Background
The immune system is an integral part of human protection against disease, but the normally protective immune mechanisms can sometimes cause detrimental reactions in the host. Such reactions are known as hypersensitivity reactions, and the study of these is termed immunopathology. The traditional classification for hypersensitivity reactions is that of Gell and Coombs and is currently the most commonly known classification system. It divides the hypersensitivity reactions into the following 4 types:
- Type I reactions (ie, immediate hypersensitivity reactions) involve immunoglobulin E (IgE)–mediated release of histamine and other mediators from mast cells and basophils.
- Type II reactions (ie, cytotoxic hypersensitivity reactions) involve immunoglobulin G or immunoglobulin M antibodies bound to cell surface antigens, with subsequent complement fixation.
- Type III reactions (ie, immune-complex reactions) involve circulating antigen-antibody immune complexes that deposit in postcapillary venules, with subsequent complement fixation.
- Type IV reactions (ie, delayed hypersensitivity reactions, cell-mediated immunity) are mediated by T cells rather than by antibodies.
Some authors believe this classification system may be too general and are now in favor of a more recent classification system proposed by Sell et al. 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 . 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 rhinitis, some types of drug reactions, and atopic dermatitis. These reactions tend to be mediated by IgE, which differentiates them from anaphylactoid reactions that involve IgE-independent mast cell and basophil degranulation. Such reactions can be caused by iodinated radiocontrast dye, opiates, or vancomycin and appear similar clinically by resulting in urticaria or anaphylaxis.
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.
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.
Pathophysiology
Immediate hypersensitivity reactions are mediated by IgE, but T and B cells play important roles in the development of these antibodies. CD4 cells or helper T (TH) cells have been divided into 2 broad classes based on the cytokines they produce.
TH1 cells produce interferon gamma, interleukin (IL)–2, and tumor necrosis factor-beta and promote a cell-mediated immune response (eg, delayed hypersensitivity reaction). TH2 cells, on the other hand, produce IL-4 and IL-13, which then act on B cells to promote the production of antigen-specific IgE. Therefore, TH2 cells play an important role in the development of immediate hypersensitivity reactions, and patients who are atopic are thought to have a higher TH2-to-TH1 cell ratio. Interestingly, the cytokines produced by TH1 cells (specifically interferon gamma) seem to diminish the production of TH2 cells.
The allergic reaction first requires sensitization to a specific allergen and occurs in genetically predisposed individuals. The allergen is either inhaled or ingested and is then processed by the dendritic cell, an antigen-presenting cell. The antigen-presenting cells then migrate to lymph nodes, where they prime naive TH cells (TH0 cells) that bear receptors for the specific antigen.
TH0 cells are undifferentiated CD4 cells that release both TH1 and TH2 cytokines and can develop into either cell type. In the case of allergen sensitization, the TH0 cells are thought to be exposed to IL-4 (from as yet unidentified sources, but including germinal-center B cells) and possibly to histamine-primed dendritic cells, both of which cause them to develop into TH2 cells. These primed TH2 cells then release more IL-4 and IL-13. IL-4 and IL-13 then act on B cells to promote production of antigen-specific IgE antibodies.
For this to occur, B cells must also bind to the allergen via allergen-specific receptors. They then internalize and process the antigen and present it to the TH2 cells on the major histocompatibility class II molecules found on B-cell surfaces. The B cell must also bind to the TH2 cell and does so by binding the CD40 expressed on its surface to the CD40 ligand on the surface of the TH2 cell. IL-4 and IL-13 released by the TH2 cells can then act on the B cell to promote class switching from immunoglobulin M production to antigen-specific IgE production.
The antigen-specific IgE antibodies can then bind to high-affinity receptors located on the surfaces of mast cells and basophils. Reexposure 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 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:
Preformed mediators
- 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, nasal mucus production, airway mucus production, pruritus, cutaneous vasodilation, and gastric acid secretion.
- Tryptase: Tryptase is a major protease released by mast cells; its exact role is uncertain, but it can cleave C3 and C3a. Tryptase is found in all human mast cells but in few other cells and 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 alpha-tryptase.
