The impact of prednisone in life-threatening idiopathic anaphylaxis: reduction in acute episodes and medical costs

Two patients with frequent episodes of well documented life-threatening idiopathic anaphylaxis were studied. Despite prior treatment with antihistamines and self-administered epinephrine, both patients continued to have episodes of anaphylaxis. At the time of presentation to the Northwestern University Allergy Service, prednisone and antihistamines with or without sympathomimetics were started. Described in this report are the substantial reductions in the frequency of hospitalizations, emergency room visits, and anaphylactic episodes after our medical management was instituted.     

Corticosteroid-dependent idiopathic anaphylaxis: a report of five cases

Idiopathic anaphylaxis (IA) is a life-threatening disease that is being increasingly recognized. In patients with frequent episodes of anaphylaxis, prednisone controls the events and then either induces remission or suppresses the manifestations of the disease until a spontaneous remission occurs. We report five patients with IA who have recurrent episodes whenever prednisone is tapered below a threshold dose, ranging from 15 to 65 mg every other day. These patients demonstrate the concept of a threshold dose of prednisone that may exist in a subset of patients with IA, and they provide further evidence of the previously reported efficacy of corticosteroids in the treatment of IA. We use the term corticosteroid-dependent IA to refer to the serious problem of chronic IA requiring maintenance prednisone therapy.     

The utility of the ISAC allergen array in the investigation of idiopathic anaphylaxis

A diagnosis of idiopathic anaphylaxis following a detailed clinical assessment remains very challenging for patients and clinicians. Risk reduction strategies such as allergen avoidance are not possible. This study investigated whether the (ISAC) allergen array with 103 allergens would add diagnostic value in patients with idiopathic anaphylaxis. We extended the specific immunoglobulin (Ig)E testing in 110 patients with a diagnosis of idiopathic anaphylaxis from five UK specialist centres using ISAC arrays. These were divided into three groups: score I identified no new allergen sensitization beyond those known by previous assessment, score II identified new sensitizations which were not thought likely to explain the anaphylaxis and score III identified new sensitizations felt to have a high likelihood of being responsible for the anaphylaxis. A proportion (50%) of score III patients underwent clinical reassessment to substantiate the link to anaphylaxis in this group. The results show that 20% of the arrays were classified as score III with a high likelihood of identifying the cause of the anaphylaxis. A wide range of major allergens were identified, the most frequent being omega‐5‐gliadin and shrimp, together accounting for 45% of the previously unrecognized sensitizations. The ISAC array contributed to the diagnosis in 20% of patients with idiopathic anaphylaxis. It may offer additional information where a careful allergy history and follow‐on testing have not revealed the cause of the anaphylaxis.     

Idiopathic anaphylaxis

Idiopathic anaphylaxis is a prednisone-responsive condition without external cause, but it can coexist with food-, medication-, or exercise-induced anaphylaxis. Mast cell activation may occur at night or after foods that have been eaten with impunity many times previously. Idiopathic anaphylaxis can be classified into frequent (if there are six or more episodes per year or two episodes in the last 2 months) or infrequent (if episodes occur less often). Idiopathic anaphylaxis-generalized consists of urticaria or angioedema associated with severe respiratory distress, syncope or hypotension, and gastrointestinal symptoms. Idiopathic anaphylaxis-angioedema consists of massive tongue enlargement or severe pharyngeal or laryngeal swelling with urticaria or peripheral angioedema. The differential diagnosis of idiopathic anaphylaxis is reviewed, and treatment approaches are presented.     

