1.      Introduction 

Idiopathic Anaphylaxis (IA) is a diagnosis of exclusion after known causes for anaphylaxis and other diseases that mimic anaphylaxis have been ruled out[1].

 The condition was first described in 1978 [2].The exact prevalence isnotknown but has been estimated to be between 20,000 and 47,000 cases in the United States[3].

IA accounts for up to 60% of cases of anaphylaxis in adults and 10% of pediatric cases[4].Given that as per the definition there are no identifiable triggers of IA, there are substantial challenges related to the diagnosis and management of these cases.There are currently no guidelines regarding the diagnostic approach including assessment for underlying diseases and useneither of confirmatory tests nor on the best management of pediatric cases of IA. The current approach to treatment is based on disease frequency; short-term treatmentfor infrequent attacks, but prophylactic treatment with glucocorticoids is recommended for patients with frequent episodes. It is well knownhoweverthatlong-term treatment with systemic glucocorticoids is associated with multiple side effects that may be particularly worrisome in the pediatric populationincluding growth failure andadrenal suppression.Althoughseveral case series have been published regarding IA, only a few small descriptive studies have focused on pediatric idiopathic anaphylaxis.

 We aim to present a series of 3 cases of pediatric IA followed by a systematic review of the literature published in the past 22 years regarding IA in children, with a focus on diagnosis and management. 

2.      Methods 

We searched the PubMed database for original scientific studies pertinent to the clinical diagnosis and management of idiopathic anaphylaxis in children. We used the search terms “Idiopathic anaphylaxis” AND “Children” and then limited the results to articles published between May 12, 1995 and May 12, 2017, that were written in English or French. 

The abstracts of the resulting papers were reviewed and those relevant to the diagnosis and management of idiopathic anaphylaxis in children were included. The initial PubMed search yielded 58 articles, which was reduced to 19 after applying previously mentioned filters and then further narrowed to 8 articles after the first and last authors (SD and MBS) assessedthe abstracts and discussed theirrelevancy to the systematic review. (Figure 1)

3.      Case presentations 

3.1.  Case 1 

An 11 year-old boy presented initially with an episode of cough and eyelid swelling 15 minutes after completing exercise (hockey game).He had eaten pasta 2 hours prior to his exercise.

A year later he developed a similar episode with angioedema, difficulty breathing and abdominal pain after eating pizza. He had done exercise 6 hours prior to eating the pizza.At that point he was seen at the emergency department and he was treated with 3 doses of IM epinephrine. 

An extensive work-up was performed. The boy had symptoms of seasonal rhino conjunctivitis. Skin prick tests were performed with common aeroallergens and sensitizations to ragweed and tree pollens was confirmed. Skin prick tests with suspectedfood allergens were negative as well as specific IgE to possible food allergens includingw-5 gliadin and alpha-gal (Alpha gal testing was performed at Thomas Platts-Mill laboratory, University of Virginia, United States). A challenge with the suspected meal was negative.

He had an elevated total IgE(571 kU/L) and his tryptase level waswithinnormal range (3.5 - 4.5 mg/L) at baseline. Tryptase levels were not documented during his attacks. He had normal levels of C3, C4 and C1 inhibitor esterase. (1.57 g/L, 0.20 g/L, 0.32 g/L respectively). Further investigation revealed no mutation for the cKIT 816 on peripheral blood (conduct based on PCR levels - Thomas Kristiansen laboratory, Dept. of Pathology, Odense University Hospital, Denmark). 

Parents refused bone marrow biopsy. 

Given the association with exercise we performed an exercise and food-dependentexercisechallengethat was normal. 

He was instructed to carry an Epipen auto-injector and in the following year he had 3 other similar episodes. The last episode occurred at 15 years of age. He had no new reactions over the last 24 months. 

3.2.  Case 2 

A 14 year-old girl presented with 2 episodes of anaphylaxis with abdominal cramps, flushing and hives. The first episode occurredin the context of exerciseaftereatingtree-nuts and wheat. Onemonth later she presented with a second episode occuring1 hour after eating meat. She was treated with Epinephrine and Reacting. 

Specific IgE levels were negative to all suspected foods including tree-nuts, wheat, milk and alpha-gal. Tryptase levels during the reaction (17.2 mg/L), with baseline levels within normal range (7.5 mg/L). 

Further investigation revealed undetectable levels of alpha-gal (Thomas Platts-Mill laboratory, University of Virginia, United States) and no mutation for the cKIT 816 on peripheral blood (Thomas Kristensen laboratory, Dept. of Pathology, Odense University Hospital, Denmark).Exercisechallenge test (with and without prior exposure to the suspected meal) and spirometryrevealed no abnormalities. 

