Urticaria and Angioedema
One in five individuals will suffer from hives at some point during his or her lifetime. These individuals usually look to their family doctor for help. As such, patients presenting with hives will be a common occurrence in the primary care setting. Clinicians will need to develop an approach that determines treatment needs based on triggers, duration, and underlying cause. If medications are recommended, these need to provide symptom relief; however, not intolerable side effects. Short-lived episodes are generally amenable to antihistamines, though chronic urticaria requires a skilled approach. Recognition of underlying causes requires diligence, but may suggest a need for modifiers of systemic autoimmune diseases. Research efforts continue to yield information on mechanisms of pathophysiology.
Patients exhibiting hives and associated soft tissue swelling are common in the outpatient setting. These complaints brought to the primary care physician generally will result in a diagnosis of urticaria and angioedema. The patients refer to the urticaria and angioedema by various descriptive terms, such as hives, welts, or an itchy rash. Indeed, the lesions that are described by patients with a variety of terms can have a diverse appearance. Categorically, urticarial lesions are pruritic and have a center portion that is elevated. The elevated center is often surrounded by an erythematous halo. This prototypical lesion morphologically has a central wheal with a surrounding flare. However, the configuration of the lesions can be quite different, with some lesions typically being round and circumscribed, whereas others can be serpiginous or diffuse. Characteristically, the lesions should blanch with pressure, and they generally resolve within 24 h, leaving no residual change to the skin. Lesions that do not blanch, do not result in pigmentation or scarring of the skin, or are not pruritic should be assessed for other dermatological processes or vasculitis.
Swelling of the subcutaneous tissue, or angioedema, commonly accompanies urticaria. This swelling generally results from the same pathophysiology. However, the actual process is occurring deeper in the tissue. As a result, the erythema that is seen surrounding superficial lesions is not observed, although the swelling can be visualized. Angioedema generally occurs on the extremities and digits as well as areas of the head, neck, face, and, in males, genitalia. Patients often describe it as being painful in comparison to urticaria, which is described as itchy.
A primary care physician will see many patients with urticaria and angioedema, which affect up to 15-20% of the general population, more commonly women. The majority of outbreaks are acute and self-limiting. Less than 10% of urticarial eruptions will become a chronic process. When urticarial lesions develop, they are associated with angioedema in as many as 50% of cases. Approximately 10% of the cases have only angioedema in the absence of urticaria, and the remaining 40% have solely urticaria.
Acute urticaria is a daily problem that primary care physicians handle frequently and effectively. The etiology is often elusive. However, its acute and self-limited character limits morbidity. Chronic urticaria and angioedema tend to be a much more vexing problem, often disabling and interfering with the patient’s quality of life. Recently, research suggests an autoimmune etiology for a subpopulation of those with chronic urticaria and angioedema, which could result in different approaches to the treatment of these patients.
Classification and etiological considerations
Urticaria and angioedema are classified by several characteristics. The most common classification scheme is based on duration. Urticaria that lasts less than 6 wk is deemed acute, and episodes that persist beyond 6 wk are classified as chronic. Designation of acute or chronic urticaria by duration is important, as it portends underlying pathophysiology and should guide both the prognosis and the therapeutic interventions.
Acute urticaria is very common in both children and adults. The acute type is a self-limited process that occurs when mast cells in the skin degranulate. This process is an isolated event and often occurs following exposure to an allergen. It is mediated by immunoglobulin E, which is affixed to the surface of mast cells in the skin. When the allergen advances via the bloodstream to the mast cells in the skin, immunoglobulin E is crosslinked, and the mast cells degranulate. This degranulation results in the release of a host of mediators of inflammation, including histamine, products of arachidonic acid metabolism, and cytokines. This acute event will result in increased vascular permeability and local edema, which is visible as the wheal. The patient will experience itching of the skin and swelling of the dermal tissue. Allergens that can result in acute urticaria include foods, antibiotics such as penicillin, and venoms from bee or fire ant stings. Virtually any antigen that can be disseminated systemically, and for which there is an immunoglobulin E response, has the potential to cause diffuse hives. If an allergen can penetrate the skin locally, hives will develop at the site of exposure. This might happen, for example, following exposure to latex from latex gloves. These individuals develop acute “contact” urticaria in the geographic distribution of the glove. If sufficient latex is absorbed through the skin and reaches the circulation, generalized urticaria can occur.
