Food Allergy And Anaphylaxis: Diagnostic Issues
Whilst it has been estimated that within the most recent two decades there has been an increase of over 300% in food related anaphylaxis hospital admissions and a 200% increase in non-food related anaphylaxis hospital admissions, anaphylaxis is still proportionately under-diagnosed and under-treated in both the hospital and out of hospital settings. Contributing factors to this include the lack of consensus on a simple and transparent definition, the selection criteria/diagnosis, and the degree of exposure and severity classification of anaphylaxis across relevant international governing bodies on allergy and clinical immunology. The basis of most anaphylactic definitions revolves around a systemic reaction with a rapid and severe onset resulting in life threatening vital signs. An allergic reaction is a misdirected and often excessive response by the immune system to an often innocuous allergen, most common being food, insect venom or some medications.
There are two types of anaphylactic reactions, those that are immunologic and are medicated through the immunoglobulin E (IgE) antibodies; and those that are non-immunologic that do not require the presence of IgE for a reaction to occur. For an IgE-mediated reaction to occur, an allergen must first be synthesised by an antigen-presenting cell such as a macrophage, which presents the antigen fragment to the T-helper cells. These T-helper cells permit the B lymphocytes to convert into plasma cells which produce large amounts of IgE. These IgE then bind to receptors on mast cells and basophils and thus sensitising an individual to the antigen. Further exposure to the antigen provokes an extensive immune and inflammatory response resulting in mast cell degranulation which releases chemical mediators, enzymes and cytokines such as histamine, platelet-aggregation factor, bradykinin, leukotrienes, prostaglandins, tryptase, serotonin and nitric oxide. The generation of newly synthesised mediators occurs rapidly and the physiologic manifestations reflect the biological effects of these mediators. Histamine is the most potent mediator as it contracts bronchial smooth muscles, increases vascular permeability, causes vasodilation and increases gastric acid secretion.
Thus the individual may experience cutaneous symptoms (e. g. puritis, erythema, urticaria and angioedema), respiratory symptoms (e. g. dyspnoea, laryngeal obstruction, and bronchial constriction/spasm), and circulatory symptoms (e. g. systemic oedema, hypotension and arrhythmia which can potentially lead to decreased tissue perfusion and impaired cellular metabolism). Comparatively, non-immunologic reactions (a. k. a. Anaphylactoid reactions) follow a similar response except it does not require the presence of IgE to initiate the degranulation of mast cells. Thus, these reactions do not require an initial exposure to the allergen to provoke a hypersensitive reaction. In addition to this there are contributing risk factors which can influence the development of allergic reactions. These can be divided into subgroups of augmenting factors, co-morbidities and cofactors. Augmenting factors (a. k. a. aggravating/amplifying factors) are those which can lower the threshold of the antigen, increase the severity of symptoms experienced of reverse the acquired clinical tolerance of the antigen. Such factors include physical exercise, acute infections disease, non-steroidal anti-inflammatory medications, alcohol and mensuration. Certain co-morbidities such as asthma, mastocytosis and cardiovascular disease can increase the risk of anaphylactic mortality by decreasing the resting efficacy and reserve of different vital systems. Cofactors are those which do not act upon the immunological reaction directly but still have the potential to impact on the development of the allergic response. Such factors include puberty, psychological stressors and regular medications such as beta blockers and ACE inhibitors. The JRCALC recommends to consider anaphylaxis in a patient if there is a sudden onset and rapid progression of Airway and/or Breathing problems (e. g. dyspnoea, hoarseness, stridor, wheeze, throat or chest tightening) and/or Circulation problems (e. g. hypotension, syncope, pronounced tachycardia) and/or Skin problems (e. g. erythema, urticaria, mucosal changes).
This diagnosis criteria highlights that a single or combination of two or more symptoms may indicate a anaphylactic reaction has or is currently developing. In addition to this it can also be suggested to confirm a clinical probability through a thorough history of exposure and past allergic reactions. Despite the various definitions, causative and contributing factors to anaphylaxis, all international guidelines recommend the same first line treatment. Following the removal of the antigen if possible, adrenaline is recommended to reverse the physiological manifestation of the allergic reaction and stop the degranulation of the mast cells. Adrenaline is a sympathetic agonist, neurotransmitter and catecholamine which works on alpha and beta receptors within the body. When adrenaline acts upon the alpha-1 and alpha-2 adrenoreceptors, cardiovascular changes are evident: smooth muscles contract causing vasoconstriction and thus increasing systemic vascular resistance, blood pressure and cerebral and coronary perfusion. When the beta adrenoreceptors are activated there is a rise in intracellular cyclic adenosine monophosphate within the mast cells and basophils which inhibits the release of further inflammatory mediators.
