3.4.5 |Studies that include Bos d 8
Nine studies[30-38] have reported on the
diagnostic accuracy of Bos d 8 serum levels. The specificity and
sensitivity of Bos d8 detection varied across studies (0.79 - 0.98 and
0.34 - 0.90, respectively). In Alessandri’s
study[31], diagnostic efficiency was affected by
the use of different testing equipment. Using a cut-off point of 0
(kUa/L) (ISAC standard unit), the sensitivity and specificity were 0.54
and 0.81, respectively. However, with a cutoff value of 0.44 (kUa/L)
(ImmunoCAP normalized unit), the sensitivity and specificity were 0.82
and 0.63, respectively. In Nieminen’s study [36],
the diagnostic sensitivity was higher in 1-2 years old children compared
to 3-14 years old children, whose sensitivities and specificities were
0.34 and 0.94, 0.11 and 0.93, respectively.
4 | DISCUSSION
An analysis of CRD accuracy in CMA
will certainly promote a better understanding of diagnostic efficacy and
contribute to more precise and individualized diagnosis in
CMA[39]. Many CRDs on food allergy have been
carried out, but only a few studies have focused on milk allergy. A
systematic review of the accuracy of CRD for milk allergy was
conducted[22], but the results are still unclear
due to the limited number of included studies and cases. Based on
previous studies, more articles were included in our study. Through a
systematic approach, we performed a more comprehensive analysis.
We analyzed the included studies on
milk components and found that the diagnostic value of sIgE levels for
Bos d 4, 5, 6, and 8 components varied greatly, with most performing
poorly overall. Bos d 4 and 8 components consistently showed high
specificity (0.78-0.98 and 0.79-0.98, respectively) but variable
sensitivity (0.50-0.82 and 0.34-0.90, respectively), while Bos d 5
showed lower specificity (0.58-0.98) than Bos d 4 and 8. The low
sensitivity indicates that a negative result for CRD cannot exclude CMA,
necessitating oral food provocation. Conversely, the high specificity
suggests that the oral food excitation test can be ignored, as the risk
of CMA is sufficiently high in this case. Our findings confirm those of
a previous DTA systematic review on CRD in milk
allergy[22], indicating that sIgE levels against
Bos d 4 can provide a highly accurate diagnostic indicator. In the
uncuoglu study [38] of the Bos d 5 component, the
test had a higher sensitivity (1.0) than specificity (0.70), while in
all other studies, specificity was significantly better than
sensitivity. These results can be extrapolated to other studies and
components analyzed (Table 2), as the determination of individual
components with the UniCAP is comparable to the diagnosis of allergy
with the oral provocation test, which does not differentiate between
different components of the same food. Thus, in the absence of UniCAP
detection of IgE against a specific ingredient, a patient may be
sensitized to another ingredient of the same food and diagnosed by OFC,
resulting in a false-negative result (decreased sensitivity).
Conversely, all positive reactions to any component will also be
positive in the oral test, resulting in a low number of false positives
(increased specificity). However, this is the first review of the
diagnostic value of Bos d 6 as a component of cow’s milk-related
allergic reactions. It was found to have high specificity but low
sensitivity. Previous studies have indicated that Bos d 6 is
characterized by high heat stability and cross-reactivity with beef
proteins[40], suggesting that children with high
levels of Bos d 6 serum IgE may also be allergic to beef. Therefore,
caution should be exercised when ingesting beef to prevent severe
allergic reactions. In this review, the diagnostic accuracy of the cow’s
milk allergy component of the component-resolved diagnosis (CRD) was
compared with that of first-line diagnostic tests, including the APT,
sIgE, and SPT, as reported in previous systematic reviews. The results
varied depending on the diagnostic test. The DTA results for Bos d 4, 5,
and 8 for milk were similar to those of the APT, which showed a
sensitivity-specificity pair of 44.2% and
86.9%[41]. However, the overall sensitivity of
all components was lower than that of sIgE and SPT (87.3% and 87.9%,
respectively), and the specificity was higher than that of sIgE and SPT
(47.7% and 67.5%, respectively)[42].
