Continuing Education Activity

Type I hypersensitivity is also known as an immediate reaction and involves immunoglobulin E (IgE) mediated release of antibodies against the soluble antigen. This activity reviews the evaluation and management of type I hypersensitivity and reviews the role of the interprofessional teams in managing patients with this condition.

Objectives:

• Identify the etiology of type I hypersensitivity medical conditions and emergencies.
• Summarize the evaluation of type I hypersensitivity.
• Outline the management options available for type I hypersensitivity.

Introduction

The immune system plays a crucial role in maintaining health and protecting the human body against microbial invasions. However, this same system can lead to exaggerated immune and inflammatory responses that result in adverse outcomes known as hypersensitivity reactions. There are four traditional classifications for hypersensitivity reactions, and these include Type I, Type II, Type III, and Type IV reactions:[1]

• Type I hypersensitivity is also known as an immediate reaction and involves immunoglobulin E (IgE) mediated release of antibodies against the soluble antigen. This results in mast cell degranulation and release of histamine and other inflammatory mediators.
• Type II hypersensitivity is also known as cytotoxic reactions and engages IgG and IgM antibodies, leading to the complement system activation and cell damage or lysis.
• Type III hypersensitivity is also known as immune complex reactions and involves IgG, IgM, and sometimes IgA antibodies. The build-up of these immune complexes results in complement system activation, which leads to polymorphonuclear leukocytes (PMNs) chemotaxis and eventually causing tissue damage.
• Type IV hypersensitivity is also known as delayed-type and involves of T-cell-mediated reactions. T-cells or macrophages are activated as a result of cytokine release, leading to tissue damage.

There has been a more recent classification introduced by Sell et al. that accounts for multiple components of the immune system and categorizes the reactions into seven parts. However, the focus of this article will be on the classic Type I hypersensitivity reactions.

Type I hypersensitivities include atopic diseases, which are an exaggerated IgE mediated immune responses (i.e., allergic: asthma, rhinitis, conjunctivitis, and dermatitis), and allergic diseases, which are immune responses to foreign allergens (i.e., anaphylaxis, urticaria, angioedema, food, and drug allergies). The allergens that result in a type I hypersensitivity may be harmless (i.e., pollen, mites, or foods, drugs, etc.) or more hazardous such as insect venoms.[2] The reaction may be manifested in different areas of the body and may result in instances such as:

• Nasal allergic rhinitis or hay fever 
• Ocular allergic conjunctivitis, potentially due to seasonal allergens such as pollen or mold spores 
• Dermatological hives, atopic eczema, or erythema
• Soft tissue angioedema
• Pulmonary reactions, such as allergic asthma or hypoxia
• Systemic reaction, which is a life-threatening medical emergency, and also known as anaphylaxis.

There are certain risk factors that increase the risk of allergic diseases. These factors include geographical distribution, environmental risks such as pollution or socioeconomic status, genetic predisposition, or the “hygiene hypothesis”. The “hygiene hypothesis” suggests that our modern society practices of good hygiene and the lack of early exposure to many microbes or antigens may result in failures of the immune system functionality. As such, the hypothesis suggests that early exposure to a diverse range of microorganisms and antigens may actually lead to overall decreased rates of allergies, asthma, and other immune disorders.[3][4][5]

Etiology

Type I hypersensitivity occurs as a result of exposure to an antigen. The response to the antigen occurs in two stages: the sensitization and the effect stage. In the sensitization stage, the host experiences an asymptomatic contact with the antigen. Subsequently, in the "effect" period, the pre-sensitized host is re-introduced to the antigen, which then leads to a type I anaphylactic or atopic immune response. There are various types of antigens that the host can be exposed to, and examples include food allergies (i.e., nuts, eggs, soy, wheat, shellfish, etc.), animal source (i.e., bee, wasp, cats, insects, rats, etc.), environmental factors (i.e., dust mites, latex, pollen, mold, etc.), atopic diseases (i.e., allergic asthma, allergic rhinitis, conjunctivitis, dermatitis, etc.), transfusion reactions, medication-induced reactions (i.e., antibiotics), and systemic reaction to an allergen (i.e., hives) or anaphylaxis.[2][6]

Epidemiology

The incidence of type I hypersensitivity is hard to predict as discrepancies occur in the assessment of the type of reaction. For instance, some document patients as having anaphylaxis reaction status-post milder symptoms, and others report anaphylaxis with a full-blown presentation. A study predicted that the frequency of an individual experiencing anaphylaxis is 1% to 2% worldwide, with the incidence increasing in the younger population.[7]

