Weight, Asthma, and Bone Mineral Density

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Weight, Asthma, and Bone Mineral Density
A Prospective Follow-Up Study
after Early Childhood Wheezing
Asthma is common disease in childhood. Obesity is increasing health
problem related to asthma. The use
of inhaled corticosteroids (ICS) for
childhood asthma has steadily increased. This long term follow-up
study contains 100 children hospitalized for wheezing in infancy and
followed until 12.3 years of age. In
the present study, we evaluated the
association between overweight and
asthma, allergies and lung function
and ICS´ effect on bone mineral density at early teenage in this asthma
risk group.
dissertations | 203 | Virpi Sidoroff | Weight, Asthma, and Bone Mineral Density
Virpi Sidoroff
Weight, Asthma, and
Bone Mineral Density
Virpi Sidoroff
Weight, Asthma, and
Bone Mineral Density
A Prospective Follow-Up Study
after Early Childhood Wheezing
Publications of the University of Eastern Finland
Dissertations in Health Sciences
Publications of the University of Eastern Finland
Dissertations in Health Sciences
isbn 978-952-61-1312-8
issn 1798-5706
Weight, Asthma, and Bone Mineral Density
A Prospective Follow-Up Study after Early Childhood
Wheezing
VIRPI SIDOROFF
Weight, Asthma, and Bone Mineral Density
A Prospective Follow-Up Study after Early Childhood Wheezing
To be presented by permission of the Faculty of Health Sciences, University of Eastern Finland for
public examination in AT100, at Joensuu Campus, Joensuu
on Saturday, December 14th 2013, at 13 noon
Publications of the University of Eastern Finland
Dissertations in Health Sciences
Number 203
Department of Paediatrics, Institute of Clinical Medicine, School of Medicine
Faculty of Health Sciences
University of Eastern Finland
Joensuu
2013
Kopiojyvä Oy
Joensuu, 2013
Series Editors:
Professor Veli-Matti Kosma, M.D., Ph.D.
Institute of Clinical Medicine, Pathology
Faculty of Health Sciences
Professor Hannele Turunen, Ph.D.
Department of Nursing Science
Faculty of Health Sciences
Professor Olli Gröhn, Ph.D.
A. I. Virtanen Institute for Molecular Sciences
Faculty of Health Sciences
Professor Kai Kaarniranta, M.D., Ph.D.
Institute of Clinical Medicine, Ophthalmology
Faculty of Health Sciences
Lecturer Veli-Pekka Ranta, Ph.D. (pharmacy)
School of Pharmacy
Faculty of Health Sciences
Distributor:
University of Eastern Finland
Kuopio Campus Library
PO Box 1627
FI-70211 Kuopio, Finland
http://www.uef.fi/kirjasto
ISBN (print): 978-952-61-1312-8
ISBN (pdf): 978-952-61-1313-5
ISSN (print): 1798-5706
ISSN (pdf): 1798-5714
ISSN-L: 1798-5706
III
Author’s address:
Department of Paediatrics
North Karelia Central Hospital
JOENSUU
FINLAND
Department of Paediatrics
Institute of Clinical Medicine, School of Medicine
University of Eastern Finland
Kuopio University Hospital
KUOPIO
FINLAND
Supervisors:
Professor Matti Korppi, M.D., Ph.D.
Paediatric Research Centre
University of Tampere
TAMPERE
FINLAND
Mari Hyvärinen, M.D., Ph.D.
Department of Paediatrics
Kuopio University Hospital
KUOPIO
FINLAND
Reviewers:
Docent Outi Mäkitie, M.D., Ph.D.
Children's Hospital
Helsinki University Central Hospital
HELSINKI
FINLAND
Docent Mikael Kuitunen, M.D., Ph.D.
Children's Hospital
Helsinki University Central Hospital
HELSINKI
FINLAND
Opponent:
Docent Merja Kajosaari, M.D., Ph.D.
Children's Hospital
Helsinki University Central Hospital
HELSINKI
FINLAND
IV
V
Sidoroff, Virpi.
Weight, Asthma and Bone Mineral Density: A Prospective Follow-Up Study after Early Childhood Wheezing
University of Eastern Finland, Faculty of Health Sciences
Publications of the University of Eastern Finland. Dissertations in Health Sciences 203. 2013. 69 p.
ISBN (print): 978-952-61-1312-8
ISBN (pdf): 978-952-61-1313-5
ISSN (print): 1798-5706
ISSN (pdf): 1798-5714
ISSN-L: 1798-5706
ABSTRACT:
Growing evidence shows that overweight children face increased asthma risk. The link between asthma,
allergy, lung function, and obesity in children is unclear. Paediatric use of inhaled corticosteroids (ICS) for
asthma has steadily increased. However, knowledge of long-term safety to bone health is insufficient.
Between 1991 and 1992, 100 children, aged 1–23 months, hospitalised for wheezing were recruited to an earlyintervention bronchiolitis study. An additional 14 children were recruited and later included in the study
group. Follow-up visits organised at median ages of 4.0, 7.2, and 12.3 years consisted of medical examinations,
weight and height measurements, and skin prick tests for common indoor and outdoor allergens. Exercise
challenge tests were performed to show bronchial hyperreactivity (BHR). At the median age of 12.3 years,
bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA) and peripheral
quantitative computed tomography (pQCT). The history of ICS consumption was collected from medical
records. Cumulative doses and the duration of ICS therapy were calculated. The participation rate was 82/100
at age 7.2 and 81/100 at age 12.3 years, and 89/114 children attended the BMD study.
At 12.3 years of age, 38% of participants were asthmatic, 33% were overweight, and 20% were
obese. There was no association between previous or current overweight or obesity and asthma or BHR at 7.2
or 12.3 years of age. The current overweight was associated with decreased FEV1/FVC (forced expiratory
volume in 1 sec/forced vital capacity) at both 7.2 and 12.3 years of age and reduced flows in small airways at
12.3 years of age. The results were similar in continuous and categorised analyses, being robust to
adjustments for viral findings at study entry and asthma medication at school age.
During follow-up, 73 children received ICS medication, and 16 did not. The mean cumulative
ICS dose was 517 mg (in the range of 31–1,813 mg). The cumulative ICS dose was associated with reduced
BMD measured by DXA in the femoral neck (r = −0.320, r2 = 0.10, adj. p < 0.05), and with a lower total bone (r =
−0.177, r2 = 0.031; adj. p = 0.016), cortical (r = −0.136, r2 = 0.019, adj. p = 0.019), and trabecular (r = −0.160, r2 =
0.026; adj. p = 0.036) BMD documented by pQCT in the radius. The lumbar spine BMD and the apparent
volumetric BMD of femoral neck were reduced when ICS were used regularly before 6 years of age (adj. p <
0.05). Similar age-specific changes were not found in the radius or the tibia. No significance was found for
distal tibia. The results remain similar after adjusting with known confounding factors.
In conclusion, overweight and obesity were significant risk factors for reduced lung function at
school age in this asthma-risk group. The present study did not reveal a connection between asthma and
overweight. The use of ICS during childhood may reduce BMD measured during early teenage years.
Children suffering from early-life wheezing should avoid excessive weight gain during childhood and use the
lowest sufficient ICS dose to maintaining adequate asthma control.
National Library of Medicine Classification: WD 210, WD 300, WE 270, WS 288
Medical Subject Headings: Hypersensitivity; Asthma/Therapy; Bone Density; Bronchial Hyperreactivity;
Bronchiolitis; Child; Absorptiometry, Photon; Follow-Up Studies; Tomography, x-ray; Obesity; Airway
Obstruction; Overweight; Spirometry; Respiratory Sounds
VI
VII
Sidoroff, Virpi
Paino, astma ja luusto, seurantatutkimus varhaisen hengenahdistuksen jälkeen
Itä-Suomen yliopisto, terveystieteiden tiedekunta
Publications of the University of Eastern Finland. Dissertations in Health Sciences 203. 2013. 69 s
ISBN (print): 978-952-61-1312-8
ISBN (pdf): 978-952-61-1313-5
ISSN (print): 1798-5706
ISSN (pdf): 1798-5714
ISSN-L: 1798-5706
TIIVISTELMÄ:
Ylipainoisten lasten astmariski on lisääntynyt, mutta yhdistävät tekijät astman, allergioiden, keuhkojen
toiminnan ja ylipainon välillä ovat epäselviä. Lasten astman hoidossa hengitettävien kortikosteroidien (ICS)
käyttö on yleistä. Tiedot ICS-lääkityksen pitkäaikaishaitoista luustolle ovat puutteelliset. Vuosina 1991 - 1992
aloitettiin seurantatutkimus astman riskitekijöistä varhaisen hengenahdistuksen jälkeen. Tutkimukseen
rekrytoitiin 100, 1-23 kuukauden ikäistä, sairaalahoitoon hengenahdistuksen takia joutunutta lasta.
Tutkimuskäynnit totetutuivat 4.0, 7.2 ja 12.3 vuoden keskimääräisessä iässä sisältäen lääkärin tutkimuksen,
pituuden ja painon mittaukset ja allergiatutkimukset ihopistokokeina. Kouluiässä tutkittiin keuhkojen
toimintaa ja hyperreaktivisuutta spirometrialla ja juoksurasituskokeella. 12.3 vuoden iässä luustontiheys
tutkittiin kahdella eri radiologisella menetelmällä: Dual energy x-ray absobtiometryllä (DXA) ja perifeerisellä
kvantitatiivisella tietokonetomografialla (pQCT). ICS-kokonaisannokset ja käyttöaika laskettiin haastatelujen
ja sairaskertomusten perusteella. Luustontiheys tutkimukseen kutsuttiin mukaan 14 lasta, jotka oli rekrytoitu
mukaan tutkimukseen, mutta jotka eivät osallistuneet alun hoitotutkimukseen.
Seurantakäynneille osallistui 82/100 lasta 7.2 vuoden iässä, 81/100 lasta 12.3 vuoden iässä ja
89/114 lasta osallistui luustotutkimukseen 12.3 vuoden iässä. Lapsista 38% oli astmaatikkoja, 33% ylipainoisia
ja 20% lihavia. Astmalla tai keuhkojen hyperreaktiivisuudella ja tutkimushetken ylipainolla 12.3 tai 7.2
vuoden iässä ei todettu keskinäistä yhteyttä. Tutkimushetken ylipainolla todettiin yhteys alentuneeseen
(nopean uloshengityksen vitaalikapasiteetin ja uloshengityksen sekuntikapasiteetin suhteeseen (FEV1/FVC)
spirometriassa 7.3 ja 12.3 vuoden keskimääräisessä iässä. Pienten ilmateiden virtaus todettiin matalammaksi
ylipainoisilla lapsilla 12.3 vuoden iässä. Todetut yhteydet säilyivät merkittävinä myös vakioitaessa analyysi
varhaisen hengenahdistuksen virusetiologialla ja astmalääkityksellä kouluiässä. Seurannan aikana 73 lasta sai
jaksoittain ICS-lääkitystä, 16 lasta ei saanut tutkimusaikana ICS-lääkitystä. Keskimääräinen
kokonaislääkeannos oli 517mg (vaihteluväli 21-1813mg). ICS-annoksen ja reisiluunkaulan matalamman
luuntiheyden (DXA) välillä todettiin yhteys (r = −0.320, r2 = 0.10, vakioitu. p < 0.05). Myös ICS-annoksen ja
matalamman radiuksen (pQCT) kokonaisluuntiheyden (r = −0.177, r2 = 0.031; vakioitu. p = 0.016), kortikaalisen
(r = −0.136, r2 = 0.019, vakioitu. p = 0.019) ja trabekulaarisen (r = −0.160, r2 = 0.026; vakioitu. p = 0.036) välillä
todettiin yhteys. Lannerangan luuntiheys (DXA) oli matalampi niillä lapsilla, joilla ICS-lääkitys oli totetunut
säännöllisesti vain alle 6-vuotiaana (vakioitu. p < 0.05). Käyttöikään sidonnaisia muutoksia ei todettu
radiuksessa tai tibiassa. Tibian osalta merkittäviä yhteyksiä luustontiheyden ja ICS-lääkityksen osalta ei
löydetty. Tulokset säilyivät samanlaisina tunnetuilla sekoittavilla tekijöillä vakioimisen jälkeen.
Yhteenvetona voidaan todeta ylipainon ja lihavuuden olevan merkittävä riskitekijä
alentuneelle keuhkojen toiminnalle kouluiässä niillä lapsilla joilla on jo suurentunut astmariski. Tämä
tutkimus ei osoittanut yhteyttä astman ja ylipainon välillä. Varhaisen hengenahdistuksen jälkeen
normaalipainoon pyrkiminen edistää keuhkojen toimintaa. Lapsuudessa käytetty ICS-lääkitys voi vaikuttaa
luustontiheyteen myöhemmässä kouluiässä ja nuoruudessa. Astmalääkitystä tarvitsevilla lapsilla tulee pyrkiä
aktiivisesti pienimpään ICS-annokseen, millä hoitotasapaino säilyy hyvänä.
Yleinen Suomalainen Asiasanasto: Allergia; Astma; Bronkioliitti; Keuhkot; Luusto, Lapset; Lihavuus; Lääkehoito;
Seurantatutkimus; Spirometria; Suomi; Ylipaino
VIII
IX
To my family
X
XI
Acknowledgements
This follow-up study was carried out in Kuopio University Hospital, Department of
Pediatrics in 1992-2004. I want to thank former heads of the department of Pediatrics who
have enabled the primary study and long follow-up time. Researchers, Tiina Reijonen, MD,
PhD, Anne Kotaniemi-Syrjänen, MD, PhD collecting the previous follow up data I used in
my study, they are warmly acknowledged.
I am honored I got Professor Matti Korppi, MD, PhD as my primary supervisor. He is the
heart and soul of this long follow up study. His guidance to the fascinating world of
research has been dedicated, warm and always encouraging. The research skills he has
taught me helped me until the end of the project and reach forward. I would like to thank
him also for companionship when travelling to congresses and our friendship that grew
during those days. It has been a pleasure to work under his guidance.
I own my deepest thanks to my second supervisor Mari Ylinen, MD, PhD for introducing
me to the data she carefully collected. I learned from her the practical skills of research
work and the conventions of presenting research to academic audiences. She has been an
excellent help and support during this project and I revere her skill to notice all incoherence
in manuscripts. She is also a dear friend of mine, which I found especially precious.
I am grateful to the official reviewers, Docent Outi Mäkitie, MD, PhD and Docent Mikael
Kuitunen, MD, PhD for their constructive criticism and advice which have certainly
improved these theses.
I express my sincere thanks to my co-writers: Eija Piippo-Savolainen, MD, PhD for
participating in the study design when I started this project, Liisa Kröger MD, PhD for her
large knowledge of children’s bone density and friendly discussions and support, Professor
Heikki Kröger, MD, PhD for encouragement with bone study and his knowledge on this
large area and Toni Rikkonen, PhD for doing bone mineral density measurements and
introducing the methods to me.
I want to thank Marja Ruotsalainen, MD and Katri Backman, MD who work at the parallel
study group, for sharing ideas and thoughts during the study, and for their companionship
in congresses.
My warm thanks belong also to personnel at the Department of Clinical Physiology and
Nuclear Medicine for organising the bone mineral density measurements I analysed in
these theses and all the other clinics I could trust when handling this follow up data.
I own my thanks to Vesa Kiviniemi, PhD.Lic and Marja-Leena Hannila, PhD.Lic for their
clear advice on statistical analyses. I also thank Mrs. Liisa Korkalainen and Mirja Pirinen for
their kind assistance in university and hospital conventions.
I want to express my thanks to all children taking part of this study and their families,
without you this research would not have been possible to perform.
XII
My special thanks belong to my colleagues in the North Karelia Central Hospital for their
interest in my research; their simple question: “How are things going with the study?”
mean a lot to me. I would also like to thank them for guidance in the clinical world of
paediatrics. My special thanks belongs to Marketta Dalla Valle, MD my tutor, for long
conversations we have had and friendship during these years, Tiina Reijonen, MD, PhD for
warm support and encouraging my self-confidence as researcher and head of department
Risto Lantto, MD for his reassuring comments.
I send my thanks also to Cambridge NHS University Hospital Addenbrookes to Dr.
