LOW BUT INCREASING AWARENESS OF FOOD PROTEIN-INDUCED ENTEROCOLITIS SYNDROME
The first manifestation of FPIES usually begins with the first or second introduction of the offending food [4,9,10▪▪,12▪,15,30,32]. Not uncommonly, however, it is only after repeated episodes that the actual diagnosis is finally made (see Tables 1–10 for the number of prediagnosis episodes). Until then, unfortunately, unnecessary procedures or medical treatments may be performed. For example, a sepsis work up was performed at many centers (A. Fiocchi, personal communication, 19–23, 49) ranging up to 28%  and 50% of cases . Furthermore, up to 22% of cases had a surgical consultation . The only population-based prospective study [10▪▪] estimated the incidence of milk FPIES as 0.34% of the newborn population. This compared with 0.5% for that described for IgE-mediated cow's milk protein (CMP) allergy, in the same population [10▪▪]. The results of a 1-year surveillance study  of FPIES in Australia, however, noted an incidence of 0.01%. The most likely explanation accounting for the differences in these two studies may relate to the low level of awareness and familiarity with this condition, among physicians at large. In fact, there were several regions of Australia in which there was not even a single report described (S. Mehr, personal communication). The low degree of awareness may be related to the lack of mortality in this disease and the high rate of spontaneous recovery. In addition, the challenge procedure is time consuming, as the reaction might be delayed up to 3–4 h after the last dose and may continue for up to 48 h [6,49]. This makes it difficult to carry out a FPIES oral food challenge (OFC) in an office-based or even a day care hospital setting. This limited availability of performing an OFC, coupled with the dramatic nature of the reaction lead to a tendency to postpone the challenge. Even in the presence of a very suggestive history, if the challenge is performed by 18 months; for example it is not uncommon that most challenges are negative (S. Mehr, personal communication). One interesting aspect of this low familiarity to FPIES is that it may explain why foods perceived to have a low allergenic profile such as rice have a greater number episodes occurring prior to diagnosis, compared with milk and soy (4 versus 2, for rice versus milk or soy, respectively) (Tables 1–3).
In recent years, however, there appears to be an increased interest in FPIES. This increased interest has translated into an increased number of publications. More than 29 publications appeared between 2011 and 2013, compared with between 2008 and 2010. Furthermore, at least two multicenter registries, in Italy (Sopo, personal communication) and Australia , were recently initiated. Finally, educational intervention programs successfully implemented in Italy (A. Fiocchi, personal communication) should reduce the time to diagnosis and decrease unnecessary procedures to be performed. These trends will hopefully provide important and validated information in the next several years.
DURATION OF DISEASE AND RATE OF RECOVERY
All experts agree that there is a high and rapid rate of recovery from FPIES. Optimally, the loss of reactivity to the offending food would be determined by a scheduled OFC. In real life, however, many patients experience an accidental exposure without a reaction and report subsequently, usually not voluntarily, that they are not sensitive any more. In Tables 1–10, the available information regarding the various foods causing FPIES, the age of first presentation and the outcome to the best of our knowledge are presented. In our cohort of milk FPIES [10▪▪], over 90% lost their reactivity by the age of 3 years and only a single patient had a challenged-proven reaction after the age of 3 years. Similar results were obtained in Korea (11 and Hwang, personal communication), Australia  and Italy [12▪]. The largest group of cow's milk FPIES, consisting of 310 patients identified by retrospective chart review, yielded different and less favorable results [8▪▪]. Only 35% outgrew their FPIES disease by the age of 2, and only 70% outgrew their sensitivity by 3 years. However, by school age (5 years old) more than 85% lost their reactivity to milk. It is possible that the differences noted with regard to the age of resolution between the studies reflect the variability in the mode of collection of data.
It would appear that the age of recovery of FPIES to soy is similar to that of milk. Among the children with FPIES to soy who were challenged, five out of six lost their reactivity by the age of three . There is no information regarding the other six soy allergic children in that study, but it is reasonable to assume that the patients who were not challenged lost their sensitivity at even a higher rate. In another study , five out of seven soy allergic children lost their sensitivity by the age of 2 years, whereas the other two were lost to follow-up. Although other series similarly noted that the age of recovery for FPIES to soy was similar to that of milk [8▪▪,12▪], there are case reports in which FPIES persists to an older age [8▪▪,26▪▪,27–51]. To our knowledge, the two cases in which FPIES persisted the longest were to soy, at age 18 [8▪▪] and 19 years old (Y. Levy, Personal communication). In addition, a patient with a late onset of FPIES at age 33 persisted through age 53 .