European research estimates that 0.3% (95% CI 0.1–0.5) of the population will undergo episodes of anaphylaxis in their lifetime.[8] While it is predicted that about 1.21% to 15.04% of the United States (US) population will experience anaphylaxis. In general, the prevalence of atopic disorders, such as food allergies, allergic rhinitis, conjunctivitis, dermatitis, asthma) has been on the rise and occurs in about 20-30% of the population.[9][10]

Pathophysiology

Allergens (or antigens) are presented to T-cells by Antigen-presenting cells (APCs) during the sensitization phase of Type I hypersensitivity. T-cells then signal for stimulation of B-cells to produce IgE antibodies, which bind to the Fc receptors on mast cells and basophils. Subsequently, the free antigen induces the crosslinking of these mast cell and basophil bound IgE antibodies. This results in the degranulation of the cells and the release of histamine, proteolytic enzymes, and other mediators (i.e., prostaglandin, cytokines, leukotrienes, platelet-activating factors, macrophage inflammatory proteins, tryptase, etc.).

As a result, there is increased vascular permeability, peripheral vasodilation, and smooth muscle contraction, which can manifest to increased mucous secretions, bronchospasm, abdominal cramping, rhinitis, and potentially hypovolemia or hypoxia. Pulmonary edema or general edema can also occur due to fluid shifting into interstitial space. Individuals can experience pruritis and local response of asthma or a systemic response of anaphylaxis.[11]

Histopathology

The histological appearance of type I hypersensitivity can be differentiated from other hypersensitivity reactions based on the type of cell responses. In hay fever and allergic asthma, neutrophils, eosinophils, and potentially basophils are found in the mucosal and submucosal tissues of the respiratory tract and bronchial wall, respectively.[12]

History and Physical

The initial step for appropriately diagnosing Type I hypersensitivity is to obtain a full history from either the patient or the patient's companions. Information about the patient's history should include:

• Signs and symptoms 
• Timing: onset of signs and symptoms 
• If the patient ingested anything or any new changes or triggers that caused the reaction 
• Any previous exposure to the allergen
• Prior history of allergic reactions 
• History of atopy (allergic rhinitis, asthma, eczema) or food allergies
• If the patient is febrile, as fever is not seen in Type I reactions
• Review of medical records and allergies, especially in patients who are unable to communicate 

Medical history alone is not sufficient to diagnose an allergic response. A complete physical examination should also be performed. The presentation depends on the organs that are involved. In general, a patient that presents with a type I hypersensitivity usually develops a reaction within one hour after exposure to an antigen. The signs and symptoms exhibited in this type of reaction involve vasoactive mediators that are released by IgE bound mast cells and basophils.

The most common chief complaint and physical symptoms may include rash, hives, erythema, pruritis, edema, flushing, bronchospasm, wheezing, rhinitis, and gastrointestinal symptoms such as abdominal cramping. The presence of "wheal-and-flare" (skin bump and redness) reactions are the hallmark of IgE mediated reactions. Patients that present with anaphylaxis may also experience episodes of loss of consciousness, nausea, vomiting, angioedema, hypotension, tachycardia, tachypnea, etc. When assessing for anaphylaxis, the first steps are to evaluate the airway, breathing, circulation, and mentation.[13]

Evaluation

There are both in-vivo and in-vitro objective testing that can help with the diagnosis of Type I hypersensitivity.[14][15][16]

In-Vitro Testing

Upon presentation, the following in-vitro laboratory markers can be ordered and used to help diagnose anaphylaxis:

• Serum tryptase, which is released by mast cells in an hour post-activation, elevated levels can indicate an increased risk of anaphylaxis.
• Eosinophil count can be increased in atopic disorders.
• Total IgE may also be elevated in atopic disorders; however, it should not be used as a definitive test for diagnosis, as normal levels may also be seen with other types of hypersensitivities.
• Allergen-specific IgE assays are preferable to in-vivo skin testing, as they can help identify food allergens or other antigens that are causing a reaction.
• Histamine levels may be collected; however, the assays are not reliable, and the levels are short-lived.
• Flow cytometric basophil activation test (BAT) can help diagnose immediate hypersensitivity to certain medications (I.e., beta-lactams, muscle relaxants, etc.). The BAT can identify markers present on the surfaces of drug-allergen activated basophils.[14]

