Specific Celiac Disease Antibodies in Children on a Gluten-Free Diet
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ARTICLES
Specific Celiac Disease Antibodies in Children on a
Gluten-Free Diet
AUTHORS: Caroline E. Hogen Esch, MD,a Victorien M. WHAT’S KNOWN ON THIS SUBJECT: Circulating celiac disease (CD)
Wolters, MD, PhD,b Susan A. M. Gerritsen, MD,b Hein antibodies at the time of diagnosis and their disappearance after a
Putter, PhD,c B. Mary von Blomberg, PhD,d Ingrid M. W. van gluten-free diet support the diagnosis of CD. Endomysial antibodies
Hoogstraten, PhD,d Roderick H. J. Houwen, MD, PhD,b Nico (EMAs) and tissue transglutaminase antibodies (anti-TG2s) are
van der Lely, MD, PhD,e and M. Luisa Mearin, MD, PhDa
useful to evaluate the compliance with the gluten-free diet.
Departments of aPediatric Gastroenterology and cMedical
Statistics, Leiden University Medical Centre, Leiden, Netherlands;
bDepartment of Pediatric Gastroenterology, University Medical
WHAT THIS STUDY ADDS: In children with CD, ⬃80% will be sero-
Centre Utrecht, Utrecht, Netherlands; dDepartment of Pathology, negative for EMAs and anti-TG2s after 2 years of gluten-free diet,
VU University Medical Centre, Amsterdam, Netherlands; and and the mean concentration of anti-TG2s will show a 74%
eDepartment of Pediatrics, Reinier de Graaf Gasthuis, Delft, decrease after 3 months of diet.
Netherlands
KEY WORDS
celiac disease, gluten enteropathy, gluten-free diet, celiac
antibodies, serology
ABBREVIATIONS
CD—celiac disease
abstract
HLA—human leukocyte antigen OBJECTIVE: Celiac disease (CD) is characterized by histologic altera-
Ig—immunoglobulin tions in small bowel biopsies. Circulating specific CD antibodies at the
EMA—endomysial antibody
anti-TG2—anti-tissue transglutaminase antibody time of diagnosis and their disappearance after a gluten-free diet sup-
CI—confidence interval port the diagnosis of CD. We aimed to determine the behavior of the CD
DGP—deamidated gliadin peptide antibodies immunoglobulin A anti-tissue transglutaminase (anti-TG2)
Drs Hogen Esch and Dr Wolters contributed equally to this work. and immunoglobulin A endomysium (EMA) in children with CD after
www.pediatrics.org/cgi/doi/10.1542/peds.2010-3762 starting a gluten-free diet.
doi:10.1542/peds.2010-3762 METHODS: This was a retrospective multicenter study in the Nether-
Accepted for publication May 6, 2011 lands between 2001 and 2009. Inclusion criteria were all newly diag-
Address correspondence to C. E. Hogen Esch, MD, Leiden nosed patients with CD younger than 19 years who had at least 1
University Medical Centre, Department of Pediatrics, J6-S-208, anti-TG2 and/or EMA measurement before and after starting a gluten-
PO Box 9600, 2300 RC Leiden, Netherlands. E-mail:
c.e.hogen_esch@lumc.nl free diet. Eight different anti-TG2 kits were used with substrates of
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
guinea pig TG2 in 1 (Sigma) and 7 human-recombinant TG2: Varelisa
and EliA Celikey Phadia-GmbH; Orgentec Diagnostica-GmbH; Diarect AG;
Copyright © 2011 by the American Academy of Pediatrics
Roboscreen GmbH; Aeskulisa Diagnostics; Binding Site Ltd. EMA was
FINANCIAL DISCLOSURE: The authors have indicated they have
no financial relationships relevant to this article to disclose. analyzed with indirect immunofluorescence tests. Statistical analyses
were performed by using mixed-model repeated measurements and
survival analysis.
RESULTS: There were 129 children with CD included (mean age: 5.6
years; SD ⫾ 4.2). The mean concentration of anti-TG2 decreased signif-
icantly within 3 months after starting a gluten-free diet (P ⬍ .0001). The
cumulative percentage of children who became negative for EMA after
1⁄2, 1, 11⁄2, and 2 years was 31%, 60%, 74%, and 87%, respectively. For
anti-TG2, a comparable trend was shown: 35%, 55%, 64%, and 78%,
respectively.
