Does this patient with urticaria/angioedema have anaphylaxis?

Signs and symptoms

Anaphylaxis is a systemic reaction. Typical features include a feeling of doom, hypotension, often with loss of consciousness, diarrhoea, vomiting and abdominal cramps, laryngeal oedema and bronchospasm. Urticaria may be present, but up to 50% of reactions may not be accompanied by this rash.⁸ Urticaria, with or without angioedema, especially when chronic, is almost never due to IgE-mediated mechanisms.

Patients with underlying asthma are at greater risk of severe reactions with bronchospasm. Risk factors for a fatal outcome to anaphylaxis may include age (and age-related comorbidities such as hypertension, ischaemic heart disease (IHD)) and drug therapy (particularly angiotensin-converting enzyme inhibi-tors (ACE-I)). Summers et al ⁹ have examined risk factors for anaphylaxis in peanut and tree nut allergic patients and found that severe pharyngeal oedema was more likely to be present in patients with severe rhinitis and those with low levels of ACE (≤37 mmol/l). Life-threatening bronchospasm was more likely in patients with severe asthma, while altered consciousness was more likely in those with severe eczema. There has been debate about whether beta-blockers have an adverse effect on outcome, but

Causes

Almost any substance is capable of triggering an IgE-mediated anaphylactic reaction. Table 1 lists the most common causes of anaphylaxis and Table 2 the differential diagnosis.

Onset of anaphylaxis is rapid. Attempts by the patient (or doctor!) to blame foods eaten the day before are erroneous. Although textbooks say that anaphylaxis may occur up to six hours after ingestion/exposure this is, in practice, exceptionally rare and two hours is really the outside limit. History should include the contribution of exercise, as symptoms may rarely become apparent only when consumption is followed by exercise¹¹ - this is an increasingly important problem. Non-steroidal anti-inflammatory drugs (NSAIDs) make it worse by increasing the passage of allergen through the gut into the blood stream in an undigested and immunoreactive form.¹¹

Not all cases of anaphylaxis are easily resolved, and a group of patients with idiopathic anaphylaxis remain. These patients often have repetitive attacks and may require continuous steroids to control them. It is important to identify mastocytosis, as this can predispose to severe and recurrent episodes of anaphylaxis. Patients with mastocytosis must be warned of the risks of drug administration, especially anaesthetics. Within the group of patients with a history of recurrent anaphylactic reactions are a small number of patients with somatoform disorders.¹²

Hereditary angioedema

Hereditary angioedema (HAE) is a very rare genetic condition, affecting approximately one in 100,000. There will be a family history in most but not all cases. Idiopathic, non-allergic angioedema is at least 100 times more common and usually has a much more rapid onset than HAE. Complement abnormalities during an attack will distinguish the two. HAE typically demonstrates very slow development of angioedema, without urticaria. In this condition, bowel oedema may occur, causing severe abdominal pain frequently mistaken for an acute abdomen. Failure to recognise this may lead to inappropriate laparotomies, often on more than one occasion. Almost all cases of angioedema presenting to A&E or admissions units will be due to causes other than HAE.

Causes

The most common identifiable causes of angioedema without urticaria are drugs, particularly ACE-Is, statins, proton-pump inhibitors and NSAIDs (Table 3). A proper drug history is therefore essential. ACE-Is cause angioedema by preventing the breakdown of bradykinin. Figures vary for the number of patients developing angioedema on ACE-Is, but it may be as high as 5%. Of patients presenting to a tertiary referral clinic with angioedema, 11% had ACE-I induced angioedema.¹³ The attacks may commence at any time after the initiation of therapy and may persist for up to three months after drug withdrawal.

Angioedema frequently develops during the night or in the early hours of the morning, waking the patient. This effectively excludes foods and other triggers consumed the day before. The predilection for angioedema to develop at this time is unknown. HAE should be considered (see above).

In older patients presenting with angioedema alone, it is important to look for rare acquired angioedema secondary to paraproteins which block C1-esterase inhibitor function (acquired angioedema). This is usually associated with splenic villous lymphomas. In younger patients, usually with systemic lupus erythematosus autoantibodies against C1-esterase inhibitor have been reported rarely.

No cause for the angioedema is identified in many patients and is frequently labelled as ‘idiopathic’. However, it is important to recognise the major role that psychosocial stressors play in the development of all types of pseudo-allergic reactions, including angioedema. Failure to identify these and advise the patient appropriately will ensure that the problem continues unabated.

