Anaphylaxis

Anaphylaxis is a potentially lethal systemic allergic response with a variable etiologies and clinical manifestations. Although immediate diagnosis and treatment of anaphylaxis is critical, both patients and healthcare professionals frequently fail to recognize and diagnose the early clinical manifestations.

Although generally, the prevalence of anaphylaxis is estimated to be up to 2% and still increasing, the fatality rate is extremely low (i.e., < 0.0001% in the general population, or < 0.5% in those hospitalized or presenting to the emergency department) and appears to be decreasing. The incidence in children worldwide varied widely, ranging from 1 to 761 per 100 000 person-years for total anaphylaxis.

Even if the diagnosis is questionable, the immediate intramuscular infusion of epinephrine into the anterolateral thigh is first-line treatment. Long-term treatment consists of specialized assessment, avoidance measures, and the supply of an epinephrine auto-injector and an individualized anaphylaxis action plan.

Anaphylaxis definition

Anaphylaxis is defined as a severe allergic reaction that has a rapid onset and can be fatal.  It usually causes an itchy rash, tongue and upper airways swelling, shortness of breath, gastrointestinal manifestations (e.g. vomiting), light-headedness, and hypotension. These symptoms usually appear over a period of minutes to hours.

Classifications of Anaphylaxis

There are three main classifications of anaphylaxis:

• Anaphylactic shock: accompanied with systemic vasodilation, which results in low blood pressure that is 30% lower than the person's baseline or below normal norms. 
• Biphasic anaphylaxis: the return of symptoms within 1–72 hours following the end of an initial anaphylactic episode is referred to as biphasic anaphylaxis. The recurrence usually happens within 8 hours. It is treated in the same way as anaphylaxis is.
• Anaphylactoid response: also known as non-immune anaphylaxis or pseudoanaphylaxis, is a kind of anaphylaxis caused by direct mast cell degranulation rather than an allergic reaction.

Epidemiology of Anaphylaxis

Anaphylaxis affects 4–100 individuals per 100,000 people per year, with a lifetime risk of 0.05–2 %. Approximately 30% of persons experience several attacks. One in every 2000 young individuals suffers from exercise-induced anaphylaxis.

Rates appear to be rising: in the 1980s, the figure was around 20 per 100,000 per year, but by the 1990s, it had risen to 50 per 100,000 per year. The rise appears to be driven mostly by food-induced anaphylaxis. Young individuals and women are most at danger.

The incidence especially in children worldwide varied widely, ranging from 1 to 761 per 100 000 person-years for total anaphylaxis and 1 to 77 per 100 000 person-years for food-induced anaphylaxis

Anaphylaxis causes 500–1,000 fatalities per year (2.7 per million) in the United States, 20 deaths per year (0.33 per million) in the United Kingdom, and 15 deaths per year in Australia (0.64 per million).

Anaphylaxis pathophysiology

Anaphylaxis is typically an IgE-mediated (type 1 hypersensitivity reaction) characterized by various release of chemical mediators from basophil and mast cell degranulation in response to re-exposure to a particular antigen. IgE crosslinking with high-affinity receptors cause the rapid release of chemical mediators that had been stored in both basophil and mast cells.

Histamine, tryptase, carboxypeptidase A, and proteoglycans are examples of chemical mediators. They subsequently create arachidonic acid metabolites such as leukotrienes, prostaglandins, and platelet-activating factors by activating phospholipase A, cyclooxygenases, and lipoxygenases. TNF-alpha (tumor necrosis factor) then mediates the inflammatory response, both as a preformed and late-phase reactant. The following is a comprehensive physiology of these chemical mediators:

• Histamine: increases vascular permeability and vasodilation causing diminished blood supply to vital organs. As a result, the body responds to these changes by increasing heart rate and cardiac output.
• Prostaglandin D: acts as a bronchoconstrictor, constricting both the cardiac and pulmonary arteries at the same time. It also increases peripheral vasodilation, which contributes to important organ hypoperfusion.
• Leukotrienes: acts as a bronchoconstrictor as prostaglandins D and induce vascular permeability, and airway remodeling.
• The platelet activation factor: a strong bronchoconstrictor that also increases vascular permeability.
• TNF-alpha: stimulates neutrophils and boosts chemokine production.