CONCLUSIONS: Doctors taking care of children with CD should be
aware that the mean concentration of anti-TG2 will show a 74% de-
crease (95% confidence interval: 69%–79%) after 3 months of gluten-
free diet, and ⬃80% of the children will be sero-negative for EMA and
anti-TG2 after 2 years of the diet. Pediatrics 2011;128:547–552
PEDIATRICS Volume 128, Number 3, September 2011 547
Downloaded from pediatrics.aappublications.org by guest on February 3, 2015Celiac disease (CD) is an autoimmune been evaluated at different time points follow-up. The ethical committee of
disorder caused by an inflammatory during an 1-year follow-up.12 In chil- Leiden University Medical Centre ap-
T-cell response to gluten proteins that dren, only the follow-up of anti-TG2 (IgA proved the study protocol.
causes damage of the small bowel mu- and IgG) has been reported during a
cosa.1–3 The treatment of CD is a life- 2-year period.14 The aim of our study Serology
long gluten-free diet, which is demand- was to determine the behavior of the For IgA anti-TG2 determinations, 8 dif-
ing for patients.4 The disorder has a specific CD antibodies, anti-TG2 and ferent kits were used with the follow-
variable clinical presentation: from a EMA, upon the start of a gluten-free ing substrates (between parenthesis
clear malabsorption syndrome with di- diet in a large cohort of children the equivocal area of the kit recom-
arrhea and failure-to-thrive in chil- with CD. mended by the manufacturer): (1)
dren, to less specific symptoms, for ex- guinea pig TG2: Sigma, in-house assay
ample, anemia, mouth ulcers, or METHODS (4 –7 U/mL), and (2) human recombi-
osteoporosis.2 CD has a strong genetic Patients nant TG2: Varelisa Celikey (5– 8 U/mL)
component, and most of the patients and EliA Celikey (7–10 U/mL), both
carry the major histocompatibility All children (18 or younger) who were
from Phadia GmbH; Orgentec Diagnos-
class II human leukocyte antigen (HLA)- consecutively diagnosed for CD be-
tica (5–10 U/mL) GmbH; Diarect AG, in-
DQ2 and/or HLA-DQ8.5 tween 2001 and 2009 and had a
house assay (3– 6 U/mL); Roboscreen
follow-up at the departments of pediat-
CD is characterized by histologic alter- GmbH, in-house assay (3– 6 U/mL);
rics of the Wilhelmina Children Hospi-
ations in the small bowel. Circulating Aeskulisa Diagnostics (10 –15 U/mL);
tal/UMC (Utrecht), Leiden University
CD antibodies at the time of diagnosis and Binding Site group Ltd (4 –10
Medical Centre (Leiden), and the
and their disappearance after a U/mL). IgA EMA determinations were
Reinier de Graaf Gasthuis (Delft), in the
gluten-free diet support the diagnosis performed by standard indirect im-
Netherlands. The diagnosis of CD was
of CD.6 The immunoglobulin A (IgA) mune fluorescence tests.17
established by the histologic results of
class CD antibodies against endomy- multiple small bowel biopsies taken by The CD cases were scored as being
sium (EMA) and tissue transglutami- upper endoscopy when the children sero-negative at diagnosis when (1)
nase (anti-TG2), have a very high sensi- consumed gluten, which revealed al- anti-TG2 and EMA were both negative,
tivity and specificity for the disease6 terations characteristics for CD. The or (2) anti-TG2 was negative and EMA
and are an essential part of the diag- histologic abnormalities were classi- was weak-positive. The patient’s sero-
nostic procedure for CD.7 It has been fied according to Marsh.16 The children logic follow-up was periodically sched-
shown that EMA and anti-TG2 are also were considered to have CD when they uled by their physician by using IgA
useful to evaluate the compliance had alterations Marsh 2 –3C. Impor- anti-TG2 and/or IgA EMA determina-
with the gluten-free diet, in both tantly, children with Marsh 2 altera- tions. The serologic data were evalu-
adults8–12 and children.8,13–15 However, tions were only considered to have CD ated retrospectively.
