Urticaria

Urticaria has been recognized since the days of Hippocrates. The name of the condition dates back to the 18th century, when the burning and edema of the skin was likened to that caused by contact with nettles (Urtica dioica). Urticaria affects 10% to 25% of the population worldwide at some point in their lives.¹ The condition is characterized by short-lived edema of the skin, mouth, and genitalia related to a transient leakage of plasma from small blood vessels into the surrounding connective tissues. Urticaria may present with superficial edema of the dermis (wheals) or deeper edema of the dermal, subcutaneous, or submucosal tissues (angioedema).² Wheals typically are itchy with a pale center, maturing into pink superficial plaques. Areas of angioedema tend to be pale and painful; last longer than wheals; and may involve the mouth and rarely the bowel.

Case Report

A 40-year-old woman in otherwise good health presented with a 5-year history of recurrent pruritic light red lesions on her chest and back. She reported that individual lesions would last up to 24 hours in one area before disappearing, while other new crops of lesions would develop in other areas of her body. She had no associated facial edema or lip or throat involvement, and she denied taking any medications. Her history failed to reveal any potential triggers for the eruptions. On physical examination, multiple elevated superficial erythematous papules and plaques were noted, with shapes varying from annular to circinate, areas of central clearing, and targetlike lesions on the trunk and extremities. The lesions blanched with pressure (Figure). The woman had no mucosal involvement, scars, or change in pigmentation. Results from the remainder of the physical examination were unremarkable.

PLEASE REFER TO THE PDF TO VIEW THE FIGURE

Because of the extent of involvement and the erythematous to violaceous aspect of certain lesions, a 3-mm punch biopsy was performed to rule out urticarial vasculitis. Histology results were consistent with urticaria with red blood extravasation but without vasculitis. Our patient initially was treated with topical clobetasol propionate ointment, 10 mg of cetirizine hydrochloride, and topical calamine lotion. At follow-up one week later, she mentioned that she had improved after 5 days of treatment but began developing new lesions 2 days prior to her second visit. Given the severity of pruritus and after a discussion of the role of corticosteroids for acute urticaria, a taper dose of prednisone was prescribed at 40 mg/d, in addition to 60 mg of fexofenadine hydrochloride twice daily. The patient was lesion- and symptom-free after 7 days of treatment, with no recurrence one month later.

Comment

Urticaria may be acute or chronic. Acute urticaria is idiopathic in more than 50% of patients but can occur as a type 1 hypersensitivity reaction to food or wasp or bee stings; an immunologic response to blood products, infection, or febrile illness; or an adverse effect of drug therapy by various mechanisms, such as penicillin or angiotensin-converting enzyme inhibitors.³ As opposed to acute urticaria, chronic urticaria is defined by recurrent episodes occurring at least twice weekly for 6 weeks.² Urticaria occurring less frequently than this, over a long period, is more accurately termed episodic because it is more likely to have an identifiable environmental trigger. All chronic urticaria implicitly go through an acute stage (<6 weeks). Although many classification systems of chronic urticaria exist, a concise clinical classification is included in the Table.² Urticarial vasculitis is a small vessel vasculitis but is included in the classification because it is clinically indistinguishable from other urticarial lesions.

PLEASE REFER TO THE PDF TO VIEW THE TABLE

Urticarial lesions in chronic urticaria typically last 4 to 36 hours and can occur in individuals of any age (though it is most common in women), usually with few systemic symptoms.⁴ Pruritus is nearly always severe, especially at night, and may prevent sleep. Fifty percent of cases resolve spontaneously by 6 months, but of those that do not, 40% still have symptoms of urticaria 10 years later.⁴ The severe effect of chronic urticaria on quality of life often is underestimated.⁵