In-Vivo Testing

In-vivo measurement can be useful to identify food allergies, venom allergy, allergic rhinitis, allergic asthma, penicillin, and other drug allergies. It involves performing a skin test in an outpatient setting that introduces small amounts of the allergen into the skin to observe for an allergic response. A positive skin reaction is represented by a wheal-and-flare response within 15-20 minutes of allergen exposure. The more invasive the testing is, the lower the incidence of false-negative, but the greater the risk of anaphylaxis. Of note, there are various methods of skin testing. These include skin prick test, scratch test, and the intradermal test.[14]

Other in-vivo tests that may be performed in an outpatient setting are:

• The gold standard test is a drug provocation test (DPT), which is a controlled administration used as the last line to confirm hypersensitivity to a certain medication. This requires a risk-vs-benefit stratification as it can pose a safety risk and potentially induce anaphylaxis.[17]
• Spirometry or pulmonary function tests can be used to assess asthma.
• Inhalation challenges with specific allergen and histamine, mannitol, and methacholine are used to assess airway hypersensitivity.
• Eosinophil count from nasal smear or induced sputum can be collected as well to confirm hypersensitivity.

Treatment / Management

The type of treatment provided to the patient for type I hypersensitivity depends on the presentation and the etiology of the reaction.[15][16]

Anaphylaxis

The need for emergent treatment is vital with anaphylaxis, at it is usually rapid in onset and may cause death. The recommendation is that if possible, the offending agent is removed immediately, and patients are placed in a supine position with the elevation of lower extremities unless there is a significant obstruction or airway inflammation. If there is marked stridor or severe respiratory distress, immediate intubation may be required. If the patient has a history of allergic reactions, they will be provided with emergency self-treatment prescriptions, which include: an epinephrine IM autoinjector or 1:1,000 solution, bronchodilators, antihistamines, and/or corticosteroids. The first-line therapy that is recommended to be administered without delay is epinephrine intramuscular (IM) injection and thereafter adjunctive therapy is utilized for symptom control:[13]

• Epinephrine:
  • Epinephrine has alpha-1, beta-1, and beta-2 adrenergic agonist effects. As such, it can increase vasoconstriction and peripheral vascular resistance and decrease airway or mucosal edema. The beta effects lead to increased inotropy, chronotropy, vasodilation, and decreased release of inflammatory mediators from both mast cells and basophils.
  • The dose for the epinephrine is weight-based and may be repeated every 5 to 15 minutes. Studies have demonstrated that in about 35% of cases, a repeat dose is required. 
    • Infants weighing <10 kg should be given an exact weight-based dose (not estimated), whenever possible. However, if drawing up an exact dose is likely to cause a significant delay in a patient with severe symptoms or who is rapidly deteriorating, the 0.1 mg dose can be given by autoinjector or by drawing up 0.1 mL of the 1 mg/mL solution. If the 0.1 mg autoinjector is not available, the 0.15 mg autoinjector can be used.
  • For weight 10 to 25 kg: the dose is 0.15 mg of epinephrine IM injected to anterior-lateral thigh
  • For weight >25 kg: the dose is 0.3 mg of epinephrine IM injected to anterior-lateral thigh
  • For the epinephrine solution of (1 per 1,000), the dose is 0.01 mg/kg per dose (maximum of 0.5 mg/dose)
  • Epinephrine may also be administered via slow continuous infusion, endotracheal, or intra-osseous route. The recommendation is to monitor blood pressure and heart rate with its administration. 
• Bronchodilators:
  • Beta-agonists, such as albuterol, are given as either metered-dose inhaler (MDI), dry-powder inhaler (DPI), or nebulized solution and are usually administered when the patient is not responsive to epinephrine for treating bronchospasm.
  • Albuterol MDI or DPI dose (90 mcg/actuation): adults are to administer 2 to 3 inhalations as needed for symptoms relief; in severe exacerbations, doses up to 8 inhalations every 20 minutes may be needed. Whereas the pediatric dose is 4 to 8 puffs every 20 minutes for up to 3 doses, data is limited in ages <4 years old.
  • Albuterol nebulization solution: (2.5 to 5 mg as needed) The nebulized solution can also be given continuously 10 to 14 mg over one hour in critically ill adult and pediatric patients.[13]
• Antihistamines: i.e., diphenhydramine (H1 antagonist), famotidine or ranitidine (H2 antagonists) 
  • Antihistamines are considered second-line adjunctive therapy and can provide relief of symptoms such as hives or pruritis. However, antihistamines should not be used as monotherapy, as they do not mitigate upper or lower airway obstruction, shock, or hypotension. Although antihistamines are usually used in combination with both an H1 antagonist and an H2 antagonist in anaphylaxis, there is a lack of direct evidence to support their administration. Second-generation H1 antagonists have fewer sedative effects than first-generation agents, and as such, they may also be considered. Some studies suggest that when H2 antagonists are given intravenously (IV), they can increase hypotension.
  • Diphenhydramine IV dose: 25 to 50 mg per dose in adult patients and 1 to 2 mg/kg/dose in pediatrics (maximum 50 mg/dose); dose may be repeated every 6 hours.
  • Ranitidine oral (PO) or IV: 1 to 2 mg/kg per dose (maximum 75 to 150 mg of oral and IV in adults and a maximum of 50 mg/dose in pediatrics).
  • Famotidine IV: 20 mg diluted to 5 ml 0.9% normal saline and pushed over two minutes in adults and 0.25 mg/kg (maximum 20 mg per dose) in pediatrics. 
• Glucocorticoids:
  • Glucocorticoids do not have an acute role in the treatment of anaphylaxis due to their delay in onset of action, and the literature lacks any randomized-controlled trials that have shown benefits for their use. However, the theoretical rationale for their use is to decrease biphasic or protracted reactions that may occur in anaphylaxis.
  • Methylprednisolone: 1 to 2 mg/kg/day (maximum 125 mg/dose) for one to two days without the need for taper.

