2. Anaphylaxis: diagnosis and management

Cofactors are sometimes required before an allergen will provoke a reaction. Factors associated with increased risk of anaphylaxis include intercurrent infection, concomitant medication/foods (particularly α-blockers, β-blockers, angiotensin-converting enzyme [ACE] inhibitors, non-steroidal anti-inflammatory drugs [NSAIDS], alcohol or spicy food), high ambient temperatures and exercise. So-called “summation anaphylaxis” may explain intermittent anaphylaxis despite frequent allergen exposure, and may account for some cases in which a cause has not been established.15 One of the most common cofactors, predominantly affecting young adults, is physical exercise. Some experience symptoms with exercise alone; others do so only if allergenic foods (most commonly wheat, celery, seafood, nuts, fruit or vegetables) are ingested within a few hours prior to exercise.

Mast cell activation results in the release of many mediators that include histamine, leukotrienes, tumour necrosis factor and various cytokines. The large numbers of mediators provide redundancy and positive feedback mechanisms whereby other effector cells are recruited to release more mediators, perpetuating the allergic response. This amplification and perpetuation, which has been referred to as a “mast cell leukocyte cytokine cascade”,16 underscores the importance of physiological antagonism with adrenaline and fluid resuscitation, rather than antagonism of a single mediator such as histamine.

Anaphylactic mediators cause vasodilation, fluid extravasation, smooth muscle contraction and increased mucosal secretions. Death may occur from hypoxaemia (due to upper airway angioedema, bronchospasm and mucus plugging) and/or shock (due to massive vasodilation, fluid shift into the extravascular space and depressed myocardial function).17 While compensatory tachycardia in response to hypotension is considered a characteristic feature, sudden bradycardia with cardiovascular collapse and cardiac arrest may occur before any skin features become apparent.18 The cause of this phenomenon is unclear, but it is an important clinical feature to recognise in order to avoid making an initial misdiagnosis of a “panic attack” or “vasovagal reaction” in cases where dyspnoea, nausea, anxiety, and bradycardia may occur just before cardiovascular collapse.

The clinical features of anaphylaxis are summarised in Box 3. Skin features are almost universal if reactions are closely observed, but erythema (and even angioedema) may be subtle and missed if not carefully looked for (Box 4). Respiratory symptoms are more common in children, whereas cardiovascular and cutaneous symptoms dominate in adults.13 In part, this may be related to the higher frequency of atopy, asthma and food allergy in children.13 Pre-existing lung disease is associated with an increased frequency of respiratory compromise from any cause,6,9 and poorly controlled asthma appears to be the main risk factor for childhood death due to food allergy.19

Confusion, collapse, unconsciousness and incontinence are strongly associated with the presence of hypotension and hypoxia. In adults, the occurrence of dyspnoea, profuse sweating, nausea, vomiting and abdominal pain are also significant, as they correlate with the presence of hypotension.9

Lack of a universally accepted definition and severity grading system for anaphylaxis, and lack of a reliable biomarker to confirm the diagnosis, has not only hampered research but has also resulted in failure to diagnose and treat anaphylaxis in a consistent and timely manner. A simple definition has been applied by the Australasian Society of Clinical Immunology and Allergy (ASCIA):

This definition will exclude some atypical yet still life-threatening reactions, and more recently, an international consensus working definition has been proposed to address these issues.1 However, no definition has yet been subject to prospective validation. Thus it may be important at times to initiate treatment for a suspected case of anaphylaxis with cardiovascular or respiratory compromise, even if consensus diagnostic criteria have not been met.

The many possible causes of hypotension should be considered in patients suffering shock. Rashes and angioedema should not be assumed to be the result of anaphylaxis. A range of conditions may be confused with some of the individual features of anaphylaxis (Box 5).

Acute management of anaphylaxis (Box 6, Box 7) includes the following:

• Place the patient in the supine position (or left lateral position for vomiting patients);

• Give intramuscular adrenaline;

• Resuscitate with intravenous saline (20 mL/kg body weight, repeated up to a total of 50 mL/kg over the first half hour);

• Support the airway and ventilation; and

• Give supplementary oxygen.17

  Intramuscular 1 : 1000 (1 mg/mL) adrenaline at a dose of 0.01 mg/kg (0.01 mL/kg) body weight up to a maximum dose of 0.5 mg (0.5 mL) injected into the lateral thigh (vastus lateralis) has the advantage that it can be given without delay, is absorbed more reliably than injections into other locations or subcutaneously,21,22 is anecdotally effective in most cases when given early, and avoids the potentially lethal effects of large intravenous bolus injections.14 The appropriate dose of EpiPen (CSL Limited, Melbourne, VIC) (Box 8) can be used instead, if available. The intramuscular dose can be repeated after 3–5 minutes if required.

If resuscitation using intramuscular adrenaline and volume expansion with intravenous saline is ineffective, an infusion of intravenous adrenaline may be required, but this should be done only by experienced hands. Intravenous boluses of adrenaline are potentially dangerous and should not be used unless cardiac arrest is imminent. Controlled intravenous infusions of adrenaline were shown to be safe and effective in one prospective Australian study.18 An infusion protocol derived from this study has been published elsewhere.17

If the patient is still unresponsive after the treatments outlined above, there are several further options:

• Persistent bronchospasm may respond to treatment with additional bronchodilators. If intubation is required, continuous puffs of salbutamol through an aerosol port directly into the ventilation circuit may help to “break” severe bronchospasm.

