Spirometry in an unselected group of 6-year-old children: the darc birth cohort study
Pediatric Pulmonology 43:806–814 (2008)
Spirometry in an Unselected Group of 6-Year-Old
Henrik Fomsgaard Kjaer, MD,1* Esben Eller, MSc,1
Summary. This study presents reference equations for spirometric parameters in 6-year-oldchildren and evaluates the ability of spirometry to discriminate healthy children from children withasthma. Baseline spirometry and respiratory symptoms were assessed in 404 childrenparticipating in a longitudinal birth cohort study. Children with known asthma, possible asthmaand a control group also performed bronchodilator measurements. At least two acceptable flow-volume curves at baseline were obtained by 368/404 children (91%). The two best values for FEV1and FVC were within 5% of each other in 88% and 83% of children, respectively. Linear regressionanalyses for 242 children included in the reference population demonstrated height to be the mainpredictor of all spirometric indices except FEV1/FVC. FEV1, FEV75, and FVC correlatedreasonably to anthropometric data in contrast to flow parameters. Gender differences were foundfor FEV1, FVC, and FEV75, but not for flow parameters. Asthma was diagnosed in 25/404 children.
Baseline lung function in healthy children and children with asthma overlapped, although asthmaticchildren could be discriminated to some extent. Bronchodilator tests showed a difference inDFEV1(mean) between healthy children and children with asthma (3.1% vs. 6.1%, P < 0.05). At acut-off point of DFEV1 ¼ 7.8%, bronchodilator tests had a sensitivity of 46% and a specificity of92% for current asthma. Spirometry including bronchodilator measurements was demonstratedto be feasible in 6-year-old children and reference values were determined. Spirometry aids thediagnosis of asthma in young children, but knowledge on sensitivity and specificity of thesemeasurements is a prerequisite. Pediatr Pulmonol. 2008; 43:806–814.
Key words: lung function tests; spirometry; reference values; preschool children;
children.3 The clinical significance of spirometry inpreschool children6–8 and in particular of bronchodilator
The diagnosis of asthma in children often represents
measurements in this age group14–16 remains unsolved.
a challenge to the clinician, as the disease presents in
The aim of this study was to evaluate the feasibility and
various ways and comprises heterogeneous symptoms.
repeatability of spirometry in an unselected cohort of
Moreover, different phenotypes of wheeze exist in
6-year-old children and to determine reference equations
preschool children with different clinical patterns and
for different spirometric indices. The purpose was
prognoses. The majority of children presenting withwheeze and cough will outgrow their symptoms,1,2 yetfor others persistent asthma will manifest. A reliable
1Department of Dermatology, Allergy Centre, Odense University Hospital,
objective tool aiding the diagnosis of asthma would
therefore be of great value. In order to evaluate dynamic
2Department of Pediatrics, Odense University Hospital, Odense, Denmark.
spirometry as such a tool in preschool children, measure-ments of lung function need to be both feasible, repeatable
The authors declare no conflicts of interests.
and reproducible.3 Furthermore, establishment of refe-rence equations and assessment of the inter-individual
Grant sponsor: John and Birthe Meyer Foundation.
biological variability of different lung function parame-
*Correspondence to: Henrik Fomsgaard Kjaer, MD, Allergy Centre,
ters are required for the interpretation of individual data
Odense University Hospital, 29 Sdr. Boulevard, Odense DK-5000,
sets. Reference equations for preschool children4–9 as
Denmark. E-mail: [email protected]
well as for school children10–13 have been published, but arecent joint publication from The American Thoracic
Received 11 February 2008; Revised 25 April 2008; Accepted 4 June 2008.
Society (ATS) and The European Respiratory Society
(ERS), emphasizes the need for development of reference
Published online 10 July 2008 in Wiley InterScience
equations that can cross from preschool- into school-age
furthermore to evaluate the discriminatory capacity of
TABLE 1— Anthropometric Data of Total Study Population
spirometry and in particular bronchodilator measurements
in differentiating children with asthma from healthy
In an ongoing non-interventional birth cohort study
of 562 unselected children concerning allergic diseases,
Numbers are expressed as mean Æ standard deviation or in %.
