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G. C. Sotiropoulos1,2, S. Nadalin2, A. Radtke1,2, H. Lang1,2
Abstract: Liver transplantation (LT) is now a standard treatment for children with end-stage liver disease,with very good 1- and 5-year survival rates, which have been achieved through the constant improvementof surgical techniques and clinical management, and use of new immunosuppressive drugs. The indicationsfor LT in infants and children include acute liver failure, chronic liver failure with pruritus, complications ofcholestasis and failure to thrive. In young children the most common liver disease leading to transplantationis biliary atresia, which accounts for at least 50% of all LTs in children and is characterized by the failure ofthe bile ducts to develop normally and drain bile from the liver. Although the majority of transplanted chil-dren enjoy an excellent quality of life, there are still many possible complications, including short-term pri-mary non-function, vascular and biliary problems, bowel perforation, severe rejection, infection, hyperten-sion with long-term renal impairment, chronic rejection, de novo autoimmunity, lymphoproliferative diseaseand cancer, most of which are related to anti-rejection drug toxicity. This paper focuses on the historical de-velopment of surgical techniques in the era of paediatric LT.
1 Department of General,Abdominal and TransplantSurgery, University Hospital,Johannes GutenbergUniversity Mainz, Germany
2 Department of General,Visceral and TransplantationSurgery, University HospitalEssen, Germany
Correspondence:
Georgios C. [email protected] Klinik für Allgemein-,Abdominal- undTransplantationschirurgie, Klinikum der JohannesGutenberg Universität Mainz, Langenbeckstraße 1, 55131 Mainz, Germany
¶·È‰È·ÙÚÈ΋ 2008;71:87-91
Introduction
Paediatric liver transplantation (LT) is an es-
tablished method of treatment for patients with
end-stage liver failure. Its mortality has de-
creased dramatically since its first description,
thanks to new strategies for immunosuppres-
sion, new surgical techniques (1,2), and the im-
proved overall condition of the patients prior to
transplantation. The introduction of the split-
liver (SL) techniques has dramatically improved
the problem of organ shortage (3,4).
Full-Size LT
The first clinical attempt at liver replacement
was made by Starzl on March 1st, 1963 on a 3
year-old child who had developed end-stage liver
disease from biliary atresia, but “he bled to death
as we worked desperately to stop the haemor-
rhage. The operation could not be completed”
(5). This attempt was followed in 1963 by trans-
plantation of livers into four adult patients, who
all died from pulmonary embolism, after other-
wise successful transplants. Starzl performed the
next eight LTs in infants and children (6) all of
whom survived surgery, but four died after 2-6
months from sepsis. This series of fatal complica-
tions was attributed to inadequate immunosup-
pression, followed by rejection. Between March
1963 and July 1976, 111 LTs were performed at
the University of Colorado, but with a 1-year sur-
vival rate of only 28%. Such poor results were at-
tributed to technical and medical problems (80%)
and acute rejection (20%) (7). From July 1976 to
December 1977, following technical and diagnos-
tic improvements the paediatric 1-year survival
rate doubled from 34 to 62%. Based on these im-
proved results, the development of other LT cen-
tres was undertaken.
In Europe, the first attempt at LT was made on
a 10 month-old child with biliary atresia on June
6th, 1968 in Cambridge, UK, by Sir Roy Calne. As
with Starzl’s first attempt, the child died during
surgery. The first successful LT in Europe was per-
formed by Otte et al. on March 17th, 1971 on a 17
month-old boy with biliary atresia. The recovery
was uneventful until the child developed acute re-
jection, which was reversed by steroids, but he
died 7 weeks after transplantation from massive
intrathoracic bleeding caused by a liver biopsy
(8). Following this case, as in the USA, there was a
long-term moratorium before the LT programme
was finally resumed in 1984. The four children
transplanted that year are still alive, including the
first patient who received a reduced liver graft and
who is currently, worldwide, the longest survivor
with her original cut-down liver (9).
All the early LT patients were treated with a
drug regimen that had been developed for kid-
ney grafts, namely azathioprine and steroids,
sometimes with the addition of antilymphocyte
globulins. Because of inadequate immunosup-
pression, long-term survival was observed in less
than one third of patients. At the beginning of the
1980s, the introduction of cyclosporine led to a
Pediatri Mar-Apr 08 07-04-08 16:23 ™ÂÏ›‰·87
significant increase of graft and patient survival rates.In March 1980, the liver trials with cyclosporine A im-munosuppression began in Denver. Twelve patientsentered the study between March and September1980, of whom 11 lived for one year or longer (10).
In October 1986 representatives of the eight cen-tres in Europe and the USA with experience of at least20 paediatric LTs (i.e., Boston, Brussels, Cambridge,Dallas, Hannover, Minneapolis, Pittsburgh and LosAngeles) met for an update on the status of paediatricLT: long-term (>1 year) patient survival had reached57-83%; all centres were using cyclosporine-basedprimary immunosuppression; the major indications -biliary atresia being the most frequent - were alreadyclearly delineated.
Since the implementation of LT for end-stage liverdisease there has been a strong disparity between organdemand and the cadaveric donor supply for children.This initially resulted in a pre-transplant mortality for
children on the waiting list for LT of around 25%,which was disproportionably high compared with thatof adult patients (11). The problem of size mismatchand the different epidemiology of paediatric donorshipand terminally diseased children were responsible forthe disparity (12). This stimulated the development oftechnical innovations, based on the segmental anatomyof the liver, which facilitated transplanting parts of alarge cadaveric donor liver into smaller recipients: i.e.reduced size LT, split LT and living donor LT.
Reduced size liver transplantation (RSLT)
The first step in solving the size mismatch prob-lem was the introduction of reduced-size techniques.With this approach, after harvesting the liver from acadaver donor, liver resection is performed on theback table to tailor the size of the graft to that of onesingle recipient. The remaining resected liver tissue isdiscarded. In paediatric RSLT either the left lateral
Figure 1b. Adult split liver transplantationRight versus left liver split for an adult recipient, 3-dimensionalreconstruction of the hepatic veins. The line of division lies exactlyover the MHV-middle hepatic vein (yellow). RHV-right hepaticvein (blue), LHV-left hepatic vein (red).
Figure 1c. Adult split liver transplantationLeft liver graft segments 1-4 for an adult recipient, 3-dimensionalreconstruction. The right-sided border of the MHV-middlehepatic vein (yellow) can be seen exposed on the transectionsurface. All tributaries from segments 5 and 8 are exposed at theirconfluence with the MHV trunk. RHV-right hepatic vein (blue),LHV-left hepatic vein (red).
88 G. C. Sotiropoulos et al.
Paediatriki 2008;71:87-91
Figure 1a. Adult split liver transplantationRight versus left liver split for an adult recipient, 3-dimensionalreconstruction. Right graft segments 5-8 (green), left graft segments1-4 (brown). RHV-right hepatic vein (blue), MHV-middle hepaticvein (yellow), LHV-left hepatic vein (red).
Figure 1d. Adult split liver transplantationRight liver graft segments 5-8 for an adult recipient, 3-dimensionalreconstruction. The left-sided border of the MHV-middle hepaticvein (yellow) can be seen exposed on the transection surface. Alltributaries from segments 4a and 4b are exposed at their confluencewith the MHV trunk. RHV-right hepatic vein (blue), LHV-lefthepatic vein (red).
Pediatri Mar-Apr 08 10-04-08 12:37 ™ÂÏ›‰·88
segment (Couinaud's segments II-III) or the full left
lobe (Couinaud's segments II-IV) is usually retained.
The technique as originally described by Bismuth and
Houssin (13) was validated in the late 1980s and later
became standard practice worldwide with 1-year sur-
vival rates of about 80% (14-18).
Although RSLT increases the number of paediatric
donor organs, it does not increase the total number of
organs available for LT, and indeed, it is actually dis-
advantageous to the adult recipient pool, which is
continuously growing (19).
Split liver transplantation (SLT)
The disadvantage of RSLT, namely, a discarded
liver segment, was solved by the introduction of split
liver techniques. SLT evolved from the RSLT and was
first described by Pichlmayr (20). This technique al-
lowed the preparation of two split grafts by dividing
all vascular and biliary structures and parenchyma for
the benefit of two recipients, one recipient receiving a
right lobe graft, and the other receiving either a left
lobe (segments 2-4, Figure 1) or left lateral segment
graft (segments 2-3, Figure 2). Usually the right lobe istransplanted into an adult and the left lobe or the leftlateral segment into a child. In 1989, Pichlmayr andcolleagues were the first to report the transplantationof one donor liver into two recipients (20,21). Thefirst series was reported by Broelsch and co-workers atthe University of Chicago (22) and in the early 1990sthe technique was further validated (23-25).
Technically, SLT is a complex procedure that canbe performed in two ways, ex situ or in situ, both ofwhich require precise knowledge of the liver anatomyand extensive experience with liver resection tech-niques and all the technical modalities of liver graftimplantation. Unfortunately, the wider application ofthe split technique is still hindered by the lack of ex-perience and unwillingness of some centres to splitevery suitable donor liver (26). Recent comprehensivestudies confirm that SLTs generally lead to lessfavourable results for individual recipients, but they
Figure 2d. Pediatric split liver transplantationRemnant liver (segments 1,4-8) including RHV-right hepatic vein(blue) and MHV-middle hepatic vein (yellow) after retrieval of a leftlateral liver graft (segments 2-3) including LHV-left hepatic vein(red) for a child, 3-dimensional reconstruction.
89Paediatric liver transplantation
¶·È‰È·ÙÚÈ΋ 2008;71:87-91
Figure 2b. Pediatric split liver transplantationLeft lateral liver split for a child, 3-dimensional reconstruction of thehepatic veins. The line of division lies exactly over the LHV-lefthepatic vein (red). Main tributaries of the MHV-middle hepaticvein (yellow) draining segments IVa/IVb in the remnant liver arepreserved. RHV-right hepatic vein (blue).
Figure 2c. Pediatric split liver transplantationLeft lateral graft (segments 2-3) including LHV-left hepatic vein(red) for a child, 3-dimensional reconstruction. RHV-right hepaticvein (blue), MHV-middle hepatic vein (yellow) remained with theremnant liver.
has been driven by the shortage of donor organs in
spite of the use of innovative techniques for cadaveric
LT, such as RSLT and SLT (27). In Japan, where organ
procurement from brain-dead donors was not legal
until recently, LDLT was the only option.
LDLT was first reported by Raia et al. in two pa-
tients in 1989 (28). Both recipients died shortly after
the procedure of medical complications, but lived long
enough for the technical feasibility of the procedure to
be established. This was soon followed by a report
from Strong et al. in Australia, where the first success-
ful LT of a child using its mother's left lobe was per-
formed in July 1989 (29). Even before the initial re-
ports by Raia and Strong, an extensive ethical appraisal
of the concept of LDLT was in progress at the Univer-
sity of Chicago, where clinical ethicists and transplant
physicians convened a yearlong series of seminars and
discussions open to the entire university community
(30). The introduction of LDLT required a balance be-
tween the presumed benefits of an elective transplant
for the recipient and the risk of morbidity or even
mortality from LDLT for the donor. At the outset the
main ethical problems the Chicago group had to deal
with for the introduction of paediatric LDLT were the
principle of equipoise and the principle of coercion
(30,31). A proposal derived from these meetings was
submitted to the institutional review board and a suc-
cessful LDLT was performed in November 1989 by Dr.
