Eight Years of Severe Allergic Reactions in Finland: A Register-Based Report

Background No data have been available on severe allergic reactions in Finland. Materials and Methods We summarize the data accumulated from 2000 to 2007 in the national register established at the Skin and Allergy Hospital of the Helsinki University Central Hospital, where physicians voluntarily report on patients with severe allergic reactions. Results During the period, the 530 reported cases of severe allergic reactions represented an annual frequency of 0.001%. Of the patients, 66% were adults and 56% were female, with a median age of 27 years. Food was the causative agent in 53% of the cases, drugs in 26%, allergen preparations in 12%, and insects in 8%. Dermatologic symptoms were reported in 85%, respiratory in 76%, cardiovascular in 50%, gastrointestinal in 33%, and eye/nose symptoms in 18%. The reaction was a life-threatening anaphylactic shock in 26% of the cases, with no deaths reported. Patients were treated with intramuscular adrenaline in 75% of the cases. Not only nuts and seeds, but also fruit and vegetables were the most important allergens for the adults. Nuts were also important allergens for children, along with milk, egg, and wheat. In addition, many "exotic" allergens were identified: patent blue, carmine dye, yeast, buckwheat, and macrogol. Conclusions Severe allergic reactions are underreported, but a register reflects the real-life situation and helps to identify new causative agents. It also contributes to improvements in first aid treatment practice.

A naphylaxis is an immunoglobulin E (IgE)Y or nonY IgE-mediated, severe, life-threatening systemic allergic reaction, with a rapid onset and multiple organ system involvement. 1,2 Independent of the mechanism, the first aid treatment of choice is intramuscular adrenaline. Because of the risk of recurrent severe reaction, the causative allergen must be recognized and avoided when possible.
To our knowledge, nationwide anaphylaxis registers or similar organizations exist at least in Denmark, France-Belgium, Germany-Austria-Switzerland, Italy, the Netherlands, Norway, Sweden, the United Kingdom and Ireland, and also in the United States (Table 1). 3Y7 Maintaining a comprehensive anaphylaxis register involves several difficulties, for example, the lack of internationally accepted clinical definition of anaphylaxis has made it difficult to diagnose an anaphylactic reaction ( Table 2).
No data reveal actual frequency of severe allergic reactions in Finland. The literature has reported incidence figures of 7.9 to 21 anaphylaxis cases per 100,000 personyears, 8Y10 along with increasing allergy prevalence and hospital admission figures during the past decade. 11Y13 In the United States, approximately 30,000 cases of food anaphylaxis occur annually, 150 to 200 of which are fatal. 14 In the United Kingdom, the incidence of fatal reactions is one in 3 million person-years, and its National Anaphylaxis Campaign was set up in 1994 for guidance and information on allergens and allergic reactions. 15Y17 In 2000, the Finnish register of severe allergic reactions was established at the Skin and Allergy Hospital of the Helsinki University Central Hospital, where physiciansV mostly allergologistsVvoluntarily report patients with severe allergic reactions independently of the causative agent. A 1-page questionnaire form is available on the Internet.

MATERIALS AND METHODS
We summarize the first 530 cases reported to the register between 2000 and 2007. Our results are based on the anonymous patient data provided by the physicians in the questionnaire form evaluated by an allergy specialist.
Any adverse reactions from vaccines that were reported to the National Public Health Institute are absent from the present article.

Reports on Severe Allergic Reactions
A total of 530 cases of severe allergic reactions were reported between 2000 and 2007 throughout the country, mostly (65%) from the Helsinki capital area, which represents 25% of the entire population of 5.2 million. This represents an annual incidence of 0.001%.

Patients
Of the 530 cases, 348 (66%) were adults and 182 (34%) were children younger than 16 years. Females accounted for 295 (56%). Median age was 27 years; range was from 2 months to 92 years. Two peaks in age distribution were for children younger than 5 years and young adults aged 25 to 35 years.
The reactions were regarded as severe anaphylactic shock reactions in 26% of the cases, with a systolic blood pressure in adults less than 90 mm Hg or with severe respiratory symptoms such as bronchospasm and upper airway angioedema. 18 Other severe allergic reactions included nonshock reactions with symptoms in at least two of the following organs: skin, respiratory tract, cardiovascular system, or gastrointestinal tract. 18

Symptoms and Treatment
In 74% of the cases, the first symptoms predicting severe allergic reaction appeared less than 30 minutes after contact with the inciting allergen.
Most frequently, corticosteroids were used for treatment, in 84%, followed by adrenaline in 75%, and antihistamine in 67%. Of the adrenaline-treated patients, 10% used a readyto-use adrenaline autoinjector.