She was instructed to carry an Epipen auto-injector and we advised to begin a treatment with Reactine 20 mg daily. Parents refused a bone marrow biopsy at this point.At a 24-month follow-up she remained in remission. 

3.3.  Case 3 

The third patient presented at 16 years of age with recurrent anaphylaxis. Her episodes were characterized by acute abdominal pain, vomiting, diarrhea followed by itchiness and hives. The episodes would occur 6 to 7 times per month, usually at night between 10-11 pm (2 hours after eating). She would do exercise 1 hour prior to eating (30 min on a stationary bike). The episodes seemed to occur in the context of her menstruation (a few daysbefore, during or a few days after). Otherwise, nocleartriggers could be identified. In between episodes she was symptom-free and had no constitutional symptoms. 

She had an extensive work-up with negative skin prick tests and specific IgE for the relevant food allergens. Her total IgE was significantly elevated (4032 kU/L)and tryptase levels were elevated during attacks (17.4 mg/L) and normal at baseline (3.4 mg/L).There were undetectable levels of alpha-gal (Thomas Platts-Mill laboratory, University of Virginia, United States)and the cKIT816 mutation was not detected in peripheral blood(Thomas Kristensen laboratory, Dept. of Pathology, Odense University Hospital, Denmark). 

Given the severity of episodes and the prominent gastrointestinal manifestations, an abdominal ultrasound was done and revealed no abnormalities. Urine collection over 24 hoursfor 5HIAA and VMA was normal. 

A bone marrow biopsy was performed revealing no abnormal mast cell infiltrates and normal staining for cKIT and tryptase. 

She was instructed to carry an Epipen auto-injector and we advised to begin treatmentwith Reacting 20 mg daily that did not improve her symptoms. 

TreatmentwithOmalizumab 300 mg monthly was started and she has been in remission since then, for one year. Four months after stopping Omalizumab treatment she has not experienced new episodes consistent with anaphylaxis. 

The findings for each patient are listed in (Table 2).

4.      Results 

4.1.  Diagnosis of IA

Idiopathic anaphylaxis is a diagnosis of exclusion and should be made only after extensive evaluation to exclude other potential causes of anaphylaxis and other diseases with similar manifestations.

The classification of IA is based on frequency of episodes and clinical manifestations. 

The majority of studies included in this review (Table 1) describeanextensiveevaluation in adults and children with anaphylaxis of unknown origin including diagnostic testing forpossible triggers of IgE mediated anaphylaxis such as food, drugs and exercise 4 hours prior to reaction. In patients with an atopic history, Skin Prick Tests (SPT) to aeroallergens is usually performed. C1-inhibitorlevels are measured in patients presenting with angioedema to rule out hereditary angioedema.Rare diseasessuch as systemic mastocytosis, carcinoid syndrome orpheochromocytomaare usually considered. The extensive diagnostic work-up makes the diagnosis of IA highly probablein those series [4,5]. 

In a large cases series of 335 patients, including adults and children, authors concluded that SPT for foods and laboratory testing (CBC, complement and serum chemistry) were non-contributory and should be reserved for selected patients[6]. 

In a case series published by Hogan et al, 8 children were evaluated for IA when no identifiable allergen was found and in the absence of other systemic disease. However, the diagnostic tests performedwerenotelaboratedonin the manuscript[7]. 

In a Spanish series published in 2005, including mostly adults and a small proportion of children(mean age 30.0 +17.3 years, age range 5-73 years), all patients had an extensive evaluation as previously described as well as excluding insect bites, latex and other rare causes such as anaphylaxis attributed to Anisakis simplex or rupture of hydatid cyst. Psychiatric disorders were ruled out as well as other known mimickers such as systemic mastocytosis and pheochromocytoma[8] 

In a large retrospective review of 601 cases of anaphylaxis of unknown origin with a majority of adult patients, an identifiable trigger was found in 41% of cases including food, drugs and exercise. IA accountedfor 59% of cases and 3 patients (0.005%) were diagnosed with systemic mastocytosis in contrast to previously mentioned studies in which no systemic diseases were found[4]. 

More recently, 3 case reports of IA were published in which all 3 patients had a thorough investigation as previously described[5]. 

The authors suggest that rare disorders that may mimic IA include delayed anaphylaxis to red meat. In contrast withimmediate food-mediated anaphylaxis, symptoms may occur more than 2 hours after exposure. Reaction to mammalian oligosaccharide a-gal in these 3 cases was excludedbased on medical history (no data or signs of tick bites, and no symptoms related to ingestion of mammalian products). 