404 children (72%) attended the clinic at 6 years of age.
A detailed description of the establishment of the cohort
Daily volume check (and calibration if needed) was
and the mode of selection has previously been pub-
performed with a 3 L calibration syringe according to the
lished.17 No differences were found between the children
manufacturer’s instruction. Children were at rest at least
originally declining participation in the study and the
15 min prior to lung function measurements. All measure-
final cohort, nor between the cohort and the analyzed
ments were carried out by the same investigator. Standing
subsample at 6 years of age on a number of character-
height and weight without shoes were measured. Each
istics.18 Follow up examinations at 3, 6, 9, 12, 18, 36,
child was instructed thoroughly to take the deepest breath
and 72 months of age included detailed assessment of
possible and then to blow as hard, fast and for as
respiratory symptoms through extensive questionnaire
long time as possible into the mouthpiece. The technique
based interviews (regarding atopic heredity, medical
was demonstrated by the investigator repeatedly, and
history, environmental and demographic factors), clinical
before any measurements were performed the child
examination by a physician, skin-prick-testing and IgE
practiced on the mouthpiece alone under supervision.
measurements. Measurement of lung function by dynamic
Individual flow-volume curves were then made with the
spirometry was attempted in all children attending the
child standing wearing a nose clip. At least three
clinic at 6 years of age. A subgroup of healthy children
acceptable flow-volume curves were recorded whenever
suitable for the establishment of reference equations for
possible. All individual curves were visually inspected
different pulmonary function parameters was identified.
Excluded from this group were children who fulfilled atleast one of the following criteria:
(1) The flow-volume curve demonstrated a rapid rise to
peak flow and a gradual flow decrease with no signs
(1) Doctor’s diagnosis of asthma (or other chronic
of abrupt end (sharp drop of flow) or evidence of
cough or glottic closure. A distinct peak (and one
(2) Wheeze, shortness of breath or episodes of cough
(apart from upper respiratory infections) at least once
(2) The ATS start of test criterion (Vbe (volume back
within the last year or reported at least twice during
extrapolated) <0.15 L) was fulfilled.19
(3) The volume-time trace was approaching a horizontal
(3) Respiratory infection within the last 3 weeks.
(4) The duration of expiration was !1 sec.
Anthropometric data of the study population are
From acceptable curves, the highest FEV1, FEV75, and
presented in Table 1. Written consent for the study was
FVC were reported even if they were not from the same
obtained from the parents, verbal assent from the children.
curve. For the analyses of repeatability (short-term
The study protocol was approved by the local ethics
variability) these values were compared with the second
highest value of the same indices from acceptable curves.
All flow indices reported (MEF25, MEF50, MEF75,
MMEF, and PEF) were selected from the ‘‘best manoeu-vre’’ defined as the curve with the largest sum of FEV
Spirometry was performed using the MicroLoop
equipment (Micro Medical Ltd., Rochester, UK) andthe corresponding SPIDA Spirometry Software V 5.0
including a computer-animated volume driven incentive(‘‘the bubblegum kid’’). All tests were performed between
Depending on the information given in the interview
December 2004 and January 2006. All children were
about respiratory symptoms, children could be divided
completely inexperienced in performing spirometry.
(1) Children with a doctor’s diagnosis of asthma
For all three criteria, a clear subjective or objective
established before the present evaluation (at 6 years).
response to treatment with b2-agonists and/or inhaled
(2) Children with possible asthma (defined as at least
corticosteroids was demanded for the diagnosis of asthma.