Broelsch, who subsequently initiated the systematic
use of LDLT for children with end-stage liver disease
(32). Between November 1989 and July 1996, 100
LDLTs were performed, with 1-year patient and graft
survival rates of 88% and 72%, respectively. Similar re-
sults were reproduced worldwide, confirming the ef-
fectiveness of the procedure (33,34).
LDLT has several advantages for the child and for
the transplant population as a whole. First, it increases
the number of organs directly available for the paedi-
atric population. Second, most recipients receive their
transplants on an elective basis and thus should incur
lower morbidity and mortality rates and decreased
overall cost. Third, the minimal cold ischaemia time
and the use of healthy donors may contribute to theabsence of primary non-function. The application ofLDLT for children with end-stage liver disease had aprofound impact on organ waiting list times and de-creased waiting list mortality markedly (35). Paedi-atric LDLT is now accepted therapy for childrenthroughout the world and frequently accounts for50% or more of all paediatric LTs performed at re-gional referral centres (35).
Despite the impressive results of LDLT, consider-able debate persists concerning donor safety. Therisks to the donor include those associated with inva-sive pre-surgical testing and with the surgical proce-dure. These risks are accepted by the potential donorsin exchange for the knowledge that the child's life maybe saved without the uncertainty of the cadavericwaiting list. The most recent donor outcomes frommultiple centres have been excellent (36-38).
The development of segmental hepatic grafts hasexpanded the supply of size-appropriate organs, al-lowing children who otherwise would have died onthe waiting list the opportunity to undergo LT. Re-cently the association between graft type, recipient ageand graft survival has been better defined: amongchildren <3 years of age, LDLT provides superiorgraft survival compared to RLT and SLT. In olderchildren it appears that cadaveric organs may offer abetter outcome (39,40). While RLT and SLT graftsproduce an overall inferior outcome in the nationalexperience, they remain an important and necessarytool in paediatric centre armamentarium. They pro-vide appropriately sized grafts for children with nosuitable living donor and for those for whom no ca-daveric paediatric donor is available, and they canyield an excellent outcome in experienced centres. Itis apparent that the technical complexities and peri-operative events surrounding these procedures have asignificant impact on the outcome. This emphasizesthe importance of experience, attention to continuedtechnical refinement, and judicious selection of ap-propriate donors for specific recipients.
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92 ∞¡∞™∫√¶∏™∏ REVIEW ARTICLE
Paediatriki 2008;71:92-95
The definition of childhood obesity
The Body Mass Index (BMI) is the most prac-
tical measure of obesity and it is used in growth
monitoring to assess fatness. The BMI charts for
boys and girls (Tables 1 and 2) show the recom-
mended International Obesity Task Force cut-off
points for obesity and overweight in children. Th-
ese correspond to the adult definitions of over-
weight (BMI >25) and obesity (BMI >30) at age
18 years. Rapid changes in BMI can occur during
normal growth. The BMI is recommended as a
practical estimate of overweight in children and
adolescents, but it needs to be interpreted with
caution as it is not a direct measure of adiposity.
For epidemiological purposes overweight
should be defined as BMI greater than or equal to
the 85th centile of the 1990 reference data, and
obesity as BMI greater than or equal to the 95th
centile of the 1990 reference data.
The international epidemic of childhood
obesity
The definitions of overweight and obesity in
children differ between epidemiological studies,
making comparisons of cross-sectional data dif-ficult. The rates have increased threefold over 25years in the USA and fourfold over 18 years inEgypt (see the international childhood obesitymap) (1,2).
Consequences of childhood obesity
Childhood obesity is a multisystem diseasewith potentially devastating consequences. Itcauses hypertension, dyslipidaemia, increasedblood clotting tendency, endothelial dysfunctionand hyperinsulinism. Type 2 diabetes mellitus,once virtually unknown in adolescence, is largelyattributable to childhood obesity (4). A prediabet-ic state of glucose intolerance and insulin resis-tance appears to be highly prevalent among se-verely obese children irrespective of ethnic group.Type 2 diabetes is almost entirely attributable tothe childhood obesity epidemic, although heredi-tary and life-style factors affect individual risk.
Pulmonary complications include sleep-dis-ordered breathing (sleep apnoea), asthma andexercise intolerance. The development of exer-cise intolerance in an obese child can limit phys-ical activity and thus lead to further weight gain.
Childhood obesity – A public health crisis across the
European Union
A. J. Nicholson, S. Del Torso, A. Hadjipanyidis, D. Van Esso
Abstract: In the past, a fat child meant a healthy child, but in the last decade, excessive fatness or obesityhas become the primary paediatric health issue in the EU. It is known that some 10% of children are eitheroverweight or obese, and that obesity worldwide, apart from in sub-Saharan Africa, has reached epidemicproportions, with a threefold or more rise in most European countries since the 1980s (1,2,14,18). The maincauses of the obesity epidemic are clear - overeating, especially of foods rich in fats, extracted sugars orrefined starches, and a progressive decline in physical activity. The management of this epidemic dependson the successful motivation of people to eat less, to eat healthier foods and to exercise more, all of whichare difficult to achieve in societies where fruit and vegetables are less available than high-fat processedfoods, and where exercise no longer plays a regular part in most people’s lives. Management of childhoodobesity is time-consuming, frustrating, difficult and expensive (18). Adult obesity is the strongest predictorof childhood obesity; if both parents are obese, the chance of their child being obese increases tenfold.Breast feeding exerts a small protective effect against obesity. Television viewing is important, as it is knownthat for each additional hour of television watched at 5 years of age, the risk of adult obesity rises by 8%(7,8,18). Long-term increase or decrease in activity levels will influence whether a child becomes obese.Studies have implicated inactivity, with over 4 hours TV or computer use, and consumption of takeawayfoods more than twice weekly and fizzy drinks in the rising rates of obesity. Prevention of obesity will occuronly if there are fundamental changes in society, involving the production and availability of cheap healthyfoods, urban planning to ensure that people exercise more, education about eating, beginning in schools,and a global code to promote only healthy food and drink to children and adolescents. The vast majority ofobese children have primary obesity due to a disturbed energy balance. A very small percentage (5%) havea genetic cause for their obesity, and only very rarely are hormonal causes found.
Primary / Secondary CareGroup of the EuropeanAcademy of Paediatrics
Correspondence:
Alf [email protected] Lady of Lourdes Hospital,Drogheda, Co. Louth, Ireland
Pediatri Mar-Apr 08 07-04-08 16:23 ™ÂÏ›‰·92
93Childhood obesity
¶·È‰È·ÙÚÈ΋ 2008;71:92-95
Childhood obesity, of course, has substantial psy-chosocial consequences, and overweight children candevelop a negative self-image at as early as 5 years ofage, while obese adolescents show diminishing de-grees of self-esteem associated with sadness, loneli-ness and risk-taking behaviour (3,15).
Causes of childhood obesity
Genetic causes
In 1997, two massively obese Pakistani children ofconsanguineous parents were found to have a muta-tion in the gene encoding leptin and since then fivegenetic mutations causing obesity have been identi-fied, all presenting in childhood (5,6).
Prader-Willi syndrome (PWS) is a rare cause ofobesity, with a deletion of chromosome 15 and fea-tures of a voracious appetite, poor linear growth,small hands and genitalia and dysmorphic features.Progress has been made in mapping the genetic loci ofPWS but the molecular cause of this obesity syn-drome has not yet been identified.
Thus, single gene defects account for a very smallfraction of human obesity and predisposition to obe-sity appears to be related to a complex interaction be-tween at least 250 obesity-associated genes.
Physical activity
A lifestyle characterized by a lack of physical activ-ity and excessive television viewing has been shown tobe associated with childhood obesity. Among chil-dren from Mexico City, the risk of obesity decreasedby 10% for each hour of moderate to vigorous physi-cal activity and increased by 12% for each hour perday of television viewing.
Television viewing
Television viewing is thought to promote weightgain not only by displacing physical activity but alsoby increasing energy intake (7,8). Children tend topassively consume excessive amounts of energy-dense
foods while watching television. Furthermore, televi-
sion advertising could adversely influence dietary pat-
terns at other times throughout the day. Screen time
for children of over 2 years should be limited to no
more than 1 to 2 hours per day (18).
Diet
Children who were bottle fed appear to be at
greater risk of obesity later in childhood than those
who were breast fed (9).
Sugar-sweetened soft drinks have been the subject of
several studies, which have shown that the total energy
intake was 10% greater among children who consumed
soft drinks than in those who did not (18). Increasing
portion sizes are also a factor. Fast food typically incor-
porates potentially adverse dietary factors including sat-
urated fat, a high glycaemic index, high energy density
and, increasingly, large portion size. A large fast food
meal could contain 2,200 kcal, which, at 85 kcal per
mile, would require a full Marathon to burn off.
Breakfast skipping, snacking and eating out (in par-
ticular at fast food establishments) are all associated
with obesity (18). The ‘traffic light diet’, recommended
for consumption by children in the age-group 6 to 12
years, consists of low energy, high nutrient foods such
as fruit and vegetables (green), moderate energy foods
(orange) and high energy foods (red). ‘Green’ foods
may be eaten often, ‘orange’ foods in moderation and
‘red’ foods should be eaten sparingly (10,18).
Family factors
Parent-child interactions and the home environ-
ment can affect the risk of developing obesity. Tradi-
tional family meals tend to decrease television viewing
and improve dietary quality; the child takes a diet with
less saturated and trans fats, less fried foods, lower
glycaemic load, more fibre, fewer soft drinks and
more fruit and vegetables.
Table 2. Tests to be considered in obesity
Secondary causes of obesity are exceedingly rare; most obesityis what is termed simple obesity, and no investigations arerequired. - Short stature/hypertension/striae - morning and evening
cortisol levels (to exclude Cushings disease)- Short stature/goitre/hip pain - thyroid function tests , hip
X-ray to exclude slipped capital femoral epiphysis- Small hands and feet/voracious appetite - karyotype, FISH
blood sugar levels, glucose tolerance test (Diabetes)- Hirsutism/obesity/absence of periods - blood testosterone
level, ultrasound scan of ovaries showing numerous cysts(polycystic ovary syndrome)
Table 1. Complications of obesity
Short-term Long-term
Poor self-esteem/depression Persistence of obesityAsthma Social stigmatisation Sleep apnoea Sleep apnoeaType 2 diabetes mellitus Type 2 diabetes mellitusOrthopaedic problems Osteoarthritis(e.g. slipped epiphysis)Hypertension/ Hypertension/high cholesterol high cholesterolEarly puberty/ Menstrual irregularities/polycystic ovaries hirsutismGallstones Gallstones
Pediatri Mar-Apr 08 07-04-08 16:23 ™ÂÏ›‰·93
Prevention and treatment
Prevention and treatment ultimately involves eat-
ing less and exercising more. Most efforts to reduce
obesity in children have used family-based or school-
based approaches and only in severe cases are phar-
macological and surgical treatments considered. Fol-
lowing a review of randomised controlled trials, Eb-
stein et al. (10) concluded, somewhat soberly, that
most interventions to treat childhood obesity are
marked by only small changes in weight or BMI and
very high rates of subsequent relapse.
