Immediate Hypersensitivity Reactions 

Updated: Aug 11, 2020
Author: Becky Buelow, MD, MS; Chief Editor: Michael A Kaliner, MD 

Overview

Background

The immune system is an integral part of human protection against disease. The normally protective immune mechanisms can sometimes cause detrimental effects in the host called hypersensitivity reactions. A hypersensitivity reaction is an inappropriate or exaggerated response to an antigen or an allergen. The traditional classification for hypersensitivity reactions is that of Gell and Coombs and is currently the most commonly known classification system.[1] It divides the hypersensitivity reactions into the following 4 types:

  • Type I reactions (i.e., immediate hypersensitivity reactions) involve immunoglobulin E (IgE)–mediated release of histamine and other mediators from mast cells and basophils.[2] Examples include anaphylaxis and allergic rhinoconjunctivitis.

  • Type II reactions (i.e., cytotoxic hypersensitivity reactions) involve immunoglobulin G or immunoglobulin M antibodies bound to cell surface antigens, with subsequent complement fixation. An example is drug-induced hemolytic anemia.

  • Type III reactions (i.e., immune-complex reactions) involve circulating antigen-antibody immune complexes that deposit in postcapillary venules, with subsequent complement fixation. An example is serum sickness.

  • Type IV reactions (i.e., delayed hypersensitivity reactions, cell-mediated immunity) are mediated by T cells rather than by antibodies. An example is contact dermatitis from poison ivy or nickel allergy.

Some authors believe this classification system may be too general and favor a more recent classification system proposed by Sell et al.[3] This system divides immunopathologic responses into the following 7 categories:

  • Inactivation/activation antibody reactions

  • Cytotoxic or cytolytic antibody reactions

  • Immune-complex reactions

  • Allergic reactions

  • T-cell cytotoxic reactions

  • Delayed hypersensitivity reactions

  • Granulomatous reactions

This system accounts for the fact that multiple components of the immune system can be involved in various types of hypersensitivity reactions. For example, T cells play an important role in the pathophysiology of allergic reactions (see Pathophysiology). In addition, the term immediate hypersensitivity is somewhat of a misnomer because it does not account for the late-phase reaction or for the chronic allergic inflammation that often occurs with these types of reactions.

Allergic reactions manifest clinically as anaphylaxis, allergic asthma, urticaria, angioedema, allergic rhinoconjunctivitis, some types of drug reactions, and atopic dermatitis. These reactions tend to be mediated by IgE, which differentiates them from non-IgE-mediated (formerly called anaphylactoid) reactions that involve IgE-independent mast cell and basophil degranulation. Such reactions can be caused by iodinated radiocontrast media (RCM), opiates, or vancomycin and appear similar clinically to urticaria or even anaphylaxis.[4, 5, 79]

Patients prone to IgE-mediated allergic reactions are said to be atopic. Atopy is the genetic predisposition to make IgE antibodies in response to allergen exposure.[6]

The focus of this article is allergic reactions in general. Although some of the clinical manifestations listed previously are briefly mentioned, refer to the articles on these topics for more detail. For example, see Allergic and Environmental Asthma; Anaphylaxis; Food Allergies; Rhinitis, Allergic; and Urticaria.

Pathophysiology

Immediate hypersensitivity reactions are mediated by IgE, and T and B cells play important roles in the development of these antibodies. CD4+ T-cells are subdivided into classes: effector T-cells (TH1, TH2, TH17 cells), memory T-cells, and T-regulatory (Treg) cells. TH1 cells produce interferon-gamma and interleukin (IL)-2, and promote a cell-mediated immune response. TH2 cells produce IL-4 and IL-13, which then act on B-cells to promote the production of antigen-specific IgE. TH17 cells produce IL-17, IL-21, and IL-22 to help fight extracellular pathogens, to produce antimicrobial peptides, and to promote neutrophil inflammation essential for immunity at the skin and mucosal surfaces.[57]  Memory T-cells rapidly differentiate into effector T-cells in secondary immune responses. CD4+CD25+FOXP3+ Treg cells are essential in peripheral tolerance and serve to suppress dysregulated immune responses.  CD4+CD25+FOXP3+Tregs inhibit TH2 cytokine production through the secretion and action of IL-10 and TGF-β. Proper function of CD4+CD25+FOXP3+ Treg cells has been shown to be important in the tolerance of allergens.[8]  Abnormalities in the CD4+CD25+FOXP3+ Treg population may play a role in the development of allergic disease.

The allergic reaction first requires sensitization to a specific allergen and it occurs in genetically predisposed individuals. The allergen is typically introduced through the respiratory tract (inhaled), through the gastrointestinal tract (ingested) or through contact of the integument (on the skin). The allergen/antigen is then processed by an antigen-presenting cell (APC), such as a dendritic cell, macrophage, or B-cell.[78]  The antigen-presenting cell(s) then migrate to lymph nodes, where they prime naïve T-helper cells that bear receptors for the specific antigen.

After antigen priming, naïve T-helper cells differentiate into TH1, TH2, or TH17 cells based upon antigen and cytokine signaling. In the case of allergen sensitization, the differentiation of naïve T-helper cells is skewed toward a TH2 phenotype. These allergen-primed TH2 cells then release IL-4, IL-5, IL-9, and IL-13. IL-5 plays a role in eosinophil development, recruitment, and activation. IL-9 plays a regulatory role in mast cell activation. IL-4 and IL-13 act on B cells to promote production of antigen-specific IgE antibodies.

In order for B cells to produce antigen-specific IgE, the B cells must internalize the recognized antigen. The antigen is then processed via the major histocompatibility complex (MHC) class II antigen processing pathway where the MHC class II molecule presents the antigenic peptide on the B cell surface to the TH2 cell. The peptide:MHC class II complex is then recognized by the T-cell receptor (TCR) on the TH2 cell. This interaction requires co-stimulation where CD40 on the B cell interacts with CD40L on the TH2 cell surface to activate the signaling cascade in the TH2 cell to produce IL-4 and IL-13. The CD40:CD40L interaction is essential for the activation of the activation-induced cytosine deaminase (AICD) enzyme in B cells for isotype switching from IgM to IgE in the presence of IL-4 and IL-13 (see image below).

Immediate hypersensitivity reactions. Sensitizatio Immediate hypersensitivity reactions. Sensitization phase of an immunoglobulin E–mediated allergic reaction.

The antigen-specific IgE antibodies produced can then bind to high-affinity IgE receptors located on the surfaces of mast cells and basophils. Re-exposure to the antigen can then result in the antigen binding to and cross-linking the bound IgE antibodies on the mast cells and basophils. This causes the release and formation of chemical mediators from these cells. These mediators include preformed mediators, newly synthesized mediators, and cytokines. The major mediators and their functions are described as follows:[9, 10]

Preformed mediators

See the list below:

  • Histamine: This mediator acts on histamine 1 (H1) and histamine 2 (H2) receptors to cause contraction of smooth muscles of the airway and GI tract, increased vasopermeability and vasodilation, enhanced mucous production, pruritus, cutaneous vasodilation, and gastric acid secretion.[88]

  • Tryptase: Tryptase is a major protease released by mast cells. It has many roles where it degrades allergens and cross-linked IgE, potentiates histamine release, increases heart rate and airway smooth muscle contractility, activates TGF-β, generates C3a and bradykinin and plays a role in airway remodeling through the stimulation of collagen and fibroblast proliferation.[11, 8, 88]  Tryptase is found in all human mast cells but in few other cells, thus is a good marker of mast cell activation.

  • Proteoglycans: Proteoglycans include heparin and chondroitin sulfate. The role of the latter is unknown; heparin seems to be important in storing the preformed proteases and may play a role in the production of α-tryptase.

  • Chymase: Chymase plays a role in mucous secretion; degradation of IL-4 and extracellular matrix; decrease T-cell adhesion to airway smooth muscle; and releasing stem cell factor.[88]

Newly formed mediators

Arachidonic acid metabolites

Leukotrienes - Produced via the lipoxygenase pathway:

  • Leukotriene B4 - Neutrophil chemotaxis and activation, augmentation of vascular permeability

  • Leukotrienes C4 and D4 - Potent bronchoconstrictors with airway smooth muscle proliferation, increase vascular permeability to cause tissue edema, enhance tissue fibrosis and arteriolar constriction

  • Leukotriene E4 - Enhances bronchial responsiveness and increases vascular permeability

  • Leukotrienes C4, D4, and E4 - Comprise what was previously known as the slow-reacting substance of anaphylaxis

Cyclooxygenase products:

  • Prostaglandin D2 - Produced mainly by mast cells; bronchoconstrictor, peripheral vasodilator to cause tissue edema, coronary and pulmonary artery vasoconstrictor, platelet aggregation inhibitor, neutrophil and eosinophil chemoattractant, and enhancer of histamine release from basophils 

  • Prostaglandin F2-α - Bronchoconstrictor, peripheral vasodilator, coronary vasoconstrictor, and platelet aggregation inhibitor

  • Thromboxane A2 - Causes vasoconstriction, platelet aggregation, and bronchoconstriction

Platelet-activating factor (PAF): PAF is synthesized from membrane phospholipids via a different pathway from arachidonic acid. It aggregates platelets but is also a very potent mediator in allergic reactions. It increases vascular permeability, causes bronchoconstriction, and causes chemotaxis and degranulation of eosinophils and neutrophils.