one confirmatory answer to questions about wheeze,coughing episodes apart from during colds, breathing
problems or reduced physical activity within the last
Reference equations were generated through multiple
linear regression analysis assessing the relationship
(3) Children with no respiratory symptoms within the
between the spirometric indices and the explanatory
variables height, weight and gender in the healthysubpopulation. Since all children were the same age,
Children in the first two groups were submitted to
inclusion of that variable added no information. Linear
bronchodilator testing irrespective of their baseline lung
relationships between dependent and explanatory varia-
function. A control group chosen randomly as every
bles showed the best correlations (compared to quadratic,
eighth child examined with no previous respiratory
logarithmic and exponential models) evaluated by the
disease or symptoms (apart from during colds) was
explained fraction of variance (i.e., the adjusted R2) and
submitted to bronchodilator testing. Four doses of
the distribution of residuals. Regression coefficients were
Bricanyl1, AstraZeneca (0.25 mg/dose) were admini-
regarded significant when P < 0.05. The 95% prediction
stered to the child via NES-spacer1 after baseline testing
intervals were calculated as Æ2 RMSE (root mean squared
and spirometric measurements repeated 15 min later.
error) from the regression line. Z-scores defined as
The test was regarded positive if DFEV1 (as a percentage
observed value-predicted value/RMSE of the reference
of the baseline value) !12% (between the highest FEV1
population were calculated from our reference equations.
from technically acceptable pre- and post-bronchodilator
The Wilcoxon rank sum test was used for comparison
between groups. All statistical analyses were performed
If any of the above symptoms were related to physical
with Stata 9.1 (Stata Corporation, College Station, TX).
activity (or information was given on reduced physicalactivity), an exercise test was performed after the baseline
testing (and before bronchodilator measurements). Theexercise test was adjusted to the age group and interpreted
At least one acceptable flow-volume curve was
produced by 376/404 children (93%). The remainingchildren either refused measurements (n ¼ 10), were
unable to produce any acceptable curves (n ¼ 10) or theirdata were lost due to software error (n ¼ 8). At least two
All children attending the clinic at 6 years of age were
acceptable flow-volume curves were achieved by 368/404
thoroughly evaluated for asthma. If asthma was suspected
children (91%). The difference between the two best
and a clear cut diagnosis could not be obtained at the initial
curves could be demonstrated to be 5% for 88% and 83%
visit, a follow up visit was scheduled 3 months later to
repeat clinical assessment and spirometric testing. Spiro-
compared to 97% and 98% using a 10% repeatability
metric data presented in this article are exclusively from
the children’s initial visit to the clinic.
Asthma was diagnosed if one of the following criteria
The data for 368 children with at least two acceptable
(1) Recurrence of at least two of the three symptoms
flow-volume curves were used for further analysis. Of
cough, wheeze and shortness of breath within the
these children, 242 (66%) were part of the reference
previous 12 months (symptoms not triggered only by
population; 131 girls and 111 boys. Linear regression
analyses on the reference population for one explanatory
(2) Doctors diagnosis of asthma prior to follow up visit
variable (height, weight, gender) at a time, demonstrated
(in combination with ongoing treatment).
height to be the main predictor for all spirometric indices
(3) Symptoms suggestive of asthma in combination with
except for FEV1/FVC. In the analysis of FEV1 and height
a positive exercise- or bronchodilator test. Symptoms
only, the explained fraction of variance (R2) was 47% and
suggestive of asthma were isolated persistent cough,
based on a single explanatory variable the reference
wheeze or shortness of breath (apart from during
colds), exercise induced symptoms or reduced phys-ical activity.
FEV1 ¼ À1:489 þ 0:24 Â height ðcmÞ;
Fig. 1. FEV1 (L) by height (cm) for children in the reference
Fig. 2. MMEF (L/s) by height (cm) for children in the reference
population (n ¼ 242) (a) and outside the reference population
population (n ¼ 242) (a) and outside the reference population
(n ¼ 126) (b) presented with the regression line and 95%
(n ¼ 126) (b) presented with the regression line and 95%
prediction intervals. The dashed line (– – –) in (a) indicates the
prediction intervals. The dashed line (– – –) in (a) indicates the
regression line found by Eigen et al.4 for comparison.
regression line found by Eigen et al.4 for comparison.
