Recurrent idiopathic anaphylaxis

Recurrent
(Idiopathic?)
Anaphylaxis
By
Wat Mitthamsiri, MD.
Allergy and Clinical Immunology Fellow
King Chulalongkorn Memorial Hospital

Outline
Case presentation
Review of anaphylaxis
– Definition
– Diagnostic criteria
Review of idiopathic anaphylaxis
– Definition
– Estimated incidence
– Classification
– Theories of pathogenesis
– Differential diagnosis
– Investigations
– Approach
– Therapy and management
– Prognosis and future therapy

A 40 years old Thai woman
Oct 2012
• Facial edema, no wheezing
• -> Dx: R/O anaphylaxis from “Tiffy”
Nov 2012
• Wrist pain with multiple PIP pain and
erythematous rash on extremities
• -> W/U RF&ANA: Negative
• -> On NSAIDs -> Improved -> Stop NSAID
21 Feb 2013
• Facial edema and wheezing
• -> Dx: Anaphylaxis, Admit

26 Feb 2013
• Edema occurred again
• No medical Rx
20 Mar 2013
• Oral ulcer -> Got colchicine from
clinic
• After 9 tablets taken (1 hr after last
tablet) -> facial edema, lungs clear

20 Mar 2013
• Hx of penicillin, Bactrim, Brufen, ASA,
colchicines, diclofenac allergy (no detail
about symptom)
• W/U:
– Serum tryptase 1.9
– C3=1.23, C4=0.4 (0.1-0.4), CH50 = 75%
• R/O Complement deficiency
• HM: Atarax, CPM, cetirizine
• Refer to KCMH

9 Apr 2013
• At GenMed Clinic -> Initial W/U
• CBC: Hct 39.4, Hb 13.4, WBC 9010
(N 47, L 44, E 2.3), plt 334000
• AST 17, ALT 24, ALP 68
• UA WNL
• -> Sent to Allergy Clinic

23 Apr 2013: 1st KCMH Allergy Clinic
visit
• Hx of facial/orbital angioedema
– Probable anaphylactic reaction R/O from
Tiffy, ASA, Brufen
• Symptoms usually occurred 15-30 min
post tablet and persisted for 2 days
• There were 2 episodes that occurred
without any medication
• PH: Mild AR, no AA, no CRS
• PE: No nasal polyp

23 Apr 2013: (Continued)
• Imp:
– Recurrent severe angioedema with
probable anaphylaxis
– NSAIDs/analgesic sensitivity (angioedema)
• W/U: SIgE to mixed food -> Negative
• Rx: Adrenaline kit, cetirizine 1x2,
montelukast 1x2, prednisolone(5) 3x2
• After went home and do some cleaning
-> symptoms occurred again

29 Apr 2013
• Symptom occurred 40 min after
meal with “นํ้าพริก”
7 May 2013
• F/U -> Taper Prednisolone(5) to
2x2, continue montelukast, cetirizine

17 May 2013
• After exhaustive workout (without
any medication, or food within 5
hr), she had erythroderma at
extremities, facial edema, no itching
• She went to a hospital
– > Adrenaline im
– > 10 min after that, symptoms
improved
– > Completely resolved after 1 day

17 May 2013 (continued)
• PE: Steroid acne found
• W/U: Baseline serum tryptase
• Rx:
– Stop antihistamine (prevention of
obscuring late detection of anaphylaxis)
– Increased prednisolone(5) to 4x3 for 10
days, then 3x3
– Continue cetirizine, montelukast
– Add ranitidine(150) 1x1

9 Jul 2013
• During June, she had 2 severe
generalized urticaria episodes with
mild angioedema
– 1 of these had chest tightness without
wheezing.
– She self-injected adrenaline both times
-> symptoms improved within 10 min
but completely resolved after 1 day

9 Jul 2013 (continued)
• She said that eating jackfruit caused
neck tightness without other
symptom
• BUT she can wear rubber gloves and
boots
• W/U: ANA, CH50, C3, C4
• Rx: RM 17 May 2013