Adenosine: This is a bronchoconstrictor that also potentiates IgE-induced mast cell mediator release.

Bradykinin: Kininogenase released from the mast cell can act on plasma kininogens to produce bradykinin. An additional (or alternative) route of kinin generation, involving activation of the contact system via factor XII by mast cell–released heparin, has been described.[12, 13] Bradykinin increases vasopermeability, vasodilation, hypotension, smooth muscle contraction, pain, and activation of arachidonic acid metabolites. However, its role in IgE-mediated allergic reactions has not been clearly demonstrated.[4]

Cytokines

See the list below:

  • IL-4: IL-4 stimulates and maintains TH2 cell differentiation and proliferation as well as switches B cells to IgE synthesis.[88]

  • IL-5: IL-5 is key in the maturation, chemotaxis, activation, and survival of eosinophils. IL-5 primes basophils for histamine and leukotriene release.[88]

  • IL-6: IL-6 promotes mucus production, increases IgE secretion, and enhances the survival of mast cells.[88]

  • IL-13: IL-13 has many of the same effects as IL-4.[88]

  • Tumor necrosis factor-α: Tumor necrosis factor-α is a pro-inflammatory cytokine which activates neutrophils and eosinophils; increases monocyte chemotaxis; promotes histamine and tryptase secretion from mast cells; upregulation of MHC class II and IL2R expression.[14, 8, 88]

The collective biological activities of the aforementioned mediators can cause variable clinical responses depending on which organ systems are affected, as follows:

  • Urticaria/angioedema: Release of the above mediators in the superficial layers of the skin can cause pruritic wheals with surrounding erythema. If deeper layers of the dermis and subcutaneous tissues are involved, angioedema results. Angioedema is swelling of the affected area; it tends to be painful rather than pruritic.

  • Allergic rhinoconjunctivitis: Release of the above mediators in the upper respiratory tract can result in sneezing, itching, nasal congestion, rhinorrhea, and itchy or watery eyes.

  • Allergic asthma: Release of the above mediators in the lower respiratory tract can cause bronchoconstriction, mucus production, and inflammation of the airways, resulting in chest tightness, cough, shortness of breath, and wheezing.

  • Anaphylaxis: Systemic release of the above mediators, resulting in symptoms in two or more organ systems, is considered anaphylaxis. In addition to the foregoing symptoms, the GI system can also be affected with nausea, abdominal cramping, bloating, and diarrhea. Systemic vasodilation and vasopermeability can result in significant hypotension and is referred to as anaphylactic shock. Anaphylactic shock is one of the two most common causes for death in anaphylaxis; the other is throat swelling and asphyxiation.[4, 10]

Allergic reactions can occur as immediate reactions, late-phase reactions, and/or chronic allergic inflammation. Immediate or acute-phase reactions occur within seconds to minutes after allergen exposure. Some of the mediators released by mast cells and basophils cause eosinophil and neutrophil chemotaxis. Attracted eosinophils and resident lymphocytes are activated by mast cell mediators.

These and other cells (e.g., monocytes, T cells) are believed to cause the late-phase reactions that can occur hours after antigen exposure and after the signs or symptoms of the acute-phase reaction have resolved. The signs and symptoms of the late-phase reaction can include redness and swelling of the skin, nasal discharge, airway narrowing, sneezing, coughing, and wheezing. These effects can last a few hours and usually resolve within 24-72 hours.

Finally, continuous or repeated exposure to an allergen (e.g., a cat-allergic patient who owns a cat) can result in chronic allergic inflammation. Tissue from sites of chronic allergic inflammation contains eosinophils and T cells (particularly TH2 cells). Eosinophils can release many mediators (e.g., major basic protein), which can cause tissue damage and thus increase inflammation. Collectively, this results in structural and functional changes to the affected tissue. Furthermore, a repeated allergen challenge can result in increased levels of antigen-specific IgE, which ultimately can cause further release of IL-4 and IL-13, thus increasing the propensity for TH2 cell/IgE–mediated responses.[10]

Epidemiology

Frequency

The prevalence of atopic diseases (i.e., asthma, allergic rhinitis, food allergy, and atopic dermatitis) have increased since the year 2000.[8]

Food allergy prevalence in developed and developing countries is reportedly on the rise over the last 10–15 years.[92]

Allergic rhinitis is the most prevalent allergic disease;[6] it affects approximately 17-22% or more of the population.[15]

Asthma was estimated to affect approximately 25.7 million people in the United States in 2010. Asthma prevalence increased from 7.3% in 2001 to 8.4% in 2010.[16]  The annual percentage increase in current asthma prevalence from 2001 to 2009 was 1.2%, while there are large variations in population subgroups. [93]

Atopic dermatitis has increased in prevalence in the US.[93]

The prevalence of severe anaphylaxis is estimated between 0.065% and 2% in the US.[94]

Approximately 300 million people worldwide are estimated to have asthma.[18]  Prevalence rates vary around the world and are estimated to be from 3–38% in children[18]  and 2–12% in adults.[19]  

The International Study of Asthma and Allergies in Childhood (ISAAC) is an epidemiological research program that was established in 1991 to evaluate asthma, atopic dermatitis, and allergic rhinoconjunctivitis in children worldwide. The study is composed of three phases. Phase one used questionnaires designed to assess the prevalence and severity of asthma and allergic disease in defined populations in centers around the world. Phase two was designed to assess possible etiological factors based on information gathered from phase one. Phase three was a repetition of phase one to assess trends in prevalence.[20] Data from ISAAC showed prevalence variations in allergic diseases between countries but the overall mean prevalence did increase for all three disorders (asthma, atopic dermatitis and allergic rhinconjunctivitis) investigated.[21]  ISAAC researchers found significant variability in the prevalence of allergic rhinoconjunctivitis in children from 56 countries. Rates varied from 1.4–45.1% and, although sites varied, a general trend of increasing prevalence of allergic rhinoconjunctivitis was found over the 7 years between phases one and three.[21]  The prevalence in atopic dermatitis also varies widely between countries; 1.4% in China to 22.3% in Sweden, and prevalence is generally increasing.[21, 8] Lastly, asthma prevalence ranged greatly from 2.8% to 37.6%.[21]  The ISAAC project is the only study of its kind to help establish prevalence trends of atopic disease in children in many areas of the world.

The trend of asthma prevalence is hard to truly attain and no study has demonstrated a trend over time for adults like the ISAAC project has for children. In 2010 a systematic review evaluated the trend of the prevalence of asthma, which did not show a decrease, but, again, an increase in many parts of the world. Moreover, according to the World Health Survey, the global prevalence of physician-diagnosed asthma is 4.3% with a wide range in prevalence amongst 70 countries included in this study. China had 0.2% prevalence where Australia had a prevalence of 21%. Contrary to China's low prevalence reported by the WHS, a 2019 cross-sectional study in China identified 45.7 million Chinese adults with asthma (4.2% prevalence).[69] Risk factors associated with asthma were cigarette smoking, allergic rhinitis, childhood pneumonia or bronchitis, parental history of respiratory disease, and low education attainment.[69]  The European Community Health Respiratory Survey (ECHRS) assessed adult asthma prevalence in many, albeit more developed, countries. There was a six-fold variation in the prevalence with high rates in Australia, United States, and the UK with lower prevalence in Iceland, Italy, Germany, Algeria and India.[91] Again, these studies indicate the range of asthma prevalence in different parts of the world. 

