A comprehensive evaluation of symptom scores designed to
inform the triage and diagnosis of cow’s milk protein allergy in
children: a systematic review of the research
evidence
Running title: Symptom scores for milk allergy
Georgina Thompson1, Zhivko Zhelev1,
Jaime Peters1, Sara Khalid2, Simon
Briscoe2, Liz Shaw2, Michael
Nunns2, Sian Ludman3, Christopher
Hyde1
1 Exeter Test Group, University of Exeter Medical
School, University of Exeter, Exeter, UK
2 University of Exeter Medical School, University of
Exeter, Exeter, UK
3 Royal Devon and Exeter NHS Foundation Trust, Exeter,
UK
Acknowledgements
We would like to acknowledge the contributions of Professor Stuart Logan
at University of Exeter Medical School and Flamingos Allergy Toddler
Group in developing this systematic review.
Abstract
Background: Cow’s milk protein allergy (CMPA) is an
immune-mediated allergic response to proteins in milk, a common infant
food allergy. The wide range and frequency of CMPA symptoms make
diagnosis a challenge, particularly in primary care. Symptom scores may
improve a clinician’s awareness of symptoms, thus indicating a need for
further testing. This systematic review examined the development and
evaluation of such symptom scores for use in infants.
Methods: Four databases were searched from inception to 3
December 2019, for diagnostic accuracy studies, randomised controlled
trials, observational studies, economic evaluations, qualitative
studies, and studies reporting on the development of the tools. Experts
were consulted for additional studies. Data were not suitable for
meta-analysis due to heterogeneity, so were narratively synthesised.
Results: We found two symptom scores evaluated in one and
fourteen studies, respectively. Estimated sensitivity and specificity
ranged from 37-98% and 38-93%. The evaluations of each tool were at
high risk of bias or failed to address issues such as clinical and
cost-effectiveness.
Conclusions: Estimates of accuracy of symptom scores for CMPA
offered so far should be interpreted cautiously. Rigorous research based
on well-defined roles for the tools and free of potential conflicts of
interest is urgently required.
Key words
Cow’s milk allergy; Symptom score; Systematic review
Background
Cow’s milk protein allergy (CMPA) is an immune-mediated allergic
response to proteins in milk, one of the most common infant food
allergies. The reported cumulative incidence by age 2 in the UK is 2.4%
(an estimated 18,100 infants born in 2017).1 Depending
on the underlying pathophysiology and clinical presentation, CMPA is
classified as immunoglobulin E (IgE) mediated, non-IgE mediated or
mixed. IgE-mediated reactions typically occur immediately after
ingestion whereas non-IgE mediated are delayed, taking up to 48 hours to
develop, but still involve the immune system.2 In
infants, CMPA can present with a wide range of symptoms, from acute
reactions, such as pruritus, angioedema and anaphylaxis, to non-acute
symptoms, such as faltering growth, and gastro-intestinal and
dermatological manifestations.3 Seventy percent of
cases are classified as non-IgE mediated CMPA, which are most commonly
associated with non-acute, generalised symptoms.1
The wide range and frequency of these symptoms makes this a diagnostic
challenge, particularly in the primary care setting.4Whereas IgE-mediated and mixed reactions may be identified by skin prick
testing (SPT), food allergen-specific serum IgE (sIgE) determination,
and oral food challenges (OFC), non-IgE-mediated reactions are more
difficult to identify with currently available
techniques.2 Furthermore, pooled accuracy of such
techniques is modest with sensitivities of 88% (95 % CI 76–94), and
87% (95% CI 75–94) and specificities of 68% (95% CI 56–77), and
48% (95% CI 36–59), for SPT and sIgE,
respectively.5 The double-blind, placebo-controlled
food challenge (DBPCFC) is considered the gold standard for diagnosis of
food allergy. However, it is difficult to perform, expensive, and may
not be readily available in many clinical settings. Moreover,
non-IgE-mediated reactions depend on the quantity of exposure and may
have a prolonged delay for symptom onset, which may further lead to
under diagnosis based on OFC leading to poor nutritional intake, failure
to thrive, or worsening eczema.6,7 NICE guidelines
recommend that where CMPA is suspected, an allergy-focused history