Ordinary Urticaria

Patients previously classified as having chronic idiopathic or "ordinary" urticaria are now divided into 2 groups: 50% to 60% of these patients have chronic idiopathic urticaria (CIU), and the remainder have chronic autoimmune urticaria (CAU).⁶ Results from a study in children demonstrated that autoimmune urticaria occurs in children in as many as 30% of chronic cases.⁷ CAU is caused by an immunoglobulin (Ig) G antibody to the α subunit of the IgE receptor (35%–40% of cases) or to IgE (5%–10% of cases).⁶ The IgG subclasses that appear to be pathogenic are IgG1; IgG3; and, to a lesser degree, IgG4 (though not IgG2).⁶ Complement activation augments histamine secretion by release of C5a.⁸ CAU has been reported to be associated with antithyroid antibodies (27% of cases)^6,9; autoimmune conditions such as vitiligo, rheumatoid arthritis, and pernicious anemia; and low vitamin B₁₂ levels.¹⁰ Patients with demonstrable histamine-releasing autoantibodies have a very strong association with HLA-DR4 and its associated allele HLA-DQ8.¹¹

Histologically, the 2 groups of urticaria are indistinguishable.6 Advanced techniques show a perivascular nonnecrotizing infiltrate of CD4⁺ lymphocytes consisting of a mixture of T_H1 and T_H2 subtypes, plus monocytes, neutrophils, eosinophils, and basophils. These cells are recruited because of interactions with C5a, cell priming cytokines, chemokines, and adhesion molecules.⁶ A recent study also found inflammatory cells and mediator up-regulation in uninvolved CIU skin as a sign of prolonged and widespread "urticarial status."¹²

Physical Urticaria

Physical urticaria are classified and induced by a physical stimulus. Most physical urticaria occur within minutes of provocation and resolve within 2 hours, with the exception of delayed pressure urticaria, which may persist for 24 hours or longer.¹³ Angioedema may occur in all physical urticaria except dermographism. Overlap between groups is common, and physical urticaria often occur as an added feature of chronic urticaria.

The most common type of physical urticaria is simple immediate dermographism, presenting with linear wheals at sites of scratching or friction. It occurs in about 1.4% to 5% of the population worldwide¹⁴ and may be viewed as an exaggerated physiologic response. On average, dermographism runs a course of 2 to 3 years before usually resolving spontaneously.¹⁵

Delayed-pressure urticaria is a response to sustained pressure to the skin, presenting with deep erythematous edema after a delay of unknown cause lasting 30 minutes to 12 hours.^14,16 An increased level of interleukin 6 has been found in suction blister fluid over induced lesions.^2,15 The edema tends to be deeper, pruritic, and painful, and it may persist for days. Systemic features such as malaise, flulike symptoms, and arthralgia may occur. The prognosis is variable, but the mean duration is 6 to 9 years.¹⁷ The response to antihistamines often is poor, and oral corticosteroids may be needed for disease control.²

Cholinergic urticaria usually presents with multiple, transient, pruritic, small, red macules or papules on the neck, trunk, forearms, wrists, and thighs in response to heat, often surrounded by an obvious flare. It mainly affects young adults, with an overall prevalence of 11% in this group.¹⁸ Fifty percent of patients are atopic.¹⁵ Angioedema and systemic manifestations such as headache, palpitations, abdominal pain, wheezing, and syncope may occur. The cholinergic sympathetic innervation of sweat glands is involved because the eruption can be blocked by topical anticholinergic drugs,¹⁹ but how this leads to urticaria is unclear. The routine treatment is with low-sedation H₁-type antihistamines, with or without an anxiolytic such as oral propranolol. In severe cases, the anabolic steroid stanazolol has been used.¹⁵

