Anaphylaxis is a severe allergic reaction – the extreme end of the allergic spectrum. Causes include food, insect stings, latex and drugs. But sometimes there may be no obvious trigger. If, after a diagnostic investigation, no cause can be found, the anaphylactic reaction is termed idiopathic. This does not necessarily mean the reaction took place without something triggering it – but simply that no trigger can be identified. It might mean that there is an external trigger (such as a food), but tests fail to pick it up. However, it can also mean that there is no external trigger and the cause is a temporary increase in the reactivity of the immune system. This increased reactivity usually clears up within a few weeks or a few months, although in some cases the condition may take a year or two to settle. A key message in all cases is to visit your GP and ask for a referral to an NHS allergy specialist. This factsheet aims to answer some of the questions that you and your family might have if you are diagnosed with idiopathicanaphylaxis. Our aim is to provide information that will help you
Idiopathicanaphylaxis (IA) is a diagnosis of exclusion after known causes for anaphylaxis and other diseases that mimic anaphylaxis have been ruled out 1 . Known causes of anaphylaxis include mainly foods, medications and venom. IA was ﬁ rst described in 1978 by Bacal et al. 2 Currently, there are four reported main phenotypes accounting for anaphylaxis: type I (IgE mediated related to food allergens mainly), cytokine released (associated with monoclonal antibodies/chemotherapy), mixed (associated with chemotherapy/monoclonal antibodies) and complement mediated (associated with contrast material, dialysis membranes, glycosaminoglycans and chondroitin sulfate). 3 The pathogenesis in cases of IA, however, has not yet been well established. From previously published studies, it can be inferred that IA may cause a substantial decline in quality of life. Previous investigations on the quality of life in children with food allergies and their respective caregivers suggest that stress and anxiety associated with continuous allergen avoidance and the looming threat of anaphylaxis were associated with signi ﬁ cantly impaired food allergy quality of life (FAQOL). 4,5 Although no studies have been conducted to investigate the quality of
To raise awareness of this little known condition and help those affected, the Anaphylaxis Campaign has updated its factsheet on Idiopathicanaphylaxis. Anaphylaxis is the most severe form of allergic reaction and can be fatal in the worst cases, yet is more common than you might think. Food allergy alone is thought to affect 1 - 2% of the adult population and 4-6% of children and there are estimated to be around 30,000 cases of hospitalisation due to anaphylaxis every year. In some cases, these reactions will be termed idiopathic, as even after intense diagnostic investigation, no discernable cause can be found.
Investigations done on this patient are shown in Table 1. Initially, she was treated with a suppressive regimen for idiopathicanaphylaxis using prednisone at a daily dose of 50 mg PO. This failed to suppress her re- actions. Prophylactic treatment with cetiri- zine 10 mg twice daily in combination with ketotifen 4 mg twice daily failed to control her symptoms. Celecoxib, a cyclooxygenase 2 (cox-2) inhibitor was tried, but this caused episodes of angioedema. Finally, leuprolide (Lupron), a luteinizing hormone releasing hormone (LHRH) agonist, was started, with no recurrence of her symptoms during a one-year follow-up period.
anaphylaxis are: foods, particularly, peanuts, tree nuts, shellfish and fish, cow’s milk, eggs and wheat; medica- tions (most commonly penicillin), and natural rubber latex. Exercise, aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), opiates, and radiocontrast agents can also cause anaphylaxis, but anaphylactic reactions to these agents often result from non-IgE-mediated mechanisms. In other cases, the cause of anaphylactic reactions is unknown (idiopathicanaphylaxis). In chil- dren, anaphylaxis is most often caused by foods, while venom- and drug-induced anaphylaxis is more common in adults [4,7-9]. Table 1 provides a more comprehen- sive list of the potential causes of anaphylaxis.