Multivariate regression analysis with respect to height,
metric parameters based on the explanatory variables
weight and gender was then performed. For FEV1 the
inclusion of gender (in addition to height) improved R2to 52%, whereas weight added no further explanation tothe variance. Inclusion of a gender-difference in reference
equations is often done by assuming similar slope coeffi-
According to the criteria outlined, asthma was diag-
cients for girls and boys, making the regression line for
nosed in 25/404 children (6.2%) at 6 years of age. Of these,
one gender a parallel shift of the other. A more adequate
16/25 children had a doctors diagnosis of asthma before
approach would be to perform gender-specific regression
visiting the clinic, while 9/25 were diagnosed at the visit
analysis. In doing so, the addition of weight to the equation
(Table 3). Two children with asthma could not perform
proved significant for boys with a slight increase in R2
spirometry (ID 3 and 13, Table 3). Lung function
from 50% to 51%. The reference equation for boys based
parameters measured at baseline for children with asthma
overlapped the values of healthy children, although
children diagnosed with asthma at this follow up could
be separated from healthy children to some extent
The explained fraction of variance for FVC in the crude
(Figs. 1b and 2b). Depending on the cut off point chosen,
linear regression analysis was 49%, but improved in the
MMEF and MEF50 showed slightly higher discriminatory
multivariate analysis with inclusion of gender (R2 ¼ 55%)
capacity at baseline compared to FEV1, but this was not
and slightly if weight was included in addition to height
significant (data not shown). Children with asthma
and gender (R2 ¼ 57%). In the gender-specific regression
diagnosed prior to the visit could not be discriminated
analysis weight was only a significant regression co-
from the rest of the population as exemplified by FEV1 and
efficient for boys. Height was the only significant expla-
MMEF (Figs. 1b and 2b). Since the treatment of asthma in
natory variable for all flow parameters, but the explained
these children had already been initiated by a doctor, the
fraction of variance was low as exemplified by MMEF
reason for this finding is probably that a subgroup were
(R2 ¼ 9%) (Fig. 2a). Reference equations for all spiro-
treated with inhaled corticosteroids at time of testing,
TABLE 2— Regression Coefficients (With 95% Confidence Intervals [CI]) for Different Spirometric Indices in 242 HealthyChildren (111 Boys, 131 Girls) Satisfying Our Criteria for the Healthy Reference Population
*Regression coefficient not significant (P ! 0.05).
TABLE 3— Characteristics of Children Diagnosed With Current Asthma
1Current asthma, but diagnosed before the examination at 6 years of age.
2Ongoing treatment regime at time of 6 years examination. ICS: inhaled corticosteroids, b2: b2-agonists.
3Symptoms within the last year and unrelated to common colds/respiratory infections.
4Positive bronchodilator test.
5Positive exercise test.
6Asthma criterion fulfilled. Some children fulfilled more than one criterion, but listed here is the ‘‘main criteria’’ prioritized in the order 1, 2, and 3,respectively.
7Unable to perform spirometry.
8Inhaled corticosteroids prevented these children from experiencing severe symptoms within the last year (but were paused at time of 6 yearsexamination).
while the remaining children had mild asthma (treated
group. A total of 8 children (9%) in the three groups could
only with b2-agonists) and therefore normal lung function
not achieve any acceptable bronchodilator curves. The
results of all bronchodilator tests are presented in Figure 3.
The mean bronchodilator-induced change in FEV1differed between healthy subjects and those with con-
firmed asthma according to our criteria (3.1% vs. 6.1%,P < 0.05), but clearly the overlap between these groups
On the basis of information given in the interviews,
complicates the interpretation of individual results. A cut-
the 404 children could be divided into three main groups;
18 children with asthma already diagnosed before the visit
asthma from the rest of the children with bronchodilator
(of whom 16 children could be confirmed to have current
results with a specificity of 92%, but a sensitivity of only
asthma), 44 children with respiratory symptoms within the
last year apart from during colds (‘‘possible asthma’’) and342 asymptomatic children. Acceptable measurementof the bronchodilator response was possible in 16/18
children with known asthma and 34/44 children with
This study describes the assessment of baseline lung
possible asthma. In the latter group, the bronchodilator test
function and bronchodilator responses in an unselected
was omitted for 8 children, since the symptoms reported
group of 6-year-old children. Reference equations are
occurred only once and were vague and clearly not related
presented and the ability of spirometry to discriminate
to asthma. Successful measurement of the bronchodilator
healthy children from children with asthma is evaluated.
