This document discusses anaphylactic reactions to vaccines in paediatric patients. It defines anaphylaxis as a severe allergic reaction that can affect multiple body systems like the skin, respiratory tract, gastrointestinal tract and cardiovascular system. Common triggers of anaphylaxis include vaccines, foods and medications. The pathophysiology involves activation of mast cells and basophils leading to release of inflammatory mediators. Diagnosis is based on involvement of two or more body systems within hours of exposure to a known allergen. Treatment involves epinephrine and antihistamines. Components of vaccines like gelatin, egg and yeast are known causes of allergic reactions. The document provides guidelines for managing suspected adverse vaccine reactions.

1. ANAPHYLACTIC REACTIONS TO
VACCINE IN PAEDIATRIC PATIENTS
- Kanmani.S
Department of Pharmacy Practice,
C L Baid Metha College Of Pharmacy.

2. DEFINITION
 Anaphylaxis is a type of allergic reaction, in which the immune
system responds to otherwise harmless substances from the
environment.
 Reaction may begin within minutes or even seconds of exposure,
and rapidly progress to cause airway constriction, skin and
intestinal irritation, and altered heart rhythms. In severe cases,
it can result in complete airway obstruction, shock, and death.
 The term is commonly used to denote the clinical reaction seen with
system IgE-mediated hypersensitivity reaction
 Angioedema of the face such that the boy cannot open his eyes. This
reaction was caused by an allergen exposure

3.  It typically causes more than one of the following: an itchy rash, throat or tongue
swelling, shortness of breath, vomiting, light headedness, and low blood
pressure. These symptoms typically come on over minutes to hours.

4.  Anaphylaxis can occur in response to almost any foreign substance.
 Common triggers include :
 venom from insect bites or stings
 foods, and medications.
 Less common causes include: food additives such as monosodium glutamate and
food colors, and topical medications. Physical factors such as exercise (known as
exercise-induced anaphylaxis) or temperature (either hot or cold) may also act as
triggers through their direct effects on mast cells. Events caused by exercise are
frequently associated with the ingestion of certain foods. During anesthesia,
neuromuscular blocking agents, antibiotics, and latex are the most common
causes. The cause remains unknown in 32–50% of cases, referred to as
"idiopathic anaphylaxis”.
 Six vaccines (MMR, varicella, influenza, hepatitis B, tetanus, meningococcal) are
recognized as a cause for anaphylaxis, and HPV may cause anaphylaxis

5.  Medications
 Any medication may potentially trigger anaphylaxis.
 The most common are β-lactam antibiotics (such as penicillin) followed by aspirin
and NSAIDs. Other relatively common causes include chemotherapy, vaccines,
protamine and herbal preparations. Some medications (vancomycin, morphine, x-
ray contrast among others) cause anaphylaxis by directly triggering mast cell
degranulation.
 Anaphylaxis to penicillin occurs once in every 2,000 to 10,000 courses of
treatment, with death occurring in fewer than one in every 50,000 courses of
treatment. Anaphylaxis to aspirin and NSAIDs occurs in about one in every 50,000
persons. If someone has a reaction to penicillins, his or her risk of a reaction to
cephalosporins is greater but still less than one in 1,000

7. PATHOPHYSIOLOGY
Arise from the activation of mast cells and basophils through a
mechanism generally understood to involve crosslinking of
immunoglobulin (Ig) E and aggregation of the high-affinity
receptors for IgE, FcRI.
Upon activation, mast cells and/or basophils quickly release
preformed mediators from secretory granules that include
histamine, tryptase, carboxypeptidase A, and proteoglycans.
Downstream activation of phopholipase A2 (PLA2), followed
by cyclooxygenases and lipoxygenases, produces arachidonic
acid metabolites, including prostaglandins, leukotrienes, and
platelet activating factor (PAF). The inflammatory cytokine,
tumor necrosis factor-α (TNF-α) is released as a preformed
mediator, and also as a late-phase mediator with other cytokines
and chemokines.