11 Aug 2013
• During housekeeping -> palpitation,
facial edema, rash
• -> Adrenaline self-injection
25 Sept 2013
• During housekeeping -> palpitation,
facial edema, rash
• -> Adrenaline self-injection

1 Oct 2013
• Result W/U came back:
– Serum tryptase 2.21 (<13.5 ug/L)
– ANA <1:80
– CH50 – 39.5, C3 = 136, C4 = 38.8
• Additional W/U: total IgE level
• Assessment:
– Decreasing severity on each attack

1 Oct 2013
• Rx:
– Stop montelukast
– Continue prednisolone(5) 3x3, cetirizine,
ranitidine
– Add ketotifen 1x2
7 Jan 2014
• F/U
– > Decrease prednisolone(5) to 2x3 for 2 wk,
then 6x1 for 2 wk, then 6x1 AD + 5x1 AD

9 Feb 2014
• 2 days after adjusting prednisolone to
6x1, at about 17.00, while sitting on
the back of a truck
– > Chest tightness with erythroderma
without wheezing
– > Adrenaline self-injection and went to a
hospital
– > Received 3 more unknown iv injection and
observed until 23.00
– > HM: Prednisolone(5) 3x3 until 25 Feb
2014, then 6x1
– > Continued other medication

3 Mar 3014
• F/U:
• Lab results back:
– Total IgE 453 (normal <100) IU/mL
• Rx:
– Prednisolone(5) 6x1 for 1 mo, then 5x1
for 1 mo, then 4x1 for 1 mo

Summary of attacks
• Totally 11 probable anaphylaxis
attacks in 1 year and 5 months
– 2 R/O from drugs (Tiffy, colchicine)
– 1 R/O from food (นํ้าพริก)
– 1 R/O from contact banyan resin
– 4 R/O from exertion
– 4 attacks occurred spontaneously

Definitions
• A “severe, life-threatening,
generalized or systemic
hypersensitivity reaction.”
– Allergic anaphylaxis: Mediated by an
immunologic mechanism
• e.g., IgE, IgG, and immune-complex-
complement related
– Nonallergic anaphylaxis: Anaphylaxis
from a nonimmunologic reaction
S G A Brown, et al., Middleton’s Allergy 8th edition, 2013, 1237-1259.

Definitions

Diagnostic criteria: 1 of these
• 1) Acute onset of an illness (minutes to
several hours)
– With involvement of the skin, mucosal
tissues, or both (e.g., generalized hives,
pruritus or flushing, swollen lips-tongue-
uvula)
– And at least one of the following:
• Respiratory compromise (e.g., dyspnea, wheeze-
bronchospasm, stridor, reduced PEF,
hypoxemia)
• Reduced BP or associated symptoms of end-
organ dysfunction (e.g., hypotonia [collapse],
syncope, incontinence)
Sampson HA et al.. J Allergy Clin Immunol 2006;117: 391-7.

• 2) >/=2 of the following that occur rapidly
after exposure to a likely allergen for that
patient (minutes to several hours):
– Involvement of skin-mucosal tissue
• e.g., generalized hives, itch-flush, swollen lips-tongue-
uvula
– Respiratory compromise
• e.g., dyspnea, wheeze-bronchospasm, stridor, reduced
PEF, hypoxemia
– Reduced BP or associated symptoms of end-organ
dysfunction
• e.g., hypotonia [collapse], syncope, incontinence
– Persistent gastrointestinal symptoms
• e.g., crampy abdominal pain, vomiting

• 3) Reduced BP after exposure to
known allergen for that patient
(minutes to several hours):
– Infants and children:
• Low systolic BP (age specific) or greater
than 30% decrease in systolic BP*
– Adults:
• Systolic BP less than 90 mm Hg or greater
than 30% decrease from their baseline

REVIEWS
Idiopathic anaphylaxis

Idiopathic anaphylaxis
Definition
• Idiopathic anaphylaxis is anaphylaxis
not explained by a proved or
presumptive cause or stimulus
• A diagnosis of exclusion after other
causes have been considered
PA. Greenberger, Immunol Allergy Clin N Am 27 (2007) 273–293