response was obtained for 33/37 children in the control
Strict quality control of all individual curves obtained
by spirometry is essential for the reliability of thesemeasurements. Some of the ATS/ERS criteria23 for theacceptability of spirometric curves are not suitable forpreschool children,24 but very intriguing work onvalidated criteria for this particular age group has recentlybeen published.3,7,24,25 Our criteria for the acceptance ofindividual curves were selected on the basis of therecommendations in these publications. The upper limitfor Vbe of 150 ml in this study (default in our software) isprobably too high in this age group, although a definitelimit still needs validation and should be used only as aguide for the mandatory visual inspection of curves.3,24,25Not all preschool children can achieve the end-of-testcriteria recommended demanding a forced expiratory time(FET) !3 sec.23 Quality control studies for our particularage group suggest a limit for FET of !1 sec (assuming noabrupt end of expiratory flow and a volume-time traceapproaching a plateau).7,24 According to the selectioncriteria described, 376/404 (93%) of the children studiedachieved one acceptable flow-volume curve, 368/404(91%) at least two. The repeatability of our measurementswas high; 88% and 83% of the children fulfilled the 5%repeatability criterion for FEV1 and FVC, respectively.
This is in agreement with Arets et al.24 (91% and 83%respectively for children <8 years), but most studiesreport lower success rates for fulfillment of this strictcriterion,5,25–27 in some cases explained by slightlyyounger study populations than ours. Almost all childrenin this age group apply to the 10% repeatabilitycriterion,4,5,25,27 as also supported by our study (97%
Fig. 3. Bronchodilator responses (DFEV1(%) of FEV1 baseline) in
and 98% for FEV1 and FVC, respectively).
four groups of children tested for different reasons. Indicated
The normative data presented in this article has
is also if a diagnosis of asthma could be confirmed accordingto the criteria described: * (Criterion 1), & (Criterion 2), and
strengths and limitations. As studies on preschool
children4–6,9,27 and school children10–13 mainly includes
younger and older children than this study, only one prior
spirometry can aid the diagnosis of asthma in some
publication include a very high number of 6-year-old
children if results are interpreted on a basis of knowledge
children.28 On the other hand, the narrow age span of our
on sensitivity and specificity of these tests. Although no
population (6.10 Æ 0.14 years) is an important limitation
parameter was found superior to FEV1 in discriminating
to the usefulness of our reference equations. Strictly, our
healthy children from children with asthma at baseline,
normative data are only suitable for use within our age
we found that MEF50 and MMEF were the most dis-
range (5.8–7.1 years) and height range (100–130.5 cm),
criminatory indices, in line with similar studies in 5- and
but since age has been shown to have little or no
7-year-old children.1,7 A few studies have published
effect on lung function parameters when adjusted for
reduced spirometric parameters in preschool children with
height,4,6,9,10,27 reference equations should primarily be
asthma and wheeze.6–8 Vilozni et al.8 interestingly found
chosen on the basis of the height range. The explained
that children with mild asthma did not differ from healthy
fraction of variance (R2) between height and FEV1 and
children regarding spirometric indices, children with
FVC respectively, varies between 0.34–0.85 for FEV1
moderate asthma had FEV1 and FVC values within the
and 0.33–0.86 for FVC in different studies 4–9 compared
healthy range, but flows at low lung volumes significantly
to our values in the crude analysis of 0.52 and 0.57 for
lower than healthy children. In children with severe
FEV1 and FVC, respectively. Low values of the explained
asthma they found all spirometric indices significantly
fraction of variance will result in wide normal values, but
reduced. These findings are highly important, but also
if the high variance is a true reflection of the healthy
underline the limitations of spirometry as a diagnostic
population, the reference values should be wide. Low
tool, since the children that are most difficult to diagnose
values could also reflect insufficient selection of curves or
overlap substantially with the healthy population regar-
insufficient efforts by the children, but if quality control
criteria are followed this should be a minor problem. Since
Our evaluation of bronchodilator testing as a discri-
no consensus has been reached on the criteria defining a
minatory tool has limitations. A positive bronchodilator
reference population, this matter relies mostly on arbitrary
test according to the definition described is used in our
(although quite similar) choices in the studies published so
diagnostic criteria for asthma with the possibility of
far. Anyhow, the identification of children with symptoms
arguing in a circle (three children are diagnosed with
in the past is far more reliable in a prospective study
asthma because they have high bronchodilator responses
recording symptoms when they occur and thereby
in combination with symptoms). Still, our results indicate
diminishing the risk of recall bias.