Causes of Anaphylaxis

Most anaphylactic reactions are caused by an immunologic process involving immunoglobulin E, which causes mast cell and basophil degranulation and the subsequent release of chemical mediators such as histamine, platelet activating factor, leukotrienes, tryptase, and prostaglandins.

Although any item has the potential to induce anaphylaxis, drugs, and stinging insects are the most prevalent causes of IgE-mediated anaphylaxis. Anaphylaxis can also be caused by exercise, and radiocontrast agents, however anaphylactic reactions to these agents are frequently caused by non-IgE-mediated pathways. The reason of anaphylactic responses in other situations is uncertain (idiopathic anaphylaxis). Anaphylaxis is most commonly triggered by the following common etiologies.

• Foods: most commonly peanuts, tree nuts, egg, fish, shellfish, cow’s milk, and wheat.
• Medications: most commonly antibiotics, aspirin, opioids, NSAID and topical medications (e.g., chlorhexidine, polysporin)
• Allergen immunotherapy.
• Insect stings (bees and wasps).
• Idiopathic anaphylaxis.
• Transfusions.

Co-morbidities and drugs can also have an impact on the severity of anaphylactic responses and the patient's responsiveness to therapy. Patients with asthma and cardiovascular disease, for example, are more likely to have a bad result from anaphylaxis.

Concurrent beta-blocker therapy can impair the patient's capacity to respond to epinephrine, the first-line treatment for anaphylaxis. Furthermore, although data is inconsistent, the use of angiotensin-converting enzyme (ACE) inhibitors may alter a patient's compensatory physiologic response to anaphylaxis, resulting to more severe responses.

Anaphylaxis Signs and Symptoms

As anaphylaxis is a generalized systemic reaction, a wide variety of clinical signs and symptoms involving the skin, gastrointestinal and respiratory tracts, and cardiovascular system can be observed. The most common clinical manifestations are cutaneous symptoms, including urticaria and angioedema, erythema, and itching. Patients also often describe an impending sense of death.

Death due to anaphylaxis usually occurs as a result of respiratory obstruction or cardiovascular collapse, or both. It is important to note that the signs and symptoms of anaphylaxis are unpredictable and may vary from patient to patient and from one reaction to another. The common clinical presentation of anaphylaxis is summarized as follows:

Dermatological manifestations:

• Urticaria
• Angioedema
• Erythema (flushing)
• Pruritus
• Eczema

Respiratory manifestations:

• Nasal congestion
• Sneezing
• Hoarseness
• Cough
• Laryngeal edema
• Dyspnea
• Cough
• Bronchospasm
• Wheezing
• Chest tightness

Cardiovascular manifestations:

• Hypotension
• Dizziness
• Syncope
• Tachycardia

Gastrointestinal manifestations:

• Nausea
• Vomiting
• Abdominal pain
• Diarrhea

Neurologic symptoms:

• Lightheadedness
• Dizziness
• Confusion
• Pruritus, tingling
• Angioedema

Anaphylaxis symptoms usually appear within minutes of being exposed to the offending antigen, although they might appear as late as 1 hour later. Symptoms normally have a uniphasic course, with symptoms disappearing within hours following therapy. However, between 0.4 and 15% of responses had a biphasic course, with an asymptomatic interval of many hours (1–36 h; mean of 10 h in one case series) followed by repeated symptoms.

Anaphylaxis diagnosis

The clinical history is the most significant tool for determining the etiology of anaphylaxis and should always take precedence over diagnostic procedures. It can provide information about clinical manifestations for example, urticaria, angioedema, flushing, pruritus, airway obstruction, gastrointestinal symptoms, syncope, and hypotension, agents encountered immediately before the onset of the reaction (for example, foods, medications, or insect bites/stings), and the patient's activities preceding the event (e.g., exercise).

The lack of cutaneous symptoms calls the diagnosis into doubt, because cutaneous symptoms are present in the majority of anaphylactic episodes; nevertheless, their absence does not rule out anaphylaxis.

The findings of skin testing may help to confirm the diagnosis of a specific cause of anaphylaxis. Specific IgE antibodies to foods, drugs (e.g., penicillin), and stinging insects can be detected using this test.

