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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
CASE
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
A 40 years old Thai woman
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
A 40 years old Thai woman
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
A 40 years old Thai woman
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
A 40 years old Thai woman
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
A 40 years old Thai woman
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
A 40 years old Thai woman
29 Apr 2013 • Symptom occurred 40 min after
meal with “นํา้พริก” 7 May 2013 • F/U -> Taper Prednisolone(5) to
2x2, continue montelukast, cetirizine
A 40 years old Thai woman
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
A 40 years old Thai woman
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
A 40 years old Thai woman
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
A 40 years old Thai woman
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
A 40 years old Thai woman
11 Aug 2013 • During housekeeping -> palpitation,
facial edema, rash • -> Adrenaline self-injection
25 Sept 2013 • During housekeeping -> palpitation,
facial edema, rash • -> Adrenaline self-injection
A 40 years old Thai woman
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
A 40 years old Thai woman
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
A 40 years old Thai woman
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
A 40 years old Thai woman
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 (นํา้พริก)
– 1 R/O from contact banyan resin – 4 R/O from exertion – 4 attacks occurred spontaneously
REVIEWS
Anaphylaxis
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
S G A Brown, et al., Middleton’s Allergy 8th edition, 2013, 1237-1259.
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.
Diagnostic criteria: 1 of these
• 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
Sampson HA et al.. J Allergy Clin Immunol 2006;117: 391-7.
Diagnostic criteria: 1 of these
• 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
Sampson HA et al.. J Allergy Clin Immunol 2006;117: 391-7.
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 S G A Brown, et al., Middleton’s Allergy 8th edition, 2013, 1237-1259.
Estimated incidence
S G A Brown, et al., Middleton’s Allergy 8th edition, 2013, 1237-1259.
Estimated incidence
S G A Brown, et al., Middleton’s Allergy 8th edition, 2013, 1237-1259.
Classification
• By frequency and presentation
PA. Greenberger, Immunol Allergy Clin N Am 27 (2007) 273–293 K Lenchner, et al., Curr Opin Allergy Clin Immunol 3 (2003) 305–311
Classification
• By treatment difficulty
PA. Greenberger, Immunol Allergy Clin N Am 27 (2007) 273–293 K Lenchner, et al., Curr Opin Allergy Clin Immunol 3 (2003) 305–311
Classification
• By variations
PA. Greenberger, Immunol Allergy Clin N Am 27 (2007) 273–293 K Lenchner, et al., Curr Opin Allergy Clin Immunol 3 (2003) 305–311
Theories of pathogenesis
PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014
• Hidden allergen – Food additives? – Food itself? – Latex?
Theories of pathogenesis
PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014
• Aberrant cytokine profile lowering the threshold for mast cell degranulation – Increase in Th2 cytokines (IL-4, IL-5,
and IL-13)
Theories of pathogenesis
PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014
• Female hormone effect on mast cells and/or basophils – Episodes are more common in females
patients… why?
Theories of pathogenesis
PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014
• 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
Theories of pathogenesis
PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014
• 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
Theories of pathogenesis
PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014
• Presence of serum histamine releasing factor
• Presence of IgE autoantibodies – No evidence whether these antibodies
are active in producing mast cell degranulation
Theories of pathogenesis
PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014
• 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
PA. Greenberger, Immunol Allergy Clin N Am 27 (2007) 273–293
Differential diagnosis
PA. Greenberger, Immunol Allergy Clin N Am 27 (2007) 273–293
Differential diagnosis
PA. Greenberger, Immunol Allergy Clin N Am 27 (2007) 273–293
Differential diagnosis
PA. Greenberger, Immunol Allergy Clin N Am 27 (2007) 273–293
Differential diagnosis
PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014
Differential diagnosis
PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014
Differential diagnosis
PA. Greenberger, Immunol Allergy Clin N Am 27 (2007) 273–293
Investigations
PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014
• 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
PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014
• 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
PA. Greenberger, Immunol Allergy Clin N Am 27 (2007) 273–293
• Peripheral blood c-KIT mutation for codon D816V
• Bone marrow examination
• Skin biopsy • Bone scan • Complement (C4) determination
Approach
K Lenchner, et al., Curr Opin Allergy Clin Immunol 3 (2003) 305–311
Approach
K Lenchner, et al., Curr Opin Allergy Clin Immunol 3 (2003) 305–311
Approach
K Lenchner, et al., Curr Opin Allergy Clin Immunol 3 (2003) 305–311
Approach
K Lenchner, et al., Curr Opin Allergy Clin Immunol 3 (2003) 305–311
Therapy of anaphylaxis
S G A Brown, et al., Middleton’s Allergy 8th edition, 2013, 1237-1259.
• 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
Therapy of anaphylaxis
S G A Brown, et al., Middleton’s Allergy 8th edition, 2013, 1237-1259.
• DEPENDENT ON EVALUATION – Start peripheral intravenous fluids – H1 and H2 antihistamines – Vasopressors – Corticosteroids – Aminophylline – Glucagon – Atropine – Electrocardiographic monitoring – Transfer to hospital
Therapy of anaphylaxis
S G A Brown, et al., Middleton’s Allergy 8th edition, 2013, 1237-1259.
Therapy of anaphylaxis
S G A Brown, et al., Middleton’s Allergy 8th edition, 2013, 1237-1259.
Therapy of anaphylaxis
S G A Brown, et al., Middleton’s Allergy 8th edition, 2013, 1237-1259.
Long-term managements
PA. Greenberger, Immunol Allergy Clin N Am 27 (2007) 273–293
• 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
PA. Greenberger, Immunol Allergy Clin N Am 27 (2007) 273–293
• 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
S G A Brown, et al., Middleton’s Allergy 8th edition, 2013, 1237-1259.
• 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
Additional managements
S G A Brown, et al., Middleton’s Allergy 8th edition, 2013, 1237-1259.
• Have patient wear and carry warning identification tags
Additional managements
S G A Brown, et al., Middleton’s Allergy 8th edition, 2013, 1237-1259.
• Teach self-injection of epinephrine, and advise patients to carry an epinephrine autoinjector.
Additional managements
S G A Brown, et al., Middleton’s Allergy 8th edition, 2013, 1237-1259.
• Use preventive techniques when patients undergo a procedure or take an agent that places them at risk – Pretreatment – Provocative dose challenge – Desensitization
Additional managements
PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014
• 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
PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014
• Beta-adrenergic blocking agents – Antagonize the beta- stimulatory
effects of endogenously secreted and exogenously administered epinephrine.
Drug avoidance
PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014
• 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
PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014
• MAOI – Prevent epinephrine catabolism by
inhibiting its degradation by monoamine oxidase
Drug avoidance
PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014
• TCA – Prevent epinephrine catabolism by
preventing reuptake of norepinephrine at nerve endings
Additional managements
PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014
Additional managements
PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014
Prognosis
PA. Greenberger, Immunol Allergy Clin N Am 27 (2007) 273–293
• 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
PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014
• 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
PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014
T J Pitt, et al., J Allergy Clin Immunol (2010) 126:2, 415
Future therapy
PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014
• 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