should be taken before deciding whether and what further tests to
perform.8 Despite this, a lack of awareness of the
existing guidelines amongst GPs and inconsistency across the guidelines
themselves, leads to uncertainty and variation in
diagnosis.9-11
Accurate and timely identification of CMPA will improve outcomes for
infants and their families, reduce the need for unnecessary invasive and
expensive investigations in symptomatic infants, and reduce the economic
burden of management.12 Delays in appropriate
diagnosis of CMPA reflect both poor awareness of the condition and
insufficient capacity in primary care to effectively apply the
recommended diagnostic strategy.9 Symptom scores, such
as the commercially available Cow’s Milk-related Symptom Score
(CoMiSSTM), have been created to be used in the
clinical setting for increasing awareness of CMPA in
infants.13 They are lists of symptoms where the
presence of a certain number of symptoms is interpreted as a possible
indicator of CMPA. Despite being widely available online, there is
limited information on the development, validity and accuracy of symptom
scores for CMPA.14 Evaluating the quality and
performance of these tools will help clinicians to make informed
decisions about their use, and their limitations, in the clinical
setting, and improve the early stages of the diagnostic process. We have
systematically reviewed the research evidence pertaining to the
development and evaluation of symptom scores used to raise awareness of
CMPA.
Methods
We followed Cochrane Collaboration recommendations for best
practice,15 and the review protocol is registered on
PROSPERO (registration number CRD42020165606).
Inclusion and exclusion
criteria
We included diagnostic accuracy studies, randomised controlled trials
and observational studies, economic evaluations, and qualitative
studies, including systematic reviews, reporting on the development and
evaluation of symptom score tools for suspected CMPA. Study subjects
included infants aged 0-36 months. Case reports, conference abstracts
and meeting reports were excluded.
Search strategy
The search strategy was developed by GT and SB. We searched CENTRAL (via
the Cochrane Library), MEDLINE (via Ovid), Embase (via Ovid), and CINAHL
(via EBSCO) from inception to 3 December 2019. No language or study type
restrictions were applied. Search strategies combined indexing (e.g.
MeSH in MEDLINE) and title and abstract keyword terms for ‘milk’,
‘allergy’ and ‘infant’ and ‘score’ (see Supplementary file 1). We also
searched the World Health Organisation International Clinical Trials
Registry Platform and conducted forward and backward citation searches
on included studies. Forward citation searching was conducted using
ResearchGate and backward citation searching was conducted by manually
inspecting the reference lists of included studies. Topic experts were
contacted to check for additional publications or relevant unpublished
data. Search results were exported to and managed using Endnote X8
reference management software.
Study selection
Two authors (GT, SK) independently reviewed the titles and abstracts,
and subsequently the full texts of studies identified from the
literature search. Any disagreements were resolved by discussion. Study
authors were contacted as needed for clarification.
Data extraction and quality
appraisal
A standardised data extraction form was developed and piloted (GT, ZZ)
(see Supplementary file 2). One author (GT) extracted all data, which
were then checked by a second (SK). Three authors (GT, ZZ, JP)
independently assessed the methodological quality of the included
studies and resolved any disagreements through discussion. We used
QUADAS-2 for test accuracy studies and PROBAST for studies reporting the
development and piloting of the symptom scores.16,17Although these studies did not report development or validation of
prediction models, we felt that aspects of PROBAST would be useful in
appraising their quality. Studies in which a symptom score was used to
assess the effectiveness of specialist milk formula were included for
completeness, but since they did not report data on the performance of
the tool no quality assessment was carried out.
Data analysis, synthesis and
reporting
Summary tables for each evaluation were created. Symptom scores were
analysed separately, and comparisons between them were made narratively.