• Persistent stridor may respond to continuous nebulised adrenaline (5 mg in 5 mL [ie, five 1 mg ampoules]) in addition to parenteral adrenaline. Surgical airway intervention (cricothyrotomy) may be required.

• Persistent hypotension may be due to either profound vasodilation or cardiac failure. Anecdotally, vasodilation may respond to vasopressors such as metaraminol or vasopressin.26-28 In patients who have pre-existing heart failure or are taking β-blockers, a phosphodiesterase inhibitor such as glucagon may be tried.29,30

Medications such as antihistamines, H2 receptor antagonists, corticosteroids and antileukotrienes have no proven impact on the immediate and dangerous effects of anaphylaxis, although they may ameliorate mild allergic reactions confined to the skin. The only registered antihistamine for parenteral use in Australia, promethazine, can worsen vasodilation and hypotension, and its use is not advised.17,31 Until human research clarifies the potential risks and benefits of antihistamines, it is prudent to restrict antihistamine use to oral, selective, non-drowsiness-inducing antihistamines, with or without oral or injectable corticosteroids, for the symptomatic relief of mild skin symptoms. Based on their use in treating asthma, corticosteroids are commonly given to reduce the risk of biphasic anaphylaxis (see below), although there is currently no evidence to support their effectiveness for this purpose.

Anaphylaxis remains a largely clinical diagnosis. Serum mast cell tryptase concentration can be determined, but this is an insensitive biomarker for anaphylaxis, although serial measurements (eg, on arrival, 1 hour later and before discharge) may improve sensitivity and specificity.32 An elevated tryptase level may be a useful clue when the diagnosis is uncertain, but a normal result does not exclude anaphylaxis.

The time course of anaphylaxis can be classified as “uniphasic”, “protracted” or “biphasic”.33 Although most reactions respond rapidly to treatment and do not recur (uniphasic reactions), an observation period is recommended. This is because, in some patients, symptoms may fail to improve or may worsen as the effect of adrenaline wears off (protracted anaphylaxis) or may return after early resolution (biphasic reaction). No clinical feature consistently identifies patients at risk of a biphasic reaction. Expert consensus is that a reasonable length of observation after symptom resolution is 4–6 hours in most patients, with more prolonged observation in those with severe or refractory symptoms and those with reactive airway disease, as most fatalities associated with anaphylaxis occur in these patients.1

Poorly controlled asthma is the main risk factor for death in children. Age over 35 years and previous severe reactions are the main risk factors for hypotension and death in adults.

In-vitro testing for allergen-specific IgE (using a radioallergosorbent test [RAST] or ImmunoCAP [Phadia AB, Uppsala, Sweden]) is a useful initial screening test for a variety of allergens. In-vitro testing has limitations because the test lacks sensitivity and is limited by the range of allergens available and the ability to claim Medicare rebates for only four allergens at a time.

Skin prick testing, to assess sensitisation to food, and skin prick testing (or sometimes intradermal testing), to assess allergy to medications or insect venom, are more sensitive than in-vitro testing. As these carry a small risk of inducing anaphylaxis, they should only be carried out in an environment in which resources for treating anaphylaxis are available. Measurement of total IgE and in-vitro testing using food mixes frequently provide misleading or irrelevant results and should not be requested.

There is currently no test to confirm tick bite allergy. Skin testing for jack jumper ant allergy is not yet available outside the Royal Hobart Hospital in Tasmania, although an in-vitro test is available from SouthPath Laboratories in South Australia (this detects only 80% of cases, and, while the subject of ongoing research, there is no validated test to detect allergy to related ant species).

Some drug reactions (eg, to NSAIDS, radiographic contrast agents) are independent of IgE, and there are numerous difficulties in assessing some cases of antibiotic allergy. To establish a diagnosis in cases in which the causative agent is in doubt, challenge testing under controlled conditions may sometimes be required, although a negative challenge test does not always exclude the diagnosis.

There is no scientific validity for “alternative” therapies such as cytotoxic or Vega testing, hair analysis and kinesiology, and their use should be discouraged.34

Specialist evaluation is recommended after a diagnosis of possible anaphylaxis — to identify or confirm the cause, to educate regarding appropriate avoidance strategies, to help in drafting an emergency action plan and to advise whether immunotherapy is appropriate. There is anecdotal evidence that certain medications used to manage blood pressure and heart problems (α-blockers, β-blockers and ACE inhibitors) may worsen anaphylaxis or interfere with the action of adrenaline administered in an emergency. However, this poorly defined risk needs to be balanced against the proven benefits that these medications provide. For patients taking cardiac medications, the relative risks and benefits of their use should be considered in consultation with an allergist and/or other specialists.

Despite the frightening nature of anaphylactic episodes, compliance with advice to avoid known triggers and to carry and use injectable adrenaline is nowhere near 100%.2 Denial and “acting out” by teenagers is also common, and peer pressure or bullying at school may prompt some patients to take unnecessary risks. Review from time to time or after further episodes offers an opportunity to re-educate patients on the use of EpiPen and to ensure that the device is renewed at appropriate intervals. Psychological morbidity and negative impact on quality of life are not uncommon in patients and their caregivers, and some require emotional support and counselling as well as medical advice.