that there is a large overlap between healthy children and
The predicted values presented in this article are in
children with asthma, underlining the need for knowledge
agreement with most other studies on preschool children
on sensitivity and specificity of this diagnostic test. The
of the same height4,5,9 but differ from the values obtained
fact that a large proportion of the asthmatic children in our
in a large Australian cohort study.28 Eigen et al. and
study exhibits low bronchodilator responses may have
Zapletal et al. found no gender differences with respect to
different explanations. As mentioned, two-thirds of our
FEV1, whereas Nystad et al. and Joseph-Bowen et al. both
asthmatic children were diagnosed before the visit and
published gender differences very similar to our results.
half of them treated with inhaled corticosteroids with the
Our reference equations for flow parameters are also in
aim of reducing the bronchial hyperresponsiveness in
line with these studies, but as a recent published study of
these children. Furthermore, the proportion of children
5-year-old children,7 we found the correlation between
with severe asthma likely to exhibit the largest broncho-
dilator response was low in our cohort. An important study
Our evaluation of spirometry as a tool to separate
regarding the use of bronchodilator tests in children with
healthy children from children with asthma has certain
mild intermittent asthma was conducted by Dundas et al.15
strengths as well as limitations. An important strength is
They found the optimal cut-off point for previous wheeze
the extensive diagnostic work-up for asthma. Most studies
to be a 9% change in predicted FEV1 with a resulting
rely solely on questionnaire based information in defining
sensitivity of 50% and a specificity of 86%, close to the
important endpoints used for discriminatory analyses
findings in this study. Our bronchodilator results were also
and furthermore use endpoints like wheeze or a history of
confirmed by Bibi et al.14 In contrast, Marotta et al.16
asthma. The most important limitation in our analysis of
found the change in FEV1 after bronchodilation to be
the discriminatory capacity of spirometry is the size and
higher in the control group as opposed to asthmatic
the composition of the asthma group. Not only is the total
children, although not statistically significant.
number of children with asthma small, two-thirds were
All studies on the discriminatory power of lung
also diagnosed before this examination and the children
functions measurements face the same difficult obstacles.
with more severe asthma treated with inhaled cortico-
The definition of asthma needs to be precise in order to
steroids affecting their lung function measurements. With
evaluate spirometry as a diagnostic tool. On the other
these limitations borne in mind, we found that baseline
hand, the group of children with more vague symptoms is
difficult to categorize and these are exactly the children,
7. Turner SW, Craig LC, Harbour PJ, Forbes SH, McNeill G, Seaton
where spirometry could be most helpful in aiding the
A, Devereux G, Helms PJ. Spirometry in 5-year-olds-validation
of current guidelines and the relation with asthma. PediatrPulmonol 2007;42:1144–1151.