Cold urticaria is a heterogeneous condition in which whealing occurs within minutes in response to cold exposure, most frequently in children and young adults. Wheals usually arise at the site of localized cooling but may be generalized following lowering of the body temperature.¹⁶ Diagnosis may be confirmed by applying an ice cube for 5 to 15 minutes to the skin, allowing an interval for skin rewarming, and observing the development of whealing that occurs on skin rewarming. Systemic symptoms such as flushing, headache, abdominal pain, and syncope can occur if large areas are affected. The cause is unknown, but a serum factor, possibly IgM or IgE, has been implicated.²⁰ A heterozygous deficiency of the protease inhibitor α1-antichymotrypsin has been demonstrated and may be etiologically important in some patients.²¹ The prognosis is good, with spontaneous improvement in an average of 2 to 3 years.¹⁵ Ninety-six percent of cases of cold urticaria are primary.²² The diagnosis of secondary acquired cold urticaria depends on being able to demonstrate cryoglobulins, cold agglutinins, or possibly cryofibrinogens.¹⁷ These findings should, in turn, lead to investigations for an underlying cause, such as hepatitis B or C infection, lymphoproliferative disease, or infectious mononucleosis.¹⁵

Other uncommon forms of physical urticaria include adrenergic urticaria, which develops during phases of stress and has been associated with an increase in the plasma concentrations of norepinephrine, epinephrine, and prolactin.²³ Aquagenic urticaria is precipitated by skin contact with water of any temperature.³ Exercise-induced anaphylaxis involves urticaria, respiratory distress, or hypotension after exercise. In localized heat urticaria, wheals occur on skin in direct contact with warm objects. Solar urticaria is a rare condition that occurs within minutes of exposure to UV light waves ranging from 280 to 760 nm¹⁴; it usually disappears in less than one hour. Vibratory urticaria occurs after a vibratory stimulus and can be a hereditary autosomaldominant disorder or an acquired sporadic disease.²⁴

Urticarial Vasculitis

Urticarial vasculitis describes a distinct entity in which the gross cutaneous lesions resemble urticaria and histologically show features of a vasculitis. The diagnosis is suggested clinically by wheals lasting more than 24 hours and residual bruising.²⁵ Although the clinical lesions may present as typical urticaria, pathophysiologically, it is a different disease caused by deposition of antigen-antibody complexes in vessel walls, a type 3 reaction causing vascular damage.¹⁷ Lesions often occur at pressure points and may resolve with residual purpura. Extracutaneous manifestations include transient and migratory arthralgia (50%); gastrointestinal symptoms (20%); and pulmonary obstructive disease (20%), particularly in smokers and patients with renal disease (5%–10%).¹⁷ Normocomplementemic urticarial vasculitis usually is idiopathic, but hypocomplementemic urticarial vasculitis may be associated with underlying systemic lupus erythematosus, Sjögren syndrome, or cryoglobulinemia.² Primary urticarial vasculitis can occasionally evolve into systemic lupus erythematosus.²⁶ Patients with urticarial vasculitis often improve on nonsteroidal anti-inflammatory drugs (NSAIDs), but some patients may need immunosuppressive therapy.

Contact Urticaria

Contact urticaria develops at the site(s) of contact of an urticant and can be divided into an allergic subgroup caused by an IgE-allergen interaction and a nonallergic subgroup that is IgE independent. The allergic form typically is seen in children with atopic dermatitis sensitized to environmental allergens such as grass, animals, food, or latex, and it may be complicated by anaphylaxis. Natural rubber latex is one of the most important causes today.²⁷ This type appears within minutes, fades within 2 hours, and is partially inhibited by antihistamines. Nonallergic contact urticaria is caused by the direct effect of the urticant on blood vessels and includes irritants such as benzoic acid and cinnamic aldehyde in cosmetics. It may take 45 minutes for lesions to appear and urticaria is partially inhibited by NSAIDs.

Angioedema Without Wheals

It is useful to classify angioedema occurring without wheals as a separate entity because its etiology may be associated with hereditary angioedema, which must be excluded. The condition usually is idiopathic or caused by a drug reaction to angiotensin-converting enzyme inhibitors, aspirin, or NSAIDs. Hereditary angioedema is a rare autosomal-dominant condition with a prevalence between 1:10,000 and 1:150,000 in the general population and is caused by a deficiency (type 1, 85%) or dysfunction (type 2, 15%) of C1 inhibitor.²⁸ A low level of C4 in the serum is a constant and diagnostic feature. A third type affecting primarily women and exacerbated by estrogens recently has been described.²⁸ Patients have lifelong episodic angioedema and may experience colicky abdominal pain. Laryngeal involvement can be life threatening. Treatment is difficult and involves fluid replacement and purified C1 inhibitor concentrate for acute attacks (not approved in the United States) and prophylactic treatment with anabolic androgens and antifibrinolytics.²⁸