- Chemotactic factors: An eosinophilic chemotactic factor of anaphylaxis causes eosinophil chemotaxis; an inflammatory factor of anaphylaxis results in neutrophil chemotaxis. Eosinophils release major basic protein and, together with the activity of neutrophils, can cause significant tissue damage in the later phases of allergic reactions.
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, increase vascular permeability, and cause 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, coronary and pulmonary artery vasoconstrictor, platelet aggregation inhibitor, neutrophil chemoattractant, and enhancer of histamine release from basophils
- Prostaglandin F2 - Bronchoconstrictor, peripheral vasodilator, coronary vasoconstrictor, and platelet aggregation inhibitor
- Thromboxane A2 - Causes vasoconstriction, platelet aggregation, and bronchoconstriction
- Platelet-activating factor: This 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, and it potentiates IgE-induced mast cell mediator release.
- Bradykinin: Kininogenase released from the mast cell can act on plasma kinins to produce bradykinin. 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.
Cytokines
- IL-4: This stimulates and maintains TH2 cell proliferation and switches B cells to IgE synthesis.
- IL-5: This cytokine is key in the maturation, chemotaxis, activation, and survival of eosinophils. IL-5 primes basophils for histamine and leukotriene release.
- IL-6: IL-6 promotes mucus production.
- IL-13: This cytokine has many of the same effects as IL-4.
- Tumor necrosis factor-alpha: This activates neutrophils, increases monocyte chemotaxis, and enhances production of other cytokines by T cells.
The actions of the above 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 then pruritic.
- Allergic rhinitis: Release of the above mediators in the upper respiratory tract can result in sneezing, 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, shortness of breath, and wheezing.
- Anaphylaxis: Release of the above mediators that affect more than one system is known as anaphylaxis. In addition to the foregoing, the GI system can also be affected with symptoms of nausea, abdominal cramping, and diarrhea. Systemic vasodilation and vasopermeability can result in significant hypotension and is referred to as anaphylactic shock. This can be life threatening.
Allergic reactions can occur as immediate reactions, late-phase reactions, 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.
These and other cells (eg, 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 24-48 hours.
Finally, continuous or repeated exposure to an allergen (eg, a cat-owning patient who is allergic to cats) 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 (eg, major basic protein), which can cause tissue damage and thus increase inflammation. This can result 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.
Frequency
United States
- The prevalence of atopic diseases has increased significantly over the past 2 decades in Western societies.
- Allergic rhinitis is the most prevalent allergic disease; it affects approximately 22% or more of the population.
- Asthma is estimated to affect more than 20 million people. Ninety-five percent of asthma cases in children are estimated to be allergic, compared with 50-70% in adults.
- Atopic dermatitis has also increased in prevalence over the past 20 years; prevalence in the United States is likely similar to that in Europe (see below, Internationally).
- The prevalence of anaphylaxis has been much more difficult to assess.
International
- The estimated prevalence of atopic dermatitis among school children in various European countries is 15-20%.
- Asthma, as with other atopic diseases, is increasing in prevalence.
- Studies in Africa and Europe have shown a greater prevalence of reversible bronchospasm in urban populations compared with rural populations. This was initially thought to be related to environmental pollution, but the results from studies of asthma prevalence before and after the unification of Germany contradict this theory.
- The prevalence of asthma in East Germany prior to 1990 was lower than in West Germany, despite the fact that East Germany had more air pollution.
- Over the 10 years after unification, the prevalence of asthma in the former East Germany increased and is now comparable with that of former West Germany.
- Studies in Africa and Europe have shown a greater prevalence of reversible bronchospasm in urban populations compared with rural populations. This was initially thought to be related to environmental pollution, but the results from studies of asthma prevalence before and after the unification of Germany contradict this theory.
- In addition, children placed in day care and with older siblings have a lower likelihood of developing atopic disease.
- These findings have led to the hygiene hypothesis, which proposes that early exposure to infectious agents helps direct the immune system toward a TH1 cell–predominant response that, in turn, inhibits the production of TH2 cells.
Mortality/Morbidity
- Mortality from allergic diseases occurs primarily from anaphylaxis and asthma, although deaths from asthma are relatively rare. In 1995, 5579 people died from asthma in the United States. Approximately 500 people die annually from anaphylaxis in the United States.