FPIES to solid foods tend to appear at a later age, likely reflecting the later age of introduction of these foods to the diet [8▪▪,16]. Furthermore, in the Italian cohort, the age of resolution of FPIES to solid foods was later than that of milk or soy [12▪]. The median age of resolution for FPIES to fish and egg was exceptionally high, at approximately 60 months (Tables 4 and 6). On the contrary, Ruffner et al.[8▪▪] found no difference in the age of resolution between FPIES reactions mediated by solid foods and liquids (42.1 ± 3.8 versus 32.9 ± 0.95, respectively). Confounding the data is the low catchment for the age of resolution for those reported in this study [8▪▪]. In many of the studies ([11,16,28,52], A.S. Bansal, personal communication), resolution of FPIES was determined by reports after accidental exposure that could have been many months after the true resolution.
MULTIPLE FOODS CAUSING FOOD PROTEIN-INDUCED ENTEROCOLITIS SYNDROME
Not uncommonly, a patient may have FPIES reactions to multiple foods. Thus, an important question arises as to what the replacement food should be and as to how other foods should be introduced into the diet. This problem is reinforced by the fact that there is no laboratory test such as a skin prick test (SPT) or a sIgE that could exclude the possibility of sensitivity. For example, the most common food to cause FPIES is cow's milk, a situation in which a soy-based formula would be considered as a natural candidate for replacement. But, many using a ‘common knowledge’ assume that patients with FPIES to cow's milk are reactive to soy as well . With regard to this issue, there is a sharp discrepancy in the reported prevalence of FPIES to soy in cases of milk-mediated FPIES. Although in the cohorts described from Australia , Israel [10▪▪] and Italy [12▪] not a single case of milk-mediated FPIES reacted to soy, in reports emanating from the United States, soy-mediated FPIES was not uncommon among patients with FPIES to milk [8▪▪]. Although in one study  this was noted in a tertiary highly selected population, in a more recent and largest report of FPIES to date, 29% of patients with milk mediated FPIES also had FPIES to soy [8▪▪]. In this last study, those that were positive to soy were sensitive to other foods and not only milk. The issue of soy reactivity among cow's milk-mediated FPIES patients, is only one of the questions that will have to be answered by future large-scale population-based multicenter international prospective studies.
In solid food-mediated FPIES, it is common to have FPIES to an additional food. In the recent data from the United States over 40% of patients with grain FPIES had sensitivity to two or more grains and 20% with grain FPIES additionally reacted to soy, milk or both [8▪▪]. In the study  from Australia, patients with FPIES-mediated reactivity to both rice and oat were common. On the contrary, in the few reports of FPIES to egg and peanut, no other FPIES-type reactions were mentioned to other foods (Tables 4 and 5).
To date, no risk factors were identified for the appearance of FPIES. Factors analyzed included breastfeeding versus no breastfeeding [8▪▪,10▪▪], the presence or absence of family history and whether the presence of an infant with FPIES increased the risk for a sibling to have FPIES .
SEVERITY OF FOOD PROTEIN-INDUCED ENTEROCOLITIS SYNDROME
In many reports, the description of a FPIES reaction during a natural exposure or challenge is quite dramatic. As discussed above, in many cases, infants with accidental exposures to inducing foods prior to diagnosis were treated as having sepsis because of the life-threatening nature of their reaction. Furthermore, there are cases with documented decreases in blood pressure [11,24] and even shock . This led to the common practice at least in some centers to perform an OFC to diagnose FPIES with an intravenous line in place . However, unlike in IgE-mediated food allergic reactions [53,54], no cases of mortality have been reported in FPIES. This may be related to the early age of presentation and resolution for FPIES; no fatal IgE-mediated food allergic reactions were ever reported in infants younger than 2 years old.