The management of anaphylaxis in childhood: position paper of the European academy of allergology and clinical immunology

Anaphylaxis is a growing paediatric clinical emergency that is difficult to diagnose because a consensus definition was lacking until recently. Many European countries have no specific guidelines for anaphylaxis. This position paper prepared by the EAACI Taskforce on Anaphylaxis in Children aims to provide practical guidelines for managing anaphylaxis in childhood based on the limited evidence available. Intramuscular adrenaline is the acknowledged first-line therapy for anaphylaxis, in hospital and in the community, and should be given as soon as the condition is recognized. Additional therapies such as volume support, nebulized bronchodilators, antihistamines or corticosteroids are supplementary to adrenaline. There are no absolute contraindications to administering adrenaline in children. Allergy assessment is mandatory in all children with a history of anaphylaxis because it is essential to identify and avoid the allergen to prevent its recurrence. A tailored anaphylaxis management plan is needed, based on an individual risk assessment, which is influenced by the child's previous allergic reactions, other medical conditions and social circumstances. Collaborative partnerships should be established, involving school staff, healthcare professionals and patients' organizations. Absolute indications for prescribing self-injectable adrenaline are prior cardiorespiratory reactions, exercise-induced anaphylaxis, idiopathic anaphylaxis and persistent asthma with food allergy. Relative indications include peanut or tree nut allergy, reactions to small quantities of a given food, food allergy in teenagers and living far away from a medical facility. The creation of national and European databases is expected to generate better-quality data and help develop a stepwise approach for a better management of paediatric anaphylaxis.     

The occurrence of multiple physical allergies in the same patient: Report of three cases

The syndromes of idiopathic anaphylaxis, exercise-induced anaphylaxis, and other physical allergies are well described as separate entities. This article describes the combination of these problems in the same patient. Two patients with idiopathic anaphylaxis are described. One also has exercise-induced anaphylaxis, and one also has exercise-induced bronchospasm and exercise-induced urticaria and angioedema. A third patient with exercise-induced anaphylaxis, idiopathic urticaria, angioedema, cholinergic urticaria, and dermatographism is described.     

A Case of Idiopathic Anaphylaxis Followed by Acute Liver Injury

Idiopathic anaphylaxis is characterized by recurrent anaphylaxis without a known trigger. The coexistence of acute liver injury with idiopathic anaphylaxis is rare, even in cases of severe anaphylaxis such as shock. An unusual case involving repeated episodes of anaphylactic shock accompanied by acute liver injury is described here. A 36-year-old woman who experienced anaphylaxis due to an unknown cause was referred to our hospital because of marked elevations in her liver enzyme levels. After a thorough evaluation to determine the cause of the acute liver injury, viral infection, drug use, and autoimmune hepatitis were excluded. The episodes were accompanied by elevated liver enzymes, which suggested that this was a case of anaphylaxis followed by acute liver injury. The patient will have to use self-injectable epinephrine to prevent future hepatic failure.     

Identification of alpha‐gal sensitivity in patients with a diagnosis of idiopathic anaphylaxis

IgE antibodies (Ab) specific to galactose‐α‐1,3‐galactose (alpha‐gal) are responsible for a delayed form of anaphylaxis that occurs 3‐6 hours after red meat ingestion. In a unique prospective study of seventy participants referred with a diagnosis of idiopathic anaphylaxis (IA), six (9%) were found to have IgE to alpha‐gal. Upon institution of a diet free of red meat, all patients had no further episodes of anaphylaxis. Two of these individuals had indolent systemic mastocytosis (ISM). Those with ISM had more severe clinical reactions but lower specific IgE to alpha‐gal and higher serum tryptase levels, reflective of the mast cell burden. The identification of alpha‐gal syndrome in patients with IA supports the need for routine screening for this sensitivity as a cause of anaphylaxis, where reactions to alpha‐gal are delayed and thus may be overlooked.     

Age, sex, geographical and socio-economic variations in admissions for anaphylaxis: analysis of four years of English hospital data.