Diagnosis

The diagnosis of urticaria is primarily clinical; extensive laboratory tests are very rarely needed—only when indicated by the patient history.³ Some authors argue that laboratory investigations are unnecessary for mild ordinary urticaria responding to antihistamines.²⁹ Taking a thorough patient history has been found to be almost as effective in identifying a cause as a complete diagnostic evaluation.³⁰ In acute urticaria, if the history indicates a type 1 hypersensitivity reaction, confirmation is possible by a prick test or laboratory radioallergosorbent tests.³ Many physical and contact urticaria can be confirmed by a challenge of the offending agent. An initial baseline investigation with a complete blood count and erythrocyte sedimentation rate should be taken in more severe cases to identify any internal disease or raise the possibility of urticarial vasculitis.¹⁷ Of note, a biopsy is more sensitive and specific for ruling out urticarial vasculitis than are a complete blood count and erythrocyte sedimentation rate.

A search for thyroid autoantibodies is appropriate for all chronic urticaria not responding to first-line therapies with antihistamines, especially when autoimmune urticaria is suspected.² Further investigations are guided by clinical suspicion, which may include a skin biopsy, autoimmune screening, urinalysis, serum cryoglobulins, and hepatitis B and C serology.³¹ The only available test to screen for autoantibodies against the IgE receptor is the autologous serum skin test. This test should be performed with care because infections could be transmitted, particularly if, by mistake, patients were not injected with their own serum.³¹ Measurement of C4 is indicated only in patients who present with angioedema alone and should be followed by a determination of the levels and function of C1 inhibitor, if C4 is below reference range.²⁹

Management and Treatment

Management of urticaria depends on its cause. Aggravating factors should be identified from the history, and triggering stimuli for physical urticaria should be avoided. Simple cooling lotions such as menthol 1% or 2% in an aqueous cream often are useful.³² Aspirin and NSAIDs should be avoided because they aggravate symptoms in 30% of patients.³³ Patients taking low-dose aspirin for its antithrombotic properties usually can continue regular treatment. Avoiding codeine and other opiates also is recommended because an enhanced skin test reaction may be found in chronic urticaria.³⁴ Avoiding dietary pseudoallergens, such as food coloring and natural salicylates, is controversial.^14,35 This generally has only a small role unless proven by a double-blinded placebo-controlled challenge.²

The mainstays for treatment of urticaria are oral antihistamines, as they reduce pruritus and wheal duration and numbers. Oral antihistamines have been reported to produce moderate or good response in 44% to 91% of patients with all types of urticaria.^36,37 Antihistamines can be grouped into first-generation (sedating), second generation (minimally sedating), third-generation (nonsedating), and H₂ antagonists.¹⁷ The physiologic and pathologic actions of histamine are mediated through 4 histamine receptor subtypes: H₁, H₂, H₃, and H₄.³⁸ The erythema, wheal formation, and itching associated with urticaria are mainly due to activation of H₁ receptors and the less contributory role of H₂ receptors.³⁸ Histamine H₃ receptors are located presynaptically on postganglionic sympathetic norepinephric nerves, including sympathetics innervating the heart and blood vessels. The contribution of H₃ receptors to skin responses mediated by histamine has not been fully elucidated. However, in a recent experimental study, the authors reported that the combination of H1 and H3 antagonists might be a novel approach for the treatment of urticaria.³⁸