Acute urticaria can result from nonspecific stimulation of mast cells as well. This occurs when a physiochemical process degranulates mast cells in the absence of an allergen. Thus, immunoglobulin E on the surface of mast cells is not directly involved. An example in which mast cells can be degranulated directly is exposure to certain radiocontrast media. This type of exposure to radiocontrast media during a radiographic procedure will change the osmolality of the environment in which the mast cell resides and can result in degranulation. Complement may also be directly activated by these agents, and C5a anaphylatoxin can contribute to mast cell degranulation. These patients will develop acute urticarial eruptions that can progress to anaphylaxis with hypotension and bronchospasm. The use of low-ionic radiocontrast media has lessened the occurrence of this acute urticarial event. Other etiological factors that should be considered in individuals with acute urticaria include coincident viral illnesses. Acute viral prodromes in children are associated commonly with nonspecific urticarial eruptions. However, often these patients are also taking penicillin, which can confound the issue. Noteworthy, although many medications can result in a specific immunoglobulin E-mediated degranulation of mast cells, codeine and other opioid-derived medications can cause nonspecific degranulation of mast cells via opioid receptors. This acute urticarial eruption does not require immunoglobulin E and is not a specific allergic process, although it does result in an urticarial eruption and is treated similarly.
In certain individuals, urticaria and angioedema are the result of agents that alter the metabolism of arachidonic acid. The occurrence of hives and angioedema is of an acute nature and is often self-limiting. Once again, this interaction occurs in the absence of a specific response with the involvement of immunoglobulin E. Therapeutic agents included in this category are aspirin and nonsteroidal anti-inflammatory drugs (nonsteroidal anti-inflammatory drugs). Rarely, these responses to nonsteroidal anti-inflammatory drugs can be fulminant and life-threatening.
Thus, when a child or an adult has an isolated event of a short duration of urticaria, the clinician must attempt to identify a specific cause or exposure. In the child, typical allergens causing acute urticaria include medications such as antibiotics. A common inciting group is penicillin or other p-lactams regularly used for respiratory tract infections. Food is another common cause of acute urticaria in children, with the leading allergens being derived from egg, milk, soy, peanut, or wheat. In adults, foods more commonly encountered that result in allergic urticaria include shellfish and tree nuts (walnuts, hazelnuts, pecans, etc.). Virtually any food can result in an allergic reaction. However, historical evidence will usually reveal that a particular food resulted in the outbreak of hives shortly after ingestion. In addition, repeated ingestion of that food will result in repeat episodes of acute urticaria. One should be very suspicious of an individual who believes that he or she is allergic to a certain food even though the individual has ingested it on other occasions without typical urticarial or allergic symptoms.
In children, the possibility should always be considered that an acute viral illness is responsible for the urticarial eruption. If the child is also taking an antibiotic for a presumed bacterial infection, it should be determined whether the eruption is from an underlying viral etiology or exposure to the antibiotics. In making this determination, skin testing for penicillin allergy, for example, might be indicated, in contrast to the unsubstantiated conclusion that the child is “penicillin allergic.”
The widespread acceptance of nonsteroidal anti-inflammatory drugs for musculoskeletal symptoms and their availability as an over-the-counter medication have resulted in many episodes of urticaria and angioedema following their use. Careful review of all recently used medications could help assess this etiological consideration. Note that adults are not the only individuals who use nonsteroidal anti-inflammatory drugs; this group of medications is commonly used by the public in the treatment of febrile illnesses for children. Furthermore, aspirin enjoys popularity because of its benefit in preventing heart disease and can be the cause of an acute urticarial eruption. Thus, careful questioning regarding over-the-counter preparations must be pursued in adults and children alike.
Chronic urticaria and angioedema, by definition, result in a skin process of greater than 6 wk in duration. Patients with this classification of urticarial disease tend to be a far more troublesome group with severe, protracted and often disabling disease. Typically, they make multiple visits to their primary care physicians because of lack of efficacy from therapeutic regimens. This group of patients does require a more intense effort on behalf of the clinician to rule out (at least initially) the possibility of recurrent episodes of acute urticaria. Once it has been determined that this protracted episode of urticaria is not a result of repetitive exposures to an allergen or agent that results in recurrent acute urticaria, the diagnosis of chronic urticaria and angioedema may be established.
