recurrent idiopathic anaphylaxis
DESCRIPTION
Recurrent idiopathic anaphylaxis Presented by Wat Mitthamsiri, M.D. May2, 2014TRANSCRIPT
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