Beta Agonists
Beta agonists increase intracellular levels of cyclic adenosine monophosphate (cAMP), thereby reducing mediator release by mast cells and promoting vasoconstriction of cutaneous vascu-lature. Any explosive, generalized urticaria demands the subcutaneous administration of 0.2 ml of aqueous epinephrine 1:1000 (which has combined alpha-agonist and beta-agonist properties), in addition to H1 antagonists and H2 antagonists (e.g., doxepin, 10 mg). This is the treatment of choice for ana-phylaxis (see below).
Oral beta agonists have been tried for chronic urticaria and angioedema in conjunction with H1 antagonists and H2 antagonists. Terbutaline (2.5 to 5.0 mg q.i.d.) deserves a trial in patients not responding to standard treatment. Some studies have demonstrated efficacy, and others have found none.52,53
Corticosteroids
Because corticosteroids do not inhibit cutaneous mast cell degranulation, they have no effect on acute urticaria. However, these agents are often used in patients with persistent urticaria whose symptoms are disabling and unresponsive to maximum standard therapy.54 In these cases, steroids are given in a pulse dose to break the cycle of a resistant episode. The recommended starting dosage of prednisone for persistent urticaria is 0.5 to 1.0 mg/kg/day. This dosage should not be reduced until the patient shows definite clinical improvement.
A protocol for steroid therapy for patients with persistent urticaria has been recommended by the Parameters of Care Committee of the American Academy of Allergy, Asthma and Immunology.55 Daily steroids are recommended only during the first 1 or 2 weeks for patients with persistent urticaria who have had no relief for a protracted period. The goal is then to utilize an alternate-day regimen with a gradually decreasing dosage over a period of months. Patients should be started on a daily dose of prednisone, 0.5 to 1.0 mg/kg (while continuing the maximum antihistamine regimen). If the symptoms become tolerable, the prednisone dose is decreased by 5 mg every 1 to 3 days until 25 mg a day is reached. The patient’s progress is then reassessed every 1 to 2 weeks. Once the patient’s condition stabilizes, the dose is decreased by 2.5 to 5 mg every 2 to 3 weeks. When the lowest dose is reached, alternate-day therapy may be tried. Usually, the alternate-day dose is 1.5 times the daily dose. Should some rebound occur on the off day, the alternate-day treatment can be given in divided doses (at 8 A.M. and at 5 P.M.). Once a maintenance dose is reached, the dose of prednisone should be reduced by 1 mg every 1 to 2 weeks.
Other Agents
There are recent reports of success using the anabolic steroid stanozolol for chronic urticaria,56 aquagenic urticaria,57 familial cold urticaria,58 and cholinergic urticaria. Nifedipine, 20 mg three times daily, has been reported effective for chronic ur-ticaria.59 This treatment deserves further evaluation. Patients with chronic urticaria are advised to avoid aspirin and all NSAIDs, yet there are anecdotal reports of patients with urticaria who benefit from these drugs. Indomethacin has been used successfully in the management of urticarial vasculitis.60
Cyclosporine has proved effective in some cases of chronic idiopathic urticaria refractory to antihistamines, as well as in urticarial vasculitis and solar urticaria.61 Doses used are 2.5 to 6 mg/kg daily. Higher doses can cause elevation in the blood urea nitrogen (BUN) and serum creatinine levels, but these have returned to normal on discontinuance of the drug.
Leukotriene antagonists have been combined with antihista-mines for the management of allergic rhinitis and have been noted to be more effective than the antihistamine alone. Therefore, many allergists have tried this combination for urticaria, with some anecdotal success. There is nothing in the literature to support its use, however, and in my experience, the use of a leukotriene antagonist with an antihistamine offers no advantage for persistent urticaria without angioedema.