Allergens and Exposure
Foods were the causative agent in 279 (53%) cases, drugs and medical interventions in 136 (26%), allergen preparations for diagnostic work and immunotherapy in 64 (12%), and insects in 40 (8%) (Fig. 1). In 13 patients (2%), other causes were noted, and only 6 cases (1%) were idiopathic or without any recognizable cause (Table 3). In 7 cases, both food and a drug were suspect causative agents. An additional known or suspected factor in 29 cases (5%) was exercise.

Food
Food (n = 279) was the most common cause of severe allergic reaction (53%). Of these patients, 53% were adults, 64% of whom were females, but most (60%) of the children were boys. The home was the most common place for food reaction (36%).
An allergen-containing food was accidentally given to 53 patients, 60% of whom were children. These included milk, wheat, egg, fish, nuts, and seeds. Most episodes (77%) took place outside the home.
Most food-related reactions were from peanuts, tree nuts, and seeds (21%), 36% of which occurred in children (Table 3). One adult experienced anaphylaxis after eating home-delivered Thai food that contained soft-treated peanuts, which the patient assumed were beans. Tree nuts were  involved in 53% of the nut/seed cases. Hidden or nonrecognized nuts were the causative agent in bread and in ice cream. Two other patients (1 child and 1 adult) had anaphylaxis after eating tahini sauce not recognized by the patients as being a sesame seed product. Fruits and vegetables were reported in 16% of the food anaphylaxis cases, of which kiwi, apple, and celery were the most common allergens. In 2 birch pollenYallergic adults, even the first ingestion of an exotic fruit such as jackfruit or lychee when abroad resulted in severe anaphylactic reactions.
Regarding grains, reports numbered 14% of the cases, 72% of which were from wheat. One wheat-allergic child had a severe reaction after eating gluten-free pasta, and another child after eating a wheat-free bun made of buckwheat to which the child had developed an allergy during a 3-year wheat-free diet. Buckwheat in a blin was unexpectedly allergenic to 1 adult patient, whereas another adult experienced anaphylaxis from a bun in which the marzipan was dyed with a red color from cochineal insects (carmine, E120).
Milk was the causative agent in 14% of the food-related anaphylaxis cases. Heavy exercise together with milk proteinYcontaining pills caused a severe reaction in a milkallergic adult to whom the terms casein and whey were unknown. The patient had an adrenaline autoinjector, but she did not dare use it. One adult experienced anaphylaxis from cow's milk feta cheese, but she tolerated goat's milk feta, whereas another adult experienced anaphylaxis from goat cheese without a cow's milk allergy (Fig. 2).
Egg was reported in 9% of the food reactions, all but one in children, and 7 of which were accidents outside the home. In 1 case, a hidden allergen was suspected.
Fish or seafood was reported in 8% of the cases. Fish nuggets were given to a child instead of chicken nuggets (the Finnish word for fish is kala, for chicken, kana). Five reports were toxic reactions from tuna fish in which a high histamine content was suspected as the causative agent because no fish allergy was evident. Eight cases were from shrimp and one from roe in the absence of fish allergy. 19 Soy was reported or suspected in 9 cases, 4 of which occurred in birch pollenYallergic patients after a soy drink. A skin prick test with native soy bean was positive, whereas a commercial serum soy-specific IgE test was negative, indicating the missing labile cross-reactive soy allergen (Gly m 4). 20 In other cases, soy was suspected as a hidden allergen in the food offered in day care centers.
Yeast used as a flavoring agent in a spaghetti sauce repeatedly caused severe anaphylactic reactions in a mouldsensitive patient. 21 Drinks were reported in 11 cases (4%), mostly (73%) in adults. Reported drinks included red and white wine, beer, long drink, cider, juice, and glühwein. One patient repeatedly experienced anaphylaxis when dancing the tango after drinking a beer.
Antibiotics in 29% and painkillers in 24% were the most commonly reported in drug-related reactions. Cephalosporins and penicillins comprised 58% of the antibiotics, whereas acetylsalicylic acid (ASA) and ibuprofen accounted for 45% of painkillers. In 4 cases, ASA in a combination product was not recognized by the patient as such.
In 68% of the operation-related reactions, a neuromuscular blocking agent (rocuronium) was suspected as the causative agent either alone or with other anesthetic agents. Three cases were caused by the patent blue dye (E 131) used to locate sentinel lymph nodes. One reaction was caused by chlorhexidine used as skin disinfectant. 22 Local anesthetics were reported in 8 cases, in one of which methylprednisolone used simultaneously proved to be the anaphylactic agent based on positive intradermal testing. Nine cases were from contrast media and one from iodinated povidone (Betadine).
In a drug, the active ingredient is not always the agent causing harm. One case of penicillin anaphylaxis was caused by macrogol (polyethylene glycol) used as an excipient in the tablet vehicle. 23

WAO Journal & November 2008
Allergen preparations were the causative agent in 64 cases (12%), 18 of which occurred in children. Ten reports with mild reactions were from skin prick testing with fish, egg, penicillin, moulds, pollens, animals, chironomid, or carmine dye (E120). Carmine IgE was positive in in-house immunospot test but remained negative in the commercial IgE test, which, however, was improved in collaboration with our laboratory.
Of all reports, 54 (10%) concerned specific immunotherapy (SIT). In 83% of the reactions, timothy grass was the causative allergen, either alone or with other pollen allergens. Nine patients were on a maintenance dose; some for several years.