8.  Many of these mediators are believed responsible for the pathophysiology of anaphylaxis.
Histamine stimulates vasodilation, and increases vascular permeability, heart rate, cardiac
contraction, and glandular secretion. Prostaglandin D2 is a bronchoconstrictor, pulmonary and
coronary vasoconstrictor, and a peripheral vasodilator. Leukotrienes produce
bronchoconstriction, increase vascular permeability, and promote airway remodeling. PAF is
also a potent bronchoconstrictor and increases vascular permeability. TNF-α activates
neutrophils, recruits other effector cells, and enhances chemokine synthesis
 These overlapping and synergistic physiological effects contribute to the overall
pathophysiology of anaphylaxis that variably presents with generalized urticaria and
angioedema, bronchospasm, and all related symptoms

9. SIGNS AND SYMPTOMS

10. CLASSIFICATION
 There are three main classifications of anaphylaxis:
 Anaphylactic shock is associated with systemic vasodilation that causes low blood pressure
 Biphasic anaphylaxis is the recurrence of symptoms within 1–72 hours with no further
exposure to the allergen.The recurrence typically occurs within 8 hours. It is managed in the
same manner as anaphylaxis.
 Pseudoanaphylaxis or anaphylactoid reactions are a type of anaphylaxis that does not
involve an allergic reaction but is due to direct mast cell degranulation Non-immune
anaphylaxis is the current term used by the World Allergy Organization.
 Probable anaphylactic reaction: reaction occurring within 4 hr of vaccination and S/S ≥ 1
systems
Dermatologic,Respiratory,Cardiovascular,GI
 Possible anaphylactic reaction
S/S from only 1 system, S/S from ≥ 1 system but occurring > 4 hr after vaccination

11. CRITERIA
 There are three diagnostic criteria, each
reflecting a different clinical presentation
of anaphylaxis.
 Anaphylaxis is highly likely when any of
the following criteria is fullfilled.

12. CRITERIA 1
 Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal
tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula)
AND AT LEAST ONE OF THE FOLLOWING:
 Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak
expiratory function [PEF], hypoxemia)
 Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (eg, hypotonia
[collapse], syncope, incontinence)
 Because the majority of anaphylactic reactions (>80%) include skin symptoms, it was judged
that at least 80% of anaphylactic reactions should be identified by criterion 1 — even when
the allergic status of the patient and potential cause of the reaction is unknown. However,
cutaneous symptoms might be absent in up to 20% of anaphylactic reactions in children with
food or insect sting allergy.

13. CRITERIA 2
 Two or more of the following that occur rapidly after exposure to a likely allergen for that
patient (minutes to several hours):
1. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen lips-
tongue-uvula)
2. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF,
hypoxemia)
3. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, incontinence)
4. Persistent GI symptoms (eg, cramping abdominal pain, vomiting).
 In patients with a known allergic history and possible exposure, criterion 2 should provide
ample evidence that an anaphylactic reaction is occurring.

14. CRITERIA 3
 Reduced BP after exposure to known allergen for that patient (minutes to several
hours):
1. Infants and children: low systolic BP* (age specific) or greater than 30% decrease
in systolic BP
2. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that
person’s baseline
 Criterion 3 should identify the rare patients who experience an acute hypotensive
episode after exposure to a known allergen.

15. DIAGNOSIS
When any one of the following three occurs within minutes or hours of exposure to an
allergen there is a high likelihood of anaphylaxis:
1.Involvement of the skin or mucosal tissue plus either respiratory difficulty or a low blood
pressure causing symptoms
2.Two or more of the following symptoms after a likely contact with an allergen:
a. Involvement of the skin or mucosa
b. Respiratory difficulties
c. Low blood pressure
d. Gastrointestinal symptoms
3.Low blood pressure after exposure to a known allergen

16.  Skin involvement may include:
Hives, itchiness or a swollen tongue among others
 Respiratory difficulties may include:
Shortness of breath, stridor, or low oxygen levels among others.
 Low blood pressure is defined as a greater than 30% decrease from a person's usual
blood pressure. In adults a systolic blood pressure of less than 90 mmHg is often
used.
 During an attack, blood tests for tryptase or histamine (released from mast cells)
might be useful in diagnosing anaphylaxis due to insect stings or medications.
However these tests are of limited use if the cause is food or if the person has a
normal blood pressure, and they are not specific for the diagnosis.