BACKGROUND: Although the most severe of the allergic disorders, the epidemiology of anaphylaxis remains poorly described. Hospital admissions for anaphylaxis in England more than doubled during the 1990s. OBJECTIVE: To provide baseline data for assessing future trends, and to assess whether there is sufficient regional variation in incidence to allow efficient testing of aetiological hypotheses, we sought to identify any age, sex, geographical and socio-economic variations in hospital inpatient admissions for anaphylaxis. METHODS: We studied all emergency admissions for anaphylaxis to English NHS hospitals between 1991 and 1995. Poisson regression modelling was used to calculate rates of anaphylaxis admission per 100 000 emergency admissions by age, sex, deprivation and by residence in urban/rural, North/South and East/West England. RESULTS: Of the 13.5 million emergency inpatient admissions, 2323 patients had a primary diagnosis of anaphylaxis. Poisson regression analyses showed significant age, gender, geographical and socio-economic variations in emergency admissions for anaphylaxis: adjusted Female rate ratio 1.19 (95% CI 1.09-1.29), South rate ratio 1.35 (95% CI 1.25-1.47), Rural rate ratio 1.35 (95% CI 1.17, 1.59), and Non-deprived rate ratio 1.32 (95% CI 1.19, 1.46). CONCLUSION: This study identifies striking national age, sex, geographical and socio-economic variations in the incidence of inpatient admissions for anaphylaxis in England, affording important opportunities to generate and test aetiological hypotheses. Risk of anaphylaxis admission is considerably increased in females of child-bearing age and those residing in southern, rural, and affluent areas are independent risk factors for anaphylaxis admission.     

Anaphylaxis: risk factors for recurrence

BACKGROUND: There are few studies on the incidence or recurrence of anaphylaxis. OBJECTIVE : To examine the incidence of anaphylaxis and risk factors for recurrence. METHODS: A prospective study of 432 patients referred to a community-based specialist practice in the Australian Capital Territory with anaphylaxis, followed by a survey to obtain information on recurrence. RESULTS: Of 432 patients (48% male, 73% atopic, mean 27.4 years, SD 19.5, median 26) with anaphylaxis, 260 patients were seen after their first episode; 172 experienced 584 previous reactions. fifty-four percent of index episodes were treated in hospital. Aetiology was identified in 91.6% patients: food (61%), stinging insects (20.4%) or medication (8.3%). The minimum occurrence and incidence of new cases of anaphylaxis was estimated at 12.6 and 9.9 episodes/100,000 patient-years, respectively. Follow-up data were obtained from 304 patients (674 patient-years). One hundred and thirty experienced further symptoms (45 serious), 35 required hospitalization and 19 administered adrenaline. Accidental ingestion of peanut/tree nut caused the largest number of relapses, but the highest risk of recurrence was associated with sensitivity to wheat and/or exercise. Rates of overall and serious recurrence were 57 and 10 episodes/100 patient-years, respectively. Of those prescribed adrenaline, 3/4 carried it, 2/3 were in date, and only 1/2 patients faced with serious symptoms administered adrenaline. Five patients each developed new triggers for anaphylaxis, or re-presented with significant psychiatric symptoms. CONCLUSION: In any 1 year, 1/12 patients who have suffered anaphylaxis will experience recurrence, and 1/50 will require hospital treatment or use adrenaline. Compliance with carrying and using adrenaline is poor. Occasional patients develop new triggers or suffer psychiatric morbidity.     

The economic costs of severe anaphylaxis in France: an inquiry carried out by the Allergy Vigilance Network

Background:  The prevalence of severe anaphylaxis, between 1 and 3 per 10 000, has increased sharply over recent years, with a rate of lethality of 1%. The economic burden is unknown.
Objective:  The aim of this study was to estimate the economic costs of anaphylaxis, including direct costs of treatment, hospitalization, preventive and long-care measures, and the indirect cost: absenteeism.
Methods:  Analysis of 402 patients of anaphylaxis declared by 384 allergists was reported to the Allergy Vigilance Network. The global cost was estimated from the national data of hospital admissions: ICD-10 coding available for 2003, 2004 and 2005.
Results:  Three work/classroom days were lost per patient. Diagnosis required oral challenge with hospitalization in 18% of cases. The estimated mean total cost was 1895€ for food- and drug-related anaphylaxis (5610€ for the most severe), and 4053€ for Hymenoptera anaphylaxis. National statistics recorded 2575 patients in 2005; 22% more than in 2003. The estimated annual cost was 4 789 500 €. The possible reasons for this being an under-estimate include: data coming only from hospitalized patients, poor identification by medical teams unfamiliar with ICD-10 codes, peri-operative anaphylaxis being insufficiently declared, rush-immunotherapy and maintenance treatments for Hymenoptera anaphylaxis. Similarly, the extra cost of cow milk substitutes, as well as insurance costs where deaths are followed by litigation were not taken into account.
Conclusions:  The mean cost of anaphylaxis was 1895–5610€ in nonfatal patients. The prevalence was under-estimated because of many biases, leading to under-estimation of the national cost. Further studies would be necessary to evaluate the value of preventive strategies.     