Acute Urticaria and Angioderma
• Less than 6 wk in duration
• Short-lived and self-limiting
• More common in children
• Associated with isolated exposure to allergens (foods, drugs, bee sting, latex)
• Associated with exposure to agents resulting in nonspecific reactions (radiocontrast dye, nonsteroidal anti-inflammatory drugs, codeine)
Patients with chronic urticaria and angioedema typically are observed for immunoglobulin E-medi-ated causes (allergies) that result in their recurring hives. However, this is generally unrewarding, as true allergy(i.e., immunoglobulin E-mediated hypersensitivity) is rarely the etiological factor responsible for chronic urticaria. Food-elimination diets and skin testing for foods, although generally negative, often help to convince the patient and the clinician alike that foods are not contributing to this process. When positive, eliminating the suspected offender should quickly reveal whether it is relevant to the patient’s symptoms. Only strongly positive reactions should be seriously considered. In addition, a thorough review of the patient’s medications will disclose whether any agents might be causing a chronic urticarial eruption, although this is uncommon. The use of angiotensin-converting enzyme inhibitors can result in recurrent episodes of angioedema. However, urticarial skin lesions are not observed. The swelling is thought to be a result of increased bradykinin levels because kininase normally inactivates bradykinin and angiotensin-converting enzyme inhibitors interfere with the normal activity of kininase. This is an example of a metabolic or pharmacological cause of swelling that is not immune.
Once the diagnosis of chronic urticaria and angioedema has been established and they are believed not to be secondary to allergens such as foods or drugs or recurrent exposure to nonspecific agents such as codeine or nonsteroidal anti-inflammatory drugs, the possibility of underlying systemic disease must be entertained. Atypical aspects of the gross appearance of the hives should heighten concern that a systemic process could be involved. Lesions that do not blanch or are associated with petechiae or purpura suggest vasculitis. Lesions that result in pigment changes, scarring, or blistering or in which individual lesions persist longer than 36 h suggest systemic diseases that could be resulting in lesions that resemble hives.
Once the evaluation has been completed and the chronic hives do not appear to be associated with any other systemic disease, the lesions are, by exclusion, deemed idiopathic. In the past, more than 95 % of all chronic urticaria was suspected to be of idiopathic classification, assuming that physical causes of hives such as dermatographism had been excluded. Recently, information has resulted in an improved understanding of the cause of chronic idiopathic urticaria. Evidence from research suggests an autoimmune etiology in a large number of the cases that have been previously deemed idiopathic urticaria. Recent data suggest that perhaps 35-45 % of individuals with chronic idiopathic urticaria actually do have an underlying autoimmune disease.
Physical urticaria includes a group of urticarial eruptions and angioedema that occur secondary to a physical stimulus. They can be of the acute or chronic type with respect to their duration, but typically are present for many months and in that sense are chronic. They result from a specific thermomechanical or physical stimulus. These stimuli include exposure to cold or hot temperatures, tensile movement of the skin, application of pressure to the skin, exposure to light of various wavelengths, and the induction of a cholin-ergic response with sweating. Practitioners often encounter physical urticaria that is described as dermatographism. This results when scratching of otherwise normal-appearing skin produces a linear hive that lasts less than 2 h. This is true of all physically induced hives, with the exception of pressure-induced urticaria, and distinguishes this group of patients from the aforementioned groups with chronic urticaria in which individual lesions last more than 4 h and often 8-24 h. Dermatographism can follow or coexist with acute or chronic urticaria. Mast cell degranulation occurs when the skin is disturbed by the physical stimulus of tensile force. Other mechanical stimuli that can result in urticaria or angioedema include pressure and vibration. Pressure applied to the skin and subcutaneous tissue often can cause the development of hives at the point of pressure or the development of swelling several hours later. The specific stimulus of vibration also can result in angioedema. Individuals who use mechanical devices that result in vibrations, such as jackhammers and vortexes in laboratories, describe soft tissue swelling. Individuals who ride motorcycles report development of swelling and/or hives on their inner thighs.
Table Physical and Physiological Stimuli That Can Result in Urticaria and Angioedema (Physical Urticaria)
| Thermal stimuli | Cold: idiopathic cold urticaria |
| Heat: cholinergic urticaria, local heat urticaria | |
| Mechanical stimuli | Dermatographism |
| Delayed pressure urticaria/angioedema | |
| Vibratory urticaria/angioedema | |
| Light-induced urticaria | Solar urticaria, types I-VI |
| Exercise stimuli | Cholinergic urticaria |
| Exercise-induced anaphylaxis (with urticaria) |
Thermal stimuli can result in urticaria and angioedema. Exposure to cold is a common stimulus for the development of hives on the face and hands. Patients will describe hives on the parts of their bodies that are exposed to cold water or cool air. If they have significant exposure to cold water over a sufficient portion of their bodies, they can develop hypotension, which may lead to a life-threatening episode. Swimming is a classic example. Heat applied to the skin can also result in urticaria. This is a rare disorder termed local heat urticaria. More commonly, systemic overheating or exercise results in a cholinergic response of sweating with the development of urticaria. Cholinergic urticarial lesions have a characteristic appearance in that they are punctate (1-5 mm) and intensely pruritic. They resolve within 1 h following removal of the stimulus or cessation from exercise. Note, however, that an entity deemed exercise-induced anaphylaxis occurs when an individual develops multiple manifestations of mast cell degranulation, including urticaria, bronchospasm, and cardiovascular collapse, in association with exercise. The distinguishing feature that separates cholinergic urticaria from exercise-induced anaphylaxis is that individuals with cholinergic urticaria develop their hives reproducibly following an increase in core body temperature from exposure to a warm climate, exercise or hot showers. They react within 5-10 min. Individuals with exercise-induced anaphylaxis must undergo a major physiological challenge of exercise such as jogging to develop symptoms, and do not develop hives solely when exposed to a warmer environment (i.e., hot showers or passive sweating). Furthermore, it does not occur reproducibly with every challenge; the exercise often has to occur for a protracted period, and the hives are large. On the other hand, respiratory symptoms or hypotension are rarely, if ever, seen with cholinergic urticaria.