- Allergic diseases are a significant cause of morbidity. In 1990, the economic impact of allergic diseases in the United States was estimated to be $6.4 billion from health care costs and lost productivity. Children with untreated allergic rhinitis do worse on aptitude tests than their nonatopic peers.
Race
- Any differences in the prevalence of allergic diseases with respect to race seem to be more related to environmental factors than to true racial differences. For example, in the United States, the prevalence of asthma is 2.5 times higher in African Americans than in whites. Asthma is more prevalent in inner-city populations, and this may explain the difference.
Sex
- Some unexplained differences exist in the prevalence of allergic diseases between the sexes. Asthma is more prevalent in boys during the first decade of life; after puberty, prevalence is higher in females. The male-to-female ratio of children who have atopic disease is approximately 1.8:1.
- Skin test reactivity in women can fluctuate with the menstrual cycle, but this is not clinically significant.
Age
- In general, allergic rhinitis symptoms (and skin test reactivity) tend to wane with increasing age.
- Food allergies and subsequent anaphylaxis are more prevalent in children. Some children may outgrow their allergies to certain foods, or their reactions may diminish over time. However, anaphylaxis from food and other triggers is still a threat in adults.
- Childhood asthma is more prevalent in boys and can often resolve by adulthood. However, females tend to develop asthma later in life (beginning in adolescence) and can also have asthma that is more severe.
Medical Care
- Anaphylaxis
- Assessment of the reaction is described as follows:
- Withdraw the offending agent if applicable (eg, 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.
- Withdraw the offending agent if applicable (eg, stop drug infusion).
- Treatment is as follows:
- Administer epinephrine immediately .
- Start intravenous fluids; these should be administered rapidly and as blood pressure and overall fluid status warrant.
- Consider other vasopressors (eg, 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. Cimetidine, when combined with any of several H1 antihistamines, has been demonstrated to block histamine-induced hypotension. Other H2 blockers have not been studied in this context.
- 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.
- Administer epinephrine immediately .
- Prevention is as follows:
- Avoid the triggering allergen as much as possible.
- Patients should be given a prescription for at least 2 predosed epinephrine pens (EpiPens) and instructed in their proper use. Importantly, patients must carry these pens at all times.
- Patients should be taught what measures to take in case of a future anaphylactic reaction, ie, immediately administer epinephrine, call emergency services (eg, 911), or go to the nearest emergency department (even if feeling better after the epinephrine).
- Avoid the triggering allergen as much as possible.
- Assessment of the reaction is described as follows:
- Allergic rhinitis
- Avoid the offending allergen, if possible.
- 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.
- Other topical nasal agents include azelastine (an H1-receptor blocker) and cromolyn (a mast cell stabilizer).
- Topical decongestants, mast cell stabilizers, or antihistamines can be used for ocular symptoms; artificial tears might be helpful in mild cases, and this product can be refrigerated for an extra cooling effect. Cold compresses can also be used.
- Antigen-injection immunotherapy should be considered for symptoms not well controlled with medications. The mechanism of action of immunotherapy is not yet fully elucidated. Immunotherapy causes antigen-specific immunoglobulin G to be formed and lowers antigen-specific IgE over time. Some authorities theorize that immunotherapy results in an increase in the TH1-to-TH2 cell ratio. Regulatory T cells may also play an important role.
- Avoid the offending allergen, if possible.
- 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.
- Patients should have an albuterol metered-dose inhaler (MDI) (or nebulizers for young children) to use as needed.
- Long-acting beta-agonists and inhaled glucocorticosteroids should be added if appropriate. In general, these medications are used if symptoms occur more than twice weekly or if spirometry findings are abnormal in the absence of symptoms.
- Leukotriene inhibitors can also be added.
- Systemic steroid bursts may need to be used for exacerbations of severe cases.
- In patients refractory to the usual medications and who have antigen-specific IgE to environmental aeroallergens (positive skin test or RAST result), therapy with omalizumab (Xolair), a humanized monoclonal antibody that prevents binding of IgE to high-affinity IgE receptors on mast cells and basophils, may result in improvement.
- Patients should have an albuterol metered-dose inhaler (MDI) (or nebulizers for young children) to use as needed.