School-based interventions have been oriented to-
wards prevention of obesity, targeting all children. The
Pathways programme (12), for American Indian chil-
dren at high risk of type 2 diabetes and cardiovascular
disease, aimed to reduce dietary fat consumption and
increase physical activity. This 3-year programme pro-
duced a significant decrease in fat consumption and a
trend towards increased physical activity but the BMI
did not differ between children in the intervention and
the control schools at the end of the programme. The
Planet Earth trial (11) focussed largely on changing the
school environment over two school years to include
reduced television viewing, increased physical activity,
decreased fat intake, increased fruit and vegetable in-
take, altered class curricula and extensive education of
families. In this trial there was a significant reduction
in obesity in girls (absolute risk 0.47, CI 0.24-0.93),
with trends in the same direction in boys, although not
reaching statistical significance. The authors reported
that the effect observed was largely attributable to ob-
served reductions in television viewing.
Most children managed in the community will have
simple obesity with no underlying medical cause and
without comorbidity. Treatment should be offered
when the obese child and family are willing to make the
necessary life-style changes. For children who are over-
weight and most children who are obese, weight main-
tenance is an acceptable goal (13). Weight maintenance
can only be achieved by sustained behavioural changes,
including healthier eating, an increase in physical activ-
ity to a minimum of 30 minutes per day and reduction
of physical inactivity (e.g., watching television or play-
ing computer games) to less than 2 hours per day. Par-
ticular attention should be given to methods for in-
creasing physical activity in adolescents (18).
Suggestions for parents
Suggestions for increasing physical activity:
- any increase in activity will help,
- aim for simple changes at first, such as walking,
cycling and using stairs rather than lifts,
- develop an active life-style for the whole family,
- encourage active play that is enjoyable and do all
you can to keep exercise fun,
- decrease TV viewing and other sedentary activities,
- schedule unstructured free playtime on a daily
basis.
Dietary suggestions:
- a balanced, varied diet for the whole family,
- serve meals at regular times; avoid ‘grazing’ and
TV snacks,
- serve smaller portions,
- avoid snacks as rewards or treats,
- offer healthy snacks (e.g., fruit) as alternatives to
sweets, chocolates, potato crisps, biscuits and cakes,
- use less energy dense food (e.g., semi-skimmed
milks and low fat spreads),
- provide whole foods that take time to eat (e.g.,
fruits and wholemeal bread),
- promote low calorie drinks (preferably water),
- ensure at least five portions of fruit and vegeta-
bles per day,
- grill, boil or bake foods rather than frying them,
- “Eat to live, don’t live to eat”,
- pare down the amount of ‘junk’ food in the house,
- comfort with attention, listening and hugs in-
stead of food.
The perfect meal plan
Modern families may rarely sit down to a meal
all together, and one major suggestion is to bring
back the traditional family meal; the perfect meal
plan entails:
- firstly turn off the TV,
- involve children in the cooking process,
- switch mobile phones to silent,
- make sure that everyone sits down together at the
table,
- serve the plates from a central location to ensure
control over portion sizes,
- the meal should last at least 20 minutes,
- share the positive events of the day,
- be mindful while eating of the colour, texture
and smell of the food,
- make dessert a continuation of the meal and not
something too special,
- substitute fruit for dessert at times,
- parents, not children, should be responsible for
food decision making,
- limit soft drink consumption.
Drug treatment for obesity
Drug treatment is not recommended for chil-
dren under 12 years, and in adolescence it is only
94 A. J. Nicholson et al.
Paediatriki 2008;71:92-95
Pediatri Mar-Apr 08 09-04-08 10:36 ™ÂÏ›‰·94
95Childhood obesity
¶·È‰È·ÙÚÈ΋ 2008;71:92-95
recommended in situations where there are medicalcomplications (orthopaedic complications or sleep ap-noea) or severe psychological issues arising from theobesity. Medication used as part of a structured life-stylemodification produces an average weight loss of 5 to10%, which typically reaches a plateau at 4 to 6 monthsof treatment, and weight regain is common after thedrug is withdrawn (16,18). Prescribing should be madeby a specialist multidisciplinary team. The drugs usedare orlistat and sibutramine and they are generally usedfor a 6-12 month trial with regular reviews of effective-ness, adverse effects and adherence. Sibutramine is anappetite suppressant and orlistat works as a reversible li-pase inhibitor (18). Drug treatment may be used to helpthe adolescent maintain weight loss as well as to contin-ue to lose weight. Four experimental drugs have pro-duced weight loss in small studies involving childrenwith special conditions, specifically, metformin in obeseadolescents with insulin resistance, octeotride for hypo-thalamic obesity, growth hormone in Prader-Willi syn-drome and leptin for congenital leptin deficiency (17).
Bariatric surgery for obesity
Surgery is generally not recommended for chil-dren and adolescents and constitutes, at best, a last re-sort for severely obese adolescents. Exceptional cir-cumstances in which surgery might be considered arewhen the BMI is >40, or when in the case of a signifi-cant complication, such as hypertension or type 2 di-abetes that could be improved by weight loss, all ap-propriate non-surgical measures have failed or whenthey are receiving intensive care.
Key points to remember
- Obesity is now the commonest chronic condi-tion affecting children across the EU.
- Obesity is due to an imbalance between energyconsumption and energy expenditure. Obese childrendo not have low energy needs.
- Family support is necessary for treatment tosucceed.
- Generally the aim of treatment is to help childrenand adolescents to maintain their weight.
- In younger children the main impact of obesity issocial and emotional rather than medical.
- A medical cause for obesity is more likely in chil-dren who are both short and obese for age.
- Most children are not obese because of an under-lying medical problem, but rather as a result of theirlife-style.
- Weight reduction or stabilization goals shouldalways be kept reasonable.
- The major calorie culprits are high-fat fast food,large portions and sugar-containing soft drinks.
- If a child is at risk of obesity due to family histo-
ry, the earlier the modifications (e.g., reducing TV
time) the better.
References
1. Strauss RS, Pollack HA. Epidemic increase in childhood
overweight, 1986-1998. JAMA 2001;286:2845-2848.
2. Ebbeling CB, Pawlak DB, Ludwig DS. Childhood obesity:
public-health crisis, common sense cure. Lancet 2002;360:
473-482.
3. Strauss RS. Childhood obesity and self-esteem. Paediatrics
16. Glazer G. Long-term pharmacotherapy of obesity 2000: a
review of efficacy and safety. Arch Intern Med 2001;161:
1814-1824.
17. Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham
CH, Prentice AM, et al. Effects of recombinant leptin ther-
apy in a child with congenital leptin deficiency. N Eng J
Med 1999;341:879-884.
18. Spear BA, Barlow SE, Ervin C, Ludwig DS, Saelens BE,
Schetzina KE, et al. Recommendations for treatment of
child and adolescent overweight and obesity. Pediatrics
2007;120:S254-S288.
Pediatri Mar-Apr 08 09-04-08 10:36 ™ÂÏ›‰·95
96 ∞¡∞™∫√¶∏™∏ REVIEW ARTICLE
Paediatriki 2008;71:96-104
Use of the new World Health Organization growth standards
in the prevention of childhood overweight and obesity
M. Ponce-Rivera, D. Fuentes-Lugo
Abstract: The prevalence of overweight and obesity in young children continues to rise in most parts ofthe world. Obese children have a significantly higher risk of becoming obese adults, which underlinesthe importance of adequate growth monitoring from early ages. Different international references forgrowth assessment are currently being used by paediatricians in most countries. This review examinesthe differences between the Centers for Disease Control (CDC) growth reference and the new WorldHealth Organization (WHO) growth standards for children of less than five years when used asdiagnostic tools for the detection of excess weight. It also includes preliminary results from aretrospective study conducted in a cohort of 300 healthy children from a paediatric clinic in Mexicoevaluating differences in overweight prevalence depending on the growth reference employed. Resultsshowed a higher prevalence of overweight and obesity with WHO standards than with the CDCreference in children from 1 through 5 years of age, independent of gender, in agreement with otherstudies. Use of the new WHO growth standards is emphatically encouraged for both routine clinicalpractice and epidemiological research, in order to avoid potential pitfalls and inaccuracies whenmonitoring child growth and to detect childhood overweight and obesity effectively. The new WHOstandards provide a unique opportunity for redesigning child overweight surveillance and preventionprogrammes so that they become more useful for detection and decision making and less complicatedfor gathering epidemiological data.
both sexes, rectal cancer and malignant melanoma in
men, and gallbladder, pancreas, endometrial and post-
menopausal breast cancers in women.
Several theories have been formulated to account
for the obesity epidemic. Clearly, the main causes are
overeating and lack of physical activity. However, it is
of paramount importance to identify all the risk factors
that predispose an individual to become obese (17).
There appears to be a direct causal relationship be-
tween childhood overweight and maternal pre-preg-
nancy body size, maternal smoking during pregnancy
(18), early weaning (19), rapid growth (20) and chil-
dren’s use of television and media, while breastfeeding
appears to have a protective effect against overweight
(21). Further studies are needed to elucidate the exact
mechanisms by which these factors influence child-
hood adiposity, for example, its relationship with so-
cioeconomic status (22). Some authors have claimed
that, although clinically irrelevant, temperament may
be slightly related to overweight and rapid early weight
gain in infants (23). Others have proposed that a high
early protein intake, particularly from dairy products,
increases obesity risk (24,25). Some studies suggest that
sleep deprivation may influence weight through effects
on appetite, physical activity, and thermoregulation
(26). Short sleep duration appears independently asso-
ciated with weight gain in younger age groups (27).
Unfortunately, to date, scientific evidence regarding
risk factors for childhood obesity is still insufficient,
with much of the literature being of limited quality, in-
conclusive and contradictory (28).
There is strong evidence to suggest a direct rela-
tionship between weight status in childhood and
eventual adult obesity, but many studies are based on
cross-sectional data or have relatively long periods of
time between measurements. It is now accepted that
obesity in adolescence is highly predictive of obesity
in adulthood. Therefore, an important next step will
be to identify those young children at greatest risk of
developing obesity in adolescence, and to intervene
before chronic overweight is established during early
childhood. Children who are found to be overweight
at least once at ages 24, 36 or 54 months during the
preschool period are 5 times more likely to be over-
weight at age 12 years than those who are below the
85th percentile for BMI at all three of the preschool
ages. The longer a child remains in the lower range of
normal BMI, the less likelihood there is that the child
will become overweight by early adolescence (29).
Adequate detection of overweight and
obesity in childhood
Not long ago, a fat child meant a healthy child, and
the concept of “bigger is better” was widely accepted by
parents, paediatricians and caregivers. Such a point of
view belongs to the past, however (30), and at present,
child obesity is one of the most evident, yet most ne-
glected public health problems in the world. Although
the problem is well recognized, most obesity preven-
tion measures worldwide have been small, timid and
ineffective to halt the epidemic (31). Arguably, ‘globe-
sity’ might have been detectable earlier if a prescriptive
reference had been available 20 years ago, and even
now the first problem that needs to be addressed is
agreement of a definition of true obesity. Some of the
contradictory childhood obesity rates seen in the liter-
ature are a direct consequence of using different crite-
ria to define overweight and obesity. The main pur-
poses for defining overweight and obesity are to pre-
dict health risks and to provide comparisons between
populations. For practical reasons, the definitions have
usually been based on anthropometry, but regardless of
which definition is used, the increasing rates have high-
lighted the relevance of the problem (32).