Another disorder that can have similar signs and symptoms or can be a cause of anaphylaxis is mas- tocytosis. Cutaneous mastocytosis is due to prolif- eration of mast cells in the skin. 29 It is characterized by reddish-brown macules, papules, plaques, or blisters that develop urticaria in response to physi- cal trauma. Systemic mastocytosis occurs when mast cells proliferate in other tissues including bone mar- row, liver, spleen and lymph nodes. 29 Usual signs and symptoms of systemic mastocytosis overlap with signs and symptoms of anaphylaxis. Flushing, pruritis, abdominal pain, diarrhea, dyspnea, and tachycardia are seen in both. Patients with recurrent, idiopathicanaphylaxis may in fact have underlying mastocytosis. 29 Systemic mastocytosis is rare in chil- dren but might be considered with recurrent, other- wise unexplained anaphylaxis. Anaphylaxis can be seen in patients with both cutaneous and systemic mastocytosis and has been reported in children with severe diffuse cutaneous mastocytosis. 30
The diagnosis of idiopathicanaphylaxis remains one of exclu- sion. Patients with idiopathicanaphylaxis should receive careful evaluation for possible causes, with emphasis on the history of events in the 3 hours prior to an episode. Selective skin testing with foods (and if indicated to fresh food extracts) may be of value. Indolent systemic mastocytosis must be excluded. Consis- tently elevated serum tryptase levels suggest the presence of indolent systemic mastocytosis since the serum tryptase (total and a tryptase) will be elevated in the absence of episodes of anaphylaxis. In contrast, serum tryptase levels will be normal in quiescent idiopathicanaphylaxis. A bone marrow examination may be indicated in patients with a diagnosis of idiopathicanaphylaxis even in the absence or elevated tryptase levels if salmon colored, hyperpigmented macules and papules consistent with urticaria pigmentosa are found. 211,212 The differential diag- nosis of idiopathicanaphylaxis includes hereditary angioedema or acquired C1 inhibitor deficiency. Some patients with idiopathicanaphylaxis present with massive enlargement of the tongue and/ or life-threatening upper airway obstruction due to pharyngeal or laryngeal angioedema, but their C4 concentration is not reduced. The acute treatment of idiopathicanaphylaxis is the same as the treatment for other forms of anaphylaxis. Prophylactic treatment with oral prednisone at 60-100 mg daily in combination with H1 antagonists for 1-2 weeks followed by decreasing alternate day prednisone over 3 months has resulted in reduced severity and frequency of anaphylaxis. Such empiric treatment has been used for patients with 6 or more episodes/year or 2 episodes in 2 months of idiopathicanaphylaxis. 7,210 Patients should carry auto- injectible epinephrine and be instructed in its use. Patients should also carry identifying information such as by Medic Alert.
Most episodes of anaphylaxis are triggered through an immunologic mechanism involving immunoglobulin E (IgE) which leads to mast cell and basophil activation and the subsequent release of inflammatory mediators such as histamine, platelet activating factor, leukotrienes, tryptase and prostaglandins. Although any substance has the potential to cause anaphylaxis, the most common causes of IgE-mediated anaphylaxis are foods (particularly peanuts, tree nuts, shellfish and fish, cow’s milk, eggs and wheat), medications (most commonly penicillin and other antibiotics), and stinging insects . Exercise, aspirin, non-steroidal anti-inflammatory drugs (NSAID), opiates, and radiocontrast agents can also cause anaphylaxis, but anaphylactic reactions to these agents often result from non-IgE-mediated mechanisms. In other cases, the cause of anaphylactic reactions is unknown (idiopathicanaphylaxis). In children, anaphylaxis is most often caused by foods, while venom- and drug-induced anaphylaxis is more common in adults [5–8]. Table 1 provides a more comprehensive list of the potential causes of anaphylaxis.