both antibodies were found not sensi- when they had positive levels of spe-
tive enough to detect slight dietary cific CD antibodies, anti-TG2, and/or Statistical Analysis
mistakes and/or moderate mucosa EMA at diagnosis. After consultation Continuous data are expressed as
lesions.9,11,13 with a dietician, all the children mean ⫾ SD; dichotomous data as num-
For doctors who take care of children started a gluten-free diet within 2 bers and percentages. Cumulative
with CD, as well as for the children and weeks after the diagnostic biopsies. event rates (normalization of anti-TG2
their parents, it is important to know The characteristics of the patients and EMA) were assessed by Kaplan-
what time interval is expected to with CD were recorded at the moment Meier survival curves. The course of
achieve a significant decrease and of diagnosis, including the small bowel mean concentration of anti-TG2 with a
normalization of the specific CD anti- biopsy histology report. The inclu- 95% confidence interval (CI) over
bodies after starting a gluten-free diet. sion criteria were (1) all patients time was performed by repeated-
However, in children there is scarce newly diagnosed for CD, and (2) hav- measurement analysis (linear mixed
information over the long-term sero- ing at least 1 anti-TG2 and/or EMA model). The anti-TG2 results were
logic follow-up of specific CD antibod- measurement before and after start- grouped in 9 categories according to
ies measured at different time points ing a gluten-free diet. Each partici- the time point of the measurement in
during a gluten-free diet. In adults, the pating center followed its own rou- relationship to the diagnostic biopsies.
course of both anti-TG2 and EMA has tine for the clinical and serologic To compare the quantitative values of
548 HOGEN ESCH et al
Downloaded from pediatrics.aappublications.org by guest on February 3, 2015ARTICLES
FIGURE 1
Proportion of children with CD who were positive for anti-TG2 (n ⫽ 99) (A) and EMA (n⫽74) (B) after starting a gluten-free diet, presented in Kaplan-Meier
survival curves.
the different anti-TG2 tests, we calcu- the inclusion criteria. The reasons for formed). Both children responded clin-
lated the ratio of each anti-TG2 mea- exclusion of the 19 children with CD ically and serologically well to the
surement by dividing each anti-TG2 re- were that they did not have 1 anti-TG2 gluten-free diet.
sult (U/mL) by the cutoff value (U/mL) and/or EMA measurement before and The mean time of follow-up of the chil-
for negativity as recommended by the after starting a gluten-free diet (n ⫽ dren from the moment of the diagnos-
manufacturers. For each anti-TG2 kit 18), or that 1 child was sero-negative tic biopsies was 28 months (SD ⫾ 25
we have used the following cutoff val- at diagnosis and had small bowel biop- months [range: 2–93 months]). In to-
ues for negativity: (a) guinea pig TG2: sies with Marsh 2 alterations. The tal, 488 IgA anti-TG2 and 408 IgA EMA
Sigma, in-house assay (ⱕ4 U/mL) and mean age of the included CD cases at determinations were performed at dif-
(b) human recombinant TG2: Varelisa diagnosis was 5.6 years (SD ⫾ 4.2 ferent time points. The mean time in-
Celikey (ⱕ5 U/mL) and EliA Celikey (ⱕ7 years [range: 11 months to 16 years]), terval between the first serologic sam-
U/mL), both from Phadia GmbH; Orgen- 83 were girls (1:2 ratio boys to girls). ple and the biopsy was 1.3 months
tec Diagnostica (ⱕ5 U/mL) GmbH; Diar- HLA-DQ genotyping was performed in (range: 9 months before and 2 weeks
ect AG (ⱕ3 U/mL); Roboscreen (ⱕ4 48 children (37%), and all of them were after biopsy). Seven children with CD
U/mL) GmbH; Aeskulisa Diagnostics
HLA-DQ2 and/or DQ8 positive. None of (5.4%) were sero-negative at diagno-
(ⱕ10 U/mL); and Binding Site group
the children had IgA deficiency. The sis, despite their Marsh 3 alterations:
Ltd (ⱕ4 U/mL). The ratio of 1 is the
histology results of the diagnostic Marsh 3A in 4 children, Marsh 3B in 2,
cutoff point for negativity. Anti-TG2 ra-
small bowel biopsies were Marsh 2 in and Marsh 3C in 1.
