Idiopathic Anaphylaxis

Opinion statement Idiopathic anaphylaxis is a rare life-threatening disorder with symptoms similar to other forms of anaphylaxis. There is lack of a robust evidence base underpinning the treatment of anaphylaxis and even less so for idiopathic anaphylaxis. Much of the evidence therefore comes from relatively small case series and expert opinion. Idiopathic anaphylaxis is a diagnosis of exclusion, requiring a thorough history and careful diagnostic work-up investigating possible triggers and underlying predisposing factors. Key diagnostic tests include skin-prick testing, tests for specific-IgE, component-resolved diagnostics, and in some cases for allergen challenge tests. Other recognized causes of anaphylaxis, such as foods, medications, insect stings, latex, and exercise, should all be considered, as should differential diagnoses such as asthma. While the cause of idiopathic anaphylaxis remains unknown, prompt treatment with intramuscular epinephrine (adrenaline) administered into the anterolateral aspect of the thigh is associated with good prognosis. There may also be a role for H1-antihistamines and corticosteroids as second-line agents. Patients need to be carefully monitored for signs of deterioration and/or a possible protracted or biphasic reaction. Patients with frequent episodes of anaphylaxis (e.g., six or more episodes/year) should be considered for preventive therapy, which may include corticosteroids, H1- and H2-antihistamines, and, in some cases, mast cell stabilizers such as ketotifen. Alternative immune-suppressants (e.g., methotrexate) and anti-IgE may rarely also need to be considered. In many cases, the frequency of anaphylaxis declines such that regular use of corticosteroids can be discontinued after 9–12 months. Pediatric patients should be treated with similar regimens as adults, but with appropriate dose adjustments. Patients should carry their self-injectable epinephrine and other emergency medications at all times in order to deal with emergency situations.


Introduction
Anaphylaxis has been defined as a "…serious lifethreatening generalized or systemic hypersensitivity reaction," which is typically rapid in onset and associated with skin and mucosal changes; it may in some cases prove fatal [1••, 2••, 3••, 4••]. Idiopathic anaphylaxis is a rare form of anaphylaxis for which triggers cannot be identified despite a detailed history and careful diagnostic assessment [5••, 6••, [7][8][9]. Its manifestations are identical to other forms of anaphylaxis [5••, 6••, [7][8][9]. Idiopathic anaphylaxis was first described by Bacal and colleagues in 1978 in a report of 11 patients whose episodes could not be explained [10••]. Although the actual incidence and prevalence of idiopathic anaphylaxis are difficult to estimate, it has been suggested that as of 1995 in the USA alone, there were, since it was first described, at least 50,000 patients with idiopathic anaphylaxis [6••, 11••, 12]. According to most reports, idiopathic anaphylaxis appears to be more common in females than in males, with several studies indicating that over 60% of cases are females [13,14]. While idiopathic anaphylaxis was first reported amongst adults, subsequent reports show that it is a condition that may affect people of all ages, although it is more common in adults than in children [15][16][17][18].
Other known causes, such as medications, insect stings, latex, and exercise, should be considered as should a host of other differential diagnoses of anaphylaxis [1••, 2••, 3••, 4••]. In exercise-induced anaphylaxis, the immediate trigger of symptoms is exercise, but in some patients, symptoms only occur if exercise occurs after a few hours of ingesting a specific food; this is known as food-dependent, exercise-induced anaphylaxis [3••, 21,22]. The search for triggers typically includes skin-prick testing and tests of specific-IgE [ 1••, 2••, 3••, 4••] and may also include component-resolved diagnostics [22] and challenge testing. Galactose-alpha-1,3-galactose should be considered, particularly if there is a history of red meat ingestion several hours before the attack [23]. Serum tryptase levels can be very helpful in confirming the diagnosis of anaphylaxis. Systemic disorders, which may present with symptoms akin to anaphylaxis, also need to be judiciously excluded, including causes such as carcinoid syndrome, mastocytosis and mast cell activation syndromes (MCAS), and pheochromocytoma [1••, 2••, 3••, 4••]. Mast cellderived mediators can, for example, be helpful if considering the diagnosis of MCAS [24], and C4 (and in some cases C1inh) concentrations can be helpful if considering a diagnosis of hereditary angioedema [25].