Prognosis
Except for IgE-induced urticaria, which may progress to fatal anaphylaxis, the prognosis for the other urticarias is benign, although prolonged episodes of these disorders can be extremely bothersome. To date, there is no evidence that the natural history of any of the urticarial syndromes, whether induced by an identifiable cause or idiopathic, is influenced by treatment. Almost all cases of persistent urticaria eventually resolve, however; even the majority of cases of IgE-induced urticarias (especially those without anaphylaxis) are rarely permanent. Chronic urticaria tends to last longer in elderly persons than in younger ones. Studies of chronic (persistent) idiopathic urticaria have found that with or without treatment, 50% of cases will resolve within 6 to 12 months of onset; 20%, within 12 to 36 months; and another 20%, within 36 to 60 months. Less than 2% of cases persist for 25 years or longer. Over 50% of patients will have at least one recurrence.62 Interestingly, although anaphylactic or anaphylactoid reactions have been noted in patients with identifiable causes of urticaria, there have been no reports of these reactions ever occurring in patients with persistent urticaria without an identifiable cause. More than 50% of patients with idiopathic urticaria can be made comfortable with appropriate antihistamine therapy. Immunosuppression with corticosteroid dependence occurs in fewer than 5% of patients.
Angioedema
Angioedema is an episodic, asymmetrical, nonpitting swelling of loose tissue (usually skin) [see Figure 5]. It is usually non-erythematous and nonpruritic, and it may be painless. An-gioedema rarely lasts less than 2 hours, and it frequently persists for 24 hours or longer. It may occur together with urticaria. Angioedema involving the face can be disfiguring during its course. Laryngeal swelling from angioedema may compromise the airway, leading to stridor and even asphyxiation. Gastrointestinal involvement can cause crampy abdominal pain, followed by watery diarrhea. Most cases of angioede-ma are a reaction to a food or a drug, but some episodes have no identifiable trigger. There are both hereditary and acquired forms of angioedema.
Epidemiology
It is estimated that approximately 10% of the population will experience at least one episode of angioedema.63 Angioedema occurs episodically in 50% of patients with urticaria. Of patients who have angioedema as their primary disorder, approximately 20% will also experience episodes of urticaria.64
Etiology
Angioedema can be induced by a variety of mechanisms, including IgE, inhibition of the cyclooxygenase pathway of arachi-donic acid metabolism, activation of the kinin-forming system, and activation of complement. In some patients, none of these mechanisms can be identified; these cases are labeled idiopathic.
IgE
IgE-induced angioedema resembles IgE allergy and is typically provoked by foods or drugs. It tends to occur in atopic persons and can be confirmed by prick skin testing or RAST.
Cyclooxygenase Inhibition
There is increasing evidence that the inhibition of the enzyme cyclooxygenase causes the de novo release of leukotrienes, an inflammatory mediator derived from arachidonic acid, in response to injury. Of particular interest in the skin is leukotriene B4, which can induce neutrophil chemotaxis and increase vascular permeability.65 Aspirin and other NSAIDs directly inhibit the ability of cyclooxygenase to decrease the formation of pro-staglandins and thromboxanes, but not leukotrienes, from ara-chidonic acid. Angioedema (with or without urticaria) may occur in 100% of patients with hypersensitivity to aspirin or other NSAIDs.11 Interestingly, not all patients who are hypersensitive to aspirin react to other NSAIDs,66 and in one study, only 3% of patients sensitive to both aspirin and other NSAIDs reacted to the COX-2 inhibitor rofecoxib.
Activation of the Kinin-Forming System
Bradykinin increases vascular permeability. Angiotensin-converting enzyme (ACE) inhibitors inhibit the kininase enzymes required for degradation of bradykinin, and the resulting elevation in bradykinin levels may lead to angioede-ma.68 Angioedema has been reported in approximately 0.1% to 0.5% of patients who take ACE inhibitors.69 However, because these agents are so widely used, ACE inhibitor-induced an-gioedema is relatively common.
Figure 5 Angioedema of the tongue is evident in this photograph of a 54-year-old man. This episode, the patient’s fifth, was unresponsive to epinephrine, antihistamines, and prednisone; his sixth episode required intubation for 92 hours, after which the angioedema resolved spontaneously.