Observations were conducted on all studies, with a particular focus on
the diagnostic accuracy of the Bos d 4, Bos d 5, Bos d 6, and Bos d 8
components of milk due to the greater number of studies and the
significant variability of results. Possible explanations for this
variability include 1) Experimental design, which included case-control,
prospective cohorts, and retrospective cohorts. Retrospective designs
may pose a risk of information bias, leading to artificially maximized
results. Additionally, since the oral food provocation test served as
the gold standard for all studies analyzed, differences in the design of
this test should be considered a source of bias in the results. Only two
studies used the DBOFC test as the reference
standard[31, 37], while the majority of studies
used the OFC (without using double-blind or only single-blind), which
carries the risk of interpretation bias and interference of subjective
factors in the appearance of symptoms, potentially leading to bias in
patient selection. It is also important to mention the heterogeneity due
to the use of different versions of devices (ImmunoCAP, ISAC, UniCAP,
and 3gAllergy). Standardization of all CRD tests is necessary to ensure
comparable results between different tests. The ImmunoCAP ISAC is
considered by the World Health Organization as a complementary
diagnostic tool to the component-resolved diagnosis[43]. 2) Age of the patient; our results show that
there is an effect of age on diagnostic efficacy and cutoff values. In
our study, children aged 1-2 years had smaller optimal cutoff values and
higher diagnostic efficacy compared with children aged 3-14 years,
suggesting that younger children are more sensitive to smaller cutoff
values. This finding is consistent with previous studies[44-47].
However, this difference still lacks
statistical power because of the limited number of studies included and
the relatively small advantage. Moreover, negative results were noted in
our pooled analysis. Therefore, to be applied in clinical practice,
prospective studies need to be designed to evaluate the use of CRD in
diagnostic tests for suspected milk allergy, and the cutoff values for
optimal diagnostic efficacy at different ages need to be studied to
reach a consensus.
In the scientific literature,
there is a growing body of evidence demonstrating the utility of CRD in
the workup of milk allergy, suggesting that the sIgE of milk allergen
components can aid in the diagnosis of milk allergy. Using a systematic
approach, we analyzed the evidence for the diagnostic accuracy of CRD
for milk allergy within a range, filling an important research gap in
this area. The strengths of our study include a comprehensive
methodology, the use of a highly sensitive search strategy, no language
restrictions, and the involvement of multiple countries, databases, and
clinical trial registries, which allowed for a thorough literature
search. Our inclusion criteria were based on clinically relevant
information from carefully selected studies, as well as guidelines from
reputable organizations such as the European Academy of Allergy and
Clinical Immunology and the Food Allergy [48] and
Anaphylaxis Guidelines Group[49]. Furthermore, the
internal validity of the studies included in our review was strong, as
at least 50% of the participants used 0FC as the reference standard.
Our systematic review has several limitations. First, due to the limited
and relatively insufficient number of articles included in the study, a
larger dataset or a more scientific approach would be needed to more
accurately assess diagnostic accuracy. In addition, the included
population was exclusively children and there is a lack of studies in
adult populations; therefore, the role of milk CRD in adults remains to
be investigated. Finally, and most importantly, there was a great deal
of heterogeneity in our analyses, constituting an important obstacle to
meta-analysis. This may be due to the great variation in study design:
a) Differences in the level of the cutoff value chosen in different
studies (e.g95% vs. 100%) may significantly change the suggested
critical value. b) Methodological quality: type of equipment or test,
use of OFC blinding.
5 | CONCLUSIONS
The findings of this review indicate that the measurement of sIgE levels
for the Bos d 4, Bos d 6, and Bos d 8 milk components is highly specific
but not very sensitive for diagnosing cow’s milk allergy in children.
The implementation of CRD for diagnosing CMA in children may potentially
decrease the need for OFC.