In conclusion, this study confirms the feasibility and
8. Vilozni D, Barak A, Efrati O, Augarten A, Springer C, Yahav Y,
repeatability of spirometry in 6-year-old children and
Bentur L. The role of computer games in measuring spirometry in
presents reference equations for different spirometric
healthy and ‘‘asthmatic’’ preschool children. Chest 2005;128:
parameters. Our study supports the use of baseline
spirometry and bronchodilator tests in the diagnostic
9. Zapletal A, Chalupova J. Forced expiratory parameters in healthy
preschool children (3–6 years of age). Pediatr Pulmonol 2003;
evaluation of asthma in children, although clinical
decisions must be based on knowledge of the sensitivity
10. Knudson RJ, Lebowitz MD, Holberg CJ, Burrows B. Changes in
and specificity of these tests. Future follow up examina-
the normal maximal expiratory flow-volume curve with growth
tions of the cohort will not only provide important
and aging. Am Rev Respir Dis 1983;127:725–734.
knowledge on the longitudinal development of pulmonary
11. Polgar G, Promadhat V. Pulmonary function testing in children:
techniques and standards. Philadelphia: W.B. Saunders; 1971.
function in these children, but also enable an evaluation of
lung function at 6 years of age as a predictor of subsequent
12. Quanjer PH, Stocks J, Polgar G, Wise M, Karlberg J, Borsboom
G. Compilation of reference values for lung function measure-ments in children. Eur Respir J Suppl 1989;4:184S–261S.
13. Zapletal I, Samanek M, Paul T. Lung function in children and
adolescents. Methods, reference values. Prog Respir Res 1987;22:
14. Bibi H, Montgomery M, Pasterkamp H, Chernick V. Relationship
We thank the participating families for their immense
between response to inhaled salbutamol and methacholine
commitment to the project. We also express our gratitude
bronchial provocation in children with suspected asthma. Pediatr
to nurse Isabel Mejrup for her untiring work with the
children and their families and to Professor Werner Vach
15. Dundas I, Chan EY, Bridge PD, McKenzie SA. Diagnostic
for statistical advice. Funding was obtained from The John
accuracy of bronchodilator responsiveness in wheezy children.
16. Marotta A, Klinnert MD, Price MR, Larsen GL, Liu AH. Impulse
oscillometry provides an effective measure of lung dysfunction in4-year-old children at risk for persistent asthma. J Allergy Clin
17. Johnke H, Vach W, Norberg LA, Bindslev-Jensen C, Host A,
1. Illi S, von ME, Lau S, Niggemann B, Gruber C, Wahn U.
Andersen KE. A comparison between criteria for diagnosing
Perennial allergen sensitisation early in life and chronic
atopic eczema in infants. Br J Dermatol 2005;153:352–358.
asthma in children: a birth cohort study. Lancet 2006;368:763–
18. Kjaer HF, Eller E, Høst A, Andersen KE, Bindslev-Jensen C.
(e-pub ahead of print). The prevalence of allergic diseases in an
2. Wennergren G, Amark M, Amark K, Oskarsdottir S, Sten G,
unselected group of 6 year-old children. The DARC Birth Cohort
Redfors S. Wheezing bronchitis reinvestigated at the age of
Study. Pubmed; Pediatric Allergy Immunol. 2008, March 3.
10 years. Acta Paediatr 1997;86:351–355.
19. Standardization of Spirometry, 1994 Update. American Thoracic
3. Beydon N, Davis SD, Lombardi E, Allen JL, Arets HG, Aurora P,
Society. Am J Respir Crit Care Med 1995;152:1107–1136.
Bisgaard H, Davis GM, Ducharme FM, Eigen H, Gappa M,
20. Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi
Gaultier C, Gustafsson PM, Hall GL, Hantos Z, Healy MJ, Jones
R, Coates A, van der Grinten CP, Gustafsson P, Hankinson J,
MH, Klug B, Lodrup Carlsen KC, McKenzie SA, Marchal F,
Jensen R, Johnson DC, MacIntyre N, McKay R, Miller MR,
Mayer OH, Merkus PJ, Morris MG, Oostveen E, Pillow JJ,
Navajas D, Pedersen OF, Wanger J. Interpretative strategies for
Seddon PC, Silverman M, Sly PD, Stocks J, Tepper RS, Vilozni
lung function tests. Eur Respir J 2005;26:948–968.