Other adjunctive therapies for anaphylaxis include supplemental oxygenation, IV fluids for volume resuscitation, glucagon or vasopressors for refractory hypotension, and/or atropine for bradycardia. During and post anaphylaxis, the following should be ideally monitored: blood pressure, respiratory status, oxygenation, urine output, cardiac function, and heart rate at continuous intervals or frequently.[13]

Urticaria/Angioedema

Treatment of urticaria is similar to anaphylaxis where the offending agent is removed if known, and then the patient is given an H1 antihistamine and glucocorticoids (see above for dosing). There is not a need for epinephrine unless there is suspicion for anaphylaxis.[18] Patients with chronic urticaria who are refractory to H1 antihistamines may benefit from omalizumab, which is a monoclonal antibody that inhibits the binding of IgE to receptors on mast cells and basophils, or cyclosporine, which is an immunomodulator.[19]

Allergic Asthma/Allergic Rhinitis/ Allergic Conjunctivitis/Allergic Dermatitis/Eczema/Wasp or bee venom/Drug Allergy/Food Allergy 

For allergic conditions, avoidance of the offending agent is the first step in treatment. Oral or topical H1 antihistamine and oral or inhaled glucocorticoids may be used for symptomatic control. For allergic rhinitis, topical nasal or optical decongestants can provide temporary relief of symptoms. For allergic asthma, patients can be prescribed inhaled beta-agonists with or without inhaled corticosteroids based on steps of asthma therapy guidelines by the National Heart, Lung, and Blood Institute. 

Patients with significant symptoms despite avoidance of the allergen and who have a lack of relief from adjunctive therapy can undergo allergen immunotherapy, such as desensitization or hypo-sensitization (allergy shots). The patient must have a documented IgE-mediated allergy (allergic: asthma, rhinitis, conjunctivitis, dermatitis, drug allergy) prior to initiation of immunotherapy. The treatment is carried out in a clinical setting for the first doses, where certain allergens are administered in a slow escalation of subclinical doses. The route of administration is either via subcutaneous immunotherapy (SCIT), sublingual/sallow immunotherapy (SLIT), or mucosal route.

The goal of desensitization is to stimulate the production of immunoglobulin G (IgG) antibodies on mast cells instead of IgE. This technique is known as isotype switching and usually lasts for three years. Desensitization treatment is successful in about 67% of patients and is usually more beneficial in younger patients and those who have a sensitivity to a monovalent allergen. Patients need to be prescribed and educated about the proper use of epinephrine autoinjectors prior to the initiation of immunotherapy.[18][20]

Differential Diagnosis

Common diseases that can have a similar presentation to type I hypersensitivities include pulmonary diseases such as acute asthma (non-allergic) or chronic obstructive pulmonary disease (COPD) or emphysema, pneumothorax, aspiration, epiglottitis, hereditary angioedema, irritable bowel syndrome, upper respiratory infections, syncope, panic or anxiety attacks, or generalized urticaria due to infectious process or hot/cold stimuli.

Additionally, certain types of shock such has hypovolemic (i.e., ruptured ectopic pregnancy, systemic capillary leak syndrome), cardiogenic, distributive (i.e., sepsis), or obstructive (i.e., pulmonary embolism, cardiac tamponade) shock mimic anaphylaxis.