Mortality/Morbidity

Mortality from allergic diseases occurs primarily from anaphylaxis and asthma, although deaths from asthma are relatively rare.[10]

The rate of asthma deaths decreased from 15 per million in 2001 to 10 per million (n = 3518) in 2016. The death rate was higher in females and non-Hispanic blacks and nearly 5 times higher for adults than children.[95]

Approximately 1500 people die annually from anaphylaxis in the United States.[94]

Allergic diseases are a significant cause of morbidity. Asthma was the primary diagnosis for emergency room visits for 1.6 million individuals in 2017.[96]  Asthma was also the primary diagnosis in 9.8 million office visits in 2016.[96]  Furthermore allergic rhinitis affects 19.2 million adults and 5.2 million children where 12.0 million have office visits per year with allergic rhinitis as the primary diagnosis.[97]  

Race

The reason for the differences in the prevalence of allergic diseases with respect to race are complex and not completely understood. In the US, Puerto Ricans have the highest prevalence at 16.6% followed by blacks (11.1%), whites (7.8%), Asians (5.3%), then Mexicans (4.9%).[89]  Asthma prevalence also increases with increasing poverty.[89]  Thus, it is likely that differences in allergic diseases among different racial or ethnic groups is multifactorial and includes genetic, environmental, and socioeconomic factors.

Geography

In the US, the prevalence of asthma is highest in the Northeast at 9.3% and the lowest in the South at 7.5%.[89]

Sex

Some unexplained differences exist in the prevalence of allergic diseases between the sexes. Asthma is more prevalent in boys from birth to age 17 years, but females have a higher prevalence overall.[89]  Among asthmatic children, the rate of exacerbation over the last 12 months decreased from 2001 to 2016, but prevalence was higher in the birth to 4-year-old category than the 12- to 17-year-old category.[90]

Skin test reactivity in women can fluctuate with the menstrual cycle, but this is not clinically significant.[9]

Age

In general, allergic rhinitis symptoms (and skin test reactivity) tend to wane with increasing age.[15]

Food allergies and subsequent anaphylaxis are more prevalent in children; IgE-mediated food allergy is also on the rise. It is unclear the reason(s) for the increase in IgE-mediated food allergy, but a landmark article, the LEAP trial, published in 2015 showed sustained early introduction of peanut (first 11 months of life) into the diet of high risk infants significantly reduced risk of peanut allergy by 5 years of age.[85] Subsequently, the LEAP-on trial studied the same high-risk children from the LEAP trial. The children who tolerated peanut at age 5 avoided peanut protein consumption for 12 months without an increase in peanut allergy prevalence with reintroduction at age 6 years.[86]  These studies have shifted the paradigm to early introduction and sustained consumption of peanut protein. Furthermore the results of these studies could possibly be extrapolated to all highly allergenic foods being introduced into the diet of children. When IgE-mediated food allergy develops some children may outgrow their allergies to certain foods, such as milk, soy, and egg allergy. However, anaphylaxis from food and other triggers is still a threat in adults. Some food allergies, such as allergy to shellfish, tree nuts, and finned fish, may last a lifetime.

Childhood asthma is more prevalent in boys and can often resolve by adulthood. However, females tend to develop asthma later in life and can also have asthma that is more severe.[9, 8]  

 

Presentation

History

History findings vary depending on which organ systems are affected.

Anaphylaxis

Patients may report skin itching, localized or diffuse pruritus, dizziness, faintness, and diaphoresis. Difficulty breathing can result from angioedema of the pharyngeal tissue, from bronchoconstriction, or from both. Patients may also report GI symptoms, including nausea, vomiting, diarrhea, and abdominal cramping. Patients may experience uterine cramping or urinary urgency. Patients can have a sudden onset of respiratory and/or circulatory collapse and go into anaphylactic shock.

Symptoms usually begin within minutes of allergen exposure (e.g., drug administration, insect sting, food ingestion, allergen immunotherapy), but symptoms may start up to two hours after exposure. Symptoms can also recur hours after the initial exposure (late-phase reaction).

Patients may not be able to identify the allergen either because they are unaware of the allergy (e.g., first reaction to insect sting) or because they were unaware of exposure to the allergen (e.g., a patient who is allergic to peanuts who eats a processed food containing hidden peanut protein).

Particular attention should be given to new or recently changed medications. A history specific for insect stings or new environmental exposures should also be obtained. If applicable, a food history should also be obtained. Exercise-induced anaphylaxis may be associated with prior ingestion of a food (e.g., wheat, peanut, tree nuts, fish, celery) and/or drug (e.g., NSAID) that does not produce symptoms when ingested without subsequent exercise.[30]

Allergic rhinoconjunctivitis

Symptoms consist of congestion; sneezing; itchy, runny nose and eyes; and itching of the palate and inner ear. Patients may also report postnasal drip, which can cause sore throat, coughing, or throat clearing.

Rhinoconjunctivitis usually results from exposure to aeroallergens and can be seasonal or perennial. Airborne allergens typically also cause ocular symptoms consisting of itchy eyes, tearing, swelling or redness of the eyes. Worrisome ocular symptoms include photophobia, pain, and/or change in vision where the diagnoses of atopic keratoconjunctivitis or vernal keratoconjunctivitis should be entertained.

Repeated exposure to the allergen can result in chronic allergic inflammation, which causes chronic nasal congestion that can be further complicated by sinusitis.

An important piece of the history also includes whether symptoms are improved or abated with the use of allergy medications and/or with allergen avoidance. 

Allergic asthma

In 2007, the National Asthma Education and Prevention Program (NAEPP) Expert Panel from the National Heart, Lung, and Blood Institute (NHLBI) released guidelines on the diagnosis and management of asthma. The classification of an asthmatic depends on the age of the patient (ages 0-4 years of age, 5-11 years of age, and 12 years and older).[31]

Asthmatics are classified into 4 groups: intermittent, mild persistent, moderate persistent, and severe persistent.[31] Each classification is based on severity. Severity is classified by risk (exacerbations requiring oral systemic corticosteroids) and impairment (symptoms, nighttime awakenings, interference with normal activity, short-acting beta2-agonist use [not for premedication before exercise], and lung function if able to perform spirometry).[31] These symptoms are assessed each visit to make medical decisions to change or continue current medical therapy.

Acute allergen exposure can result in bronchoconstriction, and patients may report shortness of breath (e.g., difficulty getting air out), wheezing, cough, and/or chest tightness around the time of exposure. Long-term allergen exposure can cause chronic airway changes and the patient may give a history of repeated rescue inhaler use. 

Urticaria/angioedema

Diffuse hives or wheals may occur and cause significant pruritus; individual wheals resolve after minutes to hours, but new wheals can continue to form. Urticaria lesions don't typically last longer than 24 hours in one location.

Acute urticaria (lasting < 6 wks) can be caused by viral infections, foods, drugs, stinging insects, or contact allergens.

Chronic urticaria lasts longer than 6 weeks. Although many causes are possible, often a cause is not found. In many cases, the etiology is termed idiopathic.

Angioedema is localized tissue swelling that can occur in soft tissues throughout the body. Patients may report pain at the site of swelling instead of pruritus, which occurs with urticaria.

Angioedema of the laryngopharynx can obstruct the airway, and patients may report difficulty breathing. Stridor or hoarseness may be present. Angioedema of the laryngopharynx can be life threatening.

Atopic dermatitis

This condition is an eczematous cutaneous eruption more common in children than in adults; it can be exacerbated by food and/or environmental allergen exposure in some patients.

Patients report significant pruritus that causes scratching, which exacerbates the lesions. Superinfection with staphylococcal organisms can occur, particularly in severely excoriated or cracked lesions.

GI allergies

Patients may report nausea, vomiting, abdominal cramping, and diarrhea after ingestion of the offending food. Note that other mechanisms (e.g., lactose intolerance) commonly cause these symptoms, but eosinophilic gastroenteritides should also be considered in persons with predominant GI symptoms.

Physical

Physical examination findings vary with the organ system involved.

Anaphylaxis

Vital signs should be monitored closely because patients can quickly progress to circulatory and/or respiratory failure. Tachycardia may precede hypotension. Patients who are hypotensive may have reflex tachycardia, but bradycardia can also occur in 5% of cases.

Patients may have urticaria, angioedema, or both. Angioedema of the airway and throat can result in respiratory failure or asphyxiation; therefore, this dangerous occurrence must be closely monitored. Around 90% of cases of anaphylaxis have cutaneous manifestations, but the absence of them doesn't exclude anaphylaxis as being considered in the differential diagnosis. 

Patients may be wheezing during the respiratory examination, which is secondary to bronchoconstriction.

Confusion and alteration of mental status can occur.

Patients may have abdominal cramping, nausea, vomiting and/or diarrhea as well as urinary urgency.

Female patients may have uterine cramping.

Allergic rhinoconjunctivitis

Patients may sneeze, be congested, have a runny nose, or have frequent throat clearing and/or cough from postnasal drip.

Patients may have a horizontal line right below the nasal bridge (i.e., allergic salute) from repeated upward itching of the nose.

Sclera may be injected, and patients may have dark rings under the eyes (i.e., allergic shiners).