Results from test accuracy studies were summarised by the number of
false positive, false negative, true positive and true negative results,
and sensitivity and specificity estimates. Forest plots were generated
for each test pair of sensitivity and specificity across studies using
Review Manager 5.4.18 Data were not pooled due to the
small number of studies reporting both sensitivity and specificity, and
extensive heterogeneity amongst included studies.
Results
Study selection
1139 studies were identified (excluding duplicates) with 84 eligible for
full-text review. Fourteen studies met our inclusion criteria. One
further study was identified through citation searches, resulting in a
total of 15 included studies in this review. The study selection process
is shown in Figure 1.
Included studies
Two symptom scores were evaluated in the 15 included studies (see Table
1). One test accuracy study from the USA evaluated the CMPA
questionnaire. The remaining fourteen studies focused on
CoMiSSTM and were conducted in Belgium (n=7), Italy
(n=2), and one in each of Poland, United Kingdom, India, Turkey and
China; these consisted of five test accuracy studies, five effectiveness
studies using CoMiSSTM as an outcome measure, and four
studies on aspects of the development and piloting of
CoMiSSTM. No relevant economic evaluations were
identified.
Description of included symptom scores
CoMiSSTM
The symptom-based score, now known as the Cow’s Milk-related Symptom
Score (CoMiSSTM), was developed by consensus of 18
experts from 14 different hospital sites in Belgium.13It includes GI symptoms (regurgitation, altered stool composition), skin
manifestations (eczema, urticaria), respiratory tract symptoms and
general symptoms such as crying time (see Figure 2). The overall score
ranges from zero to 33, with each symptom having a maximum score of six,
apart from respiratory symptoms, with a maximum score of three. An
arbitrary cut-off point of > 12 was originally selected as
the criterion to highlight infants at risk of CMPA who require further
testing; a score of which would require the presence of at least two
severe symptoms. CoMiSSTM is made available online
through Nestlé Health Science.19
CMPA questionnaire
Gibbons et al. aimed to evaluate a multisystem questionnaire that would
help diagnose non-Ig-E-mediated early CMPA and be easy to apply and
score in a busy clinical setting.7 Symptoms for the
questionnaire were selected based on chart reviews of patients diagnosed
with CMPA and a literature review of its clinical manifestations in
infants. Each symptom scores 1 for a positive response, and 0 for a
negative response, and an overall score was calculated (see Figure 3).
Vomiting was scored based on frequency.
ROC analysis was used to
determine a cut-off point that results in balanced performance in terms
of sensitivity and specificity.
Methodological quality of included
studies
Development and piloting studies
Risk of bias for the CoMiSSTM studies was high due to:
all studies recruiting infants who were presumed healthy with no
confirmatory tests for whether they had CMPA; lack of clarity on who
completed the CoMiSSTM and whether they were blinded
to allergy status of the infant; no details provided for infants who
scored > 12.20-22 Applicability of these
studies was also poor; the CoMiSSTM was performed on
healthy infants whose CMPA status was deemed to be negative, but no
clear test or criteria for exclusion of those not having CMPA was
reported.20-22
Diagnostic test accuracy
studies
The quality of included DTA studies is summarised in Figure 4.
Methodological quality was poor in the risk of bias domains, where all
studies scored high risk in at least two domains. Three studies were at
high risk in the patient selection domain; two used a case-control study
design,7,8 and one study did not use a consecutive or
random sampling method, but instead included only infants that scored a
CoMiSSTM of > 12.23Three studies demonstrated high risk of index test interpretation bias,
due to the lack of pre-specified threshold criterion for a positive
screen and a lack of blinding to the results of the reference
standard.7,23,24 All six studies were at high risk of
bias in the reference standard domain because the reference standard
DBPCFC was not used, while, one study included the index test in the
reference standard.25 Five studies scored high risk of
bias for flow and timing; one left an interval of up to 3 months between
applying CoMiSSTM and conducting
OFC,25 two excluded eligible infants from the
analysis,7,23 and two used different reference
standards to establish CMPA.8,26 Full details on the
methodological quality of these studies can be found in Supplementary
file 3.