Estimated incidence
• Antibiotics: 22% of all drug-related episodes, 1.9-27.2 million US
• Latex: 2.7-16 million US
• Perioperative anaphylaxis: 9%-19% of complications
• Radiocontrast media: 0.16% of ionic media, 0.03% of nonionic
media administration
• Hymenoptera stings: 0.4%-0.8% of children, 3% of adults
• Food: 0.0004% of the US per year
• NSAIDs: Varied between reports
• Antisera: 2-10% of cases that used the agents
• Hemodialysis-associated: 21 cases in 260,000 dialysis
• Idiopathic:
– 2/3 of adults presenting to
allergist/immunologist
– Extrapolated data: 20,592 to 47,024 cases
in U.S. population

Estimated incidence

Classification
• By frequency and presentation
K Lenchner, et al., Curr Opin Allergy Clin Immunol 3 (2003) 305–311

Classification
• By treatment difficulty

Classification
• By variations

Theories of pathogenesis
PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014
• Hidden allergen
– Food additives?
– Food itself?
– Latex?

• Aberrant cytokine profile lowering
the threshold for mast cell
degranulation
– Increase in Th2 cytokines (IL-4, IL-5,
and IL-13)

• Female hormone effect on mast cells
and/or basophils
– Episodes are more common in females
patients… why?

• An alteration in the T-cell population
– Current acute idiopathic anaphylaxis
patients had a higher percentage of
CD3+HLA-DR+ cells than those in
remission
– Patients with breakthrough episodes during
prednisone Rx and who were in remission
had significantly higher percentage of
activated B cells (CD19+CD23+) than
normal volunteers

• Increased sensitivity to histamine at
the target organ site
– Patients with idiopathic anaphylaxis
had
• Increased sensitivity to the injection of
histamine
• Equal sensitivity to histamine as CIU
patients
• Less reactivity to histamine than
AR/asthma patients
– Impaired inactivation of PAF

• Presence of serum histamine
releasing factor
• Presence of IgE autoantibodies
– No evidence whether these antibodies
are active in producing mast cell
degranulation

• Spontaneously increased mast cells?
– A study of mast cell no. from skin Bx
• Normal, 38 cells/mm2
• Idiopathic anaphylaxis or unexplained flushing,
72 cells/mm2
• Urticaria pigmentosa or indolent systemic
mastocytosis, nonlesional skin, 168 cells/mm2
• Urticaria pigmentosa, lesional skin, 597
cells/mm2
• indolent systemic mastocytosis, lesional skin,
721 cells/mm2

Differential diagnosis

Investigations
• Skin tests to foods or to drugs
– Using standard commercially available
extracts
– Using fresh food
• Serum-specific IgE to foods and
drugs
• Diagnostic-therapeutic trial with
prednisone
• Oral challenge

Investigations
• Serum anti-alpha-gal IgE
• Baseline and during anaphylaxis
serum tryptase
• Baseline and during anaphylaxis 24-
hr urinary histamine metabolites
• Prostaglandin D2 (urine or plasma
or urinary metabolite 9a, 11b-
prostaglandin F2)

Investigations
• Peripheral blood c-KIT mutation for
codon D816V
• Bone marrow examination
• Skin biopsy
• Bone scan
• Complement (C4) determination

Approach

Therapy of anaphylaxis
• IMMEDIATE ACTION
– Perform assessment.
– Check airway and secure if needed.
– Rapidly assess level of consciousness.
– Vital signs
• TREATMENT
– Epinephrine
– Supine position, legs elevated
– Oxygen
– Tourniquet proximal to injection site

• DEPENDENT ON EVALUATION
– Start peripheral intravenous fluids
– H1 and H2 antihistamines
– Vasopressors
– Corticosteroids
– Aminophylline
– Glucagon
– Atropine
– Electrocardiographic monitoring
– Transfer to hospital