Chlorhexidine, a cationic bisguanide antiseptic and dis- infectant, is active against a broad spectrum of bacteria, mycobacteria, some viruses, and some fungi. Chlorhex- idine salts can trigger irritant dermatitis, allergic contact dermatitis, urticaria/anaphylaxis and combined urticaria/ anaphylaxis and allergic contact dermatitis [for review: (167)]. In some patients, anaphylaxis to chlorhexidine, was preceded, sometimes by years, by chlorhexidine- induced contact dermatitis (168). Evidence for an IgE- mediated hypersensitivity to chlorhexidine was ﬁrst provided in 1984 (169) and hapten inhibition studies have shown the entire chlorhexidine molecule to be complementary to the IgE antibody binding sites and the 4-chlorophenol, bisguanide and hexamethylene structures together constitute the allergenic determinant (87, 170). Symptoms of chlorhexidine anaphylaxis have been attrib- uted to cutaneous, percutaneous, mucosal, and parenteral application. Life-threatening reactions with profound hypotension, ventricular ﬁbrillation and cardiac isch-
All patients who experience an episode of anaphylaxis should be advised that their specific triggers must be identified. Important differences between the etiological diagnosis suspected in the ED and the definitive cause of anaphylaxis have been reported in recent studies in adults and children [28, 84, 85]. The triggers of anaphylaxis can be identified by allergy specialists, who will also provide information on possible cross-reacting agents and safe alternatives, especially in the case of drug hypersensi- tivity. Such an approach has proven useful for reducing the risk of severe anaphylaxis . The tools most com- monly used by allergists to this end are a detailed history/ documentation of the acute episode, skin tests, detection of allergen-specific IgE, and challenge tests. It is usu- ally accepted that the optimal time for testing is around 4 weeks after the acute episode .
Transient cardiomyopathy is an uncommon occurrence in patients with anaphylaxis and catecholamine induced direct toxicity is one of the proposed mechanisms. Epinephrine is the treatment of choice for anaphylaxis. Catecholamine-induced cardiomyopathy should be considered in children with persistent hypotension following multiple doses of epinephrine and needs myocardial function assessment.
In EIA, the release of vasoactive mediators from mast cells may play a pathogenetic role. This has been observed in skin biopsies  and it has been confirmed by findings of increased serum histamine [45-47] and tryptase  levels in patients with EIA after exercise. Release of mast cell mediators may result in vascular leakage, inflammatory cell recruitment and occurrence of anaphylaxis . The mast cell degranulation may be mediated by IgE antibodies. However, in patients with EIA, serum IgE antibodies are usually normal in patients who do not suffer from allergic diseases . Other trig- gering factors may be lactate or creatinine phosphoki- nase . Overall, it remains unclear which factors trigger mast cell degranulation. In patients with FDEIA, the ingestion of the offending food alone does not pro- voke clinical hypersensitivity reactions, even if IgE anti- bodies against the causative food allergens are usually detected by skin prick tests or in the serum. Non mutu- ally exclusive explanations have been provided for the loss of tolerance to food during exercise . Some of them are sustained by clinical findings. First, the admin- istration of sodium bicarbonate before physical activity prevents occurrence of symptoms in patients with FDEIA . Therefore it has been suggested that pH modifications might elicit the onset of anaphylaxis. Along this line, it has been reported that after physical activity, pH decreases both in serum and in muscle [54,55]. Furthermore, a reduced pH enhances mast cell degranulation . Second, aspirin appears to induce anaphylactic reaction to wheat by increasing gastrointes- tinal permeability. This is suggested by the fact that in patients with wheat dependent EIA, both wheat-exercise and wheat-aspirin challenges provoked an increased glia- din absorption and allergic symptoms. Higher serum gliadin levels may cause degranulation of mast cell with onset of anaphylaxis . Small intestinal permeability is increased by exercise . However, it has been shown that serum gladin levels are similarly increased during combination wheat-exercise test in subjects with FDEIA and in controls , ruling out a role for increased gastrointestinal permeability.