Richard Iles under whose supervision I spend magnificent three months at the summer
2012 and learned many new things about lung development and lung function of children
and to Dr. Theodore Dassios for his companionship during research exchange.
I gratefully thank all my friends for their friendship and the wonderful moments I have
shared with you. I express my deepest thanks to my mother in law Hilkka Sidoroff, for all
the help she has offered me in household work and for taking care of our children. Without
her practical help I would not be able to complete this work.
I express my loving thanks to my parents Leena and Esko Pietikäinen, from whom I have
learned the most valuable things in life. I thank them for the love and encouragement they
give me throughout my life. Alongside them I give my loving thanks to my sisters Soile
Pietikäinen and Anu zu Dohna, for all the joys and worries you have shared with me and
all the support and unofficial English language editing you have done. I also thank their
husbands Paolo Deluca and Constantin zu Dohna and my niece Venla and nephews Lari,
Mikael and Samuel for the relaxing time I have spent with you all.
Finally, the most special thanks belong to my dear husband Mikko, who has shared life
with me and whose love and never-ending trust in my ability has carried me through these
hectic years. Mikko and our beloved children Jeremia, Katariina and Irene bring sunshine
to my life every day.
Financially this study was supported by the National Paediatric Research Foundation,
Tampere Tuberculosis Foundation, and National Graduate School for Clinical
Investigations, North Karelia Central Hospital and University of Eastern Finland, which are
sincerely acknowledged.
Joensuu, November 2013
Virpi Sidoroff
XIII
List of the original publications
This dissertation is based on the following original publications:
I
II
Sidoroff V, Hyvärinen MK, Piippo-Savolainen E, Korppi M. Overweight does not
increase asthma risk, but may decrease allergy risk at school age after infantile
bronchiolitis. Acta Paediatr. 101(1): 43–47, 2012.
Sidoroff V, Hyvärinen M, Piippo-Savolainen E, Korppi M. Lung function and
overweight in school aged children after early childhood wheezing. Pediatr.
Pulmonol. 46: 435–441, 2011.
III
Sidoroff V, Hyvärinen MK, Kröger L, Kröger H, Korppi M. Inhaled
corticosteroids and bone mineral density at school age: A follow-up study after
early childhood wheezing. Pediatr. Pulmonol. In Press.
IV
Sidoroff V, Rikkonen T, Hyvärinen MK, Kröger L, Kröger H, Korppi M. Inhaled
corticosteroids and bone mineral density by quantitative computed tomography:
11-year follow-up after early-life wheezing. Submitted
The publications were adapted with the permission of the copyright owners.
XIV
XV
Contents
1
INTRODUCTION ................................................................................................................................ 1
2
REVIEW OF THE LITERATURE .................................................................................................... 2
2.1
Wheezing illnesses in childhood ................................................................................2
2.2
Asthma in childhood ...............................................................................................2
2.2.1 Worldwide prevalence .................................................................................................................................... 2
2.2.2
Asthma phenotypes and epidemiological risk factors for asthma ............................................................ 3
2.3
Guidelines to the diagnosis and management of bonchiolitis and childhood asthma .........3
2.3.1 Diagnosis and management of bronchiolitis ................................................................................................ 3
2.3.2
Diagnosis and management of childhood asthma ...................................................................................... 4
2.4
Association between asthma, lung function, allergy and overweight in childhood ............4
2.4.1 Definitions of overweight and obesity .......................................................................................................... 4
2.4.2
Epidemiology of overweight and obesity in childhood ............................................................................. 4
2.4.3
Obesity-related illnesses in childhood .......................................................................................................... 5
2.4.4
Lung function and overweight ....................................................................................................................... 5
2.4.5
Asthma and overweight; mechanism ............................................................................................................ 6
2.4.6
Asthma and overweight studies .................................................................................................................... 8
2.4.7
Lung function and overweight studies ....................................................................................................... 12
2.4.8
Allergic diseases and overweight; mechanism .......................................................................................... 13
2.4.9
Allergy and overweight studies ................................................................................................................... 14
2.5
Bone mineral density in childhood .......................................................................... 14
2.5.1 Bone development during childhood and adolescence ............................................................................ 14
2.5.2
Risk factors for low bone mineral density .................................................................................................. 15
2.5.3
Bone mineral density measurements and low bone mineral density in childhood and adolescence 16
2.6
Inhaled corticosteroids, side effects and bone health in children ................................. 16
2.6.1 Inhaled corticosteroids and bone mineral density studies ....................................................................... 17
2.6.2
Inhaled corticosteroids and fractures .......................................................................................................... 18
2.6.3
Inhaled corticosteroids´ effect on growth ................................................................................................... 19
2.6.4
Other side effects of inhaled corticosteroids .............................................................................................. 19
3
AIMS OF THE STUDY .................................................................................................................... 20
4
SUBJECTS AND METHODS ........................................................................................................ 21
4.1
Original study design, enrolment of the patients, and background data ....................... 21
4.1.1 The early childhood intervention protocol ................................................................................................. 21
4.1.2
Virus determination ....................................................................................................................................... 21
4.2
Follow-up visits during childhood ........................................................................... 21
4.2.1 Medical examination and anthropometric measurements ....................................................................... 22
4.2.2
Definition of asthma and asthma prevalence at follow-up visits ............................................................ 22
4.2.3
Allergy tests and atopic diseases ................................................................................................................. 23
4.2.4
Risk factors for asthma in this cohort .......................................................................................................... 23
4.2.5
Lung function measurements and bronchial reactivity ............................................................................ 23
4.3
Current study design and data ............................................................................... 24
4.3.1 Definition of obesity....................................................................................................................................... 24
4.3.2
Data on inhaled corticosteroid medication ................................................................................................. 24
XVI
4.3.3
Bone mineral density measurements ........................................................................................................... 25
4.3.4
Dual-energy x-ray absorptiometry ............................................................................................................... 25
4.3.5
4.4
4.5
5
Peripheral quantitative computed tomography ......................................................................................... 26
Ethics .................................................................................................................. 26
Statistics ............................................................................................................. 26
RESULTS .............................................................................................................................................. 28
5.1
Characteristics of the study population .................................................................... 28
5.2
Relation between asthma, allergy, and overweight.................................................... 28
5.3
Influence of overweight on function at school age ..................................................... 30
5.3.1 Univariate analyses ........................................................................................................................................ 30
5.3.2
Multivariate analyses ..................................................................................................................................... 33
5.3.3
Logistic regression .......................................................................................................................................... 33
5.4
Bone mineral density by dual-energy X-ray absorbtiometry ....................................... 35
5.4.1 Effect of inhaled corticosteroids on bone mineral density in the lumbar spine and femoral neck ..... 36
5.5
Bone mineral density by peripheral quantitative computed tomography ....................... 39
5.5.1 The effect of inhaled corticosteroids to the bone mineral density in distal radius and tibia measured
by peripheral quantitative computed tomography ................................................................................................ 40
6
DISCUSSION ..................................................................................................................................... 43
6.1
Relation of overweight and ashtma, lung function, and allergy in children .................... 43
6.1.1 Asthma ............................................................................................................................................................. 43
6.1.2
Lung function .................................................................................................................................................. 44
6.1.3
Allergies ........................................................................................................................................................... 45
6.2
The effect of inhaled corticosteroids´ on bone mineral density in children .................... 45
6.2.1 Dual x-ray absorptiometry ............................................................................................................................ 45
6.2.2
Peripheral quantitative computed tomography ......................................................................................... 47
6.3
Methodological aspect ........................................................................................... 47
6.3.1 Study design .................................................................................................................................................... 47
6.3.2
Strengths of the study .................................................................................................................................... 48
6.3.3
Limitations of the study ................................................................................................................................. 49
7
CONCLUSIONS ................................................................................................................................ 50
8
REFERENCES ..................................................................................................................................... 51
ORIGINAL PUBLICATIONS (I-IV)
XVII
Abbreviations
AD
Atopic dermatitis
ANOVA
Analysis of variance
aOD
Adjusted odds ratio
AR
Allergic rhinitis and allergic
aBMDvol
FEV1
Forced expiratory volume in 1
sec
FEV1/FVC Forced expiratory volume in 1
sec/forced vital capacity
rhinoconjunctivitis
FRC
Functional residual capacity
Apparent volumetric bone
FVS
Flow-volume spirometry
mineral density
FVC
Forced
BHR
Bronchial hyperreactivity
BMI
Body mass index
BMI-SDS
BMI standard deviation score
(z-score)
vital
capacityICS
Inhaled corticosteroids
MEF50
Maximal expiratory flow at
50% of FVC
MEF25
Maximal expiratory flow at
25% of FVC
BMD
Bone mineral density
BMDareal
Areal bone mineral density
NPA
Nasopharyngeal aspiration
BMDtot
Bone mineral density of total
OR
Odds ratio
bone
PBM
Peak bone mass
Bone mineral density of
PFT
Pulmonary function test
trabecular bone
pQCT
Peripheral quantitative
BMDtrab
BMDcort
computed tomography
Bone mineral density of
cortical bone
RSV
Respiratory syncytial virus
BMC
Bone mineral content
SPT
Skin prick test
CI
Confidence interval
TBMC
Total bone mineral content
cOD
Crude odds ratio
TLC
Total lung capasity
DXA
Dual-energy X-ray
TV
Tidal volume
absorptiometry
WC
Waist circumference
ECT
Exercise challenge test
WHR
Waist–hip ratio
ERV
Expiratory reserve volume
BMDvol
Volumetric
FEno
Exhaled nitric oxide
density
bone
mineral
XVIII
1 Introduction
Wheezing illnesses during childhood are common and well-known risk factors for the
later onset of asthma (1-3). There are several phenotypes of wheezing (3). The increasing
prevalence of obesity has introduced new phenotype, obesity-induced wheezing, and later
obesity-related asthma (4). The connection between overweight and asthma has been
confirmed in epidemiological studies and meta-analyses (5,6). Overweight has an
independent mechanical effect on lung function (5), and it may decrease lung compliance
(7). In children, studies have shown that there are also benefits to lung function from
weight gain (8), depending on the age during admission (9). Allergic diseases, like atopic
dermatitis, have been associated with overweight (10), however with conflicting results
(11). The mechanism may be different from the eosinophilic inflammation seen in allergic
asthma, because obesity increases more the risk for non-atopic asthma (12). Asthma, lung
function, and allergy are all related to overweight, but the interactions and causalities are
still unknown.
Inhaled corticosteroids (ICS) are recommended widely as the first line of
therapy for asthma (13,14), and the benefits of ICS treatment are undeniable (15). Growth
retardation is the most monitored side effect of ICS medication, lately shown to cause only
minor effects on adult height (16). Although safer than systemic corticosteroids, ICS can
potentially cause detrimental effects on bone health (17). In clinical trials and follow-up
studies, ICS have been safe for bone mineral density (BMD) (18-20). In childhood asthma,
ICS medication could be long lasting and continue throughout rapid growth periods in
early childhood and teenage years when BMD accretion is also rapid (21). The long-term
consequences of decreased BMD accretion in childhood and adolescence are not known.
Dual-energy x-ray absorptiometry (DXA) and peripheral quantitative computed
tomography (pQCT), both low in radiation, are accepted methods of measuring BMD in
children (22). There are references for paediatric BMD measured with DXA but not with
pQCT, but the threshold describing significantly low BMD is not known for either method
(23,24).
The purpose of the present study was to evaluate the effect of overweight on
asthma, allergies, and lung function in children known to have a higher asthma risk after
severe early childhood wheezing and to assess the impact of ICS on BMD at the median
age of 12.3 years.
2
2 Review of the Literature
2.1 WHEEZING ILLNESSES IN CHILDHOOD
The aetiology of wheezing in early childhood is multifactorial, including virus infections,
allergies, and environmental factors (2,25). Bronchiolitis is the most common acute illness
and cause of hospitalisation in infancy (26). According to American and British guidelines,
bronchiolitis is the first respiratory viral infection with symptoms and signs of respiratory
effort and wheezing in children less than 2 years of age (27,28).
The prevalence of bronchiolitis during the first year of life is 18%–32% and
9%–17% during the second year (3,27,29). The hospitalisation rate is 1%–3%;
hospitalisation is highest among babies less than 6 months of age (30). A respiratory
syncytial virus (RSV) is the most common virus resulting in hospitalisation (31,32), and
another common aetiology of bronchiolitis in older children is a human rhinovirus, a
known risk factor for later asthma (33).
Some of the children diagnosed with bronchiolitis in infancy suffer episodic
wheezing during childhood, and some of them are diagnosed with asthma later (34).
Because of the heterogeneity in the aetiology of wheezing, the diagnosis of bronchiolitis is
used only for children less than 12 months of age in some studies (25,35) and clinical
guidelines (36,37). Actually, the first classification of acute respiratory infections in
children defined bronchiolitis as being diagnosed to children under 6 months of age (38).
2.2 ASTHMA IN CHILDHOOD
2.2.1 Worldwide prevalence
Asthma is a chronic inflammatory disease with variable airflow obstruction and bronchial
hyper responsiveness. Symptoms include recurrent episodes of wheezing, shortness of
breath, and cough (13). Asthma prevalence has increased since the 1970s (39).
According to the International Study of Asthma and Allergies in Childhood
(ISAAC), the prevalence of asthma in children 6–7 years of age varies from 4% in Northern
and Eastern Europe up to 29% in Oceania and in teenagers 13–14 years of age from 5% to
22% in the respective regions (40). Further, asthma prevalence in English-speaking centres
was 28% in childhood and 20% in teenage years (40). During the last 10 years, the
prevalence of asthma symptoms has slightly decreased or reached a plateau in Western
countries (41,42).
Asthma prevalence figures from Finland are old. The prevalence has been
between 4%–8% in 13- to 14-year-old adolescents (43). In the Kuopio region, the lifetime
prevalence of asthma in a population-based study has been estimated to be 4% in 7- to 12year-old children (44).
3
2.2.2 Asthma phenotypes and epidemiological risk factors for asthma
Childhood asthma is a multi-origin disease. Several phenotypes have been illustrated with
different origins, severities, treatments and outcomes, as summarised in recent reviews
(13,45). The common phenotypes described for wheezing and asthma during childhood
are early-onset transient, early-onset persistent and late-onset wheezing (45).
Classifications into virus-induced, allergy-induced, multi trigger, exercise-induced, and
obesity-related have also been used (13).
In the longitudinal birth cohort studies, the major risk factors for asthma and
wheezing include the parents’ history of asthma, the child´s atopy or atopic dermatitis in
the first year of life, other allergic diseases, and maternal smoking during pregnancy
(2,29,45-48). In cross-sectional paediatric studies, risk factors have been similar (3,46), and
they have emphasised the role of early immunoglobulin E (IgE) sensitisation in later
wheezing symptoms (3).
The late onset of wheezing, at over 3 years of age, has been associated with
increased asthma risk (47). Persistent wheezing has been associated with abnormalities in
lung function in children 6 years of age, which could lead to asthma in adulthood (49). The
virus infections in the first years of life, especially RSV and rhinovirus infections are risk
factors for asthma (33,50-52). Rhinovirus infections are also associated with asthma
exacerbations at all ages (53).
Recently, genetic, nutritional and environmental factors have been new
focuses of asthma studies (54,55).
2.3 GUIDELINES TO THE DIAGNOSIS AND MANAGEMENT OF
BRONCHIOLITIS AND CHILDHOOD ASTHMA
2.3.1 Diagnosis and management of bronchiolitis
There is neither an explicit diagnostic tool for bronchiolitis (26) nor consensus about
treatment; therefore, the care of patients varies between hospitals (56). The national and
international guidelines recommend that diagnosis of bronchiolitis should be based on
current epidemiologic data and clinical examination; laboratory tests and a chest x-ray
should not routinely be taken (27,57).
Management of bronchiolitis should include monitoring whether oxygen
supply and proper hydration are needed (27,57). Bronchodilators should not be used
routinely and should be continued only if there is a positive response. The routine use of
corticosteroids should also be avoided (27). Although there is evidence showing that oral
dexamethasone together with inhaled adrenaline could shorten the length of
hospitalisation (36). A meta-analysis demonstrated the effectiveness of inhaled adrenaline
alone for bronchiolitis (58), but a recently published large double blind study showed a
uniform effect between racemic adrenalin and NaCl inhalations, and an on-demand
medication was more beneficial compared to the fixed schedule (59). Inhaled hypertonic
saline is a promising new therapy (36). For severe bronchiolitis, nasal continuous positive
airway pressure (NCPAP) has been used successfully, and it might decrease the need of
intubation and ventilation in small babies (60).