Long-term managements
• For IA-I patient (<5 attacks/year or <2 attacks
in 2 months)
– Expectant management with the triple
therapy should an episode occur
• Epinephrine, prednisone, and H1 antagonist
– H1 antagonist should be used daily
– Epinephrine and prednisone must be
available at all times

Long-term managements
• For IA-F patient (6 attacks/year or >/=2
attacks in 2 months)
– Empiric treatment = helpful in reducing
the frequency and severity
• Prednisone 60-100 mg OD for 7 days and
then 60 mg AD
• Cetirizine(10) OD (or equivalent H1
antagonist)
• Optional albuterol 2 mg b.i.d/t.i.d

Additional managements
• Obtain thorough Hx for drug allergy
• Administer drugs orally rather than
iv
• Check all drugs for proper labeling.
• Keep patients in the office 20 to 30
minutes after injections.
• observation period after mAb Rx:
– 2 hr for the first 3 injections
– 30 minutes for subsequent injections

• Have patient wear and carry
warning identification tags

• Teach self-injection of
epinephrine, and
advise patients to
carry an epinephrine
autoinjector.

• Use preventive techniques when
patients undergo a procedure or
take an agent that places them at
risk
– Pretreatment
– Provocative dose challenge
– Desensitization

• Avoid taking drugs that might
complicate treatment or worsen an
event
– Beta-adrenergic blocking agents
– ACEI/ARB
– Monoamine oxidase inhibitors
– Certain TCA (eg, amitriptyline)

Drug avoidance
• Beta-adrenergic blocking agents
– Antagonize the beta- stimulatory
effects of endogenously secreted and
exogenously administered epinephrine.

Drug avoidance
• ACEI/ARB
– Block the compensatory response to
hypotension that is induced by the
activity of angiotensin-2
– Prevent the catabolism of kinins, which
are synthesized during an anaphylactic
event

Drug avoidance
• MAOI
– Prevent epinephrine catabolism by
inhibiting its degradation by
monoamine oxidase

Drug avoidance
• TCA
– Prevent epinephrine catabolism by
preventing reuptake of norepinephrine
at nerve endings

Prognosis
• Rate of remission (no episodes for 1
year and no prednisone) was:
– 48% in patients who had IA-G
– 40% in patients who had IA-A
• The prognostic factors for remission
or prednisone responsiveness remain
uncertain

Prognosis
• Vast majority of patients gradually
improve
– Including patients who have frequent
episodes and require prednisone and H1
(and/or H2 antagonists or albuterol) for
months or even 2 to 3 years
• Episodes decline in frequency
• Remissions occur in many instances but
not necessarily in the absence of
empiric treatment

Future therapy
P Warrier, et al., Ann Allergy Asthma Immunol (2009) 102, 257-258
• Omalizumab
– Very helpful for prevention of attacks
– No current consensus dosage for IA
– Reported successful dosages
• 300 mg q 4 weeks for 14 months
• 375 mcg sc q 2 weeks for 12-yr old boy
T J Pitt, et al., J Allergy Clin Immunol (2010) 126:2, 415

Future therapy
• Methylene blue
– A novel potential treatment for
refractory anaphylaxis
– Competitive inhibitor of guanylate
cyclase, which may block vasodilation
caused by nitric oxide
– Adult dosage: Methylene blue 1%, 1-2
mg/kg in 100 mL of 5D/NSS iv drip
over 20 minutes

Take home message
• Idiopathic anaphylaxis is a diagnosis of
reasonable exclusion
• Acute Mx: The same as other anaphylaxis
• For IA-F
– 3-month empiric course of prednisone and H1
antagonist, +/- albuterol, be used to reduce
the number and severity
• For IA-I
– Expectant management with the triple
therapy of epinephrine, prednisone, and H1
antagonist be used

Take home message
• Epinephrine should be available to
patient at all time
• Patient education (especially self-
injection of epinephrine) and
identification tag is very important
• Remission can occur

Recurrent idiopathic anaphylaxis

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