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ORIGINAL ARTICLE

Atypical food protein-induced enterocolitis syndrome in children: is IgE sensitization an issue longitudinally?

Athina Papadopouloua*, Theano Lagousib, Elpiniki Hatzopouloub, Paraskevi Korovessia, Stavroula Kostaridoub, Despina-Zoe Mermiria

aAllergology and Pulmonology Department, Penteli’s Children’s Hospital, Athens, Greece

bDepartment of Pediatrics, Penteli’s Children’s Hospital, Athens, Greece

Abstract

Background: Food Protein-Induced Enterocolitis Syndrome (FPIES) is a clinically well-characterized, non-IgE mediated, food allergy syndrome yet its rare atypical presentation remain poorly understood.

Objective: Aim of this study was to present the 10-year experience of a referral center highlighting the atypical FPIES cases and their long-term outcome.

Methods: FPIES cases were prospectively, longitudinally evaluated in respect of food outgrowth and developing other allergic diseases with or without concomitant IgE sensitization later on in life.

Results: Out of a total of 14,188 referrals (0.7%), 100 cases were identified. At presentation, 15 cases were found sensitized to the offending food. Fish was the most frequent eliciting food, followed by cow’s milk and egg. Tolerance acquisition was earlier for cow’s milk, followed by egg and fish, while found not protracted in atypical cases. Resolution was not achieved in half of the fish cases during the 10-year follow up time. Sensitization to food was not related to infantile eczema or culprit food but was related to sensitization to aeroallergens. In the long-term evaluation, persistence of the FPIES or aeroallergen’s sensitization was significantly associated with an increased hazard risk of developing early asthma symptoms.

Conclusion: Sensitization to food was neither related to eczema, culprit food, nor to tolerance acquisition but rather to the development of allergic asthma through aero sensitization. In addition to an IgE profile in an early age, FPIES persistence may also trigger mechanisms switching FPIES cases to a Th2 immune response later in life, predisposing to atopic respiratory symptoms; albeit further research is required.

Key words: asthma, atypical food protein-induced enterocolitis syndrome, food allergy, immunoglobulin E, long term outcomes

*Corresponding author: Athina Papadopoulou MD, Pediatric EAACI Allergist, Allergology and Pulmonology Unit, Penteli Children Hospital, Athens, Greece. Email address: athinapap@yahoo.com

Received: 22 January 2021; Accepted: 2 February 2021; Available online 1 July 2021

DOI: 10.15586/aei.v49i4.193

Copyright: Papadopoulou A, et al.
License: This open access article is licensed under Creative Commons Attribution 4.0 International (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/

Introduction

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE mediated, clinically well-characterized food allergy syndrome, yet its rare atypical presentations remain poorly understood even in recently published International consensus guidelines.1,2 The term “atypical FPIES” was first coined by Sicherer et al. in 1998.3 Nowadays, it is considered for cases presenting with a clinical history consistent with FPIES, but also demonstrating allergic sensitization to the offending food.46

FPIES is mainly classified as a non-IgE-mediated disorder, with underlying distinct pathophysiological local and systemic immunological reactions, characterized by an increased production of TNF-α, profound activation of innate immune cells, and inadequate secretion of TGF-β and food specific IgA.710 Moreover, it has been shown that in cow’s milk FPIES, both humoral and cellular specific immune responses are weak or absent.11,12 The authors reported significantly low total IgE, serum food specific IgG4 and low secretion of the regulatory cytokine IL-10. On the other hand, a single case was reported with high levels of IL-4 and IL-5 cytokines and a decrease expression in IFN-γ in peripheral T cells during acute non-IGE FPIES, implying a Th2-skewed response.13 Additionally, there were few cases reporting a typical association with an IgE-mediated mechanism against the culprit food linking it to a more protracted course of the disease.2,6,1417 Moreover, it has been postulated that local production of mast cells could facilitate antigen uptake, promoting diffuse colitis.18

It remains unknown whether or not the concomitant IgE sensitization constitutes a diverse FPIES phenotype with distinct clinical characteristics and outcome pathways.6 Moreover, it is not clear if these cases follow a similar pattern with other atopic diseases regarding so-called “allergic march model,” albeit a recent review highlighted observations linking persistent non-IgE mediated food allergy to the emergence of IgE mediated comorbidities (rhinitis or asthma).19 This study was conducted aiming at assessing atypical clinical presentations and long-term outcomes of FPIES cases with or without concomitant IgE sensitization and proposing a possible non-IgE allergy march process.

