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Idiopathic Anaphylaxis: An Update

Vincent St Aubyn Crump

Idiopathic Anaphylaxis (IA) is a well-described syndrome of anaphylaxis without any recognised external trigger. These patients present with the same symptoms as patients with other types of anaphylactic reaction. The attacks occur with variable frequency. Fatalities have been reported in patients who have been diagnosed with idiopathic anaphylaxis.

Bacal et al first reported IA in 1978 [1], when they published data on 11 patients whose episode of anaphylaxis could not be explained. The series has been expanded to include over 335 patients. Atopy was noted in 48% of the patients (the same percentage implicated in the Spanish series of 81 patients).

The disease exists in all age groups and proves expensive if not diagnosed and treated early. It is reported to be more common in women, with 65% of 335 idiopathic anaphylaxis patients being women in the largest published series in the literature.

Prevalence of IA

Idiopathic anaphylaxis is one of the most common causes of anaphylaxis, accounting for approximately one third of cases in one retrospective study [2]

IA is estimated to affect 30,000 patients in the USA alone.

Clinical presentation

Symptoms & signs do not differ from other forms of anaphylaxis and include:

Hypotension & increased pulse rate
Wheezing & stridor
Hives, angioedema, flushing, & itching
Nausea, vomiting, diarrhea, difficulty swallowing
Light-headedness and loss of consciousness

In the series of Ditto et al [3] all of them experienced hives and angioedema, whereas 60% experienced symptoms of upper airway obstruction. Individual patients usually tend to have the same manifestations on repeated episodes. Progression from hives and itching to life-threatening symptoms of wheeze, loss of consciousness, and laryngeal edema may occur in 10 min to hours after onset.

Classification of Idiopathic Anaphylaxis (IA)

(Adopted from Roy Patterson, M.D. textbook on Idiopathic Anaphylaxis)

Disease Symptom
Generalized (G) Urticaria or angioedema with bronchospasm (asthma)
Hypotension (reduce blood pressure), syncope
Angioedema (A) Angioedema with upper airway compromise
(Laryngeal, pharyngeal, tongue)
Frequency of episodes More than 6 episodes per year: Frequent (F)
Less than 6 episodes per year: Infrequent (I)
Summary of Diagnoses IA-G-F, IA-A-F, IA-G-I, IA-A-I

Variations of IA Diagnoses

Corticosteroid dependent
IA- (CSD-IA)
Applied when patient is controlled by prednisone but has recurrent episodes of IA below a threshold of prednisone.
Malignant IA (M-IA); Applied when patient requires high doses of prednisone to control IA. The dose is arbitrarily set at 30mg daily
Or 60mg on alternate days but much higher doses may be required.
IA-Questionable (Q) Applied for a patient with possible IA where Documentation of objective findings is unsuccessful and diagnosis is uncertain.
IA-Variant (V) Applied when symptoms of IA vary from classical IA.
IA-V may subsequently be classified as IA-I, IA-G, IA-Q or USIA
Undifferentiated Somatoform IA (USIA) Symptoms mimic IA but no objective findings are documented and the symptoms are not responsive to the regimen of IA.

Diagnosis

Idiopathic anaphylaxis is a diagnosis of exclusion. Only after a thorough history and physical examination should the diagnosis be entertained. Skin prick testing, RAST and other lab tests are usually required to rule out culprit allergens and the numerous disease mentioned below that may masquerade as IA. A proper history (like in all diagnosis in Allergies) is probably the most important tool in the work-up, because it will guide subsequent testing.

Serum (mast cell) Tryptase can be very useful in differentiating anaaphylaxis from the many conditions that can masquerade as anaphylaxis [4]

Differential Diagnosis of Idiopathic Anaphylaxis

I. Known causes of immediate generalized reactions

A. IgE-mediated

  1. Foods — is the commonest cause of anaphylaxis and occurs in 1-2% of the population. Symptoms usually start 5 — 30 min after ingestion, occasionally after 1-2h, but rarely any longer. Consider an alternative diagnosis if symptoms began many hours after ingestion or if the patient has since eaten the suspected food without any reaction. The most common food allergens are milk, eggs, peanuts, tree nuts, fish, shellfish, soy & wheat, which account for over 90% of all food allergies. Foods commonly mistaken for IA include mustard and other spices.
  2. Drugs — are another common cause of anaphylaxis. It is important to focus on drugs / supplements / herbal preparation (bee pollen, Echinacea) and other over-the counter formulations (especially aspirin & NSAIDs) in the history taking.

