Chapter 38. Urticaria and Angioedema

Urticaria is defined as a skin lesion consisting of a wheal-and-flare reaction in which localized intracutaneous edema (wheal) is surrounded by an area of redness (erythema) that is typically pruritic. Individual hives can last as briefly as 30 minutes to as long as 36 hours. They can be as small as a millimeter or 6–8 inches in diameter (giant urticaria). They blanch with pressure as the dilated blood vessels are compressed, which also accounts for the central pallor of the wheal. The dilated blood vessels and increased permeability that characterize urticaria are present in the superficial dermis and involves the venular plexus in that location. Angioedema can be caused by the same pathogenic mechanisms as urticaria but the pathology is in the deep dermis and subcutaneous tissue and swelling is the major manifestation. The overlying skin may be erythematous or normal. There is less pruritus (fewer type C nerve endings at the deeper cutaneous levels) but there may be pain or burning.

Urticaria and angioedema are common. Age, race, sex, occupation, geographic location, and season of the year may be implicated in urticaria and angioedema only insofar as they may contribute to exposure to an eliciting agent. Of a group of college students, 15%–20% reported having experienced urticaria, while 1%–3% of the patients referred to hospital dermatology clinics in the United Kingdom noted urticaria and angioedema. In the National Ambulatory Medical Care Survey data from 1990 to 1997 in the United States, women accounted for 69% of patient visits. There was a bimodal age distribution in patients aged birth to 9 years and 30–40 years.1

Urticaria/angioedema is considered to be acute if it lasts less than 6 weeks. Most acute episodes are due to adverse reactions to medications or foods and in children, to viral illnesses. Episodes of urticaria/angioedema persisting beyond 6 weeks are considered chronic and are divided into two major subgroups: (1) chronic autoimmune urticaria (45%) and (2) chronic idiopathic urticaria (55%) with a combined incidence in the general population of 0.5%.2 Physically induced urticaria/angioedema is not included in the definition. Various types of physical urticaria/angioedema may last for years, but the individual lesions last fewer than 2 hours (except delayed pressure urticaria) and are intermittent. Whereas 85% of children experience urticaria in the absence of angioedema, 40% of adult patients with urticaria also experience angioedema.

Approximately 50% of patients with chronic urticaria (with or without angioedema) are free of lesions within 1 year, 65% within 3 years, and 85% within 5 years; fewer than 5% have lesions that last for more than 10 years. Angioedema alters the natural history, and only 25% of patients experience resolution of lesions within 1 year. There are no data regarding the remission rate in patients with only angioedema. The hereditary group is considered to be life long once the diagnosis becomes clinically manifest.

Mast Cell and Histamine Release

The mast cell is the major effector cell in most forms of urticaria and angioedema, although other cell types undoubtedly contribute. Cutaneous mast cells adhere to fibronectin and laminin through the very late activation (VLA) β1 integrins VLA-3, VLA-4, and VLA-5 and to vitronectin through the αvβ3 integrin. Cutaneous mast cells, but not those from other sites, release histamine in response to compound 48/80, C5a, morphine, and codeine. The neuropeptides substance P (SP), vasoactive intestinal peptide (VIP), and somatostatin, (but not neurotensin, neurokinins A and B, bradykinin, or calcitonin gene-related peptide), activate mast cells for histamine secretion. Dermal microdialysis studies of the application of SP on skin indicate that it induces histamine release only at 10−6 M, which suggests that after physiologic nociceptor activation, SP does not contribute significantly to histamine release.3 Yet it is a major contributor to the flare reaction induced by histamine stimulation of afferent type C fibers (mediating pruritus) with release of SP from adjacent nerve endings by antidromic conduction. Histamine is found associated with the wheal.4 Recently, the spinal cord afferent fibers mediating pruritis have, for the first time, been distinguished from pain fibers in the lateral spinothalamic tracts.5

Not all potential biologic products are produced when cutaneous mast cells are stimulated. For example, SP releases histamine from cutaneous mast cells above 10−6 M but does not generate prostaglandin D2 (PGD2). Vascular permeability in skin is produced predominantly by H1 histamine receptors (85%); H2 histamine receptors account for the remaining 15%.

The current hypothesis regarding cellular infiltration that follows mast cell degranulation suggests that the release of mast cell products (histamine, leucotrienes, cytokines, chemokines) leads to alterations in vasopermeability, upregulation of adhesion molecules on endothelial cells, and rolling and attachment of blood leukocytes, followed by chemotaxis and transendothelial cell migration.

Various forms of physical urticaria/angioedema have provided experimental models for the study of urticaria/angioedema by allowing the observation of the elicited clinical response, examination of lesional and normal skin biopsy specimens, assay of chemical mediators released into the blood or tissues, and characterization of peripheral leukocyte responses.6,7 The intracutaneous injection of specific antigen in sensitized individuals has provided an experimental model for analysis of the role of immunoglobulin (Ig) E and its interaction with the mast cell. In many subjects, the challenged cutaneous sites demonstrate a biphasic response, with a transient, pruritic, erythematous wheal-and-flare reaction followed by a tender, deep, erythematous, poorly demarcated area of swelling that persists for up to 24 hours. This is the late-phase response with recruitment of variable numbers of neutrophils, prominent eosinophils, monocytes, small numbers of basophils, and CD4+ T-lymphocytes of the TH2 subclass.8 Chemokines (chemotactic cytokines) strongly associated with Th2 lymphocyte predominance include those reactive with chemokine receptors CCR3, CCR4, and CCR8 on T lymphocytes. Characteristic cytokines produced by Th2 lymphocytes include interleukins (ILs) 4, 5, 9, 13, 25, 31 and 33. The cellular infiltrate seen in biopsy specimens of delayed pressure urticaria is a variant of a late-phase reaction while mast cell degranulation in most other physical urticarias has no associated late phase. These include typical acquired cold urticaria, cholinergic urticaria, dermatographism, and type I solar urticaria.

Autoimmunity and Chronic Urticaria

The first suggestion that patients with chronic urticaria and angioedema might have an autoimmune diathesis was the observation that there is an increased incidence of antithyroid antibodies in such patients relative to the incidence in the population at large.9 These include antimicrosomal (perioxidase) and antithyroglobulin antibodies, as seen in patients with Hashimoto's thyroiditis.10 Patients may have clinical hypothyroidism, but a small number might be hyperthyroid if inflammation is at an early stage when thyroid hormone is released into the circulation. This atypical presentation should be distinguished from the occasional patient with Grave's disease. Nevertheless, most patients are euthyroid. The incidence of antithyroid antibodies in chronic urticaria, as reported in the literature, varies between 15% and 24%,11,12 but the most recent data are closer to the latter figure12 and demonstrate segregation of antithyroid antibodies with chronic autoimmune urticaria rather than chronic idiopathic urticaria. However, the association is not absolute. The incidence in the autoimmune subgroup was 27%, in the chronic idiopathic urticaria subgroup 11%, while in the population at large it is 7%–8%. Gruber et al (1988)13 considered the possibility that patients might have circulating and anti-IgE antibodies that are functional and did indeed find these in about 5%–10% of patients. Gratten et al14,15 sought antibodies reactive with skin mast cells by performing an autologous skin test and found a 30% incidence of positive reactions in patients with chronic urticaria. There were only rare positive reactions in healthy control subjects or patients with other forms of urticaria. Subsequently, this level of positivity was shown by Hide et al16 to be due to an IgG antibody reactive with the α subunit of the IgE receptor; in addition a 5%–10% incidence of functional anti-IgE antibodies was confirmed (eFig. 38-1.1).17

Functional Assays of the Anti-Immunoglobulin E Receptors

Assays for anti-IgE receptor antibody have been included in vivo methods and in vitro assays. The autologous skin test,15,18 as noted above, provided one of the first clues that a subset of patients with chronic urticaria have an autoimmune disorder. Basophils are frequently used as an in vitro surrogate for mast cells, and secretion of histamine as a result of incubation with patient sera or purified IgG was readily demonstrated,19–21 but was not observed if the source of basophils was from a “nonreleaser,” i.e., basophils with an abnormality in the signal transduction molecules lyn or syk, which are unresponsive to signals through the IgE receptor but are normally responsive to other secreteagogues, such as the cytokine monocyte chemoattractant protein-1.22 The incidence of a positive assay result was generally higher than that observed with the autologous skin test; reported values varied between 35% and 50%.19,20,23 Absorption of sera, with cloned α subunit, decreased the percentage of histamine release as the amount of added α subunit was increased22 confirming reactivity with this receptor subunit. The assay could be made more sensitive by preincubating basophils with IL-3,24 although the percentage of positive reactions was not significantly affected. Release of leucotriene C4 and IL-3 along with histamine was also demonstrable.25,26 A representative assay is shown in Fig. 38-1. Although more cumbersome, activation of cutaneous mast cells could also be performed in vitro by using either thin skin slices27 or partially purified mast cells derived from foreskin samples.28

