long term prognosis of asthma: the impact of treatment
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Long term prognosis of asthma: The impact of treatment. Mina Gaga Athens Chest Hospital. What should we measure?. Outcomes lung function reduction in symptoms and need for rescue therapy increase in asthma control days prevention of acute exacerbations and nocturnal exacerbations - PowerPoint PPT PresentationTRANSCRIPT
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