2. Historical Background
• Discovered by Portier and Richet in 1902
– While attempting to immunize dogs to the
venom of a sea anemone, they unknowingly
sensitized the dogs
• Dogs unexpectedly reacted to a previously
nonlethal dose
– Coined the term “anaphylaxie”, meaning without, or
against, protection
3. DEFINITIONS
• Anaphylaxis
– Systemic, immediate hypersensitivity reaction caused by IgE-
mediated release of histamine and other mediators from mast
cells and basophils
– Clinical syndrome with multi-organ symptoms
• cutaneous
• respiratory
• cardiovascular
• gastrointestinal
• Anaphylactoid
– Identical symptoms as anaphylaxis
– Non-IgE-mediated mechanism
4. EPIDEMIOLOGY
• Hospitalization for Anaphylaxis
– 13 yr retrospective review of anaphylactic shock from a hospital
in Denmark
• incidence of 3.2 cases per 100,000 inhabitants per year
• mortality rate of these 20 cases was 5%
– Sørensen H et al. Allergy 1989;44:288.
• ER Visits for Anaphylaxis
– Klein individually reviewed all 19,122 ER records during a 4
month period from St. Mary’s Hospital in Rochester, MN
– Incidence of anaphylaxis was 17 per 19,122 emergency visits or
0.09%
– Only 4/17 had ICD-9 codes for anaphylaxis
• most were simply classified as having an “allergic reaction”
– Klein J, Yocum M. J Allergy Clin Immunol 1995;95:637-
8.
5. Epidemiology of Anaphylaxis
• Retrospective review of
1255 cases of
“anaphylaxis” identified
in Olmsted County from
1983-1987
• 133 residents met
criteria for anaphylaxis
and had 154 reactions
• 116 single episode
• 13 had 2 episodes
• 4 had 3 episodes
• Anaphylaxis occurrence
rate 30/100,000 person
years
• Suspect allergen found
68%
• Allergy consultation in
only 52%
• 1 patient died
• 0.65% fatality rate
Yocum MW et al. J Allergy Clin Immunol 1999;104:452-6.
6. Yocum MW et al. J Allergy Clin Immunol 1999;104:452-6.
7. Anaphylaxis: Risk factors
• Age
– More common in
adults
• Atopy
– Foods
– Exercise
– Latex
– RCM
– Idiopathic
• Exposure route
– Oral less likely
• Gender
– Males
• Hymenoptera
– Females
• Latex
• Muscle relaxant
• Idiopathic
10. CUTANEOUS SYMPTOMS
• Pruritus
– initially palms, soles, groin, and axilla
• Urticaria & Angioedema
– most common finding
– usually resolves within 24 hours
– angioedema may persist for 2-3 days
• Warmth
• Flushing
• Erythema
11. RESPIRATORY SYMPTOMS
• Lower respiratory symptoms
– Dyspnea, wheezing, and chest tightness
• Upper respiratory symptoms
– Nasal congestion, sneezing, rhinorrhea
– Laryngeal edema
– often begin with a sensation of a “lump in the
throat”
– may progress to:
dysphonia
hoarseness
drooling due to inability to swallow secretions
stridor
asphyxia
14. FREQUENCY OF ANAPHYLACTIC
SYMPTOMS
Signs & Symptoms Kemp et al.
266 cases of anaphylaxis
Ditto et al.
335 cases of IA
Urticaria, Angioedema 90% 100%
Dyspnea, Wheezing 60% 39%
Dizziness, Pre-syncope,
Syncope
29% 23%
Gastrointestinal 26% 22%
Upper airway edema 24% 63%
Hypotension 20% 23%
Rhinitis 16% ND
Conjunctivitis, Periorbital
edema
12% ND
15. BIPHASIC & PROTRACTED
ANAPHYLAXIS
• Stark & Sullivan
– Prospective study of 25
patients with anaphylaxis at
PMH
– 5 (20%) had " biphasic
anaphylaxis"
– 6 had "protracted
anaphylaxis"
– Risk Factors
• oral agent
• anaphylaxis began > 30
minutes after exposure
• Stark B, Sullivan T. J
Allergy Clin Immunol
1986;78:76-83.