Nasal mucosa can be boggy and pale, usually with clear drainage. Some patients may exhibit mouth breathing due to severe obstructive allergic edema in nasopharynx.

The pharynx may have a cobblestone appearance reflecting lymphoid hyperplasia from postnasal mucus drainage.

The patient may have frontal or maxillary sinus tenderness from chronic sinus congestion or infection.

Allergic asthma

Findings can vary depending on the patient and the severity of symptoms. Patients may be coughing or appear short of breath. Wheezing may be present, but it always present in asthmatics. Some patients may not be able to move enough air to produce wheezing (i.e., silent chest), which can be a worrisome sign of impending respiratory failure.

Breaths may be shallow or the patient may have a prolonged expiratory phase.

Cyanosis of the lips, fingers, or toes (caused by hypoxemia) may also occur.

Urticaria/angioedema

Urticaria occurs in the dermis of the skin from increased vascular permeability from the action of vasoactive substances released from mast cells and basophils.[8] It is usually represented by wheals with surrounding erythema. Wheals from allergic causes usually last a few minutes to a few hours. Wheals due to cutaneous vasculitis may last more than 24 hours, may be painful, and may leave postinflammatory hyperpigmentation upon healing.

Angioedema is localized swelling of the deep dermis, subcutaneous or submucosal tissue secondary to vascular leak. Sites of angioedema are typically the lips, tongue, pharynx, cheeks, eyes, hands and feet, penis and scrotum, and/or bowel wall. If laryngeal edema is present, a diagnosis of idiopathic anaphylaxis should be entertained.

Atopic dermatitis

The physical examination findings can vary with the severity of the disease. In less severe cases, skin can appear normal, dry, or with erythematous papules. In more severe cases, patients can have extremely dry, lichenified, cracked, and, sometimes have crusted lesions.

In infants, the head and extensor surfaces are more involved, whereas in older children and adults, the flexural surfaces tend to be more affected.

Causes

Atopic conditions

Genetics

Atopy is defined as the genetic predisposition to form IgE antibodies in response to exposure to allergens. Therefore, a genetic predisposition exists for the development of atopic diseases. Common allergic diseases are typically complex genetic disorders, as not one affected gene confers disease; but mutations or single nucleotide polymorphisms in identified at-risk genes may contribute to disease development and phenotype. Atopic conditions, such as asthma and atopic dermatitis, have been studied extensively and numerous candidate susceptibility genes are being uncovered at a rapid rate.[81]  For example, a mutation in the gene encoding the filaggrin protein confers an increased risk for the development of atopic dermatitis.[82] Furthermore, the role of genetics in pharmacology is expanding as evidenced by specific mutations in the gene encoding the beta-2-receptor, which may decrease a patient's ability to respond to albuterol for asthma symptom relief.[83]  Finally, family studies have demonstrated a heritability component in atopic conditions.[84]

Environment

Environmental factors also play an important role, although the role that exposure at an early age to certain antigens might play in either the progression to or the protection from the development of an allergic response still remains unclear. Some studies have shown that children in day care and those with older siblings may be less likely to develop allergic disease. The environment certainly can help determine the allergens to which the patient will be exposed. For example, children in inner cities are more likely to be sensitized to cockroaches than are children in suburban or rural areas. Similarly, dust mites, a potent allergen, are primarily found in humid climates, and those who have never been exposed to such a climate are less likely to be allergic to mites.

Allergic reactions

Reactions can be elicited by various aeroallergens (e.g., pollen, mold, animal dander) or insect stings.

Other possible causes are latex, drug, and food allergy.

Allergens

Allergens can be complete protein antigens or low–molecular-weight proteins capable of eliciting an IgE response. It is rare when a carbohydrate moiety induces IgE production (i.e., alpha-gal allergy or mammalian meat allergy). 

Pollen and animal dander represent complete protein antigens.

Haptens are low-molecular-weight (inorganic) antigens that are not capable of eliciting an allergic response by themselves. They must bind to serum or tissue proteins in order to elicit a response. This is a typical cause of drug hypersensitivity reactions, with IgE-mediated penicillin drug allergy as the prototypic case. Furthermore, antibiotics (like β-lactams) are the most common drugs to induce IgE-mediated reactions, but this can happen with a wide array of other periooperative medications and platinum-based chemotherapeutics.[87]  Note that all drug hypersensitivity reactions are not mediated by IgE.[87]  In addition to non-IgE-mediated reactions, drug reactions can be caused by cytotoxicity and immune-complex formation and by other immunopathologic mechanisms.[87]

Foods

The most common allergens in IgE-mediated food allergy are peanuts, tree nuts, finned fish, shellfish, eggs, milk, soy, and wheat. Sesame seed is also a food allergen that is highly allergenic and is becoming more widely recognized as such.[73]  

Certain foods can cross-react with latex allergens. These foods include banana, kiwi, chestnut, avocado, pineapple, passion fruit, apricot, and grape.

Fresh fruits and vegetables as well as peanut and some tree nuts can induce pollen-food allergy syndrome (PFAS) in individuals who have IgE to common aeroallergens. PFAS is an IgE-mediated food allergy with symptoms typically limited to the oropharynx, but a small portion can have anaphylactic reactions to the offending foods. Cooking the fresh fruits and vegetables to change the conformation of the cross-reactive protein allows affected individuals the ability to consume cooked forms of the food while avoiding the raw forms. This is not the case with nuts, so complete avoidance of these foods is warranted.

Hymenoptera

Honey bee, wasp, yellow jacket, hornet, and fire ant stings can cause IgE-mediated reactions.

While anaphylaxis is the most serious reaction, localized swelling and inflammation can also occur and do not by themselves indicate increased risk of a subsequent life-threatening reaction.

Potentially life-threatening hypersensitivity reactions to insect stings are estimated in 0.4 to 0.8% of children and 3% of adults.[75] At least 40 Americans die each year from anaphylaxis caused by a stinging insect.[74]

Non-IgE-mediated reactions

Non–IgE-mediated mast cell and basophil degranulation can occur from a variety of substances. Although the mechanisms are different, the clinical manifestations can appear the same.

Causes can include radiocontrast medium, opiates, and vancomycin (e.g., red man syndrome).

Patients can be pretreated with glucocorticosteroids and both H1 and H2 antihistamines prior to exposure to radiocontrast media. This, together with the use of low-osmolar or iso-osmolar nonionic dye which reduces the risk of a repeat reaction. Furthermore, reported radiocontrast media-adverse drug reactions are not related to iodine, so a radiocontrast media allergy should not be listed as an iodine allergy. 

Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) can also cause reactions by causing release of leukotrienes via the 5-lipoxygenase pathway of arachidonic acid metabolism. Patients susceptible to this syndrome can develop acute asthma exacerbation, nasal congestion, profuse rhinorrhea, ocular itching/injection, skin erythema, angioedema, and even life-threatening anaphylaxis with hypotension and shock after ingestion.[8] However, note that in rare cases, patients can have what are thought to be true IgE-mediated anaphylactic reactions to a specific NSAID. In these cases, no cross-reactivity occurs with other NSAIDs.

 

DDx

 

Workup

Laboratory Studies

Some laboratory tests may be helpful in determining whether a reaction is truly allergic in nature.

Obtaining a serum tryptase level soon after the onset of symptoms can be helpful in differentiating anaphylaxis from other forms of shock and from other symptom complexes that may be confused with anaphylaxis. The tryptase level can be elevated, which is indicative of mast cell degranulation. False-negative results can occur, especially when food is the cause of anaphylaxis. Ideally, the tryptase level should be drawn within 2-4 hours after the event for best evaluation. For patients with systemic reactions to venom stings, a baseline tryptase may be helpful to assess for underlying mast cell disease. 

An elevated eosinophil count may be observed in patients with atopic disease.

IgE levels may be elevated in patients who are atopic, but the level does not necessarily correlate with clinical symptoms.

In vitro assays that measure serum antigen-specific IgE (i.e., radioallergosorbent test [RAST], ImmunoCAP, Immunolite) can be useful in identifying which allergens are causing symptoms for a patient. More sensitive tests have been available in recent years and have a greater positive predictive value for foods. These tests can sometimes detect clinically irrelevant allergens, however, creating false-positive results to some foods so testing should be selected based on clinical history. Component-resolved diagnostic testing to food allergens (i.e., peanut, milk, egg) has emerged and continues to be a part of testing that can help assess food allergy diagnosis and prognosis.  Serum antigen-specific IgE testing is also available for identifying environmental allergens as well as hymenoptera antigens causing symptoms in patients.