Obesity is defined as an excess of body fat or adipose
tissue. It is actually fat and not weight which is associat-
ed with all the comorbid conditions. Measuring fat is
not as straightforward as measuring weight; therefore
weight, rather than adiposity, is the usual clinical mark-
er for identifying obesity. Although body weight tends
to be associated with adiposity, weight alone is an insuf-
ficient measure of obesity by itself, because it is correlat-
ed with height (33). To avoid this limitation, a number
of measures of weight in relation to height have been
devised over the years. The simplest and most frequent-
ly used are weight-for-height and the BMI.
BMI is a practical indirect measure of adiposity, al-
though the relationship changes according to age, sex
and ethnicity, but also degree of fatness. A child’s BMI
can be compared with a reference data set and be con-
verted into a Z-score. A BMI Z-score of 0 is equivalent
to the median or 50th percentile value, a Z-score of
+2.00 is approximately equivalent to the 98th per-
centile and a Z-score of +2.85 is >99th percentile.
Some authors postulate that even though BMI Z-score
Pediatri Mar-Apr 08 07-04-08 16:23 ™ÂÏ›‰·97
98 M. Ponce-Rivera, D. Fuentes-Lugo
Paediatriki 2008;71:96-104
is optimal for assessing adiposity on a single occasion,
it is not necessarily the best scale for measuring change
in adiposity, as the within-child variability over time
depends on the child’s level of adiposity (34).
Use of BMI index charts during a paediatric health
supervision visit increases physician recognition of
overweight patients better than height-for-weight
charts (35). Regrettably, BMI charts are not routinely
used (36) and due to ineffective detection not all chil-
dren with overweight receive either a formal diagnosis
or treatment (37). A study conducted among public
and private practice paediatricians in the US revealed
that they identified overweight in only 27% of children
with BMI at the 85th-94.9th percentile and up to 86%
with a BMI at or above the 95th percentile (38). Rate
recognition by physicians increased as the severity of
obesity increased. US paediatricians may not use BMI
charts because they recognize obesity empirically when
they see it, at least when the BMI is above the 95th per-
centile. However, they may overlook excess weight in
children with BMI at the 85th-94th percentile, perhaps
because these children seem fairly normal.
Adequate growth and weight gain should concern
not only paediatricians and child caretakers but also
parents (39). One study showed that parents of
younger children were significantly more likely to un-
derestimate overweight (65%) than parents of adoles-
cents (51%). Overweight parents were not more like-
ly to underestimate weight, nor was accuracy associat-
ed with parental education or socieconomic status.
Parental recognition of childhood overweight may be
improved with BMI screening and feedback (40).
Growth references versus growth standards:
which should be used?
Growth references are a fundamental tool for the
interpretation of anthropometric data. Classifying a
child as overweight or obese assumes that such a child
is comparable to the reference population, so choos-
ing the right tool for proper detection is mandatory
(41). In the US, reference growth charts based on na-
tionally representative surveys have been produced
since 1977. An expert committee recommended their
use for children and adolescents, with the 95th BMI
percentile for age and sex (or BMI 30 kg/m2) as the
cutoff points for overweight and the 85th percentile as
“at risk of overweight” for screening purposes. The
fact that the committee decided not to use the term
‘obese’, which they associated with excess fat rather
than weight, has lead to some confusion (42).
In May 2000 the US Centers for Disease Control
(CDC) released new growth charts to replace the 1977
NCHS reference. The CDC-2000 charts were based
on five nationally representative surveys conducted
between 1963 and 1994. This reference, currently
used in about 100 countries, is based on data from
several samples of children from a single country and
suffers from a number of technical drawbacks that
makes it inadequate for monitoring growth in early
childhood. A survey reported that CDC-2000 is the
growth reference most commonly used worldwide.
Another interesting fact from this international study
is that most paediatricians prefer using percentiles
rather than Z-scores (43). The use of Z-scores offers
advantages over the use of percentiles; for instance,
when conducting epidemiological studies, Z-scores
allow easier comparison between growth references.
In the late 1990s, the International Obesity Task
Force (IOTF) determined that although BMI was not
ideal as a measure of adiposity, it could be used to de-
fine overweight and obesity in children and adoles-
cents. IOTF recommended cutoff points based on
age-specific values that project to the adult cutoff
points of 25 kg/m2 for overweight and 30 kg/m2 for
obesity. Using data collected between 1963 and 1993
from six different populations (Great Britain, Brazil,
the Netherlands, Hong Kong, Singapore and USA)
IOTF published their reference curves in 2000 (44).
These are useful mainly for epidemiological research,
since children and adolescents can only be categorized
as non-overweight or overweight/obese. Since the
adult cutoff points of BMI 25 and 30 may not be uni-
versally applicable, the IOTF curves are inappropriate
for some child populations. A number of reports have
shown that these cutoff points substantially underes-
timate the prevalence of childhood obesity in differ-
ent settings (45). In short, the IOTF reference appears
to be a less adequate tool for detecting overweight and
obesity in clinical practice compared with methods
based on percentiles or Z-scores.
WHO 2006 Child Growth Standards
The WHO 2006 Child Growth Standards are the
product of a long systematic process which started in
the early 1990s. They are based for the first time on a
prospective, prescriptive, international sample of in-
fants selected to represent optimum growth (46). The
WHO Multicenter Growth Reference Study (MGRS)
was designed to provide data that describe how chil-
dren should grow from birth to five years under opti-
mal environmental conditions, rather than describing
their growth in a particular time and place, and there-
fore, they can be applied to all children everywhere,
regardless of ethnicity, socioeconomic status and type
of feeding (47).
The MGRS was carried out from July 1997 to
Pediatri Mar-Apr 08 07-04-08 16:23 ™ÂÏ›‰·98
December 2003 as a population-based study coveringthe cities of Davis, California, USA; Muscat, Oman;Oslo, Norway; and Pelotas, Brazil, together with se-lected affluent neighborhoods of Accra, Ghana andSouth Delhi, India. The WHO combined a longitudi-nal follow-up from birth to 24 months with a cross-sectional component of children aged 18-71 months.The study population lived under socioeconomicconditions favourable to growth. The individual in-clusion criteria were: no known health or environ-mental constraints to growth, mothers willing to fol-low MGRS feeding recommendations (exclusive orpredominant breast-feeding for at least 4 months, in-troduction of complementary foods by 6 months ofage, and continued breast-feeding to at least 12months of age), no maternal smoking before and afterdelivery, single term birth and absence of significantmorbidity (48). Prior to their release, the standardswere field-tested in four countries: Argentina, Italy,Maldives and Pakistan (49).
One important feature of the WHO standards tobear in mind is that it makes breast-feeding the bio-logical norm and establishes the breast-fed infant asthe normative growth model (50). The previous refer-ences were based mostly on the growth pattern of ar-tificially-fed children. The WHO-2006 standardsdemonstrate that healthy children from around theworld who are raised in healthy environments andfollow recommended feeding practices have similarpatterns of growth. This indicates that the same po-tential for growth should be expected in any country.It also implies that deviations from this ideal growthpattern must be assumed to reflect adverse conditionsthat require correction (51).
Since there are substantial differences in methodol-ogy, cutoff values and selected population between thevarious growth references, it is expected that signifi-cant changes would be found when one reference iscompared to another, even if they are from the samecountry. For instance, the CDC-2000 reference under-
estimates the weight-for-height Z-scores of individual
children compared to the 1977 NCHS reference, both
of which are references derived from American chil-
dren. A child classified as close to +3 Z-score using the
1977 NCHS reference will be just below +2 Z-score
when the CDC 2000 reference is applied (52).
Few studies have compared the 1977 NCHS crite-
ria for defining overweight or obesity with the CDC-
2000 reference curves and the IOTF alternative set of
cutoff points. In younger children, the IOTF curves
gave significantly lower estimates for the prevalence of
obesity. One study involving 258 Italian children (av-
erage age 4.8 years) found that the CDC -2000 refer-
ence led to a significantly higher prevalence of obesity
in both males and females when compared to the
growth charts of the IOTF (53). BMI cutoff points
from the CDC and IOTF have relatively high specifici-
ty, but lower sensitivity, meaning that children with
normal weight are unlikely to be wrongly labelled, but
overweight and obese children may be missed. Detect-
ing a child with overweight depends basically on which
reference and which cutoff value is used, and this
clearly represents a major problem (Tables 1 and 2).
When CDC-2000 reference curves are compared
with the new WHO-2006 standards, significant dif-
ferences are found that vary by age group, growth
Table 2. Body mass index (BMI) cutoff values for obesity fromIOTF and WHO-2006 growth standards in children aged 2 to 5years
indicator and Z-score curve. The main differences in
weight-for-age Z-score curves occur during infancy
(Graph 1). Regarding weight-for-length Z-score
curves for boys, estimates of overweight and obesity
are higher when based on the WHO standards (54).
The change in the shape of the curves is probably
due to issues related to study design and the charac-
teristics of the sample, as well as differences in the
type of feeding. The CDC used samples of less than
100 infants per age group during the first six
months; consequently, the CDC-2000 curves proba-
bly fail to capture the rapid and changing rate of
weight gain in early infancy. The WHO-2006 stan-
dard is based on a much larger sample size (428 boys
and 454 girls) and shorter measurement intervals.
These design characteristics allowed the WHO
curves to capture rapidly changing patterns of
growth in early infancy.
Comparison of weight-for-length and weight-for-
height chart shows that CDC-2000 children were
generally heavier than those included in the WHO-
2006 sample. The BMI-for-age curves are dramatical-
ly different, partly reflecting obesity in the US sam-
ple. This flaw makes the CDC-2000 weight-for-
height curves inadequate for monitoring obesity
from 100 cm onwards. In addition, the pattern of
lower centiles of the CDC weight-for-length chart
below 53 cm may reflect peculiarities of the birth
registry data used to design the CDC curves (55). In
summary, the CDC-2000 charts provide a growth
reference rather than a prescriptive standard, such as
the WHO-2006.
Based on this rationale, a retrospective study was
conducted in a cohort of healthy children from a sin-
gle paediatric clinic in Mexico City in order to assess
differences between the CDC-2000 reference and the
new WHO-2006 standards (56). Among the main
outcomes examined were differences in estimated
overweight/obesity prevalence. From the files with
complete weight and height records from birth up to
five years of age, 300 children (167 boys and 133 girls)
were randomly selected. Children with a history of
chronic disease were excluded. Weight-for-age,
height-for-age, weight-for-height and BMI per-
centiles and Z-scores were obtained at 0, 12, 24, 36, 48
and 60 months of age (±2 months). To classify chil-
dren with overweight or obesity, Z-score values of
+2.00 S.D. and +3.00 S.D. respectively, were used.
Anova regression analysis was performed to compare
the curves from birth to five years of age derived from
the two reference instruments.
Using weight-for-height as an anthropometric
marker, the results showed a relatively low prevalence
of overweight in the complete cohort between the first
and second years of age with both references, al-
though the prevalence using the WHO-2006 stan-
dards was significantly different from that obtained
z-BMI for girls(n=133)
Age
2 3 4 5
Z
1
0.5
0
-0.5
-1
WHO 2006
CDC 2000
Graph 3. WHO Growth Standard versus CDC Growth Reference.
z-BMI for boys(n=167)
Age
2 3 4 5
Z
1
0.5
0
-0.5
-1
WHO 2006
CDC 2000
Graph 2. WHO Growth Standard versus CDC Growth Reference.
