Risk of asthma and cost-effectiveness of multifaceted primary prevention of asthma

Asthma, an important chronic disease in childhood, exerts a great burden on the
society, is the main cause of school absence (2, 3) and reduces the quality of
life of entire families (4, 5). The prevalence of asthma is high. In Dutch
children, it amounts to 4% in children aged 4-5 years (6). The number of
asthma-related physician contacts and hospitalizations are high, which results
in substantial costs of treating asthma, i.e. 24.1% of the total health care
costs, of children aged 1-14 years, are spent on asthma (7).
For a substantial proportion of patients, asthma will be a lifelong condition.
Prevention of asthma will therefore result in considerable health gains and
reductions in health care resource use (costs).
Asthma is a polygenetic disease, which can be aggravated by exposure to a range
of environmental factors. This makes it extremely difficult to prevent the
disease by eliminating only one risk factor. In a recently published
meta-analysis of our group it was shown that multifaceted intervention studies
probably have a much greater chance of being successful than mono-intervention
studies (1). Therefore multifaceted primary prevention might be the best
possibility to reduce the incidence of (severe) asthma. To be able to give
advice as to whether and whom prevention should be offered, more insight is
needed into the cost-effectiveness of such programs.
The PREVASC program is a multifaceted intervention program that focuses on
primary prevention of asthma in children, who were selected prenatally and
followed-up by the general practitioner (8-19). Several other primary
prevention studies are being performed and are still in progress. However, in
most other programs only one or two single interventions are tested (20-25),
which may lead to underestimation of the effect of prevention. The current
opinion is that mono-interventions will not reduce asthma morbidity, while
multifaceted intervention studies might do (26-28). PREVASC was originally
set-up as a typical example of a multifaceted intervention program. To be able
to give advice as to whether and whom a prevention program should be offered,
information concerning which children bear the highest risk as well as the
(cost-) effectiveness of the prevention program is needed. Therefore, as part
of the PREVASC program, the RAKKER study was defined. The original scope of
RAKKER was to investigate high-risk identification and the cost-effectiveness
of the PREVASC intervention strategy.
For the RAKKER study a cohort of prenatally selected children with a negative
family history of asthma (i.e. no first-degree family members suffering from GP
registered asthma) was added to the program. The RAKKER study comprises two
parts. The first part [ZON 2100.0002] covered the prenatal period to the age of
two. In the second part (this study) the children will be studied at age six.
This second part is of great importance since definite conclusions can only be
drawn based on an objective diagnosis of asthma, which is not possible before
the age of six. The conclusions from part one are therefore only indicative for
whether asthma may occur at later age.
The results of part one show that in the first two years of life the PREVASC
program was not cost-effective. The intervention was more expensive than usual
care, and in addition, there was only a limited positive effect in this period
(appendix 1: fig.1, 2).
As the compliance to preventive measures (e.g. smoking behaviour) turned out to
be low and the room for improvement for other measures (e.g. reduction of
allergen exposure) was also very low the first results at age six show no
clinical effectiveness, in terms of asthma outcome, of the program. However,
since the follow-up of the children of the PREVASC program is incomplete (the
children with a negative family history of asthma have not been measured yet at
age six) and the fact that the total body of knowledge has to be actualised,
further analyses are necessary. As shown in the meta-analysis performed by our
group (1), multifaceted intervention studies probably have a substantially
greater chance of being successful than mono-intervention studies (appendix 2:
fig. 3, appendix 3: fig. 4). In terms of implementation, the purpose of the
second part of the RAKKER study is therefore to evaluate, at age six with an
objective (on lung function measurement based) asthma diagnosis, the value of a
*family history of asthma* as predictor for asthma and the influence and the
cost-effectiveness of the multifaceted intervention strategies compared to
mono-intervention strategies. For this purpose the clinical effectiveness data
(i.e. presence or absence of asthma) of the different intervention programs
included in the meta-analysis will be used to calculate the overall
effectiveness of mono- versus multifaceted interventions. The PREVASC and
RAKKER data will be part of these analyses. Information concerning the presence
of asthma in the PREVASC children (i.e. children with a positive family history
of asthma, which means at least one first-degree family member with GP
registered asthma) was collected previously in the OMEGA study (ZonMw
OMEGA:2100.0091, NAF OMEGA-PREVASK:3.2.99.38). Information concerning the
presence of asthma in the RAKKER children, has to be collected (this
application).
In this study a cost-effectiveness analysis from two different viewpoints, a
societal viewpoint and a health care viewpoint, will be performed. For the
calculation of the cost-effectiveness of the mono- and multifaceted
intervention strategies, the clinical effectiveness data from the
meta-analyses, including the information of the PREVASC program and information
concerning the quality of life (which will be collected in this second part of
the RAKKER study will be used in combination with the medical consumption data
and the costs of the intervention of the PREVASC program that will be collected
in the RAKKER study. Using decision analytic modelling techniques,
cost-effectiveness of mono- versus multifaceted intervention strategies will be
calculated. Starting point for this model will be both a societal and a health
care viewpoint and a six-year time horizon. In addition the discounting
principle will be applied. Besides baseline estimates of the cost-effectiveness
of mono- versus multifaceted intervention strategies probabilistic sensitivity
analysis will be performed. Effectiveness will be expressed as the number of
asthma cases at the age of six years. Besides the probabilistic analysis value
of information analysis will be performed. The process of modelling will
consist of two important steps. First, developing and validating the structure
of the model, for which purpose expert sessions will be organised. Based on the
validated model the second step will be to bring the relevant data into the
model and to perform the analyses. For interpreting the results a second expert
session will be organised to validate the model*s outcome.