Acquired methemoglobinemia, perhaps secondary to dehydration, is mentioned as evidence for the severity of reactions in this disease . The data are sparse on this issue and the three reports that describe this phenomenon are to both milk and soy [9,14,29,]. They occurred both following accidental and OFC exposure . Similarly, the assumption that the presence of evidence of IgE sensitization is an ominous sign [4,16,49] has not been validated .
ELICITING DOSE IN FOOD PROTEIN-INDUCED ENTEROCOLITIS SYNDROME
In the four cases reported by Bansal , the quantity of inciting food that caused subsequent reactions was several fold less than the quantities that elicited the original reaction. This was noted for rice, wheat, cod and chicken. We made the same observation for milk and this was confirmed by Sopo (personal communication). Furthermore, this phenomenon was reported in a case of soy-mediated FPIES, as well . The observed increased sensitivity upon subsequent exposures may explain the report by Monti et al. in which an infant's threshold for reaction decreased from 50 ml in the first reaction to one spoonful and subsequently by breast milk. The latter was due, presumably, to cow's milk proteins that passed through the breast milk. However, FPIES induced by breast milk was reported in three cases where no previous FPIES reactions induced directly by a food were noted .
SECONDARY IgE-MEDIATED FOOD ALLERGY FOLLOWING FOOD PROTEIN-INDUCED ENTEROCOLITIS SYNDROME MEDIATED FOOD HYPERSENSITIVITY
Several studies reported that patients with FPIES may develop an IgE-mediated allergy to the same food. The first described case was identified in 1998 , and the observation was subsequently confirmed by several additional authors ([10▪▪,23,57] and Spergel, personal communication). Although this phenomenon has been demonstrated mainly for milk, we are also aware of three additional cases in which it was seen in patients who initially had FPIES to fish (Sopo, personal communication; J. Bone, personal communication) and an additional one to egg (J. Bone, personal communication). Because of the risk for the development of IgE-mediated CMA in these patients, it is prudent to examine by SPT or sIgE for sensitization to cow's milk before an OFC challenge is carried out. Needless to say, even if sensitization is noted, the patient has to be observed for an extended period of 3–4 h after the last dose, as for FPIES. The shift from a FPIES food hypersensitivity to an IgE-mediated food allergy is puzzling, as in most cases, there were no detectable IgE antibodies to milk at the initial diagnosis of FPIES. Furthermore, there were no classical IgE-mediated symptoms at the original challenge [10▪▪]. One possible explanation is the extended period of avoidance of cow's milk protein from the diet increases the risk of developing secondary IgE-CMA. The reason that this shift was not reported more frequently probably rests with earlier ambiguity in the diagnosis of IgE-mediated milk allergy and non-IgE mediated symptoms, in young infants . Given that now the awareness and proper diagnosis of FPIES are increasing, it is expected that this phenomenon will be recognized more frequently, and likely with other foods, as well.
More is unknown than known about the natural history of FPIES. In general, FPIES is a benign condition with a favorable course. The duration of the disease is relatively short lived, with the vast majority growing out of the condition by the age of 3–5 years. Given the occurrence of reactions to more than one type of food in some of these patients, it is prudent to introduce alternative foods under medical supervision. In the case of FPIES to cow's milk protein, the possibility of developing IgE-mediated CMP allergy should be entertained. Finally, the possibility of a decreasing threshold for sensitivity to the offending food should be considered.
The authors gratefully acknowledge our colleagues for their helpful discussions and for providing their data from published and unpublished cases. A partial list of contributors includes: S.A. Fiocchi, D. Peroni, M. Ben Shoshan, A. Bansal, M. Landi, S.H. Sicherer, S.A. Bock, S. Bahna, E. Tham, B.W. Lee, MS Sopo, S. Mehr, G. Monti, J.B. Hwang, M. Don, Y. Levy and J. Bone. The authors apologize for anyone who was inadvertently omitted.
M.R.G. is funded by a Kamea grant from the Ministry of Health, Israel.
Conflicts of interest
There are no conflicts of interest.
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Papers of particular interest, published within the annual period of review, have been highlighted as:
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Keywords:Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
food hypersensitivity; food protein-induced enterocolitis syndrome; repetitive vomiting