Epidemiology of life-threatening and lethal anaphylaxis: a review

Severe anaphylaxis is a systemic reaction affecting two or more organs or systems and is due to the release of active mediators from mast cells and basophils. A four-grade classification routinely places 'severe' anaphylaxis in grades 3 and 4 (death could be graded as grade 5).

Studies are underway to determine the prevalence of severe and lethal anaphylaxis in different populations and the relative frequencies of food, drug, latex and Hymenoptera anaphylaxis. These studies will also analyse the risk arising from the lack of preventive measures applied in schools (personalized management protocols) and from the insufficient use of self-injected adrenalin.

Allergy-related conditions may account for 0.2-1% of emergency consultations. Severe anaphylaxis affects 1-3 per 10 000 people, but for the United States and Australia figures are even higher. It is estimated to cause death in 0.65-2% of patients, i.e. 1-3 per million people[1].

The prevalence of allergic disorders has more than doubled in the last two decades leading to increased community concern and anxiety, and unprecedented demand for allergy-specialist services. However, although allergic reactions are common, anaphylaxis is uncommon and fatal anaphylaxis is rare[2].

An increased prevalence has been revealed by monitoring hospitalized populations by reference to the international classification of disease (ICD) codes. The relative frequency of aetiological factors of allergy (food, drugs, insects and latex) varies in different studies. Food, drug and Hymenoptera allergies are potentially lethal. The risk of food-mediated anaphylaxis can be assessed from the number of personalized management protocols in French schools: 0.065%. Another means of assessment may be the rate of adrenalin prescriptions. However, an overestimation of the anaphylaxis risk may result from this method (0.95% of Canadian children). Data from the literature leads to several possibilities. First, a definition of severe anaphylaxis should be agreed. Secondly, prospective, multicentre enquiries, using ICD codes, should be implemented. Moreover, the high number of anaphylaxis cases for which the aetiology is not identified, and the variation in aetiology in the published series, indicate that a closer cooperation between emergency specialists and allergists is essential.

Recent studies suggest an increase in prevalence of anaphylaxis in industrialized countries. Examination of the demographic characteristics of anaphylaxis has revealed potential approaches to better recognize those at greatest risk. Novel laboratory approaches to identify patients at increased risk of severe reactions have been suggested[2].

Increased knowledge of the epidemiology of anaphylaxis has provided insights into the characteristics of those patient groups most at risk of adverse outcomes. However, these characteristics have poor specificity and limited applicability for detection of at-risk individuals in the clinical setting. Further research is required to facilitate more accurate assessment of an individual's risk for anaphylaxis or fatal outcome. This would represent a major advance in clinical management and enable better allocation of existing healthcare resources[2].

The inability to accurately predict the severity of future allergic reactions to foods in a given individual coupled with the real--although usually remote--risk of a fatal anaphylactic reaction complicates care and remains a constant source of concern to food-allergic patients, their family members, and health care providers[3].

Current epidemiologic evidence suggests that the incidence of food-induced anaphylaxis is increasing, although confidently approximating the incidence of fatal allergic reactions to foods remains difficult[3]. Advances in food allergy diagnosis include IgE epitope mapping that discloses the likelihood and severity of allergy; studies correlating likelihood of clinical reactivity on the basis of food-specific IgE to sesame, peanut, milk, and tree nuts; and an observation that a low baseline angiotensin-converting enzyme level may be associated with having pharyngeal edema during a reaction. Molecular, immunologic, and genetic studies are discerning pathways that are key in development of food allergy, identifying new modalities to interrupt mast cell degranulation, and elucidating risks associated with penicillin allergy[4].