B. Exercise Induced Anaphylaxis

C. Food-dependent, Exercise-induced Anaphylaxis

D. Non-IgE Medication-induced reactions

  1. Aspirin & NSAIDs
  2. Opiates
  3. Angiotensin-converting enzyme inhibitors (ACE-inhibitors)
  4. Radiographic contrast media
  1. Asthma masquerading as asthma
  2. Systemic Mastocytosis
  3. Hereditary Angioedema
  4. Munchausen's stridor / Anaphylaxis
  5. Undifferentiated Somatoform idiopathic anaphylaxis
  6. Miscellaneous Diagnosis

Panic Attacks
Globus Hystericus
Histamine-rich food flushing

Exercise Induced Anaphylaxis (EIA)

This is probably one of the commonest diagnosis mistaken for idiopathic anaphylaxis. It is due to mast cell activation, triggered by exercise. This results in generalised itching, urticaria, angioedema, gastrointestinal pain, or diarrhea and hypotensive collapse. This diagnosis can be difficult to make, as these patients do not always get the reaction every time they exercise. It often occurs in accomplished athletes. In one series of 266 patients with anaphylaxis 19 (7.1%) had EIA.

Some patients must ingest a specific food (commonly wheat) within two hours of exercise to have their reaction. This is known as food-related, exercise-induced anaphylaxis.

Hereditary angioedema resembles idiopathic anaphylaxis, but hives or other anaphylactic symptoms are not usually present, and the angioedema in this disorder tends to progress slowly, often painfully, and without itching. A positive family history is helpful in the diagnosis, but lack of it is not exclusionary.

Episodes may be provoked by dental procedures or other causes of local trauma. It is important to make the diagnosis as life-threatening reactions may not respond to adrenaline, but may be prevented by daily doses of androgens such as danazol or stanozolol.

Finding decreased level of complement and C1 esterase inhibitor concentration or function makes diagnosis of IA.

Systemic Mastocytosis

This is a rare condition in which the patients experience episodes of sudden generalized flushing, itchy skin, hives, abdominal pain, and sometimes hypotension. Over half of these patients will have "freckles" that urticate on stroking. Internal involvement includes mast cells infiltrating bone marrow, causing osteoporosis or live fibrosis. Patients may have peptic ulcer, enlarged liver, diarrhea, lethargy, and weight loss.

Blood tests for mast cell tryptase is usually high in between attacks and increases further after attacks. Bone scans can also help in the diagnosis of these patients.

The first Asthma attack in an adult may be difficult to differentiate from the bronchoconstriction that may accompany an episone of IA. Lack of other systemic anaphylactic symptoms should help to eliminate IA.

Munchausen's stridor / Anaphylaxis

Munchausen’s stridor presents as acute shortness of breath with stridorous sounds over the neck. This is not organic but produced by the patient. Patients with munchausen’s anaphylaxis provoke attacks of true anaphylaxis by deliberately eating foods that they know will cause anaphylaxis. An example is a patient with known peanut anaphylaxis who deliberately eats peanut and then rings the emergency medical service.

Undifferentiated somatoform idiopathic anaphylaxis (US-IA)

US-IA describes a variant form of IA in which there is a lack of documentation of objective physical findings of anaphylaxis. Patients report dizziness, ‘passing out’, throat closure, hives, and shortness of breath. Nevertheless, there is no objective evidence during the acute episode to confirm the diagnosis of any form of anaphylaxis.

Treatment of Idiopathic Anaphylaxis

Treatment depends on the severity and frequency of the attacks. Steroids seem to be universally effective in IA. If symptoms are not controlled on 60 mg daily by the end of 6 weeks, the diagnosis of IA should be questioned.

Acute Treatment

  1. Epi-pen
  2. Prednisone 60 mg
  3. Hydroxyzine 25 mg
  4. Go to the nearest emergency room

Programme for IA-F

  1. Arrange acute treatment
  2. Prednisone 40 — 60 mg daily for at least 1 week or until symptoms controlled, then decrease to alternate day and the wean by 5 — 10 mg each month.
  3. If it is proving difficult to wean off steroids ketotifen should be added [4]
  4. Cetirizine 10 mg daily or Hydroxyzine 25 mg tds
  5. Follow-up based on response to treatment

Programme for IA-I

  1. Arrange acute treatment
  2. No chronic medication
  3. Follow to assess response & compliance

References

[1] Bacal E, Patterson R et al, Evaluation of severe anaphylactic reactions.

Clin Allergy 1978; 8: 295 — 309

[2] Kemp et al, Anaphylaxis, a review of 266 cases

Arch Intern Med 1995; 155: 1749 -1754

[3] Ditto et al, Idiopathic Anaphylaxis, a series of 335 cases

Ann Allergy Asthma Immunol 1996; 77: 285 — 291

[4] Tanus T et al, Serum Tryptase in idiopathic anaphylaxis a case report and review of the literature. Ann Emergency Med 1994; 24: 104 – 107

[5] Wong S, Patterson R, et al, Efficacy of ketotifen in corticosteroid-dependent idiopathic anaphylaxis. Ann Allergy 1991; 67: 359 – 364

 

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