Overall, most studies scored low concern for applicability. Concern with
regards to patient selection was found in two studies; one selected
infants with a prior diagnosis of CMPA,8 and one
failed to provide details regarding the setting from which patients were
selected.23 Two studies scored high for concerns
regarding index test applicability because the index test was performed
after an elimination diet rather than at
presentation.8,23
Funding
Ten studies acknowledged conflicts of interest with regards to authors’
connections to pharmaceutical or milk formula industries, including
companies that have been involved in the development of
CoMiSSTM. Seven studies received funding from the
pharmaceutical or milk formula industry.13,23,24,27-30
Main findings
CoMiSSTM
Development and piloting studies
Four studies reported on the development and/or initial validation of
the CoMiSSTM tool.13,20-22 The
development study stated that the predictive value of
CoMiSSTM was 80% if the score was > 12
at the start and decreased to < 6 under an elimination diet
with extensive hydrolysate formula.13 After anonymous
voting by an expert panel, consensus was reached for all five SBS items,
with a view that CoMiSSTM could be used as an
“awareness” tool for CMPA in a primary care setting.
Two studies investigated the performance of CoMiSSTMin healthy infants aged < 6 months with the aim of providing a
scientific basis for the recommended CoMiSSTM cut-off
of > 12.20,21Vandenplas21 reported a median
CoMiSSTM score of 3 in a cohort of 413 infants from
Belgium (31.2%), Italy (18.2%), Poland (19.1%) and Spain (31.5%);
median crying, regurgitation and eczema scores differed significantly
across the age categories (p<0.001, p=0.001, p=0.039,
respectively). Bigorajska20 reported a median
CoMiSSTM score of 4 in a cohort of 226 infants in
Poland; similarly, age impacted on individual crying (p=0.001) and stool
scores (p<0.001). Neither study reported information on the
infants with a positive CoMiSSTM (score >
12) and it is not clear if some of the same infants were included in
both studies.
Vandenplas22 investigated the inter-rater (HCP vs
parent) variability of CoMiSSTM in 148 Spanish
infants. The absolute agreement was reported as excellent with an
intraclass correlation coefficient (ICC) 0.981 (95% CI 0.974–0.986, p
< 0.001). In the second phase of the study, a parent filled in
the CoMiSSTM during 3 consecutive days and was
compared to the CoMiSSTM scored by the HCP to evaluate
day-to-day variability in 72 infants; the ICC was excellent for parental
prospective scores, 0.93 (95% CI 0.90—0.96; p < 0.001), but
poorer between the HCP and parents on Day one versus Day 2, 0.53 (95%
CI 0.34–0.68; p < 0.001).
Test accuracy studies
Test accuracy of CoMiSSTM was evaluated in 5 studies;
two evaluated the accuracy of the tool to predict a positive food
challenge following an elimination diet,8,23 whilst
three evaluated the test accuracy at presentation relative to results of
confirmatory tests for CMPA.24-26 Characteristics of
the methods used to apply CoMiSSTM and reference
standards used in each study are presented in Table 2. Accuracy results
for each study are summarised in Table 3 and Figure 5.