Calvani M, et al (2008) examined the epidemiology of anaphylaxis in hospitalized children in Lazio (Central Italy) and evaluated the incidence and case fatality rate. They also verified the concordance of diagnosis between the Emergency Department and Ordinary hospitalizations. In order to obtain these results, they reviewed all ICD-9 codes indicative of anaphylaxis in all primary and secondary diagnoses from 2000 to 2003 in all Emergency Departments, Ordinary Hospitalizations and Day Hospitals in Lazio. Then, they identified 203 ICD-9 diagnoses of anaphylaxis in children aged between 0 and 17 years. Anaphylactic shock (995.0) accounted for 109 (53.7%) of cases. Food anaphylaxis (995.60 onwards) accounted for 87 (43.0%) of cases. Food anaphylaxis was more frequent in the first years of life. In fact, it decreased from 12.5/100,000 resident children/year in the first year of life to 6.1/100,000 resident children/year in the first two years of life, and less than 3/100,000 resident children/year after the seventh year (p <0.001). Only 12.5% of cases of anaphylaxis diagnosed in Ordinary Hospitalizations were subsequently diagnosed by the Emergency Department as anaphylaxis. Moreover, only 42.3% of the diagnoses of anaphylaxis made in the Emergency Department were later confirmed during ordinary hospitalization. In the four years of study, one child died from anaphylaxis. Thus, mortality was 0.038 cases/100,000 resident children/year. In conclusion, the incidence of hospitalization was highest in the first years of life, during which food anaphylaxis accounted for most hospitalizations. The inconsistency of diagnoses between Emergency Departments and Ordinary Hospitalizations suggests the need to increase awareness of anaphylaxis among health workers[5].

Decker WW, et al (2008)  performed a population-based incidence study that was conducted in Rochester, Minnesota, from 1990 through 2000. Anaphylaxis episodes were identified on the basis of symptoms and signs of mast cell and basophil mediator release plus mucocutaneous, gastrointestinal tract, respiratory tract, or cardiovascular system involvement.  Two hundred eleven cases of anaphylaxis were identified (55.9% in female subjects). The mean age was 29.3 years (SD, 18.2 years; range, 0.8-78.2 years). The overall age- and sex-adjusted incidence rate was 49.8 (95% CI, 45.0-54.5) per 100,000 person-years. Age-specific rates were highest for ages 0 to 19 years (70 per 100,000 person-years). Ingested foods accounted for 33.2% (70 cases), insect stings accounted for 18.5% (39 cases), medication accounted for 13.7% (29 cases), radiologic contrast agent accounted for 0.5% (1 case), "other" causes accounted for 9% (19 cases), and "unknown" causes accounted for 25.1% (53 cases). The "other" group included cats, latex, cleaning agents, environmental allergens, and exercise. There was an increase in the annual incidence rate during the study period from 46.9 per 100,000 persons in 1990 to 58.9 per 100,000 persons in 2000 (P = .03).

The overall incidence rate is 49.8 per 100,000 person-years, which is higher than previously reported. The annual incidence rate is also increasing. Food and insect stings continue to be major inciting agents for anaphylaxis[7].

The demographics for anaphylaxis deaths are different to those for anaphylaxis presentations. Anaphylaxis mortality rates remain low and stable, despite increasing anaphylaxis prevalence, with the exception of drug-induced anaphylaxis deaths, which have increased[6].

References

1. Moneret-Vautrin DA, Morisset M, Flabbee J, Beaudouin E, Kanny G.Epidemiology of life-threatening and lethal anaphylaxis: a review.Allergy. 2005 Apr;60(4):443-51.

2.Tang ML, Osborne N, Allen K. Epidemiology of anaphylaxis. Curr Opin Allergy Clin Immunol. 2009 Jun 5.

3. Atkins D, Bock SA. Fatal anaphylaxis to foods: epidemiology, recognition, and prevention. Curr Allergy Asthma Rep. 2009 May;9(3):179-85

4. Sicherer SH, Leung DY. Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects in 2008. J Allergy Clin Immunol. 2009 Feb;123(2):319-27.

5. Calvani M, Di Lallo D, Polo A, Spinelli A, Zappalà D, Zicari M. Hospitalizations for pediatric anaphylaxis. Int J Immunopathol Pharmacol. 2008 Oct-Dec;21(4):977-83.

6. Liew WK, Williamson E, Tang ML. Anaphylaxis fatalities and admissions in Australia. J Allergy Clin Immunol. 2009 Feb;123(2):434-42. Epub 2008 Dec 30.

7. Decker WW, Campbell RL, Manivannan V, Luke A, St Sauver JL, Weaver A, Bellolio MF, Bergstralh EJ, Stead LG, Li JT. The etiology and incidence of anaphylaxis in Rochester, Minnesota: a report from the Rochester Epidemiology Project. J Allergy Clin Immunol. 2008 Dec;122(6):1161-5. Comment in:J Allergy Clin Immunol. 2008 Dec;122(6):1166-8. J Allergy Clin Immunol. 2009 May;123(5):1194; author reply 1194-5.