Increased incidence of admissions for anaphylaxis in Spain 1998–2011

We report on trends in anaphylaxis admissions in the Spanish hospital system during the period 1998–2011. Data on admissions for anaphylaxis were obtained from the Spanish Information System for Hospital Data for the period 1998–2011. Patients were selected using the codes for anaphylaxis in the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD‐9‐CM). Poisson regression models were used to estimate incidence rate ratios. We recorded a 1.89‐fold increase in admissions for anaphylaxis in Spanish hospitals during the study period, particularly in patients aged 0–14 years (1.65‐ to 3.22‐fold until 2009 and 4.09‐ to 12.59‐fold until 2011) and in food anaphylaxis in all age groups (2.78‐fold until 2009 and 8.74‐fold until 2011). The incidence of anaphylaxis is perceived as having increased in recent years, especially anaphylaxis caused by food and anaphylaxis affecting the pediatric population.     

Outcomes of emergency room visits for asthma. I. Patient determinants

To learn how differences among individual patients influence the outcomes of their emergency room (ER) visits for asthma, we matched the results of 1209 sequential ER visits with the records of the 464 children and young adults who visited during a 37-week interval. Most patients visited the ER only once and were unlikely to be admitted. Those patients admitted once were unlikely to be admitted a second time. Only 119 patients (25.6%) made 54.7% of all ER visits and were responsible for 68.5% of admissions; they also accounted for all but eight of 92 relapses. Patients were accordingly stratified into group F, frequent visitors, and group I, infrequent visitors. A separate high-risk category (group HR) was composed of 50 other patients who received especially conservative treatment in the ER owing to prior episodes of severe asthma. HR patients included both frequent and infrequent visitors and had a very high probability of being admitted on any given visit. The patients of group F, each of whom visited the ER at least four times during the 37 weeks initially studied, were also consistently frequent visitors for comparable periods before and after the initial period. Their rate of ER relapses for exceeded their visiting rate, at least in part because some patients tended to relapse on repeated occasions. Patterns of ER use allow differentiation among groups of patients with distinctly different prognoses. These groups are similar to prognostic categories reported by previous authors. Such differences among individual patients must be taken into account when management systems are evaluated or clinical strategies are organized.     

A multicenter study on anaphylaxis caused by peanut,tree nuts,and seeds in children and adolescents

Peanut (PN) and tree nuts (TNs) are common causes of anaphylaxis in Western countries, but no information is available in Korea. To feature clinical characteristics of anaphylaxis caused by PN, TNs, and seeds, a retrospective medical record review was performed in 14 university hospitals in Korea (2009–2013). One hundred and twenty‐six cases were identified, with the mean age of 4.9 years. PN, walnut (WN), and pine nut accounted for 32.5%, 41.3%, and 7.1%, respectively. The median values of specific IgE (sIgE) to PN, WN, and pine nut were 10.50, 8.74, and 4.61 kU_A/l, respectively. Among 50 cases managed in the emergency department, 52.0% were treated with epinephrine, 66.0% with steroid, 94.0% with antihistamines, 36.0% with oxygen, and 48.0% with bronchodilator. In conclusion, WN, PN, and pine nut were the three most common triggers of anaphylaxis in Korean children, and anaphylaxis could occur at remarkably low levels of sIgE.     

