MINA GAGAATHENS CHEST HOSPITAL

Long term prognosisof asthma: The impact

of treatment

What should we measure?

Outcomes lung functionreduction in symptoms and need for rescue

therapyincrease in asthma control days prevention of acute exacerbations and

nocturnal exacerbations reduction in airway hyper-responsivenessimprovement in quality of life.

Szefler and Martin, JACI, 2010

What should we measure? Exacerbations

Rogers et al, Pharmacogenomics 2009

311 children –CAMP study-4 years randomized ICS treatment

What should we measure? Lung function

Rogers et al, Pharmacogenomics 2009

Predictors of poor response during asthma therapy differ with definition of outcome

Predictors of poor response during asthma therapy differ with definition of outcome

Predictors of recurrent asthma exacerbations are distinct from predictors of poor lung function response.

A history of prior asthma exacerbations, younger age and a higher IgE level are associated with recurrent exacerbations.

Lower bronchodilator response to albuterol and specific minor alleles (RS242941 in CRHR1 and T2206C) in FCER2 are associated with poor lung function response.

Poor lung function response does not increase the risk of exacerbations and vice versa

Rogers et al, Pharmacogenomics 2009

Long term prognosis of asthma: The impact of treatment

Which are the relevant outcomes?What is the natural course and the long term risk of

asthma and which are its risk factors?o in adults and in children?

What is the long term impact of treatment botho in terms of effect o in terms of risk ?o in adults and in children?

How should we best prevent/manage?

Outcomes measured in 159 RCTs, 1998-2007

Disease activity was measured in 99% studies,

adverse effects of therapy in 85%functional status in 16%quality of life in 13%health resource utilization in 11%

No RCT’s measured the effects of ICS on long-term physical consequences of asthma

Sinha et al, PLOS one, 2008

Sinha et al, PLOS one, 2008

We should measure outcomes in the domains of

disease activityphysical consequence of diseasefunctional statussocial outcomes and quality of lifeside effects and long term consequences of

therapy health resource utilization

o But RCT’s do not give us such long term data

RCTs vs longitudinal cohorts

Info regardingrisk factors/possible preventionLong term natural historyLong term effects of treatment

Data difficult to interpret as the effects of environmental factors such as smoking and the treatment regimen are not homogeneous nor clear/measured

Cohort studies- risk factors Australian cohort

Prospective cohort study, 2,602 children enrolled prior to birth

Wheezing lower respiratory illness in the first year of life Atopy independently associated with increased risk for

current asthma at the age of 6 yrs

Children with both factors had far higher risk of developing asthma

Oddy et al, ERJ 2002

Risk-predicting factorsDutch cohort studies

Birth cohort followed 3,963 children for 8 years 11% of children had asthma at 7/8 yrs

Eight clinical parameters independently predicted asthma : male sex, post-term delivery, parental education inhaled medication, wheezing frequency, wheeze/dyspnea apart from colds, respiratory infections, eczema.

risk score (range, 0-55 points)Symptomatic children with a score of less than 10 points had a 3% risk,

whereas children with a score of 30 points or greater had a 42% risk of asthma. Caudri et al, JACI

2009

risk factors Tucson cohort

Cohort of 1246 healthy children at birth

Data at age 22 n=858Newly diagnosed 49, inactive n=74, chronic=132, no asthma= 594

One fourth of all cases of active asthma at age 22 were newly diagnosed, of which 71% females.

Late-onset and persistent wheezing in early life sensitization to Alternaria low airway function and BHR at age 6 were independently associated with chronic asthma at age 22.

Stern et al, Lancet 2008

lung function evolution Tucson cohort

Stern et al, Lancet 2008

clinical status -30yrs follow-up Dutch cohort

119 allergic asthmatic children aged 5–14 years at visit 1 (1960’s) 21–33 years at visit 2 (1980’s) 32–42 years at visit 3 (1990’s)

at visit 3 22% in complete remission 30% was in clinical remission (total 52%);

Complete remission: no asthma symptoms, no use of inhaled corticosteroids, normal lung function, and no BHR.

Clinical remission: no asthma symptoms and no use of inhaled corticosteroids

Vonk et al, Thorax 2004

Lung function decline in asthmaassociation with inhaled corticosteroids, smoking and sex- Dutch

cohort

Dijkstra et al,Thorax 2006

Lung function decline in asthmaassociation with inhaled corticosteroids, smoking and sex

Dijkstra et al, Thorax 2006

Lung function decline: association with exacerbations Groningen cohort –untreated patients

Bai et al, ERJ 2007

FEV1 reversibility in the course of asthma

Dutch cohort

After 21–33 years, 228 adults (aged 13–44 years at baseline) with a history of asthma were re-examined to assess:

risk factors for the development of irreversible airway obstruction (IAO)

At follow up, 41% did not have airway obstruction (NAO), 43% had reversible airway obstruction (RAO), and 16% had IAO; (FEV1 <80% pred. and reversibility <9% pred. )

23% had a reduced transfer coefficient.