The objective of RAKKER2 is to study is, in terms of implementation, to get
insight in the question 'to whom' a multifaceted primary prevention program
should be offered. Therefore, in this study the predictive value of family
history of asthma will be evaluated. In addition, the cost-effectiveness of
multifaceted primary prevention of asthma compared to mono-faceted primary
prevention will be evaluated, in order to decide whether the PREVASC program
can be implemented. To be able to perform the cost-effectiveness study the
effectiveness of all international available randomised intervention studies in
*high-risk* birth cohorts as well as the *low-risk* birth cohort of the PREVASC
program, will be used as input for the calculation of the cost-effectiveness of
primary prevention of asthma in general.

Research questions
1. What is the value of a *family history of asthma* as predictor for asthma
and what is the influence of important co-variables?
2. What is the cost-effectiveness of primary prevention of asthma using
multifaceted intervention strategies compared to mono-intervention strategies?

Approach and research population
Within the School for Public Health and Primary Care, the PREVASC research line
started in 1997 (7). The scope of this research line is multifaceted primary
(prenatally started) prevention of asthma in children. In this respect
multifaceted means intervention at several aspects (breastfeeding, mite
reduction and smoking cessation) at the same time.
The PREVASC research line consists of different studies. The, in this case,
most important studies are the PREVASC and the RAKKER study (table 1). For the
randomized PREVASC trial 441 children with a positive family history of asthma
(PFH; father, mother, brother and/or sister with asthma) were prenatally
selected and randomly assigned to an (multifaceted primary) intervention or a
control group (table 1). The intervention started prenatally in order to reach
a low house dust mite and pet allergen exposure level at the time the child was
born. In addition, the intervention focused on avoidance of prenatal and
postnatal passive smoking and on avoidance of food allergens postnatally. House
dust mite (HDM) reduction intervention started before the 7th month of
pregnancy. This intervention consisted of advice on ventilation and cleaning as
well as application of HDM impermeable covers on the parents* and children*s
bed. To prevent exposure to pet allergens, the advice was given to keep pets
outdoors from the 6th month of pregnancy. Smoking intervention consisted of
advice on smoking cessation of the mother as early as possible in pregnancy and
no smoking of the father as well as the mother in the presence of the baby
postnatally. Dietary intervention contained advice on exclusively breastfeeding
(or hypo-allergen formula feeding) for at least six months and postponing
introduction of solid food until six months after birth.
To answer the questions *to whom multifaceted primary prevention should be
offered* and whether multifaceted primary prevention is cost-effective, the
RAKKER study was added to the PREVASC research line. For this study, a cohort
study, 308 children with a negative family history of asthma (NFH; no asthma in
first-degree family members) was added (table 1).
Both the children from the PREVASC and the RAKKER study were followed
prospectively until the age of two in part one of the study. All children were
selected in a primary care setting. The RAKKER group as well as the PREVASC
control group did not get preventive advices and received usual care (according
to the Guideline of the Dutch College of General Practitioners). Information
concerning atopy, respiratory tract and asthma related morbidity, serum IgE
levels in the PREVASC and RAKKER children as well as house dust mite levels,
and information on the direct and indirect costs concerning respiratory
morbidity and the costs of the primary prevention program was collected until
the children reached the age of two.
To be able to answer the research questions of the first part, different
approaches were chosen. For the research question *What is the value of a
*family history of asthma* as predictor for asthma and what is the influence of
important co-variables?*, the PREVASC control group was compared to the RAKKER
group (table 1). For answering the research question whether multifaceted
primary prevention is already cost-effective in the first two years of life,
the prevalence of a positive family history of asthma and the relative risk of
a positive family history in the development of asthma were taken into account.
Follow-up at the age of six years is a necessary next step: a definitive asthma
diagnosis has to be assessed with objective criteria. The latter requires two
aspects: firstly the children must have reached an age at which there are no
more transient wheezers. Small children often have periods of wheezing when
they suffer from infections. These periods may have a transient character and
will not necessarily lead to the development of asthma. By the age of six the
transient character of these wheezing episodes has faded. Secondly the children
must have reached an age at which objective lung function testing is possible.
Before the age of six, spirometry, reversibility and bronchial responsiveness
cannot appropriately be performed.
Therefore in the second part of the PREVASC study, the (PFH) children were
followed until they reached the age of six. At this age asthma was diagnosed
using the outcomes of spirometry and *asthma related* morbidity. For the
children of the RAKKER study (NFH), asthma will be diagnosed in the second part
at the age of 6/7, using the same methods and criteria as in the second part of
the PREVASC study.
The asthma diagnosis is one of the most important outcome measures for the
research questions of the second part of the RAKKER study. To be able to
diagnose asthma objectively, the children must have reached an age of at least
six years, as mentioned above. This means that the conclusions concerning
asthma, from the first part of the study are only indicative for the appearance
of asthma at a later stage.
However, in terms of implementation it is also important to have insight in the
question *to whom* a multifaceted primary prevention program should be offered.
In other words, which children bear the highest risk to develop asthma?
Therefore the value of a *family history of asthma* as predictor for asthma and
the influence of important co-variables will be studied?
As shown in a meta-analysis of our group (1), in which all available randomised
international intervention studies in birth cohorts with a positive family
history were compared, multifaceted primary prevention studies seem to be
effective. In addition it seems that multifaceted primary prevention studies
have a higher chance to be successful as compared to mono-intervention primary
prevention studies.
If this is the case, multifaceted primary prevention might even be more
cost-effective compared to mono-intervention. With respect to the possible
implementation of multifaceted primary prevention, it is important to know the
financial consequences of multifaceted primary prevention of asthma in
children. Until now this information is lacking.
Based on the above mentioned results we decided to place the cost-effectiveness
research question, for the second part of the RAKKER study, into a broader
perspective and study *whether multifaceted primary prevention is
cost-effective compared to mono-faceted primary prevention. By use of the data
collected already in the first part of the PREVASC and RAKKER studies, as well
as in the second part of the PREVASC study, the data from the literature and
the data that will be collected in the second part of the RAKKER study this
research question can be answered.
The indirect costs were collected prospectively over the first two years, for
both the PREVASC and the RAKKER children. At the age of six the indirect costs
were collected retrospectively over the past three months for the PREVASC
children. For the RAKKER children these costs at age 6/7 will be collected in
the same manner. It is however, not expected that there is an important
fluctuation in the indirect costs during years 3-6, which was expected in the
first two years, the period from which we have prospective data. Concerning the
direct costs, information is available for the complete study period (first and
second part).
Due to the lack of, part of, the indirect costs and the accompanying
uncertainty, the cost-effectiveness analysis will be performed in two ways,
based on a society perspective and based on a health care perspective.
To be able to analyse the data adequately and objectively, it is important to
include the information concerning the appearance of asthma at age 6/7 of
children with a negative family history (NFH; the RAKKER children). This
information will be collected in the second part of the RAKKER study.
With the available information we are able to perform a cost-effectiveness
study, using interpolation techniques and regression analysis. In addition we
are able to perform a *cost-consequence* study. Based on the fact that, in this
specific field, there are no economic evaluations yet, we think that our
research question is of additional value on the scientific knowledge and
societal applicability in this field.
Another important aspect is the fact that these kind of studies are very time
consuming and costly. Currently we have the availability of information
concerning morbidity and costs over the first six years of children with a
positive family history asthma. To be able to perform the second part of the
RAKKER study we only have to add the information of children with a negative
family history of asthma (the RAKKER children).