Materials and Methods

Patient identification and food challenge protocol

Acute and chronic FPIES were defined based on Nowak–WęgrzynA et al. criteria.2 FPIES patients, referred from central and southern Greece to the Allergology and Pulmonology Department were enrolled during a 10-year period, from Jan 2008 to Dec 2017.

Patients’ data (age, gender, implicated food, disease onset, clinical presentation, self-reported, atopic family history, and eczema) were recorded at baseline. IgE food sensitization was evaluated at diagnosis through skin prick tests (SPTs) and specific IgE determination using commercial extracts (ALK-Abello, Horsholm, Denmark, and RAST, Pharmacia Diagnostics AB, Uppsala, Sweden). SPTs included cow’s milk, egg (yolk and white), fish, nuts, cereals, and molluscs. A serum-specific IgE value higher than 0.35 KU/L or an SPT wheal diameter >3 mm was considered positive. Oral food challenge (OFC) was performed to confirm the diagnosis in inconclusive cases of FPIES and to evaluate tolerance according to the consensus protocol.2 OFC-related data were collected.

Age of resolution and long-term follow up

All cases were followed up prospectively from presentation until June 2019. Patients were evaluated at 6-months intervals (clinical assessment, other atopic symptoms, accidental contact with the culprit food, and possible reactions). Consumption of dairy products or egg (boiled or baked) was recorded. Age of tolerance was recorded either by self-resolution or OFC with full home re-introduction. Specific mention was made of cow’s milk, egg, and fish resolution age in relation to IgE profile.

Moreover, all cases were followed up prospectively in terms of developing asthma. Current respiratory symptoms were considered if present during the last year’s follow up evaluation. Spirometry, SPTs, and specific IgE (sIgE) to aeroallergens (Dermatophagoides Pteronyssinus, Dermatophagoides Farinae, Alternaria Alternata, Bermuda, Meadow Fescue and Timothy grass, Olive, Parietaria Judaica, and Officinalis) were performed guided by symptomatology.

The study protocol was approved by the Institutional Review Board of Penteli’s Children’s Hospital, and a written informed consent was obtained from the guardians of all subjects.

Statistical analysis

This is a prospective, descriptive, longitudinal study. As 100 cases were finally evaluated, when referring to the total FPIES cases, real numbers were used that also represented the corresponding percentage; in all the other cases, percentages were applied. Continuous and nominal variable were recorded and presented. The normality of our data was assessed by the Kolmogorov–Smirnov test and corresponding 95% CIs were recorded. Descriptive analysis was used to calculate central tendency and dispersion of continuous variables using Mann–Whitney U test and the Kruskal–Wallis test for nonparametric independent samples; whereas chi-square test and risk coefficients using Pearson’s r or Spearman’s ρ were used to compare nominal variables. Data were bivariate evaluated according to the type of clinical presentation (acute or chronic) and according to the presence or absence of IgE mechanism and atopic comorbidities. Kaplan–Meier survival analysis was applied as a time to event method, to estimate the age probability of outgrowing FPIES in the various foods and its relation to atopic background. Log-rank test was used to compare median time of tolerance in different clinical subgroups of FPIES cases. The Cox Regression analysis was used to evaluate the proportionality of tolerance ratio (PT, 95% CI) between cases with different foods or atopic history. If PT was equal to one, no relation between the factors was found; if PT was >1, a positive influence for outgrowing FPIES earlier was detected and if PT<1, a negative effect was reported. IgE sensitization to food or aero allergens was further analyzed using multiple regression to study correlation with respiratory allergic symptoms. Moreover, Kaplan–Meier analysis and Hazard function were also applied to evaluate the longitudinal effect of sensitization on the development of respiratory symptoms. Statistical significance was considered at a cut-off point <0.05. SPSS v20.0 (IBM, Chicago, IL, USA) was used for statistical analysis.