Vonk et al, Thorax 2003

FEV1 reversibility in the course of asthma Dutch cohort

Vonk et al, Thorax 2003

80% of patients on anti-inflammatory medication still had airway obstruction, but IAO developed less frequently

Patients with RAO-asthma-like characteristics (wheezing, asthma attacks, BHR) IAO -COPD-like symptoms (cough, phlegm, dyspnoea)

Vonk et al, Thorax 2003

Long-term prognosis of asthma is goodGreek cohort

to determine the evolution of BA and to investigate possible contributing factors

163 patients 12 year follow upquestionnaireskin tests Spirometrymethacholine challenge classified into three severity groups according to GINA of

1992 as: Mild, Moderate, and Severe asthma.

Porpodis et al, J Asthma. 2009 Aug;46(6):625-31

Long-term prognosis of asthma is good-FEV1Greek cohort

Without Continuous ICS As Needed 72

74

76

78

80

82

84

86

88

90

86,4

78.3

84.4

86.4 85.7

88.6

Visit 1

Visit 2

FE

V1

% p

red

p=0,046

Porpodis et al, J Asthma. 2009 Aug;46(6):625-31

Long-term prognosis of asthma is good-FEV1Greek cohort

Long-term prognosis of BA was good The outcome was favorably influenced by male gender, early and mild onset of disease,

absence of smoking and presence of rhinitisInhaled corticosteroid use correlated with

improvement in lung function

Porpodis et al, J Asthma. 2009 Aug;46(6):625-31

impact of ICS treatment on lung functionSTART RCT

O’Byrne et al,

Impact of treatment-ICSRisk/benefit ratio

Benefit was assessed by measuring the improvement in FEV1 and methacholine FEV1 PC20

Risk was assessed by overnight plasma cortisol suppression.

Szefler and Martin, JACI, 2010

Impact of treatment-ICSRisk/benefit ratio

Maximal FEV1 response occurred with the low and medium dose ICS o not further increased by treatment with high dose

ICS. The same pattern was seen with methacholine

FEV1 PC20.

Both BDP-MDI and FP-MDI caused dose-dependent cortisol suppression.

Szefler et al, JACI, 2002

ICS- impact on growth

Skoner et al, pediatrics 2008

ICS-Variability of response

Good (>15%) FEV1 response vs poor (<5%) FEV1 response associated with

high exhaled nitric oxide,high bronchodilator response, and a low FEV1/FVC ratio before treatment.

Good (>3 doubling dilutions) improvement in methacholine PC20 vs poor (<1 doubling dilution) improvement, associated with

high sputum eosinophil levels older age of onset of asthma.

Szefler et al, JACI, 2002

Predicting Response to Inhaled Corticosteroid Efficacy (PRICE Trial)

improvements on short term inhaled steroid correlate with

albuterol reversibility

Non-responders: asthma control remained unchanged whether ICS were continued or were substituted with a placebo

Responders: maintained asthma control longer term only if maintained on inhaled steroids

Martin et al, JACI 2007

Predicting Response to Inhaled Corticosteroid Efficacy (PRICE Trial)

Martin et al, JACI 2007

Martin et al, JACI 2007

Predicting Response to Inhaled Corticosteroid Efficacy (PRICE Trial)

Impact of other medications?

LABA: The RR of death was statistically similar over time between LABA and ICS despite changes in exposure de Vries et al, ERJ 2010

Omalizumab; steroid sparing, small subset of patients Karpel et alAnn Allergy Asthma Immunol. 2010

Impact of measures other than medication?

Exclusive breastfeeding protects against asthma

Diet- fruit, low salt, normal BMILifestyle –smoking, exerciseEducation-support

Oddy et al, ERJ 2002, Willers et al, ERJ 2010

Impact of better patient/family support

60 preschool children with asthmaIntervention : extra information and support

to parents in the form of group discussions

Results: The burden on the healthcare system was minimal, the intervention group (IG) needed fewer contacts with health care providers and parents had a better quality of life.

Hederos et al, Acta paediatrica 2009

Outcomes to measure

There have been initiatives to standardize the outcomes which are measured in clinical trials.

The most notable is the OMERACT collaboration, an international network of clinicians and patients - initially formed in response to the observation that clinical trials of patients with rheumatoid arthritis conducted in the USA measured different outcomes to those conducted in Europe.

Outcomes to measure

Structured consensus techniques to determine which outcomes should be measured in clinical trials/longitudinal studies

increase the likelihood that all important outcome domains are measured

reduce the measurement of inappropriate outcomesaid comparison and synthesis of findings between

different studies

arbitrary or inconsistent outcome selection may lead to clinical trials with unnecessarily large sample sizes and reporting biases

Team work and multifaceted approachBest long term studies and outcomes