Interestingly all 3 patients were found to have a positive Autologous Serum Tests (ASST), buta histamine release test was negative and the presence of circulating auto-antibodies against IgE and FceRIa could not be confirmed.

In addition they determined the activity of histamine -inactivating enzyme (DAO) which was very low in all three patients, indicating low histamine intolerance. 

Histamine intolerance describes a state with decreased ability to catabolyse endogenous or exogenously administered histamine, leading to histamine-mediated adverse reactions. Diagnosis is based on careful clinical history and identification of intestinal or serum activities of DAO and histamine N-methyltransferase.However, there are nolargescale studies published, establishing the sensitivity and specificity of these tests[5] 

5.      Management 

Classification of the disease is necessary to determine the appropriate treatment course for IA. Frequent episodes are defined as at least 2 episodes in the preceding 2 months or at least 6 episodes in the preceding year[9]. 

All the studies included in this review recommend a treatment for patients with frequent episodes with continuous prednisone at a dose of 40-60 mg, antihistamine (e.g. Hydroxyzine 25-50 mg or Cetirizine 10 mg) and sympathomimetics (e.g. Albuterol) with gradual taper [4-8,10]. 

Patients with infrequent episodes are treated when episodes occur with epinephrine, antihistamines and oral steroids. 

The sametreatmentregimens have been recommended for children with pediatric dose adjustments[7,10] 

The authors in published studies suggest that the current treatment regimens are successful in controlling the disease and induce remission in the majority of patients, although no large-scale studies have been conducted to assess the adequacy of control. 

The proposed regimens of prophylaxis are based on previous clinical experience in the treatment of reactions to radio-contrast media, which represent nonspecific, non-immunologic mast cell activation.

Given ethical considerations in withholding treatment in patients presenting with anaphylaxis, placebo-controlled trials are lacking to support this evidence. 

Further, patients requiring long-term prophylactic treatment with prednisone are at risk for side effects. Alternative prophylactic management strategies are limited. A few reports suggest that Ketotifen, a mast cell stabilizer, is effective in patients with cortico-steroid dependent IA[6,10]. More recently the use of biologics was suggested to benefit patients with IA. 

A first case report was published more recently describing a 12-year-old boy presenting with uncontrolled asthma, multiple food and environmental allergies, recurrent episodes of anaphylaxis of unknown origin and elevated IgE. He was treated with Omalizumab at a dose of 375 mcg every 2weeks for 10 monthswith a rapid resolution of acute episodes and asthma exacerbations[11].Three recent case reports reveal that a histamine free diet is not beneficial in cases of IA. Symptoms did not seem to improve upon histamine-free diet alone, in any of the patientsstudied. However, after introducing daily antihistamines symptoms improved in all patients. 

One of the three patients presented with frequent episodes of IA. A treatment with continuous prednisone was recommended which the parents refused given the increased risk of side effects. She started a treatment with daily antihistamines, afterwhich her symptoms improved and she went in to remission[5]. 

6.      Discussion

 Although IA accounts for only 10 % of anaphylaxis cases in children, it represents a major diagnostic and management challengegiven the lack of confirmatory tests inability to avoid potential triggers. Based on the existing literature, a diagnosis and management algorithm specifically targeting pediatric cases of IA is required. 

Based on current literature we suggestconsidering the following diagnostic tests whenevaluating a patient with possible IA: 

A thorough clinical history and physical exam should be performed followed by laboratory investigations. 

Immediate skin testing and/or in vitro tests for specific IgE to potentiallyrelevant drugs or foods may help to confirm or exclude food or drugallergy as a possible trigger including sIgE to w-5 gliadin and alpha-gal in the case of a suggestive history. 

Delayed anaphylaxis to red meat is a rare disorder that may mimic IA. It should be suspected as a culprit in any case of anaphylaxis of an unknown origin, especially in events occurring 3 to 6 hours after eating, particularly when reactions start in the early morning hours.Our 3 patients had negative sIgE to the relevant oligosaccharide galactose-a-1,3-galactose. 

Other potential causes that should be considered are exerciseand food-dependent exercise-induced anaphylaxis. 

Exercise and/or food-dependent exercise challenges should thus be considered in the case of a suggestive history. 

Other disorders that may mimic IA are systemic mastocytsis, monoclonal mast cell activation syndrome and mast cell activation syndrome.

Elevated serum tryptase levels during attacks are suggestive for IA and patients with elevated levels both at baseline and during attacks should be evaluated with a bone marrow biopsy to rule outmastocytosisor other clonal mast cell disorders. 