Results

FPIES overview and atopy sighs at presentation

Overall, 100 confirmed FPIES cases (0.7%) out of a total of 14,888 referred for various atopic conditions were included. Nine more cases were excluded given the inability to confirm the diagnosis or due to shorter than 24 months follow-up (Figure 1A). No significant gender predominance was observed (55 male). Fish was the most frequent triggering food, followed by cow’s milk, egg, chicken, and shrimp. The most common fish involved was cod; while perch, sardine, tope, and sea bream were responsible for one case each. Among FPIES cases related to egg, one was caused exclusively by egg yolk. The vast majority of cases were acute (89 cases); 11 cases were chronic, all reacting to cow’s milk. Vomiting was the predominant symptom in 90 FPIES cases (Figure 1B). Chronic cases mainly presented with diarrhea and moderate to severe gastroesophageal reflux. Vomiting was not the main presenting symptom in these cases. Only two cases showed failure to thrive whose diagnosis was delayed. Two infants presented with episodes of acute urticaria after cow’s milk consumption during the breastfeeding period, yet having no IgE-positive test. All these cases with inconclusive history developed late onset vomiting when OFC was performed to confirm the diagnosis. Among acute FPIES cases, 33 required admission, mainly for fluid resuscitation or lethargy. Milk FPIES was significantly related to hospitalization (OR, 95% CI: 2.75, 1.11–6.80). The mean age of symptoms appearance was 9.8 ± 7.4 months, depending on feeding practices and the culprit food. Thus, the mean age for cow’s milk, egg, and fish FPIES cases was 2.8 ± 2.4 months, 11 ± 5.9 and 13 ± 6.7 months, respectively.

Figure 1 (A) Flow-chart of study population (B) Presenting symptoms among FPIES cases.

IgE sensitization to the offending food was observed in 15 out of a total of 100 FPIES cases (15%). In details, 16.12% and 17.8% of fish and cow’s milk FPIES cases were sensitized, respectively. There was no significant relation between food sensitization and type of FPIES (acute or chronic) (OR, 95% CI: 1.19, 0.23–6.18). Neither history of eczema (OR, 95% CI: 2.50, 0.68–9.68) nor atopy in the family (OR, 95% CI: 1.0, 0.59–1.59) were related to sensitization.

FPIES outcome

The mean follow-up period was 92 ± 54.4 months, ranging from 24 to 144. Six fish FPIES cases denied challenge expressing fear and four others were lost to follow up. There was no significant difference in clinical and laboratory characteristics of these cases compared with the other cases. Finally, OFC was performed in 82 patients to confirm or refute tolerance acquisition, while eight cases self-reported resolution. No patients were challenged before the age of 12 months. A total of 55 patients acquired tolerance to the offending food, while in 35 patients OFC was positive. The median age of tolerance acquisition for all cases was 78 months (62–93 m). For the total number of cases, tolerance rate was 44% and 69% at 5 and 10 years of follow up, respectively (Figure 2A). PT was not correlated to the presence of eczema or family history of atopy (Table 1). Moreover, PT was not related to IgE sensitization to the offending food (Table 1, Figure 2B).

Table 1 The cox regression proportional model analyzing the proportional tolerance (PT) ratio in FPIES cases in terms of different parameters (listed in the first row).

Coefficient PT 95% CI p
Family history of atopy −0.45 0.63 0.32–1.24 0.18
Ever eczema −0.65 0.51 0.20–1.33 0.17
Sensitization to food 0.23 1.26 0.52–3.06 0.59
Sensitization to aeroallergens 0.09 0.88 1.09–0.31 0.88
Offending food (fish) −1.56 0.20 0.12–0.35 0.001

Figure 2 Kaplan–Meier functions showing the persistence of FPIES according to (A) total cases, (B) IgE to food, (C) the culprit food, (D) culprit food and IgE to food.

Milk

All patients with cow’s milk FPIES have successfully tolerated milk at a median age of 20 months (Figure 2C). Interestingly, three non-IgE cases had a positive challenge to raw milk, but they were able to consume other milk products such as yogurt or cheese uneventfully. These cases were considered to have outgrown FPIES as they could have consumed processed milk products. No significant difference in median tolerance time was recorded neither between chronic and acute nor between IgE and non-IgE milk sensitized FPIES patients (p = 0.64 and p = 0.89 respectively, Figure 2D).

Fish

Fish cases showed a significant delay in resolution compared with other FPIES cases (Table 1). Only 11% and 48% of patients successfully passed the OFC by 5 and 10 years, respectively (Figure 2C).The median age of a successful fish OFC was estimated to be 115 months. Although there was a difference in achieving tolerance in the first 6 years, no significant difference was found in the median age of tolerance acquisition between patients that were food sensitized and those that were not, for the total follow-up time (p = 0.43, Figure 2D).

Egg

Seven (all) patients with egg FPIES completed an OFC and five had outcomes that were uneventful. The median age of a successful egg challenge was 38.2 (29–48) months. By the end of the study period, 28.5% of patients with egg FPIES remained allergic to raw egg (Figure 2C), yet could consume baked egg. These cases were not able to freely tolerate egg. In this study, there were no egg FPIES patients with IgE sensitization.