Time frame
December 2008 - January 2009: Sending questionnaires
February 2009-December 2010 Blood sampling and lung function, bronchial
responsiveness
Start: data-entry, data-cleaning
Preparation publications
Developing and validating the cost-effectiveness model

November 2009 - December 2010-October 2011: Data-entry, data-cleaning,
statistical analyses
Populating the cost-effectiveness model and running the model analyses
Writing publications/thesis


Table 1: PREVASC research line (PREVASC and RAKKER studies)
PREVASC researchline
TRIAL COHORT
PFH(1) NFH(2)
Randomisation

Intervention (n=222) Control (n=221) (n=308)
PREVASC
RAKKER
Study
Study
1st part Prenatal Measurement Measurement 1st part Prenatal
Measurement
birth Measurement Measurement birth Measurement
1 year Measurement Measurement 1 years Measurement
2 years Measurement Measurement 2 years Measurement
3 years Measurement Measurement
4 years Measurement Measurement
5 years Measurement Measurement
6 years Measurement Measurement 6-7 years Measurement

(1)PFH: children with a positive family history of asthma
(2)NFH: children with a negative family history of asthma

In this study a lungfunctionmeasurement will be performed, in young children,
to diagnose possible asthma. In advance to measurement of FEV1 and FVC a
reversibility test with salbutamol will be performed. Those children who report
'asthma related' morbidity, but turn out not to be reversible, will be invited
to visit the Academic Hospital Maastricht, to undergo a histamin provocation
test. It is expected that about 10% of all the children (n=30) will be invited
to undergo a histamin provocation test.

In IgE measurement will be performed in all children. By use of a fingerprick a
small amount of blood will be collected for the measurement of IgE (total and
specific against house dust mite, cat and dog allergens).

It is not expected that the study is painfull or very aggravating for the
child. The risks of the study will be minimal, since all measurements are save
and will have, under normal circumstances, no negative consequences. The child
can get short of breath during the histamin provocation testing. Whenever this
happens, the test will be stopped immidiately and the child will receive a
bronchodilator. The measurements will be performed by trained and experienced
people.
Whenever it turns out that any test is too aggravating for the child, the test
will be stopped immediately.