• Douglas et al.
– Biphasic anaphylaxis in only
5% of 44 inpatients
• Douglas D et al. J Allergy Clin
Immunol 1994;93:977-85.
• Both Studies
– Glucocorticoid therapy did not
prevent either recurrent or
prolonged anaphylaxis
– Patients without hypotension
or laryngeal edema did not
have biphasic reactions
20. EVALUATION OF PATIENTS
WITH ANAPHYLAXIS
• Working definition of anaphylaxis
– Either
• Airway obstruction such as laryngeal, pharyngeal,
or glossal edema or severe bronchospasm
– Or
• Documented hypotension or syncope
– Plus
• Symptoms of generalized mediator release
– urticaria, angioedema, pruritus, or flushing
• Review ER records for objective findings
21. DETERMINING THE ETIOLOGY OF
ANAPHYLAXIS
• Detailed History
– Time of day
– Relationship to exercise, meals, and
medications
– Prescribed medications
• different formulations or lots of medications
– Non-prescribed ingestants
• vitamins, health food supplements, laxatives,
and suppositories
• specific ingredients of meals
• within 4 hours of episode(s)
– Women
• menses or intercourse
22. SPECIFIC IgE in ANAPHYLAXIS
• Skin testing
– Accuracy > RAST
– Risk of fatal reactions
– Allergens
• medications, anesthetics,
venoms, foods, insulin,
latex
• heterologous sera,
vaccines, and other foreign
proteins
– Specificity fairly good
– Sensitivity of many tests is ?
– Some drugs can cause
direct histamine release
– opiates, RCM , some
muscle relaxants
• RAST testing
– Without risk
– Limited applicability
due to
• lower accuracy
• Few allergens available
– venoms, foods, latex,
and the major
determinant of
penicillin
23. FOOD SKIN TESTING IN
ANAPHYLAXIS
• Stricker et al
– Panel of 79 antigens
– Identified 7 food-induced anaphylaxis of 102 patients with IA
• Stricker W et al. J Allergy Clin Immunol 1986;77:516-519.
• Patients frequently unaware of foods that caused
reactions
– Food allergic patients failed to identify causative food in 67%
of positive DBPCFC
• Atkins F. J Allergy Clin Immunol 1985;75:348-355.
– Most all patients with fatal food-induced anaphylaxis
unknowingly ingested their fatal food
• Skin testing with fresh foods
– Commercial food extracts may lack antigenic epitopes
24. MEDIATOR MEASUREMENT IN
ANAPHYLAXIS
MAST CELL
MEDIATOR
BODY FLUID COMMENTS
Histamine Plasma, Urine In circulation breifly
False positives in urine
Histamine
metabolites (MIAA)
24 hr Urine Cumbersome
More specific and sensitive
than histamine
measurements
Tryptase (G5 & B12) Serum B12-measured tryptase
commercially available
Measures total tryptase
9 ,11ß-PGF2 24 hr Urine Available from Mayo Labs
25. TRYPTASE
• Neutral protease in secretory granules of mast
cells
• Specific for mast cells
• very minimal amounts in basophils
• -tryptase
• predominant form of tryptase in circulation in both
normals and mastocytosis patients
• b-tryptase
• released from secretory granules with systemic mast
cell activation
26. TRYPTASE MEASUREMENTS
• Total tryptase
• measured with mAb B12
• measures both & b-tryptase
• normal values < 15 ng/ml
• increases detectable earlier than G5 assay
• available through commercial labs
• b-tryptase
• measured with mAb G5
• normal values < 1 ng/ml
• undetectable within 30 minutes
• peaks in 1-2 hours
• available through Dr. Schwartz’s lab at
MCV
29. LOCAL ANESTHETIC
ALLERGY
• Allergy rare and anaphylaxis extremely rare
– allergy to parabens also rare