- Avoid the offending allergen, if possible.
- Urticaria/angioedema
-
- Avoid the offending allergen if known.
- An H1-receptor blocker should be added. If symptoms are not controlled with this alone, an H2-receptor blocker, leukotriene inhibitor, or oral glucocorticosteroid can be added.
- Avoid the offending allergen if known.
- Atopic dermatitis
- Avoid the offending allergen if possible, and properly hydrate and care for the skin.
- Topical glucocorticosteroids and topical immunomodulators (eg, tacrolimus) can be used.
- Avoid the offending allergen if possible, and properly hydrate and care for the skin.
Consultations
- Consultation with a pulmonologist and/or critical care medicine specialist may be necessary for anaphylactic shock or severe asthma exacerbations.
- Consult an allergist or immunologist for the following conditions:
-
- Allergic rhinitis not easily controlled with medications
- Asthma: Of patients with asthma, 50% have allergies as factors causing or contributing to their asthmatic inflammation.
- Chronic urticaria (>6 wk)
- 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
- Allergic rhinitis not easily controlled with medications
Diet
- Patients should avoid foods to which they are allergic.
-
- Certain food proteins can cross-react with other proteins (eg, latex with avocado, banana, kiwi, chestnut, pineapple, passion fruit, apricot, and grape; ragweed with watermelon, cantaloupe, honeydew melon).
- Patients must be counseled about these possible cross-reactivities and should avoid the food if it causes symptoms.
- Certain food proteins can cross-react with other proteins (eg, latex with avocado, banana, kiwi, chestnut, pineapple, passion fruit, apricot, and grape; ragweed with watermelon, cantaloupe, honeydew melon).
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.
Drug Category: Vasopressors
First-line choice 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.
| Drug Name | Epinephrine (Adrenalin, Bronitin, EpiPen) |
|---|---|
| Description | 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). |
| Adult Dose | IM: 0.25-0.50 mL of a 1:1000 solution for moderate symptoms; repeat prn; anterior lateral thigh is preferred site for severe anaphylaxis IV: 0.5-1 mL of 1:10,000 solution for severe symptoms; repeat prn; continuous infusion at 0.1-1 mcg/kg/min may be required for anaphylactic shock ET: 1 mL of 1:10,000 solution in 10 mL NS; repeat prn Self-injection (IM): Preloaded auto-injector (EpiPen) |
| Pediatric Dose | IM: 0.01 mg/kg of 1:1000 solution; repeat q5min prn; not to exceed 0.3-0.5 mg; anterior lateral thigh is preferred site for severe anaphylaxis IV: 0.01 mg/kg of 1:10,000 solution; repeat prn ET: 0.01 mg/kg of a 1:1000 solution in 5 mL NS; repeat prn Self-injection (IM): Preloaded auto-injector (EpiPen Jr) |
| Contraindications | Documented hypersensitivity; relative (not absolute) contraindications include severe CAD, hypertension, narrow-angle glaucoma, and presence of life-threatening arrhythmias |
| Interactions | Beta-blockers decrease effectiveness; may decrease effectiveness of diabetic medications; MAOIs, methyldopa, methylphenidate, TCAs, thyroxine, and sodium bicarbonate can potentiate effects of all sympathomimetics |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Consult PDR for all possible adverse effects; caution should be used in patients with known severe CAD, advanced age, prostatic hypertrophy, hypertension, cardiovascular disease, diabetes mellitus, hyperthyroidism, and cerebrovascular insufficiency; rapid IV infusions may cause death from cerebrovascular hemorrhage or cardiac arrhythmias |
Drug Category: Bronchodilators
Inhaled bronchodilators are beta-agonists that come in short- and long-acting forms. Short-acting bronchodilators are used to treat acute bronchospasm. Can also be used prophylactically. For example, a patient with a history of asthma exacerbation in the presence of cats can use a short-acting bronchodilator before exposure to cats. Long-acting bronchodilators (eg, salmeterol) can be used twice daily and to help maintain bronchodilation over 12 h. Pirbuterol is now available and is both a short- and long-acting form. Onset of action is approximately 15 min, but effects last up to 12 h. Finally, levalbuterol is the R-enantiomer of albuterol and is available in nebulizer form. Advantage of levalbuterol is that it is less likely to cause paradoxical bronchospasm than racemic albuterol.