Other Tests

Skin tests

Skin tests can be performed in the outpatient setting in the allergist's office and are very useful in the evaluation and management of allergic rhinoconjunctivitis, allergic asthma, food allergy, venom allergy and penicillin drug allergy.

Skin prick tests involve pricking the skin where diagnostic allergen has been placed. A positive reaction consists of a wheal and flare that occurs within 15-20 minutes. Use of proper controls is a key component to interpretation of the tests but is often not included with kits marketed to nonspecialists.

Intradermal (ID) tests involve injecting allergen into the superficial dermis. ID tests have many more false positive reactions, and the clinical significance of a positive ID test is questionable. ID tests are used for drug allergy (penicillin and local anesthetic skin testing) and venom allergy testing. ID tests are never used for food allergy testing.

Food skin tests have a higher false-positive rate than skin tests for aeroallergens, but negative food skin test results can be helpful in excluding IgE-mediated allergies, including food-related exercise-induced anaphylaxis, especially if a fresh food is used as the antigen. No standardized food testing extracts are available.

For the most part, standardized diagnostic allergens are not available for drugs. Penicillin is the only drug for which a standardized diagnostic allergen exists, but even this test is only available for the major determinant, one of many possible allergens in penicillin. Nonstandardized skin tests can be performed for the minor determinants in penicillin or for other drugs (i.e., by pricking the skin where drug solution has been placed). Protocols are available for testing to certain medicines, such as penicillin and local anesthetics.

Skin tests are useful in identifying hypersensitivity to venom. Testing should only be performed in patients at any age who have systemic symptoms. Unfortunately false-negatives do occur, but if testing is positive then venom immunotherapy can be life-saving. 

Spirometry/pulmonary function tests

Spirometry or pulmonary function tests offer an objective means of assessing asthma and the degree of obstruction. Assessing reversibility (defined as improvement in FEV1 and/or FVC by 200 mL and 12% after short-acting beta-agonist administration) helps rule in asthma as a diagnosis. Absence of reversibility doesn't rule out asthma as a diagnosis. 

Peak-flow meters can also be used in the office as well as used by patients at home to monitor their status. It is important to remember readings from peak-flow meters are effort dependent. Personal spirometers that measure FEV1 are now also available for home use.

Inhalation challenge with histamine, methacholine, mannitol, and specific allergen can be used to confirm airway hypersensitivity or allergen sensitivity. Methacholine challenges are very useful in ruling out asthma during a diagnostic work-up.

Measurement of exhaled nitric oxide can be used to evaluate inflammation in the airways seen with asthma and to follow efficacy of or adherence to anti-inflammatory medications (e.g., inhaled corticosteroids).

Nasal smear tests

A nasal smear can be performed to look for eosinophils. However, regular use of a nasal corticosteroid can lower the eosinophil count.

Elevated eosinophil levels can be consistent with allergic rhinitis as well as nonallergic rhinitis with eosinophilia syndrome (NARES).

Induced sputum: Sputum induced from the airways can be evaluated for eosinophils, which is a measure of inflammation that can be seen in some diagnoses which include asthma.

 

Treatment

Medical Care

Treatment may vary depending on the type of allergic reaction. Some general observations are made below, but refer to articles on the specific topics for more details about treatment (e.g., Anaphylaxis; Rhinitis, Allergic; Allergic and Environmental Asthma; Urticaria).

Anaphylaxis

Assessment of the reaction is described as follows:

  • Withdraw the offending agent if applicable (e.g., stop drug infusion).

  • Check the airway and secure if needed. Patients with respiratory compromise may need to be intubated. If laryngeal edema causes oral intubation to be difficult, a tracheostomy must be performed.

  • Assess the level of consciousness and vital signs.

Treatment is as follows:

  • Administer epinephrine immediately (see Medication). This is the most important medication and the only medication that has been shown to decrease mortality due to anaphylaxis.

  • Patient should be placed in the supine position with legs elevated. If having respiratory compromise or vomiting, then patient should be comfortable with lower extremities again elevated. Patients should not be placed upright suddenly during event or prematurely for the fear of empty ventricle syndrome. 

  • Start intravenous fluids; these should be administered rapidly and as blood pressure and overall fluid status warrant.

  • Consider other vasopressors (e.g., dopamine) if hypotension does not respond to the above measures. Norepinephrine may be used if dopamine is not effective. Importantly, isoproterenol should not be used because it is a peripheral vasodilator. Patients with beta-adrenergic blockade may be particularly difficult to treat. They have both chronotropic and inotropic cardiac suppression and may not respond to the above treatments. Glucagon has positive inotropic and chronotropic effects and is the drug of choice in these cases. Atropine can also be used but will only be effective in treating bradycardia.

  • H1- and H2-receptor blockers can be helpful in alleviating pruritus, urticaria, rhinorrhea, and other symptoms. 

  • Use albuterol nebulizers if needed.

  • Administer a corticosteroid, which is believed to help prevent or control the late-phase reaction.

  • Transfer the patient to the hospital for further observation and care.

  • Late phase reactions can occur 4-6 hours after the initial reaction and can be as severe as or worse than the original reaction. In some cases, late phase reactions can occur up to 72 hours later. Education of the patient and observation is, therefore, important.

Prevention is as follows:

  • Avoid the triggering allergen as much as possible.

  • Patients should be given a prescription for at least 2 auto-injectable epinephrine devices and instructed in their proper use (how and when to use). Importantly, patients must carry them at all times.

  • Patients must wear a Medic Alert type of bracelet to alert emergency responders to the possibility of anaphylaxis.

  • Patients should be taught what measures to take in case of a future anaphylactic reaction, i.e., immediately administer epinephrine, call emergency services (e.g., 911), or go to the nearest emergency department (even if feeling better after the epinephrine).

  • Specific allergen immunotherapy is highly effective in preventing anaphylaxis from hymenoptera stings and should always be considered for patients who have experienced a systemic reaction after an insect sting.

Allergic rhinoconjunctivitis

Avoid the offending allergen, if possible.

Oral H1-receptor blockers are helpful for controlling itchiness, rhinorrhea, and lacrimation but most have little effect on nasal congestion.

Administer an intranasal glucocorticosteroid to control nasal symptoms, including nasal congestion. These medications need to be used regularly to be effective, and patients may need to use them for a week or more before maximum effect is seen.

Other topical nasal agents include azelastine and olopatadine (H1-receptor blockers).  Nasal azelastine and olopatadine have the advantage of treating rhinorrhea, nasal itchiness, sneezing, and also congestion. Azelastine has been shown to be helpful in treating both allergic and nonallergic vasomotor rhinitis. Nasal antihistamines have a rapid onset of action and can be used on an as-needed basis.

Topical nasal decongestants can provide immediate relief of nasal congestion and can be used temporarily and as needed. Patients should be cautioned not to use them for more than a few days, however, as they can cause rebound congestion (rhinitis medicamentosa).

Topical decongestants, mast cell stabilizers, or antihistamines can be used for ocular symptoms; artificial tears or sterile saline might be helpful in mild cases, and this product can be refrigerated for an extra cooling effect. Cold compresses can also be used.  Again, use of topical decongestants should be limited to a few days, as longer use can result in rebound vasodilation.

Antigen-injection immunotherapy is very effective in treating inhalant allergies and can be considered in patients whose symptoms do not respond well to medications or in patients who cannot avoid the allergen in question (e.g., cat owner allergic to cats). The mechanism of action of immunotherapy is not yet fully elucidated. Immunotherapy causes antigen-specific immunoglobulin G4 to be formed  and these have been shown to block the effects of antigen-specific IgE binding to effector cells. Immunotherapy is thought to dampen the TH2 response and some feel it also tips the balance of TH2 and TH1 towards a TH1 phenotype. Importantly, regulatory T cells play an important role through the production of suppressive cytokines IL-10 and TGF-β.[35, 8]  [78]

An alternative to antigen-injection immunotherapy, aka, subcutaneous immunotherapy (SCIT), is sublingual immunotherapy (SLIT), which is used in Europe and has been approved by the FDA in the United States. The SLIT formulations approved for use in the US are Ragwitek, Grastek, Oralair and Odactra. The first dose of each tablet needs to be supervised by an allergist. Each patient should be prescribed and taught how and when to use auto-injectable epinephrine.

