Abstract
Introduction: Anaphylaxis is a potentially life threatening
allergic reaction that is rapid in onset and multisystemic in nature.
Distribution of anaphylaxis tends to fluctuate based on age, gender,
race, geographical residence and socioeconomic status of the involved
subjects. Diagnosis of anaphylaxis in children is generally
underestimated particularly in developing countries, and when diagnosed,
proper management is occasionally lacking.Aim of the study: to evaluate the frequency and pattern of
anaphylaxis and mistakes in diagnosis and treatment among a group of
Egyptian children and adolescents.Subjects and methods: This observational study was conducted
over 6 months duration, from 1st of September 2019 to
the end of February 2020, in Children’s hospital, Ain Shams University,
Cairo, Egypt, on children presenting to emergency department (ED).
Anaphylaxis frequency, presentation, triggers, diagnosis, management and
long term follow up were assessed.Results: frequency rate of anaphylaxis among children and
adolescents was 0.43% (80/18816) over a year. Sixty percent of patients
were infants. Biphasic reactions were reported in 11.3% of patients.
The commonest trigger was food (22.5%) followed by medications (8.8%).
Epinephrine was given to all patients, in proper dosage and method in
most occasions (78.7%). Long term management and follow up appointment
were deficient.In conclusion: Anaphylaxis in children was relatively high,
with food being the most common trigger. Diagnosis and early management
of anaphylaxis was satisfactory, however, long term management and
follow up were defective.Key statement: Anaphylaxis is generally underdiagnosed and
maltreated particularly in children owing to the lack of data and
awareness among physicians as well as general population. In this work
we spotted the light on the frequency of anaphylaxis in children in one
of the highly rated University Hospitals in Egypt, and the most
suspected triggers, clinical presentation and steps of management.IntroductionAnaphylaxis is a severe, life-threatening, multisystemic
hypersensitivity reaction. Although it occurs in patients of all ages,
most research and guidelines are focused on adults. Elicitors and
clinical presentation of anaphylaxis in children and adolescents were
shown to be different from those in adults, calling for specific
research for pediatric populations1. Guidelines for
both adults and children stress on rapid diagnosis as being a key to
optimal management. Although cutaneous symptoms predominate in adults,
the primary presenting symptoms in children are respiratory in nature
(e.g., wheezing, shortness of breath). In addition, cardiovascular
symptoms tend to be less common in children than in adults. Moreover,
food related causes, which tend to cause respiratory manifestations, are
more common in children whereas medication and venom triggers, which
tend to cause cardiovascular reactions, are more common in
adults2.
The incidence of anaphylaxis is underestimated in various studies owing
to the problems of recognizing it and the variability of criteria of
diagnosis in different studies and countries3. The
American Academy of Allergy, Asthma and Immunology (AAAAI) Epidemiology
of Anaphylaxis Working Group concluded that the overall frequency of
anaphylaxis ranges between 30 and 950 cases per 100,000 persons per year
and lifetime prevalence 50 - 2000 episodes per 100,000 persons
(0.05-2%)4.
In children, the most common food allergens are milk products, peanuts,
tree nuts, eggs, shellfish, and fruits and
vegetables5. Biphasic allergic reactions are reported
in 1 to 23% of anaphylaxis attacks particularly in patients with severe
initial episodes or those who were not given epinephrine in the early
phase of anaphylaxis6.
Factors that increase the risk of severe or fatal anaphylactic episodes
are similar worldwide. They include age-related factors, concomitant
diseases such as asthma and other chronic respiratory diseases,
cardiovascular diseases, mastocytosis or clonal mast cell disorders, and
severe atopic disease. Some concurrent medications like beta adrenergic
blockers and ACE inhibitors might also potentiate the
risk7. The overall prognosis of anaphylaxis is good.
Early injection of epinephrine in anaphylaxis (defined as injection
before arrival at ED) can significantly reduce the likelihood of
hospital admission. Delayed injection of epinephrine has been reported
in a large case series of anaphylaxis-related
fatalities8.
Mistakes in the diagnosis of anaphylaxis may occur because of the
limited time during which the diagnosis must be made, the stressful
environment of the emergency room, the incomplete clinical features in
early anaphylaxis and the lack of useful laboratory markers.Several studies have shown that anaphylaxis is often miscoded or
misclassified. The frequency of miscoding appears to be similar in
adults and children9.
Updated World Allergy Organization (WAO) anaphylaxis guidelines
highlighted the importance of epinephrine being the only effective
treatment and that there is no role for glucocorticoids or
antihistamines in severe allergic reactions10.