4
2.3.2 Diagnosis and management of childhood asthma
There are national and international recommendations for the diagnosis and management
of childhood asthma (13,14,61). In the Finnish guidelines, asthma can be clinically
diagnosed in small children if they have had three wheezing episodes in a 1-year period,
and there are one or more risk factors for asthma (i.e., atopic disease or parental asthma
exists) (14). From 3 years of age, in both national and international guidelines, tests
showing abnormal lung function are recommended, and for school-aged children, it is
compulsory to perform spirometry and/or an exercise challenge test (ECT) for asthma
diagnosis (14,61,62).
ICS are the recommended first line of therapy for asthma in children and
adults (13,14,15). The use of ICS has improved symptom control in asthma and decreased
hospitalisation for asthma in children (15,34,63,64). Aside from and combined with ICS,
montelukast and short- and long-acting β-agonists are used for asthma medication in
children (13,14,34). ICS potentially cause side effects, and on the other hand, the common
reason for treatment failure is compliance; therefore, it is important to optimise ICS
treatment in children (65). There is evidence that the early treatment with antiinflammatory therapy could prevent irreversible airway injury and improve lung function
(65,66).
2.4 ASSOCIATION BETWEEN ASTHMA, LUNG FUNCTION, ALLERGY AND
OVERWEIGHT IN CHILDHOOD
2.4.1 Definitions of overweight and obesity
The established definitions of overweight and obesity in adults are BMI > 25 for
overweight and BMI > 30 for obesity. The definition is more complex for growing children.
Age- and sex-specific BMI cut-offs based on national references are advisable to use. If
such national references are not available, international references can be used, but that
approach is less reliable (7,67). Based on international surveys, BMI > 91st percentile has
been used to define overweight and BMI > 98th percentile to define obesity, corresponding
with BMI > 25 and BMI > 30 in young adults (7,67). Definitions vary in different studies.
For example, BMI > 95th percentile has been used as a cut-off point for overweight (68,69).
In the United States, the recommended cut-off points (70) are BMI > 85th percentile for
overweight and BMI > 95th percentile for obesity, which have been used in some studies
(69,71). The BMI percentiles can be expressed as age- and gender-specific BMI standard
deviation scores (BMI-SDS), also called z-scores.
Waist circumference (WC), waist–hip ratio (WHR), or skinfold thickness can
be used to estimate overweight and body fat content (72,73). WC has been correlated
nearly completely with age- and sex-specific BMI in children (74). Scanning methods and
bioelectrical impedance are used to measure body fat in studies (73), but not in clinical
practice.
2.4.2 Epidemiology of overweight and obesity in childhood
The prevalence of overweight and obesity is increasing in Europe (75) and worldwide
(68,69). In Europe, the prevalence of overweight varies from 10% to 36% in 7- to 11-year-
5
old children and from 8% to 23% in 14- to 17-year-old children (75). In the United States, a
plateau in the increase of overweight and obesity was reached in the 20th century (76), and
the prevalence of overweight among adolescents has stayed between 16% and 17% (69).
There is strong tracking with increased BMI from childhood and adolescence to adulthood
(77,78).
The latest prevalence figures from Finland are from 2006. At that time, 9.8% of
5-year-old boys were overweight, and 2.5% were obese. The figures were 17.7% and 2.5%,
respectively, for girls at the same age (79). At 12 years of age, the prevalence of overweight
was 23.6% and obesity 4.7% in boys, and 19.1% and 3.2% in girls, respectively (79). In the
Finnish birth cohort studies, combined information shows a trend of increased BMI in 12to15-year-old boys and in 12-year-old girls (80).
2.4.3 Obesity-related illnesses in childhood
Overweight is a growing public health issue in childhood and adolescence (72,81). Obesity
and overweight have been associated with poorer overall health, psychosocial health, as
well as health-related quality of life (81-83). Further, overweight increases health care
utilisation (84).
Overweight has been associated with low-grade inflammation, which was
thought to be the link between obesity and metabolic syndrome (85). Type 2 diabetes is
associated with obesity in adults and in children (72,86). The prevalence of non-alcoholic
fatty liver disease is increased among overweight adolescents (87). Asthma and other
respiratory illnesses and their symptoms are commonly associated with overweight
(81,84). Childhood obesity is a risk factor for cardiorespiratory diseases and is associated
with high blood pressure (88-91).
2.4.4 Lung function and overweight
Obesity causes mechanical changes in the airways, where the elasticity of the chest wall
decreases, and the airway resistance increases (7). Obesity could lead to airway smooth
muscle contraction, which induces restriction and impairment of lung function (5). In
adults, obesity decreases total lung capacity (TLC), tidal volume (TV), expiratory reserve
volume (ERV), functional residual capacity (FRC), and forced expiratory volume in 1 sec
(FEV1) (5,7,92,93). Peripheral airway obstruction due to obesity has been documented by
decreased flows at 50% of forced vital capacity (FVC) (MEF50) (93). Overall, it can be said
that the restrictive pattern of lung function disorder has been more characteristic in obesity
than the obstructive pattern.
In healthy obese children, the influence of obesity has been complex. In a
Chinese survey, lung function was studied in 2,179 schoolchildren at the median age of 10
years. Among them, asthma-presumptive symptoms were more common in obese
children, but in spirometry, FEV1 actually increased (94). In line with this, overweight had
a beneficial effect on lung function in healthy 7- to 20-year-old girls in another study (8). In
a Taiwanese study, lung function and bronchial hyperreactivity (BHR) were measured in
1,459 teenagers, and there was a decreased risk for BHR in the lowest BMI groups (95). In
a population study of 5,993 children aged 7–12 years, all variables in the spirometry were,
irrespective of BMI, within normal limits. But FEV1 and FVC in the lowest BMI quintile
6
were significantly lower than in other quintiles (96). No associations between BHR and
BMI were found, but asthma and atopy were associated with high BMI in girls (96). In the
other population study, lung function improved when weight increased in healthy 8- to
11-year-old children, but beyond that age, lung function first reached a plateau and then
decreased among the obese youths (9).
Childhood weight can affect lung function in adulthood. In a Danish
longitudinal population-based study, 193 obese and 205 non-obese men were studied, and
their age-adjusted FVC and FEV1 were compared against birth weight, weight at 7 and 13
years of age, and current weight (97). Weight at 7 years of age was positively correlated
with FEV1 and FVC in an analysis adjusted for current weight, smoking, and education.
Current overweight was strongly associated with decreased lung function in an adjusted
linear regression (97).
The exercise capacity of obese children is impaired; they have increasing
breathing effort and more dyspnoea (5). In healthy pre-teenagers, body fat has predicted
airways narrowing after exercise (98). In addition, overweight children have more
behavioural problems, and they are physically less active (99).
2.4.5 Asthma and overweight; mechanism
The epidemics of asthma and obesity have proceeded concomitantly, and plenty of studies
have evaluated the association between them. There is a consensus on the link between
obesity and asthma or respiratory symptoms (5). A meta-analysis from cohort studies
concluded that children with higher body weight are at greater risk for future asthma (6).
Obesity has been associated with more severe asthma symptoms (100-102)
and reduced responses to asthma medication (103), leading to an increased use of
medication (104). Birth weight has been associated with increased asthma risk at teenage
years (105,106), but this is not so in all studies (107). In adults, weight loss has lessened
asthma symptoms (108) and improved lung function in asthmatic patients (109).
Former studies have discussed whether obesity-related asthma is an own
asthma phenotype—asthma with non-eosinophilic inflammation and decreased response
to conventional asthma treatment (4,110).
The mechanism between obesity and asthma or lung function disorder in
children is multifactorial (Figure 1). There is some evidence that asthma and obesity might
share the same origins in early childhood (111). Common genes have been found for both
conditions (100). Early-life factors like nutrition during pregnancy, an early childhood
sedentary lifestyle, and exercise habits later might have an influence on both obesity and
asthma (5,111). The other proposed mechanisms between overweight and asthma are
reduced chest wall compliance, systemic inflammation, insulin resistance, and comorbidities like gastro-oesophageal reflux or common genetic aetiology (5).
7
Onset of
obesity
Duration of
obesity
Fat mass
Obesity
Genetics
Lean mass
IMPROVE:
Lung development
Respiratory trength
Visceral fat
Adipokines
Insulin resistance
Airway inflammation
Asthma severity
Steroid efficacy
Lung function
Figure 1. Mechanisms between obesity, asthma and lung function in children, according to
Jensen 2012 (112). Common factors can lead obesity and asthma; in obese children increased
lean mass improves lung development and increased fat mass causes negative effects on lungs
via complex pathways.
Obesity leads to low-grade inflammation and the increase of adipokines and other obesityrelated inflammatory mediators (5). Leptin, one of the adipokines, has been assumed to
modulate the connection between obesity and asthma (113), being associated with both
non-atopic (114) and atopic asthma (115). Results on other inflammatory mediators vary:
resistin had a negative association with asthma in one study (116), and low adiponectin
levels have been associated with an increased risk of allergic diseases and asthma (114),
but another study found no association (117).
The asthma symptoms related to obesity have not been associated with BHR
(100,118,119), or the results have been conflicting (119,120). Also, in studies where the
association between asthma and obesity has been evaluated together with atopic
sensitisation, the results for atopic sensitisation have been mostly negative (121,122). In
adults, obese asthmatics have had lower exhaled nitric oxide (FEno) and sputum eosinophil
levels (123). It is unlikely that allergic inflammation is the basis of the asthma-obesity
relation (12,121).
8
Obesity affects lung function itself and modifies the asthma-obesity
connection. This topic is discussed further in detail in section 3.4. Other lung-related
diseases like sleep-disordered breathing might also have an effect on obesity-related
asthma (124).
Age could be one modifying component in the asthma-obesity relation in
children, and it seems that the influence of obesity is more notable in younger children
(125,126). Sex and race might modify the relation between asthma and obesity, but the
results are too conflicting to confirm the association (104,119,127-131).
2.4.6 Asthma and overweight studies
Birth cohort studies
There are six large birth cohort studies evaluating the asthma-obesity relation in children.
The most recent prospective birth cohort study from Brazil followed 4,439 children aged
10–11 and 14–15 years (132). They assessed asthma symptoms with an ISAAC
questionnaire in both follow-up times. The prevalence of wheezing at 15 years of age and
persistent wheezing at both 11 and 15 years of age was higher in obese children in
adjusted analysis. The results were similar when obesity was measured with skinfold
thickness (132). An Australian study found a significant association between the BMI zscore at 14 years of age and a change in the z-score from 5 to 14 years of age and parentreported asthma, but the weight at 5 years of age did not predict asthma at 14 years of age
(133). The National Longitudinal Survey of Youth (NLSY), with a 14-years of follow-up
time, found an increased risk for asthma in boys—but not in girls—who were overweight
(BMI > 85th percentile) at 2–3 years of age or during the whole follow-up time (134). In
another cohort, BHR was measured, and they reported an association between persistent
or current high BMI and dyspnoea or BHR at 8 years of age (120). An earlier high BMI, if it
has become normal, was not a risk factor for either dyspnoea or BHR (120). Wheeze,
asthma, and atopy were associated with BMI in females in one birth cohort study (127).
Under school age, the risk of getting asthma diagnosis was increased in
overweight (> 85th percentile) and obese (> 95th percentile) children, especially in boys,
and in non-atopic children (135). In the birth cohort study of children with a high genetic
asthma risk, obesity at 1 year of age decreased asthma risk at 6 and 8 years of age, but
being overweight at 5 years of age increased asthma risk (136).
Population-based cohort studies
A large population-based study from the United States used medical records to collect
weight and height details and asthma diagnoses from 681,122 children at 6 to 19 years of
age, and 10.9% of children currently had asthma (104). Overweight and obese children had
higher asthma risk, and increasing weight was associated with increased corticosteroid
use and emergency department visits (104). Greek schoolchildren, 6–11 years of age were
studied in a cohort of 2,715 children; BMI > 85th percentile was an independent risk factor
for asthma, but only in girls (131). A low birth weight was associated with asthma risk and
overweight or obesity later in life amplified the risk of asthma in both girls and boys in a
large study among junior high school students in Taiwan (106).
10
5-14
14
9-26
2-16
11-12
4-11
6-14
4-11
4 393
1 000
1 179
900 1300
11 199
9 828
14 908
Age
2 911
Number
No associations
Asthma incidence in
girls
Asthma symptoms
Asthma symptoms,
BHR, medication
Asthma, ICS use,
medication
Asthma incidence,
respiratory
symptoms, lung
function
Asthma and
respiratory symptoms
Two surveys comparison,
ISAAC Questionnaire, exercise
challenge test, peak flow rate
Questionnaire, NLSCY5
Questionnaire, medical
examination, spirometry
Questionnaire
Wheeze and ICS use
in the later survey
Asthma, allergy,
ICS use
Medical record, skin prick tests,
specific IgE tests, spirometry
2
ICS use
Wheezing and
asthma in females
Asthma, allergy, BHR,
respiratory symptoms
Questionnaire, methacholine
challenge, skin prick tests,
spirometry
Asthma incidence in
boys
Asthma symptoms
Obesityassociated
findings
Asthma incidence
Asthma symptoms
End-points
Interviewing
Questionnaire
Method
The International Study of Asthma and Allergies in Childhood ISAAC
Inhaled Corticosteroids ICS
3
Bronchial hyperreactivity BHR
4
The National Longitudinal Survey of Youth NLSY
5
National Longitudinal Survey of Children and Youth NLSCY
1
Mamun, Lawlor et al. 2007
Birth cohort
Australia
Mannino, Mott et al. 2006
Birth cohort, NLSY4
US
Hancox, Milne et al. 2005
Birth cohort
New-Zeeland
Vignolo, Silvestri et al. 2005
Case-control study
Asthmatic children
North Italy
Wickens, Barry et al. 2005
Two cross-sectional surveys
New-Zeeland
To, Vydykhan et al. 2004C
ross-sectional,
US
Gold, Damokash et al. 2003
Longitudinal, prospective,
population-based
US
Figueroa-Munoz, Chinn et
al. 2001
Cross-sectional
UK
Study population
Table 1 continues
11
12
2.4.7
Lung function and overweight studies
Epidemiologic, birth cohort, cross-sectional, and case-control studies have been done to
find out how obesity modifies lung function in asthmatic children and adults. There is a
relation between asthma and obesity, but when pulmonary function and bronchial
reactivity were studied objectively, the results were mainly negative.
Birth cohort studies
In the Tucson Children’s Respiratory Study (a birth cohort of 1,246 children), lung
function, bronchodilator response, and peak expiratory flow variation were studied at 11
years of age, and respiratory symptoms and weight status were measured at 6 and 11
years of age (119). An association was revealed between weight gain before puberty and
an increased risk of new asthma diagnoses and BHR at 11 years of age (119). In another
birth cohort study from New Zealand, high BMI was associated with asthma and atopy,
but inversely associated with FEV1/FVC in 9- to 26-year-old females, and no association
between weight and BHR was found (127).
Clinical trials and case-control studies
A large clinical trial, Childhood Asthma Management study (CAMP), found an association
between higher BMI and increased FVC and FEV1, but decreased FEV1/FVC ratio (144). In
a later analysis from the CAMP study, lung function reduction was also associated with a
decreased response to inhaled budesonide in overweight and obese children compared
with normal-weight asthmatic children (103).
A case-control study from Italy compared lung functions of 118 pre-pubertal
children; the groups were obese asthmatic, normal-weight asthmatic, obese non-asthmatic,
and normal-weight non-asthmatic children (145). Asthma had an independently
significant association with lung function and airway inflammation. Obesity was related
to PEF and MEF75 in a multivariate analysis, but obesity and BRH were not related. FEno
was significantly higher in asthmatic children, but was also increased in obese nonasthmatic children compared with normal-weight non-asthmatic children, suggesting the
presence of obesity-induced pro-inflammatory changes (145). Another study with similar
groups of 7- to 11-year-old children performed the pulmonary function test in 120
children, and obese asthmatic patients had the lowest FEV1/FVC ratio when compared
with other groups (110). In an adult study, lung function was reduced in patients with
asthma and obesity, and in addition, FVC and FRC were also reduced in obese nonasthmatic adults (146).