tios were log-transformed before
2% (n ⫽ 2), Marsh 3A in 33% (n ⫽ 42), In Fig 1, the proportions of sero-
mixed-model analysis. By using the log
Marsh 3B in 39% (n ⫽ 50), and Marsh positive children for anti-TG2 and EMA
ratio, the results of the different tests
were equalized. In the mixed model, 3C in 27% (n ⫽ 35). One of the 2 chil- are shown by Kaplan-Meier survival
time (categorical) and age at diagno- dren with Marsh 2 duodenal lesions curves. Ninety-nine (77%) and 74 (57%)
sis were entered as fixed effects and was treated with prednisone for an au- children with CD could be followed for
individual as random effect. A P value toimmune hepatitis at the time of the the determination of the normalization
of ⬍.05 was considered significant. small bowel biopsies. This child was of anti-TG2 and EMA, respectively. In Ta-
The statistical program SPSS 16.0 HLA-DR3-DQ2 positive and both anti- ble 1 the cumulative percentage of the
(SPSS Inc, Chicago, IL) was used. bodies, EMA and anti-TG2, were posi- children who became sero-negative in
tive at diagnosis. The other child with time is shown. A comparable decline of
RESULTS Marsh 2 lesions presented with failure the proportion of children with CD who
A total of 129 of the 148 children who to thrive and anorexia and was positive became sero-negative for anti-TG2
were diagnosed with CD (87%) fulfilled for EMA (HLA-typing was not per- and/or EMA was shown in time. After 2
PEDIATRICS Volume 128, Number 3, September 2011 549
Downloaded from pediatrics.aappublications.org by guest on February 3, 2015TABLE 1 Cumulative Percentage of Children With CD Who Became Seronegative for Anti-TG2 (n ⫽ our results revealed that within 3
99) and EMA (n ⫽ 74) After Starting a Gluten-Free Diet
months, the mean concentration of
Months After Starting Gluten-Free Diet
anti-TG2 showed a 74% decrease (95%
3 6 9 12 18 24 CI: 69%–79%), and that within 11⁄2 years
Anti-TG2, %a 11 35 41 55 64 78 the mean concentration of anti-TG2
EMA, % 10 31 45 60 74 87
a
level in children is expected to be be-
The manufacturer’s recommended cut-off for negativity was used.
low the cutoff point for negativity.
We have found that, after 2 years of a
years of diagnosis, a total of 15 chil- point for negativity (below the ratio of gluten-free diet, 11.6% of the children
dren (11.6%) were still sero-positive 1) in most of the children with CD. (n ⫽ 15) had still positive EMA and/or
for anti-TG2 and/or EMA (Table 1). Thir- anti-TG2 antibodies (Fig1 and Table 1).
teen of the children became sero- DISCUSSION These results illustrate that, as it has
negative within 5 years, and 2 re- The serologic checkup of children with been reported before,14 the correla-
mained sero-positive after 5 years of CD on a gluten-free diet consists on the tion between antibodies decreasing
diagnosis. measurement of specific celiac anti- and clinical outcome is not 100% be-
In Fig 2, the course of the mean concen- bodies. Doctors, parents, and children cause only 3 of these 15 children had
tration for anti-TG2 is illustrated (ex- expect that the antibodies will disap- symptoms: 1 child had constipation
pressed in ratios, 95% CI; uncorrected pear after starting the gluten-free diet. and abdominal pain; another had per-
for time). After 3 and 6 months of a In this study we investigated the de- sistent isolated short stature; and a
gluten-free diet, the mean concentra- cline and normalization of anti-TG2 and third had abdominal pain and head-
tion of anti-TG2 was significantly de- EMA in children with CD after starting aches. In our series, 2 of these 15 chil-
creased for 74.3% (95% CI: 69%–79%, the treatment. First, a similar trend dren remained sero-positive for either
P ⬍ .0001) and 83.6%, respectively was seen in the proportion of children anti-TG2 or EMA after 5 years of diag-
(95% CI: 79.1%– 87.1%; P ⬍ .0001; lin- with CD that became sero-negative for nosis and treatment. One child was
ear mixed model corrected for time). EMA and anti-TG2; within 2 years both diagnosed with CD because of failure-
Within 18 months, the mean concentra- antibodies disappeared in ⬃80% of to-thrive and high anti-TG2 levels, HLA-
tion of anti-TG2 was below the cutoff children with CD on a diet. Moreover, DR3DQ2/DR4DQ8, and histologic small
bowel alterations grade Marsh 3B. Af-
ter starting the diet, the anti-TG2 levels
decreased to borderline values within
1 year, but because of errors in the
gluten-free diet the anti-TG2 levels re-
mained borderline positive, even 5
years after the start of the treatment.