Of the two studies evaluating test accuracy in response to elimination
diet, one evaluated CoMiSSTM in infants aged 0-10
months with a prior diagnosis of CMPA against OFC or skin prick test in
infants < 6 months of age.8 Authors reported
that a ≥50% decrease in CoMiSSTM score had
sensitivity of 84% (95%CI 70% to 93%) but due to study design were
unable to evaluate specificity. The lack of a healthy infant arm in this
two-gate study design, leads to potentially misleading accuracy
estimates. High sensitivity naturally leads to low specificity, and so
would generate more false positive results. The second study comprised
of 85 formula-fed infants aged 0-6 months with a baseline
CoMiSSTM score of ≥12 (mean ± SD 13.65 ± 1.75; range
12-21). Authors reported that CoMiSSTM score ≥12 at
presentation and <6 after 1-month elimination diet had
sensitivity of 76% (95%CI 63% to 86%) and specificity of 58%
(95%CI 37% to 77%) in predicting a positive OFC.23
Of the three studies evaluating test accuracy at presentation, one
examined CoMiSSTM against either OFC or an immunology
test (ImmunoCAP).26 This study of 83 infants aged 0-24
months reported moderate sensitivity of 79% (95%CI 67% to 87%) but
low specificity of 38% (95%CI 14% to 68%). A second study evaluated
CoMiSSTM against OFC in infants aged 1-12 months and
through ROC-analysis reported a moderate to high sensitivity and
specificity of 88% (95%CI 68% to 97%) and 79% (95%CI 49% to
95%), respectively, with a best diagnostic cut-off point of
5.5.24 The third examined CoMiSSTMagainst response to cow’s milk free diet without performing an
OFC.25 In 47 infants aged 1-12 months, authors
reported poor sensitivity of 37% (95%CI 16% to 62%) but high
specificity of 93%, (95%CI 75% to 99%) with a cut-off score of 12.
On ROC analysis a score of 9 was identified as the best diagnostic
cut-off point, which results in an improved sensitivity 84% (95%CI
60% to 97%) and only slightly reduced specificity of 85% (95%CI 67%
to 96%). However, the reported accuracy estimates are likely to
overestimate the real performance of the score, first because response
to elimination diet was defined as a decrease in the
CoMiSSTM score (incorporation bias) and the cutoff of
9 was based on ROC analysis.
Effectiveness studies using symptom scores as an
outcome
Five studies reported use of CoMiSSTM as an outcome
measure (see Table 5). In all studies, after symptomatic infants were
administered cow’s milk free formula, there was a significant change in
CoMiSSTM score.27-31
CMPA questionnaire
One study developed a questionnaire as a means of
investigation.7 This was a pilot study which reported
data on the internal validation of the tool. A citation search on
Gibbons yielded four journal articles, none of which reported further
evaluation of the tool. Characteristics of the pilot study are presented
in Table 2. Sensitivity and specificity test pairs are presented in
Table 3 and Figure 5. Authors evaluated test accuracy of the
questionnaire at presentation relative to the results of an elimination
diet in a cohort of 84 infants < 24 months; 43 cases of
infants with non-IgE mediated CMPA and 41 healthy controls. Authors
reported ROC-determined estimates for sensitivity and specificity of
88% (95%CI 75% to 96%) and 71% (95%CI 54% to 84%), respectively,
with a best diagnostic cut-off of ≥ 6. Feasibility, in terms of time
spent applying the questionnaire in a clinical setting, was evaluated as
a secondary measure. Authors reported a range of 3 to 6 minutes to apply
the questionnaire, which was deemed feasible in this setting.
Discussion
Symptom scores have been suggested to improve diagnosis of CMPA in
infants by helping clinicians to recognise the symptoms of CMPA and
establish the need for conclusive testing. We found two such scores
evaluated in one and fourteen studies, respectively. These comprised
evaluations of test accuracy, effectiveness studies using
CoMiSSTM as an outcome measure, and aspects of the
development and piloting of CoMiSSTM. No end-to-end
studies investigating the long-term outcomes of infants or economic
evaluations were identified. Estimated sensitivity and specificity of
the two symptom scores ranged from 37-98% and 38-93%, respectively.
Although we identified a number of studies evaluating the accuracy of
the scores, especially CoMiSSTM, we are unable to
report valid estimates of their sensitivity and specificity. Not only
were all studies deemed to be at high risk of bias, but they were also
of limited applicability and produced highly heterogeneous results. In
line with our decision not to pool the results given the extensive
heterogeneity, one study evaluating the predictive value of
CoMiSSTM after elimination diet using pooled data from
three clinical trials was excluded from this review due to inappropriate
pooling and poor reporting of findings.32 The accuracy
of a test is highly dependent on the conditions in which the test is
used. Factors such as patient profile, previous tests and the skills and
experience of the test operator could have a significant impact on the
performance of the test and are likely to vary from setting to setting.