  • Grastek is timothy grass allergen extract approved for patients 5-65 years old who have allergic rhinitis with or without allergic conjunctivitis and positive testing to grass pollen. One tablet is taken sublingually daily for 12 weeks prior to grass pollen season and throughout the season as well.[36]

  • Ragwitek is short ragweed allergen extract approved for patients 18-65 years old who have allergic rhinitis with or without allergic conjunctivitis and positive testing to short ragweed. One tablet is taken sublingually daily for 12 weeks prior to short ragweed season and throughout the season.[37]

  • Oralair is a mixture of five grass allergen extracts. It is approved for patients 5-65 years old who have allergic rhinitis with or without allergic conjunctivitis and positive testing to grass pollen. One tablet is taken sublingually for 16 weeks prior to grass pollen season and throughout the season.[38]

  • Odactra is a mixture of two house dust mite allergen extracts. It is approved for patients 18-65 years old who have allergic rhinitis with or without allergic conjunctivitis and positive testing to dust mite. One tablet is taken sublingually daily.[77]

Asthma

Avoid the offending allergen, if possible.

A key factor in controlling allergic asthma is controlling allergic rhinitis symptoms.

Therapy depends on the severity of disease as well as age of patient. In 2007, the National Asthma Education and Prevention Program (NAEPP) Expert Panel from the National Heart, Lung, and Blood Institute (NHLBI) released guidelines on the diagnosis and management of asthma. These guidelines use a stepwise treatment approach based on age and severity of the asthmatic treated.[31]

  • All asthmatics are classified as intermittent, mild persistent, moderate persistent or severe persistent based on risk and impairment (see History for asthma for details).

  • Age of the patient, along with symptoms, will also help guide treatment options. Step 1 treatment is for intermittent asthmatics while Steps 2-6 listed below are the preferred daily medications for persistent asthmatics from the guidelines.[31] Alternative treatment options are listed in the guidelines.[31]

 

Table. (Open Table in a new window)

Age

Step 1

Step 2

Step 3

Step 4

Step 5

Step 6

0-4 years

SABA PRN

Low-dose ICS

Medium-dose ICS

Medium-dose ICS plus LABA or montelukast

High-dose ICS plus LABA or montelukast

High-dose ICS plus LABA or montelukast and oral corticosteroids

5-11 years

SABA PRN

Low-dose ICS

Low-dose ICS plus LABA or LTRA or theophylline

Medium-dose ICS plus LABA

High-dose ICS plus LABA

High-dose ICS plus LABA plus oral corticosteroids

12 years or older

SABA PRN

Low-dose ICS

Low-dose ICS plus LABA or medium-dose ICS

Medium-dose ICS plus LABA

High-dose ICS plus LABA

High-dose ICS plus LABA plus oral corticosteroids

 

Symptoms and SABA use should be reassessed after starting treatment. If patients are well-controlled for 3 months, step down therapy may be employed. Conversely, if a patient’s symptoms are not well-controlled, step up therapy is warranted.

All patients with asthma should have an albuterol metered-dose inhaler (MDI) (or nebulizers for young children) to use as needed for acute symptoms but the newest GINA guidelines state ICS-LABA (LABA=formoterol) can be used in adolescents and adults for the as needed medication (please see overview of GINA guidelines below).

Patients with exercise-induced bronchospasm (EIB) should receive short-acting beta2-agonist treatment 15-20 minutes prior to exercise and/or montelukast at least 2 hours prior to exercise. 

Systemic corticosteroid bursts may need to be used for exacerbations of severe cases.

Patients with allergic asthma may respond well to specific allergen immunotherapy. This is recommended from Steps 2-4 in patients 5 years or older.[31]

In patients 12 years or older refractory to the usual medications (Steps 5 and 6) who have antigen-specific IgE to perennial environmental aeroallergens, may benefit from therapy with omalizumab (Xolair), a humanized monoclonal antibody that prevents binding of IgE to high-affinity IgE receptors on mast cells and basophils.[39, 40, 41, 31]

Global Initiative for Asthma (GINA) recently changed asthma guidelines to recommend adolescents and adults with mild asthma not be treated with as needed SABA monotherapy for two reasons: the usage of SABA doesn't protect against severe exaacerbation and frequent use of the SABA actually increases the risk of exacerbation. GINA now recommends symptom-driven or daily low dose inhaled corticosteroids to reduce the risk of serious exacerbations. The new controller options include:

--For intermittent asthma, as needed low dose ICS-formoterol or low dose ICS taken whenever SABA is taken

-OR-

--Regular ICS or ICS-LABA every day, plus as needed SABA

-OR-

--Maintenance and reliever treatment with ICS-formoterol, with the reliever being low-dose budesonide-formoterol

Please see the published GINA guidelines for more details. [98]

Urticaria/angioedema

Avoid the offending allergen if known.

A second-generation H1-receptor blocker should be added for monotherapy (i.e., cetirizine 10 mg daily).[42]

If symptoms are not controlled with this alone, the dose of the second generation H1 antagonist can be increased up to four times the recommended dose (i.e., cetirizine 20 mg BID). Alternatively, another second generation H1 antagonist (i.e., fexofenadine) or a first generation H1 antagonist (i.e., hydroxyzine at bedtime) can be added. Other possible treatments with H2 antagonists or leukotriene modifiers can also be added.[42]

If symptoms continue to occur, increasing the first generation H1 antagonist may be helpful.[42]

Omalizumab (Xolair) has been found to be useful in patients with chronic urticaria refractory to high dose treatment with H1 antihistamines (ref60) and is FDA approved for refractory chronic urticaria in patients 12 years and older. In addition, other medications such as cyclosporine may be used to treat recalcitrant chronic urticaria.[42]

Atopic dermatitis

Avoid the offending allergen if possible, and properly hydrate and care for the skin.

Topical glucocorticosteroids and topical immunomodulators (e.g., tacrolimus) can be used.[43, 44]

Dupilumab (Dupixent) is a monoclonal antibody antagonist which binds to the IL-4 receptor alpha antagonist. It is FDA approved for the treatment of moderate to severe atopic dermatitis in patients age 6 and older whose atopic dermatitis is not well controlled on topical prescription medications. [80]

 

Consultations

Consultation with an allergist, pulmonologist, and/or critical care medicine specialist may be necessary for protracted anaphylactic shock or severe asthma exacerbations.

Consult an allergist or immunologist for the following conditions:

  • Allergic rhinoconjunctivitis not easily controlled with medications

  • Nonallergic, vasomotor rhinitis

  • Asthma: Of patients with asthma, at least 50% of adults have allergies as factors causing or contributing to their asthmatic inflammation. More than 90% of children with asthma are allergic.

  • Allergy evaluation prior to the initiation of Xolair

  • Chronic urticaria or angioedema (>6 weeks), or severe intermittent urticaria or angioedema, even if individual attacks last < 6 weeks

  • History of anaphylaxis from insect bite or sting

  • History of anaphylaxis with unknown cause

  • Possible drug desensitization (if known allergy to drug for which no good alternatives are available)

  • Atopic dermatitis, moderate to severe

  • Sinusitis before proceeding to surgery; nasal polyposis

  • Food allergy 

  • Eosinophilic esophagitis or gastritis

  • Suspicion of congenital or acquired immune abnormalities

  • Diagnosis and treatment of acquired immunoglobulin deficiencies

  • Persistent pruritus

Diet

Patients should avoid foods to which they are allergic.

Certain food proteins can cross-react with other proteins (e.g., latex with avocado, banana, kiwi, chestnut, pineapple, passion fruit, apricot, and grape; ragweed with watermelon, cantaloupe, and honeydew melon; tree fruits with birch pollen).

Patients must be counseled about these possible cross-reactivities and should avoid the food if it causes symptoms.

 

 

Medication

Medication Summary

Medical therapy varies somewhat depending on which type of allergic reaction is being treated. Some of the drugs and their categories are listed here, but refer to the articles on the specific allergic reaction for more detail.

Vasopressors

Class Summary

Epinephrine is the first medication that should be used to reverse effects of systemic vasodilation and increased vasopermeability observed with anaphylaxis. Although not the first choice for bronchoconstriction, epinephrine can also relieve some symptoms of bronchospasm and rhinitis. In the past, protocols called for subcutaneous or intravenous administration of epinephrine. However, studies have shown that intramuscular epinephrine leads to higher plasma levels than subcutaneous delivery. Intramuscular administration is now preferred over subcutaneous administration.[45, 46]

Predosed autoinjectable epinephrine is available in many forms, which include EpiPen, Auvi-Q, and other epinephrine auto-injectors. Three doses of each are available (0.3 mg for EpiPen, Auvi-Q, and Epinephrine auto-injector; 0.15 mg for EpiPen Jr., Auvi-Q, or Epinephrine auto-injector; 0.1 mg for Auvi-Q). EpiPen, Auvi-Q, and other epinephrine auto-injectors all come in two-packs (i.e., 2 auto-injectors). Auvi-Q comes with a trainer and is only available in the English and Spanish language.