Binding Assays for Antireceptor Antibody

 Attempts to quantitate IgG antibody to the α subunit have, in general, been unsuccessful. Initial attempts to demonstrate the presence of antibody by means of immunoblotting23,29 have not proved useful because positive reactions can be seen in other autoimmune disorders29 or occasionally with sera23 from subjects with no history of urticaria. In addition, studies of the relationship of a positive immunoblot result with histamine release did not yield a significant correlation;22 sera with a positive blot result but negative histamine release were frequently seen. However, sera with positive histamine release and a negative blot result did have demonstrable IgG anti-α because absorption of such sera with the α subunit inhibited histamine release. Thus, lack of sensitivity of the immunoblot explained part of the discrepancy, but the cause of the false-positive blot results was not apparent. The latest observations germane to this enigma relate to the fact that the α subunit employed is cloned in an insect vector, thus glycosylation differs from that in humans; also traces of insect protein may be present. Antibody to either of these would interfere with immunoblots (glycosylation) or ELISA assays (glycosylation or contaminant).30

 Subclass analysis of the pathogenic IgG has been helpful in further delineating the relationship (or lack thereof) of binding assays versus functional methods. An early report suggested that much of the antireceptor antibody exists within the IgG1 and IgG3 subclasses, but these data were based on immunoblot analysis.29 Thus, we employed affinity chromatography to purify IgG subclasses from the sera of patients with chronic urticaria to determine which IgG subclasses have functional antireceptor antibody. When we isolated IgG2 antibody from nine patients with chronic urticaria, none of them released histamine from human basophils, irrespective of whether a positive IgG2 anti-α antibody immunoblot result was seen or not. Much of the histamine release does appear to be due to IgG1 and IgG3, and rarely due to IgG4.31

 Recently, a series of publications have demonstrated that normal serum has natural antibody to the α subunit of the IgE receptor with germ line variable region sequences that is primarily IgM.32–34 Such antibodies can be functional but appear to require stripping of IgE from donor basophils. Evidence to suggest cross-reactivity of anti-α antibody with tetanus toxoid was reported, which implied immunization as a cause of such antibodies; however, we have been unable to absorb sera with tetanus toxoid and diminish histamine release (A. Kaplan, unpublished observations), and if such antibodies are part of our innate repertoire, no external stimulus is needed to explain their presence. But some unknown stimulus or abnormal control mechanism might lead to pathogenic IgG antibody, such as we have seen.

Role of Complement

 That complement might contribute to the histamine release observed with sera from patients with chronic urticaria was suggested by studies in which complement depletion or inactivation appeared to diminish histamine release.21,29 A series of reports by Ferrer et al28 and Kikuchi and Kaplan22,35 then documented not only a role for complement but also more specifically activation of the classical pathway and generation of C5a. First, we demonstrated that the addition of purified patient IgG to normal serum (as a source of complement) but not sera deficient in C2 or C5 augmented cutaneous mast cell histamine release.28 This was confirmed with basophils.22,35 We could also reconstitute C5-deficient serum with purified C5 to recover the augmentation of histamine release provided by serum. Then we demonstrated inhibition of the complement contribution to histamine release by using an antibody to the C5a receptor.35 It is not clear why the presence of a functional anti-IgE receptor would cause symptoms limited to the skin, but among the differences between pulmonary and cutaneous mast cells is the absence of C5a receptors on lung mast cells. On the other hand, it is also not clear why the IgG2 anti-IgE receptor antibody, which is often demonstrable by means of immunoblotting, does not activate basophils or cutaneous mast cells because IgG2 anti-FcϵRIα should cross-link α subunits, as might any IgG subclass antibody directed to the α subunit. The difference might have to do with antibody affinity or differing α subunit epitopes (including the aforementioned nonhuman carbohydrate linkage) with which these antibodies react. The geometry of binding is also a factor because the Fc region of two adjacent IgG molecules must each be able to bind to one of the globular heads of C1Q to initiate complement activation (Fig. 38-2). It is theoretically possible to have binding of IgG to the IgE receptor in the absence of cross-linking (e.g., the receptors are too far apart) and still observe histamine release if the two Fc regions are sufficiently close together to activate C1. If receptors are sparse, the antibody can bind without activating either the cells or complement, whereas receptors saturated with IgE might preclude binding. These considerations may account for the marked heterogeneity in patient manifestations and severity.

Cellular Infiltrate

Mast cell degranulation certainly initiates the inflammatory process in autoimmune chronic urticaria and is assumed to also do so in idiopathic chronic urticaria. Evidence for an increased number of mast cells in chronic urticaria has been presented,36,37 but there are also publications indicating no significant differences from normal;38 these studies did not discriminate the autoimmune from the idiopathic groups. However, no alternative mechanisms for mast cell degranulation in the idiopathic groups have been suggested to date. Yet the histology of the two groups differs only in minor ways. Common to all biopsy specimens is a perivascular infiltrate that surrounds small venules within the superficial and deep venular plexus, with a prominence of CD4+ T lymphocytes and monocytes and virtually no B cells.36,39 Granulocytes are quite variable but are plentiful if the lesion undergoes biopsy early in its development. Neutrophils and eosinophils are both present,40,41 although the degree of eosinophils accumulation varies greatly.39 Even when eosinophils are not evident, major basic protein can be identified within lesions (in at least two-thirds of patients), which most likely represents evidence of prior eosinophil degranulation.42 The presence of basophils has also been recently demonstrated by using an antibody (BB1) that is specific for this cell type.41 Thus, the infiltrate resembles that of an allergic late-phase reaction, as suggested previously,43 although the percentage of each cell types differs, with neutrophils and monocytes being relatively more prominent in urticaria. Endothelial cell activation is suggested by the presence of intercellular adhesion molecule 1 and E-selectin in biopsy specimens of urticarial lesions.44 Sources of chemokines include the mast cell and the activated endothelial cell; the latter cells are stimulated not only by cytokines or monokines, such as IL-4, IL-1, and tumor necrosis factor-α (TNF-α), but also by the vasoactive factors, for example, histamine and leukotrienes released from activated mast cells.45 Complement activation and the release of C5a results not only in augmented mast cell (and basophil) histamine release, but C5a is also chemotactic for neutrophils, eosinophils, and monocytes. The presence of C5a is one of the factors that would distinguish this lesion from a typical allergen-induced cutaneous late-phase reaction. The particular chemokines released in chronic urticaria have not been studied. The presence of increased plasma IL-4 levels25 in patients with chronic urticaria provides indirect evidence of lymphocyte activation, basophil activation, or both, and isolated CD4+ lymphocytes of patients were shown to secrete greater amounts of both IL-4 and IFN-γ compared with that seen in healthy control subjects on stimulation with phorbol myristate acetate.