Also, a different level of accuracy and balance between false positive
and false negative rate will be required depending on the test’s role in
the diagnostic pathway. For this reason, the best approach in test
evaluation is to define the role of the test from the very start and to
be clear about the value proposition made for the new test: What are the
expected benefits from the test compared to the current clinical
practice? Given the above, the limitations of the studies included in
the review could be summarised as follows.
The role of the test in the diagnostic pathway is unclear. Although
CoMiSSTM is defined as an “awareness tool” and not
for diagnosis of CMPA, it is not clear how exactly clinicians should use
the test and make decisions for further testing, treatment, or ruling
out of CMPA. The ambiguous nature of this definition of
CoMiSSTM is therefore a major limitation for the
evaluation of its accuracy and impact. Initial suspicion of CMPA is
usually based on one or more of the symptoms included in the symptom
score so CoMiSSTM could be used at presentation to
help clinicians make a more structured assessment of unexplained
symptoms suggestive of CMPA. Applying the score could lead either to a
negative result (ruling out CMPA) which requires high sensitivity and
negative predictive value; or to further tests, such as elimination diet
followed by OFC. Throughout the papers, authors point out that
CoMiSSTM is not intended for diagnosis of CMPA or as a
replacement for OFC. However, ruling out CMPA is an essential part of
the diagnostic process to avoid unnecessary referrals for OFC.
In the UK, clinicians should follow the NICE CG116 when diagnosing
infants suspected of CMPA.11 As with other national
and international guidelines, the recommended first step is
allergy-focused history not only to decide whether or not the symptoms
are likely to be caused by CMPA, but also to decide on what type of CMPA
is more likely and whether IgE tests should be carried out prior to
elimination diet and OFC. It is therefore important to consider how the
results would be used relative to other clinical information such as
family history of atopy, which is absent from
CoMiSSTM, yet a significant indicator of allergy in
children, and sIgE or SPT as detailed in the NICE
guidance.11 Studies performed on presumed healthy
infants failed to provide information on those who scored a
CoMiSSTM > 12, which could demonstrate
the lack of guidance on how to follow these infants up.
Another suggested use of the test is for monitoring symptoms during
elimination diet and as a measure of change between baseline and follow
up. The advantage of using a structured symptom score is that it is less
subjective and open to individual interpretations and bias. A study
evaluating the clinician-parent inter-rater agreement of
CoMiSSTM reported positive results and also provided
some limited evidence of good consistency over time. Some authors report
that it is not possible to detect a clinically useful difference between
the score at baseline in children with and without CMPA, but that a
score of <6 after 1-month of elimination diet might be
predictive of CMPA.28 However, such use may be limited
given that the score is unable to provide conclusive results following
an elimination diet, and an OFC is still required. In many of the
studies, a significant proportion of parents (~20%)
declined OFC once symptoms became less severe or completely disappeared.
We know from epidemiological studies, such as EuroPrevall, that false
positives are possible with elimination diet, and that elimination diet
alone is not an acceptable diagnostic pathway.33 Where
OFC is refused, the change in symptom score could be used to provide
reassurance to parents that CMPA is likely and that further
investigations are necessary. This specific use of the test requires
further evaluation, in particular, where the error rate could be
accurately measured.
Nestlé suggest another role for CoMiSSTM in that it
could be filled out by parents in preparation for visiting the GP.
Again, at present, no studies have been conducted with this role in mind
and the impact of using the test in this way is unclear. This specific
role should be investigated in future studies before parents are advised
to use it. Nestle state that the score is not to be used for diagnosis
or in place of OFC, however, its use by parents could equally cause
unintended effects, such as over-diagnosis and over-treatment of CMPA.