D, Wilson NM. An official American Thoracic Society/European
21. Vilozni D, Bentur L, Efrati O, Barak A, Szeinberg A, Shoseyov D,
Respiratory Society statement: pulmonary function testing in
Yahav Y, Augarten A. Exercise challenge test in 3- to 6-year-old
preschool children. Am J Respir Crit Care Med 2007;175:1304–
asthmatic children. Chest 2007;132:497–503.
22. Niggemann B, Jacobsen L, Dreborg S, Ferdousi HA, Halken S,
4. Eigen H, Bieler H, Grant D, Christoph K, Terrill D, Heilman DK,
Host A, Koivikko A, Koller D, Norberg LA, Urbanek R, Valovirta
Ambrosius WT, Tepper RS. Spirometric pulmonary function in
E, Wahn U, Moller C. Five-year follow-up on the PAT study:
healthy preschool children. Am J Respir Crit Care Med 2001;
specific immunotherapy and long-term prevention of asthma in
children. Allergy 2006;61:855–859.
5. Nystad W, Samuelsen SO, Nafstad P, Edvardsen E, Stensrud T,
23. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R,
Jaakkola JJ. Feasibility of measuring lung function in preschool
Coates A, Crapo R, Enright P, van der Grinten CP, Gustafsson P,
children. Thorax 2002;57:1021–1027.
Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas D,
6. Piccioni P, Borraccino A, Forneris MP, Migliore E, Carena C,
Pedersen OF, Pellegrino R, Viegi G, Wanger J. Standardisation of
Bignamini E, Fassio S, Cordola G, Arossa W, Bugiani M.
spirometry. Eur Respir J 2005;26:319–338.
Reference values of Forced Expiratory Volumes and pulmonary
24. Arets HG, Brackel HJ, van der Ent CK. Forced expiratory
flows in 3–6 year children: a cross-sectional study. Respir Res
manoeuvres in children: do they meet ATS and ERS criteria for
spirometry? Eur Respir J 2001;18:655–660.
25. Aurora P, Stocks J, Oliver C, Saunders C, Castle R, Chazipar-
27. Pesant C, Santschi M, Praud JP, Geoffroy M, Niyonsenga T,
asidis G, Bush A. Quality control for spirometry in preschool
Vlachos-Mayer H. Spirometric pulmonary function in 3- to
children with and without lung disease. Am J Respir Crit Care
5-year-old children. Pediatr Pulmonol 2007;42:263–271.
28. Joseph-Bowen J, de Klerk NH, Firth MJ, Kendall GE, Holt PG,
26. Crenesse D, Berlioz M, Bourrier T, Albertini M. Spirometry in
Sly PD. Lung function, bronchial responsiveness, and asthma in a
children aged 3 to 5 years: reliability of forced expiratory
community cohort of 6-year-old children. Am J Respir Crit Care
maneuvers. Pediatr Pulmonol 2001;32:56–61.
CURRICULUM VITAE NUNO MARIA REIS DE MATOS SILVA Setembro de 2002 Pessoais 2 Habilitações Académicas Actividade Profissional em Arquitectura Por conta de outros. 3.1.1 No atelier do Arq. Michel Nazarenko. Em Limoges, França. 3.1.2 No atelier dos Arq. os João de Almeida e Pedro Ferreira Pinto. 3.1.3 Com o Arq. Manuel Vicente. 1974/1982 3.1.4 Com o A
University of Medicine and Pharmacy “Iuliu Hațieganu” Cluj-Napoca, România HABILITATION THESIS TABLE OF CONTENT 1 ABSTRACT ________________________________________________________ 3 2 SCIENTIFIC, PROFESSIONAL AND ACADEMIC ACHIEVEMENTS _______ 8 SCIENTIFIC ACHIEVEMENTS IN THE FIELD OF PHARMACOKINETICS 8 Introduction ____________________________