Insects and Other Agents
Insects were reported in 8% of the cases, 63% of which were in adults. Wasps (92%) were by far the most commonly reported. Insects caused 9% of the severe shock reactions.

DISCUSSION
Based on our study, during the 8 years, 530 severe allergic reactions were reported to the Finnish register for an annual incidence of 0.001%. Reactions are undoubtedly underreported, with higher figures per population reported elsewhere. 10 From the reactions, 26% were life-threatening circulatory or respiratory shock reactions. Adrenaline was the first aid treatment for 75%, but corticosteroids were more frequent: 84% of all cases. In a Swiss study, 48% of the anaphylaxis patients with circulatory symptoms received adrenaline, 9 whereas in an Italian study, only 6% of the patients did. 24 Finnish health care is thus reasonably well prepared to use adrenaline appropriately, but still with room for improvement.
In 5% of our cases, a late-phase reaction occurred compared with late reactions reported in 2% to 20% of cases elsewhere. 13,25 Food, drugs, and insects alternate globally as the most common causes of anaphylaxis. 9,11,13,18,26 In an overview from 1 referral clinic, 59% of the anaphylactic cases were considered idiopathic. 27 In our register, food was the most commonly reported cause (53%), and only 1% of the cases were without a known or highly suspect cause. Fruits, vegetables, nuts, and seeds were the most common causes for food reactions in adults. Similarly, fresh fruits and vegetables have been the most important allergens in adult anaphylaxis in Italy. 24 Thirteen (5%) of the food reactions involved peanut, a common cause for fatal anaphylaxis in the United States and United Kingdom, where the Anaphylaxis Campaign has also reported an increasing frequency/number of sesame anaphylaxis. 14,28 Two of our patients experienced anaphylaxis from sesame sauce tahini. Fish and shellfish were rather seldom reported (8%) but are common causes of anaphylaxis in Italy, Asia, and the United States. 13,14,24,27 No deaths from food are known in Finland.
Diagnostics and other interventions are not without risks. 8Y10,13,15,28,29 Of our cases, 42% were from drugs, operations, diagnostics, and other interventions. In line with the reports of neuromuscular blocking agents as the most frequently implicated anesthetic drug, rocuronium was the causative agent in 68% of the surgical anaphylaxis cases. 10,29,30 Severe allergic reactions from allergy diagnostics (skin test and food/drug challenge test) and allergy treatment (SIT) comprised 18% of the cases, and a high frequency of SIT anaphylaxis has been reported only by Mehl et al. 26 Timothy pollen SIT, but not birch pollen SIT, seems to be associated with a relatively high risk for severe reactions, a fact practitioners giving SIT in Finland have been warned about.
Insects are important anaphylactic allergens in Switzerland and in the United Kingdom but account for only 8% of the reports in Finland, wasps being the most frequently reported. 8,9 Because commercial skin prick and serum IgE tests are not always sufficiently sensitive and specific to identify the sensitizing insect, for SIT assessment in our hospital, an in-house immunospot method with several venom samples differentiates between wasps and honey bees. 21 No deaths were reported, although such fatalities are estimated to occur approximately every second year in Finland.
We found only 1 report on severe reaction from latex, an important allergen in France and the United States. 10,18,25,27,30 To avoid is to identify. Our register has been proven to be valuable for identifying causes for severe allergic reactions in Finland. Thus far, poorly recognized allergens and allergen sources have been detected, such as patent blue, carmine, yeast, buckwheat, soy drink, and macrogol. In addition, hidden allergens have been demonstrated in food and drugs. In France, hidden allergens have accounted for 13% of severe anaphylactic reactions. 10 Our register has also contributed to first aid treatment practice by highlighting the importance of intramuscular adrenaline as first-line treatment.
All patients experiencing a severe allergic reaction should be sent to an allergologist who will evaluate the causative agent, provide guidance for avoidance and prevention, and also consider SIT. The patient, family members, and caregivers must be instructed on how to use an adrenaline autoinjector.

ACKNOWLEDGMENT
This article is associated with the Finnish Allergy Programme 2008Y2018 and the World Health Organization In-house immunospot method demonstrates serum IgE to the inner part of the goat cheese delivered by the patient with anaphylaxis, 1 but not to cow's milk. 8 Other examples are the mouldy surface of the goat cheese, 2 cow milk casein, 3 sheep milk casein, 4 carrageen used in the cheese, 5 cacao also suspected as an allergen, 6 egg white, 7 and goat cheese from the laboratory repertory. 9