18. Classification
of
Vaccine Allergy

19. IgE-MEDIATED REACTION TO VACCINES
IgE- mediated reaction to vaccines are more often caused by additive or
vaccine component, such as gelatin, rather than microbial immunizing agent
itself.
GELATIN
Partially hydrolyzed collagen of bovine or porcine origin.
A stabilizer in many vaccines.
Responsible for many anaphylactic reactions to MMR, varicella, JE vaccines.

20. GELATIN CONTENT OF VACCINES

21. EGG
 Concern has existed over administration of vaccines ‘grown in eggs’
to egg-allergic recipients.
: MMR vaccine
: PCEC rabies vaccine
: Influenza vaccine
: Yellow fever vaccine

22. EGG CONTENT IN VACCINE
Vaccine Grown in Egg protein content
Approach in egg-
allergic patient
Measles and mumps Chick embryo fibroblast
cell cultures
Picograms to Administer in usual
manner
Purified chick embryo
rabies
Chick embryo fibroblast
cell cultures
Picograms to Administer in usual
manner
Influenza (killed injected
and live attenuated
nasal)
Chick extra-embryonic
allantoic fluid
Micrograms Skin test with vaccine
prior to administration
Yellow fever Chick embryos Micrograms Skin test with vaccine
prior to administration

23.  LATEX
 If a person reports a severe (anaphylactic) allergy to latex, vaccines supplied in vials
or syringes that contain DNR should not be administered.
 For other latex allergies (e.g., a history of contact allergy to latex gloves), vaccines
supplied in vials or syringes that contain DNR or rubber latex can be administered.
 YEAST
 HBV prepared by harvesting hepatitis B surface Ag from culture of Saccharomyces
cerevisiae contain up to 5% of yeast protein.
 Yeast associated anaphylaxis after HBV in sensitized patient appear to be rare event.
 HBV & HPV4 contained yeast protein.

24. YEAST CONTENT OF VACCINES

25.  ANTIMICROBIAL AGENTS
 Neomycin, polymyxin B, and streptomycin.
 A single report of immediate-type allergic reaction to MMR vaccine in person with a
history of MP rash to topical neomycin.
 If a patient gives a history of an immediate-type reaction, it is appropriate to
investigate before immunization with vaccine containing this antibiotic.
 DIPHTHERIA-TETANUS-PERTUSSIS
DTP vaccines induce production of IgE in substantial percentage of recipients
who go on to receive subsequent dose without systemic reaction.
CRM 197
Mutant diphtheria protein
H influenzae vaccine (HibTITER), Pneumococcal vaccine (Prevnar),
Meningococcal vaccine (Meningitec, Menjugate, Menveo)

26. JAPANESE ENCEPHALITIS VACCINE
Immediate-type allergic reactions, consisting of urticaria with or without wheezing
occurring 5–60 minutes after vaccination.
Unusual, late-onset urticaria and angioedema reaction
1% of recipients, median interval = 2–3 days
Usually confined to the skin, some cases have involved hypotension or
respiratory distress.
HBV VACCINES
Risk to be 1:600,000 vaccine doses.
180,895 reports to VAERS
107 reports of pre-existing yeast allergies
The possible association between reaction to HBV and yeast allergy.

27. MMR & VARICELLA VACCINES
MMR VACCINE
 Anaphylactic reactions: 2–
10 per million doses.
 Allergy to gelatin has been
determined to be likely
cause (27–92%).
 No relationship with egg
allergy.
VARICELLA VACCINE
 Anaphylactic reactions : 3 per
million doses.
 Gelatin allergy is the cause of
some of these reactions.

28. INFLUENZA & YELLOW FEVER VACCINES
YELLOW FEVER VACCINE
 Anaphylaxis reactions 7 per
million doses.
 Related to egg, chicken, and
gelatin.
INFLUENZA VACCINE
 Anaphylaxis 0.024 per
100,000 doses.
 None of which was fatal,
and none of which occurred
in persons known to be
allergic to eggs.

29. NON-IgE-MEDIATED REACTION TO VACCINES
 NEOMYCIN
 1% of the general population demonstrates DTH by patch testing to neomycin.
 Skin patch testing: 100-1000 mcg of neomycin.
 Delayed-type contact dermatitis to neomycin
Small, temporary erythematous, pruritic papules at the injection sites 48-96
hours after vaccination.
Immunization can proceed in the usual fashion.