Idiopathic anaphylaxis

Idiopathic anaphylaxis (IA) or spontaneous anaphylaxis is a diagnosis of exclusion when no cause can be identified. The exact incidence and prevalence of IA are not known. The clinical manifestations of IA are similar to other known causes of anaphylaxis. A typical attack is usually acute in onset and can worsen over minutes to a few hours. The pathophysiology of IA has not yet been fully elucidated, although an IgE‐mediated pathway by hitherto unidentified trigger/s might be the main underlying mechanism. Elevated concentrations of urinary histamine and its metabolite, methylimidazole acetic acid, plasma histamine and serum tryptase have been reported, consistent with mast cell activation. There is some evidence that corticosteroids reduce the frequency and severity of episodes of IA, consistent with a steroid‐responsive condition. Important differential diagnoses of IA include galactose alpha‐1,3 galactose (a carbohydrate contained in red meat) allergy, pigeon tick bite (Argax reflexus), wheat‐dependent exercise‐induced anaphylaxis, Anisakis simplex allergy and mast cell disorders. Other differential diagnoses include “allergy‐mimics” such as asthma masquerading as anaphylaxis, undifferentiated somatoform disorder, panic attacks, globus hystericus, vocal cord dysfunction, scombroid poisoning, vasoactive amine intolerance, carcinoid syndrome and phaeochromocytoma. Acute treatment of IA is the same as for other forms of anaphylaxis. Long‐term management is individualized and dictated by frequency and severity of symptoms and involves treatment with H1 and H2 receptor blockers, leukotriene receptor antagonist and consideration for prolonged reducing courses of oral corticosteroids. Patients should possess an epinephrine autoinjector with an anaphylaxis self‐management plan. There are anecdotal reports regarding the use of omalizumab. For reasons that remain unclear, the prognosis of IA is generally favourable with appropriate treatment and patient education. If remission cannot be achieved, the diagnosis should be reconsidered.     

Lymphocyte subsets and activation markers in patients with acute episodes of idiopathic anaphylaxis.

BACKGROUND: Idiopathic anaphylaxis (IA), a type of anaphylaxis in which no external allergen can be identified, is a corticosteroid-responsive disease, that suggests that it may have an immunologic pathogenesis. OBJECTIVE: The objective of this study is to compare patients with acute episodes of IA with normals, patients with chronic idiopathic urticaria, and patients with IA in remission relative to lymphocyte subsets and activation markers. METHODS: This is a prospective cohort study of 38 adults: 5 normals, 4 idiopathic urticaria, 11 IA patients in remission, 9 IA patients with acute attacks who had not yet received prednisone, and 9 IA patients who had received prednisone. The main outcome measures were lymphocyte subset and activation markers determined by two and three color flow cytometry (CD2, CD3, CD4, CD5, CD8, CD16, CD19, CD23, CD25, CD56, and HLA-DR). RESULTS: Comparing patients with acute IA with those in remission, the only significant difference was that the acute IA patients had a significantly higher percentage of CD3+HLA-DR+ cells. Normals had a significantly lower percentage of CD3+ HLA-DR+ cells than all other groups. Patients with acute IA on prednisone as well as IA patients in remission had a significantly higher percentage of CD 19+ CD23+ cells than normals. CONCLUSIONS: These results suggest that there are more activated T cells in patients with acute episodes of IA than in patients in remission. Perhaps, these activated T cells have a role in the pathogenesis of IA.     

Pattern of hospitalizations for angioedema in New York between 1990 and 2003.

BACKGROUND: The epidemiologic characteristics of angioedema have not been well described in the United States, especially regarding hospitalization patterns. This fact is particularly relevant given the increased use of angiotensin-converting enzyme inhibitors, a known cause of angioedema. OBJECTIVE: To profile hospital admissions for angioedema in New York State with respect to age, sex, race, comorbidities, and year. METHODS: A database of all acute hospitalizations in New York State was examined between 1990 and 2003. Patient admissions that had the principal admission diagnoses of angioedema and other acute allergic disorders (anaphylaxis, urticaria, or allergy unspecified) were extracted. Characteristics of angioedema admissions were tabulated and compared with those of other acute allergic disease admissions with respect to demographic variables and comorbidities. RESULTS: There were 6,775 hospitalizations for angioedema during the study period. The number of angioedema hospitalizations increased progressively from 293 in 1990 to 636 in 2003, which exceeded the number of hospitalizations for anaphylaxis that year. African Americans constituted 42% of the angioedema admissions despite being less than 16% of the state population. The increase in hospitalizations for angioedema was most marked in patients with a diagnosis of hypertension, and for each study year, patients admitted with angioedema were consistently older than those admitted with other allergic disorders. CONCLUSIONS: Angioedema has become the most common nonasthmatic acute allergic disorder that results in hospitalization in New York State. The predilection for angioedema occurring in patients with hypertension suggests that angiotensin-converting enzyme inhibitor use may play a role in this trend.     

