Is Oral Food Challenge as Safe Enough as It Seems?

Background

Oral food challenges (OFCs) assist in the diagnosis of food allergies and are essential to determine whether an allergy has been outgrown. During the OFC, a medical procedure e introduces foods suspected to be allergenic orally in increasing doses. Mild skin reactions such as urticaria or rarely serious life-threatening reactions such as anaphylaxis may develop.

Objective

In this study, we aimed to retrospectively evaluate the clinical and laboratory characteristics of patients who experienced anaphylaxis during open OFCs in a tertiary care children’s hospital.

Methods

Patients who underwent OFCs to confirm the presence of a food allergy or to assess tolerance status at the University of Health Sciences, Ankara, Dr. Sami Ulus Maternity and Children Training and Research Hospital, Pediatric Allergy and Immunology Outpatient Clinic between 1 January 2013 and 1 February 2016, were included in the study. Patients’ data were obtained retrospectively from electronic medical records and challenge chart reviews.

Results

A total of 623 OFCs were performed during the period studied. Nine patients (1.4%) between 13 and 67 months of age (mean age: 38.3 months) developed anaphylaxis during their OFC.

Conclusion

OFCs should be performed in a hospital or outpatient office under medical supervision that is adequate for anaphylaxis intervention by an allergy specialist. Close observation of objective and subjective symptoms is essential during the challenge because there are no laboratory tests that can predict an anaphylactic diagnosis or the severity of the reaction.

INTRODUCTION

Food allergy is a complex immunologically mediated disorder that is rapidly increasing in prevalence for reasons that remain unknown. It affects nearly 5% of adults and 8% of children [1]. Oral food challenges (OFCs) assist in the diagnosis of food allergies and are essential to determine whether an allergy has been outgrown. During the OFC, a medical procedure introduces foods suspected to be allergenic orally in increasing doses. Mild skin reactions such as urticaria or rarely serious life-threatening reactions such as anaphylaxis may develop.

For a safe OFC, cut-off values for specific IgE and skin prick test induration diameters varying with different foods were determined in various studies. However, anaphylaxis cannot be predicted with 100% certainty. Therefore, it is difficult for allergists to make decisions in clinical practice. When applying this method, which is the gold standard in food allergy diagnosis, the possibility of it resulting in a life-threatening reaction should always be kept in mind.

There is a limited number of studies available in the literature evaluating the results of OFCs in children [2, 3]. The aim of this study was to retrospectively evaluate the clinical and laboratory characteristics of patients who experienced anaphylaxis during open OFCs in a tertiary care children’s hospital.

MATERIALS AND METHODS

Case selection—data collection

Patients who underwent OFCs to confirm the presence of a food allergy or to assess tolerance status, at the University of Health Sciences, Ankara, Dr. Sami Ulus Maternity and Children Training and Research Hospital, Pediatric Allergy and Immunology Outpatient Clinic between 1 January 2013 and 1 February 2016 were included in the study. Patients’ data were obtained retrospectively from the electronic medical records and challenge chart reviews.

Ethical statement

The study was approved by the Dr. Sami Ulus Maternity and Children Training and Research Hospital Clinical Research Ethics Committee. Written informed consent was obtained from the parents before the OFCs. The study was carried out in accordance with the principles of the Declaration of Helsinki.

Open oral food challenge

The OFC was performed at least 4–6 weeks after a previous food reaction to confirm the diagnosis of allergic conditions or to determine if tolerance had progressed during the patient’s follow-up.

Blood samples were obtained for food-specific IgE (Immulite 2000 CLIA-I; Siemens, Germany), serum total IgE (ImmunoCAP, Phadia AB, Uppsala, Sweden) and peripheral eosinophilia percentage values (Beckman Coulter, Fullerton, CA, USA). Skin prick tests were performed before the OFC in all patients. The skin prick tests were performed with a panel containing standard food allergens (Stallergenes, Antony, France) such as cow’s milk, hen’s egg, tree nuts and legumes. The panel was expanded individually to include each food suspected of being allergenic. Saline was used as a negative control, and histamine (10 mg/ml) was used as a positive control.