30. NEOMYCIN CONTENT OF VACCINES

31.  ALUMINUM
 Enhance immunogenicity of vaccines.
 Subcutaneous nodules are relatively common but usually resolve within a few
weeks to months.
 Higher incidence of contact allergy to aluminum.
 No reports of anaphylaxis have been attributed specifically to aluminum.
 TETANUS TOXOID
 Mild local reactions are relatively common.
 Arthus reaction has been postulated.
 In such individuals antitoxin levels should be evaluated before determining the
need for a subsequent booster.

32. RABIES VACCINE
 Many cases consistent with serum sickness have been reported.
 The timing of the reactions is from 2 to 21 days after vaccine administration.
 The symptoms have included those typical of serum sickness such as arthralgia,
fever, malaise, urticaria has been prominent feature.

33. SUGGESTED APPROACH TO SUSPECTED ADVERSE VACCINE REACTION

34. MANAGEMENT
 1) If itching and swelling are confined to the injection site where the vaccination was given, observe
patient closely for the development of generalized symptoms.
 2) If symptoms are generalized, activate the medical emergency and notify patient’s physician. This
should be done by a second person, while the primary healthcare professional assesses the airway,
breathing, circulation, and level of consciousness of the patient. Vital signs should be monitored
continuously.
 3) drug dosing information: The first-line and most important therapy in anaphylaxis is epinephrine.
There are NO contraindications to epinephrine in the setting of anaphylaxis.
 a. First-line treatment: Administer aqueous epinephrine 1:1000 dilution (i.e., 1 mg/mL)
intramuscularly; the standard dose is 0.01 mg/kg body weight, up to 0.5 mg maximum single dose in
children and adolescents.
 b. Optional treatment: H₁ antihistamines for hives or itching, you may also administer
diphenhydramine (either orally or by intramuscular injection; the standard dose is 1–2 mg/kg body
weight, up to 50 mg maximum dose in children and adolescents*) hydroxyzine (orally; the standard
dose is 0.5–1 mg/kg/dose up to 50–100 mg maximum per day in children and adolescents).
*According to AAP’s Red Book, for children age ≥12 years, the diphenhydramine maximum single
dose is 100 mg.

35.  4) Monitor the patient closely until EMS arrives. Perform cardiopulmonary resuscitation (CPR), if necessary, and
maintain airway. Keep patient in supine position (flat on back) unless he or she is having breathing
difficulty. If breathing is difficult, patient’s head may be elevated, provided blood pressure is adequate to
prevent loss of consciousness. If blood pressure is low, elevate legs. Monitor blood pressure and pulse
every 5 minutes.
 5) If EMS has not arrived and symptoms are still present, repeat dose of epinephrine every 5–15
minutes for up to 3 doses, depending on patient’s response.
 6) Record the adverse event (e.g., hives, anaphylaxis) to the vaccine, all vital signs, medications
administered to the patient, including the time, dosage, response, and the name of the medical personnel
who administered the medication, and other relevant clinical information. Report the incident to the
Vaccine Adverse Event Reporting System (VAERS).
Needed medications for a community immunization clinic first-line medication Epinephrine, aqueous
1:1000 dilution, in ampules, vials of solution, or prefilled syringes, including epinephrine autoinjectors (e.g.,
EpiPen and Auvi-Q). If autoinjectors are stocked, at least three should be available (both pediatric and adult
formulations). Optional medication: H₁ antihistamines Diphenhydramine (e.g., Benadryl) oral (12.5 mg/5
mL liquid, 25 or 50 mg capsules/tablets) or injectable (50 mg/mL solution). Hydroxyzine (e.g., Atarax,
Vistaril) oral (10 mg/5 mL or 25 mg/5 mL liquid, 10 mg or 25 mg tablets, or 25 mg capsules

39.  There are NO absolute contraindications for epinephrine use in anaphylaxis.
CAUTION:
1. Patients with cardiovascular diseases
2. Patients receiving MAO and tricyclic antidepressants
3. Recent intracranial surgery, aortic aneurism, uncontrolled hyperthyroidism
4. Patients receiving stimulants
5. Cocaine abused

40. REFERENCES
 Kelso JM. Adverse reactions to vaccines for infectious disease.In: Middleton’s Allergy Principles and Practice. 7th
ed.2009:1189-1204