Angiotensin II receptor blockers (ARBs), such as losartan and valsartan, do not increase bradykinin levels. Nevertheless, rare instances of angioedema have been reported with the use of ARBs.70
Complement Activation
Increased susceptibility to angioedema can result from either an inherited defect in C1-esterase inhibitor (C1-INH) activity or an acquired deficiency of C1-INH. The inherited form of the disease, known as hereditary angioedema, is rare. There are two principal types of hereditary angioedema: type 1, which accounts for 80% to 85% of cases and is caused by decreased production of C1-INH, and type 2, in which normal or elevated amounts of functionally deficient C1-INH are produced.71 A third, very rare form of hereditary angioedema that may be X-linked has recently been described in women.72
Acquired angioedema results from increased metabolism or destruction of C1-INH. Two types of acquired angioedema have been described. Type 1, which is caused by excessive activation of complement and subsequent consumption of C1-INH, typically occurs in patients with rheumatologic disorders and B cell lymphoproliferative diseases. Patients with type 2 produce autoantibodies against C1-INH, leading to its inactivation.73,74
Pathogenesis
Angioedema is consistently described as a variant of urticaria in which the subcutaneous tissues, rather than the dermis, are mainly involved. However, unlike urticaria, which seems to be mediated primarily by histamine, angioedema seems to be mediated primarily by bradykinin and leukotrienes. Anecdotal evidence indicates that although urticaria can be elicited with a histamine prick or intradermal injection, the injection of hista-mine deeper in the dermis does not produce angioedema. On the other hand, there are patients whose angioedema will dissipate with the administration of antihistamines (especially the combination of H1 and H2 receptor antagonists).75 These observations suggest that several vasoactive mediators are capable of producing angioedema.
Unfortunately, angioedema is almost never biopsied, so there are no documented pathologic descriptions of the disorder. The histopathology is always included with urticaria, and its morphology seems to be assumed. Teleologically, the va-sodilatation and vascular leakage occur deeper in the skin, and the specific cellular infiltrate, if any, remains uncertain.
Diagnosis
Diagnosis of angioedema is usually straightforward. Celluli-tis, edematous states, trauma (stings), and fasciitis occasionally are considerations in the differential diagnosis. Insights into causes and mechanisms of induction are derived primarily from the history.
The history in a patient with angioedema—especially one who has had repeated episodes—should include the following questions: (1) Is the angioedema always, sometimes, or never associated with urticaria? (2) Is the swelling pruritic? (3) Are there accompanying gastrointestinal symptoms (e.g., pain, nausea and vomiting, or diarrhea)? (4) Is the patient taking any medications? (5) Can the patient identify any apparent triggers for the angioedema?
Patients with IgE-induced angioedema are most likely to present with concomitant urticaria. This form of angioedema may be pruritic and may progress to an anaphylactic reaction. Typically, IgE-induced angioedema occurs within 30 minutes after contact with the IgE antigen. It is most likely to occur in atopic patients. Gastrointestinal symptoms may occur but are uncommon. IgE-induced angioedema often occurs as a drug reaction, with P-lactam antibiotics being the most common trigger.
Cyclooxygenase inhibitors (i.e., aspirin or other NSAIDs) are more apt to cause nonpruritic angioedema. NSAID-in-duced angioedema is occasionally accompanied by urticaria.
Angioedema induced by ACE inhibitors is nonpruritic and rarely occurs with urticaria. No sex predominance has been noted in patients without gastrointestinal tract involvement, but all patients with GI involvement have been women.76
Complement-activated angioedema is never pruritic and is not accompanied by urticaria. In 20% to 25% of patients with hereditary angioedema, there is no family history of the disease (these cases may represent new mutations).77 Therefore, a positive family history of hereditary angioedema is not a prerequisite for the consideration of this disorder in the differential diagnosis when typical symptoms are present. Symptoms of hereditary angioedema are usually mild or nonexistent during childhood, typically first manifesting during the second decade of life. Acquired angioedema usually develops during or after the fourth decade of life.
Hereditary and acquired angioedema have similar clinical presentations. Episodes can occur without provocation, but some episodes may be associated with trauma, medical procedures, emotional stress, menstruation, oral contraceptive use, infections, or the use of medications such as ACE inhibitors.71 Manifestations include marked edema of the skin and lining of hollow visceral organs. GI tract involvement results in varying degrees of intestinal obstruction, with severe abdominal pain, nausea, and vomiting. Despite the absence of fever and leuko-cytosis, these cases are often mistaken for an acute abdomen, which occasionally leads to unnecessary surgical exploration of the abdomen. Typically, the attacks last about 2 to 5 days before resolving spontaneously.