Given studies supporting the comparison of serum tryptase levels at baseline and during reaction to confirm the presence of anaphylaxis [12], patientswith IA should have tryptase levels done at these two time points. 

All 3 of ourpatients had a normal baseline tryptase and a negative cKit 816 mutation analysis on peripheral blood. Our third patient who presented with generalized frequent episodes of IA had a normal bone marrow biopsy. 

Pheochromocytoma and carcinoid syndrome are rare disorders in which patients may present with symptoms similar to anaphylaxis, such as flushing induced by release of vasoactive substances (vanillylmandelic acid or VMA in pheochromocytoma and 5-hydroxyindoleacetic acid or % 5HIAA in carcinoid syndrome). Detection of these mediators in 24-hour urine may help excludeorconfirm the diagnosis in patients with a suggestive history.Our third patient had a normal abdominal ultrasound as well as a normal 24 urine for 5HIAA and VMA and hence repeated tests are required if symptomspersist and suspicion is high. 

Hereditary angioedema may mimic IA presenting with recurrent episodes of angioedema as principal symptom. Laboratory findings should include serum levels of C4 and C1 inhibitor in selected patients. 

More recently, 3 previously described case reports with IA werereportedwith positive autologous serum skin testing suggestive of mast-cell activating auto-antibodies against IgE or IgE receptor. However, the basophil histamine-release assay was negative in all 3 patients and specific autoantibodiescould not be demonstrated, suggestive of a different possible cause of auto-reactivity. 

More interestingly, decreased DAO levels, indicative of histamine intolerance were demonstrated in all 3 patients[5].Whether these findings are coincidental or play a role in the underlying pathogenesis of IA remains to be further evaluated. Given the small number of patients, it would be interesting to confirm these findings in larger studies and to look at ASST and DAO levels in patients presenting with IA.(Table 3) summarizes diagnostictesting to consider in patients with possible IA. 

The current proposed treatment regimens are based on small studies from long ago, and dailytreatmentwith systemic steroids in children is associated with an increased risk of long-term side effects.As the risks of systemic steroids often outweigh the benefits in children, we do not recommend systemic steroids for treatment of IA in children.Based on recently published case reports and our own clinical experience, we would suggest the following algorithm for the management of pediatric IA: 

All patients should be instructed on the management of acute episodes and should be prescribedan epinephrine auto-injector. 

In patients with frequent episodes, dailyH1-antihistamines at regular dosesshould be prescribed and the patient should have close clinical follow-up. 

If no improvement after 1 month the physician should consider increasing thedaily dose to 2 times and up to 4 times the regulardose.

If no improvement upon increased daily anti-histamines after 1 or 2 months,treatmentwith Omalizumabshould be considered.

Omalizumab is a 95% humanizedmonoclonal antibody that recognizes and binds to the FC portion of IgE. Allergen specific IgEplays a central role in IgE mediated anaphylaxis. Cross-linking of receptor bound IgE on mast cells and basophilsbyallergens leads to activation of those cells and subsequent release of inflammatory mediators causing anaphylaxis. The exact mechanism in IA remains unknown but it has been postulated that the high affinity IgE receptors may be cross-linked by autoimmune mechanisms. 

Omalizumab may prevent IgE expression on effectors cells and subsequent cross-linking of IgE. It has been a successful treatment in other IgE-mediatedconditionssuch as asthma and chronic urticaria. 

Here we report a second case of pediatric IA successfully treated with Omalizumab.Although we could argue that time could have played a role in achieving remission, the rapid and significant improvement supports the positive therapeutic effect of Omalizumab. 

7.      Conclusion

In conclusion few studies have evaluated diagnosis and management of pediatric idiopathic anaphylaxis. Future studies are needed to optimize treatment regimens for IA in children,who are particularly at risk for potentialsideeffects of oral steroids. 

Omalizumabmaybeatherapeutic option for pediatric IA as a novel approach to treatment.Basedonourclinicalexperience we would recommend treatment of acute attacks with epinephrine for patient with infrequent episodes and a stepwise approach for patients using apotentialalgorithmwe have constructed for the diagnosis and management of IA. The usefulness and accuracy of these algorithms should be assessed in future large-scale studies.

Figure 1:Results of the systematic review using PubMed database. Excluded papers were either review articles rather than original papers or not relevant to the diagnosis or management of idiopathic anaphylaxis in children.

Table 1: The articles that were reviewed are summarized in table.

Table 2:Patient characteristics.

Table 3: Diagnostic tests to consider in a patient with possible IA.

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