Cross-sectional and cohort studies
Recently, a cross-sectional French study explored the relation of weight status and asthma
characteristics in 491 asthmatic children aged 6–15 years (147) and found a positive
association between weight and FVC or FEV1 in females, but overweight and obese
children had reduced TLC and residual volume/TLC (147).
In a large population-based study from Israel, obese children wheezed more
frequently, and asthma diagnoses were more common among them, but no association
between overweight or obesity and lung function was found (148). In fact, BHR was more
13
common among non-obese asthmatic children compared with obese asthmatic children
(148). In another study, peak expiratory flow rates (PEFR) from 1,322 asthmatic children
aged 4–9 years were similar in obese (> 95th percentile) and normal-weight children, but
obese children had more symptoms, emergency hospital visits, and oral corticosteroids
intake (149). In a Greek schoolchildren cohort, a high BMI was an independent risk factor
for asthma and atopy. In addition, FVC, FEV1, MEF25–75%, and FEV1/FVC were reduced
in overweight (> 85th percentile) children, but no difference was found between asthmatic
and non-asthmatic children (131). In an asthma referral population, no differences were
found in lung function between obese and normal-weight 4- to 18-year-old children (150).
In adults, obese (BMI > 30) patients with difficult-to-treat asthma had higher
FEV1% and lower FRC/TLC% than non-obese patients, with no correlation between
obesity and FEno (123). Also, an epidemiological study failed to show any association
between obesity and obstruction or BHR in a population where weight and asthma and
airway symptoms were associated with one another (151).
In summary, overweight might have an independent effect on lung function, but studies
are too controversial to make any final conclusions. Obesity seems not to provoke BHR in
children.
2.4.8 Allergic diseases and overweight; mechanism
Allergy and overweight have increased concomitantly like asthma and overweight, but
the connection is less studied. Allergic diseases were surveyed in the ISAAC study (152).
The trends in prevalence of allergic diseases varied and allergic rhinitis/rhinoconjunctivitis
(AR) and atopic dermatitis (AD) have increased more than asthma in the last decade (152).
AR prevalence in Europe varies between 2.9%–10% in younger children and between
4.5%–20% in teenagers, and AD prevalence varies between 2.5%–22% and 2%–15.6%,
respectively (152).
There are studies where atopy or allergic diseases are associated with
overweight (95,96,127,131,153), but several studies have not been able to confirm the
association (120,139,154,155). High BMI has not been an independent risk factor for allergy
when adjusted with asthma (121,122). The connection between allergic diseases and
obesity is complex and dependent on age (10) and sex (11,139). The increased eosinophilic
inflammation due to overweight is probably not the main mechanism between atopy and
overweight (12).
Fat tissue produces inflammatory mediators; these changes in inflammatory
mechanism have been assumed to explain the relation between overweight and allergic
diseases like overweight and asthma association. In a large German study, low
adiponectin levels and symptoms of AD and diagnosed AD correlated, whereas high
leptin was associated with higher incidence of non-allergic asthma, but no associations
were found between adipokines and hay fever or AR (114).
14
2.4.9 Allergy and overweight studies
Population-based studies
In the large National Health and Nutritional Examination Survey (NHANES) 2005–2006
from a cohort of over 4,000 children, overweight and obesity were associated with higher
IgE levels, and atopy and food allergies increased among obese children (153). A Japanese
questionnaire study found conflicting results; in 50,086 non-selected schoolchildren,
obesity was related to higher atopic sensitization and AD prevalence, but lower BMI was
related to higher AR and atopic conjunctivitis prevalence and the association was stronger
in boys (11). A third large population study was done in Belgium in 1,576 non-selected
schoolchildren, where atopic sensitization was increased among underweight girls, but no
association was found between obesity and allergic respiratory symptoms, AD, or AR
(139). When clinical data of 5,999 children from seven epidemiological studies were
combined, a significant association was found between allergy and overweight, but only
in girls (96).
Case-control and longitudinal birth cohort studies
In a practice-based case-control study, 414 children and adolescents with AD were
compared with 828 healthy controls aged 1–21 years during a 7-year follow-up time (10).
Early childhood obesity, starting before 5 years of age, and prolonged obesity in childhood
was risk factors for AD, and obesity was associated with more severe AD (10).
The longitudinal birth cohort follow-up study also found an association
between weight gain and AD at 5 and 8 years of age, but no association between BMI and
sensitisation in prick test was found (154). In a birth cohort study from New Zealand, 1,000
individuals were followed until 9–26 years of age, and an association was found between
higher BMI and allergy in females, but not in males (127).
Cross-sectional studies
In a multi-centre cross-sectional study of 15,454 young adults from Europe, Australia,
New Zealand, and the United States, obesity was not associated with AR or with atopic
sensitization (155). In a cross-sectional Taiwanese study of 1,459 high school children,
highest BMI quintiles had an increased risk for atopy (positive skin prick tests) and AR in
adjusted analysis, but only for females (95). The more recent Taiwanese study of
unselected schoolchildren reported a high prevalence of AR (47.8%) and eczema (10.8%)
and atopic sensitization (57.3%) measured by IgE levels (156). Allergic diseases were more
common among boys, and eczema incidence was slightly increased in obese children
(156).
In Summary, the connection between obesity and AD has been documented,
but for other atopic diseases, the results have varied.
2.5 BONE MINERAL DENSITY IN CHILDHOOD
2.5.1 Bone development during childhood and adolescence
Infancy and puberty are times of rapid bone accretion during childhood (21). Bones grow
in size in parallel with BMD accrual (157). Bone mineralisation with the modelling and
15
remodelling process is essential for normal bone growth (158). The peak bone mass (PBM)
is gained mostly during teenage years (159). The most rapid increase of BMD is at Tanner
stages 4 and 5, and bone mass accretion continues over puberty (21,160). It has been
estimated that 40%–62% of BMD is genetically determined (161). Normal skeletal
development and bone growth are dependent on multiple factors, such as balanced
nutrition, hormonal influences, and physical activity (24,158).
2.5.2 Risk factors for low bone mineral density
Race, sex, and ethnicity affect BMD. Individuals of Caucasian origin have lower BMD than
blacks, already seen in childhood and adolescence (158,162,163). Females have lower BMD
than males since adolescence, when adjusted with pubertal state (162). Late onset of
puberty is an independent risk factor for low BMD (164).
The main nutritional variables affecting BMD are calcium and vitamin D. The
American Academy of Pediatrics (AAP) guidelines recommended a daily dose of 10 µg
vitamin D (165), and the Finnish national guidelines recommend 10 µg supplementation
for children less than 2 years of age and 7.5 µg for children more than 2 years of age (166).
New studies have shown that a low vitamin D level is more detrimental to Caucasians
than blacks (163). The recommended daily calcium intake is 800–1,500 mg. An increase in
the intake of milk and other dairy products is beneficial to bone mineralisation during
childhood (167).
BMD is dependent also on physical activity (158,159,168). It has been
estimated that an active lifestyle can be responsible for up to 17% of the BMD variation
(159). How physical activity affects BMD is dependent on age and sex (161).
The impact of overweight on BMD has been controversial in previous studies.
A recent study found an overweight-related decrease of cortical BMD in adult males, and
an increase of trabecular BMD in adult females, who had overweight in adolescence (169).
In another study, a reduced bone size was associated with high fat mass in 8-18 years old
children (170). Two previous studies have reported negative results between overweight
and BMD in children and adolescents when adjusted with fat mass, lean mass, and/or
body weight (171,172). In a Finnish study, normal body fat content was beneficial to bone
health during growth, whereas both obese and low-weight children and adolescents had
lower BMD (173). Obese and overweight children and adolescents are prone to have
fractures compared with normal-weight controls, though the mechanism is unknown and
likely multifactorial (173,174). There is a remarkable tracking in BMD; children who have
low BMD are also more likely to have low BMD in adulthood if effective interventions are
not performed (175).
Chronic underlying illnesses including different neuromuscular disorders,
endocrine diseases, gastrointestinal diseases, cystic fibrosis, juvenile arthritis and
iatrogenic factors like corticosteroids and cancer treatments as well as a history of earlier
fractures are significant risk factors for decreased BMD (24,176).
16
2.5.3 Bone mineral density measurements and low bone mineral density in childhood
and adolescence
Bone is a composite tissue; it includes organic collagen and inorganic minerals forming a
bone matrix and non-bone tissue (176). Trabecular and cortical bone are arranged
differently depending on both the composition and geometrical structure. When
measuring BMD, it is important to consider the bone’s tissue type, mass, and volume
(176). During growth, the proportions of trabecular and cortical bone vary, and therefore,
the total BMD is usually used to measure BMD changes during childhood (176). The
difference between bone growth and actual BMD accretion needs attention when
measuring BMD in children. In areal BMD (BMDareal), BMD increases when the bone size
grows, though volumetric BMD (BMDvol) remains the same (176). BMDareal is highly
dependent on the bone size and height of the child, and thus, BMD is underestimated in
children of short stature (177,178). Therefore, mathematical models have been developed
to estimate apparent volumetric BMD (aBMDvol) (179,180).
DXA is the most common method for measuring BMD in children and adults.
The common sites are whole body, lumbar spine and femoral neck. DXA measures twodimensional BMDareal (g/cm2). Quantitative ultrasound (QUS) is easy to use for peripheral
bone sites like calcaneus or tibia, and no radiation is needed for measuring. However, both
bone size and cortical thickness affect the results; this is the limitation of the method (176).
pQCT allows the measurement of BMDvol (g/cm3) in radius or tibia and the evaluation of
cortical and trabecular bone separately, and, in addition, the approximation of bone
strength (176,181). The radiation dose in both DXA and pQCT is low, and it is acceptable
to use these methods for evaluating growth and development of bone in growing children
(22). In pQCT examinations, the radiation is < 3 µSv per scanning (182). The natural
background radiation in Finland is 0.04–0.30 µSv/h (183).
The International Society for Clinical Densitometry (ISCD) has published
recommendations for paediatric bone density measured by DXA (184). Age-, gender-, and
height-specific reference values should be used and presented as z-scores. Instead of
osteopenia or osteoporosis, the term “low bone mass for chronologic age” is
recommended to be used when the BMD z-score is less than −2.0 SD (184). The
osteoporosis diagnosis should be based on a clinically significant fracture history and a
low BMD in DXA measurement (177,184). The threshold for an increased fracture risk in
children is not known (24,177).
2.6 INHALED CORTICOSTEROIDS, SIDE EFFECTS AND BONE
HEALTH IN CHILDREN
ICS are the drug of choice for an anti-inflammatory therapy of asthma. Beclomethasone
dipropionate, budesonide, fluticasone propionate, and triamcinolone are in clinical use in
Finland. ICS have different efficacy and safety profiles (185). Altogether, absorption from
the lungs, absorption of swallowed ICS, and first-pass inactivation influence the level of
corticosteroids in systemic circulation and systemic side effects (185).
Systemic corticosteroids have severe side effects on bone metabolism,
mineralisation, and growth (185). Direct effects on bone tissue consist of the suppression of
17
osteoblast activity and the promotion of osteoclast activity, and indirect effects are due to
secondary hypogonadism, secondary hyperparathyroidism, and decreased secretion of
adrenal androgens (185). Corticosteroids cause a decrease in both cortical and trabecular
BMD (186). ICS have less side effects than systemic corticosteroids, and the benefits of ICS
in the treatment of asthma are undeniable (15,17). The main concerns when ICS have been
used for a long time are the potential harmful effects on children’s growth and BMD.
2.6.1 Inhaled corticosteroids and bone mineral density studies
Short-term observational studies
Most of the studies evaluating the association between ICS therapy and BMD in children
and adolescents have been cross-sectional or short-term longitudinal studies. The studies
have not been able to reveal any association between ICS use and BMD or bone
biomarkers (187-195). In these studies, BMDareal has been measured by DXA in the lumbar
spine region.
The most recent study examined 230 asthmatic pre-pubertal children and 170
controls at the median age of 8.9 years (196). Participants had used fluticasone propionate
for at least 5 years with a 200 µg mean daily dose, and controls were newly diagnosed
asthma patients with no history of ICS medication. BMD was measured from the lumbar
spine with DXA, and z-scores were compared between cases and controls. There were no
significant differences between the groups in BMD or in cortisol and osteocalcin levels
measured at the same time (196).
Density-related ultrasound was applied in one study (187). Some tendency to
reduced BMD was observed in 173 asthmatic children, among whom 56% used ICS. The
medium daily dose as fluticasone equivalents was 286 µg for 6 months, and in this group,
there were significantly more children with reduced BMD. As expected, consumed ICS
doses were dependent on asthma severity, and higher physical activity was associated
with better asthma control (187).
High-dose observational studies
The use of ICS with high doses was evaluated in two studies (197,198). In a cross-sectional
study, 49 asthmatic children aged 5–19 years who were treated with a daily dose of > 1,000
µg inhaled fluticasone propionate were compared with 32 healthy controls. There were no
significant differences in biochemical markers or in sex-specific, age-related, bone agecorrected BMD, measured from the total body and from the lumbar spine (197). In
contrast, a study of 76 pre-pubertal asthmatic children receiving budesonide propionate >
800 µg and, in addition, periodical oral corticosteroids had lower weight-adjusted BMD in
the lumbar spine compared with children receiving 400–800 µg of budesonide propionate
or no ICS at all (198). Weight was an independent predictor of BMD in multivariate
analysis (198).
Long-term observational studies
Long-term studies have not revealed significant changes in BMD in children treated with
ICS (18,19,63).
18
In the longest follow-up of children with asthma thus far, the CAMP study,
the cumulative ICS dose was associated with decreased bone mineral accretion, seen only
in boys, in 7 years’ follow-up time (18). Oral corticosteroids were allowed when necessary,
and their use produced a dose-dependent reduction in bone mineral accretion, again seen
only in boys (18).
In a Danish study, 157 asthmatic children receiving inhaled budesonide and
111 without ICS medication were followed up for 3–6 years. The total body BMD was
measured by DXA, and no significant differences were observed in BMD, bone mineral
content, total body calcium, or body composition between the groups (19).
The dependence between height and BMD needs special attention in longterm follow-up studies, in which the measured BMDareal could increase when the bone
grows without any increase in BMDvol (24).
Randomised and controlled trials
Three randomised and controlled studies were done to test the ICS effect on BMD
(20,63,199,200). In the French study, 174 children aged 6 to 14 years with persistent asthma
were randomised to receive 200 µg of inhaled fluticasone propionate or 8 mg of
nedocromil sodium daily. BMD was measured by DXA in the lumbar spine and the
femoral neck at baseline, and 12 and 24 months later, and no significant differences were
found between the groups (63).
The Finnish randomised, controlled, double-blind study included 136 children
aged 5–10 years with recently diagnosed asthma (20). Two study groups received 200 µg
of budesonide daily for 18 months or 200 µg of periodical budesonide daily when needed
based on symptoms, and the control group received disodium cromoglycate daily for 18
months. BMD in the lumbar spine was measured by DXA before and after intervention.
Daily treatment, but not periodical treatment, with budesonide diminished both BMD and
height velocity compared with the group treated with daily disodium cromoglycate.
However, the findings change to insignificant when adjusted with height. Authors
concluded that changes in BMD interacting with changes in height suggest that a followup of children´s height might give an approximation of ICS effects on bone (20).
In a 15 years old randomised, controlled, double-blind trial, 23 children
diagnosed with asthma, but without history of recurrent ICS medication, were allocated to
receive 200 µg of fluticasone propionate and 400 µg of beclomethasone per day and were
followed up for 20 months (199). DXA was performed at the baseline, and at the end of the
study, and no significant difference in BMD between groups was found (199). The clear
shortcoming of the study was the lack of control group with no ICS therapy; in addition,
confounding factors were not included in the analysis (199).