Laboratory Tests
IgE-induced drug reactions are readily identifiable with skin-prick tests or RAST. In complement-activated angioedema, a low level of the complement component C4 is a constant finding and therefore represents a sensitive screening test. A normal level, especially during an attack, rules out both hereditary and acquired angioedema. In patients with suspected complement-activated angioedema, confirmation of the diagnosis can be obtained by measuring antigenic levels of C1-INH, which are low in 85% of patients, or functional levels, which are low in 100% of patients. Hereditary forms of complement-activated angioede-ma can be distinguished from acquired forms by measurement of C1q complement—levels of which are normal in hereditary forms but decreased in acquired forms.
Treatment
Discontinuance of the causative agent is an obvious initial step in angioedema. Emergency measures are necessary to secure the airway if there is airway obstruction by a swollen tongue, uvula, or epiglottis. Monitoring the airway in these patients until the angioedema resolves is imperative. Subcutaneous epinephrine should be given and is helpful in most types of angioedema, except those associated with low levels of C1-INH. Aerosolized epinephrine sprayed on the swollen mucous membrane may at times be helpful.
Antihistamines (both H1 and H2 receptor antagonists) are indicated for IgE-induced angioedema (see above). Idiopathic an-gioedema has been split into those presentations that respond to antihistamine therapy and those that do not.78 Doxepin (see above) should be given to all patients with idiopathic angioedema, but results are often disappointing if this agent is administered without epinephrine. Leukotriene inhibitors counteract the vasodilation produced by leukotrienes and can reduce the edema.
Intramuscular or intravenous glucocorticoids (prednisone, 0.5 to 1 mg/kg/day, or methylprednisolone, 0.4 to 0.8 mg/kg/ day) can be used as adjunctive treatment. However, the anti-inflammatory action of these agents does not affect the underlying cause of the inflammation, and they require hours to take effect. Injectable C1-INH concentrate has been developed and is effective in treating patients with hereditary angioedema,79 but it is difficult to obtain.
To prevent future episodes of angioedema, patients should avoid identified triggers. ACE inhibitors are contraindicated in patients with idiopathic or C1-INH deficiency, and ARBs should be used only with extreme caution. Patients with idio-pathic angioedema should undergo an annual general medical evaluation to identify any underlying occult disease.
Anaphylaxis
Anaphylaxis is an explosive, massive activation of mast cells, with release of their inflammatory mediators in the skin, respiratory tract, and circulatory system resulting in urticaria, wheezing, and hypotension.
The term anaphylaxis has been restricted to IgE-mediated mast cell and basophil activation. Anaphylactoid reactions, although similar in presentation, result from non-IgE-dependent mechanisms and are less likely to have a fatal outcome.80 For practical purposes, however, it does not matter whether the patient is having true anaphylaxis or an anaphylactoid reaction, because the clinical manifestations and the treatment of these two types of reactions are identical.
Epidemiology
The authors of all epidemiologic reports regarding anaphy-laxis believe the incidence to be underestimated because of failure to report or recognize every episode. A Dutch study estimated that only 4% to 8% of anaphylactic reactions were reported.81 From the combined results of reported series, several significant conclusions can be drawn: First, the occurrence of atopy in anaphylaxis patients can be as high as 53%.82 Second, the incidence of females predisposed to anaphylactic episodes can be as high as 61%.83 Third, when the cause of anaphylaxis is found, food and drugs head the list, with peanuts and shellfish being the most common offending foods and NSAIDs and antibiotics being the most common drug offenders.84 Fourth, cutaneous symptoms are by far the most common manifestation.85 Fifth, the risk of anaphylaxis in hospitalized patients is reported to be 196 per million population, with the risk being highest in women and in persons younger than 30 years.86
Etiology
A number of substances are known to cause anaphylactic and anaphylactoid reactions [see Table 5]. IgE-mediated anaphylaxis is caused by agents that act as haptens (e.g., P-lactam antibiotics) or by complete antigens (e.g., venoms, foods, allergen extracts). Anaphylatoxins (C3a and C5a) often mediate reactions to human plasma and blood products. The nonim-munologic mast cell activators include radiocontrast media, opiates, and some muscle relaxants. Other anaphylactoid-in-ducing agents include those agents that modulate arachidonic acid metabolism (i.e., aspirin and other NSAIDs). In a number of cases, the mechanism that leads to anaphylactic or anaphy-lactoid reactions is unknown (i.e., idiopathic, exercise, and cold urticaria or cholinergic urticaria with anaphylaxis; mastocyto-sis; and some drug-induced reactions).87 Patients with idiopath-ic persistent urticaria or episodic urticaria do not experience anaphylaxis.
Pathogenesis
Any of the mast cell secretagogues [see Table 3] have the potential to induce an anaphylactic or anaphylactoid reaction. Activation of the mast cell through the FceRI receptor by an antigen releases the greatest amount of histamine. The physiologic responses to the release of inflammatory mediators include smooth-muscle spasm in the bronchi and GI tract, vasodilata-tion, increased vascular permeability, and stimulation of noci-ceptor nerve endings.
Diagnosis
The classic symptoms of anaphylaxis include flushing, urticaria, angioedema, pruritus, bronchospasm, and abdominal cramping with nausea, vomiting, and diarrhea. Hypotension and shock can result from intravascular volume loss, vasodi-latation, and myocardial dysfunction. Symptoms usually begin within 5 to 30 minutes after the causative agent is introduced into the body and within 2 hours after it is ingested. The shorter the latent period, the more ominous the prognosis. In rare cases, symptoms can be delayed in onset for several hours. These are called late reactions. The biphasic reaction, which includes both immediate and late reactions, tends not to be recognized and therefore is more likely to result in a fatal outcome. Least common is the protracted reaction, in which the immediate reaction persists for hours.
Table 5 Estimated Incidence or Prevalence of Acute Anaphylactic Reactions91
|
Cause |
Incidence/Prevalence |
|
General cause |
1 per 2,700 hospitalized patients |
|
Insect sting |
0.4%-0.8% of United States population |
|
Radiocontrast medium |
1 per 1,000-14,000 procedures |
|
Penicillin (fatal outcome) |
1.0-7.5 per million treatments |
|
General anesthesia |
1 per 300 inductions |
|
Hemodialysis |
1 per 1,000-5,000 sessions |
|
Immunotherapy (severe reactions) |
0.1 per million injections |
Table 6 Grading System for Anaphylaxis
|
Group |
Clinical Manifestations |
|
I |
Pruritus, flushing, urticaria, or angioedema |
|
II |
Pruritus, flushing, urticaria, or angioedema |
|
Nausea, dyspnea, tachycardia, or hypotension |
|
|
III |
Pruritus, flushing, urticaria, or angioedema |
|
Nausea, dyspnea, tachycardia, or hypotension |
|
|
Bronchospasm and shock |
|
|
IV |
Respiratory arrest |
|
Cardiac arrest |
|
|
Other manifestations may be present |
At the onset of anaphylaxis, patients often initially experience a sense of impending doom, accompanied by generalized pruritus and flushing. Almost all patients with anaphylaxis present with cutaneous manifestations that include pruritus, flushing, urticaria, or angioedema.
Anaphylaxis is graded by its clinical presentation [see Table 6]. Cases with signs and symptoms limited to the skin are designated as group I. Group II comprises cutaneous manifestations plus nausea, dyspnea, tachycardia, or hypotension; group III includes all the manifestations of groups I and II plus broncho-spasm and true shock. Group IV consists of respiratory arrest, cardiac arrest, or both, with or without other manifestations.
Physical Examination
Cutaneous involvement Flushing, urticaria, and angioede-ma have been reported in 88% to 100% of patients experiencing anaphylaxis. Pruritus, especially of the scalp, soft palate, palms, soles, and anogenital areas, usually heralds an impending ana-phylactic or anaphylactoid reaction or may be the only cutaneous signs of the episode. Conjunctival pruritus, injection, and edema are not unusual.
Respiratory involvement Nasal congestion (occurring in up to 56% of patients), rhinorrhea (16%), laryngeal edema, dyspnea (47%), bronchospasm (24% to 47%), cough, and hoarseness may all be part of the anaphylaxis syndrome.
Gastrointestinal involvement GI symptoms, including nausea, vomiting, diarrhea, abdominal cramps, and bloating occur in 30% of patients with anaphylaxis.
Neurologic involvement Dizziness or syncope (33%), headache (up to 15%), and seizures (1.5%) may be among the presenting symptoms of anaphylaxis.
Laboratory Evaluation
Anaphylaxis is a clinical diagnosis. Laboratory studies are rarely helpful. Postmortem testing may help clarify the diagnosis in cases of so-called sudden death or in patients who are dead on arrival at the emergency department.