The other child, who presented with
failure-to-thrive and lassitude, was di-
agnosed with CD on the basis of strong
positive EMA and histologic small
bowel lesions grade Marsh 3A (HLA-
typing was not performed). Because of
poor compliance with the diet, the pa-
tient did not improve clinically or sero-
logically despite the urge of the pedia-
trician and dietician to eat gluten-free.
The other 13 children who were sero-
positive after 2 years of diet became
sero-negative within 5 years after diag-
nosis (between 24.1 and 59 months).
FIGURE 2 The main reason of their long-term
Mean anti-TG2 levels (ratio, 95% CI) in children with CD on a gluten-free diet (in months). sero-positivity is possibly the long in-
550 HOGEN ESCH et al
Downloaded from pediatrics.aappublications.org by guest on February 3, 2015ARTICLES
tervals, of ⬎1 year, between the differ- to our findings. However, in that study with CD had a histologic recovery
ent serologic measurements. This as- EMA declined faster in time than anti- within 2 years of treatment,14 which
pect is a limitation of our study TG2, which is different to our findings confirms previous findings in chil-
because the participating centers did that revealed a similar trend of nor- dren.19 This suggests that the 2-year
not follow a standardized protocol malization for EMA and anti-TG2. It period that is necessary for the histo-
with specific time points for the mea- would have been interesting to evalu- logic recovery correlates with the time
surement of the CD antibodies, but fol- ate the course of DGP in our patients, needed for normalization of the CD an-
lowed their local control protocols. We but the antibody determinations were tibodies. In our series, only 16 of the
cannot be sure that the children were performed between 2001 and 2009, 129 children (12%) had a second bi-
already sero-negative before the mo- when the DGP’s were not established opsy after a mean time of 1.5 years
ment of measurement. For these rea- yet in the standard serologic analyses (SD ⫾ 0.4 years) on a gluten-free diet,
sons we describe in this study the max- for CD. A 2-year follow-up for anti-TG2 and 15 of them had normalization of the
imum time for disappearance of the (IgA and IgG) in Spanish children with small bowel mucosa and were sero-
specific antibodies in childhood CD. CD, measured at different time points negative at the moment of the control
Another limitation of our study is that during a gluten-free diet, has been re-
biopsy. The CD-specific antibodies de-
we have used 8 different anti-TG2 tests ported previously.14 The findings were
crease and histologic recovery corre-
in our patients. To compare the quan- similar to the ones in our study, and
lated well in these children, except for 1
titative values from the different anti- within the first 3 months of a gluten-
child who had still small bowel lesions
TG2 tests, we have solved this problem free diet the mean concentration of
(M3B) after a 1.6-year gluten-free diet,
by calculating the ratio of each anti- anti-TG2 (IgA and IgG) decreased signif-
despite having negative antibodies after
TG2 measurement. icantly. Moreover, 2 years after the
9 months on the diet. As described in the
Serologic follow-up of specific CD anti- start of the diet, 85% of the children
were IgA anti-TG2 negative, which is child’s patient file, he had a poor compli-
bodies measured at different time ance with the diet.