Initially, a minimally sedating second- or third-generation antihistamine, such as loratadine,³⁹ fexofenadine hydrochloride,⁴⁰ and cetirizine hydrochloride,^41-44 should be given at a once-daily oral dosing. When one antihistamine is not helpful, it is usually worth trying a different one, and some physicians combine 2 or more antihistamines at the same time.³ It is common practice to exceed the licensed dose in severely affected patients.³¹ High doses of antihistamines have effects beyond the blockade of histamine receptors, and actions that are not due to antagonism of H₁ receptors may account for the efficacy of older antihistamines.⁴⁵ As a general rule, antihistamines are safe and have few substantial adverse effects; drug interactions are rare. If possible, it is best to avoid all antihistamines in pregnancy, though none have been proven teratogenic. If one is used, the consensus is that chlorpheniramine maleate is among the safest.⁴⁶

Addition of a sedating first-generation antihistamine such as hydroxyzine at night can be helpful, especially if nocturnal pruritus prevents sleep. The use of a sedating antihistamine as monotherapy is less desirable because of impairment of cognitive function, including driving performance and concentration. The addition of a H₂ antagonist to conventional H₁ antihistamines may be helpful in some patients.^3,47 Doxepin hydrochloride at low doses (10–50 mg) is used for its potent H1 and H2 receptor antagonist properties. Doxepin hydrochloride is highly sedative and especially suitable for patients with associated depression.⁴⁸

Oral corticosteroids given in short reducing courses may be needed for severe exacerbations not responding to full-dose antihistamines. Relatively high doses of up to 40 to 60 mg of prednisone may be needed for disease control. Alternate-day ste-roids may be used for patients with severe disease.⁶ Long-term administration should be avoided.¹

Many patients feel reassured by carrying an epinephrine pen for self-administration if they are prone to severe attacks. Leukotriene antagonists (zafirlukast and montelukast sodium) have been shown to be superior to placebo in the treatment of patients with chronic urticaria.^49,50 Nifedipine has a small effect in chronic urticaria and often is used for patients with concomitant hypertension. Thyroxine recently was reported to suppress CIU symptoms associated with antithyroid autoantibodies in some patients.⁵¹

Given the role of the immune system in a subset of patients, immunosuppressive therapy is considered for patients with a severe disabling course. Cyclosporine at 2.5 to 5 mg/kg per day is of proven value in autoantibody-positive chronic urticaria⁵² but also is effective in most cases of severe autoantibody-negative disease.¹⁵ Tacrolimus also has shown promise in a recent trial.⁵³ Other options include plasmapheresis⁵⁴ and intravenous immunoglobulin.^55,56 Optimal treatment protocols have yet to be confirmed. Treatments for CIU with only limited or anecdotal supportive evidence include sulfasalazine, methotrexate, rofecoxib, colchicine, dapsone, and cyclophosphamide.³

Future treatment may involve development of selective immunotherapy targeting the IgE receptor or vaccinations to down-regulate and induce tolerance to the IgE receptor. Other potential strategies include blocking formation of C5a and use of therapeutic antibodies such as anti-IgE, anti–tumor necrosis factor α, and anti–interleukin 5.²

Conclusion

There is no single way to manage urticaria and angioedema. Most patients are treated successfully with antihistamines. However, patients with severe antihistamine-resistant urticaria may be very disabled by their disease, and the treatment can pose a major challenge to the physician.

Urticaria has been recognized since the days of Hippocrates. The name of the condition dates back to the 18th century, when the burning and edema of the skin was likened to that caused by contact with nettles (Urtica dioica). Urticaria affects 10% to 25% of the population worldwide at some point in their lives.¹ The condition is characterized by short-lived edema of the skin, mouth, and genitalia related to a transient leakage of plasma from small blood vessels into the surrounding connective tissues. Urticaria may present with superficial edema of the dermis (wheals) or deeper edema of the dermal, subcutaneous, or submucosal tissues (angioedema).² Wheals typically are itchy with a pale center, maturing into pink superficial plaques. Areas of angioedema tend to be pale and painful; last longer than wheals; and may involve the mouth and rarely the bowel.