The presence of higher amounts of mast cell and basophil mediators such as plasma histamine or serum or plasma total tryptase can occasionally support the clinical diagnosis of anaphylaxis. However, because increases are temporary, it is crucial to acquire blood samples for these assays as soon as possible following the beginning of symptoms.

Clinical criteria for diagnosing anaphylaxis

Anaphylaxis is extremely likely if any of the following three conditions are met after being exposed to an allergen:

1- Acute onset of the disease involving the skin, mucosal tissue, or both (e.g., widespread hives, itching or flushing, swollen lips-tongue-uvula) with at least one of the following symptoms:

• Respiratory compromise (e.g. shortness of breath, wheezy chest, bronchospasm, stridor, hypoxemia)
• Hypotension or associated symptoms of end-organ dysfunction (e.g. collapse, syncope, incontinence)

2-Two or more of the following that occur rapidly after exposure to a likely allergen for that patient:

• Involvement of the skin or mucosal tissue (e.g., generalized hives, itching, flush, swollen lips and tongue.).
• Respiratory manifestations (e.g. dyspnea, wheezy chest, bronchoconstriction, stridor, hypoxemia).
• Hypotension or associated symptoms (e.g. syncope, incontinence).
• Persistent gastrointestinal manifestations (e.g., painful abdominal cramps, nausea, vomiting).

3-Hypotension after exposure to a known allergen for that patient:

• Infants and children: low systolic blood pressure (age specific) or > 30% decrease in systolic blood pressure.
• Adults: systolic blood pressure < 90 mmHg or > 30% decrease from that person’s baseline.

Anaphylaxis treatment

Acute management:

Anaphylaxis is treated acutely by doing a fast examination of circulation and respiration, followed by the immediate injection of epinephrine. The medication of choice for anaphylaxis is epinephrine, which should be administered quickly to any patient with suspected anaphylaxis. Because there is no contraindication to the use of epinephrine, treatment should be offered even if the diagnosis is unknown.

For anaphylaxis, the recommended dose of epinephrine is 0.01 mg/kg (maximum 0.5 mg) delivered intramuscularly every 5–15 minutes as needed. When compared to subcutaneous or intramuscular treatment in the upper arm, intramuscular delivery into the anterolateral thigh allowed for faster absorption and greater plasma epinephrine levels. In individuals using beta-blockers, glucagon should also be evaluated.

All patients who receive emergency epinephrine must be immediately taken to a hospital (preferably by ambulance) for examination and observation. Unless the respiratory deficit precludes it, patients should be put in a recumbent (supine) position to avoid or counteract impending circulatory collapse. Patients who are pregnant should be positioned on their left side. Patients should not be permitted to sit up until they are obviously totally stabilized, due to the risk of 'empty ventricle syndrome,' which can result in a significant drop in blood pressure and mortality.

Asthmatic individuals, particularly those with poorly managed asthma, are at a higher risk of a deadly response. Anaphylaxis may be misdiagnosed as an asthma exacerbation in some people, and they may be treated merely with asthma inhalers. As a result, if an individual with known anaphylaxis has continuing asthma symptoms, epinephrine should be administered.

Supportive treatment, such as inhaled beta2-agonists and antihistamines (for cutaneous symptoms), can be beneficial, but should never be used in place of epinephrine as first-line therapy. Oxygen treatment should also be explored in any patient with anaphylactic symptoms, especially those who have protracted responses.

Because significant fluid changes can occur fast in anaphylaxis due to enhanced vascular permeability, intravenous crystalloid solutions should also be administered. Volume replenishment is especially critical in individuals who continue to suffer hypotension despite epinephrine injections. If epinephrine injections and volume expansion with intravenous fluids fail to relieve hypotension, vasopressors such as dopamine may be explored.

Because corticosteroids have a slow beginning of action, they have not been proved to be beneficial for the immediate treatment of anaphylaxis. However, in theory, they may prevent biphasic or delayed responses and, as a result, are frequently provided on an empirical basis. 

If intramuscular epinephrine and IV fluids fail to relieve anaphylaxis, an intravenous administration of epinephrine may be required; however, these infusions should be administered by a physician who is trained and well experienced in its use and has the capacity for continuous blood pressure and cardiac monitoring.