A direct comparison between cutaneous late-phase reactions and the histology of chronic urticaria revealed that infiltrating cells had characteristics of both TH1 and TH2 cells, with production of IFN-γ by the former cells and IL-4 and IL-5 by the latter.46 Alternatively, this might represent activated TH0 cells (i.e., activated CD4+ lymphocytes that are not differentiated to TH1 or TH2 cells). When the histology of autoimmuneand idiopathic chronic urticarias was compared,41 the autoimmune subgroup had greater prominence of granulocytes within the infiltrate, whereas other infiltrating cells were quite similar, with a small increment in cytokine levels in the autoimmune group and greater tryptase positivity (? less degranulation) in the autoantibody-negative group. The patients with autoimmune chronic urticaria generally had more severe symptoms than those with idiopathic chronic urticaria.47

Basophil Releasibility

(Figs. 38-1 and 38-2)

The basophils of patients with chronic urticaria have been shown to be hyporesponsive to anti-IgE, an observation made by Kern and Lichtenstein48 long before there were any clues to the pathogenesis of this disorder. These findings were confirmed49 and appeared to be associated with basopenia50 and to segregate with the autoimmune subgroup. One obvious interpretation is that there is in vivo desensitization of basophils in the presence of circulating anti-IgE receptor. Vonakis et al have demonstrated that patients’ basophil hyporesponsiveness to anti-IgE is due to augmented levels of SHIP phosphatase51 that limits phosphorylation reactions critical for histamine secretion. Although manifest in about half the patients with chronic urticaria (and not segregated with either the autoimmune or idiopathic subgroups), the abnormality appears to reverse when patients remit. Thus, it may be a marker of disease activity. We have found a paradoxical result when the isolated basophils of patients with chronic urticaria were activated and compared with the basophils of healthy control subjects. Although the basophils of the patients with urticaria were clearly less responsive to anti-IgE, they demonstrated augmented histamine release when incubated with serum and it did not matter whether the sera were taken from normal subjects, other patients with chronic urticaria, or was their own.52

Role of the Extrinsic Coagulation Cascade

Studies of the plasma of patient with chronic urticaria demonstrate the presence of d-dimer and prothrombin 1 and 2 fragments indicating activation of prothrombin to thrombin as well as digestion of fibrinogen by thrombin.53 The reaction is not specific for chronic urticaria as similar observations have been noted in multiple nonsteroidal hypersensitivity syndrome.54 Nevertheless, the data are of considerable interest and activation of the coagulation cascade is dependent on tissue factor rather than factor XII, i.e., the extrinsic coagulation cascade. Although activated endothelial cells are a well-known source of the tissue factor, histologic studies suggest that eosinophils are a prominent source.55 The relationship of these observations to histamine release by basophils or mast cells is not clear. Whereas thrombin activation of mast cells has been reported, the amounts required are large and the observations thus far are confined to rodent mast cells. One publication relating to eosinophil to histamine release found IgG antibody to FceRII in the serum of patients with chronic urticaria which activates eosinophils to release cationic proteins.56 They propose basophil activation by these eosinophil cationic proteins but do not demonstrate it; however, they offer an additional mechanism for basophil and possibly mast cell histamine release.

Bradykinin: Role in Angioedema

Kinins are low-molecular-weight peptides that participate in inflammatory processes by virtue of their ability to activate endothelial cells and, as a consequence, lead to vasodilatation, increased vascular permeability, production of nitric oxide, and mobilization of arachidonic acid. Kinins also stimulate sensory nerve endings to cause a burning dysesthesia. Thus, the classical parameters of inflammation (i.e., redness, heat, swelling, and pain) can all result from kinin formation. Bradykinin is the best characterized of this group of vasoactive substances.

There are two general pathways by which bradykinin is generated. The simpler of the two has only two components: (1) an enzyme tissue kallikrein57 and (2) a plasma substrate, low-molecular-weight kininogen.58,59 Tissue kallikrein is secreted by many cells throughout the body; however, certain tissues produce particularly large quantities. These include glandular tissues (salivary and sweat glands and pancreatic exocrine gland) and the lung, kidney, intestine, and brain.

The second pathway for bradykinin formation is far more complex and is part of the initiating mechanism by which the intrinsic coagulation pathway is activated (eFig. 38-1.2).60 Factor XII is the initiating protein that binds to certain negatively charged macromolecular surfaces and autoactivates (autodigests) to form factor XIIa.61,62 This is synonymous with Hageman factor as designated in the figure. There are two plasma substrates of factor XIIa, namely (1) prekallikrein63 and (2) factor XI,64,65 and each of these circulates as a complex with high-molecular-weight kininogen (HK).66,67 These complexes also attach to initiating surfaces, and the major attachment sites are on two of the domains of HK, which thereby places both prekallikrein and factor XI in optimal conformation for cleavage to kallikrein (plasma kallikrein) and factor XIa, respectively. It is important to note that plasma kallikrein and tissue kallikrein are separate gene products and have little amino acid sequence homology, although they have related functions (i.e., cleavage of kininogens). Tissue kallikrein prefers low-molecular-weight kininogen but is capable of cleaving HK, whereas plasma kallikrein cleaves HK exclusively. The two kininogens have an identical amino acid sequence starting at the N-terminus and continuing to 12 amino acids beyond the bradykinin moiety59 but differ in C-terminal domains because of alternative splicing at the transcription level.68,69 Both factor XII and HK bind to endothelial cells (which may function as the “natural” surface in the presence of physiologic zinc ion), thus activation may occur at the cell surface.70,71

A scheme for both production and degradation of kinins is shown in eFig. 38-1.2. The enzymes that destroy bradykinin consist of kininases I and II. Kininase I is also known as plasma carboxypeptidase N,72 which removes the C-terminal arg from bradykinin or kallidin to yield des-arg73 bradykinin or des-arg74 kallidin, respectively.75 It is the same enzyme that cleaves the C-terminal arg from the complement anaphylatoxins C3a and C5a. Kininase II is identical to angiotensin-converting enzyme (ACE).76 Kininase II is a dipeptidase that cleaves the C-terminal phe-arg from bradykinin to yield a heptapeptide, which is cleaved once again to remove ser-pro and to leave the pentapeptide arg-pro-pro-gly-phe.75 If the C-terminal arg of bradykinin is first removed with kininase I, then ACE functions as a tripeptidase to remove ser-pro-phe and to leave the above pentapeptide.77 Bradykinin and kallidin stimulate constitutively produced B2 receptors,78 whereas des-arg73-BK or des-arg74 lys-BK both stimulate B1 receptors,79 which are induced as a result of inflammation. Stimuli for B1 receptor transcription include IL-1 and TNF-α.80,81

Circumscribed, raised, erythematous, usually pruritic, evanescent areas of edema that involve the superficial portion of the dermis are known as urticaria (Fig. 38-3); when the edematous process extends into the deep dermis and/or subcutaneous and submucosal layers, it is known as angioedema. Urticaria and angioedema may occur in any location together or individually. Angioedema commonly affects the face or a portion of an extremity, may be painful but not pruritic, and may last several days. Involvement of the lips, cheeks, and periorbital areas is common, but angioedema also may affect the tongue, pharynx, or larynx. The individual lesions of urticaria arise suddenly, rarely persist longer than 24–36 hours, and may continue to recur for indefinite periods. They are highly pruritic.

Immunologic: Immunoglobulin E- and Immunoglobulin E Receptor-Dependent Urticaria/Angioedema

Atopic Diathesis

Episodes of acute urticaria/angioedema that occur in individuals with a personal or family history of asthma, rhinitis, or eczema are presumed to be IgE dependent. However, in clinical practice, urticaria/angioedema infrequently accompanies an exacerbation of asthma, rhinitis, or eczema. The prevalence of chronic urticaria/angioedema is not increased in atopic individuals.

Specific Antigen Sensitivity

Common examples of specific antigens that provoke urticaria/angioedema include foods such as shellfish, nuts, and chocolate; drugs and therapeutic agents notably penicillin; aeroallergens; and Hymenoptera venom (see Fig. 38-3). Urticaria in patients with helminthic infestations has been attributed to IgE-dependent processes; however, proof of this relationship is often lacking. Specific allergens and nonspecific stimuli may activate local reactions termed recall urticaria at sites previously injected with allergen immunotherapy.

Physical Urticaria/Angioedema5,6

Dermographism

Dermographism is the most common form of physical urticaria and is the one most likely to be confused with chronic urticaria. A lesion appears as a linear wheal with a flare at a site in which the skin is briskly stroked with a firm object (Fig. 38-4). A transient wheal appears rapidly and usually fades within 30 minutes; however, the patient's normal skin is typically pruritic so that an itch–scratch sequence may appear. The prevalence of dermographism in the general population was reported as 1.5% and 4.2%, respectively, in two studies, and its prevalence in patients with chronic urticaria is 22%. It is not associated with atopy. The peak prevalence occurs in the second and third decades. In one study, the duration of dermographism was greater than 5 years in 22% of individuals and greater than 10 years in 10%.