Additionally, when the beta-1 adrenoreceptors are activated there is positive inotropic and chronotropic effects with an increase in heart rate and contractility resulting in an increase in cardiac output. Activation of the beta-2 adrenoreceptors result in pulmonary changes such an bronchodilation within the lungs. A rapid intramuscular (IM) injection into the anterolateral aspect of the thigh of Adrenaline 1: 1000 is the recommended dose and route of administration due to rapid bioavailability. The JRCALC recommends 500 micrograms for adults (12+years) and 150-300 micrograms for children (11 years and under). There has been some debate around the intravenous administration of Adrenaline 1: 10,000 reserved for those patients who are in cardiac arrest or experiencing severe hypotension which is resistant to intramuscular doses. The risks surrounding this route (despite drug dose difference 1: 10,000 IV vs 1: 1000 IM) is that if administered too quickly, inadequately diluted or in excessive doses the patient is at risk to extreme blood pressure rises, ischemia, intracerebral bleeding, cardiac arrhythmia or infarction. For these reasons a recommended 100 micrograms titrated slow bolus infusion is not recommended for a time critical life threatening anaphylactic event. Secondary to IM Adrenaline 1: 1000, antihistamine can be administered as an adjunct therapy to mitigate the clinical impact of histamine release. Such medication is more beneficial for the cutaneous symptoms of anaphylaxis as there is little to no effect on the circulatory, respiratory and gastrointestinal symptoms. Ideal antihistamines should be a combination of H1 and H2 antagonist. Whilst Chlorphenamine is only an H1 antagonist it is the JRCALC recommended antihistamine to administer following Adrenaline 1: 1000 IM. The recommended adult (12+ years) dose is 10 milligrams IV/IM and child (1-11 years) dose of 2. 5-10 milligrams. Following this a corticosteroid is recommended to reduce the risk of possible biphasic reactions due to the slow onset of action. Biphasic reactions are the reoccurrence of anaphylactic reactions within 1-72 hours after complete improvement and is prevalent in up to 20% of anaphylactic patient’s. Such reactions can vary in severity in comparison from the initial anaphylactic reaction and therefore warrant close observation and monitoring I hospital. The JRCALC recommended corticosteroid for use in conjunction with IM Adrenaline 1: 1000 is Hydrocortisone.
This medication restores blood pressure, blood sugar, cardiac synchronicity and volume, and the suppression on inflammation and immune response. The JRCALC recommended dose for an anaphylactic reaction is 200 milligrams for an adult (12+ years) IV/IM and 10-100 milligrams for children (11 years and under). In addition to this treatment pathway, nebuliser bronchodilators (e. g. salbutamol) with high flow supplemental oxygen can further activate beta-2 adrenoreceptors to relieve bronchial spasms and subsequent wheezing; and crystalloid solutions (e. g. sodium chloride) should also be considered for fluid resuscitation due to the experiences hypotension and relative hypovolemia. In some cases, adrenaline can be ineffective in relieving anaphylactic symptoms, especially if there are other contributing factors. For example, the regular use of beta blockers can prevent the endogenous adrenergic response to an allergic reaction, therefore increasing the severity of the reaction of causing catecholamine resistance to treatment. In such instances other vasopressors and treatments can be considered such as Glucagon. In an anaphylactic event this medication is a polypeptide hormone that exerts positive inotropic and chronotropic effects on the heart by bypassing the beta adrenergic system to increase myocardial contractility and heart rate. Glucagon has also shown to decrease cardiac histamine and other free radical release and stabilise the mast cells through the increase in nitric oxide. Whilst nitric oxide is an immunologic mediator released from the degranulation of mast cells, in low doses it has protective properties against myocardial injury. The definitive use of glucagon in anaphylaxis is unclear in recent literature and highlights the potential benefit for future research studies.