Long term management:

Specialist assessment, a prescription for an epinephrine auto-injector, patient and caregiver education on avoidance measures, and the creation of a personalized anaphylaxis action plan are the cornerstones of long-term therapy for patients who have suffered anaphylaxis.

Specialist assessment:

Following acute anaphylaxis, individuals should be evaluated for their future risk of anaphylaxis, preferably by an allergist. These experts are skilled in determining and confirming the source of anaphylaxis, educating patients on suitable avoidance measures, developing an anaphylactic action plan, and advising on whether immunotherapy is necessary.

Prescription for an epinephrine auto-injector:

All patients who have previously suffered anaphylaxis, as well as those who have had any rapid-onset systemic allergic response, should be prescribed an epinephrine auto-injector.

When an epinephrine auto-injector is prescribed, healthcare practitioners must advise the patient on how and when to use the device. Instructions for correct usage should be reviewed verbally and supplemented by online links and/or written information, and should be reiterated on a yearly basis.

The needle lengths of the currently available epinephrine auto-injectors are around 13 and 15 mm for the 0.15 and 0.30 mg dosages, respectively. Recent research suggests that at these needle lengths, children weighing less than 15 kg are more likely to be injected into the bone, while adult females are more likely to be injected subcutaneously. As a result, extra counselling on proper epinephrine delivery may be required in these individuals.

Avoidance/recognition of co-factors for increased anaphylaxis risk:

Patients should be educated on various co-factors that might cause anaphylactic reactions to become progressively severe. Exercise can raise the likelihood and/or severity of allergy responses considerably. Other relevant cofactors include the usage of aspirin/NSAIDs, alcohol, menstruation, and concurrent viral infections.

Differential diagnosis of Anaphylaxis

It can sometimes be difficult to distinguish anaphylaxis from asthma, syncope, and panic attacks. Asthma however typically does not entail itching or gastrointestinal symptoms, syncope presents with pallor rather than a rash, and a panic attack may have flushing but does not have hives.

Prevention of Anaphylaxis

It is best to avoid the cause of anaphylaxis. Desensitization may be an alternative in circumstances when this is not possible. Immunotherapy using Hymenoptera venoms successfully treats allergies to bees, wasps, hornets, and fire ants in 80–90% of adults and 98 % of children.

Although oral immunotherapy may be beneficial in desensitizing some persons to particular foods such as milk, eggs, almonds, and peanuts, side effects are prevalent. During immunotherapy, for example, many patients have an itchy throat, cough, or lip swelling. Many drugs can be desensitized, although it is recommended that most patients simply avoid the substance in issue. It is crucial for persons who react to latex to avoid cross-reactive foods such as avocados, bananas, and potatoes, among others.

Prognosis of Anaphylaxis

The prognosis is favorable for individuals whose etiology is identified and immediate therapy is available. Even if the etiology is unclear, the prognosis is typically favorable if proper preventative treatment is available.

Anaphylaxis may result in respiratory failure, shock, multiorgan system failure, and disseminated intravascular coagulation. Between 5% and 20% of children may experience a recurrence of anaphylaxis 8-12 hours after the initial presentation. Prolonged symptoms can last up to 32 hours despite treatment.

If death occurs, it is usually due to either respiratory (often asphyxia) or cardiovascular (shock) reasons. There have been instances where death occurred within minutes. The majority of persons with exercise-induced anaphylaxis have positive outcomes, with fewer and less severe episodes as they become older.

Conclusion

Anaphylaxis is a potentially lethal acute systemic response with a variety of causes and clinical manifestations. Anaphylaxis must be recognized and treated as soon as possible; yet, both patients and healthcare professionals frequently fail to detect and diagnose anaphylaxis in its early stages.

Diagnostic criteria that take into consideration the many clinical presentations of anaphylaxis are now available and can help healthcare practitioners identify the illness early. First-line treatment for anaphylaxis is intramuscular epinephrine injection into the anterolateral thigh. Acute care may also include oxygen treatment, intravenous fluids, and supplementary medicines such antihistamines or inhaled beta2-agonists.

Specialist assessment, a prescription for an epinephrine auto-injector, patient and caregiver education on avoidance measures, and the provision of a personalized anaphylaxis action plan are the pillars of long-term therapy.