International research agenda for anaphylaxis was concerned with the
unmet needs in anaphylaxis in high, mid and low income
countries11.
To our knowledge, there are few registries concerning anaphylaxis in
Egypt, therefore we aimed to evaluate the frequency and pattern of
anaphylaxis and mistakes in diagnosis and treatment among a group of
Egyptian children and adolescents presented to Children’s hospital, Ain
Shams University, Cairo, Egypt.Patients and Methods:This observational cross-sectional study was conducted on all the
children and adolescents who presented to ED of Children’s hospital, Ain
Shams University, Cairo, Egypt, in the period from 1st of September 2019
to the end of February 2020. All patients were examined properly by the
investigator for possibility of anaphylaxis diagnosis based on the
updated criteria settled by WAO at 2011. Diagnosis of
anaphylaxis was declared when the patient fulfilled one of the following
scenarios12:I- Sudden onset (minutes to several hours) of muco-cutaneous
manifestations involving skin, mucosal tissue or both (generalized
hives, urticaria, pruritus and flushing, swollen lips, tongue or uvula)
and at least one of the followings:
• Respiratory compromise (bronchospasm, wheeze, stridor, hypoxemia,
reduced peak expiratory flow).
• Reduced blood pressure (BP) or associated symptoms and signs of
end-organ dysfunction (collapse, syncope, incontinence).
II-Two or more of the following that occur rapidly after exposure to a
likely allergen for that patient (minutes to several hours):
• Muco-cutaneous manifestations as described above.
• Respiratory compromise as described above.
• Reduced BP or associated signs and symptoms of end-organ dysfunction.
• Persistent gastrointestinal signs and symptoms (crampy abdominal pain,
nausea, vomiting or diarrhea).
III- Reduced BP after exposure to a known allergen for that patient
(minutes to several hours):
• Reduced BP in adults is defined as a systolic BP (SBP) of less than 90
mmHg or 30% decrease in that patient’s baseline.
• In infants and children, reduced BP is defined as low systolic BP (age
specific) or greater than 30% decrease in SBP.Exclusion criteria:
Patients with neurological illness affecting their conscious level
Patients with congenital heart diseases because of the possible
confusing symptoms with anaphylaxis
All children presented to ED (except those in the exclusion criteria)
during the duration of the study were examined for anaphylaxis. Those
who fulfilled the criteria of diagnosis were recruited in the study and
observed properly until they were sent home.Methods:All the included patients were subjected to the following:
Detailed history taking: including socio-demographic data, personal or
family history of atopy, previous severe allergic
reactions/anaphylaxis, their description and management.
Description of the current anaphylactic reaction through history and
examination as regards:
- Presenting symptoms and signs
- Possible culprit trigger
- The initial diagnosis at ED
- The initial management of anaphylaxis at ED
- Second line medications given for the patients
- Long term management of anaphylaxis including patient and family
education, providing a written plan, prescribing epinephrine as needed
and arranging a follow up appointment at the Allergy clinic in
Children’s hospital, Ain Shams University.
The researcher introduced himself to parents of all participants in this
study and written consent was taken; however, he did not interfere with
the management provided for those patients. Ethical committee approval
was gained prior to the start of this work.
The collected data was revised, coded, tabulated and introduced to a PC
using Statistical Program for Social Science version 22 (SPSS Inc.,
Chicago, IL, USA, 2001). Data were presented and suitable analysis was
done according to the type of data obtained for each parameter.Results:We defined 80 patients with anaphylaxis out of 18816 representing all
the ED visitors at the period of the study with frequency rate 0.43%.
The studied children were 47 (58.8%) males and 33 (41.3%) females with
mean age 2.94 ± 3.44 years. Age of affected patients varied widely with
the majority being infants. Age distribution is shown in figure1.
Unexpectedly, most of patients were not known to be atopic. The atopic
patients were suffering mainly of food allergy and allergic rhinitis,
followed by bronchial asthma and eczema; with family history of atopy in
more than half of those atopic patients. Only one patient had a previous
attack of anaphylaxis (table1). The culprit trigger was unidentified in
more than half of patients. However, food was the most offending
identified trigger followed by medications (figure2). Drug-induced
anaphylaxis represented 8.8% of the studied cases, divided between
antibiotics (57.14%) and NSAID (42.86%). Age groups that suffered from
drug-induced anaphylaxis were infants (71.4%) followed by preschoolers
(28.6%). Non-steroid anti-inflammatory drugs (NSAIDs) allergy was
limited to infants while antibiotics induced anaphylaxis was equally
distributed between infants and Pre-school age groups as shown in
figure3.