Elevations in blood histamine levels have been documented in some patients after experimental scratching, and increased levels of histamine,82 tryptase, SP, and VIP, but not calcitonin gene-related peptide, have been detected in experimental suction-blister aspirates. The dermographic response has been passively transferred to the skin of normal subjects with serum or IgE.83

In delayed dermographism, lesions develop 3–6 hours after stimulation, either with or without an immediate reaction, and last 24–48 hours. The eruption is composed of linear red indurated wheals. This condition may be associated with delayed pressure urticaria and these two may, in fact, represent the same entity. Cold-dependent dermographism is a condition characterized by marked augmentation of the dermatographic response when the skin is chilled.84

Pressure Urticaria

Delayed pressure urticaria appears as erythematous, deep, local swellings, often painful, that arise from 3 to 6 hours after sustained pressure has been applied to the skin.85,86 Spontaneous episodes are elicited on areas of contact after sitting on a hard chair, under shoulder straps and belts, on the feet after running, and on the hands after manual labor. The peak prevalence occurs in the third decade. Delayed pressure urticaria may occasionally be associated with fever, chills, arthralgias, and myalgias, as well as with an elevated erythrocyte sedimentation rate and leukocytosis. In one study, it accompanied chronic urticaria in 37% of patients. This is far more commonly seen than patients with pressure urticaria and no spontaneously occurring hives. An IgE-mediated mechanism has not been demonstrated; however, histamine and IL-6 have been detected in lesional experimental suction-blister aspirates and in fluid from skin chambers, respectively.87–89

Vibratory Angioedema

Vibratory angioedema may occur as an acquired idiopathic disorder, in association with cholinergic urticaria, or after several years of occupational exposure to vibration.90 It has been described in families with an autosomal dominant pattern of inheritance.91 The heritable form often is accompanied by facial flushing. An increase in the level of plasma histamine was detected during an experimental attack in patients with the hereditary form and in patients with acquired disease.91,92 A typical symptom is hives across the back when toweling off after a shower (in the absence of dermatographism).

Cold Urticaria

There are both acquired and inherited forms of cold urticaria/angioedema; however, the familial form is rare. Idiopathic or primary acquired cold urticaria may be associated with headache, hypotension, syncope, wheezing, shortness of breath, palpitations, nausea, vomiting, and diarrhea. Attacks occur within minutes after exposures that include changes in ambient temperature and direct contact with cold objects. The elicitation of a wheal after the application of ice has been called a diagnostic cold contact test (Fig. 38-5). This can be performed with thermoelectric elements with graded temperatures so that the temperature threshold for producing a wheal can be determined and a dose-response (sensitivity) in terms of stimulus duration can be readily obtained.92 If the entire body is cooled (as in swimming), hypotension and syncope, which are potentially lethal events (by drowning), may occur. In rare instances, acquired cold urticaria has been associated with circulating cryoglobulins, cryofibrinogens, cold agglutinins, and cold hemolysins, especially in children with infectious mononucleosis.93–95

Passive transfer of cold urticaria by intracutaneous injection of serum or IgE to the skin of normal recipients has been documented.96,97 Histamine, chemotactic factors for eosinophils and neutrophils, PGD2, cysteinyl leukotrienes, platelet-activating factor, and TNF-α have been released into the circulation after experimental challenge.98–104 Histamine, SP, and VIP, but not calcitonin gene-related peptide, have been detected in experimental suction-blister aspirates. Histamine has been released in vitro from chilled skin biopsy specimens that have been rewarmed.105 Neutrophils harvested from the blood of an experimentally cold-challenged arm manifested an impaired chemotactic response suggesting in vivo desensitization. Whereas complement has no role in primary acquired cold urticaria, cold challenge of patients with cold urticaria who have circulating immune complexes (such as cryoglobulins) can provoke a cutaneous necrotizing venulitis with complement activation.106–109

Rare forms of acquired cold urticaria have been described mainly in case reports include systemic cold urticaria,84 localized cold urticaria,110 cold-induced cholinergic urticaria, cold-dependent dermographism,84 and localized cold reflex urticaria.111,112 Three forms of dominantly inherited cold urticaria have been described. Familial cold urticaria which has been termed familial cold autoinflammatory syndrome and is considered a type of periodic fever.113 It is a disorder showing an autosomal dominant pattern of inheritance with a genetic linkage to chromosomes 1q44. The responsible gene has been identified as CIASI, which codes for a protein involved in regulation of inflammation and apoptosis.114 The eruption occurs as erythematous macules and infrequent wheals and is associated with burning or pruritus. Fever, headaches, conjunctivitis, arthralgias, and a neutrophilic leukocytosis are features of attacks. The delay between cold exposure and onset of symptoms is 2.5 hours, and the average duration of an episode is 12 hours. Renal disease with amyloidosis occurs infrequently. Skin biopsy specimens show mast cell degranulation and an infiltrate of neutrophils. Results of the cold contact test and passive transfer with serum have been negative. Serum levels of IL-6 and granulocyte colony stimulating factor were elevated in one patient. Other studies suggest a pathogenic role for IL-1. Delayed cold urticaria occurs as erythematous, edematous, deep swellings that appear 9–18 hours after cold challenge. Lesional biopsy specimens show edema with minimal numbers of mononuclear cells; mast cells are not degranulated; and neither complement proteins nor immunoglobulins are detected. Cold immersion does not release histamine, and the condition cannot be passively transferred. Recently, a new form of familial cold urticaria with dominant inheritance has been reported with pruritus, erythema, and urticaria with cold exposure that can progress to syncope. The ice cube test is negative and it lacks the fever, and flu-like symptoms associated with familial cold autoinflammatory syndrome.115

Cholinergic Urticaria

Cholinergic urticaria develops after an increase in core body temperature, such as during a warm bath, prolonged exercise, or episodes of fever.116 The highest prevalence is observed in individuals aged 23–28 years. The eruption appears as distinctive, pruritic, small, 1- to 2-mm wheals that are surrounded by large areas of erythema (Fig. 38-6). Occasionally, the lesions may become confluent, or angioedema may develop. Systemic features include dizziness, headache, syncope, flushing, wheezing, shortness of breath, nausea, vomiting, and diarrhea. An increased prevalence of atopy has been reported. The intracutaneous injection of cholinergic agents, such as methacholine chloride, produces a wheal with satellite lesions in approximately one-third of patients.117,118 Alterations in pulmonary function have been documented during experimental exercise challenge119 or after the inhalation of acetylcholine, but most are asymptomatic.

A major subpopulation of patients with cholinergic urticaria have a positive skin test result and in vitro histamine release in response to autologous sweat.120 It is not clear whether this is IgE mediated and any antigen present in sweat is unidentified. This is the same subpopulation with a positive methacholine skin test with satellite lesions and a nonfollicular distribution of the wheals. The remaining patients had negative results on autologous sweat skin tests or in vitro histamine release. Results of the methacholine skin test are negative for satellite lesions and the hives tend to be follicular in distribution.

Familial cases have been reported only in men in four families.121 This observation suggests an autosomal dominant pattern of inheritance. One of these individuals had coexisting dermographism and aquagenic urticaria.

After exercise challenge, histamine and factors chemotactic for eosinophils and neutrophils have been released into the circulation.99,119 Tryptase has been detected in lesional suction-blister aspirates. The urticarial response has been passively transferred on one occasion; however, most other attempts to do so have been unsuccessful.

Cold urticaria and cholinergic urticaria are not uncommonly seen together122,123 and cold-induced cholinergic urticaria represents an unusual variant in which typical “cholinergic” appearing lesions occur with exercise, but only if the person is chilled, for example, with exercise outside on a winter's day. The ice cube test and methacholine skin test are both negative.124

Local Heat Urticaria

Local heat urticaria is a rare form of urticaria in which wheals develop within minutes after exposure to locally applied heat. An increased incidence of atopy has been reported. Passive transfer has been negative. Histamine, neutrophil chemotactic activity, and PGD2 have been detected in the circulation after experimental challenge.125 A familial delayed form of local heat urticaria in which the urticaria occurred in 1–2 hours after challenge and lasted up to 10 hours has been described.