Previously, MDIs were made using chlorofluorocarbons (CFCs) as the propellant. However, the use of CFCs is being phased out because of environmental concerns. For this reason companies are now making MDIs with hydrofluoroalkane-134A, which is not damaging to the ozone layer. By 2006, products will no longer contain CFCs. Importantly, note that while a spacer should be used with traditional MDIs, spacers are not necessary for inhalers with hydrofluoroalkane-134A.
| Drug Name | Albuterol (Ventolin, Ventolin HFA, Airet, Proventil, Proventil HFA) |
|---|---|
| Description | 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. |
| Adult Dose | 1.25-5 mg in 2-5 mL of sterile 0.9% NS solution via nebulization 2-4 puffs via MDI q4-6h prn; not to exceed 12 puffs/d |
| Pediatric Dose | PO 2-5 years: 0.1-0.2 mg/kg/dose divided tid; not to exceed 12 mg/d 5-12 years: 2 mg/dose divided tid or qid; not to exceed 24 mg/d MDI <12 years: 1-2 puffs qid with tube spacer >12 years: Administer as in adults Nebulizer <5 years: 1.25-2.5 mg in 1-2.5 mL q4-6h; to make solution, dilute 0.25-0.5 mL (1.25-2.5 mg) of 0.5% inhalation solution in 1-2.5 mL of NS >5 years: Administer as in adults |
| Contraindications | Documented hypersensitivity; relative contraindications include severe CAD, hypertension, narrow-angle glaucoma, and presence of life-threatening arrhythmias |
| Interactions | Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of bronchodilation; cardiovascular effects may increase with MAOIs, inhaled anesthetics, TCAs, and sympathomimetic agents |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Anecdotally, has been used during pregnancy for approximately 40 y and detrimental effects have not been reported; consult PDR for all possible adverse effects; caution in hyperthyroidism, diabetes mellitus, and cardiovascular disorders |
Drug Category: Corticosteroids
Immunosuppressing agents and, thus, can decrease inflammation. Have particular efficacy in skin eruptions and bronchospasm. Role in anaphylactic shock is limited, although believed to help prevent delayed type of anaphylaxis.
Several different formulations are available; only one is listed. Others include methylprednisolone, dexamethasone, prednisolone (often used in children), and hydrocortisone. 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.
Inhaled corticosteroids are another form of corticosteroids and are key in controlling inflammation of bronchial airways and nasal mucosa. Similarly, topical corticosteroids are useful in treating atopic dermatitis.
| Drug Name | Prednisone (Deltasone, Orasone, Meticorten) |
|---|---|
| Description | Believed to ameliorate delayed effects of anaphylactic reactions and may limit biphasic anaphylaxis. Doses below are general guidelines for usage; dosing is highly individualized. |
| Adult Dose | 5-60 mg/d PO qd or divided bid/qid; taper over 2 wk as symptoms resolve |
| Pediatric Dose | 1-2 mg/kg PO qd or divided bid/qid; taper over 2 wk as symptoms resolve |
| Contraindications | Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connective-tissue infections, and fungal or tubercular infections; GI disease |
| Interactions | Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Abrupt discontinuation after long-term use (4-6 wk) can result in adrenal insufficiency/crisis; although relatively safe for short-term usage, long-term use can result in undesirable adverse effects, including osteoporosis, cataracts, and weight gain; patients who are on long-term steroids should be placed on a bisphosphonate and calcium/vitamin D supplementation for osteoporosis prevention; consult PDR for all possible adverse effects; may worsen diabetes mellitus, congestive heart failure, infections, peptic ulcer disease, volume status, myasthenia gravis, and psychoses; hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications |
Drug Category: Histamine1-receptor antagonists (antihistamines)
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 and nonsedating second-generation H1 antihistamines are available. Typically, sedating antihistamines have more adverse anticholinergic effects. Sedating antihistamines include diphenhydramine, hydroxyzine, cyproheptadine, chlorpheniramine, and brompheniramine. Nonsedating antihistamines include cetirizine (cause drowsiness in 15% people), fexofenadine, loratadine, and desloratadine. Desloratadine and fexofenadine may also help decrease nasal congestion.