2.6.2 Inhaled corticosteroids and fractures
ICS consumption can impair on BMD, but BMD is not parallel to fracture risk in childhood
(201). Asthma is associated with an increased risk for injuries (202,203), and ICS use and
bronchodilator therapies both have been associated with an increased fracture risk in
children (201). Maybe, asthma itself, not inhaled medication to asthma, is the main factor for
19
increased fracture risk. The asthmatic children may have alterations in cortical bone geometry, not
related to therapy, but seem to be related to an increased fracture risk (204).
2.6.3 Inhaled corticosteroids´ effect on growth
Glucocorticoids inhibit growth due to the decrease in growth hormone secretion, insulinlike growth hormone secretion, and direct inhibition of collagen synthesis (205). The use of
ICS has been associated with temporary growth retardation in childhood, however with
no significant effect on height in adulthood (17,206,207). This was confirmed in a recent
review (208). Although the CAMP study reported a 1.2 cm decrease in adult height in
children who used ISC during childhood, the decrease was seen after 2 years’ treatment,
and it was not progressive or cumulative (16). There is preliminary evidence of the
benefits of a new ICS, ciclesonide, which has resulted in less growth reduction than other
ICS during the first years of treatment (208).
2.6.4 Other side effects of inhaled corticosteroids
The potential side effects of corticosteroids include adrenal insufficiency and
hypothalamus-pituitary axis insufficiency, but the risk of hypoglycaemia is small if ICS are
used with conventional doses (209,210). The risk increases if a high dose of ICS, especially
fluticasone propionate, is used for a long time aside with topical and intranasal steroids
(209). Patients using ICS have a dose-dependent risk of skin thinning and bruises as well
as a risk of a cataract in adults (17). Available data does not show an increased risk to these
less common side effects in children if low or moderate doses are used (210).
20
3 Aims of the Study
The principal aims of the present post-early-life wheezing study were to evaluate the
association between weight status and asthma, allergy, and lung function at school age
and to explore the association between the use of ICS during childhood and BMD assessed
at later school age in children who suffered from severe wheezing in infancy.
The specific aims of the study were as follows:
1. to evaluate the association between weight status and asthma or allergy at
preschool and school age after early childhood wheezing, with a special focus on
the influence of emerging overweight, including the association between weight
status and atopic sensitisation or bronchial reactivity;
2. to explore the association between overweight or obesity and lung function at
school age after early childhood wheezing, with a special focus on the influence of
an emerging overweight;
3. to study the association between the use of ICS during childhood and the BMDareal
during adolescence by DXA in the lumbar spine and femoral neck and to compare
BMDareal measurements and aBMDvol results;
4. to evaluate the association between the use of ICS during childhood and BMDvol
during adolescence by pQCT in the distal tibia and radius.
21
4 Subjects and Methods
4.1 ORIGINAL STUDY DESIGN, ENROLMENT OF THE PATIENTS, AND
BACKGROUND DATA
One hundred consecutive children hospitalised for respiratory-infection-associated
wheezing at the age of 1–23 months were recruited into this follow-up study in 1992–1993
(211). Exclusion criteria were maintenance therapy for asthma, presence of a chronic
cardiopulmonary disease or respiratory failure in admission. The wheezing episode was
the first one in 87% of the included children (211).
Background data were collected by interviewing the parents during
hospitalisation using a structured questionnaire, which included history of wheezing and
AD, family history of asthma and other atopic diseases, information on maternal smoking
during pregnancy, later exposure to tobacco smoke, and pets at home and day care
attendance (212). Seven respiratory viruses, including RSV, were studied using antigen
and antibody assays (213).
The aims of the primary study were to evaluate the acute-phase treatment of
bronchiolitis and to start the prospective follow-up study to explore the impact of an
early-life intervention with anti-inflammatory medicines, including ICS (212), and to
reveal risk factors for asthma after early-life wheezing (213).
4.1.1 The early childhood intervention protocol
After hospitalisation, children were randomised into three intervention groups; 34 were
treated with inhaled budesonide 1,000 µg per day for 8 weeks and then 500 µg per day for
a further 8 weeks, and 34 were treated for 8 weeks with 80 mg of sodium cromoglycate per
day and then 60 mg per day for a further 8 weeks (212). The control group consisted of 32
children who had no anti-inflammatory medication. The follow-up protocol included
visits at 6 and at 16 weeks and at 8 and 12 months after the beginning of the study (213).
4.1.2 Virus determination
Seven viral pathogens were studied in nasopharyngeal aspirates (NPA) and paired sera,
including both antigen and antibody tests for RSV (213). Later, frozen NPA samples were
studied by polymerase chain reaction for RSV and rhinoviruses (214,215). In all, RSV was
identified in 29 of 100 cases and rhinovirus in 27 of 81 cases (216).
4.2 FOLLOW-UP VISITS DURING CHILDHOOD
Three follow-up visits were prospectively organised after the intervention (Figure 2).
Three years after the index wheezing, 83 children attended the preschool-age visit at 4.0
years of median age (217). Six years after the index wheezing, 82 children attended the
early school-age visit at 6.3 years of median age (218). The third follow-up visit was
arranged 11 years after the index wheezing, and 81 of 100 children attended the later
school-age visit at 12.3 years of median age (50).
22
Original study
group
n=100
Control visit at 4.0 years of age
n=83
Control visit at 6.2 years of age
n=82
Control visit at 12.3 years of age
Asthma and allergy studygroup
n=81
Children recruited,
but not included in
the intervention study
n=14
Spirometry – study-group
n= 79
BMD – study-group
n= 89/82
Figure 2. Control visits, numbers of children attending the visits and the forming of study
groups of the present study.
4.2.1 Medical examination and anthropometric measurements
A research doctor performed the medical examination at all follow-up visits (50,213,216,218).
During each visit, an experienced nurse measured weight and height using a stadiometer
and a calibrated weight scale. At the late school-age visit, a pubertal stage was examined
and recorded (50,219,220). Parents and children were interviewed using a structured
questionnaire and asthma and allergic symptoms during the preceding 12 months were
recorded. Ongoing asthma medication was registered, and the use of ICS between followup visits was noted (50).
4.2.2 Definition of asthma and asthma prevalence at follow-up visits
At the preschool-age follow-up visit at 4.0 years of median age, 45 (51%) of 89 children
were considered having asthma. The criteria for asthma were as follows: the child had
continuous anti-inflammatory medication for asthma, or the child had suffered from two
or more doctor-diagnosed wheezing episodes after the index wheezing (217). In the early
school-age follow-up visit, asthma was present in 33 (40%) of 82 children. The criteria for
asthma were as follows: the child had continuous inhaled anti-inflammatory medication
for asthma, or the child had two or more parent-reported, doctor-diagnosed wheezing
episodes or parent-reported prolonged (> 4 weeks) cough without infection during the
preceding 12 months and the exercise challenge test (ECT) was pathological (218). At late
23
school-age visit, 32 (40%) of 81 children had asthma with the following criteria: the child
had continuous or intermittent inhaled anti-inflammatory medication for asthma during
the preceding 12 months, or the child had two or more parent-reported, doctor-diagnosed
wheezing episodes or prolonged (> 4 weeks) cough apart from infection during the
preceding 12 months and the ECT was pathological (50).
4.2.3 Allergy tests and atopic diseases
Allergen-specific IgE antibodies were measured at 2000, from frozen samples collected
during index wheezing (50). At the control visits, doctor-diagnosed AD and AR during the
preceding 12 months were recorded (50,217,218). Skin prick tests (SPTs) were performed at
school-age control visits against common indoor and outdoor allergens like pollens and
animal dander (50,218). The reactions with a mean diameter of at least 3 mm were defined
to be positive, and no reactions were allowed for negative controls (saline). Atopic
sensitisation was defined as the presence of at least one positive result in SPTs to indoor or
outdoor allergens (50,218).
4.2.4 Risk factors for asthma in this cohort
In the previous studies from this cohort, predictive factors for asthma at 12.3 years of
median age were AD and specific IgE sensitisation to inhalant, but not to food allergens as
group, registered during index wheezing (50). Asthma was more common in children who
were > 12 months old when hospitalised for wheezing (50). Parental asthma or atopic
diseases, or exposure to pets or maternal smoking during pregnancy, were not risk factors
for asthma during adolescence in the adjusted analysis (50). The non-RSV aetiology for
bronchiolitis was a significant risk factor for later asthma at 7.2 years of median age
(214,216).
4.2.5 Lung function measurements and bronchial reactivity
Lung function was studied using flow-volume spirometry (FVS) (Medikro, Kuopio,
Finland) at 7.2 and 12.3 years of median age (221,222). The parameters were expressed as
percentages of the gender-specific height-related reference values (% predicted) for
Finnish children (222,223). FVC, FEV1/FVC, MEF50, and MEF25 were registered. The
measurement with the highest FEV1 was recorded for analysis in the early school-age
study (221). In the later school-age visit, the composite maximal curve for each child was
recorded (222). The used cut-off limits for abnormal values were 80% for FEV1, 88% for
FEV1/FVC, 62% for MEF50, and 48% for MEF25 (221,222,224). Lung function data were
available from 79 children at 7.2 years of median age and from 81 children at 12.3 years of
median age (221,222).
BHR was studied at both school-age control visits (221,222). The ECT was
performed as an 8-minute free outdoor running test, including heart rate monitoring
(Polar Sport Testes; Polar Electro, Kempele, Finland), and done after baseline FVS. At the
early school-age visit, FVS was repeated 10 minutes after exercise, and the two FEV1 falls
of > 12% and > 15% were used as cut-off points for increased bronchial reactivity (221). At
the late school-age visit, the FVS was repeated 5, 10, and 15 minutes after exercise, and >
24
10% fall in FEV1 was regarded as positive BHR (222). In addition, metacholine challenge
test was performed at 12.3 years of age (222).
4.3 CURRENT STUDY DESIGN AND DATA
The data concerning lung function, bronchial reactivity, allergic sensitisation, and asthma
were collected during the study visits. Data were analysed together with the weight and
height data from the same study visits to explore the effect of overweight and obesity on
these parameters. The BMD was measured at the follow-up visit at 12.3 years of age.
Fourteen children, hospitalised for wheezing during enrolment to the primary study in the
Kuopio University Hospital, but not willing to attend the intervention trial, were invited
to the follow-up study visit at 12.3 years of median age. Their background information
was collected with a questionnaire and by interviewing the parents. Their data were used
in the BMD study only. The ICS consumption history for all participants was collected,
with the parents' written consent, from the hospital and primary health care medical
records.
4.3.1 Definition of obesity
For the evaluation of the weight status, the body mass index (BMI) was calculated by
using the following equation: weight (kg) / [height (m2)]. BMI standard deviation scores
(BMI-SDS), also called z-scores, were calculated by using the freely available obesity
calculator (225). This calculator applies British age- and sex-specific growth references
from 1990, produced by the LMS method in 1995 (226,227) and revised in 1996 (228). The
LMS method summarises the distribution of BMI at each age by its median (M), coefficient
of variation (S), and skewness expressed as a Box-Cox power (L) required to transform the
data to normal (229).
The International Obesity Task Force workshop for childhood obesity
evaluation recommends the use of BMD > 91st percentile as a cut-off point for overweight
and > 98th percentile for obesity, corresponding to BMIs > 25 and > 30 kg/m2, respectively,
in 18-year-old young adults (67). In this study, we used the corresponding BMI-SDS cutoff points: BMI-SDS > 1.3 for overweight and BMI-SDS > 2.0 for obesity (7,67).
The Finnish national growth charts, presenting weight for height, are used to
evaluate the weight in clinical practice (230). In weight for height, the cut-off point for
overweight and obesity varies depending age, and the method is not in international use.
Finnish sex-specific and age-related BMI references were published in 2011 (231), and thus
were not available for the present study.
4.3.2 Data on inhaled corticosteroid medication
None of the children had asthma or had used ICS before recruitment in the study (213). As
a part of the early-life intervention, 23 of 84 children had received budesonide for 16
weeks immediately after hospitalisation (213). Later in childhood, 40%–50% of the children
had been diagnosed with asthma and 15%–37% were on ICS medication for asthma during
the follow-up period (50).
25
There was no scheduled protocol for maintenance medication with ICS after
the 16-week early childhood intervention. Asthma medication was prescribed when
required, based on the presence of asthma diagnosis, symptoms, and individual clinicians’
decisions. The data on ICS consumption during childhood were collected at the later
school-age visit by charting the hospital and primary health care records and by
interviewing the parents using structured questionnaires. The durations and daily doses
of ICS therapy were collected. The dose of fluticasone propionate was multiplied by 2 to
be equivalent with the doses of budesonide and beclomethasone dipropionate in the
calculations; with the awareness of the fact the ICS are not equal to each other (185). The
cumulative doses and the total time of ICS therapy were calculated and also noted
separately for the two age periods: 0–6 years and 6–12.3 years (median). A continuous or
intermittent use of ICS for 6 months or longer during the 6-year age period was
considered as a regular use.
Oral and parenteral corticosteroid courses were collected and presented as
cumulative doses and classified with the cut-off points at the 10th, 50th, and 90th
percentiles. Children who never received ICS formed the control group of the study.
4.3.3 Bone mineral density measurements
The BMD was measured at the late school-age visit in the Department of Clinical
Physiology and Nuclear Medicine, Kuopio University Hospital. BMD was measured by
two separate methods, DXA and pQCT. BMD was measured in children followed from the
index wheezing episode onwards, and from those additional 14 children invited to the
BMD study at the late school-age visit.
4.3.4 Dual-energy x-ray absorptiometry
DXA measurements were performed by trained nurses, using the same scanner (Lunar
Radiation Corp., Madison, WI) for all 89 children. Measurements were obtained from the
lumbar spine at the L2–L4 level and from the femoral neck region. Quality assurance tests
using the Lunar DPX scanner have shown an inter-assay variation ranging between 0.08%
(for lumbar spine) and 2.3% (for femoral neck) in children (232).
DXA measures the BMDareal (g/cm2), which is dependent on bone size
(179,233,234). The aBMDvol (g/cm3) was calculated to minimise the effect of bone size on
the results (179). Femoral neck aBMDvol was calculated according to the following
equation: aBMDvol = BMD × [(4/π) × (height for measurement area / measurement area for
femoral neck)]; and lumbar spine aBMDvol was calculated according to the following
equation: aBMDvol = BMD × [4 / (π × width of measurement area in the lumbar spine)
(232). Finnish and international reference values are available for both BMDareal and
aBMDvol, allowing expression of the results in z-scores (232,235). However, there are no
specific cut-off points for an increased risk of clinical manifestations such as fractures (23).
We used both BMDareal and aBMDvol as continuous variables without reference-based
classifications.
26
4.3.5 Peripheral quantitative computed tomography
pQCT was performed to measure volumetric total BMD, trabecular BMD, and cortical
BMD (BMDtot, BMDtrab, and BMDcort, respectively) (Stratec XCT 2000; Stratec
Medizintechnik, Pforzheim, Germany) at the distal radius and distal tibia. Image data
were analysed using commercial pQCT analysis software (Bonalyse Geanie 2.1, Jyväskylä,
Finland). Volumetric thresholds were adjusted within the software for the automated
analysis to match the current adolescence bone density values. After the completion of
autoanalysis, results were visually verified by the researcher (Toni Rikkonen, Ph.D.). BMD
and cortical thickness were measured at the distal radius (4% site) and distal tibia
measurements from the medial malleolus to the medial condyle (33% site). There are no
Finnish reference values for pQCT for children available, neither are there specific cut-off
points for an increased risk of clinical manifestations (23). Therefore, we analysed the
BMD as continuous variables without reference-based classifications.
4.4 ETHICS
The study was approved by the Research Ethics Committee of Kuopio University and
Kuopio University Hospital. Informed written consent was obtained from the parents of
the children. The methods used in the study, like blood tests, lung function tests, and BMD
measurement with DXA, are routinely used in pediatric clinical practice. Only pQCT is a
new method not routinely used, but the level of radiation is low, and concerns only
peripheral parts of the body, that is radius and tibia in the present study. Both DXA and
pQCT are internationally accepted methods to the measurement of BMD in children for
research purposes.