Table 3. Prevalence of overweight (including obesity) usingweight-for-height Z-scores from the CDC-2000 growth referenceand WHO-2006 growth standards during the first year of life
Boys GirlsWHO CDC WHO CDC
+2 S.D. +2 S.D. +2 S.D. +2 S.D.
Birth 0% 0.59% 0% 3%1 year 2.39% 0% 2.25% 2.25%
100 M. Ponce-Rivera, D. Fuentes-Lugo
Paediatriki 2008;71:96-104
0.80.60.40.2
0-0.2-0.4-0.6-0.8
0 1 2 3 4 5 6 7 8 9 10 11 12Age (months)
Mean weight-for-age Z-scores
NCHSCDCWHO
Graph 1. WHO Growth Standard versus CDC-2000 and NCHS-1977 Growth References (adapted from references 52 and 54).
Pediatri Mar-Apr 08 07-04-08 16:23 ™ÂÏ›‰·100
101Prevention of childhood overweight and obesity
¶·È‰È·ÙÚÈ΋ 2008;71:96-104
with the CDC-2000 reference (1.33% versus 0.66%
overweight). The main differences in the weight-for-
height Z-score were observed from 12 to 36 months of
age. At 1 year of age, differences were found for the
boys but not the girls (Table 3). The prevalence of
overweight increased markedly at age 4-5, but with
significant differences between CDC and WHO
scores regardless of gender.
It was not possible to compare Z-BMI curves be-
tween the two references during the first two years be-
cause such data is not included in the CDC-2000
growth curves. When BMI Z-score was used to iden-
tify overweight (+2.0) and obesity (+3.0), there were
statistically significant differences between the two
references (p<0.001) for both boys and girls from 2 to
5 years of age. Although the median values of the BMI
Z-score were within the normal weight range with
both references, the WHO-2006 curve pattern was al-
ways above the CDC curve pattern for both boys and
girls from age 2 years to 5 years (Graphs 2 and 3). In
addition, the prevalence of overweight and obesity us-
ing WHO standards was higher than the prevalence
found when CDC growth references were used
(Graphs 4 and 5). Furthermore, as pointed out else-
where, the weight-for-height Z-score proved to be of
lesser sensitivity in detecting overweight accurately
when compared to the BMI Z-score, with both refer-
ences (p<0.001).
Final comments
The shift to the new WHO standards provides a
unique opportunity not only to monitor linear
growth, but also to redesign surveillance programmes
so that they are more useful for problem detection
and decision making, and less complicated for gather-
ing epidemiological data (57). The WHO standards
would set a markedly lower standard for weight gain
beyond 4 months of age, and could thus support ef-
forts to avoid future childhood obesity (58). Howev-
er, there is evidence that they might not be appropri-
ate for use across all populations, and specifically
some populations in Asia (59) and Africa (60). One
study conducted in refugee camps in Algeria, Kenya
and Bangladesh showed important differences in the
weight-for-height cutoff points used for defining
acute malnutrition between those obtained from the
WHO standards and those derived from the NCHS
reference. The WHO standards apparently resulted in
a higher measured prevalence of severe acute malnu-
trition. For such reasons, assessment of the new WHO
growth standards in different populations and envi-
ronments is recommended. Compared to previous
international references they appear to be more accu-
rate and easier to interpret. In addition, last year
WHO published a second set of standards that in-
clude head circumference-for-age, arm circumfer-
ence-for-age, triceps and subscapular skinfold-for-
age, and new international growth standards for the
screening, surveillance and monitoring of school-age
children and adolescents (61-63), all available at the
WHO website.
Prevention is perhaps the only effective way to stop
this childhood obesity epidemic, and the first step for
proper prevention, is proper detection. The WHO
2006 standards were created basically for that purpose.
The authors agree with others who suggest that all the
demographic surveys should now be derived using the
Table 4. Prevalence of overweight (including obesity) using bodymass index (BMI) Z-scores from the CDC-2000 growth referenceand WHO-2006 growth standards
Graph 4. Prevalence of overweight/obesity in boys (BMI Z-score=/>2.0) (n=167).
WHO 2006CDC 2000
Age (years)2 3 4 5
7
6
5
4
3
2
1
0
%
Graph 5. Prevalence of overweight/obesity in girls (BMI Z-score=/>2.0) (n=133).
Pediatri Mar-Apr 08 07-04-08 16:23 ™ÂÏ›‰·101
WHO standards (64). Perhaps in the future techno-logical advances will allow a more direct assessment ofadiposity than BMI, and new charts will need to becreated (65). Currently, there are few reports in theliterature of studies assessing the level of body fat inchildhood (66-68) and only one that has actually pro-duced body fat reference curves for children aged old-er than five (69).
There is a marked mismatch between the publichealth importance of childhood obesity and thenumber and quality of studies conducted so far toassess preventive interventions (70,71). There is anurgent need for well-designed intervention studiesto demonstrate the long-term effectiveness of pre-ventive strategies that would provide a basis for evi-dence-based recommendations (72,73). In Europe, aseries of initiatives and actions have been launchedin recent years, one of which is the creation of na-tional centres for collecting country-specific data toback up concrete strategies for future policy building(74). In the US, the new National Children’s Studywill seek information on enviromental risks and in-dividual susceptibility factors for obesity, amongother diseases. This will be conducted in a cohort of100,000 US born children, which will be followedfrom conception to 21 years of age. Environmentalexposures will be assessed repeatedly during preg-nancy and throughout childhood in the children’shomes, schools and communities. Chemical assayswill be performed by the CDC and banks of biologi-cal and genetic material and environmental sampleswill be collected. Recruitment started in 2007 at 7sites and will be extended to 105 sites across the US(75). Unfortunately, it will be a long time before pre-liminary results are available. In the meantime, untilall these studies start to answer some of the numer-ous questions regarding childhood obesity, it wouldbe advisable to promote physical activity and healthyeating habits among children and to encourage ade-quate monitoring of growth and weight gain fromearly infancy.
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105∞¡∞™∫√¶∏™∏ REVIEW ARTICLE
¶·È‰È·ÙÚÈ΋ 2008;71:105-115
™˘ÓÙÔÌÔÁڷʛ˜:
PCR Polymerase Chain ReactiondNTP diNucleotideTriPhosphataseddNTP didiNucleotideTriPhosphataseQRT PCR Quantitative Real Time PCRRFLP Restriction Fragment Length
PolymorphismVNTR Variable Number Tandem RepeatSTR Short Tandem RepeatDHPLC Denaturant High Performance Liquid
Basic techniques of molecular biology and their applications in the
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Abstract: Efforts to imitate human milk for feeding the infant led to serious miscalculations of the levelsof supplementation needed, with resultant dangers. As the exact content of human milk is difficult toestimate due to its wide fluctuations, only limited information can be deduced from measurement ofthe levels of specific components of human milk. In addition, there may be possible differences inbioavailability and substances other than components of human milk may be needed to achieve thedesired effect. This article provides a critical review of these factors, which include nucleotides,polyunsaturated fatty acids, glutamine, arginine, carnitine, iron, prebiotics, probiotics and high energyformulae. Following discussion of these nutrients, it is concluded that for some of them there isinsufficient data to justify their use and that there may even be potential dangers from their inclusion.Independent scientific bodies should evaluate any proposed modification of infant formulae beyondthe established standards before permission is given for introduction of such products into the market.It is important that such research considers not only the short-term effects of the nutrients on growth,but also safety aspects and the possibility of evaluating long-term effects on neurodevelopmentalachievement and the incidence of chronic diseases.
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Indications for administering growth hormone to children and
adolescents
∂. Kousta, A. Papathanassiou, C. Hadjiathanassiou†
Abstract: Recombinant growth hormone (GH) was used exclusively for the treatment of children withsevere growth retardation due to GH deficiency (GHD) up until the end of the 1980’s. GHD is characterizedby a combination of clinical, radiological, metabolic and hormonal abnormalities. The selection of cases forwhom there is a need to proceed to stimulation tests requires accurate auxological data and correctinterpretation of the growth curve. GH treatment in children with GHD leads to acceleration of growthvelocity and, if treatment is started early enough, to a final height within the normal range. Treatment withGH improves not only the height, but also body composition, by decreasing fat mass and increasing bonedensity, without significant side effects. During the last 20 years, the indications for treatment with GH havebeen expanded and its use has been approved for girls with Turner syndrome and for children with chronicrenal failure and Prader-Willi syndrome. In the USA and some countries of the EU, GH treatment is approvedfor children born small for gestational age. Treatment for idiopathic short stature has been approved only inthe USA. These indications have not been approved in Greece. Over the last few years its use has beenextended to adolescents and adults with severe GH deficiency. GH treatment is an expensive therapy andregular monitoring of its use needs to be made in specialised centres.
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3. Burman P, Ritzén EM, Lindgren AC. Endocrine dysfunc-tion in Prader-Willi syndrome: a review with special refer-ence to GH. Endocr Rev 2001;22:787-799.
4. Ong K, Beardsall K, de Zegher F. Growth hormone therapyin short children born small for gestational age. Early HumDev 2005;81:973-980.
5. Cuttler L. Safety and efficacy of growth hormone treatmentfor idiopathic short stature. J Clin Endocrinol Metab 2005;90:5502-5504.
6. Saggese G, Baroncelli GI, Vanacore T, Fiore L, Ruggieri S,Federico G. Indications and strategies for continuing GHtreatment during transition from late adolescence to earlyadulthood in patients with GH deficiency: the impact onbone mass. J Endocrinol Invest 2004;27:596-602.
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14. Growth Hormone Research Society. Consensus guidelinesfor the diagnosis and treatment of growth hormone (GH)deficiency in childhood and adolescence: summary state-ment of the GH Research Society. GH Research Society. JClin Endocrinol Metab 2000;85:3990-3993.
15. Frasier SD. Editorial: the diagnosis and treatment of child-hood and adolescent growth hormone deficiency--consen-sus or confusion? J Clin Endocrinol Metab 2000;85:3988-3989.
16. Juul A, Bernasconi S, Clayton PE, Kiess W, DeMuinck-Keizer Schrama S; Drugs and Therapeutics Committee ofthe European Society for Paediatric Endocrinology(ESPE). European audit of current practice in diagnosisand treatment of childhood growth hormone deficiency.Horm Res 2002;58:233-241.
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18. Rao E, Weiss B, Fukami M, Rump A, Niesler B, Mertz A, etal. Pseudoautosomal deletions encompassing a novelhomeobox gene cause growth failure in idiopathic shortstature and Turner syndrome. Nat Genet 1997;16:54-63.
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20. Stephure DK; Canadian Growth Hormone Advisory Com-mittee. Impact of growth hormone supplementation onadult height in turner syndrome: results of the Canadianrandomized controlled trial. J Clin Endocrinol Metab2005;90:3360-3366.
21. Baxter L, Bryant J, Cave CB, Milne R. Recombinant growthhormone for children and adolescents with Turner syn-drome. Cochrane Database Syst Rev 2007;(1):CD003887.
22. Ranke MB, Lindberg A, Ferrãandez Long ãas A, DarendelilerF, Albertsson-Wikland K, Dunger D, et al. Major determi-nants of height development in Turner syndrome (TS) pa-tients treated with GH: analysis of 987 patients from KIGS.Pediatr Res 2007;61:105-110.