• Non-cross-reacting local anesthetic groups
– defined based on patch testing for contact
dermatitis
– unclear if any relevance to anaphylaxis
• Skin testing & incremental challenge
– validated method
– recommended for evaluation of possible allergy
31. THE MYTH OF SEAFOOD ALLERGY &
RCM REACTIONS
• Despite the common belief that
individuals with seafood allergy have a
higher risk of RCM reactions, there is no
data to support this and it has no
theoretical basis
– Shellfish allergic patients are allergic to
muscle proteins, not iodide
– RCM reactions are not caused by iodide
– Low-ionic RCM have a lower incidence of
anaphylactoid reactions despite containing
more iodide per particle than traditional RCM
34. ACUTE TREATMENT OF
ANAPHYLAXIS
• Early recognition and treatment
– delays in therapy are associated with fatalities
• Assessing the nature and severity of the
reaction
• Brief history
– identify allergen if possible
• initiate steps to reduce further absorption
– medications (especially b-blockers)
• General Therapy
– supplemental oxygen, IVF, vital signs, cardiac
monitoring
• Goals of therapy
– ABC’s
35. EPINEPHRINE
• First-line drug of
choice in anaphylaxis
• Mechanisms of action
– agonist
• increase BP by peripheral
vasoconstriction
– b-agonist
• reverse bronchoconstriction
• positive ionotropic and
chronotropic activity
• increases cyclic AMP levels
– inhibit further mediator
release from mast cells
and basophils
• Subcutaneous
administration
– dose: 0.3 to 0.5 mg of a
1:1,000 dilution prn q 10-
15 min
– IV epinephrine for
cardiovascular collapse
• Side effects
– severe hypertension,
arrhythmias, myocardial
ischemia and infarction
• DO NOT WITHHOLD
EPINEPHRINE BECAUSE OF
CARDIAC HISTORY
36. Simons FER et al. J Allergy Clin Immunol 1998;101:33-7.
Epinephrine Absorption: SQ vs. IM
39. Simons FER et al. J Allergy Clin Immunol 1998;101:33-7.
Outdated EpiPens
40. Simons FER et al. J Allergy Clin Immunol 2000;105:1025-30.
41. Use of EpiPen in Children with
Anaphylaxis
• Retrospective survey of children with
anaphylaxis who attended an allergy clinic in
North Adelaide Australia
• 45 episodes of anaphylaxis
• EpiPen given 13 (29%)
• EpiPen not given 32 (71%)
• Hospitalization for anaphylaxis
• EpiPen given 2 (14%) p< .05
• EpiPen not given 15 (47%)
Gold MS, Sainsbury R. J Allergy Clin Immunol 2000;106:171-6.
42. ANTIHISTAMINES IN ANAPHYLAXIS
• Not a substitute for epinephrine
• H1-antagonists
– useful for cutaneous symptoms
• H2-antagonists
– somewhat controversial
– combination of H1 and H2 antagonists was
required for optimal prevention of hypotension in
studies of histamine infusions
– overall evidence favors the addition of H2-
antagonists
• especially in the presence of hypotension
43. b -BLOCKED
ANAPHYLAXIS
• Beta blockade
– increase release of
mediators
– enhance the responsiveness
of pulmonary,
cardiovascular, and
cutaneous systems to
mediators
– paradoxical responses to
epinephrine
• bronchoconstriction and
bradycardia
– unopposed -
adrenergic and
reflex vagotonic
effects
• May be especially refractory
to therapy
• Treatment
– high doses of
isoproterenol or
dopamine
– atropine
– glucagon
• increases c-AMP
independent of b-
receptor
• nausea and vomiting
common
44. PREVENTION OF ANAPHYLAXIS
• Referral to BC/BE allergist
– Determine an etiology
• skin testing
• challenges
• desensitization.