| Drug Name | Diphenhydramine (Benadryl, Dihydrex injection, Belix) |
|---|---|
| Description | Most widely available antihistamine (available OTC). Sedating antihistamines may be necessary to control more severe allergic reactions because they are very potent. Dosing interval of diphenhydramine is 4-6 h. Nonsedating antihistamines are all now available in a 24-h formulation but can only be administered PO. |
| Adult Dose | 12.5-50 mg PO/IV/IM q4-6h; not to exceed 400 mg qd |
| Pediatric Dose | <6 years: 5 mg/kg/d PO/IV; not to exceed 300 mg qd 6-12 years: 12.5-25 mg PO q6-8h; not to exceed 300 mg qd >12 years: Administer as in adults |
| Contraindications | Documented hypersensitivity; MAOIs |
| Interactions | Potentiates effect of CNS depressants; because of alcohol content, do not administer syrup dosage form to patients taking medications that can cause disulfiramlike reactions |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Warn patients to not drive or operate heavy machinery; administer with caution to elderly patients, patients with a seizure history, and children; can have additive adverse anticholinergic effects and can cause somnolence; may exacerbate angle-closure glaucoma, hyperthyroidism, peptic ulcer, or urinary tract obstruction; xerostomia may occur; consult PDR for all possible adverse effects |
Drug Category: Histamine2- antagonists
Can be administered in addition to H1-receptor blockers for additional control of urticaria and angioedema. Examples include ranitidine, famotidine, and cimetidine. Cimetidine has been studied more extensively for this indication than other members of this class.
| Drug Name | Ranitidine (Zantac) |
|---|---|
| Description | Multiple formulations are available. Cimetidine was first to be widely used but tends to have more drug interactions than other H2-receptor blockers. If no response to H1-receptor antagonist alone, coadministration with an H2-receptor antagonist can help relieve symptoms of itching and flushing in anaphylaxis, pruritus, and urticaria. Cimetidine plus an H1 blocker blocks cardiovascular effects of histamine. |
| Adult Dose | 150 mg PO bid; not to exceed 600 mg/d; alternatively, 50 mg/dose IV/IM q6-8h |
| Pediatric Dose | <12 years: Not established >12 years: 1.25-1.5 mg/kg/dose PO q12h; not to exceed 300 mg/d; alternatively, 0.75-1.5 mg/kg/dose IV/IM q6-8h; not to exceed 400 mg/d |
| Contraindications | Documented hypersensitivity |
| Interactions | May decrease effects of ketoconazole and itraconazole; may alter serum levels of ferrous sulfate, diazepam, nondepolarizing muscle relaxants, and oxaprozin |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Caution in renal or liver impairment; if changes in renal function occur during therapy, consider adjusting dose or discontinuing treatment; consult PDR for all possible adverse effects |
Drug Category: Leukotriene inhibitors
Synthesized by degranulated mast cells and basophils and likely contribute significantly to symptoms of allergic reactions. Three leukotriene inhibitors are now available in the United States. Montelukast and zafirlukast act as leukotriene-receptor blockers, whereas zileuton acts to inhibit production of leukotrienes. Disadvantage of the latter medication is its qid dosing.
| Drug Name | Montelukast (Singulair) |
|---|---|
| Description | Leukotriene inhibitors can be a helpful addition to asthma and allergic rhinitis not well controlled with H1-receptor blockers and inhaled corticosteroids. |
| Adult Dose | 10 mg PO qd |
| Pediatric Dose | <2 years: Not established 2-5 years: 4 mg PO every pm 6-14 years: 5 mg PO every pm |
| Contraindications | Documented hypersensitivity |
| Interactions | Phenobarbital and rifampin reduce effects |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Not indicated to reverse acute asthma attacks; not for use as monotherapy in management of exercise-induced bronchospasm; consult PDR for all possible adverse effects |
Drug Category: Immunomodulators
Tacrolimus is an immunomodulator initially used in oral form as an immunosuppressant for transplantation patients. It has since been developed in topical form (Protopic) and can be used to treat atopic dermatitis that does not respond well to topical corticosteroids. A similar topical agent, pimecrolimus (Elidel), became available in the past few years and is indicated for mild atopic dermatitis. Trials are currently underway to assess possible benefit of inhaled tacrolimus for asthma.