Long-term respiratory atopic manifestations

During the study period (92 ± 54.4 months), 25 patients had asthma symptoms, 14 of whom (56%) had IgE sensitization to aeroallergens during the study period (Table 2). FPIES patients with IgE sensitization to food ran a statistically significant higher risk of additional sensitization to aeroallergens. In turn, sensitization was positively correlated with family history of atopy and respiratory symptoms as opposed to history of eczema. Moreover, respiratory symptoms were significantly associated with fish FPIES cases (Table 2). These findings were also confirmed by the multiple regression analysis, while probability function revealed the longitudinal effect of sensitization on respiratory symptoms. All cases with aero sensitization developed asthma at a much earlier time than non-sensitized cases (Figure 3A). In addition, the cumulative hazard ratio for developing asthma symptoms over time was significantly higher in cases with sensitization to aeroallergens compared with those without sensitization or with sensitization only to food (Figure 3B i). Moreover, the time at which tolerance was achieved, regardless of the offending food, was found to be a significant factor for the development of respiratory symptoms. The longer the allergy persistence, the higher the hazard risk (Figure 3B ii)

Table 2 P values and OR(95% CI) comparing atopy syndromes with the offending food, IgE sensitization, and family history of atopy in FPIES cases. Sensitization to food allergens was related to sensitization to aeroallergens. Family history of atopy and fish FPIES were related to asthma and sensitization to aeroallergens.

Eczema Ever asthma IgE to food IgE to aeroallergens
Offending food
All
FISH
MILK
EGG
p
OR (95% CI)

16
13
3
0
0.15
2.85 (0.74–10.9)

25
22
2
1
0.004
1.12 (1.43–6.58)

15
10
5
0
0.64
1.38 (0.48–1.56)

14
13
1
0
0.03
1.15 (1.07–9.17)
IgE to food
p
OR (95% CI)
4
0.16
2.5 (0.68–9.68)
7
0.37
1.04 (0.03–3.56)
_ 7
0.007
1.90 (1.68–26.6)
IgE to aerollergens
p
OR (95% CI)
2
0.47
0.48 (0.08–2.60)
12
0.008
6.30 (1.60–24.0)
7
0.007
1.90 (1.68–26.6)
_
Family history of atopy
p
OR (95% CI)
6
0.58
0.65 (0.21–1.57)
16
0.04
2.66 (1.05–7.00)
6
0.97
1.0 (0.59–1.59)
12
0.02
1.68 (1.22–23.3)

Statistical significance was set at p < 0.05.

Figure 3 (A) Probability function of developing respiratory symptoms according to aero sensitization (B) Hazard function of developing respiratory symptoms according to B (i) sensitization and B (ii) culprit food and tolerance.

Discussion

We present one of the largest European series of FPIES patients published to date, from one of the major referral Allergy centers in our country. The lengthy follow-up period allowed a reliable clinical assessment that included the recognition of atypical cases, the confirmation of persistency or tolerance in relation to IgE sensitization, and the emergence of delayed atopic symptoms.

The majority of patients with FPIES have undetectable food IgE to the suspected food. Although testing for IgE sensitization is not routinely recommended in patients with FPIES, 2–20% were sensitized to the offending FPIES-related food.1921 Previous studies have shown that IgE sensitization to the offending food was associated with persistent allergy to the involved antigen while sensitization to other food proteins did not appear to delay tolerance acquisition.2,14,15,22,23 This was not the case in this study, as no significant correlation between IgE sensitization to the offending food and tolerance acquisition was encountered.

FPIES is pathophysiologically a non-IgE-mediated disorder, yet, atopic disease and a family history of allergy frequently coexist.1923 Eczema is worldwide the most common concomitant atopic disorder at diagnosis. Rates of eczema and family history of atopy vary between studies, with higher rates often reported in studies from the USA and Australia compared with those from Israel and Italy. In our study, eczema and family history of atopy in FPIES cases at baseline were compatible with data reporting lower rates. History of eczema was not significantly correlated neither with IgE sensitization to food nor to aeroallergens. Therefore, one could assume that in our patients IgE sensitization does not occur through a severe impaired skin barrier.