Case Report

A 40-year-old woman in otherwise good health presented with a 5-year history of recurrent pruritic light red lesions on her chest and back. She reported that individual lesions would last up to 24 hours in one area before disappearing, while other new crops of lesions would develop in other areas of her body. She had no associated facial edema or lip or throat involvement, and she denied taking any medications. Her history failed to reveal any potential triggers for the eruptions. On physical examination, multiple elevated superficial erythematous papules and plaques were noted, with shapes varying from annular to circinate, areas of central clearing, and targetlike lesions on the trunk and extremities. The lesions blanched with pressure (Figure). The woman had no mucosal involvement, scars, or change in pigmentation. Results from the remainder of the physical examination were unremarkable.

PLEASE REFER TO THE PDF TO VIEW THE FIGURE

Because of the extent of involvement and the erythematous to violaceous aspect of certain lesions, a 3-mm punch biopsy was performed to rule out urticarial vasculitis. Histology results were consistent with urticaria with red blood extravasation but without vasculitis. Our patient initially was treated with topical clobetasol propionate ointment, 10 mg of cetirizine hydrochloride, and topical calamine lotion. At follow-up one week later, she mentioned that she had improved after 5 days of treatment but began developing new lesions 2 days prior to her second visit. Given the severity of pruritus and after a discussion of the role of corticosteroids for acute urticaria, a taper dose of prednisone was prescribed at 40 mg/d, in addition to 60 mg of fexofenadine hydrochloride twice daily. The patient was lesion- and symptom-free after 7 days of treatment, with no recurrence one month later.

Comment

Urticaria may be acute or chronic. Acute urticaria is idiopathic in more than 50% of patients but can occur as a type 1 hypersensitivity reaction to food or wasp or bee stings; an immunologic response to blood products, infection, or febrile illness; or an adverse effect of drug therapy by various mechanisms, such as penicillin or angiotensin-converting enzyme inhibitors.³ As opposed to acute urticaria, chronic urticaria is defined by recurrent episodes occurring at least twice weekly for 6 weeks.² Urticaria occurring less frequently than this, over a long period, is more accurately termed episodic because it is more likely to have an identifiable environmental trigger. All chronic urticaria implicitly go through an acute stage (<6 weeks). Although many classification systems of chronic urticaria exist, a concise clinical classification is included in the Table.² Urticarial vasculitis is a small vessel vasculitis but is included in the classification because it is clinically indistinguishable from other urticarial lesions.

PLEASE REFER TO THE PDF TO VIEW THE TABLE

Urticarial lesions in chronic urticaria typically last 4 to 36 hours and can occur in individuals of any age (though it is most common in women), usually with few systemic symptoms.⁴ Pruritus is nearly always severe, especially at night, and may prevent sleep. Fifty percent of cases resolve spontaneously by 6 months, but of those that do not, 40% still have symptoms of urticaria 10 years later.⁴ The severe effect of chronic urticaria on quality of life often is underestimated.⁵

Ordinary Urticaria

Patients previously classified as having chronic idiopathic or "ordinary" urticaria are now divided into 2 groups: 50% to 60% of these patients have chronic idiopathic urticaria (CIU), and the remainder have chronic autoimmune urticaria (CAU).⁶ Results from a study in children demonstrated that autoimmune urticaria occurs in children in as many as 30% of chronic cases.⁷ CAU is caused by an immunoglobulin (Ig) G antibody to the α subunit of the IgE receptor (35%–40% of cases) or to IgE (5%–10% of cases).⁶ The IgG subclasses that appear to be pathogenic are IgG1; IgG3; and, to a lesser degree, IgG4 (though not IgG2).⁶ Complement activation augments histamine secretion by release of C5a.⁸ CAU has been reported to be associated with antithyroid antibodies (27% of cases)^6,9; autoimmune conditions such as vitiligo, rheumatoid arthritis, and pernicious anemia; and low vitamin B₁₂ levels.¹⁰ Patients with demonstrable histamine-releasing autoantibodies have a very strong association with HLA-DR4 and its associated allele HLA-DQ8.¹¹