Solar Urticaria

Solar urticaria occurs as pruritus, erythema, wheals, and occasionally angioedema that develop within minutes after exposure to sun or artificial light sources. Headache, syncope, dizziness, wheezing, and nausea are systemic features. Most commonly, solar urticaria appears during the third decade.126 In one study, 48% of patients had a history of atopy. Although solar urticaria may be associated with systemic lupus erythematosus and polymorphous light eruption, it is usually idiopathic. The development of skin lesions under experimental conditions in response to specific wavelengths has allowed classification into six subtypes; however, individuals may respond to more than one portion of the light spectrum. In type I, elicited by wavelengths of 285–320 nm, and in type IV, elicited by wavelengths of 400–500 nm, the responses have been passively transferred with serum, suggesting a role for IgE antibody. In type I, the wavelengths are blocked by window glass.127,128 Type VI, which is identical to erythropoietic protoporphyria, is due to ferrochelatase (hemesynthetase) deficiency (see Chapter 132).74 There is evidence that an antigen on skin may become evident once irradiated with the appropriate wave length of light followed by complement activation and release of C5a.129–131

Histamine and chemotactic factors for eosinophils and neutrophils have been identified in blood after exposure of the individuals to ultraviolet A, ultraviolet B, and visible light.132,133 In some individuals, uncharacterized serum factors with molecular weights ranging from 25 to 1,000 kDa, which elicit cutaneous wheal-and-erythema reactions after intracutaneous injection, have been implicated in the development of lesions.

Exercise-Induced Anaphylaxis

Exercise-induced anaphylaxis is a clinical symptom complex consisting of pruritus, urticaria, angioedema respiratory distress, and syncope that is distinct from cholinergic urticaria.134–137 In most patients, the wheals are not punctate and resemble the hives seen in acute or chronic urticaria. The symptom complex is not readily reproduced by exercise challenges as is cholinergic urticaria. There is a high prevalence of an atopic diathesis. Some cases are food dependent, i.e., exercise will lead to an anaphylaxis-like episode only if food was ingested within 5 hours of the exercise. The food dependency is subdivided into two groups: in the first the nature of the food eaten is not relevant, whereas in the second a specific food to which there is IgE-mediated hypersensitivity must be eaten for hives to appear.138–141 Yet in these cases, eating the food without exercise does not result in urticaria. The food-dependent group is easier to treat because avoidance of food (or a specific food) for 5–6 hours before exercise prevents episodes. Cases not related to food require therapy for acute episodes and attempts to prevent episodes with high-dose antihistaminics or avoidance of exercise. Results of a questionnaire study of individuals who had had exercise-induced anaphylaxis for more than a decade142 disclosed that the frequency of attacks had decreased in 47% and had stabilized in 46%. Forty-one percent had been free of attacks for 1 year. Rare familial forms have been described. In exercise-induced anaphylaxis, baseline pulmonary function tests are normal. Biopsy specimens show mast cell degranulation, and histamine and tryptase are released into the circulation when symptoms appear.

Adrenergic Urticaria

Adrenergic urticaria occurs as wheals surrounded by a white halo that develop during emotional stress. The lesions can be elicited by the intracutaneous injection of norepinephrine.

Aquagenic Urticaria and Aquagenic Pruritis

Contact of the skin with water of any temperature may result in pruritus alone or, more rarely, urticaria. The eruption consists of small wheals that are reminiscent of cholinergic urticaria. Aquagenic urticaria has been reported in more than one member in five families.143 Aquagenic pruritus without urticaria is usually idiopathic but also occurs in elderly persons with dry skin and in patients with polycythemia vera, Hodgkin's disease, the myelodysplastic syndrome, and the hypereosinophilic syndrome. Patients with aquagenic pruritus should be evaluated for the emergence of a hematologic disorder. After experimental challenge, blood histamine levels were elevated in subjects with aquagenic pruritus and with aquagenic urticaria. Mast cell degranulation was present in lesional tissues. Passive transfer was negative.

Contact Urticaria

Urticaria may occur after direct contact with a variety of substances. It may be IgE mediated or nonimmunologic. The transient eruption appears within minutes, and when it is IgE mediated, it may be associated with systemic manifestations. Passive transfer has been documented in some instances. Proteins from latex products are a prominent cause of IgE-mediated contact urticaria.144 Latex proteins also may become airborne allergens, as demonstrated by allergen-loaded airborne glove powder used in inhalation challenge tests. These patients may manifest cross-reactivity to fruits, such as bananas, avocado, and kiwi.145 Associated manifestations include rhinitis, conjunctivitis, dyspnea, and shock. The risk group is dominated by biomedical workers and individuals with frequent contact with latex, such as children with spina bifida. Agents such as stinging nettles, arthropod hairs, and chemicals may release histamine directly from mast cells.

Papular Urticaria

Papular urticari occurs as episodic, symmetrically distributed, pruritic, 3- to 10-mm urticarial papules that result from a hypersensitivity reaction to the bites of insects such as mosquitoes, fleas, and bedbugs. This condition appears mainly in children. The lesions tend to appear in groups on exposed areas such as the extensor aspects of the extremities.146

Urticaria/Angioedema Mediated by Bradykinin, the Complement System or Other Effector Mechanisms

Kinins and C1 Inhibitor Deficiency

C1 inhibitor (C1 INH) is the sole plasma inhibitor of factor XIIa and factor XIIf,147,148 and it is one of the major inhibitors of kallikrein149 as well as factor XIa.150 Thus, in the absence of C1 INH, stimuli that activate the kinin-forming pathway will do so in a markedly augmented fashion; the amount of active enzyme and the duration of action of the enzymes are prolonged. C1 INH deficiency can be familial, in which there is a mutant C1 INH gene, or it can be acquired. Both the hereditary and acquired disorders have two subtypes. For the hereditary disorder, type I hereditary angioedema (HAE) (85%) is an autosomal dominant disorder with a mutant gene (often with duplication, deletions, or frame shifts) leading to markedly suppressed C1 INH protein levels as a result of abnormal secretion or intracellular degradation.151 Type 2 HAE (15%) is also a dominantly inherited disorder, typically with a point (missense) mutation leading to synthesis of a dysfunctional protein.152 The C1 INH protein level may be normal or even elevated, and a functional assay is needed to assess activity. The acquired disorder has been portrayed as having two forms, but they clearly overlap and have in common B cell activation that is often clonal. One group is associated with B-cell lymphoma153–155 or connective tissue disease,156 in which there is consumption of C1 INH. Examples are systemic lupus erythematosus and cryoglobulinemia, in which complement activation is prominent, and B-cell lymphomas, in which immune complexes are formed by anti-idiotypic antibodies to monoclonal immunoglobulin expressed by the transformed B lymphocytes.157 A second group has a prominence of a circulating IgG antibody to INH itself,158–160 but this may be seen with lymphoma or systemic lupus erythematosus as well. Acquired types have depressed C1q levels, whereas hereditary types do not, and depressed C4 levels characterize all forms of C1 INH deficiency. The acquired autoimmune subgroup has a circulating 95-kDa cleavage product of C1 INH because the antibody depresses C1 INH function yet allows cleavage by enzymes with which it usually interacts.159–162

It is now clear that depletion of C4 and C2 during episodes of swelling163,164 is a marker of complement activation but does not lead to release of a vasoactive peptide responsible for the swelling. Bradykinin is, in fact, the mediator of the swelling165–167 and the evidence in support of this conclusion is summarized below. Patients with HAE are hyperresponsive to cutaneous injection of kallikrein.168 They have elevated bradykinin levels, and low prekallikrein and HK levels during attacks of swelling.169–171 The augmentation in complement activation seen at those times may be due to activation of C1r and C1s by factor XIIf.172 The presence of kallikrein-like activity in induced blisters of patients with HAE also supports this notion,173 as does the progressive generation of bradykinin on incubation of HAE plasma in plastic (noncontact-activated) tubes165,166 as well as the presence of activated factor XII and cleaved HK levels seen during attacks.174 One unique family has been described in which there is a point mutation in the C1 INH (A1a 443 → Val) leading to an inability to inhibit complement but normal inhibition of factor XIIa and kallikrein.175,176 No family member of this type 2 mutation has had angioedema,175 although complement activation is present. In recent studies plasma bradykinin levels have been shown to be elevated during attacks of swelling in both hereditary and acquired C1 inhibitor deficiency,169 and local bradykinin generation has been documented at the sites of swelling.177 It is not known whether bradykinin generation is predominantly seen in the fluid phase, occurs along cell (endothelial) surfaces, or both. A rodent model of HAE demonstrated that angioedema can be prevented by “knockout” of the B-2 receptor.178 Figure 38-7 depicts a patient with facial swelling due to HAE. Figure 38-8 is a diagram depicting the steps in the bradykinin-forming cascade that are inhibitable by C1 INH.