– Educate the patient on avoidance
• proper use and indications of injectable epinephrine
• when to seek medical attention
• obtain a Medic-Alert® bracelet
– Develop a management plan
• prevent and reduce further anaphylactic episodes
• Select an alternative drug if on b-blocker
45. ACUTE DESENSITIZATION
• Indications
– Patients allergic to an essential therapeutic agent
– Systemic reactions to venoms (optional)
• Technique
– Escalating doses of antigen administered over a brief period
– Oral route preferred when possible
• Desensitization procedures are dangerous
• Mechanism of desensitization
– Unknown
– Desensitized state is antigen specific
• not due to tachyphylaxis to mediators, mast cell
depletion, or unresponsiveness to any IgE signal
46. CASE REPORT
• LB is a 62 yo WM who presented with
recurrent syncopal episodes. These episodes
were associated with pruritus, urticaria,
lightheadedness, and syncope with urinary &
fecal incontinence and occurred after playing
basketball or ping-pong. However, he has
performed more vigorous exercise without
reactions. An echocardiogram, Holter
monitor and head CT were all normal.
• Physical examination was unremarkable
47. EXERCISE-INDUCED
ANAPHYLAXIS
• Classification
– Food dependent EIA
• Specific food dependent EIA
– occurs only if exercise after eating specific food(s)
– implicated foods
shellfish, wheat, celery, tomato, apple, grapes,
litchi, hazlenut, chestnut, peanut, milk, rice,
potato
• Non-specific food dependent EIA
– occurs if exercising after eating any food
– Food independent EIA
48. POSSIBLE MECHANISMS OF EIA
• Subthreshold amount of mast cell associated IgE cross-
linking
– Endogenous opioid stimulus can trigger primed mast
cells to degranulate
– Increases in codeine skin test reactivity after exercise
– Increased wheal response to compound 48/80 in
individuals with food-dependent EIA, but only after
challenges with specific foods and exercise.
– Gastrin can stimulate mediator release from mast
cells
• Abnormal responses of the autonomic nervous system
– Increases in parasympathetic responses
– Decreases in sympathetic activity
49. CLINICAL FEATURES OF EIA
• 7% of anaphylaxis due to
EIA
• Symptoms & signs of EIA
similar to other forms of
anaphylaxis
– premonitory symptoms
• generalized warmth,
pruritus
• urticaria are usually
10-15 mm in
diameter
• angioedema of face,
palms, and soles
– reactions occur while
exercising or shortly
thereafter
– duration of 0.5 to 4
hours
• Exercise triggers
– Tennis, warmups, dancing,
soccer, basketball, running
– vaginal delivery
• Predisposing factors
– personal or family history of
atopy
• familial EIA has been
reported
– aspirin ingestion prior to
exercise may trigger 30%
– exercising in warm or humid
weather
– menses
50. THERAPY OF EIA
• Acute treatment
– epinephrine
• available while exercising
• Prevention
– exercise with a partner
– limiting or discontinuing exercise at the first sign of prodromal
symptoms
– avoid NSAID’s
– avoiding foods for 4-5 hours prior to exercise
– antihistamines - unable to totally prevent attacks
– oral disodium cromoglycate
– “exercise desensitization”
51. Natural History of EIA
• 279 EIA patients completed mailed survey
• Clinical course
– Attacks/yr decreased from 14.5 to 8.3
– 47% decrease in attacks
– 46% same
– 7% increased
• Food Associated EIA
– 37% patients
– Shellfish, alcohol, tomato most common triggers
• Avoidance behaviors
– Avoid exercise in extreme hot/cold or allergy season
– Avoid eating before exercise
Shadick NA et al. J Allergy Clin Immunol 1999;104:123-7.
52. Case Report
• CW is a 14 yo WF with a history of large
local reactions to “bees”. 3 weeks prior to
evaluation she was bit in the forehead by
an ant and within 5 minutes developed
facial urticaria, chest tightness, and throat
tightness which improved with H1 & H2
antagonists administered by her father a
cardiologist.