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26. Eiholzer U. Deaths in children with Prader-Willi syn-drome. A contribution to the debate about the safety ofgrowth hormone treatment in children with PWS. HormRes 2005;63:33-39.
27. Clayton PE, Cianfarani S, Czernichow P, Johannsson G,Rapaport R, Rogol A. Management of the child born smallfor gestational age through to adulthood: a consensusstatement of the International Societies of Pediatric En-docrinology and the Growth Hormone Research Society. JClin Endocrinol Metab 2007;92:804-810.
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Final height of children with growth hormone deficiency who
received replacement treatment
M. Papadopoulou1, S. Douma2, K. Kitsios3, N. Kadoglou3, K. Kosta1, I. Tsiouris1
Abstract
Background: The aim of the study was the evaluation of the final height of children with Growth Hormone(GH) deficiency treated with recombinant GH, and of the factors related to their final height.
Methods: Seventy two children (25 prepubertal) with isolated (61/72) or combined (11/72) GHdeficiency, diagnosed after measurement of GH following stimulation tests with clonidin or insulin, weremonitored. The children were treated with 3, 6 or 7 weekly subcutaneous injections of recombinant GH.The target height (TH) was calculated for each child. Height, bone age, growth velocity and pubertal stagewere recorded at the beginning of treatment and every 6 months. Final height was defined as the heightat the time of the complete fusion of the epiphyses observed in a plain X-ray of the hand and wrist.
Results: The difference in the SDS of the mean final height before and after GH treatment was 1.3. Twentythree children (32%) reached the TH. The final height was associated statistically with the initial height, theTH and the number of weekly injections, while no relationship was observed with the age at the beginningof treatment, the duration of treatment, the growth velocity during the first year of treatment or the sex ofthe child. Children with combined hormone deficiency gained more height than those with isolated GHdeficiency, but they also had a greater TH.
Conclusions: GH replacement therapy is beneficial for children with small height due to deficiency of thehormone. The final height in these children appears to be highly predictable by the TH and the number ofGH injections given weekly.
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20. Ranke MB, Guilbaud O. Growth response in prepubertalchildren with idiopathic growth hormone deficiency dur-ing the first two years of treatment with human growthhormone. Analysis of the Kabi Pharmacia InternationalGrowth Stydy. Acta Paediatr Scand Suppl 1991;379:109-115.
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22. Ranke MB, Price DA, Albertsson-Wikland K, Maes M,Lindberg A. Factors determining pubertal growth and finalheight in growth hormone treatment of idiopathic growthhormone deficiency. Analysis of 195 Patients of the KabiPharmacia International Growth Study. Horm Res1997;48:62-71.
23. Ranke MB, Guilbaud O, Lindberg A, Cole T. Prediction ofthe growth response in children with various growth disor-ders treated with growth hormone: analyses of data fromthe Kabi Pharmacia International Growth Study. Interna-tional Board of the Kabi Pharmacia International GrowthStudy. Acta Paediatr Suppl 1993;82 Suppl 391:82-88.
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Study of the immunophenotype of peripheral blood lymphocyte
subsets in children with Epstein-Barr virus and cytomegalovirus
infection: association with outcome
E. Papadopoulou-Alataki1, A. Fleva2, V. Antari1, A. Pavlitou-Tsiontsi2, M. Moskofidis3, G. Varlamis1
Abstract
Background: The purpose of this study was to identify the immunophenotype of children withinfectious mononucleosis during the acute phase of the disease and convalescence and to investigateits association with the disease outcome.
Methods: A study was made of 26 children aged 6.6±3.5 years, affected by infectious mononucleosis. Theclinical presentation, spleen size, peripheral blood count, anti-virus specific antibodies, levels of SGOT,SGPT, Á-GT, IgG, IgA and IgM, and immunophenotype of blood T, B and NK cells were studied during theacute phase and 3-6 months later.
Results: Of the 26 children, 69% were infected by Epstein-Barr virus (EBV) and 31% by cytomegalovirus(CMV). At 3-6 month reevaluation a significant decrease in IgM and an increase in IgG antivirus antibodieswere observed, and the splenomegaly, lymphocytosis and high initial levels of SGOT were restored tonormal. At the time of onset of symptoms, the CD3+/CD8+ cells were considerably increased, CD19+ andCD3+/CD4+ percentages were low and a marked lowering of the CD4+/CD8+ ratio was observed. Atreevaluation, CD3+ and CD3+/CD8+ were lower, while CD3+/CD4+, CD19+ cells and the CD4+/CD8+ ratiowere significantly increased.
Conclusions: The increase in CD3+/CD8+ cells represents the cytotoxic response to the proliferation of EBVand CMV antigens, and may be related with the remission of symptoms. Immunophenotyping ofperipheral blood could be helpful in the follow-up of children with persistent infectious mononucleosis.
8. Roth DE, Jones A, Smith L, Lai R, Preiksaitis J, Robinson J.
Severe chronic active Epstein-Barr virus infection mimic-
king steroid-dependent inflammatory bowel disease. Pedi-atr Infect Dis J 2005;24:261-264.
9. Sugaya N, Kimura H, Hara S, Hoshino Y, Kojima S, Mor-ishima T, et al. Quantitative analysis of Epstein-Barr virus(EBV)-specific CD8+ T cells in patients with chronic activeEBV infection. J Infect Dis 2004;190:985-988.
10. Yuge A, Kinoshita E, Moriuchi M, Ohno Y, Haga H, Mo-riuchi H. Persistent hepatitis associated with chronic ac-tive Epstein-Barr virus infection. Pediatr Infect Dis J 2004;23:74-76.
11. Okano M, Kawa K, Kimura H, Yachie A, Wakiguchi H,Maeda A, et al. Proposed guidelines for diagnosing chron-ic active Epstein-Barr virus infection. Am J Hematol2005;80:64-69.
12. Hara S, Hoshino Y, Naitou T, Nagano K, Iwai M, SuzukiK, et al. Association of virus infected-T cell in severe he-patitis caused by primary Epstein-Barr virus infection. JClin Virol 2006;35:250-256.
14. Chan CW, Chiang AK, Chan KH, Lau AS. Epstein-Barrvirus-associated infectious mononucleosis in Chinese chil-dren. Pediatr Infect Dis J 2003;22:974-978.
15. Novitskii VV, Urazova OI, Naslednikova IO, PomogaevaAP, Syusina LV. Subpopulation composition of peripheralblood lymphocytes in children with infectious mononu-cleosis. Bull Exp Biol Med 2002;134:57-59.
16. Grotto I, Mimouni D, Huerta M, Mimouni M, Cohen D,Robin G, et al. Clinical and Laboratory presentation ofEBV positive infectious mononucleosis in young adults.Epidemiol Infect 2003;131:683-689.
18. Cohen JI. Epstein-Barr virus infection. New Engl J Med2000;343:481-492.
19. Rea TD, Russo JE, Katon W, Ashley RL, Buchwald DS.Prospective study of the natural history of infectiousmononucleosis caused by Epstein-Barr virus. J Am BoardFam Pract 2001;14:234-242.
20. Cameron B, Bharadwaj M, Burrows J, Fazou C, WakefieldD, Hickie I, et al; Dubbo Infection Outcomes Study. Pro-longed illness after infectious mononucleosis is associatedwith altered immunity but not with increased viral load. JInfect Dis 2006;193:664-671.
21. Fafi-Kremer S, Morand P, Brion JP, Pavese P, Baccard M,Germi R, et al. Long-term shedding of infectious Epstein-Barr virus after infectious mononucleosis. J Infect Dis2005;191:985-989.
22. Williams H, Macsween K, McAulay K, Higgins C, Harri-son N, Swerdlow A, et al. Analysis of immune activationand clinical events in acute infectious mononucleosis. J In-fect Dis 2004;190:63-71.
23. Weisberger J, Cornfield D, Gorczyca W, Liu Z. Down-regu-lation of pan-T-cell antigens, particularly CD7, in acute in-fectious mononucleosis. Am J Clin Pathol 2003;120:49-55.
24. Ohga S, Nomura A, Takada H, Hara T. Immunological as-pects of Epstein-Barr virus infection. Crit Rev Oncol He-matol 2002;44:203-215.
25. Lima M, Teixeira Mdos A, Queirfis ML, Santos AH, Gon-çalves C, Correia J, et al. Immunophenotype and TCR-Vbeta repertoire of peripheral blood T-cells in acute infec-tious mononucleosis. Blood Cells Mol Dis 2003;30:1-12.
Liver transplantation in children: 15 years experience in one center
O. Vrani1, M. Pantikidou1, G. Imvrios2, I. Xinias1, V. Demertzidou1, K. Kantziou1, A. Mavroudi1,
D. Takoudas2, T. Papastaurou1, K. Spyroglou1
Abstract
Background: Liver transplantation (LT) is the only treatment for children with irreversible liver failure. Thisis a report of the follow-up of a series of 16 children who underwent LT.
Methods: Since 1990, 16 patients of the 3rd Paediatric Clinic of the Hippocration General Hospital of Thes-saloniki, aged 6 months to 13 years, underwent LT. Nine children presented initially with extrahepatic bil-iary atresia, 2 with acute liver failure following toxic mushroom ingestion, 1 with Alagille syndrome, 1 withnon-syndromic intrahepatic biliary paucity, 1 with Wilson’s disease, 1 with primary hyperoxaluria and 1with hepatoblastoma. Ten children underwent LT in the Organ Transplantation Unit of the Aristotle Univer-sity of Thessaloniki and the others in various medical centers in other countries. Three transplants came fromliving-related donors and 13 from deceased donors. Six children went under immunosuppressive treatmentwith cyclosporine, MMF and corticosteroids and seven with tacrolimus, MMF and corticosteroids.
Results: Three of the 16 children died within the first month after transplantation due to post-transplantcomplications, and eleven have survived. Three children presented with acute rejection and one with chron-ic organ rejection, which was successfully managed. Five children developed CMV infection, 5 EBV infection,2 HSV infection, 2 Parvo B19 virus and 1 Candida Albicans infection. One child had upper GI haemorrhageand one presented with small biliary paucity. The outcome was satisfactory in most cases, with good graftfunction, except in the case of the patient with small biliary paucity, who required retransplantation.
Conclusions: The long-term clinical course of children following LT is good, provided that they are moni-tored in specialized centres.
1. 3rd Department ofPaediatrics, AristotleUniversity,Hippokration GeneralHospital, Thessaloniki,Greece
2. Department of Surgery,Organ TransplantationUnit, Aristotle University,Hippokration GeneralHospital, Thessaloniki,Greece
Correspondence:
∫leomenis [email protected] Department of Paediatrics, Aristotle University,Hippokration GeneralHospital of Thessaloniki49 Konstantinoupoleos St.,546 39, Thessaloniki,Greece
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Economic evaluation of new vaccines against varicella, serogroup C
meningococcus and pneumococcus
V. Tsiantou1, A. Karokis2, E. Pavi1, G. Kyriopoulos1
Abstract
Background: Vaccines are one of the most important tools for the primary prevention of infectiousdiseases. Decisions on the inclusion of new vaccines in the National Immunization Schedule need toaddress competing priorities, which stem from the lack of health care resources and the growing healthcare needs of the population. The objective of this study is to highlight the importance of economicevaluation in the sensitive field of immunization programs and vaccines.