Before the OFCs, each patient’s physical examination was performed, and vital signs were recorded. Every open OFC was preceded by 2 weeks of suspected food elimination. OFCs were postponed when patients were otherwise ill at the time of their appointment. Antihistamines, beta-agonists and other medications that may alter symptoms of a reaction were discontinued according to their half-lives.

The OFC with suspected food was performed according to protein amounts of specific foods as proposed by the European Academy of Allergology and Clinical Immunology [4].

After the final dose, the patients were observed closely for at least 2 h in the observation room under the supervision of a physician and nurse. They were evaluated in terms of physical examination and vital signs at regular intervals. In the presence of objective symptoms, the challenge was considered positive and terminated [5].

Anaphylaxis diagnosis

Patients who met the diagnostic criteria for anaphylaxis by developing severe reactions during the OFC were accepted as anaphylaxis and 0.01 mg/kg of intramuscular epinephrine (1:1000) was administered. These patients were observed for at least 24 h [6]. Serum total tryptase measurements were obtained within 15 min to 3 h of symptom onset.

RESULTS

A total of 623 OFCs were performed at the Pediatric Allergy and Immunology Outpatient Clinic between January 2013 and February 2016. Table 1 provides the distribution of foods investigated by the OFCs.

Nine patients (1.4%) between 13 and 67 months of age (mean age: 38.3 months) developed anaphylaxis during the OFC. Fifty-five and a half percent of the patients were male. Three patients had a family history of allergic diseases (allergic rhinitis and atopic dermatitis). One patient had been operated on for pulmonary stenosis and patent foremen ovale. The remaining other patients had no additional diseases. None of the patients were using the medication regularly.

Anaphylaxis was caused by eggs in three patients. Five patients experienced anaphylaxis due to cow’s milk and one from yoghurt. In patients with anaphylaxis, the first clinical finding occurred at the earliest 65 min and at the latest 240 min (mean time: 115 min).

The first clinical manifestations of anaphylaxis were urticaria in three patients, angioedema in one patient, cough in two patients, vomiting in one patient, sneezing in one patient and restlessness in one patient. The demographic characteristics and clinical features of patients who developed anaphylaxis are summarized in Table 2.

Epinephrine therapy was given to all of the patients after their diagnosis. Additionally, according to clinical findings, antihistamines, oral steroids, inhaled salbutamol and intravenous liquid infusions were administered. Patients were kept under observation for at least 24 h and discharged after epinephrine autoinjector training was provided.

Patients with a diagnosis of anaphylaxis were evaluated with laboratory investigations. The mean eosinophil percentage and serum total IgE values of the six patients who reacted to dairy products were 5.6% and 179.8 IU/ml, respectively.

The mean eosinophil percentage and serum total IgE values of the patients who reacted to the boiled egg challenge were 4.4%, and 179.3 IU/ml, respectively. All of the skin prick tests with egg and dairy product commercial allergen extracts were positive.

A serum sample for the tryptase value was sent from five of the patients within the first 4 h after diagnosis. The serum tryptase concentration was not high in any of the patients (the cut-off value was accepted as 11.4 µg/l) [7, 8].

The laboratory findings and skin prick test results of the patients who experienced anaphylaxis are summarized in Table 3.

DISCUSSION

With the increasing frequency of allergic diseases in recent years, specific allergy tests like the challenge test are becoming more commonly used in daily practice. Challenge tests with food aim to confirm the existence of allergic disease and determine if tolerance has occurred or is in the process of developing. A double-blind placebo-controlled challenge test is the gold standard method for IgE-mediated food allergy. However, this is very time-consuming, requires experienced staff, and is relatively costly, so OFCs are being used more often at this time [9]. We prefer to conduct double-blind placebo-controlled challenge tests in our clinic when we encounter subjective symptoms.