– Prick testing to imported fire ants was positive
53. IMPORTED FIRE ANTS
• IFA most common cause of anaphylaxis to
stinging insects in this area
• Imported fire ant species
– Solenopsis richteri
• introduced from Uruguay or Argentina accidentally into
the USA through the port of Mobile, Alabama in 1918
• localized to northeastern Mississippi and northwestern
Alabama
– Solenopsis invicta
• Brazilian species introduced later between 1933-1941
54. Fire Ant Anaphylaxis
• 0.6% to 2% of patients requiring medical treatment for stings
• Texas has the 2nd highest number of IFA sting fatalities
• Diagnosis
– anaphylaxis history after sting with development of a pustule
– fire ant-specific IgE by skin tests
• 25% of nonallergic individuals in endemic areas have IFA
specific IgE
• Immunotherapy
– Indicated for patients with systemic reactions, especially
anaphylaxis
– IFA whole body immunotherapy efficacy
• field re-stings
– 2.1% risk of anaphylaxis
• intentional sting challenge
– 0/30 reactions
• Optimal duration of immunotherapy unknown
55. CASE REPORT
• 34 yo BF with recurrent episodes of pruritus,
urticaria, angioedema, chest tightness, and syncope.
One episode required ER treatment and hypotension
was documented. All episodes occurred shortly after
sexual intercourse. She was seen initially by a
neurologist who thought she was having
hypoglycemic attacks and recommended eating prior
to intercourse which did not help. She also had an
ETT performed and the cardiologist thought she
“was crazy”.
• Skin testing with her partners semen at 1:1,000
dilution was markedly positive while her partner was
skin test negative
• Condom use was recommended and prevented the
attacks
56. HUMAN SEMINAL PLASMA ANAPHYLAXIS
• First reported by Specken in 1958
• Pathogenesis
– Halpern et al. (1967)
• Evaluated a woman with anaphylaxis occurring 15-30
minutes after coitus
• Scratch tests were positive to
– husband’s whole sperm & seminal fluid devoid of
spermatozoa
– donor seminal fluid devoid of spermatozoa
• Scratch tests negative to
– husband’s serum
– semen from rabbit, guinea-pig, horse and bull
• Passive transfer (Prausnitz-Küstner reaction)
– positive in 5 female controls as well as in monkeys
• Chromatography and electrophoresis of seminal fluid
identified basic protein fractions that were the most
antigenic
57. HUMAN SEMINAL PLASMA
ANAPHYLAXIS
• Antigens
– Isolated to seminal plasma
• reactions can occur with vasectomized partners
• only one case reported of a women reactive to spermatozoa
and HSP
• canine sperm can also induce anaphylaxis due to bestiality
– Antigenic fraction of seminal fluid
• MW of 20,000 to 30,000 daltons
• heat stable
• prostatic origin
• prostate specific antigen (PSA) may be a major allergen
58. THERAPY OF HSP ANAPHYLAXIS
• Condoms
– universally successful
– may induce remission if
used for prolonged periods
• Prophylactic
antihistamines
– may control local HSP
reactions
– ineffective for systemic
reactions
• Pregnancy
– successful impregnation
may be achieved using
artificial insemination with
isolated spermatozoa
• Immunotherapy
– extracts of antigenic
fractions of HSP most
successful
• Immunologic changes
variable
– decrease in IgE
– progressive rise in
IgG
– rapid desensitization
• parenteral and local
(intravaginal)
– long term success
• up to 8 years after
immunotherapy
• maintaining sexual
activity 2-3 times per
week
59. Idiopathic Anaphylaxis
• Diagnosis of exclusion
– Careful evaluation for known causes should be performed
• Mechanism is unknown
• Patients present with the same constellation of
symptoms as others with anaphylaxis
• Treatment approach is the same
– Preventative therapy with qd or qod prednisone may be required
• Patients require education and support as part of their
disease management
60. CONCLUSIONS
• Anaphylaxis is the most dramatic and potentially
fatal manifestation of immediate hypersensitivity
• Majority of reactions are due to medications, insect
stings, radiocontrast media and food, however many
are idiopathic
• Most anaphylactic reactions respond to aggressive
therapy, but fatalities still occur, especially if
treatment is delayed
• Epinephrine is still underutilized in many patients
• Almost all cases of anaphylaxis should be referred to
an allergist