points has been described before in comparable to our findings.14 In an-
patients with CD, but the present study other study, it has also been shown
CONCLUSIONS
is the first to report the results for that in IgA-deficient children, IgG anti-
both anti-TG2 and EMA in a large cohort TG2 decreases more slowly than IgA en Parents, children (if age-appropriate),
of children with CD children. In adults, IgG anti-TG2 in IgA-competent chil- and doctors who care for children with
a 1-year follow-up was performed for dren.14,18 Most of the IgA-deficient chil- CD should be aware that the mean con-
anti-TG2, EMA, and for IgA and IgG anti- dren were still positive for IgG anti-TG2 centration of anti-TG2 will have a 74%
deamidated gliadin peptides (DGPs).12 after ⬎2 or 3 years on a gluten-free decrease after 3 months of gluten-free
The significant decline of the mean diet.18 diet, and that ⬃80% of the children will
concentration of anti-TG2, and anti- In the Spanish follow-up study it was be sero-negative for EMA and anti-TG2
DGP, within 3 months was comparable shown that the majority of children after 2 years of diet.
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SODA REVIVAL: “The sodas were really good,” said my wife. She was talking
about the carbonated drinks that a friend of the family had made for her that
evening. We don’t drink much soda in our house so my wife’s enthusiasm was
surprising. When she suggested that we should investigate purchasing a small
home soda making system, I was pretty much floored. “You can mix all kinds of
syrups and flavors” she explained. Little did she realize that not only was she
describing soda production at the turn of the 20th century, but also my father’s
first job. In the early 20th century, refrigeration was still uncommon. Fizzy water
was a novelty and associated with curative medicinal powers. People looking
for a refreshing drink could order any one of myriad sodas, or carbonated
beverages, from a store that had a soda fountain—the machine that carbon-
ated the fluid. The soda makers were called soda jerks, a title that my father still
wears proudly, because of the motion they made while mixing the drink. Before
iceless refrigeration became more commonplace the drinks were initially
chilled with blocks of ice. Once carbonated beverages could be easily capped
and people could buy a soda almost anywhere, the job of the soda jerk disap-
peared. So did much of the variation in sodas. However, according to an article
in The New York Times (Dining: July 5, 2011), soda fountains and soda jerks may
be making a small comeback, particularly in large metropolitan centers. Mod-
ern soda jerks have embraced the locavore movement and offer high quality
seasonal, home-made, locally sourced drinks often with eclectic flavors. Instead
of serving a cola drink, modern soda jerks may create new drinks incorporating
vanilla, milk, olive oil, and salt or recreate old fashioned recipes with phos-
phoric acid and tea. Regardless of the flavor, all soda jerks agree that a soda
fountain must have a carbonator and taps as that is the only way to generate
vigorous bubbles. As for us, we have yet to purchase a home carbonator system,
but I certainly have enjoyed discussing sodas with my father. As a former expert
soda jerk, he promises to teach me how to make flips, fizzes, ades, yips, and even
malts. I am not sure what they all are, but I am certainly willing to try them.
Noted by WVR, MD
552 HOGEN ESCH et al
Downloaded from pediatrics.aappublications.org by guest on February 3, 2015Specific Celiac Disease Antibodies in Children on a Gluten-Free Diet
Caroline E. Hogen Esch, Victorien M. Wolters, Susan A. M. Gerritsen, Hein Putter, B.
Mary von Blomberg, Ingrid M. W. van Hoogstraten, Roderick H. J. Houwen, Nico
van der Lely and M. Luisa Mearin
Pediatrics 2011;128;547; originally published online August 22, 2011;
DOI: 10.1542/peds.2010-3762
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
Grove Village, Illinois, 60007. Copyright © 2011 by the American Academy of Pediatrics. All
rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
Downloaded from pediatrics.aappublications.org by guest on February 3, 2015Specific Celiac Disease Antibodies in Children on a Gluten-Free Diet
Caroline E. Hogen Esch, Victorien M. Wolters, Susan A. M. Gerritsen, Hein Putter, B.
Mary von Blomberg, Ingrid M. W. van Hoogstraten, Roderick H. J. Houwen, Nico
van der Lely and M. Luisa Mearin
Pediatrics 2011;128;547; originally published online August 22, 2011;
DOI: 10.1542/peds.2010-3762
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/128/3/547.full.html
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2011 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
Downloaded from pediatrics.aappublications.org by guest on February 3, 2015You can also read