| Drug Name | Tacrolimus (Protopic) |
|---|---|
| Description | Reduces itching and inflammation by suppressing release of cytokines from T cells. Can be used in patients as young as 2 y. More expensive than topical corticosteroids. |
| Adult Dose | Apply 0.03% ointment or 0.1% ointment to affected areas bid |
| Pediatric Dose | <2 years: Not established >2 years: Administer as in adults |
| Contraindications | Documented hypersensitivity to tacrolimus or components of ointment |
| Interactions | None reported |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | May cause burning sensation during first few days of application; skin can become photosensitive, and patients should be cautioned about exposure to direct or artificial sunlight and to use sunscreen; safety and efficacy in infected atopic dermatitis is not known; application under occlusion, which may promote systemic exposure, has not been evaluated (do not use with occlusive dressings); absorption following topical applications is minimal (relative to systemic administration), but tacrolimus is excreted in human milk, and thus, a decision should be made whether to discontinue nursing or to discontinue drug, taking into account importance of drug to mother (potential for serious adverse reactions in nursing infants should also be a concern); consult PDR for listing of all adverse effects |
Drug Category: Monoclonal antibodies
Omalizumab (Xolair) is a monoclonal anti-IgE antibody indicated for refractory asthma. Has been shown to greatly improve severity of asthma in patients and can be used to help patients dependent on oral steroids to be weaned from steroids. Omalizumab has also been shown to decrease allergic response to peanuts in patients with severe peanut allergy. This could be helpful in preventing anaphylaxis from accidental peanut exposure in patients who normally would not tolerate even the slightest exposure to peanut allergen, but it only has FDA approval for asthma at this time. Patients should undergo a full allergy evaluation prior to starting omalizumab, if needed, because it interferes with prick skin test and RAST results.
| Drug Name | Omalizumab (Xolair) |
|---|---|
| Description | Binds to IgE and thereby prevents IgE from binding to mast cells and basophils. |
| Adult Dose | Dependent on serum IgE level and body weight Serum IgE 30-100 30-90 kg: 150 mg SC monthly 90-150 kg: 300 mg SC monthly Serum IgE levels 101-200 30-90 kg: 300 mg SC monthly 90-150 kg: 225 mg twice monthly Serum IgE 201-300 30-60 kg: 300 mg monthly 61-90 kg: 225 mg twice monthly 91-150 kg: 300 mg q2wk Serum IgE levels 301-400 30-70 kg: 225 mg twice monthly 71-90 kg: 300 mg q2wk Serum IgE 401-500 30-70 kg: 300 mg q2wk 70-90 kg: 375 mg twice monthly Serum IgE 501-600 30-60 kg: 300 mg q2wk 61-70 kg: 375 mg q2wk Serum IgE 601-700 30-60 kg: 375 mg q2wk Manufacturer did not seek approval for dosing with IgE >700 or for IgE 601-700 for people weighing >60 kg because high resultant doses would be cost prohibitive |
| Pediatric Dose | >12 years: Administer as in adults |
| Contraindications | Documented hypersensitivity |
| Interactions | No formal drug interaction studies have been performed |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Not indicated to reverse acute asthma attacks; systemic or inhaled corticosteroids should not be abruptly discontinued with initiation of omalizumab; serum IgE levels increase after initiation of therapy because of omalizumab-IgE complex formation and may remain high up to 1 y after discontinuation; therefore, serum IgE levels should not be routinely checked; patients may have false-negative skin prick test and RAST results |
FOLLOW-UP
Deterrence/Prevention
- Avoidance of the allergen is the best method of prevention, but this is not always possible (eg, avoiding insect stings). For this reason, patients should always have their rescue medications with them (eg, EpiPen, albuterol MDI).
Patient Education
- Patients with a known inciting agent should be advised in avoidance techniques, including immunologic cross-reactivity as is encountered in latex allergies.
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- Patients must be educated in the proper use of their maintenance and rescue medications.
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