Methods: A systematic review of papers on the economic evaluation of new vaccines published inscientific journals between 1999 and 2006 was conducted through PubMed.
Results: In the majority of the health care systems of developed countries, ex ante economic evaluationswere published, which evaluated all the possible scenarios and factors influencing the cost-effectivenessratio of the vaccines before their introduction.
Conclusions: Economic evaluations were not always clearly in favour of the introduction of new vaccinesinto the vaccination schedules. However, countries usually adopted the vaccines for inclusion in theNational Immunization Schedules after assessing additional parameters, such as the mortality andmorbidity ratios, the economic and social burden of disease and the anxiety of the population regardingthe risk of infection.
14. Trotter CL, Edmunds WJ. Modelling cost-effectiveness of
meningococcal serogroup C conjugate vaccination cam-
paign in England and Wales. BMJ 2002;324:809.
15. Ruedin HJ, Ess S, Zimmermann HP, Szucks T. Invasive
meningococcal and pneumococcal disease in Switzerland:
cost-utility analysis of different vaccine strategies. Vaccine
2003;21:4145-4152.
16. Welte R, Van den Dobbelsteen G, Bos JM, de Melker H,
van Alphen L, Spanjaard L, et al, Economic evaluation of
meningococcal serogroup C conjugate vaccination pro-
grammes in The Netherlands and its impact on decision-
making. Vaccine 2004;23:470-479.
155√ÈÎÔÓÔÌÈ΋ ·ÍÈÔÏfiÁËÛË Ó¤ˆÓ ÂÌ‚ÔÏ›ˆÓ
¶·È‰È·ÙÚÈ΋ 2008;71:148-156
Pediatri Mar-Apr 08 07-04-08 16:23 ™ÂÏ›‰·155
17. De Wals P, Nguyen VH, Erickson LJ, Guay M, Drapeau J,St-Laurent J. Cost-effectiveness of immunization strategiesfor the control of serogroup C meningococcal disease. Vac-cine 2004;22:1233-1240.
18. Beutels P, Thiry N, Van Damme P. Convincing or confus-ing? Economic evaluations of childhood pneumococcalconjugate vaccination - a review (2002-2006). Vaccine 2007;25:1355-1367.
19. Zissis NP, Syriopoulou V, Kafetzis D, Daikos GL, Tsil-imingaki A, Galanakis E, et al. Serotype distribution andantimicrobial susceptibility of Streptococcus pneumoniaecausing invasive infections and acute otitis media in chil-dren. Eur J Pediatr 2004;163:364-368.
20. Black S, Lieu TA, Ray GT, Capra A, Shinefield HR. Assess-ing costs and cost effectiveness of pneumococcal diseaseand vaccination within Kaiser Permanente. Vaccine 2000;19:S83-S86.
21. De Wals P, Petit G, Erickson LJ, Guay M, Tam T, Law B, etal. Benefits and costs of immunization of children withpneumococcal conjugate vaccine in Canada. Vaccine2003;21:3757-3764.
22. Bos JM, Rumke H, Welte R, Postma MJ. Epidemiologicimpact and cost-effectiveness of universal infant vaccina-tion with a 7-valent conjugated pneumococcal vaccine inthe Netherlands. Clin Ther 2003;25:2614-2630.
23. Claes C, Schulenburg JM Graf von der. Cost effectivenessof pneumococcal vaccination for infants and children withthe conjugate vaccine PnC-7 in Germany. Pharmacoeco-nomics 2003;21:587-600.
24. Asensi F, De Jose M, Lorente M, Moraga F, Ciuryla V,Arikian S, et al. A pharmacoeconomic evaluation of seven-valent pneumococcal conjugate vaccine in Spain. ValueHealth 2004;7:36-51.
25. Butler JR, McIntyre P, MacIntyre CR, Gilmour R, HowarthAL, Sander B. The Cost- Effectiveness of pneumococcal con-jugate vaccination in Australia. Vaccine 2004;22:1138-1149.
26. McIntosh ED, Conway P, Willingham J, Hollingsworth R,Lloyd A. Pneumococcal pneumonia in the UK - how herdimmunity affects the cost-effectiveness of 7-valent pneumo-coccal conjugate vaccine (PCV). Vaccine 2005;23:1739-1745.
27. Marchetti M, Colombo GL. Cost-effectiveness of universalpneumococcal vaccination for infants in Italy. Vaccine2005;23:4565-4576.
28. Wisloff T, Abrahamsen T, Bergsaker MA, Lovoll O, MollerP, Pedersen MK, et al. Cost effectiveness of adding 7-valentpneumococcal conjugate (PCV-7) vaccine to the Norwe-gian childhood vaccination program. Vaccine 2006;24:5690-5699.
29. Ray GT, Whitney CG, Fireman BH, Ciuryla V, Black SB.Cost-effectiveness of pneumococcal conjugate vaccine: evi-dence from the first 5 years of use in the United States incor-porating herd effects. Pediatr Infect Dis J 2006;25:494-501.
31. Scuffham PA, Lowin AV, Burgess MA. The cost-effective-ness of varicella vaccine programs for Australia. Vaccine1999;18:407-415.
32. Brisson M, Edmunds WJ. The cost-effectiveness of varicel-la vaccination in Canada. Vaccine 2002;20:1113-1125.
33. Brisson M, Edmunds WJ. Varicella vaccination in Englandand Wales: cost-utility analysis. Arch Dis Child 2003;88:862-869.
34. Coudeville L, Paree F, Lebrun T, Sailly J. The value of vari-cella vaccination in healthy children: cost-benefit analysisof the situation in France. Vaccine 1999;17:142-151.
35. Lenne X, Diez Domingo J, Gil A, Ridao M, Lluch J, Der-vaux B. Economic evaluation of varicella vaccination inSpain: results from a dynamic model. Vaccine 2006;24:6980-6989.
36. Trotter CL, Edmunds WJ. Reassessing the cost-effective-ness of meningococcal serogroup C conjugate (MCC) vac-cines using a transmission dynamic model. Med DecisMaking 2006;26:38-47.
37. McIntosh ED, Conway P, Willingham J, Hollingsworth R,Lloyd A. Pneumococcal pneumonia in the UK - how herdimmunity affects the cost-effectiveness of 7-valent pneu-mococcal conjugate vaccine (PCV). Vaccine 2005;23:1739-1745.
38. Diez Domingo J, Ridao M, Latour J, Ballester A, Morant A.A cost benefit analysis of routine varicella vaccination inSpain. Vaccine 1999;17:1306-1311.
39. Nguyen HQ, Jumaan AO, Seward JF. Decline in mortalitydue to varicella after implementation of varicella vaccina-tion in the United States. N Engl J Med 2005;352:450-458.
40. Rentier B, Gershon AA; European Working Group on Vari-cella. Consensus: varicella vaccination of healthy children - achallenge for Europe. Pediatr Infect Dis J 2004;23: 379-389.
41. Welte R, Trotter CL, Edmunds WJ, Postma MJ, Beutels P.The role of economic evaluation in vaccine decision mak-ing: focus on meningococcal group C conjugate vaccine.Pharmacoeconomics 2005;23:855-874.
Childhood and adolescent nutrition for promoting health and
growth and preventing chronic diseases
A. Kafatos
Abstract: Paediatric obesity has been increasing since the 1980s in an epidemic mode. Due to this fact,it has become necessary to provide information for paediatricians and parents about the dietappropriate for growth and avoidance of obesity of children. The primary target should be theelimination of foods of high energy density and low nutrient content (e.g., chips, chocolate biscuits)from the diet of children, with emphasis on the traditional Greek diet. The intake of essential nutrientsis ensured when children consume the recommended portions from each of the 5 categories of foods,and when these portions are distributed between 3 main and 2 smaller intermediate meals on a dailybasis. Particular effort is required on the part of the parents to ensure that children consume 2-3portions of small oily fish per week, 2-8 portions of vegetables daily, depending on age, and 2-5portions of fruits and 2-3 portions of dairy products on a daily basis. The best way of teaching childrenabout diet and physical activity is for parents to set an example by practising these habits themselves athome. The adoption of the traditional Greek diet, low in saturated fat and high in olive oil, vegetables,fruit and legumes, with at least 2-3 hours of daily intense physical activity will ensure excellent growthand development of the children and help in the prevention of chronic diseases.
2. Dietary Reference Intakes for Calcium, Phosphorus, Mag-nesium, Vitamin D, and Fluoride. National Academy ofSciences; 1997.
3. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin,Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin,and Choline. Washington DC: Food and Nutrition Board,Institute of Medicine, National Academy Press; 1998.
4. Dietary Reference Intakes for Vitamin C, Vitamin E, Seleni-um, and Carotenoids. National Academy of Sciences; 2000.
5. Dietary Reference Intakes for Vitamin A, Vitamin K,Arsenic, Boron, Chromium, Copper, Iodine, Iron, Man-ganese, Molybdenum, Nickel, Silicon, Vanadium, andZinc National Academy of Sciences; 2001.
6. Williams SR. Nutrition and Diet Therapy. 8th ed. St Louis:Mosby Publishing Co.; 1997.
Recurrent Respiratory Papillomatosis: case report and
literature review
D. A. Nunez
Abstract: Juvenile onset recurrent respiratory papillomatosis (RRP) is a rare but potentially lifethreatening disease caused by Human papilloma virus (HPV) infection, primarily HPV types 6 and 11. Ittypically presents in children with an onset at 3-4 years. The incidence estimates vary widely, but inEurope a rate of approximately 3.5 cases per million is reported. The vocal folds are the commonest siteof involvement. Dysphonia and/or stridor are the main clinical features of respiratory papillomatosis. Atypical case in a 3 year-old boy is presented. Laryngoscopy to visualise the larynx is required to arrive atthe diagnosis. The mainstay of treatment is surgical resection using the CO2 laser or the laryngeal micro-shaver (microdebrider) under micro-laryngoscopic control. It is not unusual for a typical case to require3 surgical interventions a year over a period of several years. In more aggressive cases adjuvanttreatment is indicated, which includes systemic interferon and intra-lesional Cidofovir. Fatality isassociated with loss of the airway, distal spread into the lungs or malignant transformation. An overviewof the clinical condition and current treatment is presented.
Key words: Larynx, papilloma, Human papilloma virus 6, Human papilloma virus 11, voice disorders.
Academic Unit ofOtolaryngology,North Bristol NHS Trust, Southmead Hospital,
Correspondence:
D. A. Nunez [email protected] Unit of Otolaryngology, North Bristol NHS Trust, Southmead Hospital, Bristol BS10 5NB, United Kingdom
Case Report
A 3 year-old boy presented to his paediatri-
cian with a 4-month history of a persistent
hoarse voice, with no history of preceding upper
respiratory tract infection or trauma. He had no
dysphagia or dyspnoea. His single mother re-
ported that he was her first child, delivered nor-
mally at full term when she was 19 years old, af-
ter an uncomplicated pregnancy and delivery.
On examination he was apyrexial and not
distressed, and he was not jaundiced. He
weighed 15 kg and was 105 cm tall. There was no
stridor or cyanosis, his respiratory rate was 24
per minute, the trachea was central and the chest
clear on auscultation. There were no abnormal
heart sounds. Anterior rhinoscopy and oral cav-
ity examination were normal.