That IgG1 can induce anaphylaxis was demonstrated by PSA. The only activating FcR having an affinity for IgG1 is FcγRIIIA (17, 18). Depletion of basophils using specific mAbs abrogated IgG1-induced PSA (10), although mast cells and neutrophils also express FcγRIIIA. A model of basophil-deficient mice, however, challenges this result (14). Mast cells are necessary for IgE-induced PSA, although basophils also express FcεRI. Noticeably, IgE- induced PSA was abolished in 5KO mice (data not shown). FcγRIV that can bind IgE with a low affinity (17) is therefore insufficient to trigger this reaction. IgG1 is the predominant antibody sub- class following immunization in alum, but also in CFA/IFA. IgG1 antibodies are likely to act as the main players in ASA by engag- ing FcγRIIIA. BSA immunizations in alum induced specific IgG1, but not specific IgG2 (Supplemental Figure 4D), indicating that FcγRIIIA, but not FcγRIV, were engaged during ASA following this immunization protocol. Supporting this conclusion, FcγRIV was not sufficient to induce ASA in 5KO mice following immunization in alum (Supplemental Figure 4E).
Many allergists recognize ethanol as risk factor for food allergy anaphylaxis, however, there is very little pub- lished literature on this [58, 59]. Ethanol, like other rec- reational drugs, can be associated with reduced awareness, risk taking, and recognition of symptoms, as well as interfering with an individual’s timely treatment response to severe food allergy. Physiologically, ethanol activates the TRPV1 channel, lowering the threshold to activation by the multiple endogenous products of the allergic response that act via this ion channel [54, 60]. Activation of the TRPV1 ion channel on sensory nerves results in release of neuromediators including calcitonin nerve related peptide to cause vasodilation . The vasodilation effect from ethanol could contribute to a more severe shock in food allergy. Alcohol may also cause gastritis, permitting greater allergen absorption.
Consistent with the above approaches, the results presented here support a definition of anaphylaxis that includes any of the features listed in the moderate and severe grades, as these are associated with hypoxia and/or hypotension. Clinicians should be aware that a history of any of these symptoms suggests the possibility of hypoxia or hypotension when direct observation has not been possible. This study did not find angioedema to be associated with hypoxia or hypotension. The relative abundance of unknown etiologies in the mild (skin only)
Infants receive numerous vaccinations in the first 2 years of life. Immunizations are not considered to be a significant risk factor for anaphylaxis, but the occurrence has been documented. In one prospective observational cohort study conducted in Ireland from 2006 to 2010, the urban emer- gency department administered vaccinations on referral for pediatric patients considered at high risk for an allergic reaction. A total of 446 vaccines were administered to 374 patients in the emergency department. Of these patients, 310 received the measles, mumps, and rubella vaccine (MMR) and 64 received a non-MMR vaccine. Suspected egg allergy was the main reason for the majority of referrals for MMR administration (seen in 261 of 310 patients who received the MMR in the emergency department). Among the 446 vaccinations administered, six (1.3%) resulted in reactions, all of which were minor. The authors concluded that significant concerns related to potential allergic reac- tions can delay administration of the vaccine and may not be warranted. 13 In another study conducted in the United
Anaphylaxis is a severe, generalized allergic or hypersensitivity reaction that is rapid in onset and may cause death. Epinephrine (adrenaline) can be life-saving when administered as rapidly as possible once anaphylaxis is recognized. This clinical report from the American Academy of Pediatrics is an update of the 2007 clinical report on this topic. It provides information to help clinicians identify patients at risk of anaphylaxis and new information about epinephrine and epinephrine autoinjectors (EAs). The report also highlights the importance of patient and family education about the recognition and management of anaphylaxis in the community. Key points emphasized include the following: (1) validated clinical criteria are available to facilitate prompt diagnosis of anaphylaxis; (2) prompt intramuscular epinephrine injection in the mid-outer thigh reduces hospitalizations, morbidity, and mortality; (3) prescribing EAs facilitates timely epinephrine injection in community settings for patients with a history of anaphylaxis and, if speciﬁ c circumstances warrant, for some high-risk patients who have not previously experienced anaphylaxis; (4) prescribing epinephrine for infants and young children weighing <15 kg, especially those who weigh 7.5 kg and under, currently presents a dilemma, because the lowest dose available in EAs, 0.15 mg, is a high dose for many infants and some young children; (5) effective management of anaphylaxis in the community requires a comprehensive approach involving children, families, preschools, schools, camps, and sports organizations; and (6) prevention of anaphylaxis recurrences involves conﬁ rmation of the trigger, discussion of speciﬁ c allergen avoidance, allergen immunotherapy (eg, with stinging insect venom, if relevant), and a written, personalized anaphylaxis emergency action plan; and (7) the management of anaphylaxis also involves education of children and supervising adults about anaphylaxis recognition and ﬁ rst-aid treatment.