Signs and symptoms of anaphylaxis at time of presentation were variable
among children. Urticarial hives and facial edema were the most common
presenting symptom followed by respiratory symptoms (dyspnea, cough,
wheezes) and gastrointestinal symptoms (nausea/vomiting, abdominal
cramps). Two patients out of 80 had hypotension at time of presentation
(table2). Biphasic reaction was reported in 11.3% of patients within
6-8 hours after the first attack, distributed in different age groups as
follows: infants (6.3%), preschoolers (11.8%), schoolers (33.3%) and
none of the adolescents.
All patients presented with anaphylaxis were correctly diagnosed in ED
of our University hospital, thus all of them were provided intramuscular
epinephrine given in the anterolateral aspect of the thigh, calculated
in the correct dose; however, 21.3% of patients were given diluted
(1:10000) epinephrine instead of concentrated shots (figure4). More than
one shot of epinephrine was needed in 22.5% of patients. One patient
had protracted anaphylaxis that necessitated ICU admission and
intravenous infusion of epinephrine. As regards the outcome of those
patients, the majority were stabilized after the initial management and
sent home, 2 patients were admitted to hospital (drug-induced
anaphylaxis) and the patient who experienced protracted anaphylaxis, has
passed away (table3).
Second line treatment was given to all patients in the form of
glucocorticoids and anti-histamines type1. Unfortunately, long term
management was defective. None of the patients were given a written plan
for possible future anaphylactic reactions, prescribed epinephrine for
emergencies or scheduled for an Allergy Clinic visit for follow up and
further management.
Discussion:
In this study, we have identified 80 patients with anaphylactic
reactions out of 18816 over 6 months with frequency rate 0.43%. This
frequency rate is relatively higher than what was reported in different
studies and this might be attributed to the rarity of centers having
specialized Allergy units in Egypt, in addition to the University
hospital being a tertiary referral one. Anagnostou and colleagues, as an
example, reported an incidence rate of 50-112 per 100000 (0.05-0.112%
per year); and estimated lifetime prevalence of anaphylaxis between
0.5%- 2%13. A meta-analysis, done on 59 studies
conducted on children, estimated that incidence rate of anaphylaxis was
ranging from 1 to 761 per 100000-year (0.001-0.76%); however, studies
from developed countries were underrepresented6. The
European anaphylaxis registry has identified 1970 patients with
anaphylaxis aged younger than 18 years in the duration between July 2007
and March 20155. In an Irish study conducted over 4
years on children aged 14 years old and lower, the number of children
with at least one anaphylactic reaction was 6314. A
prospective study from Denmark conducted on children and adults has
identified 180 anaphylactic patients over a year representing 0.3-0.4%
of all contacts in ED with children’s incidence rate of 26.8 per 100000
year (0.027%) 15. A Korean single center study has
recorded 107 children with anaphylaxis over 3 years16.
Males were more represented in this study than females with the majority
of patients being infants. Anaphylaxis was reported in higher rates in
males in more than one study5,6,14,16. It was
noticeable in many studies that anaphylaxis is more prevalent in
children compared with adults, however, the reactions used to be milder5,6. Castells and colleagues stated that severe
reactions are 9-fold for adults compared with
children17. We noticed in this study that frequency
rate of anaphylaxis decreased with age’ being higher-most in infants and
lowermost in adolescents, however, the study duration and population
were relatively limited being a single center. Wide based studies like
the European anaphylaxis registry, has collected data from 90 study
center representing 10 countries and they reported, on the contrary,
lowermost cases in the infants and highest incidence in the preschool
children followed by school aged then adolescents5.
Atopy as a risk factor of anaphylaxis and a determinant factor of
severity of episodes was reported in less than one third of our studied
children and more than half of their families with food allergy and
allergic rhinitis being the most frequently documented. Atopy was
repeatedly visualized as a risk factor that might worsen the clinical
outcome of anaphylaxis19. Abunada and colleagues
showed that personal history of atopy for asthma, atopic dermatitis and
allergic rhinitis were noted among patients with anaphylaxis; and 56.9%
of patients had positive family history which matches our
findings20. Although a few studies showed no such
significant association between atopy and anaphylaxis, several studies
stated that anaphylaxis was common among atopic
patients5,16.