He was referred to an otolaryngologist who
undertook a micro-laryngoscopic examination.
The laryngoscopic appearance is as illustrated in
the clinical photograph (Figure 1).
Discussion
Figure 1 shows a larynx of grossly abnormal
appearance, in stark contrast to the appearance of
the normal larynx, Figure 2. The mucosa of the
vocal folds and vestibular folds is oedematous and
polypoid in keeping with the typical appearance
of widespread laryngeal papillomatosis. This pat-
tern of presentation is to be distinguished from
the single solitary often pedunculated upper aero-
digestive tract papilloma. The latter is more com-
mon and often presents in the oropharynx arising
from the soft palate, uvula or palatopharyngeal
arches. Excision is usually curative.
The laryngeal papilloma is the commonest
benign neoplasm of the larynx (1). Laryngeal in-
volvement when widespread, as demonstrated in
this case, is not easily cured and the condition is
known as recurrent laryngeal papillomatosis or
recurrent respiratory papillomatosis (RRP). The
term RRP is to be preferred because while the
larynx at the level of the vocal cords (glottis) is
the site predominantly affected, the papillomata
may extend above and below this level into the
trachea and bronchi. RRP is an uncommon con-
dition with a bimodal peak age incidence of 3-5
years in children and in the third decade in
adults (2). The distribution of age of onset has
lead to the condition being sub-classified as ju-
venile onset RRP or adult onset RRP.
RRP can be life threatening because of airway
compromise, especially in children, or due to ma-
lignant degeneration (3). The reported prevalence
of juvenile onset laryngeal papillomatosis is lower
in Europe (approximately 3.5 per million) than in
the US (4.3 per 100,000) (4,5). The presenting fea-
tures are hoarseness and stridor (2). Males and fe-
males are equally affected in childhood but in the
adult onset disease males are more commonly af-
fected in the ratio of 2-4 to 1 (6,7).
The Human papilloma (wart) virus (HPV) is
Pediatri Mar-Apr 08 07-04-08 16:23 ™ÂÏ›‰·162
163Recurrent Respiratory Papillomatosis
¶·È‰È·ÙÚÈ΋ 2008;71:162-164
the causative agent for RRP, and specifically HPV sub-
types 6 and 11 (8). There are reports that HPV 11 la-
ryngeal disease is more aggressive, with a greater
predilection for relapse and malignant degeneration
(9). Malignant degeneration is usually associated with
other cofactors such as tobacco use (10), or irradiation,
which was an early therapy for RRP, however some cas-
es undergo malignant change in the absence of any
known cofactors (11). HPV subtypes 6 and 11 are not
associated with a high risk of malignant change, in con-
trast to other subtypes such as 16 and 18, which have
been established as causative agents of cancer of the
uterine cervix (12,13). In the head and neck region high
risk types of HPV have been isolated, predominantly
from cancers of the oral cavity and oropharynx but al-
so from the larynx. The degree of positivity, depending
on the identification method, varies between 0% and
75% (14). This is in contrast to uterine cervical invasive
squamous cell carcinoma, where the level of positivity
is 86-94% (15). It would therefore seem that HPV has a
causative role only in certain anatomical sites in the
head and neck or in particular subgroups of patients.
The mechanism of HPV transmission is uncertain
but vertical materno-fetal transmission is the most
favoured route. This is supported by the 231-fold in-
crease in risk of juvenile onset recurrent respiratory
papillomatosis in children born to mothers with cer-
vical condoylomata (16). The birth canal is not the
only route of transmission, as Armbruster-Moraes
and colleagues demonstrated that HPV DNA can be
isolated in amniotic fluid aspirates from women who
had clinical and slot hybridisation evidence of cervical
papilloma, providing evidence of in-utero transmis-
sion (17). This can explain the failure of Caesarean
section to abolish the development of juvenile onset
laryngeal papilloma disease (18,19).
The presence of HPV6 and/or 11 is not in itself suf-
ficient to cause the development of laryngeal papillo-
matosis, as up to 25% of histologically normal larynges
are positive for HPV6 and 11 DNA (20). Restricted
host immune response is believed to play a role.
The mainstay of treatment is surgery. Microlaryn-
goscopy provides the opportunity not only for tissue
diagnosis by biopsy but also for excision of the papil-
lomata. The surgeon must exercise caution in the pur-
suit of disease eradication in order to avoid damage to
the laryngeal structure and thus irreversible impair-
ment of laryngeal function. Stenosis and webbing of
the anterior glottis can leave the patient with the same
symptoms that the therapy is intended to treat, name-
ly a restricted airway and a life-long hoarse voice. A
CO2 laser beam controlled by a micromanipulator
gives the surgeon microscopic guided accuracy in the
control of papilloma excision. The 10,600 nm wave-
length CO2 provides the advantage of haemostasis
and this is the technique most widely used for treat-
ment of laryngeal papillomata in the UK (21). A num-
ber of other laser types are also used, including the
potassium titanyl phosphate laser delivered by a flexi-
ble fibre that facilitates treatment of papillomata in
the tracheobronchial tree (1).
A recent survey of members of American Society
of Paediatric Otolaryngologists demonstrated the
popularity of the laryngeal shaver (microdebrider)
(22). This is a sleeved rotating blade with continuous
saline irrigation and suction allowing for almost
bloodless removal of laryngeal papillomata.
RRP is a difficult condition to treat in many pa-
tients and in some patients it follows a relentless
course requiring multiple surgeries with only short in-
tervals between treatment schedules when the patient
is clinically free of disease. This is due to the difficulty
Figure 1. Figure 2.
Pediatri Mar-Apr 08 07-04-08 16:23 ™ÂÏ›‰·163
of eradicating the papilloma virus, which is presenteven in normal appearing laryngeal tissue of the affect-ed patients (19). For this reason a number of adjuvanttreatments have been tried and put into use with theaim of reducing the relapse rate. Alpha interferon andindole-3-carbinol are two popular adjuvant therapiesbut they are not always effective (1,22). Intra-lesionalCidofovir is gaining in popularity because of the goodearly results obtained with this antimetabolite by someclinicians in controlling the disease (23). Photodynam-ic therapy is also under investigation (24). The launchof a highly efficacious HPV vaccine that targets HPV 6and 11 in addition to 16 and 18 (25) offers the potentialto eradicate this disease for future generations.
2. Quiney RE, Hall D, Croft CB. Laryngeal papillomatosis:analysis of 113 patients. Clin Otolaryngol Allied Sci1989;14:217-225.
3. Zarod AP, Rutherford JD, Corbitt G. Malignant progres-sion of laryngeal papilloma associated with human papillo-ma virus type 6 (HPV-6) DNA. J Clin Pathol 1988;41:280-283.
4. Silverberg MJ, Thorsen P, Lindeberg H, Ahdieh-Grant L,Shah KV. Clinical course of recurrent respiratory papillo-matosis in Danish children. Arch Otolaryngol Head NeckSurg 2004;130:711-716.
5. Derkay CS. Task force on recurrent respiratory papillomas.A preliminary report. Arch Otolaryngol Head Neck Surg1995;121:1386-1391.
6. Lindeberg H, Elbro/nd O. Laryngeal papillomas: clinical as-pects in a series of 231 patients. Clin Otolaryngol Allied Sci1989;14:333-342.
7. Capper JW, Bailey CM, Michaels L. Squamous papillomasof the larynx in adults. A review of 63 cases. Clin Otolaryn-gol 1983;8:109-119.
8. Terry RM, Lewis FA, Griffiths S, Wells M, Bird CC. De-monstration of human papillomavirus types 6 and 11 injuvenile laryngeal papillomatosis by in-situ DNA hy-bridization. J Pathol 1987;153:245-248.
9. Rimell FL, Shoemaker DL, Pou AM, Jordan JA, Post JC,Ehrlich GD. Pediatric respiratory papillomatosis: prognos-tic role of viral typing and cofactors. Laryngoscope 1997;107:915-918.
10. Kashima HK, Mounts P, Shah K. Recurrent respiratory pa-pillomatosis. Obstet Gynecol Clin North Am 1996;23:699-706.
11. Lindeberg H, Elbro/nd O. Malignant tumours in patients
with a history of multiple laryngeal papillomas: the signifi-cance of irradiation. Clin Otolaryngol Allied Sci 1991;16:149-151.
12. Zur Hausen H. Human papillomaviruses in the pathogen-esis of anogenital cancer. Virology 1991;184:9-13.
13. Zur Hausen H. Papillomaviruses in human cancer. ApplPathol 1987;5:19-24.
14. McKaig RG, Baric RS, Olshan AF. Human papillomavirusand head and neck cancer: epidemiology and molecular bi-ology. Head Neck 1998;20:250-265.
15. Smith JS, Lindsay L, Hoots B, Keys J, Franceschi S, WinerR, et al. Human papillomavirus type distribution in inva-sive cervical cancer and high-grade cervical lesions: a meta-analysis update. Int J Cancer. 2007 Aug 1;121(3):621-632.
16. Silverberg MJ, Thorsen P, Lindeberg H, Grant LA, ShahKV. Condyloma in pregnancy is strongly predictive of ju-venile-onset recurrent respiratory papillomatosis. ObstetGynecol 2003;101:645-652.
17. Armbruster-Moraes E, Ioshimoto LM, Lea~o E, Zugaib M.Presence of human papillomavirus DNA in amniotic fluidsof pregnant women with cervical lesions. Gynecol Oncol1994;54:152-158.
18. Shah K, Kashima H, Polk BF, Shah F, Abbey H, AbramsonA. Rarity of cesarean delivery in cases of juvenile-onset res-piratory papillomatosis. Obstet Gynecol 1986;68:795-799.
19. Abramson AL, Steinberg BM, Winkler B. Laryngeal papil-lomatosis: clinical, histopathologic and molecular studies.Laryngoscope 1987;97:678-685.
20. Nunez DA, Astley SM, Lewis FA, Wells M. Human papillo-ma viruses: a study of their prevalence in the normal lar-ynx. J Laryngol Otol 1994;108:319-320.
21. Tasca RA, McCormick M, Clarke RW. British Associationof Paediatric Otorhinolaryngology members experiencewith recurrent respiratory papillomatosis. Int J PediatrOtorhinolaryngol 2006;70:1183-1187.
22. Schraff S, Derkay CS, Burke B, Lawson L. American Societyof Pediatric Otolaryngology members' experience with re-current respiratory papillomatosis and the use of adjuvanttherapy. Arch Otolaryngol Head Neck Surg 2004;130:1039-1042.
23. Naiman AN, Ayari S, Nicollas R, Landry G, Colombeau B,Froehlich P. Intermediate-term and long-term results aftertreatment by cidofovir and excision in juvenile laryngeal pa-pillomatosis. Ann Otol Rhinol Laryngol 2006;115:667-672.
24. Shikowitz MJ, Abramson AL, Freeman K, Steinberg BM,Nouri M. Efficacy of DHE photodynamic therapy for res-piratory papillomatosis: immediate and long-term results.Laryngoscope 1998;108:962-967.
25. Ault KA; Future II Study Group. Effect of prophylactic hu-man papillomavirus L1 virus-like-particle vaccine on riskof cervical intraepithelial neoplasia grade 2, grade 3, andadenocarcinoma in situ: a combined analysis of four ran-domised clinical trials. Lancet. 2007;369:1861-1868.