DISCUSSION
Our study describes infants under 1 year of age with confirmed CMPA
through clearly defined criteria. They were predominantly born by C -
section delivery, mostly males, with an important group of malnutrition
at diagnosis, with a history of predominant familial allergic
respiratory diseases; and with a similar distribution regarding the type
of diet at the time of diagnosis. This clinical pattern is also found in
countries of the region, as shown by Errázuriz G. et al in Chile in a
retrospective study in 106 infants under 1 year of age with clinical
suspicion of CMPA between 2009 and 2011 in a gastroenterology unit in a
clinic, where they observed a predominance of males and a family history
of atopy, and a similar distribution in the type of diet, although they
were predominantly healthy and not malnourished children (8). This was
also shown in prospective studies such as that of Arancibia ME et al in
a private center in Chile (9). However, in other regions of the world,
such as France, the same clinical background pattern can be found, but
with significant differences in the proportion of exclusive
breastfeeding at the time of diagnosis, as demonstrated by Kalach N. et
al in a retrospective cohort study where 116 infants under 1 year of age
with a diagnosis of CMPA were identified in a university hospital in a
French community with a predominance of dystocic deliveries and a
frequency of patients with exclusive breastfeeding at the onset of
symptoms of 33%, less to that found in our study (10). Although
exclusive breastfeeding was slightly more present in the diagnosis of
our patients with CMPA (51.66% vs 48.44), it turns out to be more
protective for the development of CMPA than the use of infant formulas
at an early age, as demonstrated by the systematic review of De Silva D.
et al in which a RR of 0.1 was found (11).
Most infants with CMPA in our study were diagnosed during the first 5
months of age, predominantly with gastrointestinal symptoms, followed by
dermatologic and respiratory manifestations. Of the gastrointestinal
manifestations, colic and diarrhea were the most frequent;
regurgitation/vomiting and proctocolitis were less frequently found.
These findings are consistent with what has been reported in various
regions of the world (8, 10).
Many of the gastrointestinal manifestations described in the clinical
presentation of CMPA, such as regurgitation, colic, or constipation, may
be part of functional conditions that can be frequently seen in healthy
infants; therefore, a directed clinical history and physical evaluation
is important to determine if these symptoms are part of a pathological
condition such as CMPA. In our study, all the patients who had
gastrointestinal symptoms underwent DBPCFC with which the diagnoses were
confirmed; however, this confirmation cannot be made in all clinical
scenarios in our environment, which requires our clinicians to have a
correct approach from the medical history (12).
The study also evaluated the nutritional status (measured with the Z
score) of our infants at the beginning of the diagnosis, and found that
an important group of them (35.93%) had some degree of malnutrition
that reflects as in other countries of LATAM deficiencies in public
health systems, poverty and lack of educational strategies for the
population. In the context of CMPA this result highlights the importance
of regular pediatric control, where a well-directed clinical history and
a complete physical examination carried out on a regular basis will
allow us to establish correct differential diagnoses and an adequate
work plan, to know the natural history of CMPA if we are suspecting it,
and to manage it appropriately. We also observed that 1 year after the
CMPA diagnosis, the number of malnourished patients decreased
considerably to 17.18%, so, early detection of CMPA would play an
important role (13).
IgE - mediated responses were explored with the Prick and ImmunoCAP
tests, finding positivity to fresh milk in 6 of the 64 infants with
confirmed CMPA (9%). Of these 6 infants, 2 presented anaphylaxis, both
with predominant skin and respiratory compromise (hives and
bronchospasm). Thus, the majority of our infants with confirmed CMPA
(91%) were of the non - IgE mediated type, the most frequent type of
CMPA described in multiple publications (14, 15). The studies published
in Latin America (LATAM) on the frequency of IgE mediated vs. non - IgE
mediated CMPA are variable; Arancibia ME. et al, in a study of the
prevalence of CMPA in which open oral challenges were performed, found
20 patients with CMPA, none of them with IgE - mediated CMPA; while
Mehaudy R. et al (16) in Argentina found a 27.6% frequency of IgE -
mediated CMPA. Probably the age of diagnosis, the specialist who makes
the diagnoses, and even the origin and socioeconomic level of the
patient are playing an important role in these differences. In our
study, the majority of patients were diagnosed at an age younger than 5
months, referred by an allergist, and from a socioeconomic level above
that of the population average.
There are few studies in LATAM in which the diagnosis of CMPA has been
made by DBPCFC; Errazuriz G. et al carried it out in 14% of their
patients; Arancibia ME. Y cols performed it in all of their patients,
though these were open oral challenges; while Goncalves LCP. et al in
Brazil performed single - blind oral challenges (17). In our study we
performed it in 91% of our patients and in all cases of suspected non -
IgE mediated CMPA, obtaining a positivity of 86%. The positivity of a
DBPCFC is highly variable in the medical literature (18, 19) and
probably depends on the time of previous elimination diet, the age of
diagnosis, the main symptom of CMPA, and the experience of the clinician
in the initial suspicion, among other factors.
The use of fecal biomarkers in the diagnosis of non - IgE mediated CMPA
is still under investigation. Trillo C. et al. (20) in Spain found that
in 40 person with CMPA vs controls, a FC lower than 138 micrograms/g
could exclude a non – IgE - mediated CMPA; and even, in their
prospective observation of CMPA patients at 1 and 3 months after
diagnosis, reduced FC was found. Likewise, Rycyk A. et al (21) in 27
patients with non – IgE - mediated CMPA, FC (88.9%) and EDN (84%)
were prevalent. However, studies such as that of Roca M. et al. (22) in
30 patients with non – IgE - mediated CMPA did not find significant
differences vs. controls in either FC or EDN, although not all patients
were diagnosed by oral challenges. In our study, all patients with non
– IgE - mediated CMPA were evaluated for both FC and EDN. Significant
differences were demonstrated in FC when the non – IgE - mediated CMPA
was due to regurgitation/vomiting. In patients who had had recent
symptoms (2 weeks prior), we found significant differences in EDN in the
presentations of diarrhea and regurgitation/vomiting. After 1 year of
observation, a significant median difference in the reduction of FC (p
< 0.0001) was demonstrated. Larger scale studies and specific
designs to assess the accuracy of these tests would be important.
The acquisition of tolerance to cow’s milk proteins 1 year after the
diagnosis was similar to studies from other regions (8) and in the
analysis of patients who used nutritional replacement formulas, we
observed that those who had used Nutramigen LGG presented greater
tolerance acquisition (94%) and a greater reduction in FC levels than
those who had used another type of formula (71%), although the p value
did not reach significance p: 0.08 and 0.12 respectively. This trend
found in our study has been corroborated in some previous clinical
trials (23).
Our study is one of the few studies in the region that describes the
clinical characteristics, laboratory tests, and DBPCFC of patients with
CMPA in infants younger than 1 year of age, and probably the first in
the region that explores the levels of fecal biomarkers in non – IgE -
mediated CMPA in patients diagnosed with DBPCFC. Our findings constitute
a good starting point for future studies that explore the diagnosis and
tolerance acquisition of CMPA patients with the particularities of our
region.
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