Other physical stimuli have been noted to result in urticarial eruptions. Cases in which individuals develop urticaria when the skin is exposed to water are deemed aquagenic. Furthermore, several cases have been described in which a combination of physical stimuli can result in urticarial eruptions. For example, hives that develop following exercise in a cold environment are classified as cold-induced, cholinergic urticaria. Pressure-induced urticaria is an exception: the lesions develop 4-6 h after the stimulus, and the appearance of the hives resembles those of chronic urticaria visually and histologically. The term chronic idiopathic urticariapresumes seemingly spontaneously occurring hives or swelling in the absence of a physical stimulus or identifiable allergen.
Evaluation
Pathophysiology of Urticaria And Angioedema
Treatment of urticaria and angioedema
Conclusion
The primary care physician will encounter many cases of urticaria and angioedema. The most common presentation will be of an acute episode following ingestion of a food to which the individual is allergic or use of a medication to which the individual has developed an allergy. The primary treatment will be empiric with avoidance of the allergen and the use of H1 antihistamines. A short course of systemic steroids should be reserved for the most severe cases. Generally, the patient will be warned of the predisposition to further allergic reactions, which can be more severe in intensity. An evaluation can include skin testing for foods, penicillin, or cephalosporins if deemed necessary. A Medic-Alert bracelet is often useful to emergency health care providers, should the patient be at risk for life-threatening attacks in the future. A self-injectable epinephrine syringe (EpiPen™, Twinject™) is appropriate if future life-threatening episodes are possible.
Physically induced hives are suspected based on the history and can be confirmed by challenge (e.g., exercise to the point of sweating for cholinergic urticaria, scratching the skin for dermatographism, or a 5-min application of ice on the forearm for cold urticaria). The treatment employs antihistamines in dosages differing with the severity.
The more troublesome cases of urticaria and angioedema are those of the chronic classification. These patients often have persistent or severe disease that is refractory to antihistamine therapy. They might require maximum doses of both H1 and H2 antihistamines. An evaluation can be extended to ensure that underlying systemic disease is not responsible for the mast cell degranulation. With information recently developed regarding the autoimmune aspects of chronic idiopathic urticaria, the use of immunomodulators might be appropriate in select cases. The most commonly utilized is alternate-day low-dose prednisone. The possibility of coincident thyroid disease should be investigated in all individuals with chronic idiopathic urticaria, because up to 25% of these individuals
will have the presence of thyroid autoantibodies. In addition, many of these individuals will develop overt clinical or chemical hypothyroidism. Studies presently focused on the relevance of the anti-immunoglobulin E receptor antibody are expected to be illuminating. The contribution of this autoantibody to the fundamental pathogenesis could reveal future therapeutic directions that will be helpful in the long-term management of these patients. Until such time that the relevance of the anti-immunoglobulin E receptor antibody as well as other histamine-releasing factors to the pathogenesis has been determined, the use of immunomodulators, immunosuppressives, or plasmapheresis cannot be recommended routinely. Finally, no consensus suggests the uniform benefit of thyroid supplementation in individuals who have elevated thyroid autoantibodies but are chemically and clinically euthyroid. Further study of populations of patients with chronic idiopathic urticaria and coincident autoimmune thyroid disease will need to be performed to evaluate their progression to overt hypothyroidism. It should be emphasized that if an autoimmune origin proves to be correct for 35-45% of patients with chronic urticaria, the remaining 55-65 % are still “idiopathic.” But the cause appears most likely to be an endogenous abnormality affecting the skin rather than a response to an exogenous substance not yet identified.
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