In our clinic, 623 open food challenge tests were performed between January 2013 and February 2016. Cow’s milk and other dairy products (yoghurt, baked cake) and eggs were commonly used foods in open OFC tests. This is consistent with the most common food allergies in childhood [10].

In general, mild reactions such as cutaneous findings are seen during challenge tests, but in rare cases, serious reactions like anaphylaxis can occur and be lethal without urgent intervention [11].

Anaphylaxis developed in 9 patients (1.4%) during a total of 623 open OFCs conducted in our clinic over 3 years. Lieberman, et al. [11] found a rate of anaphylaxis of 1.7% in their 701 open OFCs. In another study, the incidence of anaphylaxis was found to be 1.1% of 526 oral food provocation tests [4]. The frequency of anaphylaxis during OFCs in this study is compatible with previous studies.

In our patients with anaphylaxis the first clinical finding was seen at an average of 115 min. This supports the importance of the first 2 h of follow-up However, the first symptom in the form of a cough may develop as late as 240 min, which means that it might be necessary to continue follow-up for longer in some patients. Moreover, it is important to educate parents about the possible late reactions they might encounter at home [12].

The first clinical findings of anaphylaxis in this study were urticaria in three patients, angioedema in one patient, cough in two patients, vomiting in one patient, sneezing in one patient and restlessness in one patient. It should not be forgotten that the first clinical findings of anaphylaxis can be subjective symptoms such as restlessness, as well as objective findings (such as urticaria, cough and vomiting) that can be more easily recognized. Especially, considering that the average age of the patients in this study was 38 months, the observations of the healthcare personnel who follow these patients become more important because this age group cannot express their complaints clearly. In the presence of subjective symptoms, it would be prudent to consider repeating the open OFC test or to confirm the findings with a double-blind placebo-controlled challenge test.

Before challenge tests clinical history, skin prick test results and specific IgE measurements are all evaluated together to ensure appropriate patient selection. However, the diagnosis of IgE–mediated food allergy is known to have low specificity, even though it has good sensitivity. It is impossible to predict whether a reaction will occur during the test or how severe the reaction might be [13].

Previous studies have shown that the detection of specific IgE for milk >5 kU/l under 2 years of age and >15 kU/l over 2 years of age has a high positive predictive value for milk allergy. Egg cut-off values of 2 kU/l for patients under 2 years of age and 7 kU/l for patients over 2 years old have been predictive values of a clinical reaction [14, 15]. Studies have reported that a diameter of induration for skin prick tests over 8 mm for milk and over 7 mm for egg has 95% positive predictive value [13].

In this study, there were two cases of anaphylaxis even though the specific IgE and skin prick test were below the cut-off values of induration diameter. This is important because it reinforces the fact that the possibility of a reaction during OFC tests cannot be predicted.

Measuring serum tryptase levels may provide diagnostic benefit as a marker of mast cell activation in anaphylactic diagnosis. It is known, however, that it does not always rise during anaphylaxis. In a study conducted by Cunill, et al. [7], approximately one-third of the cases with clinically diagnosed anaphylaxis did not have elevated tryptase levels at the time of diagnosis. In this study, although the number of cases was low and basal tryptase levels were unknown, tryptase elevation was not observed.

In our patient group, anaphylaxis was observed even in patients who were initially thought to be within safe limits. This demonstrates that it is still not possible to predict anaphylaxis and anaphylaxis can be observed in patients with any clinical condition. Although close observation is recommended for the first 2 h after an OFC, family education is extremely important in terms of late reactions that may occur.

In conclusion, OFCs should be performed in a hospital or outpatient office under medical supervision that is adequate for anaphylaxis intervention by an allergy specialist. Close observation of objective and subjective symptoms is essential during the challenge because there are no laboratory tests that can predict an anaphylactic diagnosis or the severity of the reaction.

REFERENCES