4.5 STATISTICS
In the analysis between asthma, allergy, and weight status, logistic regression was used for
both univariate and multivariate analyses. The results were expressed as crude odds ratio
(cOD) and adjusted odds ratio (aOD) with 95% confidence intervals (95% CI). The analysis
for an association between weight status and asthma or BHR was adjusted for AD in the
infancy and RSV aetiology of wheezing. The analysis for an association between weight
status and allergy or atopic sensitization was adjusted for sex and RSV aetiology of
wheezing. The presence of AD in infancy had a strong interaction with later allergy and
atopic sensitization; therefore, AD was not included in the analyses. The age on admission,
although interacting with the viral aetiology of bronchiolitis, was included in all analyses
as a continuous variable.
In the analysis of lung function data, the Mann–Whitney U-test was used in
univariate analyses and the analysis of variance (ANOVA) was used in multivariate
analyses for continuous FVS parameters. The ANOVA analyses were adjusted for the RSV
aetiology of index wheezing, in addition to adjustment with anti-inflammatory asthma
medication during the preceding 12 months before the study visit. Logistic regression
analysis, adjusted for the RSV aetiology of index wheezing and anti-inflammatory asthma
medication during the 12 preceding months before the study visit, was applied for
27
categorised (by the limits of abnormal values in % predicted) FVS parameters, and the
results were expressed as aOR with 95% CI. Sex and age were not included in ANOVA or
logistic regression, while the FVS references were age and sex specific.
In the BMD study, Student’s t-test was used for continuous variables in
univariate analyses and ANOVA in multivariate analyses for the BMD measured by DXA.
The analysis was adjusted for age, sex, weight as BMI-SDS (normal, overweight, and
obesity), and the pubertal stage (pre-puberty and early puberty vs. puberty), and use of
systemic corticosteroids (10th, 50th, and 90th percentiles). Height was also included in the
model when BMDareal was the outcome. The results are expressed as means with 95% CI.
Pearson’s correlation coefficients (r, r2) were used for estimating correlations.
Student’s t-test was used to analyse pQCT data for continuous variables in the
univariate analyses and ANOVA in multivariate analyses. Multivariate analysis was
adjusted for age, sex, weight as BMI-SDS (normal, overweight, obesity) and the pubertal
stage (prepuberty and early puberty vs. puberty), and use of systemic corticosteroids
(10th, 50th, and 90th percentiles). The results are expressed as means with 95% CI.
Pearson’s correlation coefficients (r, r2) were used for estimating correlations
Data were analysed using SPSS version 17 for weight study data and DXA data and
SPSS version 19 for pQCT data (SPSS Inc., Chicago, IL).
29
Table 2. Asthma and allergic diseases at early and late school age in children after early
childhood wheezing: an association with overweight
Asthma or
allergic
diseases at the
school-age
control visits
Overweight at
7.2 years of
age1
Yes
n = 19
No
n = 63
Asthma
n = 33/31
8
25
Bronchial
hyperreactivity3
n = 13/17
4
Atopic dermatitis
n = 26
Allergic rhinitis
n = 33/27
aOR
(95% CI)2
Overweight at
12.3 years of
age1
aOR
(95% CI)2
Yes
n = 27
No
n = 54
1.14
(0.35–3.65)
12
19
2.05
(0.70–6.00)
9
1.41
(0.36–5.51)
7
10
1.76
(0.51–6.07)
9
33
0.83
(0.29–2.37)
8
18
0.87
(0.30–2.50)
6
27
0.46
(0.15–1.47)
10
17
1.18
(0.43–3.25)
Atopic
1.32
0.53
11
27
14
36
sensitisation4
(0.42–4.18)
(0.20–1.45)
n = 38/50
1
BMI-SDS > 1.3.
2
Odds ratio (aOR), and 95% confidence interval (95%CI) by logistic regression: Asthma and
BHR were adjusted for age, atopic dermatitis in infancy, and RSV aetiology of bronchiolitis; AD,
AR and AS were adjusted for age, sex, and RSV aetiology of bronchiolitis.
3
FEV1 decrease > 12% in the exercise challenge.
4
At least one positive reaction in SPTs.
Sensitisations to indoor and outdoor allergens were analysed separately at the
late school-age visit, and previous sensitisation at 7.3 years of age was added to the
adjusted model. Current overweight and obesity at the late school-age visit were
associated with a decreased risk for sensitisation to outdoor allergens; aOR = 0.10, 95% CI
= 0.02–0.52 for overweight and aOR = 0.03, 95% CI = 0.00–0.27 for obesity.
The previous overweight at 7.2 years of median age was not associated with
asthma, BHR, AD, AR, or atopic sensitisation at 12.3 years of median age (Table 3),
corresponding association were non-significant also for obesity (I/Table 3).
30
Table 3. Asthma and allergic diseases at late school age and overweight at early school age in
children after early childhood wheezing: an association with overweight
Overweight at 7.2 years of age1
Asthma or allergic diseases
at the late school-age
control visit
Yes n=16
No n=58
aOR4 (95% CI)2
Asthma n=28
7
21
1.98 (0.56-7.07)
Bronchial hyperreactivity2 n=17
3
14
0.73 (0.16-3.26)
Atopic dermatitis n=24
3
21
0.87 (0.30-2.50)
Allergic rhinitis n=24
4
20
1.18 (0.43-3.25)
Atopic sensitisation3 n=45
8
37
0.53 (0.20-1.45)
1
Overweight BMI-SDS >1.3; b Obesity BMI-SDS >2 (Body mass index standard
deviation score = Z-score)
2
FEV1 decrease >12% in the exercise challenge
3
At least one positive reaction: 36 to indoor and 38 to outdoor allergens.
4
Odds ratio (aOR), and 95% confidence interval (95%CI) by logistic regression: asthma and
BHR adjusted for age, atopic dermatitis in infancy and RSV aetiology of bronchiolitis; AD, AR
and AS adjusted for age, gender and RSV aetiology of bronchiolitis.
5.3 INFLUENCE OF OVERWEIGHT ON LUNG FUNCTION AT SCHOOL AGE
5.3.1 Univariate analyses
At the early school-age visit, current overweight was associated significantly with lower
FEV1/FVC (Table 4). There were no significant associations between other FVS parameters
and overweight (Table 4) or obesity (II/Table 1). Previous overweight (Table 5) at the
preschool-age control visit had no significant association with any FVS parameters at 7.2
years of median age. There was not possibility to evaluate effect of previous obesity
because low incidence of obesity.
31
Table 4. Flow-volume spirometry at 7.2 years of median age in relation to current overweight
Current overweight1
Parameters in
Yes
No
Univariate
Multivariate
FVS2
(N=16)
(N=58)
p3
p4
Mean, (SD)
Mean, (SD)
FVC
108.71 (19.75)
102.06 (16.48)
0.252
0.219
FEV1
100.16 (14.16)
99.95 (13.94)
0.977
0.890
FEV1/FVC
92.63 (8.95)
98.47 (8.93)
0.017
0.025
MEF50
84.00 (17.73)
85.10 (20.39)
0.700
0.814
MEF25
66.00 (19.85)
71.27 (22.76)
0.394
0.454
1
Overweight BMI-SDS >1.3
FVC (forced vital capacity), FEV1 (forced expiratory volume in one second), FEV1/FCV, MEF50
(maximal expiratory flow at 50% of FVC) and MEF25 (maximal expiratory flow at 25% of FVC),
expressed as % of predicted.
3
Mann-Whitney U -test
4
Analysis of variance, adjusted for RSV aetiology of early wheezing and current antiinflammatory asthma medication (during the preceding 12 months).
2
Table 5. Flow volume spirometry at 7.2 years of median age and association to weight at the
preschool-age
Weight at 4.0 years of age
FVS at 7.2 years
Overweight1
Normal weight
p2
of age
n=5
n = 67
FVC
107.95 (8.8)
NS
102.91 (8.47)
FEV1
98.39 (13.27)
NS
99.81 (14.52)
FEV%
90.99 (9.53)
NS
97.64 (9.41)
MEF50
79.44 (23.23)
NS
85.56 (19.72)
MEF25
59.43 (21.44)
NS
71.15 (23.06)
Data are presented as mean (SD). FVC, forced vital capacity; FEV1, forced expiratory volume
in 1 sec; FEV1/FCV and MEF50, maximal expiratory flow at 50% of FVC; MEF25, maximal
expiratory flow at 25% of FVC, expressed as % predicted.
1
Overweight BMI-SDS > 1.3.
2
Mann-Whitney U-test and ANOVA, adjusted for the RSV aetiology of early wheezing and
current anti-inflammatory asthma medication.
There was no significant association between FVC or FEV1 and overweight or
obesity at school-age visits (Table 4 and II/Tables 2 and 3). Previous overweight and
obesity at 7.2 years of median age associated significantly with lower FEV1/FVC at 12.3
years of median age (Table 6). Current overweight and obesity associated significantly
with lower FEV1/FVC, MEF50% (Table 6) and with MEF25 (p 0.006 and p 0.021
respectively) at late school age (II/Tables 2 and 3).
99.05 (9.47)
97.95 (12.65)
100.56 (11.50)
96.38 (12.68)
98.39 (9.12)
Yes
(n = 6)
No
(n = 68)
Yes
(n = 27)
No
(n = 53)
Yes
(n = 16)
97.64 (13.12)
97.21 (13.20)
No
(n = 58)
No
(n = 64)
101.03 (8.40)
0.674
0.162
0.797
0.131
Univariate
p4
0.837
0.164
0.769
0.306
Multivariate
p5
95.97 (7.51)
88.85 (9.78)
96.81 (7.36)
90.09 (8.81)
95.12 (8.57)
87.76 (6.99)
96.01 (7.63)
89.15 (10.06)
Mean (SD)
0.010
0.001
0.022
0.013
Univariate
p4
FEV1/FVS3
0.002
0.001
0.026
0.003
Multivariate
p5
83.87 (18.41)
71.68 (18.81)
84.39 (17.70)
75.63 (20.47)
82.97 (19.52)
70.46 (15.72)
83.91 (18.82)
74.88 (20.68)
Mean (SD)
0.025
0.037
0.132
0.121
Univariate
p4
MEF 50%3
2
0.028
0.076
0.107
0.095
Multivariate
p5
BMI-SDS > 1.3, at 7.2 and 12.3 years of age.
BMI-SDS > 2.0, at 7.2 and 12.3 years of age.
3
FVC, forced vital capacity; FEV1/FCV and MEF50, maximal expiratory flow at 50% of FVC, expressed as % predicted.
4
Mann-Whitney U-test.
5
ANOVA, adjusted for RSV aetiology of early wheezing and current anti-inflammatory asthma medication (during the preceding 12 months)
1
Current
obesity2
Current
overweight1
Previous
obesity2
Previous
overweight1
Yes
(n = 16)
Mean (SD)
FVC3
Table 6. Spirometry in the 80 study subjects at 12.3 years of median age in relation to previous and current overweight and obesity. Pvalues refer to the difference between patients with and without previous or current overweight or obesity
32
33
5.3.2 Multivariate analyses
In the multivariate analysis at the early school-age visit, both overweight and obesity
associated significantly with decreased FEV1/FVC (Table 4 and II/Table 1). At the later
school-age visit, the association of current overweight with FEV1/FVC and MEF25%
remained as significant after adjusting with RSV aetiology of index wheezing and current
anti-inflammatory asthma medication, but the association with MEF50 became nonsignificant (Table 6 and II/Tables 2 and 3).
5.3.3 Logistic regression
Previous and current overweight were significant risk factors for decreased FEV1/FVC (<
88% of predicted) at the early school-age (Table 7) and late school-age visits (Table 8). At
late school age, current obesity was also a significant risk factor for abnormal FEV1/FVC (<
88%) (aOR = 8.07, 95% CI = 2.10–31.05) and MEF25 (< 48%) (aOR = 4.34, 95% CI = 1.06–
17.79). The weight did not associate to decreased FEV1 (Table 7 and 8).
Because overweight was highly persistent between the study visits, previous
and current overweight could not be incorporated in the same multivariate model.
Therefore, it was not reliable to evaluate causality and influences separately.
Table 7. Logistic regression: abnormal lung function in FVS at the early school-age visit, in
relation to previous and current overweight
7.2 years of age
Abnormal
FVS2
1
Previous
overweight1,4
Yes
No
n=5
n = 69
aOR (95% CI)3
Current
overweight1,5
Yes
No
n = 17
n = 57
aOR (95% CI)3
FEV <80%
-
4
-
1
3
1.01 (0.10–10.58)
FEV1/FVC
< 88%
3
10
15.46
(1.65–145.26)
6
7
3.71 (1.01–13.60)
MEF50 <
62%
2
11
6.46 (0.77–33.95)
3
11
0.89 (0.21–3.80)
BMI-SDS > 1.3.
FEV1/FCV and MEF50, maximal expiratory flow at 50% of FVC, expressed as % predicted.
3
Odds ratio (95% CI) adjusted for RSV aetiology of early wheezing and current antiinflammatory asthma medication (during the preceding 12 months).
4
Overweight at 4.0 years of median age.
5
Overweight at 7.2 years of median age.
2
34
Table 8. Logistic regression: abnormal lung function in FVS at the late school-age visit, in
relation to previous and current overweight
12.3 years of median age
Abnormal
FVS2
1
Previous
overweight1,4
Yes
n = 16
No
n = 58
FEV1
<80%
2
10
FEV1/FVC
< 88%
6
MEF50 <
62%
3
3
aOR (95% CI)
Current
overweight1,5
aOR (95% CI)3
Yes
n = 24
No
n = 50
0.70
(0.13–3.60)
5
9
1.00
(0.29–3.46)
6
5.64
(1.43–22.20)
8
5
4.02
(1.14–14.22)
9
1.29
(0.30–5.54)
7
6
2.64
(0.78–8.97)
BMI-SDS > 1.3.
FEV1/FCV and MEF50, maximal expiratory flow at 50% of FVC, expressed as % predicted.
3
Odds ratio (95% CI) adjusted for RSV aetiology of early wheezing and current antiinflammatory asthma medication (during the preceding 12 months).
4
Overweight at 7.2 years of median age.
5
Overweight at 12.3 years of median age.
2
35
5.4 BONE MINERAL DENSITY BY DUAL-ENERGY X-RAY
ABSORPTIOMETRY
BMDareal was measured and aBMDvol was calculated for 65 boys and 24 girls by DXA.
Among these 89 children, 37% were overweight and 24% were obese, and 28% of boys and
38% of girls were at puberty (M/G3-5). Pubertal children had higher BMDareal and aBMDvol
in the lumbar spine and higher BMDareal in the femoral neck compared with prepubertal
children (Table 9). In the lumbar spine, BMDareal and aBMDvol were lower in boys than in
girls (Table 9). Overweight or obesity had no significant association with BMDareal or
aBMDvol in the lumbar spine or femoral neck (Table 9).
Table 9. The association between BMDs measured by DXA and gender, pubertal stage, and
weight at 12.3 years of age in 89 children hospitalised for wheezing in early childhood
BMDareal
mean (95% CI)1
aBMDvol
mean (95% CI)2
n
Lumbar spine
L2–L4
Femoral neck
Lumbar
spine L2–L4
Femoral neck
Female
24
0.95
(0.88–1.02)*
0.91
(0.84–0.98)
0.33
(0.31–0.35)*
0.41
(0.39–0.44)
Male
65
0.83
(0.80–0.85)
0.91
(0.89–0.94)
0.29
(0.28–0.30)
0.39
(0.38–0.41)
Pre- and early
pubertal3
64
0.82
(0.80–0.85)*
0.88
(0.86–0.91)*
0.29
(0.28–0.30)*
0.40
(0.38–0.41)
Pubertal3
24
0.97
(0.91–1.03)
1.00
(0.95–1.06)
0.32
(0.30–0.34)
0.42
(0.39–0.44)
Normal weight4
56
0.85
(0.81–0.88)
0.89
(0.86–0.92)
0.30
(0.29–0.31)
0.40
(0.39–0.41)
Overweight4
33
0.89
(0.82–0.96)
0.96
(0.88–1.04)
0.30
(0.29–0.32)
0.40
(0.38–0.42)
1
Areal BMD (g/cm2) measured by DXA.
Apparent volumetric BMD (g/cm3) calculated from DXA measurements.
3
Tanner stages M1-2 and G1-2 as pre-puberty and early puberty, M3-5 and G3-5 as puberty.
4
Normal weight BMI-SDS < 1.3 SD, overweight BMI-SDS > 1.3 SD.