Epinephrine (Adrenalin, EpiPen, Auvi-Q, Symjepi)

Should be administered immediately for anaphylaxis/anaphylactic shock. Multiple preparations allow for delivery SC, IM, IV, or ET. Doses can be repeated q5min prn to maintain blood pressure (and as heart rate allows).

Bronchodilators

Class Summary

Inhaled bronchodilators are beta-agonists that come in short- and long-acting forms.

Short-acting bronchodilators (i.e., albuterol, levalbuterol) are used to treat acute bronchospasm. Can also be used prophylactically before activity if needed. Levalbuterol is the R-enantiomer of albuterol and is available in nebulizer and metered dose inhaler (MDI) forms. Advantage of levalbuterol is that it is less likely to cause paradoxical bronchospasm than racemic albuterol.

Long-acting bronchodilators (e.g., salmeterol, formoterol) can be used twice daily in conjunction with inhaled glucocorticoids and to help maintain bronchodilation over 12 hours. Long acting beta-agonists are not recommended as monotherapy.[47] The FDA had issued a “black box warning” on medications containing long-acting beta-agonists due to concern for increased risk of asthma but this “black box warning” has been removed as treatment with an inhaled corticosteroid plus a long acting beta-agonist has been found to be safe and efficacious in the treatment of asthma.[48]

Formoterol have both short- and long-acting activity. Onset of action is approximately 15 min, but effects last up to 12 hours. Again, this medication should be combined with an inhaled corticosteroid and it now is being recommended for maintenance as well as rescue for asthma treatment.

Previously, MDIs were made using chlorofluorocarbons (CFCs) as the propellant. However, the use of CFCs has been phased out because of environmental concerns. For this reason, companies are now making MDIs with hydrofluoroalkane-134a (HFA), which is not damaging to the ozone layer. CFC inhalers are no longer available in the United States. The MDI formulations should be used with spacer or spacer and mask for administration.

Albuterol (ProAir HFA, Ventolin HFA, Proventil HFA)

Sympathomimetic that stimulates beta-2 receptors, leading to bronchodilation. Used for bronchospasm refractory to epinephrine with anaphylaxis. First-line choice for acute bronchospasm associated with asthma.

Salmeterol/fluticasone inhaled (Advair Diskus, Advair HFA, AirDuo RespiClick, Wixela Inhub)

Salmeterol: Selective LABA; stimulates intracellular adenyl cyclase resulting in increased cAMP levels causing bronchial smooth muscle relaxation; also inhibits release of mediators of immediate hypersensitivity from cells, especially from mast cells.

Fluticasone: Trifluorinated corticosteroid with potent anti-inflammatory activity; inhibits multiple cell types (e.g., mast cells, eosinophils, basophils, lymphocytes, macrophages, neutrophils) and mediator production or secretion (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in the asthmatic response.

Formoterol and budesonide (Symbicort)

Formoterol: Long-acting selective beta2-adrenergic agonist with rapid onset of action; acts locally as bronchodilator; stimulates intracellular adenyl cyclase, which results in increased cyclic adenosine monophosphate levels, causing relaxation of bronchial smooth muscle and inhibition of release of mast cell mediators.

Budesonide: Anti-inflammatory corticosteroid; has potent glucocorticoid activity and weak mineralocorticoid activity.

Formoterol and mometasone (Dulera)

Mometasone: Glucocorticoid; elicits local anti-inflammatory effects on respiratory tract with minimal systemic absorption.

Formoterol: Long-acting selective beta2-adrenergic agonist with rapid onset of action; acts locally as bronchodilator; stimulates intracellular adenyl cyclase, which results in increased cyclic adenosine monophosphate levels, causing relaxation of bronchial smooth muscle and inhibition of release of mast cell mediators.

Levalbuterol (Xopenex)

Used for treatment or prevention of bronchospasm. A selective beta2-agonist agent. Albuterol is a racemic mixture, while levalbuterol contains only the active R- enantiomer of albuterol. The S-enantiomer does not bind to beta2-receptors, but may be responsible for some adverse effects of racemic albuterol, including bronchial hyperreactivity and reduced pulmonary function during prolonged use.

Corticosteroids

Class Summary

Immunosuppressing agents, such as corticosteroids, can decrease inflammation. They are particularly efficacious in the treatment of skin eruptions and the underlying inflammation in asthma. Additionally, the role of corticosteroids in anaphylactic shock is limited, although believed to help prevent delayed type or biphasic of anaphylaxis.

Several different formulations are available. Depending on type of corticosteroid, oral, intravenous, and topical forms may be available. In more severe cases of anaphylaxis and asthma, intravenous forms of corticosteroids can be used initially. These can later be switched to oral forms as doses are tapered. Oral steroids are typically used to treat asthma exacerbations where prednisone, prednisolone and dexamethasone are common forms used. Dosing and duration vary greatly.

Inhaled corticosteroids are another form of corticosteroids and are key in controlling inflammation of bronchial airways and nasal mucosa in such cases in persistent asthma and allergic rhinitis. Similarly, topical corticosteroids are useful in treating atopic dermatitis.

Prednisone (Rayos)

Believed to ameliorate delayed effects of anaphylactic reactions and may limit biphasic anaphylaxis. Doses below are general guidelines for usage; dosing is highly individualized.

Dosing for asthma exacerbation is 2 mg/kg/day up to 60 mg daily for 5 days.

Methylprednisolone (Medrol, Solu-Medrol, Depo-Medrol)

Potent glucocorticoid with minimal-to-no mineralocorticoid activity.

Modulates carbohydrate, protein, and lipid metabolism and maintenance of fluid and electrolyte homeostasis.

Controls or prevents inflammation by controlling rate of protein synthesis, suppressing migration of polymorphonuclear leukocytes (PMNs) and fibroblasts, reversing capillary permeability, and stabilizing lysosomes at cellular level.

Dexamethasone (Decadron)

Believed to ameliorate delayed effects of anaphylactic reactions and may limit biphasic anaphylaxis.

Dosing for asthma exacerbation is 0.6 mg/kg/day up to 16 mg daily for 2 days.

Prednisolone (Orapred ODT, Millipred, Pediapred)

Glucocorticosteroid; elicits mild mineralocorticoid activity and moderate anti-inflammatory effects; controls or prevents inflammation by controlling rate of protein synthesis, suppressing migration of polymorphonuclear leukocytes (PMNs) and fibroblasts, reversing capillary permeability, and stabilizing lysosomes at cellular level.

Dosing for asthma exacerbation is 2 mg/kg/day up to 60 mg daily for 5 days.

Hydrocortisone (Cortef, Solu-Cortef)

Glucocorticoid; elicits mild mineralocorticoid activity and moderate anti-inflammatory effects; controls or prevents inflammation by controlling rate of protein synthesis, suppressing migration of polymorphonuclear leukocytes (PMNs) and fibroblasts, and reversing capillary permeability.

Histamine 1 receptor antagonists (antihistamines)

Class Summary

Type 1 histamine-receptor blockers act to block action of histamine on H1 receptor after its release from mast cells and basophils. Most effective when used prophylactically. Sedating first-generation and nonsedating second-generation formulations are available. Typically, sedating antihistamines have more adverse anticholinergic effects. Sedating antihistamines include diphenhydramine, hydroxyzine, cyproheptadine, chlorpheniramine, and brompheniramine. The use of sedating antihistamines are discouraged because the nonsedating antihistamines, such as cetirizine and fexofenadine, are highly efficacious with reduced central nervous system side effects. Other nonsedating antihistamines include loratadine (not as efficacious as cetirizine or fexofenadine), levocetirizine, and desloratadine. Intranasal antihistamines azelastine and olopatadine can directly help with nasal congestion. 

Oral antihistamines are indicated for allergic rhinoconjunctivitis, urticaria and/or certain types of angioedema, and an adjuvant for anaphylaxis. Second generation oral antihistamines can be dosed up to 4 times the recommended dosage for the treatment of recalcitrant chronic urticaria. 

Intranasal antihistamines are indicated for seasonal allergic rhinitis (olopatadine and azelastine), perennial allergic rhinitis (azelastine) and vasomotor rhinitis (azelastine).

Fexofenadine (Allegra)

Selectively inhibits histamine H1 receptor sites in blood vessels, GI tract, and respiratory tract, which in turn inhibits physiologic effects that histamine normally induces at H1 receptor sites. Once-daily dosing is convenient.

Cetirizine (Zyrtec, Quzyttir)

Selectively inhibits histamine H1 receptor sites in blood vessels, GI tract, and respiratory tract, which in turn inhibits physiologic effects that histamine normally induces at H1 receptor sites. Once-daily dosing is convenient. Bedtime dosing may be useful as sedation occurs in 10-15% of persons using cetirizine.