An estrogen-dependent form of hereditary angioedema has been recognized that is now designated type 3 HAE. One of the first reports involved a single family with seven affected individuals in three generations, which suggests a hereditary (autosomal dominant) pattern.73 Clinical features include angioedema without urticaria, laryngeal edema, and abdominal pain with vomiting. Attacks occur during pregnancy and with the administration of exogenous estrogen. Numerous subsequent reports support these observations.179 In one subgroup, there is a mutation in factor XII such that the activated form (factor XIIa) is more potent than normal.180 These patients all have normal C4 and normal C1 INH protein and function. Bradykinin is the likely mediator; for those with a factor XII mutation, the active enzyme may be less readily inhibited. Although uncommon, a male with the disorder has been described181 and a bradykinin receptor antagonist (Icatibanit) has provided effective therapy for acute episodes.

Angiotensin-Converting Enzyme Inhibitors

Angioedema has been associated with the administration of ACE inhibitors.182 The frequency of angioedema occurring after ACE inhibitor therapy is 0.1%–0.7%. There is a predilection to ACE inhibitor reactions in the African-American population that may relate to polymorphisms in the genes encoding other enzymes that catabolize bradykinin such as aminopeptidase P or neutral endopeptidase. Low levels of these would predispose to bradykinin accumulation. Angioedema develops during the first week of therapy in up to 72% of affected individuals and usually involves the head and neck, including the mouth, tongue, pharynx, and larynx. Urticaria occurs only rarely. Cough and angioedema of the gastrointestinal tract are associated features. It has been suggested that therapy with ACE inhibitors is contraindicated in patients with a prior history of idiopathic angioedema, HAE, and acquired C1 INH deficiency.183 It appears that this swelling is also a consequence of elevated levels of bradykinin;169 however, the accumulation of bradykinin is due to a defect in degradation rather than an excessive production. ACE, being identical to kininase II, is the major enzyme responsible for bradykinin degradation (See eFig. 38-1.2) and although it is present in plasma, the vascular endothelium of the lung appears to be its major site of action.184 The action of ACE always leads to the formation of degradation products with no activity, whereas kininase I alone yields the des-arg products, which are capable of stimulating B1 receptors.

The excessive accumulation of bradykinin implies that production is ongoing, with activation of the plasma cascade or release of tissue kallikrein faulty inactivation of bradykinin then leads to swelling. Continuous turnover of the plasma cascade is implied by data demonstrating activation along the surface of cells and cellular expression or secretion of a prekallikrein activator other than factor XIIa.185,186

Urticarial Venulitis

Chronic urticaria and angioedema may be manifestations of cutaneous necrotizing venulitis, which is known as urticarial venulitis (See Chapter 163).187,188 Associated features include fever, malaise, arthralgia, abdominal pain, and less commonly conjunctivitis, uveitis, diffuse glomerulonephritis, obstructive and restrictive pulmonary disease, and benign intracranial hypertension. The term hypocomplementemic urticarial vasculitis syndrome is used in patients with more severe clinical manifestations of urticarial venulitis with hypocomplementemia and a low-molecular-weight C1q-precipitin that has been identified as an IgG autoantibody directed against the collagen-like region of C1q.

Serum Sickness

Serum sickness, which was defined originally as an adverse reaction that resulted from the administration of heterologous serum to humans, but may similarly occur after the administration of drugs. Serum sickness occurs 7–21 days after the administration of the offending agent and is manifested by fever, urticaria, lymphadenopathy, myalgia, arthralgia, and arthritis. Symptoms are usually self-limited and last 4–5 days. More than 70% of patients with serum sickness experience urticaria that may be pruritic or painful. The initial manifestation of urticaria may appear at the site of injection.189–197

Reactions to the Administration of Blood Products

Urticaria/angioedema may develop after the administration of blood products. It usually is the result of immune complex formation and complement activation that leads to direct vascular and smooth muscle alterations and indirectly, via anaphylatoxins, to mast cell mediator release. Aggregated IgG may also be responsible for human reactions to immunoglobulins as evidenced by the fact that the administration of IgG from which aggregates have been removed is not associated with urticaria or anaphylaxis.

An uncommon mechanism for the development of urticaria after the administration of blood products is the transfusion of IgE of donor origin directed toward an antigen to which the recipient is subsequently exposed. Another mechanism may be the transfusion of a soluble antigen present in the donor preparation into a previously sensitized recipient.

Infections

Episodes of acute urticaria can be associated with upper respiratory tract viral infections, most commonly in children.198 The acute urticaria resolves within 3 weeks. Hepatitis B virus infection has been associated with episodes of urticaria lasting up to 1 week that are accompanied by fever and arthralgias as part of the prodrome. The mechanism is analogous to that seen in serum sickness-like reactions with virus–antibody immune complexes. The mechanism for urticaria occasionally associated with infectious monomucleosis may be analogous.

Urticaria/Angioedema after Direct Mast Cell Degranulation

Various therapeutic and diagnostic agents have been associated with urticaria/angioedema. Up to 8% of patients receiving radiographic contrast media experience such reactions, which occur most commonly after intravenous administration. Decreased serum alternative pathway complement protein levels and increased serum histamine levels have been detected in patients receiving radiocontrast media. Opiate analgesics, polymyxin B, curare, and d-tubocurarine induce release of histamine from mast cells and basophils.

Urticaria/Angioedema Relating to Abnormalities of Arachidonic Acid Metabolism

Intolerance to aspirin manifested as urticaria/angioedema occurs in otherwise normal individuals or in patients with allergic rhinitis and/or bronchial asthma. Urticaria/angioedema in response to aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) occurred in approximately 10%–20% of individuals referred to a hospital dermatology clinic in the United Kingdom. Patients intolerant of aspirin also may react to indomethacin and to other NSAIDs.

Reactions to aspirin are shared with other NSAIDs because they reflect inhibition of prostaglandin endoperoxide synthase 1 (PGHS-1, cyclooxygenase I)199 as well as inhibition of the inducible PGHS-2 (cyclooxygenase 2). Sodium salicylate and choline salicylate generally are well tolerated because of their weak activity against PGHS-1. PGHS-2 inhibitors are generally well tolerated in those with NSAID-induced urticaria.200,201 Reactions to NSAIDs increase the levels of cysteinyl leukotrienes,202 which may relate to the appearance of urticaria, although their role in NSAID-induced asthma is better characterized. Prick skin tests are of no diagnostic value, passive transfer reactions are negative, and neither IgG nor IgE antibodies have been associated with clinical disease. The clinical manifestations elicited by aspirin challenge of aspirin-intolerant patients are blocked when such patients are protected with a cysteinyl leucotriene receptor blocker or biosynthetic inhibitor; this finding confirms a pathobiologic role for the cysteinyl leukotrienes.

Chronic Idiopathic Urticaria and Idiopathic Angioedema

Because the clinical entities of chronic idiopathic urticaria (with or without angioedema) and idiopathic angioedema are frequently encountered, have a capricious course, and are recognized easily, they are frequently associated with concomitant events. Such attributions must be interpreted with caution. Although infections, food allergies, adverse reactions to food additives, metabolic and hormonal abnormalities, malignant conditions, and emotional factors have been claimed as causes, proof of their etiologic relationship often is lacking. Among the recent considerations is chronic urticaria as a consequence of infection with Helicobacter pylori. Articles both supporting203–205 and denying206–209 a relationship are numerous and a definite answer is not available. However, the H. pylori infection rate in the population at large is far greater than the incidence of chronic urticaria and in the opinion of this author, the association is spurious. The controversy has been put in perspective by M. Greaves.210 Idiopathic angioedema is diagnosed when angioedema is recurrent, when urticaria is absent, and when no exogenous agent or underlying abnormality is identifiable. An extensive review of angioedema has been recently published.184

Cyclic episodic angioedema has been associated with fever, weight gain, absence of internal organ damage, a benign course, and peripheral blood eosinophilia.211 Biopsy specimens of tissues show eosinophils, eosinophil granule proteins, and CD4 lymphocytes exhibiting HLA-OR. Blood levels of IL-1, soluble IL-2 receptor, and IL-5 are elevated.