Histologically, the 2 groups of urticaria are indistinguishable.6 Advanced techniques show a perivascular nonnecrotizing infiltrate of CD4⁺ lymphocytes consisting of a mixture of T_H1 and T_H2 subtypes, plus monocytes, neutrophils, eosinophils, and basophils. These cells are recruited because of interactions with C5a, cell priming cytokines, chemokines, and adhesion molecules.⁶ A recent study also found inflammatory cells and mediator up-regulation in uninvolved CIU skin as a sign of prolonged and widespread "urticarial status."¹²

Physical Urticaria

Physical urticaria are classified and induced by a physical stimulus. Most physical urticaria occur within minutes of provocation and resolve within 2 hours, with the exception of delayed pressure urticaria, which may persist for 24 hours or longer.¹³ Angioedema may occur in all physical urticaria except dermographism. Overlap between groups is common, and physical urticaria often occur as an added feature of chronic urticaria.

The most common type of physical urticaria is simple immediate dermographism, presenting with linear wheals at sites of scratching or friction. It occurs in about 1.4% to 5% of the population worldwide¹⁴ and may be viewed as an exaggerated physiologic response. On average, dermographism runs a course of 2 to 3 years before usually resolving spontaneously.¹⁵

Delayed-pressure urticaria is a response to sustained pressure to the skin, presenting with deep erythematous edema after a delay of unknown cause lasting 30 minutes to 12 hours.^14,16 An increased level of interleukin 6 has been found in suction blister fluid over induced lesions.^2,15 The edema tends to be deeper, pruritic, and painful, and it may persist for days. Systemic features such as malaise, flulike symptoms, and arthralgia may occur. The prognosis is variable, but the mean duration is 6 to 9 years.¹⁷ The response to antihistamines often is poor, and oral corticosteroids may be needed for disease control.²

Cholinergic urticaria usually presents with multiple, transient, pruritic, small, red macules or papules on the neck, trunk, forearms, wrists, and thighs in response to heat, often surrounded by an obvious flare. It mainly affects young adults, with an overall prevalence of 11% in this group.¹⁸ Fifty percent of patients are atopic.¹⁵ Angioedema and systemic manifestations such as headache, palpitations, abdominal pain, wheezing, and syncope may occur. The cholinergic sympathetic innervation of sweat glands is involved because the eruption can be blocked by topical anticholinergic drugs,¹⁹ but how this leads to urticaria is unclear. The routine treatment is with low-sedation H₁-type antihistamines, with or without an anxiolytic such as oral propranolol. In severe cases, the anabolic steroid stanazolol has been used.¹⁵

Cold urticaria is a heterogeneous condition in which whealing occurs within minutes in response to cold exposure, most frequently in children and young adults. Wheals usually arise at the site of localized cooling but may be generalized following lowering of the body temperature.¹⁶ Diagnosis may be confirmed by applying an ice cube for 5 to 15 minutes to the skin, allowing an interval for skin rewarming, and observing the development of whealing that occurs on skin rewarming. Systemic symptoms such as flushing, headache, abdominal pain, and syncope can occur if large areas are affected. The cause is unknown, but a serum factor, possibly IgM or IgE, has been implicated.²⁰ A heterozygous deficiency of the protease inhibitor α1-antichymotrypsin has been demonstrated and may be etiologically important in some patients.²¹ The prognosis is good, with spontaneous improvement in an average of 2 to 3 years.¹⁵ Ninety-six percent of cases of cold urticaria are primary.²² The diagnosis of secondary acquired cold urticaria depends on being able to demonstrate cryoglobulins, cold agglutinins, or possibly cryofibrinogens.¹⁷ These findings should, in turn, lead to investigations for an underlying cause, such as hepatitis B or C infection, lymphoproliferative disease, or infectious mononucleosis.¹⁵