Triggers of anaphylaxis varied widely. On the top of list was food
allergens followed by drug and insect bites, albeit unidentified
triggers were reported in more than half of the studied patients. It was
agreed worldwide, based on findings reported by many studies, that food
allergens were the most common triggers of anaphylaxis in children in
contrast to adults whereas drug-induced anaphylaxis comes first5,6,14,16. In our study, 8.8% of anaphylactic
children were triggered by drugs, mainly antibiotics and NSAIDs with the
latter being more obvious in the infantile age group. We had lost one
patient out of anaphylaxis which was antibiotic induced. Retrigo and
colleagues documented drug triggered anaphylaxis in 3.1% of
preschoolers, 4.1% of school aged and 12.1% of adolescents with
analgesics being on the top of list21. It is to be
noted that majority of anaphylaxis fatalities reported in other studies
were caused by medications; with antibiotics and analgesics carrying the
highest risk20,21.
Obviously, presenting signs and symptoms of anaphylaxis were widely
variable. Cutaneous manifestations were the most common followed by
gastrointestinal and respiratory ones. Only two patients out of 80 were
hypotensive. This wide variation in the clinical presentation of
anaphylaxis was documented in many single and multi-center studies with
the age being the most determinant factor5,22. In the
current research, pruritus and gastrointestinal symptoms were more
dominant in the infants and young children. On the other hand,
respiratory symptoms were more obvious in older children and
adolescents. This agrees with the reported findings of many other
studies5,14,16,23. Biphasic reaction was recorded in
11.3% of our studied patients being more common in scholar age group
followed by preschoolers. The severity of those reactions was generally
mild and occurred within 6 to 8 hours after the first attack being more
evident in those patients who presented late to ED and hence were
delayed in receiving epinephrine. Compared to other studies, we recorded
a relatively high rate of biphasic reactions. Jeon and colleagues
reported biphasic reaction in 4.7% of their studied
patients24. A study in Thailand documented 6.3% of
the anaphylaxis patients experienced biphasic reaction and that the time
interval from onset to administration of epinephrine was a
predicator25. A multi-institution research on
pediatric anaphylaxis in Turkey reported biphasic reaction in 3.1% of
anaphylactic patients26. Milder or similar second
attacks of anaphylaxis in children were documented in many studies23.
As known, diagnosis of anaphylaxis is a challenge owing to the wide
differential diagnoses and similarities in manifestations. Indeed,
errors in diagnosing and managing anaphylaxis by health providers and
junior medical staff are a documented problem worldwide25-27. Fortunately, in this study, all patients with
anaphylaxis were properly diagnosed and treated with epinephrine,
although less than quarter of them was given epinephrine in improper
way, being diluted instead of concentrated shots. Epinephrine is a
life-saving medication and proper use during an anaphylactic reaction is
of paramount importance. In a study done by Castilano and colleagues in
one of the university hospitals in USA, they found that only 20% of
those diagnosed as anaphylaxis in ED were given intramuscular
epinephrine, thus many patients needed hospital admission. One of the
reported barriers to the proper use of epinephrine is lack of proper
training with regard to the correct technique27.
Oropeza and colleagues multicenter research recorded that only 25% of
patients with anaphylaxis were given epinephrine15.
European anaphylaxis registry has documented treatment with epinephrine
at ED in only 28% of anaphylactic patients5. Another
study conducted in Australia on anaphylaxis in children reported missed
diagnosis of anaphylaxis in about 50% of patients fulfilling the
criteria and that 85.7% of those who were confirmed had received
epinephrine injection28. Lee and colleagues found that
71% of the patients with anaphylaxis were given IM epinephrine16.
Second line medications in the form of glucocorticoids and type1
antihistamines were supplied to all the studied patients. Although they
have no role in the management of anaphylaxis as recommended by
WAO10 and National Institute of Allergy, Immunology,
and Infectious Diseases (NIAID) guidelines29,
glucocorticoids and histamine1 blockers were commonly prescribed to
control the muco-cutaneous manifestations and to reduce hospitalization
of anaphylactic patients30. Unfortunately, long term
management was not provided to any of our studied patients including
proper family education or scheduled appointment for follow up in the
Specialized Allergy Clinic in our University hospital. The latter was
partly attributed to COVID19 pandemic which lead to strict regulations
of follow up. The lack of providing parents with adequate clarification
and education about anaphylaxis will definitely lead to increased
morbidities and mortalities. This problem was reported in many studies
particularly not providing a written anaphylaxis action plan16,27.
In conclusion, anaphylaxis is a growing problem and it is relatively
high in children particularly in infants with food being the most common
trigger. Diagnosis and early management of anaphylaxis was satisfactory,
however, long term management, follow up and patient education still
needs many efforts. A wide scale registry of anaphylaxis from different
governments of Egypt is recommended. Educational sessions should be
designed to healthcare providers for better orientation about the proper
management of anaphylaxis and the paramount importance of patient and
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