Once the role of the test is defined and the value proposition over
current practice is clear, the test needs to be evaluated in good
quality studies that go beyond accuracy and look at the impact of
testing on patient outcomes and cost-effectiveness of alternative
diagnostic-treatment pathways. Longitudinal studies are particularly
important to establish how the results of the test are used alongside
other clinical information in the diagnostic work-up for CMPA. Such
studies need to consider the recruitment of relevant patients, given the
pre-specified role of the test; the skills and expertise expected from
clinicians who will be using the test, and any training requirements;
provisions to deal with attrition bias, given that most studies reported
high dropout rates; use of DBPCFC as a reference standard, to provide
robust diagnosis of CMPA. Despite some evidence to suggest that it may
not be appropriate to be performed in infants, DBPCFC is the optimum
reference standard test for confirmation of CMPA in
children.34 Our definition of applicability of the
reference standard was one that aims to diagnose CMPA, however, further
elaboration on the issue of applicability of reference standards other
than DBPCFC may be necessary in future studies.
The strengths of this review include the use of internationally
recommended methods for study identification and methodological quality
assessment and a pre-specified protocol was registered on PROSPERO. The
main limitation was the poor reporting and quality of included studies,
and that too few, heterogenous studies were identified to perform
meta-analysis.
Conclusions
Just two tools for the diagnosis of CMPA were identified. The
evaluations of these were either at high risk of bias or failed to
address key issues such as clinical and cost-effectiveness. Estimates of
accuracy offered so far should therefore be interpreted extremely
cautiously. Rigorous research based on a well-defined role for the tools
and free of potential conflicts of interest is urgently required.
Author contributions
GT contributed to search strategy, data collection, data analysis and
manuscript. ZZ contributed to the study design, data collection, data
analysis and manuscript. JP contributed to the study design, data
collection, data analysis and manuscript. SK contributed data collection
and manuscript. SB contributed to the search strategy and study design.
LS, MN and SL contributed to study design and development of the
protocol. CH contributed to the study design, data analysis and
manuscript. All authors read and approved the final manuscript.
Funding
None declared
Conflicts of interest
None declared
Word count: 4181
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21. Vandenplas Y, Salvatore S, Ribes-Koninckx C, Carvajal E, Szajewska
H, Huysentruyt K. The cow milk symptom score (CoMiSSTM) in presumed
healthy infants. PLoS ONE. 2018;13(7):e0200603.
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23. Vandenplas Y, Althera Study G, Steenhout P, Grathwohl D. A pilot
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26. Prasad R, Venkata RSA, Ghokale P, Chakravarty P, Anwar F. Cow’s
Milk-related symptom Score as a predictive tool for cow’s milk allergy
in Indian children aged 0-24 months. Asia Pacific Allergy.2018;8(4):e36.
27. Dupont C, Bradatan E, Soulaines P, Nocerino R, Berni-Canani R.
Tolerance and growth in children with cow’s milk allergy fed a thickened
extensively hydrolyzed casein-based formula. BMC Pediatrics.2016;16(1):96.
28. Vandenplas Y, De Greef E. Extensive protein hydrolysate formula
effectively reduces regurgitation in infants with positive and negative
challenge tests for cow’s milk allergy. Acta Paediatrica,
International Journal of Paediatrics. 2014;103(6):e243-e250.
29. Vandenplas Y, De Greef E, Hauser B. Safety and tolerance of a new
extensively hydrolyzed rice protein-based formula in the management of
infants with cow’s milk protein allergy. European Journal of
Pediatrics. 2014;173(9):1209-1216.
30. Vandenplas Y, Steenhout P, Planoudis Y, Grathwohl D. Treating cow’s
milk protein allergy: A double-blind randomized trial comparing two
extensively hydrolysed formulas with probiotics. Acta Paediatrica,
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cow’s milk allergy. World journal of clinical cases.2019;7(16):2256-2268.
32. Vandenplas Y, Steenhout P, Jarvi A, Garreau A-S, Mukherjee R. Pooled
Analysis of the Cow’s Milk-related-Symptom-Score (CoMiSSTM) as a
Predictor for Cow’s Milk Related Symptoms. Pediatric
gastroenterology, hepatology & nutrition. 2017;20(1):22-26.
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Table 1 : Summary of included studies.