died.

•  Prescribing errors widespread •  Asthma attacks poorly

managed •  Severe asthmatics not always

referred to a specialist when should have been

•  Overall quality of asthma care received by those that died judged to reflect good practice for just 4% of ≤19 years old

Published 2015

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Shift to better understanding

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Persisting concern about mortality

Pavord et al Lancet 2017

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Phenotypes vs. Endotypes

pattern recognition

understanding

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Systems medicine approach to better understanding

U-BIOPRED. Wheelock CE et al. ERJ 2013

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U-BIOPRED clinical contour plots in children

Fleming L et al. ERJ 2015

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Mechanistic pathways: Asthma

Edwards et al ERJ 2017, EARIP

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Mechanistic pathways: Asthma exacerbations

Edwards et al ERJ 2017, EARIP

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BTS 2016

Step wise approach to Mx e.g. BTS guidelines

Importance of the correct diagnosis!

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Omalizumab (Xolair) in children with uncontrolled asthma

•  improves asthma control, reduces incidence & exacn frequency

•  reduces burden of corticosteroids •  might be efficacious alternative to

OCSs (needs trial) •  few issues with tolerability

•  evidence support guideline recommendations for omalizumab as a useful add-on treatment in children ≥6 years with uncontrolled persistent allergic asthma

Chipps et al JACI 2017

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Effect of omalizumab (Xolair) on seasonal exacerbations

Busse et al NEJM 2010

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Targeting cytokines

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Mepolizumab •  Very few adolescent

patients enrolled across these studies to date (total n=28)

•  Disconnect between serum and airway eosinophilia –  75% of a cohort with

severe asthma had no serum eosinophilia but had airway eosinophilia

Ortgea et al Lancet Resp Med 2016

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“the first biologic to have substantial positive effect on two important markers of the inflammation of asthma —… blood eosinophil counts and FeNO.” “the broadest and most promising biologic for the treatment of persistent uncontrolled asthma to date” Bel accompanying editorial

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Inflammatory phenotypes guided therapy Adjuncts to current therapy

eosinophilic neutrophilic

Mixed

paucigranulocytic

IgE T2 blockers (IL4, IL5, IL13)

Macrolides Statins IL-17

Thermoplasty c-FMS kinase inhibitor

Vijverberg SJH, et al. Biologics 2013

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Macrolides in Asthma

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Multidisciplinary approach to problematic asthma

•  Based on Royal Brompton model •  Chair and Primary respiratory physician •  Complex asthma CNC and CNS 2 •  Psychological medicine and Adolescent medicine •  Allergy and Immunology •  Others as required e.g. RFU, CPU, social work, CNCs sleep medicine •  Open to the junior staff

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Compliance – The Elephant in the Room Pharma embracing electronic monitoring…

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•  Examined influence of mite allergen exposure in bedding on asthma exacerbations •  Strengths

•  sufficient sample size objectively monitor changes in acute episodes among mite-sensitized children within a 12-month window - enrolled across 14 hospitals in Northern England

•  materials used for active and placebo bedding encasings were carefully selected based on properties of fabrics known to prevent or allow the passage of allergens

•  protocol included all relevant beds (children not confined to a single bed). •  Strategy à highly significant decrease in levels of the major dust mite allergen

(Der p 1), in mattress dust of active group, maintained at 1 year.

Murray et al AJRCCM 2017 Plat-Mills accompanying editorial

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Effective and cost effective strategy

Effective intervention

Reduced exacerbations

Increased time to exacerbation

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In summary •  Despite evidence of improvements over time, ongoing

concern about asthma-related morbidity and mortality •  Recent switch to better understanding of asthma

phenotypes and endotypes –  offers improved insight into management strategies –  Highlights some limitations of previous step wise management

approaches

•  Don’t forget the simple measures –  Compliance is an ongoing issue which needs to be better

addressed –  HDM measures