Other atopic diseases including asthma and allergic rhinitis were reported in a recent study highlighting that there was no direct causation between FPIES and atopic comorbidities.20 Similarly, in our study, comorbid atopic symptoms were found in accordance to the general population prevalence.24 However, patients with FPIES and food IgE sensitization, were two times at a higher risk of developing IgE sensitization to aeroallergens independent of other factors. In turn, aero sensitization was the leading factor for developing respiratory symptoms during preschool years in the majority of cases. Conversely, food sensitization, if not followed by aero sensitization, did not constitute a risk factor. The above observations have been previously described in other reports highlighting that sensitization to food in infancy is a marker of increased risk of sensitization to inhaled allergens and consequently asthma symptoms later on in life.25,26 Therefore, based on our data, IgE sensitization may not necessarily affect FPIES outcome but may predispose to asthma, later in life.

Fish FPIES was associated with an increased hazard of developing sensitization to aeroallergens and asthma during infancy. An explanation for this might be the fact that the majority of our FPIES cases were fish driven; this possibly might have biased our results. On the other hand, tolerance to fish FPIES, if ever achieved, is generally delayed, driving inflammatory molecular mechanisms toward an IgE switching. We believe that the emergence of an IgE allergic mechanism is not specific to the allergen but rather driven by the persistent allergic response. This was supported by the fact that the delay or absence of tolerance was also related to an increased hazard of developing aero sensitization and subsequent respiratory symptoms regardless of the offending food. In a recent report by Meyer et al., the authors proposed an integrated non-IgE and IgE-mediated allergic march. In this model, we observe that a delayed-resolving FPIES coincides with the emergence of an IgE comorbidity namely rhinitis and asthma.19 We propose an explanatory underlying mechanism whereby the persistent non-IgE allergy in predisposed individuals results in increased production of TNF-α, disrupted epithelial barrier, and subsequent sensitization with aeroallergens with ultimate development of rhinitis and asthma.

In this study, fish was the most commonly reported triggering food. Similar results have been previously reported in the Mediterranean countries14,22,2729 in contrast to data from the US and Sweden.22,28 Concerning the type of offending fish, our finding that five cases tolerated a type of fish other than the culprit one, strengthened previous data from Italy.30 The immunopathology behind these observations remains foggy. Perhaps, there are species-specific parvalbumin epitopes associated with an increase in TNF-α and HLA-DR marker.31

Cow’s milk was the second most common triggering food in our study, although it is the most commonly reported one throughout the world.14,23,28,29 Failure to thrive was the main clinical finding in a minority of cases most likely due to prompt diagnosis. Thus, awareness of the disease and early diagnosis ensured adequate infantile growth in chronic FPIES cases. Notably, two patients were admitted due to urticaria after milk consumption, yet non-IgE sensitization was found. Urticaria is primarily an IgE-mediated disease; however, it occasionally occurs through non-IgE-mediated mechanisms namely by degranulation of mast cells and basophils with subsequent histamine and by the release of other inflammatory mediators.32 Therefore, cell-mediated mechanisms shared in common with both urticaria and FPIES may explain the coexistence of both the entities.

Egg was the next in frequency culprit food recorded. One egg FPIES case was caused exclusively by egg yolk. The difference in the antigenicity resulting in FPIES symptoms between egg white and egg yolk has been previously described in a few cases.33 Chicken serum albumin (Gal d 5) and YGP42 (Gal d 6) were suggested to be the major allergens of IgE-mediated egg yolk allergy.34,35 However, the components of egg yolk inducing gastrointestinal symptoms in FPIES cases remain to be elucidated.

The median age of tolerance acquisition varied according to the offending food and paralleled the age of onset. Resolution of milk FPIES was achieved at a younger age, followed by egg. Tolerance to fish was clearly delayed, while almost half of fish and one- third of the egg FPIES cases had not outgrown FPIES, till the end of the study period. Remarkably, fish FPIES presented with severe clinical manifestations, as previously reported, a fact that may have delayed or restrained patients from proceeding to OFC.31,36 In addition, a previous study showed that the consumption of fish among Greek children was relatively low, implying that fish was not widely considered an important nutritive food.37 These two points might explain the fact that a few fish cases, were lost to follow up or refused OFC.