Certain medications and disease states can also cause flushing reactions that are not attributed to anaphylaxis, such as the fast infusion of vancomycin resulting in red man syndrome, alcohol, carcinoid syndrome, or perimenopause. In addition, there are other nonorganic diseases that need to be differentiated, such as psychosomatic episodes, or Munchausen stridor, or anaphylaxis in which the patient self-induces the reaction by purposely ingesting the offending agent.[21]

Staging

There are two stages in the course of Type I hypersensitivity: immediate reaction and late-phase reaction. During the initial phase, there is a sudden response within minutes of exposure to the allergen. While the late-phase may develop 4 to 12 hours post early phase reaction and can last for up to 24 to 73 hours. Late-phase reaction, as mediated by eosinophils, neutrophils, and lymphocytes, can result in increased release of more mediators, which can lead to further tissue damage, swelling, increased erythema, cough, wheezing and secretions.[13]

Prognosis

The prognosis of type I hypersensitivity depends on the extent of the reaction. In general, the reaction is short-lived, and as long as symptoms are controlled or antigen is avoided, there is a low risk of harm. However, death can occur within minutes of the onset of signs or symptoms of angioedema, anaphylaxis, or rarely severe asthma, if not identified and treated immediately. Risk of death increases with age, with about a 7-times fold in adults compared to children, and approximately 75% greater in blacks versus whites, and 30% increased risk in females.[22]

Complications

As previously stated, the most life-threatening complication of Type I hypersensitivity is anaphylaxis, which can increase the risk of mortality. During an anaphylactic reaction, the patient may experience hypotension, difficulty in breathing or hypoxia, and/or circulatory failure (distributive shock).

Deterrence and Patient Education

Patients should be educated about:

• Confirmation of anaphylaxis causes and an emergency care plan, which is available online to be printed in different languages (such as Food Allergy Research and Education [FARE])
• Proper treatment of anaphylaxis
• Proper use of rescue medications, including inhalers
• Importance of picking up a prescription for epinephrine as soon as possible
• Proper administration and storage of epinephrine auto-injectors
• Avoiding the allergen
• Following up with a primary care provider and an allergist 
• Foods and other medications or agents that may have cross-reactivity with allergen

Pearls and Other Issues

It is important to note that a late phase reaction can develop 4-6 hours post first signs and symptoms of anaphylaxis or type I hypersensitivity. As such, patients with moderate to severe anaphylaxis who do not respond initially to epinephrine should be admitted for observation, while patients who do respond to epinephrine should be observed for a minimum of four hours. Furthermore, treatment errors can occur with improper administration of appropriate doses of medications. For instance, epinephrine should be given as soon as anaphylaxis is suspected post-exposure to the allergen. It is important to recognize that antihistamines and other therapies are used as adjunctive treatment and never as monotherapy. 

The risk for annual recurrence for anaphylaxis was found to be about 18% in over 300 patients identified in a prospective study.[23] Therefore, appropriate education to patients who present with anaphylaxis is important. When counseling patients, the mnemonic “SAFE” can be used to remind patients about the steps that need to be completed once they are discharged from an institution post anaphylaxis. SAFE represents: Seek support, Allergen identification, and avoidance, Follow-up for specialty care, Epinephrine for emergencies. 

Prevention is the most important treatment for allergic responses, which includes contact avoidance and elimination of the offending agents. There is conflicting data that suggests breastfeeding can be beneficial in preventing asthma and atopic dermatitis. In addition, the expert panel (EP) as part of the guidelines for the diagnosis and management of food allergies in the United States suggests that breastfeeding may also help prevent food allergies. This same EP also suggests that solid foods should be introduced into the child’s diet before 4 to 6 months of age to help with the prevention of allergies.[16]

Enhancing Healthcare Team Outcomes

Consultation to specialists, such as an allergist or pulmonologist, is appropriate with type I hypersensitivities, especially if adjunctive therapies are not able to control symptoms. Pulmonologists will be beneficial to asthmatic patients as they would be able to appropriately monitor the patient and escalate based on the step therapies, including monitoring of pulmonary function tests. Cooperating with pharmacists to provide more thorough counseling of appropriate use of medications and education on epinephrine auto-injectors is beneficial to patients. Pharmacists can also develop protocols for medication desensitization. Nurses can help educate patients on diet, anaphylaxis, and signs and symptoms to monitor. Nurses can also continue to assess the patient in an acute setting post initial allergic response.