Treatment
Despite the uncertainty of its etiology, idiopathic anaphylaxis is now a wellrecognized entity which, if appropriately treated, is associated with a good prognosis All patients with a diagnosis of idiopathic anaphylaxis should be instructed in the management of an acute episode. This primarily involves early recognition of the condition and the prompt use of epinephrine. Patients/carers should be prescribed and instructed in the use of an epinephrine auto-injector and encouraged to carry it with them at all times along with an H1-antihistamine and corticosteroids [1••, 2••, 3••, 4••]. This advice is best communicated through a written and/or electronic self-management plan [27].
Longer-term management of patients with idiopathic anaphylaxis is primarily determined by the frequency and severity of episodes and is initiated on an individual basis. There are no standard treatment regimens for this condition and

Pharmacologic treatment
Classical pharmacologic treatment options for the management of idiopathic anaphylaxis include epinephrine, H1-antihistamines, and glucocorticoids; each will be considered in turn below [5••, 6••, 7, 9, 11••]. Other treatments sometimes used include H2-antihistamines, mast cell stabilizers, anti-leukotrienes, and anti-IgE. In clinical practice, these treatments may be used ahead of regular use of steroids to minimize the side effects associated with long-term use of systemic steroids.

H1-and H2-antihistamines
H1-antihistamines are often used in the management of acute attacks of anaphylaxis where they may help to relieve cutaneous symptoms. They may also be used in longer term as a preventive approach in those with idiopathic anaphylaxis [5••, 6••, 7, 9, 11••]. H1-antihistamines used for idiopathic anaphylaxis include the first-generation hydroxyzine 25-50 mg and diphenhydramine 25-50 mg and the second-generation fexofenadine 180 mg and cetirizine 10 mg [6••, 7, 11••]. When used, each of these H1 blockers is used once or twice daily in the stated doses. The secondgeneration H1 blockers are preferred to the first-generation types as second-generation H1 blockers allow for selective antagonism of peripheral histamine H1 receptors and do not cause sedation as do the firstgeneration H1 blockers [6••, 7, 11••]. Side effects associated with the use of H1-antihistamines may include diarrhea, dizziness, headaches, and dyspepsia [11••]. They should be used with caution in patients with renal insufficiency [6••, 7, 11••]. Caution should also be exercised to ensure that sedating H1-antihistamines are not used [31]. For long-term management, it is recommended to use a combined regimen of steroids and H1-antihistamines and there is evidence that up to 50% of patients go into remission after completing the recommended regimen [6••, 7, 11••]. Patients whose symptoms are not controlled with an H1-antihistamine may benefit from addition of H2-antihistamines [32].

Emerging therapies Omalizumab
Omalizumab is a humanized monoclonal antibody that recognizes and binds to the Fc portion of the IgE molecule, thus blocking IgE binding to mast cells and basophils [33][34][35][36]. It is a recognized treatment option for chronic, moderate, and severe persistent allergic asthma [37] and has also been shown to play important therapeutic role in other IgE-mediated conditions such as seasonal and perennial allergic rhinitis and chronic idiopathic urticaria [38][39][40]. Recently, in a series of case studies, omalizumab has been used to treat idiopathic anaphylaxis [33][34][35][36]. Idiopathic anaphylactic patients administered 300-375 mg dose of omalizumab once every 2 to 4 weeks, after corticosteroid and antihistamine treatments did not reduce the frequency of attacks, were found to be without any anaphylactic episodes in about 6-12 months of using omalizumab [33][34][35][36]. This is however an emerging therapy in the context of idiopathic anaphylaxis as it has only been demonstrated in a few cases. Omalizumab is a very expensive treatment regimen and there are current concerns that it can also in some cases cause anaphylaxis; therefore, patients receiving it require a period of observation after the injections [11••].

Pediatric considerations
Pediatric idiopathic anaphylactic patients should be classified and treated with similar regimens as adults but with dose adjustments for steroids, epinephrine, and antihistamines [2••]. Omalizumab is licensed for use in those 12 years and older [33][34][35][36].

Conclusions
Since it was first described 40 years ago, it has been possible to identify the trigger factor in a small proportion of those who previously would have been diagnosed as having idiopathic anaphylaxis. It remains a diagnosis of exclusion, which if appropriately treated is associated with a good prognosis. Selfinjectable epinephrine should be promptly administered intramuscularly and plans should then be made to transfer patients to an emergency department for monitoring. Repeated doses of epinephrine can be administered every 5-15 min, if necessary. Preventive approaches for those with frequent episodes include regular use of prednisone and non-sedating H1-antihistamines. Ketotifen, anti-leukotrienes, and omalizumab may all need to be considered to reduce the frequency of attacks and/or reduce the steroid load. Similar regimens used for treatment of idiopathic anaphylaxis in adults can also be used in the pediatric population although with appropriate adjustments of the doses of steroids, epinephrine, and antihistamines. It is hoped that further advances into the epidemiology and mechanisms of anaphylaxis will help to reduce the numbers of patients labelled as having idiopathic anaphylaxis.

Compliance with Ethical Standards
Conflict of Interest Bright Nwaru declares that he has no conflict of interest. Sangeeta Dhami declares that she has no conflict of interest. Aziz Sheikh declares that he has no conflict of interest.

Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: