David H. Dreyfus, MD, PhD
Department of Pediatrics, Waterbury Hospital, Waterbury, CT, USA
Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA
The Center for Allergy, Asthma and Immunology, Waterbury, CT, USA
Urticaria and angioedema are common allergic manifestations and some forms of this disorder may be increasing in both prevalence and severity due to changes in medications, environment and other unknown factors. This review focuses on a rational approach to differential diagnosis and therapy of the most common forms of urticaria and angioedema.
angioedema, anaphylaxis, complications, diagnosis, drug therapy, drug toxicity, hypersensitivity, urticaria
Urticaria and angioedema with duration of less than 6-8 weeks is termed acute urticaria.1-3 In contrast, several forms of chronic urticaria such as physical, autoimmune, and inflammatory urticaria1-3 usually persist for more than 6-8 weeks. Herein, an algorithmic perspective is offered for the various diagnostic possibilities of chronic urticaria (Figure 1). A checklist for office visits is also included to assist the clinician in formulating a rational approach to diagnosis and therapy of patients presenting with either acute or chronic urticaria (Figure 2).
Urticaria of less than 6 weeks duration with features indicating progression to a chronic illness should be periodically reevaluated clinically until the diagnosis is clarified. The distinction of 6-8 weeks as a dividing interval between acute and chronic urticaria, while arbitrary, is useful because the most common cause of acute urticaria and angioedema, particularly in children, are transient viral infections.4-11 Related to this important distinction, acute urticaria and angioedema (in contrast to chronic urticaria/angioedema), can often be associated with a specific cause or trigger.
The terms “acute” and “chronic” do not relate to the severity of urticaria, but only to its duration.1 Urticaria associated with signs and symptoms affecting organs other than the skin, such as the pulmonary tract (wheezing, cough), gastrointestinal system (vomiting, diarrhea), nervous system (dizziness, loss of consciousness) or cardiac system (changes in blood pressure or heart rate) should be excluded from the diagnosis. Urticaria that is not confined to the skin and associated with any systemic symptoms is more properly termed anaphylaxis, irrespective of the duration or intensity of symptoms.
It is important to exclude anaphylaxis in patients presenting with acute urticaria.12 Like urticaria, anaphylaxis can be idiopathic or associated with specific triggers such as foods13,14 or medications.15 Physicians should consider prescribing epinephrine in patients with urticaria until the diagnosis of anaphylaxis is excluded.16
|Allergic||•Cutaneous and systemic||→•Anaphylactoid reaction (non-IgE-mediated)|
|•Cutaneous only||→•IgE-mediated||→Contact allergy|
|Toxin/Sensitizer Medication||•Scombroid toxin||→•Other food toxin|
|•ACE inhibitors, NSAIDs|
|Inflammatory||•Genetic/urticarial syndromes||→•Muckle-Wells, TRAPS, other|
•Other malignancy (e.g., Hodgkin’s lymphoma)
|Chronic (> 6-8 weeks)||•Idiopathic|
|•CD203c, ANA thyroid autoimmune disorders||→•Vasculitis|
|Figure 1. Differential diagnosis of urticaria and angioedema|
ACE = angiotensin-converting enzyme; ANA = antinuclear antibody; C1q = complement protein required for innate immune responses; CD203c = basophil activation marker for allergy detection; IgE = immunoglobulin E antibody; NSAIDs = nonsteroidal anti-inflammatory drugs; TRAPS = TNFRSF1A-associated periodic syndrome
|1. Review of history, medications, previous therapy|
|2. Discontinue medications (e.g., antibiotics, NSAIDs, ACE inhibitors) associated with illness if possible|
|Follow-up Visits at approximately 2 week intervals until remission of symptoms or stable improvement documented|
|1. Review response to previous therapy, laboratory testing, allergies, physical or other triggers if present|
|2. Therapy: alternate day oral corticosteroids 5-20 mg if partial response to therapy|
|3. Discuss alternative therapies, risks and benefits|
|Follow-up Visits at 3 month intervals when stable on medication or yearly if in remission off therapy|
|Figure 2. Checklist for outpatient evaluation of urticaria and angioedema|
anti-TNF-alpha = anti-tumor necrosis factor-alpha; C1 inh = C1-esterase inhibitor; CBC = complete blood count; FACS = fluorescence-activated cell sorting; HSV = herpes simplex virus; TSH = thyroid-stimulating hormone
Diagnosis of Acute Urticaria and Angioedema
Acute urticaria can be considered as a symptom of many diseases rather than a disease itself.17 The possible causes of acute urticaria and angioedema include physical, allergic, medication, toxin or sensitizer reactions, or most commonly inflammatory triggers due to viral or other infections.4-11 Physical urticaria causing mast cell activation in the absence of chronic inflammation can be mistaken for acute urticaria, which is discussed in more detail elsewhere in this review. Allergic urticaria, associated with specific immunoglobulin E (IgE) bound to mast cells, can be identified by focused skin testing or laboratory immunoassay.1,2,6,13,14,18-20
Acute urticaria can be triggered by ingesting high levels of histamine and other vasoactive amines in scombroid fish.21-23 Urticaria due to a toxic reaction from scombroid fish can usually be identified by the clinical history, often with multiple patient reports of symptoms localized to a particular restaurant or dish. Inflammation from parasitic or other acute non-viral infections can also trigger acute urticaria.24,25
Hereditary conditions such as hereditary angioedema (HAE) due to a deficiency or functional abnormality of C1 inhibitor protein can present as acute angioedema and be prevented with appropriate therapy.26-30 A variety of rare inflammatory conditions31 such as familial Mediterranean fever (FMF)32,33 or Muckle-Wells syndrome34 can present as either urticaria or angioedema and more information regarding these conditions is available through a registry termed “Infevers”32. Pregnancyinduced urticaria (pruritic urticarial papules and plaques of pregnancy or PUPPs) is a self-limiting inflammatory condition.35 Photodermatitis can also mimic acute urticaria36 as can malignancy or other inflammatory conditions such as Sweet’s syndrome.37-40
Extensive and unfocused skin testing or laboratory evaluation for allergy to foods, food additives, or aeroallergens unsupported by clinical history is usually not productive. Although many cases of acute urticaria are caused by viral or other infectious illness,4-11 extensive evaluation for specific viral pathogens or antiviral therapy are not indicated unless suggested by the clinical history.
Skin testing or immunoassay to identify specific triggers to acute urticaria and angioedema can sometimes be helpful, particularly if an allergic etiology is suggested by the history.13,15 Skin testing in this scenario would usually be done after the resolution of acute hives with suspension of antihistamines or serologic testing in the presence of significant dermatographism. Allergy to latex or other hidden allergens, such as food antigens,19,41-44 may masquerade as acute urticaria if the antigenic nature of the stimulus is not identified through a combination of history, immunoassay, and prick and patch testing. More unusual, food contact or aeroallergen triggers of acute urticaria, such as reaction to fish food in tropical fish breeders or foods in food handlers, may also masquerade as acute or chronic urticaria and should be investigated if there is a suggestive clinical or occupational history.20,45
Skin testing or IgE immunoassay to a limited number of common food antigens, hidden antigens such as dust mites, or other aeroallergens suggested by the history may also be indicated to reassure parents of pediatric patients or patients who may have been mistakenly informed that they are having an allergic reaction to foods or aeroallergens. Unnecessary dietary limitations should be avoided if skin testing to common foods is negative. Often patients with acute urticaria will erroneously associate the symptoms with triggers to foods or aeroallergens.
Acute urticaria is usually not associated with evidence of chronic inflammation or cellular infiltrates of the skin (refer to sections on chronic and autoimmune urticaria and differential diagnosis). For this reason, skin biopsy is rarely indicated as long as the lesions are typical of urticaria, i.e., duration less than 24 hours without bruising or purpura.1 A skin biopsy may be indicated if symptoms and examination suggest mastocytosis, either congenital or acquired.46 Most often, acute urticaria is a selflimiting condition that will resolve spontaneously in less than 6-8 weeks, and extensive evaluation for rare causes is usually not productive.1,47 Therefore, independent of the severity of the urticaria, patients should be reassured that in the absence of the triggering agent or with resolution of infection symptoms, most cases will resolve without aggressive therapy.
If symptoms persist beyond the 6-8 week interval typical of acute urticaria or are associated with bruising, pain or fixed in one location, then a more extensive evaluation including a skin biopsy is indicated to exclude the possibility of vasculitis or malignancy. Serum tryptase and other laboratory studies may be useful in determining whether a malignancy such as mastocytosis is present. For example, the alpha form of tryptase may be more specific for mastocytosis, while the beta form of tryptase can be elevated in both anaphylaxis and mastocytosis.
Urticaria or angioedema related to the use of medications requires a careful history, particularly with respect to angiotensinconverting enzyme (ACE) inhibitors, which can cause angioedema after months or even years of therapy.29,48,49 Over-the-counter medications such as aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs), or herbal remedies containing aspirin or aspirinlike compounds, are often not reported to physicians without specific questioning.15,23,50-55 The potential risk posed by herbal or other natural or homeopathic medications (e.g., given as oral or sublingual immunotherapy) should be considered if suggested by the history. The herbs feverfew and nettle tea are commonly used in alternative medicine, as evidenced by unsubstantiated testimonials on the internet, which suggest patients may take along with conventional medical therapy. Thus, further studies are warranted to determine the risks and benefits of herbal remedies for urticaria and allergy.
Medications such as aspirin and NSAIDs should be discontinued with substitution of an equally efficacious alternative (such as acetaminophen or a selective COX-2 inhibitor) not usually associated with urticaria.52,55 Estrogen in oral contraception or in the female hormonal cycle can be associated with flares of urticaria and angioedema, or may also be confused with NSAID allergy, since NSAIDs are often taken at specific times in the menstrual cycle. With the increasing use of ACE inhibitors and related therapy directed at the angiotensin receptor, acute angioedema due to these compounds has eclipsed all other causes of hospitalization for this condition. Additionally, this class of drugs should be discontinued if clinically suspected as the cause (based upon the history) even if the patients have been taking the medications for prolonged periods.29,48,49 Substitution of an angiotensin receptor blocker (ARB) can be considered, but it should be recognized that ARB inhibitors have also been associated with angioedema.
Therapy of Urticaria and Angioedema
Therapy of both acute and chronic urticaria and angioedema should be directed at eliminating specific triggers if suggested by the history and focused testing, as well as providing symptomatic relief.1 Once identifiable triggers of acute urticaria and angioedema have been eliminated, evidence supports the use of antihistamines as first-line therapy for persistent symptoms.1 Although specific dosing guidelines for common prescription antihistamines (e.g., hydroxyzine, desloratadine, levocetirizine, and serotonin/histamine antagonists such as doxepin) and nonprescription antihistamines (e.g. diphenhydramine, loratadine, cetirizine, and fexofenadine) are provided by the manufacturer, these instructions are generally less useful than individual titration of dosing because patients will vary widely in their tolerance and response. Clinical experience suggests that the therapeutic dose for a particular patient is that which maximizes control of symptoms with tolerable side effects, most commonly sedation and anti-cholinergic effects.
However, in adjusting antihistamine therapy, the differences between non-sedating and sedating agents may be useful. Nonsedating antihistamines (prototypes loratadine, desloratadine, and fexofenadine), also termed “second generation” antihistamines, are designed through chemical modifications that limit transfer across the blood-brain barrier and induce minimal sedating effects, as compared with “first generation” antihistamines such as hydroxyzine and diphenhydramine. Cetirizine and levoceterizine are usually considered intermediate (between the two classes) in terms of their sedating properties. Although first generation antihistamines are rapidly acting and effective in both pediatric and adult patients, they may have a common side effect of sedation and impaired motor skills due to their ability to cross the blood-brain barrier. In contrast, these impairments are less evident or not evident in second generation antihistamines as a class.56-80 However, tolerance to the sedating effects of first generation antihistamines can develop with regular use and patients may take higher than recommended doses of second generation antihistamines with unknown consequences on sedation and driving ability. It is worth noting that different antihistamines can interact unpredictably with other medications or alcohol and patients may tolerate first generation antihistamines and even prefer these agents for their sedating properties, especially in cases where urticaria interferes with sleep.
In an effort to simplify antihistamine dosing, multiple studies have compared first and second generation antihistamines, which differ in vivo and in vitro in parameters such as histamine receptor binding affinity, onset of activity, and metabolism.1,81-84 Second generation antihistamines have demonstrated efficacy and long-term safety (even for small children) in acute urticaria when used on a regular basis and titrated to an effective dose in most patients.11 However, in vitro studies are not a substitute for experience in individual patients. In summary, individual patient responses to different antihistamines will vary unpredictably, both with respect to efficacy as well as dose related effects on sedation, driving, and impairment of fine motor performance. Therefore, individual pharmacotherapeutic adjustments will often be required, including office follow-up to monitor for side effects and treatment response.
Although this has not been explored in large placebo-controlled studies, a short course of oral corticosteroids may be considered if symptoms are severe or not resolving on antihistamines.1,85 A single study in adults demonstrated that time to resolution of acute urticaria was decreased with the addition of oral corticosteroids to antihistamines in an emergency room setting,86 while another small study in both adults and children showed more rapid resolution of acute urticaria with oral corticosteroids in comparison to antihistamines.87 However, despite these findings suggesting a benefit of oral corticosteroids for acute urticaria, there remains insufficient data to warrant routine use of oral corticosteroids over antihistamines.17,88
Remarkably, a single evidence based questionnaire study89 suggests that use of oral corticosteroids for the treatment of acute urticaria is common or even routine in an adult emergency room setting, but such a strategy is much less commonly used by pediatric clinicians in an outpatient setting, where therapeutic decision-making may be based primarily on clinical judgement. These contrasting approaches further support the need for additional studies in order to generate evidence based consensus recommendations. Dose-related side effects of oral corticosteroids, such as adrenal suppression and effects on growth or bone mineralization, are usually not an issue for short-term use (less than 2 weeks). Nonetheless, patients should be aware of medication related changes in moods, gastroesophageal reflux, and transient weight gain, as well as the possibility of recurrence of symptoms when oral corticosteroids are discontinued. Oral corticosteroid dosing has not been determined in controlled studies, but is based instead upon clinical judgment. Since oral corticosteroid dosing and responses will vary significantly and unpredictably, patients receiving therapy should be clinically monitored for response to treatment, side effects, and effects on co-morbid conditions such as hypertension and diabetes.
Other therapies directed at histamine receptors (e.g., doxepin), H2 blockers (e.g., ranitidine), or combination of histamine H1 and H2 receptor antagonists may be considered as additional therapeutic options for acute urticaria.1 Therapy directed at other mediators of urticaria and angioedema (e.g., leukotrienes) can be targeted with leukotriene antagonists such as montelukast or zileuton; however, meta-analysis of several studies has not shown convincing benefit.90 If an underlying viral illness is clinically suspected, a short course of antiviral agents (e.g., acyclovir) may be effective. Other inflammatory mediators such as cytokines may not respond to existing therapies.91,92 More potent antiinflammatory or immunosuppressive agents (e.g., cyclosporine, omalizumab, or B-lymphocyte depletion with rituximab) have a role in severe chronic urticaria and angioedema, but are not indicated in acute urticaria and angioedema, which by definition will resolve spontaneously.
Recent studies demonstrate that mast cells and basophils responsible for acute urticaria and angioedema contribute to both immunity to parasitic infections as well as inactivation of snake and spider venom.93-95 Because of the critical role played by these cells in the innate and acquired immune response, they express multiple receptors that respond to specific antigens, as well as multiple and often nonspecific triggers, such as changes in blood pressure and immunologic activation. Thus, it is likely that in addition to the classical allergic IgE-mediated pathways, a variety of different receptors on mast cells including receptors for complement fragments, circulating immune complexes binding IgG and IgM, and cytokines cause mast cell activation in acute urticaria and angioedema.8,17,44,92,96 For example, a specific mast cell receptor for proteases, including those in dust mite antigens and enzymatic proteins (e.g., papain) explains the highly allergenic nature of proteases in aeroallergens and foods, as well as proteases in the complement response to infectious agents, thereby suggesting a role for serum proteases in acute urticaria.97 Recently identified is another large family of innate immune receptors (termed the “inflammasome”) that is distinct from IgE, glucocorticoid, complement, and histamine receptors in many rare genetic syndromes with a component of urticaria.32 Potentially, the inflammasome could also be implicated in acute post-viral, infectious, or other inflammatory urticarias and, thus, respond to novel anti-inflammasome directed therapy, a subject for future study.
A rational approach to diagnosis and therapy of urticaria and angioedema should be adopted by clinicians, despite the fact that in many or most cases the specific cause of the illness may not be evident or confirmed by allergy or laboratory testing. Some general considerations such as whether the urticaria and angioedema is acute or chronic, allergic or non-allergic, or associated with other systemic or autoimmune diseases may help to guide diagnosis and therapy. Primary therapeutic options (e.g., sedating or non-sedating antihistamines) and whether or when to include other medications (e.g., corticosteroids, antivirals, antibiotics, or anti-inflammatories) should be reviewed with patients. Risks and benefits, including any patient concerns about off-label use (Figure 2), should also be addressed. In general, offlabel prescribing of medications that are commonly used in the treatment of urticaria and angioedema should only be considered after careful exclusion of other diagnoses such as vasculitis, malignancy, or other systemic illness, and must be accompanied by written patient consent.
Etiology of acute urticaria and angioedema, particularly due to viral infections, may involve nonspecific inflammatory responses that are not related to IgE or histamine and, therefore, will not be detected by skin testing or immunoassay. Because acute urticaria is a symptom, rather than a single disease, reflecting multiple mediators and involvement of both the acquired and innate immune system, the role of the clinician should be to exclude obvious causes and reassure the patient while providing adequate symptomatic relief.
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