Idiopathic angioedema is characterized by recurrent episodes of angioedema in the absence of any urticaria, which may include the face (lips, tongue, periorbital region, pharynx), extremities, and genitalia, but is not associated with laryngeal edema or massive tongue/pharyngeal swelling that yield airway obstruction. It may not be a continuum with chronic urticaria with or without concomitant angioedema, as is often considered, because the incidence in men and women is about the same and the presence of antithyroid antibodies or anti-IgE receptor antibodies is far less. Extreme cases, particularly if associated with laryngeal edema, could represent type 3 HAE in a patient with a new mutation (i.e., no family history) or a variant of idiopathic anaphylaxis.

Miscellaneous

Muckle–Wells syndrome consists of urticaria, amyloidosis, and nerve deafness and is due to the same gene defect as is seen in familial cold urticaria.114 Schnitzler syndrome is a chronic urticaria with histology resembling an urticarial vasculitis associated with fever, joint pain, an IgM monoclonal protein, and osteosclerosis. An antibody to IL-1α has been shown to be present.212

The evaluation of patients with urticaria/angioedema (Fig. 38-9) begins with a comprehensive history, with particular emphasis on the recognized causes, and a physical examination. Some varieties of urticaria may be identified by their characteristic appearance, such as the small wheals with a large erythematous flare of cholinergic urticaria, the linear wheals in dermographism, and the localization of lesions to exposed areas in light- or cold-induced urticaria. If suggested by the history, the physical examination in all patients with urticaria should include tests for physical urticaria, such as a brisk stroke to elicit dermographism, the use of a weight to elicit delayed pressure urticaria, and application of a cold or warm stimulus for cold-induced urticaria and localized heat urticaria, respectively. Exercise, such as running in place, may elicit cholinergic urticaria and, in some instances, exercise-induced anaphylaxis. Phototests to elicit solar urticaria usually are performed in referral centers, as are challenges for exercise-induced anaphylaxis.

When urticaria has been present for days or weeks at a time (but less than 6 weeks) or occurs recurrently for similar intervals, the main considerations are allergic reactions (IgE mediated) to food or drugs. A careful history regarding possibilities is essential. Skin testing can corroborate IgE-mediated hypersensitivity to foods or can provide suspects when the history is unrevealing. Double-blind placebo-controlled food challenge can demonstrate clinical relevance in cases in which the role of a food is uncertain. Non-IgE-mediated causes of urticaria include adverse reactions to NSAIDs and opiates. Any of these can be associated with concomitant angioedema or, less commonly, present as angioedema in the absence of urticaria. Children may have acute urticaria in association with viral illnesses; it is unclear whether infection with bacteria such as Streptococcus can induce urticaria as well, but neither form occurs in adults with the exception of urticaria in association with infectious mononucleosis (Epstein–Barr virus) or as a prodrome to hepatitis B infection. In each of these circumstances, individual lesions last anywhere from 4 hours to 24 hours and fade without associated purpura. If hives last less than 2 hours, the cause is usually physical urticaria, the most common being dermatographism, cholinergic urticaria, and cold urticaria. The main exception is delayed pressure urticaria, in which lesions typically last 12–36 hours and first appear 3–6 hours after the initiating stimuli. Once urticaria continues for longer than 6 weeks (particularly if present for many months or years) chronic urticaria is present. The term chronic spontaneous urticaria has been employed recently to eliminate confusion with physical urticarias. Chronic urticaria is now divided into chronic idiopathic urticaria for which a cause has not yet been found and chronic autoimmune urticaria. Angioedema accompanies chronic urticaria in 40% of cases and is more problematic in the autoimmune subgroup. Swelling in association with chronic urticaria can affect hands, feet, eyes, cheeks, lips, tongue, and pharynx, but not the larynx. When angioedema is present in the absence of an identifiable antigen or exogenous stimulus, the main entities to consider are C1 INH deficiency (hereditary or acquired) and idiopathic angioedema. Approximately 0.5% of patients have an urticarial vasculitis with palpable purpura or other stigmata of a possible vasculitis, such as fever, elevated sedimentation rate, petechiae or purpura, elevated white blood cell count, or lesions of unusual duration (36–72 hours). The differential diagnosis of acute, chronic, and physical urticaria/angioedema is summarized in Box 38-1.

In most patients with chronic urticaria/angioedema, no underlying disorders or causes can be discerned. Diagnostic studies should be based on findings elicited by the history and physical examination. Evaluation of chronic urticaria/angioedema should include thyroid function tests, assays for antimicrosomal and antithyroglobulin antibodies, and the autologous skin test can be done, even in an office setting.213 Routine screening laboratory tests are of little value. The histamine release assay for anti-IgE receptor or anti-IgE antibodies are now available in specialized laboratories. Serum hypocomplementemia is not present in chronic idiopathic urticaria or chronic autoimmune urticaria and mean levels of serum IgE in these patients are not different from the general population in which the incidence of atopy is 20%.

Cryoproteins should be sought in patients with acquired cold urticaria. An antinuclear antibody test should be obtained in patients with solar urticaria. Assessment of serum complement proteins may be helpful in identifying patients with urticarial venulitis or serum sickness (C4-, C3-, C1q-binding assay for circulatory immune complexes), as well as those with hereditary and acquired forms of C1 INH deficiency (C4, C1 INH by protein and function, C1q level).

Skin biopsy of chronic urticarial lesions should be undertaken to identify urticarial venulitis or to assess rashes where the urticarial nature is not clear.

There is little role for routine prick skin testing or the radioallergosorbent test in the diagnosis of specific IgE-mediated antigen sensitivity in chronic urticaria/angioedema. Inhalant materials are uncommon causes of urticaria/angioedema, and food skin tests may be difficult to interpret. The tests for drugs are limited to penicillin but cannot be performed in patients with dermographism. The radioallergosorbent test should be reserved for those in whom skin testing is contraindicated, unavailable, or unrevealing despite a highly suspected history.

A finding of the release of histamine from peripheral basophilic leukocytes has supported the diagnosis of anaphylactic sensitivity to a variety of antigens, which include pollens and insect venom.

Histopathology

Edema involving the superficial portion of the dermis is characteristic of urticaria, whereas angioedema involves the deeper dermis and subcutaneous tissue. Both disorders are associated with dilatation of the venules.

In chronic urticaria, the dermal infiltrating inflammatory cells may be sparse or dense and include more CD4 than CD8 T lymphocytes, neutrophils, eosinophils, and basophils46,214 without B lymphocytes or natural killer (NK) cells. NKT cells have not been assessed. Increased expression of TNF-α and IL-3 on endothelial cells and perivascular cells was detected in the upper dermis of patients with acute urticaria, chronic idiopathic urticaria, and delayed-pressure urticaria and in one patient with cold urticaria.215 TNF-α also was detected on epidermal keratinocytes in lesional and nonlesional biopsy specimens. In chronic idiopathic urticaria, CD11b and CD18 cells were detected about the blood vessels in the superficial and deep dermis. Direct immunofluorescence tests for immunoglobulins and complement proteins were negative.

Major basic protein and eosinophil cationic protein, which are derived from the eosinophils granule, are present around blood vessels and are dispersed in the dermis in lesions of acute urticaria, chronic idiopathic urticaria, delayed-pressure urticaria, cholinergic urticaria, and solar urticaria. In chronic idiopathic urticaria, free eosinophil granules in the dermis were increased in wheals of greater than 24 hours’ duration as compared with wheals lasting fewer than 24 hours. The secreted form of eosinophil cationic protein and eosinophil-derived neurotoxin were detected on cells in greater amounts in biopsy specimens from patients with chronic urticaria without autoantibodies than in those with autoantibodies. P-selectin, E-selectin, intercellular adhesion molecules 1, and vascular cellular adhesion molecule 1 have been demonstrated on the vascular endothelium of patients with chronic idiopathic urticaria and dermographism. Major histocompatability complex class II antigen also is upregulated on the endothelial cells of patients with chronic urticaria, and the peripheral blood lymphocytes have increased CD40 ligand expression and higher Bcl-2 expression; these observations suggest an augmentation of autoimmune phenomena.216

In papular urticaria, the epidermis is thick with intercellular edema and lymphocytes. In the dermis, there is edema with an infiltrate containing T lymphocytes, macrophages, eosinophils, and neutrophils without B lymphocytes or the deposition of immunoglobulins, fibrin and C3.