Adrenaline

The treatment of anaphylaxis involves the prompt administration of adrenaline, which must be given by the intramuscular (im) route. First-response dose of adrenaline is usually 0.3–0.6 mg im for adult patients. A recent Cochrane review concluded that the use of adrenaline in anaphylaxis is based on tradition and on evidence from fatality series in which most individuals dying from anaphylaxis had not received prompt adrenaline treatment.¹⁵

Many patients will have self-injection devices such as Epipen or Anapen. Prescribers should be aware that the mechanisms for triggering these devices are different and therefore they should not be used interchangeably. If intravenous (iv) adrenaline is used, it must be diluted via an infusion pump (10 ml 1 in 10,000 adrenaline, diluted with 100 ml normal saline) with ECG monitoring. Significant complications can occur from using iv adrenaline including cardiac ischaemia, arrhythmias and death. It should be used only in a hospital setting by experienced specialists.

Steroids

Steroids should be administered at the earliest opportunity, not for any immediate benefit but to prevent both the production of leukotrienes and late-phase reactions (rare but preventable). The optimal dose of steroid is not known. Current guidelines suggest a dose of 200 mg hydrocortisone iv for adults.¹⁴ An attempted meta-analysis of the use of steroids identified no suitable studies so the actual value is uncertain.¹⁶ Until appropriate studies are done, custom and practice indicate that steroids should be administered.

Antihistamines

Chlorphenamine 10 mg iv is usually given. Its value is dubious once there has been massive histamine release, particularly as it is a weak antihistamine compared with third-generation antihistamines such as cetirizine or fexofenadine. It is sedating, which may be valuable in reducing anxiety. Oral administration of cetirizine 20 mg may be better if the patient can swallow. A Cochrane Review¹⁷ has found no satisfactory trials addressing the value of antihistamines in this setting. It is probable that there never will be any trials because of the logistic difficulties.

Observation

A patient who has had an anaphylactic reaction must be kept under medical observation for a minimum of six hours in case of late-phase reactions. After a period of observation, the patient may be discharged if fully recovered. (Admission to hospital is not required unless there are continuing problems.) Adrenaline for self-injection should be prescribed only for patients who have had a severe systemic reaction to an unknown or unavoidable allergen, and then only if full training of the patient is given (Table 4). Patients who have had reactions to drugs should not receive injectable adrenaline devices, but instead clear instructions about drug avoidance, backed up by information to GPs.

Hereditary angioedema

Hereditary angioedema does not respond well to adrenaline, steroids or antihistamines. Treatment has largely been with purified C1-esterase inhibitor, but new treatments are now available. Management should be discussed with a clinical immunologist.

Anaphylaxis

For a patient not previously known to suffer from anaphylaxis, it is essential that rapid follow-up is arranged with a clinical service experienced in the investigation and management of anaphylaxis. This may be carried out either by a clinical immunologist or an allergist and can be undertaken as an outpatient once the patient is stable and can be discharged from hospital. Any information about food exposure at the time of the reaction should be preserved or noted until this review as it may give valuable clues to further investigation.

If there is deemed to be a risk of further systemic reactions and the allergen is unavoidable, a self-treatment kit with adrenaline for self-injection (minimum of two pens), together with cetirizine 20 mg and prednisolone 20 mg as stat oral doses should be provided (Table 4). Clearly, patients with risk factors such as asthma, severe rhinitis, elevated serum tryptase levels and low ACE levels should be prioritised to receive adrenaline. Caution should be observed in giving adrenaline to patients with known or suspected IHD, uncontrolled hypertension, or those taking tricyclic antidepressants or cocaine, due to the risks of ventricular arrhythmias. The dose of adrenaline in those on beta-blockers should be reduced by 50% to prevent unopposed alpha activity and paradoxical hypertension. Whether beta-blockers should be stopped is debatable and should involve a discussion between the patient's cardiologist and immunologist/allergist.¹⁰

Urticaria and angioedema

Patients with recurrent urticaria and angioedema who have frequent attacks may benefit from regular preventative antihistamines, using long-acting, non-sedating antihistamines. Doses may need to be escalated above those normally recommended in the BNF (30 mg bd for cetirizine). For nocturnal symptoms, sedating antihistamines including chlorphenamine and hydroxyzine may be considered. Cimetidine, which has unusual immunosuppressive properties, has been suggested as an additional treatment but benefit appears to be limited. It is unclear whether other H2-blockers have the same effect. Doxepin has potent antihistaminic activity but is very sedating. Mirtazipine is also very effective and has fewer side effects. As noted, long-term steroids should be avoided. For angioedema alone without urticaria, antihistamines may be effective, but better results may often be obtained with tranexamic acid (1 g qds). Monitoring of liver function is necessary and regular ultrasound scans of the liver (every three years) are recommended if treatment is long-term.