If a patient is seen shortly after an episode, plasma hista-mine, urinary histamine, or serum tryptase may be helpful in confirming the diagnosis. Plasma histamine levels rise within 10 minutes, but they fall again within 1 hour. Serum P-tryptase levels peak by 1 hour and may remain elevated for as long as 5 hours. However, a negative histamine and tryptase study does not completely rule out the diagnosis of anaphylaxis. Skin testing and RAST for the causative agent (e.g., food, Hymenoptera venom, latex, or drug), if indicated, should be performed 4 to 6 weeks after the episode for greatest sensitivity.
Treatment in the field
The essential steps in the treatment of anaphylaxis are (1) prevention, (2) recognition, (3) prompt therapy, and (4) early transport to an emergency care facility.
Prevention
Prevention depends on recognition of persons at risk. Use of oral rather than parenteral medications should always be considered in patients at high risk for anaphylaxis. This includes patients with atopy or those with a possible history of allergic reactions to drugs. If drugs are administered parenterally, such patients should remain in a medically supervised area for at least 30 minutes afterward. Patients with known food or drug allergies must read labels to avoid the foods or drugs to which they are allergic. Severely food-allergic patients must be especially careful when dining out and may wish to avoid eating in restaurants altogether. Patients with a history of anaphylactic reaction to Hymenoptera venom should be given information on avoiding future stings and should be referred to an allergist for consideration of venom immunotherapy [see 6:V Allergic Reactions to Hymenoptera]. Patients with a history of anaphylaxis should always carry an epinephrine autoinjector (Epi-Pen).
Recognition
Immediate diagnosis of a developing reaction is imperative. Because of the risk of respiratory and cardiovascular collapse, the patient’s airway, breathing, and circulation (the so-called emergency ABCs) must be rapidly assessed.
Prompt Initiation of Therapy
Anaphylaxis can rarely be overtreated. Treatment must be expeditious and appropriate. A protocol and supplies for prompt treatment should be in place at every medical office or facility. A protocol for diagnosis and management of anaphylaxis has been developed by the Joint Task Force on Practice Parameters.88 The supplies should include oxygen, aqueous epi-nephrine, injectable antihistamines, intravenous or intramuscular glucocorticoids, oropharyngeal airways, and I.V. fluids. If the clinical assessment even suggests an anaphylactic reaction, it is best to call 911 and initiate therapy.
Whenever possible, decrease the absorption of the antigen. With insect bites and stings on an extremity, for example, apply a tourniquet above the injection site to block venous return and remove the insect stinger. Inject epinephrine (1:1000) locally.
Give supplemental oxygen, 6 to 8 L/min, and administer epinephrine (1:1000) subcutaneously or intramuscularly. The epinephrine dose is 0.2 to 0.5 mg in adults and 0.01 mg/kg in children. If the patient is in cardiopulmonary arrest, epinephrine (1:10,000) should be administered intravenously, in a dose of 0.1 to 1.0 mg for adults and 0.001 to 0.002 mg in children. Patients and their caregivers should recognize that more than one dose of epinephrine may be required.89
Intravenous H1 antihistamines (e.g., diphenhydramine, 50 mg) and H2 antihistamines (e.g., ranitidine, 50 mg, or cimetidine, 300 mg) should be given. If the patient can swallow, H2 antihista-mines can be given orally. Bronchospasm may be treated with aerosolized beta-adrenergic agonists (albuterol). Severe bron-chospasm may require endotracheal intubation or cricothyro-tomy. Respiratory failure can occur with or without upper airway compromise. Persistent hypoperfusion and ischemia may lead to myocardial infarction, cerebral ischemia, or renal failure.
Once the acute reaction is under control, systemic cortico-steroids (e.g., hydrocortisone sodium phosphate, 100 mg every 2 to 4 hours) may be administered. The patient can be transferred to the emergency department.
Prognosis
Most patients experience only a single episode of anaphylax-is,82 but some patients have three or more episodes.90 Death from anaphylaxis is uncommon. Complications are also unusual; most patients recover completely. However, respiratory failure from severe bronchospasm or laryngeal edema can cause hy-poxia, which if prolonged could lead to brain injury. Hypotension and hypoxia may lead to cardiac ischemia or arrhythmias.