*Two independent-samples t-test, p < 0.05, between males and females or pre-pubertal/early
pubertal and pubertal children.
2
The mean cumulative dose of systemic corticosteroids during the follow-up
period was 161 mg (range = 10–1,784 mg, SD = 346, n = 34), showing no correlation with
lumbar spine BMDareal (r = 0.058, r2 = 0.00) or aBMDvol (r = −0.137, r2 = 0.02), nor with
femoral neck BMDareal (r = −0.026, r2 = 0.00) and aBMDvol (r = −0.088, r2 = 0.01). When
analysed as categorised (at the 10th, 50th, and 90th percentiles), there was no significant
association between systemic corticosteroids use and BMD in the lumbar spine or femoral
neck.
36
5.4.1
Effect of inhaled corticosteroids on bone mineral density in the lumbar spine
and femoral neck
The mean cumulative dose of ICS expressed as budesonide equivalents during the whole
follow-up period was 517 mg (range = 31–1,813 mg). There was a significant negative
association between the cumulative ICS dose and the BMDareal (adj. p = 0.000) and aBMDvol
(adj. p = 0.006) in the femoral neck (Figure 4 and III/Figures 1A and 1B). The analysis of
variance was adjusted for use of systemic corticosteroids, age, sex, weight status by BMI-SDS and
pubertal stage, and height in the analysis of areal BMD. However, the correlations were weak:
for BMDareal, r = −0.32, r2 = 0.10; for aBMDvol, r = −0.28, r2 = 0.08. There was no significant
association between the cumulative ICS dose and the BMD in the lumbar spine (Figure 4
and III/Figures 2A and 2B).
r2 = 0.03
adj. p = 0.076
r2 = 0.10
adj. p = 0.000
Figure 4. The distribution of BMDareal in lumbar spine and femoral neck at 12.3 years of median
age in relation to the cumulative dose of ICS used during follow-up time. The presence of
puberty is shown in figures.
In the lumbar spine, both BMDareal and aBMDvol were significantly lower in
those 12 children who were treated with regular ICS medication only at less than 6 years
of age compared with those 21 children who never received ICS therapy (Table 10). The
findings were similar after adjusting with age, sex, pubertal stage, weight status, and the
use of systemic corticosteroids, and in the case of BMDareal with the additional adjustment
for height. Concerning the femoral neck, such association was found only with aBMDvol
(p= 0.031) (III/Table 2). Twelve children had used ICS regularly only between 6 and 12.3
years of age, and there was no significant association with BMD at age 12.3 years (Table 10
and Figure 5 and III/Table 2).
N=
12
N=
21
Only at
6-12.2 years
No ICS use
during the
12.2 years
follow-up
(0.90-0.98)
(0.82-0.93)
(0.86-1.05)
0.96
(0.83-1.00)
0.91
Femoral neck
0.94
0.514
0.010
p4
0.85
(0.77-0.99)
0.88
(0.74-0.90)
0.81
Lumbar spine
L2-4
BMDareal1 (mean, 95% CI) 3
0.784
0.059
p4
(0.28-0.31)
0.30
(0.28-0.35)
0.31
(0.25-0.30)
0.27
Lumbar spine
L2-4
0.454
0.006
p4
(0.39-0.44)
0.41
(0.38-0.46)
0.42
(0.36-0.40)
0.38
Femoral neck
aBMDvol1 (mean, 95% CI) 3
0.886
0.031
p4
2
BMD measured by dual energy X-ray absorptiometry (DXA), apparent volumetric BMD calculated
Regular use; over 6 months use of ICS during the 6-year age period
3
95% confidence interval
4
th
th
th
The analysis of variance adjusted for the cumulative dose of systemic corticosteroids (mg) classified with cut-off points at the 10 , 50 and 90 percentiles), gender,
pubertal stage (Tanner stage M1-2 and G1-2 as pre- and early pubertal, M3-5 and G3-5 pubertal), age and weight as BMI-SDS (normal, overweight, obesity). Height (cm) was
included in the model for analysis of areal BMD.
1
N=
12
Only at
0-6 years
Regular use of ICS
during childhood2
school age and at school age, compared to children who had never used ICS
Table 10. Bone mineral density at the median age of 12.2 years in children who had regularly used inhaled corticosteroids (ICS) before
37
38
*
*
*
Figure 5. Areal BMDareal and aBMDvol in the lumbar spine and femoral neck of children who
newer used ICS and in those who regularly used ICS only before school age or only at school
age.
* Adjusted p < 0.05 between children never received ICS and children received ICS regularly
before school age.
39
5.5 BONE MINERAL DENSITY BY PERIPHERAL QUANTITATIVE
COMPUTED TOMOGRAPHY
BMDvol was measured for 62 boys and 20 girls by pQCT. Among these 82 children, 38%
were overweight and 26% were obese, and 19% of boys and 40% of girls were at puberty
(M/G3-5). BMDtot and BMDcort were higher in girls than boys in the tibia (Table 11). Pubertal
children had higher BMDtot and BMDcort in the radius compared with pre-pubertal or early
pubertal children (Table 11). Age and weight status, as classified by BMI-SDS (normal
weight, overweight, and obesity), had no correlation with BMD in the radius (radius
BMDtot, r = 0.247, r2 = 0.06) or tibia (BMDtot. r = 0.073, r2 = 0.01). Systemic corticosteroid use
had no significant associations with BMD in the radius (BMDtot, r = 0.063, r2 = 0.00) or tibia
(BMDtot, r = 0.062, r2 = 0.00).
Table 11. The association between BMDvol (g/cm3) in distal tibia and radius (mean, 95% CI) and
sex and pubertal stage at the median age of 12.3 years in 81/82 children hospitalized for
wheezing in infancy
Bone Mineral Density in Tibia and Radius1
Mean, (95% CI)2
1
Female
N=20
Male
N=61/62
Pre- and
early
pubertal3
N=59/60
Pubertal
N=20
Tibia BMDtot
383.8
(360.7-406.9)
350.8
(341.2-360.3)*
356.6
(346.2-367.1)
367.4
(343.5-391.2)
Tibia BMDcort
585.00
(572.2-597.9)
564.4
(559.5-569.3)*
567.8
(562.2-573.4)
575.0
(561.9-588.1)
Radius BMDtot
118,1
(103.6-132.7)
124.9
(120.4-129.3)
119.7
(114.7-124.7)
133.8
(121.7-146.0)*
Radius BMDtrad
84.8
(73.6-96.0)
92.5
(88.0-7.0)
88.3
(83.4-93.2)
98.1
(88.6-107.7)
Radius BMDcort
203.3
(178.2-228.3)
209.8
(204.4-215.2)
202.8
(196.3-209.3)
222.5
(201.2-243.7)*
BMD measured by pQCT
95% confidence interval
3
Tanner stage M1-2 and G1-2 as pre- and early pubertal, M3-5 and G3-5 pubertal, two boys
refused pubertal examination
* Two independent-samples t-test, p < 0.05, between males and females or pre-pubertal/early
pubertal and pubertal children
2
40
The correlation between BMDtot and BMDcort in the radius and tibia was as
follows: for BMDtot, r = 0.376, r2 = 0.14; and for BMDcort, r = 0.348, r2 = 0.12 (Figure 6).
Figure 6. The correlation between BMDtot and BMDcort in the distal radius and in tibia, r2 = 0.14,
r2=0.12 respectively.
5.5.1 The effect of inhaled corticosteroids to the bone mineral density in distal radius
and tibia measured by peripheral quantitative computed tomography
The cumulative ICS dose (mean = 537 mg, range = 31–1,813 mg) as budesonide equivalents
had a significant negative correlation with BMDtot (r = −0.175, r2 = 0.031, adj. p = 0.016), BMDcort (r
= −0.138, r2 = 0.019, adj. p = 0.016), and BMDtrab (r = −0.155, r2 = 0.022, adj. p = 0.039) in the radius.
The correlations were weak (figure 7). For associations, the analysis of variance was adjusted for
use of systemic corticosteroids, age, sex, weight status by BMI-SDS and pubertal stage (Figure 7).
The correlations were weak. The corresponding correlations were weaker and associations nonsignificant for cortical thickness, or for BMDtot and BMDcort in the tibia.
41
r2 = 0.031
r2 = 0.019
adj. p = 0.016
adj. p = 0.016
r2 = 0.022
adj. p = 0.039
Figure 7. The distribution of BMDtot, BMDcort and BMDtrab in radius at 12.3 years of median age in
relation to the cumulative dose of ICS used during follow-up time. Correlations and association
in adjusted ANOVA shown in figures.
When the regular ICS use was analysed separately for consumption at less than
6 years of age and between 6 and 12.3 years of age, there were no significant differences in
BMDtot in the radius or tibia between children who used ICS regularly and children who
never used ICS (Table 12). Results were non-significant also for BMDcort and BMDtrab in the
radius and BMDcort in the tibia (Data not shown).
42
Table 12. MBDtot (g/cm3) in radius and tibia at the median age of 12.3 years in children with
regular ICS use only before 6 years of age or between 6 to 12.3 years of age, compared to
BMDtot in radius in children who had never used ICS
MBDtot in radius
MBDtot in tibia
Regular ICS use1
p3
p3
2
(mean, 95% CI)
(mean, 95% CI)2
Only at age
0-6 years
N=
12
127,50
(113.58-140.49)
ns
334.58
(315.39-353.78.90)
ns
Only at age
6-12.3 years
N=
10
132.70
(112.83-152.57)
ns
387.60
(458.41-416.79)
ns
No ICS use
during the 12.3
years follow up
N=
18
123.11
(116.02-130.21)
1
357.28
(336.85-377.70)
Regular use; over 6 month use of ICS during the 6-year age period
95% confidence interval
3
The analysis of variance adjusted for sex, pubertal stage (Tanner stage M1-2 and G1-2 as pre
and early pubertal, M3-5 and G3-5 pubertal), age, height (cm) and weight as BMI-SDS (normal,
overweight, obesity) and used systemic corticosteroids (classified by 10th, 50th and 90th
percentiles)
2
43
6 Discussion
6.1 RELATION OF OVERWEIGHT AND ASTHMA, LUNG FUNCTION, AND
ALLERGY IN CHILDREN
6.1.1 Asthma
This prospective follow up study comprised the children who experienced severe wheezing
in early childhood and were followed longitudinally for 11 years and thus enables to
inspect the influence of weight developed and ICS consumptions to the outcomes asthma,
like lung function and BMD. The present study did not find any association between
asthma and earlier or current obesity or overweight. Reasons may be the rather low
proportion of overweight (33%) and especially obese (20%) children, although the
proportions were higher than on average in Finnish children (19.1%–23.6% and 3.2%–4.7%,
respectively) (80) and the cohort being small. In line with the present study, when
objectively measured BHR was demanded for the asthma diagnosis, the other studies have
been negative also (96,118,151).
In previous studies, most often the asthma symptoms and diagnoses have been asked from
parents and have been based on subjective observations (11,132,133,148,149) and the
connection between asthma and obesity is known (5,6,236).
In the present study, we did not find connections between BHR and earlier
weight at 7.2 or current weight at 12.3 years of age, in line with results from another asthma
study (237). In longitudinal studies, the results have varied. In a 9-month follow-up, obese
(BMI > 95 %) children had more wheezing, more use of medicines, and more emergency
room visits, but no association was found with PEF rates monitored at home (149). Another
study did not find any associations between asthma, AR, AD, or BHR at 10 years of age and
current or previous weight status (237). In a birth cohort, an earlier persistent and current
overweight associated with both dyspnoea and BHR at 8 years of age, whereas earlier
overweight did not predict BHR if weight had normalised (120).
The asthma severity might be one factor modifying the asthma-obesity relation.
In the present study, we did not monitor asthma severity or the sedentary lifestyle, and
both might affect the results. Poor asthma control could lower the level of physical activity
and further lead to weight gain. Another notable issue, the possible causality between
obesity and asthma, was not possible to evaluate in the present study. In a large
retrospective cohort study, 5- to 17-year-old obese asthmatic children used more β-agonists
and more oral corticosteroids, with a conclusion that obesity is associated with a risk of
worse asthma control (101). In the National Longitudinal Survey of Youth (NLSY) with a
14-year follow-up time, boys had an increased risk of asthma if they became overweight
(BMI > 85th percentile) at 2–3 years of age or were overweight during the whole follow-up
time (134). Also, girls who gained weight at school age had an increased risk of asthma in
another study (137).
Age, puberty and sex have a role in the asthma-obesity relation. In the present
study, we did not evaluate an association between overweight during the index wheezing
episode at less than 2 years of age and later asthma, mainly because of the small numbers of
overweight children at that age. In addition, the cohort was too small, not allowing a
relevant analysis for boys and girls separately. Therefore, age on admission and sex were
44
included as the confounding factors in the adjusted analyses. In literature, one longitudinal
study, higher weight at 1 year of age was associated with better lung function at 6 and 8
years of age, but later, overweight changed to be a risk factor (136). In another study,
obesity reduced lung function without any major symptoms before puberty. During
adolescence, FEV1% and FEV1/FVC was reduced in obese girls; and in adults, there were
no differences in lung function between obese and non-obese subjects (125). In the Tucson
Children´s Respiratory Study, early puberty and obesity were both associated with
unremitting asthma after puberty (238). In available studies, the results are rather
conflicting due to sex interactions (119,127,128,131).
These inconsistent findings support, that although obesity increases the asthma
risk at the population level, it might cause more asthmatic symptoms rather than effect the
asthma prevalence per se. Asthma associated with obesity differs from atopic asthma and
may even be an own phenotype (4,110,239,240). Obesity decreases responses to asthma
medication, and weight reduction improves lung function; both can be seen as a
demonstration of causality in the asthma-obesity relation (Shore, Johnston 2006), but more
likely, as a sign of obese asthma phenotype characterised by non-atopic airway
inflammation (4,110).
To clarify the complex interaction between weight and asthma, longitudinal
preferably prospective and stratified studies with multivariate models are needed to
answer the following questions: Is excessive weight gain an independent significant risk
factor for asthma? Are there certain risk groups that should obtain special attention? Do
obese asthmatic children need a different treatment compared with allergic asthmatic
children?
6.1.2 Lung function
The results of the present long-term follow-up study after early childhood wheezing
showed that overweight was associated significantly with reduced FEV1/FVC at school age
and with reduced MEF50 and MEF25 at late school age.
In healthy children, overweight has had a beneficial effect on lung function
(8,9), but decreased lung function related to obesity has also been reported (131). However,
benefits might change during adolescence; lung function seems first to reach a plateau and
then to decrease among the obese youths (9). Normal weight is probably the most beneficial
to lung health; also, low weight was associated with significantly lower FEV1 and FVC
compared with normal weight children (96).
Overweight might have a different effect on lung function in asthmatic than in
non-asthmatic children; approximately 40% of our patients had asthma, and all had
wheezed in early childhood. In line with the findings of the present study, in the CAMP
study, an increasing BMI was associated with increasing FEV1 and FVC but decreasing
FEV1/FVC (144). In the post hoc analysis of the CAMP data, overweight children had
decreased responses to ICS when assessed with lung function measurements (103). Obesityrelated lower FEV1/FVC has been reported in a birth cohort study (127), lower residual
volume/TLC ratios in a case-control study (110) and in a cross-sectional study (147).
The decrease of MEF50 and MEF25 values in the overweight and obese
children at the teenage visit indicates that overweight and obesity might narrow the small
peripheral airways, as described to occur in obese subjects (93). In addition, the decreased
compliance of either the lungs due to the narrow peripheral airways or the chest wall due
45
to body adiposity may lead to subnormal lung function, including both decreased airway
flows, which means an obstructive lung function disorder, and decreased lung volumes,
which means a restrictive lung function disorder (241).
In a Danish study on the effect of childhood weight on lung function in
adulthood, FEV1 and FVC values were reduced in obese men at 27 years of age, but the
childhood BMI at 7 years of age was positively associated with both FEV1 and FVC (97).
The results of the different studies seem confusing, but there might be some
consistency; mild overweight may be beneficial, but when substantial overweight or
obesity develops, the effect turns to detrimental. The effect of excessive weight gain on lung
function may be age dependent, and different multifactorial mechanisms may influence
children and adults.