Levocetirizine (Xyzal)

Selectively inhibits histamine H1 receptor sites in blood vessels, GI tract, and respiratory tract, which in turn inhibits physiologic effects that histamine normally induces at H1 receptor sites.

Desloratadine (Clarinex)

Long-acting antihistamine (H1 receptor antagonist). Selectively inhibits receptor sites in blood vessels, GI tract, and respiratory tract, which in turn inhibits physiologic effects that histamine normally induces at H1 receptor sites.

Loratadine (Claritin, Alavert)

Long-acting antihistamine (H1 receptor antagonist). Selectively inhibits receptor sites in blood vessels, GI tract, and respiratory tract, which in turn inhibits physiologic effects that histamine normally induces at H1 receptor sites.

Azelastine (Astepro)

Effective antihistamine delivered via the intranasal route. Mechanism is similar to oral antihistamines. Systemic absorption occurs and may cause sedation, headache, and nasal burning. Forms complex with histamine for H1-receptor sites in blood vessels, GI tract, and respiratory tract.

Use prn or qd. Use alone or in combination with other medications. Unlike oral antihistamines, has some effect on nasal congestion. Helpful for vasomotor rhinitis. Some patients experience a bitter taste. Systemic absorption may occur, resulting in sedation (reported in approximately 11% of patients).

Olopatadine intranasal (Patanase)

Effective antihistamine delivered via the intranasal route. Mechanism is similar to oral antihistamines. Systemic absorption occurs and may cause sedation, headache, and nasal burning. Forms complex with histamine for H1-receptor sites in blood vessels, GI tract, and respiratory tract.

Administer once daily or as necessary. Use alone or in combination with other medications. Unlike oral antihistamines, has some effect on nasal congestion. Helpful for vasomotor rhinitis. Some patients experience a bitter taste. Systemic absorption may occur, resulting in sedation (reported in approximately 11% of patients).

Histamine 2 receptor antagonists (H2 antagonists)

Class Summary

Examples include ranitidine, famotidine, and cimetidine. Even though cimetidine has been studied more extensively than ranitidine and famotidine for allergic problems; ranitidine and famotidine should be used given the significant drug interactions of cimetidine with other medications.

Ranitidine (Zantac)

On 4/1/2020, the FDA requested all manufacturers withdraw all prescription and over-the-counter ranitidine drugs from the market immediately. This request was due to the presence of a contaminant in ranitidine called NMDA (N-Nitrosodimethylamine).

Used in the treatment of chronic idiopathic urticaria: If no response to H1-receptor antagonists alone, coadministration with an H2-receptor antagonist can help relieve symptoms

Also used as an adjuvant in anaphylaxis therapy.

Famotidine (Pepcid, Heartburn Relief Max)

H2 receptor antagonist. used in the treatment of chronic idiopathic urticaria: If no response to H1-receptor antagonists alone, coadministration with an H2-receptor antagonist can help relieve symptoms.

Also used as an adjuvant in anaphylaxis therapy.

Leukotriene inhibitors

Class Summary

Leukotrienes are synthesized by degranulated mast cells and basophils and contribute to symptoms of asthma (smooth muscle contraction, airway edema) and allergic rhinitis.

Montelukast (Singulair)

A selective and competitive inhibitor of the cysteinyl leukotriene receptor. Cysteinyl leukotrienes and leukotriene receptor binding has been associated with inflammatory process that contributes to the symptoms and signs of asthma.

FDA approved for asthma, allergic rhinitis (perennial and seasonal), and exercise-induced bronchoconstriction (administered 2 hr before activity). Used off-label for chronic urticaria.

The prescribing information includes a black box warning for neuropsychiatric side effects including suicidal ideations.

Zafirlukast (Accolate)

Inhibits bronchoconstriction as competitive receptor antagonist of leukotrienes D4 & E4; receptor occupation and cysteinyl leukotriene production have been associated with the pathophysiology of asthma. 

 

Immunomodulators

Class Summary

Topical tacrolimus and pimecolimus are calcineurin inhibitors that can be used to treat atopic dermatitis that does not respond well to topical corticosteroids. Systemic calcineurin inhibitors have been shown to cause immunosuppression and certain malignancies such as lymphoma. In January 2006, the FDA issued a black box warning for topical tacrolimus and pimecrolimus for these reasons.[43] To date, studies have not shown significant systemic absorption, systemic immunosuppression, or increased risk of malignancy with the topical formulations. 

Tacrolimus ointment (Protopic)

Reduces itching and inflammation by suppressing release of cytokines from T cells. Suppresses cellular immunity (inhibits T-lymphocyte activation), by binding to an intracellular protein, FKBP-12 and complexes with calcineurin-dependent proteins to inhibit calcineurin phosphatase activity. FDA approved for the treatment of moderate-to-severe atopic dermatitis

Pimecrolimus (Elidel)

Calcineurin inhibitor; inhibits T-cell activation; also shown to inhibit release of inflammatory mediators from mast cells. Inhibits T-cell activation by binding with high affinity to macrophilin-12 (FKBP-12) and inhibiting the calcium-dependent phosphatase, calcineurin. As a consequence, it inhibits T cell activation by blocking the transcription of inflammatory cytokines.

 

Monoclonal Antibodies

Class Summary

Monoclonal antibodies can greatly improve severity of allergic reactions and prevent anaphylaxis.

Omalizumab (Xolair)

Binds free IgE thereby preventing IgE from binding to the high-affinity IgE receptor on mast cells and basophils. Also decreases free total IgE to down-regulate expression of the high-affinity IgE receptor. FDA approved for patients with moderate-to-severe persistent asthma with sensitization to a perennial aeroallergen and uncontrolled on inhaled corticosteroid therapy. 

Also shown to decrease allergic response to peanuts in patients with severe peanut allergy, which could be helpful in preventing anaphylaxis from accidental peanut exposure. 

Patients should undergo a full allergy evaluation prior to starting therapy, if needed, because it interferes with prick skin test and in vitro serum specific IgE assay results.

Mepolizumab (Nucala)

Monoclonal antibody that binds and inhibits the bioactivity of IL-5, the cytokine responsible for growth and differentiation, activation, recruitment, and survival of eosinophils. FDA approved as add-on maintenance therapy for patients with severe eosinophilic asthma.

Dupilumab (Dupixent)

Monoclonal antibody that binds to IL-4R alpha subunit (shared by IL-4 and IL-13) to inhibit IL-4 and IL-13 cytokine-induced inflammatory responses. FDA approved as add-on maintenance therapy in patients with moderate-to-severe asthma in patients with an eosinophilic phenotype or with oral corticosteroid-dependent asthma.

Also approved for moderate-to-severe atopic dermatitis in patients whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. It may be used with or without topical corticosteroids

Approved also as add-on maintenance treatment in patients with inadequately controlled chronic rhinosinusitis with nasal polyposis.

Benralizumab (Fasenra)

Monoclonal antibody that directly binds to the alpha-subunit of the human interleukin-5 receptor to reduce the production and survival of basophils and eosinophils through antibody-dependent cell-mediated cytotoxicity.

FDA approved as add-on maintenance therapy of severe asthma in patients with an eosinophilic phenotype.

Reslizumab (Cinqair)

Monoclonal antibody that binds free interleukin-5 (IL-5) to reduce the production and survival of eosinophils, a cell type involved in inflammatory responses.

FDA-approved as add-on maintenance therapy for severe asthma with an eosinophilic phenotype.

5-Lipoxygenase Inhibitors

Class Summary

These agents inhibit leukotriene formation.

Zileuton (Zyflo, Zyflo CR)

Inhibitor of 5-lipoxygenase, which inhibits formation of leukotrienes (LTB4, LTC4, LTD4, & LTE4). Inhibition of leukotriene formation reduces eosinophil and neutrophil migration, neutrophil and monocyte aggregation, capillary permeability, and smooth muscle contraction.

FDA-approved as add-on maintenance therapy in asthma patients.

 

Follow-up

Deterrence/Prevention

Avoidance of the allergen is the best method of prevention, but this is not always possible (e.g., avoiding insect stings). For this reason, patients should always have their rescue medications with them (e.g., EpiPen, albuterol MDI). Allergen-specific immunotherapy is known to be disease modifying for aeroallergens and stinging insect venom.

Patient Education

Patients with a known inciting agent should be advised in avoidance techniques, including immunologic cross-reactivity as is encountered in latex allergies.

Patients must be educated in the proper use of their maintenance and rescue medications.

For patient education resources, see the Allergic Reaction and Anaphylactic Shock Center and Skin, Hair, and Nails Center, as well as Severe Allergic Reaction (Anaphylactic Shock) and Hives and Angioedema.