Rhinitis therapy and the prevention of hospital care for asthma: a case-control study

BACKGROUND: Although clinical trials have demonstrated that rhinitis therapy improves subjective and objective measures of asthma, it is uncertain whether treatment of allergic rhinitis significantly affects the frequency of asthma exacerbations. OBJECTIVE: The objective of this study was to determine whether treatment with intranasal corticosteroids and/or second-generation antihistamines is associated with changes in rates of asthma exacerbations resulting in emergency room visits and/or hospitalizations in patients with asthma and allergic rhinitis. METHODS: This was a nested, case-control study. RESULTS: Treatment with either nasal corticosteroids or second-generation antihistamines was associated with a lower risk of asthma-related emergency room treatment and hospitalization (adjusted odds ratio [OR], 0.51; 95% CI, 0.34 to 0.77 and 0.34, 0.18 to 0.62, respectively). Patients who used nasal corticosteroids had a significantly lower risk of both asthma-related emergency room treatment and hospitalization (adjusted OR, 0.75; 95% CI, 0.62 to 0.91 and 0.56, 0.42 to 0.76, respectively), whereas there was a trend toward lower risk of emergency room treatment and hospitalization in patients who used second-generation antihistamines (adjusted OR, 0.88; 95% CI, 0.62 to 1.26 and 0.68, 0.40 to 1.14, respectively). Combined treatment with both medications was associated with a further lowering of the risk of both emergency room treatment and hospitalization (adjusted OR, 0.37; 95% CI, 0.19 to 0.73 and 0.22, 0.07 to 0.63). CONCLUSIONS: In patients with asthma, treatment of concomitant allergic rhinitis was associated with significant reductions in risk of emergency room treatment and hospitalization for asthma.     

Incidence of anaphylaxis with circulatory symptoms: a study over a 3-year period comprising 940 000 inhabitants of the Swiss Canton Bern

BACKGROUND: Diagnosis of anaphylaxis is clinically based and usually straightforward. However, data on the epidemiology of anaphylaxis, particularly the most profound and life-threatening form such as anaphylactic shock are limited and thought to be under-reported. OBJECTIVE: The primary aim of this study was to investigate the incidence and the causes of severe anaphylaxis with circulatory signs in the Canton Bern, which comprises about 940 000 inhabitants or approximately one-seventh of the population of Switzerland. METHODS: During a 3-year period, 1 January 1996 to 31 December 1998, all medical records (7739 documents) from the two allergy clinics of the Canton Bern have been reviewed. In addition, all seven board-certified specialists of the Foederatio Medicorum Helveticorum (FMH) in Allergology and Clinical Immunology of this Canton as well as all 17 hospitals with emergency units of this area have been contacted for cases with an anaphylactic event not referred to the allergy clinics. RESULTS: Overall, 226 individuals, 106 females (47%) with a mean age of 41 years (range, 5-74 years) and 120 males (53%) with a mean age of 38 years (8 months-83 years) were diagnosed as having presented generalized, life-threatening anaphylaxis with circulatory symptoms. Altogether, these patients experienced 246 episodes of severe systemic reactions. In addition, death due to anaphylaxis occurred in three subjects. The annual incidence of anaphylaxis per 100 000 inhabitants per year ranged between 7.9 and 9.6 cases. Hymenoptera stings (58.8%), drugs (18.1%), and foods (10.1%) were the most commonly identified culprits for anaphylaxis. In 5.3% of all anaphylactic events, the cause could not be identified. CONCLUSION: The incidence rate of severe life-threatening anaphylaxis with circulatory signs in the Canton Bern, Switzerland, with 7.9-9.6 per 100 000 inhabitants per year is comparable to the findings of other epidemiological investigations. In most events, a causal agent or allergen could be identified by a careful allergological examination.