It is worth mentioning that there were some FPIES cases that reacted differently when the offending food was cooked or modified. Three cow’s milk FPIES cases reacted to raw milk but were able to consume yogurt or cheese. Even though none of these cases had an IgE allergy profile, a similar phenomenon has been reported in cases with a specific IgE against β-lactoglobulin gastrointestinal phenotype. These patients also benefited from a diet with other dairy products.38 Moreover, two egg FPIES patients could consume baked egg. Tolerance of small amount of the cooked offending food that has been recently described may be due to the fact that FPIES reaction is dose dependent.39 Yet, degradation of the responsible conformational epitope could help some FPIES phenotypes tolerate the offending food, if well-cooked. Alternatively, the glycosylation of ovalbumin with monosaccharides (i.e., mannose), affected specific dendritic cell receptors integration, MHC antigen presentation, and antigen-specific T cell activation differently – resulting in an attenuated allergic response to egg allergy.40

Based on the described endoscopic and immunologic findings in infants with FPIES, several underlying potential mechanisms have been suggested.813,17,18 Trying to incorporate the various immunological interactions and clinical presentations involved in the pathophysiology of FPIES, a potential schematic illustration is depicted in Figure 4. Although the cell ultimately responsible for antigen recognition and reaction initiation in FPIES remains unknown, it is recognized that children presenting with FPIES produce high levels of TNF-α and they have substantially low levels of TGF-β. Therefore in acute FPIES, it is believed that a form of antigen presentation activates Th1 cells producing TNF-α. In the absence of the regulatory role of TGF-β, a local inflammatory reaction takes place with the accumulation and activation of neutrophils and eosinophils with enhancement of their cytotoxicity. TNF-α acts also on the epithelium increasing its permeability altering the intestinal tight junction barrier. Besides, TNF-α acts directly on the hypothalamus increasing body temperature and on the liver promoting the production of acute phase proteins (i.e., CRP) resulting in systemic inflammation. The inflammatory process is further enhanced by the absence of the regulatory role of TGF-β. In distinct cases, a Th2-skewed response may be involved implying an increase in IL-4 and IL-5 and a decrease in IFN-γ expression by peripheral T cells.13 This, consecutively switches B cells, in predisposed individuals, towards the production of specific IgE to food and/or aeroallergens, leading eventually to a classic IgE-mediated reaction. Additionally, in persistent FPIES cases (i.e., fish or egg), the prolonged immune-deviation described above, leads to persistent inflammation of the intestinal mucosa increasing its permeability to aeroallergens, predisposing to respiratory atopic symptoms (Figure 4).

Figure 4 A schematic representation of the possible immunologic pathways resulting in FPIES’s clinical symptoms and TH2 skewing. Following antigen presentation, in the absence of the regulatory role of TGF-β, TNF-α alters the intestinal tight junction barrier. As a result, a local cytotoxic inflammatory response is produced with profound local enhancement of neutrophils and eosinophils. Systemic action of TNF-α on the liver induces the production of acute phase proteins and on the hypothalamus increasing body temperature. In distinct cases, a Th2-skewed response may be involved implying an increase in IL-4 and IL-5 and a decrease in IFN-γ expression by peripheral T cells. This consecutively switches B cells, in predisposed individuals, toward the production of specific IgE to food and/or aeroallergens, leading eventually to a classic IgE-mediated reaction. Additionally, in persistent FPIES cases (i.e., fish or egg) the above mentioned prolonged immune-deviation, leads to persistent inflammation of the intestinal mucosa increasing its permeability to aeroallergens predisposing to respiratory atopic symptom.

Certain limitations have to be taken into consideration. Then arrow range of type of offending food in the present study might not be representative of the whole allergens responsible in the community. Moreover, as egg was the culprit allergen in the minority of our patients, safe conclusions cannot be drawn concerning the long-term outcome in relation to IgE sensitization. In addition, the precise time of tolerance could not be reliably determined as it was bounded by the predefined time intervals of prospective evaluation. Even though FPIES cases were prospectively and consistently recorded by specialized personnel for a lengthy time period, higher numbers of IgE FPIES cases are definitely needed to extrapolate robust correlations. However, the main results were repeatedly confirmed by many statistical approaches, enhancing the reliability of our findings.

Conclusion

The vast majority of FPIES cases presented with the acute form of the disease and the most common offending food in our Greek cohort was fish. Food IgE sensitization was not the cause of an underlying impaired skin barrier and did not affect tolerance but was rather linked to IgE aeroallergens’ sensitization, which was predisposed to asthma. Moreover, delay in tolerance acquisition may also lead to prolonged and consistent Th2 immune activation, predisposed to respiratory symptoms. Larger population studies and longer follow-up periods and assessments of the underlying immunological mechanisms are required to shed light on the relation between FPIES, atopy, and IgE sensitization.

Acknowledgements

The authors thank Dr Fani Giannoula for children’s management; Mrs Cathy Lazarou for English editing; the nurses of Allergology and Pulmonology Department for their valuable help and all parents and children who volunteered to participate in this study.

Funding

This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.

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