A woman, 70 years of age, presents to a tertiary emergency department with severe abdominal pain and hypotension. She is prepared for an urgent laparotomy for a suspected ruptured abdominal aortic aneurysm but one of the doctors notices that, although she does not have any typical skin features of anaphylaxis, her skin is not as cool and clammy as one would expect for a ruptured aneurysm. Further history reveals that she had a single amoxicillin tablet 30 minutes before the pain began. She responds to an adrenaline infusion and avoids surgery A woman, 30 years of age, collapses and vomits after a jack jumper ant sting. She recovers spontaneously and is noted to be bradycardic and to have an ‘anxious disposition’. In the absence of any other features she is diagnosed as having had an anxiety or ‘vasovagal’ attack. However, she also volunteers to participate in a randomised controlled trial of venom immunotherapy. 19 As part of this trial, she has an insect sting challenge and suffers severe anaphylaxis with a marked rise in mast cell tryptase*
We report the largest series of anaphylaxis in chil- dren. Our data confirm that anaphylaxis is a not- uncommon childhood emergency that most often occurs at home or in other out-of-hospital settings. Because of this, it is imperative that parents are ed- ucated to recognize the common presenting clinical manifestations of this disease readily. In our series, these were most often either dermatologic (60%) or respiratory (25%). Of the 55 children enrolled, 17 presented first with urticaria, and 6 presented with facial or lip swelling. In 8 children wheezing or dif- ficulty breathing was the first abnormality noted. This trend continued for most children; dermatologic and/or respiratory symptoms developed in 93% of
Physicians also under-prescribe epinephrine. For exam- ple, Friesen et al.  reported a retrospective review of 886 charts taken from a university pediatric emergency department and a regional university emergency depart- ment between 1994 and 2001. Only 44% of children and 47% of adults were given epinephrine. In an earlier report , they also found that only 14% of children presenting to a pediatric emergency department be- tween 1994 and 2001 received epinephrine before admission. Mehra et al. , in a study of 32 food- related deaths from anaphylaxis that occurred in Ontario between 1986 and 2000, found that 30 out of 32 individuals had known they were food allergic, and only 11 of these had been prescribed epinephrine. Only four of them had it available at the time of the reaction, and in one instance the device had expired 2 years previously. Clark et al.  found that only 80% of patients presenting with bee sting allergy in an emergency room received epinephrine, and only 11%, upon discharge from the emergency department, were given a prescription for self-injectable epinephrine. In addition, even when patients are prescribed epi- nephrine, administration errors caused by incorrect technique can occur partly because physicians, nurses, and emergency medical technicians are not facile with the technique of administration, thus instructing patients incorrectly, or simply fail to give instructions regarding the use of an automatic epinephrine injector [29,36,38]. In one study involving emergency room physicians, pediatricians, and family practitioners , only a quarter could demonstrate the proper technique for use, and only 14% had a placebo to demonstrate the correct usage. Sicherer et al.  documented similar results in a study of pediatricians. In a study of 78 senior house ofﬁcers [46 . ], although all knew that epinephrine should be administered, 55% did not know the preferred route and only 5% knew both the correct route and dose.