Therapy of acute urticaria uses antihistamines as described in Fig. 38-10; however, the rash can be severe and generalized, and angioedema may be present as well. Thus, if relief provided by nonsedating antihistamines appears insufficient, one can try hydroxyzine or diphenhydramine at 25–50 mg qid.217 Alternatively nonsedating antihistamines can be tried employing up to 4–6 tablets/day as has been reported for treatment of cold urticaria.92 A course of corticosteroid can be used, for example, 40–60 mg/day for 3 days and taper by 5–10 mg/day. Epinephrine can relieve severe symptoms of urticaria or angioedema (generalized urticaria, severe pruritus, accelerating angioedema) and is indicated if laryngeal edema is present. Edema of the posterior tongue and/or pharyngeal edema can be confused with it.

The ideal treatment for urticaria/angioedema is identification and removal of its cause. Many patients with acute urticaria and angioedema probably are not treated by physicians because the cause is identified by the individual or the course is limited. Treatment of chronic urticaria focuses on measures that provide symptomatic relief. The physician should provide not only medications but also support and reassurance. In a questionnaire study, patients with chronic idiopathic urticaria considered the worst aspects to be pruritus and the unpredictable nature of the attacks. The presence of facial angioedema can be particularly disconcerting and tongue and/or pharyngeal edema is often considered life threatening. This is not the case and is confused with the potential for laryngeal edema seen with anaphylaxis, or anaphylactic-like reactions, C1 INH deficiency, or reactivity to ACE inhibitors. Affected individuals reported sleep disturbances, diminished energy, social isolation, and altered emotional reactions as well as difficulties in relation to work, home activities, social life, and sex life.218,219 Another study showed a correlation between the severity of chronic idiopathic urticaria and depression. In a questionnaire study, individuals with delayed pressure urticaria and cholinergic urticaria had the most quality-of-life impairment.220 Those with cholinergic urticaria suffered in relation to their sporting activities and sexual relationships. Although urticaria/angioedema may be a source of frustration to both physicians and patients, most individuals can achieve acceptable symptomatic control of their disease without identification of the cause. In some individuals, it is important to avoid aspirin and other NSAIDs. Antipruritic lotions, cool compresses, and ice packs may provide temporary relief. H1-type antihistaminic drugs are the mainstays in the management of urticaria/angioedema. The older H1-type antihistaminics are known as classic, traditional, or first generation H1-type antihistamines. Newer, low-sedating, or second- and third-generation H1-type antihistamines with reduced sedative and anticholinergic side effects have become the initial therapeutic agents of choice. The drug should be taken on a regular basis and not as needed. If the initial drug chosen is ineffective, an agent from a different pharmacological class should be used and nonsedating antihistaminics can be combined or the dose of any one of them increased. When this is ineffective, doses of hydroxyzine or diphenhydramine in the 25–50 mg qid may be tried. The same is true for the treatment of dermatographism when it is particularly severe. It should be noted that if the molar release of histamine in the skin exceeds that of the delivered antihistamine (as can be seen with dermatographism), the histamine will keep the receptors to which it is bound in the active conformation, and therapeutic efficacy with the antihistamine will be achieved only when its molar concentration is much greater than that of histamine. Diphenhydramine is an alternative to hydroxyzine or cetirizine for dermatographism but not for cholinergic urticaria.221,222 Cold urticaria can be treated with most antihistaminics but cyproheptadine at 4–8 mg tid or qid seems to be particularly effective.223–226 Excellent results have been recently reported with desloratadine at four times/day.92 Local heat urticaria is treated with antihistaminics; no regimen is particularly favored. Although anecdotal reports suggest that delayed pressure urticaria will respond to NSAIDs, dapsone, cetirizine, or sulfasalazine, most require corticosteroids (used as in chronic urticaria) to control symptoms and cyclosporine can be a particularly effective alternative. Familial cold autoinflammatory syndrome (urticaria) responds to parenteral IL-1 receptor antagonist (anakinra) as does some cases of Schnitzler syndrome.

Treatment choices for chronic urticaria (idiopathic or autoimmune) have been reviewed227 and are summarized in Fig. 38-10. It is important to use first-generation antihistamines at a maximal dose if nonsedating antihistamines have not been helpful before resorting to corticosteroids or cyclosporine. H2-receptor antagonists may yield some additional histamine receptor blockade, although their contribution is usually modest. The efficacy of leucotriene antagonists is controversial, with equal numbers of pro and con articles. If steroids are used, this author recommends not exceeding 25 mg q.o.d. or 10 mg daily. With either approach, attempts to slowly taper the dose should be made every 2–3 weeks. One mg prednisone tablets can be very helpful when the daily dose is less than 10 mg. Double-blind placebo-controlled studies of cyclosporine indicate that it is a good alternative to corticosteroid,228,229 and can be safer when used appropriately. Measurement of blood pressure, blood urea nitrogen level, and creatinine level, and a urinalysis should be done every 6–8 weeks. The starting adult dose is 100 mg bid; it can be slowly advanced to 100 mg tid, but not higher. The response rate is 75% in the autoimmune groups and 50% in the idiopathic group. No comparable studies (or clinical effects) have been obtained with dapsone, hydroxychloroquine, colchicine, sulfasalazine, or methotrexate and only small numbers cases have been treated successfully with intravenous γ globulin or plasmapheresis.230,231 Successful treatment of chronic autoimmune urticaria has been reported with Omalizumab232 with results comparable to that seen with cyclosporine. The rate of response can be very striking, for example, remission with a single dose. Additional articles have appeared,233,234 although uncontrolled.

Urticarial vasculitis is treated with antihistamines and if severe, with low-dose corticosteroid. Here dapsone or hydroxychloroquine may be steroid sparing. When urticarial vasculitis is part of a systemic disease, the treatment will focus on what is needed for the underlying disorders. The drug of choice for the hypocomplementemic urticarial vasculitis syndrome (with circulating immune complexes due to IgG anti-C1q)195 is hydroxychloroquine.235

Angioedema caused by ACE inhibitors can be an acute emergency with laryngeal edema or tongue or pharyngeal edema that is so extensive the patient cannot manage secretions and intubation is necessary. Supportive therapy, epinephrine, and time are needed; there is no response to antihistamines or corticosteroids. Other antihypertensive agents can be substituted, including those that block angiotensin II receptors.

Acute attacks of HAE are unresponsive to antihistaminics or corticosteroid. Epinephrine may be given but a positive response is actually uncommon. Intubation or tracheostomy may be needed when severe laryngeal edema is encountered. Recently, a preparation of C1 INH (Berinert) has been approved in the United States for intravenous infusion to treat acute attacks of HAE. It is effective and has been available and employed in Europe and Brazil for over two decades. Icatibant,236 a bradykinin B-2 receptor antagonist, has been approved for acute treatment in Europe but not in the United States. It is given by subcutaneous injection. Kalbitor, a plasma kallikrein inhibitor (ecallantide), has been approved for the treatment of acute attacks of HAE in the United States. It too is administered by subcutaneous injection.237 In the past, fresh frozen plasma was an option. It has been used with excellent success for years, but occasional dramatic worsening of symptoms has been reported because all the plasma factors needed for bradykinin generation are also being infused.

A second C1 INH nanofiltered preparation (Cinryze) has been approved in the United States for prophylactic treatment of AHE types I and II. It is administered by intravenous injection up to twice weekly. Prophylaxis with androgens such as Danazol (200 mg tablets) or Stanazolol (2 mg tablets)238,239 or antifibrinolytics such as E-aminocaprioc acid or tranexamic acid240 have been employed (used) successfully for many years.241,242 The androgens are more commonly used—one watches for hirsutisum, irregular menses, and abnormal liver chemistries, as potential side effects. In the long term, hepatic adenomas may appear. Increased dosages may be used when a patient undergoes elective surgical procedures (e.g., 3 tablets/day for 2–3 days before the procedure, the day of the procedure, and 1 day after). Fresh frozen plasma is a safe alternative given a few hours prior to the procedure and clearly C1 INH concentrate can be used. Acquired C1 INH deficiency can be treated with low-dose androgens in addition to therapy for the underlying condition. C1 INH concentrate may be helpful but the presence of anti-C1 INH will limit responsiveness to reasonable doses. Plasmapheresis and/or cytotoxic agents may be used.

I wish to thank Dr Nicholas Soter who reviewed this manuscript, made many helpful suggestions, and contributed two of the photos.