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 “นํา้พริก” 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 (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


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 S G A Brown, et al., Middleton’s Allergy 8th edition, 2013, 1237-1259.

Estimated incidence


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


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

K Lenchner, et al., Curr Opin Allergy Clin Immunol 3 (2003) 305–311

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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