6.1.3 Allergies
In the present study, excessive weight gain at late school age decreased the occurrence of
AD and sensitisation to outdoor allergens. There are only a few other follow-up studies
concerning the relation between weight status and atopic diseases (127,154). Contrary to the
present study, atopy and IgE levels associated with height and weight in the birth cohort
study (127), and AD was connected to weight gain (11,154). In the previous studies, AR has
been less common in obese children (11), and underweight children even had a higher risk
for atopy in one study (123).
The association between allergy and weight may be sex dependent
(95,96,114,127). In pooled data from seven epidemiological studies, allergy and overweight
associated in girls (96), in line with the birth cohort studies (127). The present data were too
small for relevant stratified sex-based analyses on the association between overweight or
obesity and atopic diseases.
The link between weight status and asthma is poorly known. The most
common presumption is that overweight or obesity reduces the production of
inflammatory mediators which further modify the development of allergy. However the
mechanism probably differs from the asthma obesity connection, which seems to be
stronger in non-atopic individuals (12).
6.2 THE EFFECT OF INHALED CORTICOSTEROIDS’ ON BONE MINERAL
DENSITY IN CHILDREN
6.2.1 Dual x-ray absorptiometry
The present follow-up study reveals the association between ICS use and reduced BMD
measured by DXA at 12.3 years of age. The impact of ICS was seen in two separate ways:
high cumulative ICS doses associated with reduced BMD in the femoral neck, and a
significant negative effect on BMD in the lumbar spine and in the femoral neck emerged
when ICSs has been used regularly before 6 years of age. Well-known confounding factors
such as age, gender, pubertal stage, height, and weight status and the use of systemic
corticosteroids were included in adjusted analyses with no substantial changes in results.
Unfortunately, we did not have the exact data of physical activity and dietary habits to add
in to the model.
Previous long-term follow-up studies have not found similar impacts on BMD,
or findings have only been marginal (18,19,63). In the largest CAMP study with 4–7 years of
follow-up time, the use of 200 µg of budesonide daily was associated with decreased bone
46
mineral accretion, and oral corticosteroids produced a dose-dependent reduction in bone
mineral accretion in the lumbar spine, but only in boys (18). The Danish study did not find
any significant differences in total BMD, bone mineral content, or total body calcium
between the ICS and the non-ICS groups during 3–6 years of follow-up time (19). The most
recent retrospective cross-sectional study did not find significant differences in lumbar
BMD between pre-pubertal children using intermittent fluticasone with a 200 µg mean
daily dose for 5 years and newly diagnosed asthmatic children with no history of ICS
medication (196).
Studies with intermediate follow-up times have similar results. Fluticasone use
for 2 years did not affect BMD accretion in the lumbar spine and femoral neck compared
with nedocromil sodium (63). In line with the present study, an Australian study reported
that the ICS therapy for 9–20 months reduced total bone mineral content in pre-pubertal
children when compared with controls (190), but unfortunately, long-term follow-up
results are not available.
The median cumulative ICS dose was higher in the present study than in the
three previous studies (20,63,190,196). The high cumulative dose of ICS up to 1,800 mg
might be one reason for positive results in this study.
Bone size influences the BMDareal values; this can be minimised by the
calculated aBMDvol, which is similar in large and small bones (242). In the present study,
aBMDvol and BMDareal gave similar results, and BMDareal results were stable when adjusting
with height. In the Helsinki Early Intervention Childhood Asthma study, daily treatment
with budesonide reduced BMD compared with daily disodium cromoglycate in the crude
analysis, but the results changed to negative when adjusted with height (20). The
researchers discussed, that monitoring height growth is sufficient for BMD monitoring. The
interaction between height and BMD requires special attention in long-term follow-up
studies. Bone size growth is not equal with the accretion of bone mineral content during
growth (24). Thus, if the baseline BMD is low, it could stay low despite height growth (175).
Therefore, the suggested height monitoring alone (20) may not be sensitive enough to
estimate all significant changes in BMD in children receiving ICS medication.
Two separate findings of the present study might be explainable by bone
physiology. The lumbar spine consists mainly of trabecular bone that has a rapid turnover,
and the femoral neck consists mainly of cortical bone that has a slower turnover; therefore,
lumbar spine is more susceptible to hormonal and metabolic effects (24). The previous
studies in children have focused on the lumbar spine, thus mainly reflecting the effects on
trabecular bone (18-20,63), and only one study has also assessed femoral neck (63). In this
study, high cumulative doses during childhood were associated with changes in the
femoral neck representing less frequently studied cortical bone. On the other hand, there
might be a critical period in early childhood for changes in the lumbar spine representing
trabecular bone.
BMD is dependent on age, sex, pubertal stage, and race (162,181). Physical
activity increases BMD, and overweight could decrease BMD, but the effects seem to be sex
and age specific (161,169,170). The number of study subjects in the present study was too
small for sex-specific analyses, but the sex, age and pubertal stage were taken into account
in the analyses. In addition, we could not evaluate the effects of ICS on growth in height
because bone age was not studied by radiology. The Tanner classification is not sufficiently
exact for the estimation of pubertal stage in growth studies. Also, the ICS preparation can
47
affect the results; the swallowed fluticasone propionate has low bioavailability and
therefore negative results in studies done with it cannot be generalized to concern other
ICS´s (196). In the present study, children used various drugs, and doses were estimated as
the budesonide equivalents.
6.2.2 Peripheral quantitative computed tomography
To our knowledge, there are no previous paediatric studies on the effect of ICS on BMD
measured with pQCT. In the present study, the use of ICS for asthma during childhood was
associated with reduced BMDvol measured by pQCT at the median age of 12.3 years. The
pQCT results are in accordance with the findings with DXA. Increasing cumulative ICS
doses associated with decreasing BMDtot, BMDcort and BMDtrab in the distal radius. The
results were similar after adjusting with potential confounding factors, such as age, sex,
pubertal stage and weight status, and the use of systemic corticosteroids. There were no
significant associations with BMD in the tibia. The present study did not find any agespecific differences in the ICS effect on BMD in pQCT measurements, and we could not
confirm the finding that pre-schoolers are in the critical age for ICS side effects to BMD,
which occurs in the DXA study.
Another new method, the density-related ultrasound, was applied in one study
observing a tendency to reduced BMD in the calcaneal bone of children using ICS
compared with a non-ICS group (187,187). In that study, asthma severity was associated
with decreased BMD and physical activity with higher BMD; both are well-known
confounding factors in BMD measurements. However, the ultrasonography is not
comparable to DXA in diagnostic accuracy (243).
In the present study, data on physical activity were not systematically
collected. Significant findings were in distal radius, whereas BMD in the tibia was not
affected. Tibia is under substantial physical loading, which could prevent bones from
detrimental effects of ICS. The benefits of physical activity to BMD and bone development
are well known (159,161). In the present study, BMD was lower in the radius than that in
the tibia, in agreement with earlier studies, but the correlation between the tibia and the
radius BMD was lower than that in other studies (244).
6.3 METHODOLOGICAL ASPECT
6.3.1 Study design
This study was originally planned to evaluate the treatment of young wheezy children and
to prevent recurrent obstructions, both being common, thus far unresolved issues in
paediatrics. One hundred children younger than 2 years of age were recruited, most of
them during their first wheezing episode. Background data were collected during the index
wheezing episode in hospital, and follow-up data were collected during the prospectively
scheduled follow-up visits, at 4.0, 7.2 and 12.3 years of median age. Only doctor-diagnosed
asthma and other diseases were accepted. During this long-term follow-up study, the term
bronchiolitis was originally used for index wheezing leading to hospitalisation at less than
24 months of age. Currently, early childhood wheezing is the more proper term for virusinduced wheezing in this age group, and it is used in the present thesis.
Increasing evidence has confirmed the relation between asthma and obesity,
obtained mostly from epidemiological and birth cohort studies. At least in adults, asthma
related to obesity is not equal to atopic asthma. This selected data give new information
48
about how obesity affects lung function in children who have suffered from wheezing
provoked by infection in early childhood and are at risk of developing asthma. However,
since obesity was strongly tracked from early school age to later school age, it was not
possible to do any conclusions about the causality. The pulmonary function test results,
both at early and later school age, gave opportunity to evaluate age differences in the
influence of obesity. Atopic sensitisation was also possible to be estimated at both ages.
We used international references to define overweight and obesity, applying a
British reference calculator for counting BMI-SDS. When starting the analyses of this thesis,
the Finnish BMI-SDS curves based on national data were not available, but weight-forheight definitions of childhood overweight and obesity were used. The weight-for-height
definitions vary between preschool-aged and school-aged children and are not
internationally used. The new Finnish age- and height-related, sex-specific BMI curves are
now available (231). The prevalence of obesity, calculated by new references, has remained
nearly the same in boys (4.7% earlier vs. 4.4% currently), but for girls, the new Finnish
references give notably lower figures of obesity (3.2% vs. 1.8%) (79,231). Thus, the
prevalence of obesity would have been slightly lower in the present data, if the new Finnish
BMI-for-age curves would have been used.
The attendance rate at the age of 12.3 years was good, 81% among those
participating in the intervention trial, although the follow-up time was long. In addition, 14
children were hospitalised at the same time, and having fulfilled the inclusion criteria but
refused to participate in the early intervention study, they attended the study visit at a later
school age. This enables statistically relevant combined analyses in the BMD study. The
follow-up data and entry to medical cards gave us reliable information about ICS use and
other used corticosteroid medication. Nutritional, sport, and other lifestyle habits were not
collected during the interview, which may have confounded the BMD results.
In the present study, no control group were recruited. One-third of the children
had not been diagnosed as asthmatic, but only 21 children had never used any ICS; they
were used as an internal control group in the BMD analyses.
In the BMD analyses, ICS use continuously or intermittent, more than 6 months
was considered as a regular use. ICS medication for the prevention of recurrent wheezing
in children at risk of asthma seldom continues for a long time; for asthma, it could continue
through childhood. The overall ICS duration varied greatly, and therefore, we had
difficulties to place the most appropriate time limit for regular use. We decided to use the
shortest period used in previous studies to evaluate association between ICS and BMD,
which has been 6 months (192-194). One aim of the study was to evaluate if there are agespecific associations between ICS use and BMD. Many children need ICS at preschool age
but “grow out” of the wheezing tendency at school age. Because of the limited number of
asthma patients and the varying periods of ICS use, the ICS use was analysed only in two
groups, under school aged and school-aged use.
The results of this study can be generalised to concern children who have
suffered from severe early childhood wheezing. The BMD study results can be assumed
also to reflect changes in BMD in other children using ICS medication.
6.3.2 Strengths of the study
The main strength of this prospective, longitudinal post-bronchiolitis study is the long
follow-up time, up to the median age of 12.3 years and a high participation rate. The viral
49
aetiology of wheezing infection was verified and the atopic sensitisation was tested
(50,216,218,245). The diagnosis of asthma and AD were based on medical examination and
strict criteria (50,212,218). Weights and heights were measured at all control visits with
objective standard methods, allowing a reliable longitudinal BMI monitoring. Risk factors
were carefully evaluated in the previous studies from the same cohort, allowing a proper
use of adjusted analyses. In addition, data on the important confounding factors, such as
pubertal stage and systemic corticosteroid use, were available, together with basic
demographic information.
Although data on the use of ICS were collected retrospectively, which can be
considered as a weakness of the study, ICS use was recorded relatively accurately due to
participation in the follow-up study. In Finland, the diagnosis of asthma and the
prescription of medication for asthma are performed by a paediatrician; hence, diagnostic
accuracy can be considered to be good. The researcher had access to all medical cards, in
hospital and primary health care, to collect the ICS data and data on the systemic
corticosteroid medications.
6.3.3 Limitations of the study
The small number of the patients is a main limitation of the study. The study was evidently
underpowered to reveal all associations between the studied variables. In addition, the
material of the study was selected lessening the generalizability of the results. On the other
hand, the group consisting of children hospitalised for wheezing in early life is important in
health care; their risk for later pulmonary disorders is increased, and therefore, the
knowledge of potential risk factors like obesity is important particularly in them.
Another shortcoming in the BMD study was the lack of bone age measurement
because the Tanner classification is not sufficiently exact in the estimation of pubertal stage
in growth studies. Therefore, we were not able to evaluate the effects of ICS on growth in
height. Physical activities and diets, including vitamin D and calcium intake, were not
systematically recorded, which is also a clear shortcoming of the study.
The numbers of children in the present study were too small for any relevant sexspecific analyses, which need to be counted as a shortcoming because sex is assumed to be one
modifying factor between weight and asthma and atopic diseases. Also, results in previous BMD
studies have been sex specific.
50
7 Conclusions
This prospective follow-up study had two focuses: the associations between weight status
and asthma, atopy, and lung function during teenage years after hospitalisation for
wheezing in infancy and the effect of ICS use during childhood on BMD in early
adolescence. All children had suffered from severe bronchiolitis in infancy, about one-third
of the patients had persistent asthma diagnosis later, and about one-fourth did not receive
any corticosteroid medication during the follow-up time.
In the present study, there was no association between previous or current
overweight or obesity and asthma or BHR at 7.2 or 12.3 years of (median) age. Overweight
was associated with bronchial obstruction, as manifested by decreased FEV1/FVC at 7.2
years and 12.3 years of age and decreased flows in small airways at 12.3 years of age.
Overweight and obesity at early school age preceded reduced FEV1/FVC at age 12.3 years.
Nevertheless, since overweight was highly persistent from early to late school age, the
influence of previous and current overweight could not be assessed separately, and the
present study could not estimate causality. Preliminary evidence was found that obesity
may associate with a reduced risk of allergy at late school age, but the biological
mechanism for this association is unknown and we could not estimate if there is any
causality in this outcome either.
The BMD study revealed that the use of ICS during childhood may reduce
BMD measured at teen age in children hospitalised for wheezing in infancy. High
cumulative ICS doses were associated with reduced BMD in the femoral neck. Reduced
BMD in the lumbar spine and in the femoral neck when apparent volumetric BMD was
calculated was associated to regular ICS use before 6 years of age. Height-adjusted areal
BMD and apparent volumetric BMD gave almost similar results. High cumulative doses
during childhood were also associated with changes in volumetric BMD in the distal
radius, including all its components: total, cortical, and trabecular bone. There were no
significant associations between ICS use and BMD in tibia. The results remain similar when
adjusted for known potential confounding factors: age, gender, pubertal stage, and weight
status and use of systemic corticosteroids.
These results stress the importance of prevention of excessive weight gain in
preschool-aged and school-aged children after early childhood wheezing. The prevention
of overweight may prevent asthma and at least asthma-like symptoms. Asthma treatment
with ICS can have detrimental effects on BMD. However, the clinical manifestations can
occur later, in middle-aged adults or even in the elderly. Titrating ICS medication is
recommended to the lowest possible dose to maintain asthma control. Also, proper asthma
diagnosis with pulmonary function tests is important to target the needed long-term
medication for children. Based on these preliminary results, we recommend considering the
measurement of BMD in children with a long history of ICS medication, especially if they
have other risk factors for low BMD.
Long-term follow-up studies are needed to clarify the complex connections and
causality between asthma, allergic diseases, and weight. Further studies on how ICS during
childhood affects adult BMD and bone mass are needed.
51
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70
A Prospective Follow-Up Study
after Early Childhood Wheezing
Asthma is common disease in childhood. Obesity is increasing health
problem related to asthma. The use
of inhaled corticosteroids (ICS) for
childhood asthma has steadily increased. This long term follow-up
study contains 100 children hospitalized for wheezing in infancy and
followed until 12.3 years of age. In
the present study, we evaluated the
association between overweight and
asthma, allergies and lung function
and ICS´ effect on bone mineral density at early teenage in this asthma
risk group.
dissertations | 203 | Virpi Sidoroff | Weight, Asthma, and Bone Mineral Density
Virpi Sidoroff
Weight, Asthma, and
Bone Mineral Density
Virpi Sidoroff
Weight, Asthma, and
Bone Mineral Density
A Prospective Follow-Up Study
after Early Childhood Wheezing
Publications of the University of Eastern Finland
Dissertations in Health Sciences
Publications of the University of Eastern Finland
Dissertations in Health Sciences
isbn 978-952-61-1312-8
issn 1798-5706

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