Other uncommon forms of physical urticaria include adrenergic urticaria, which develops during phases of stress and has been associated with an increase in the plasma concentrations of norepinephrine, epinephrine, and prolactin.²³ Aquagenic urticaria is precipitated by skin contact with water of any temperature.³ Exercise-induced anaphylaxis involves urticaria, respiratory distress, or hypotension after exercise. In localized heat urticaria, wheals occur on skin in direct contact with warm objects. Solar urticaria is a rare condition that occurs within minutes of exposure to UV light waves ranging from 280 to 760 nm¹⁴; it usually disappears in less than one hour. Vibratory urticaria occurs after a vibratory stimulus and can be a hereditary autosomaldominant disorder or an acquired sporadic disease.²⁴

Urticarial Vasculitis

Urticarial vasculitis describes a distinct entity in which the gross cutaneous lesions resemble urticaria and histologically show features of a vasculitis. The diagnosis is suggested clinically by wheals lasting more than 24 hours and residual bruising.²⁵ Although the clinical lesions may present as typical urticaria, pathophysiologically, it is a different disease caused by deposition of antigen-antibody complexes in vessel walls, a type 3 reaction causing vascular damage.¹⁷ Lesions often occur at pressure points and may resolve with residual purpura. Extracutaneous manifestations include transient and migratory arthralgia (50%); gastrointestinal symptoms (20%); and pulmonary obstructive disease (20%), particularly in smokers and patients with renal disease (5%–10%).¹⁷ Normocomplementemic urticarial vasculitis usually is idiopathic, but hypocomplementemic urticarial vasculitis may be associated with underlying systemic lupus erythematosus, Sjögren syndrome, or cryoglobulinemia.² Primary urticarial vasculitis can occasionally evolve into systemic lupus erythematosus.²⁶ Patients with urticarial vasculitis often improve on nonsteroidal anti-inflammatory drugs (NSAIDs), but some patients may need immunosuppressive therapy.

Contact Urticaria

Contact urticaria develops at the site(s) of contact of an urticant and can be divided into an allergic subgroup caused by an IgE-allergen interaction and a nonallergic subgroup that is IgE independent. The allergic form typically is seen in children with atopic dermatitis sensitized to environmental allergens such as grass, animals, food, or latex, and it may be complicated by anaphylaxis. Natural rubber latex is one of the most important causes today.²⁷ This type appears within minutes, fades within 2 hours, and is partially inhibited by antihistamines. Nonallergic contact urticaria is caused by the direct effect of the urticant on blood vessels and includes irritants such as benzoic acid and cinnamic aldehyde in cosmetics. It may take 45 minutes for lesions to appear and urticaria is partially inhibited by NSAIDs.

Angioedema Without Wheals

It is useful to classify angioedema occurring without wheals as a separate entity because its etiology may be associated with hereditary angioedema, which must be excluded. The condition usually is idiopathic or caused by a drug reaction to angiotensin-converting enzyme inhibitors, aspirin, or NSAIDs. Hereditary angioedema is a rare autosomal-dominant condition with a prevalence between 1:10,000 and 1:150,000 in the general population and is caused by a deficiency (type 1, 85%) or dysfunction (type 2, 15%) of C1 inhibitor.²⁸ A low level of C4 in the serum is a constant and diagnostic feature. A third type affecting primarily women and exacerbated by estrogens recently has been described.²⁸ Patients have lifelong episodic angioedema and may experience colicky abdominal pain. Laryngeal involvement can be life threatening. Treatment is difficult and involves fluid replacement and purified C1 inhibitor concentrate for acute attacks (not approved in the United States) and prophylactic treatment with anabolic androgens and antifibrinolytics.²⁸

Diagnosis

The diagnosis of urticaria is primarily clinical; extensive laboratory tests are very rarely needed—only when indicated by the patient history.³ Some authors argue that laboratory investigations are unnecessary for mild ordinary urticaria responding to antihistamines.²⁹ Taking a thorough patient history has been found to be almost as effective in identifying a cause as a complete diagnostic evaluation.³⁰ In acute urticaria, if the history indicates a type 1 hypersensitivity reaction, confirmation is possible by a prick test or laboratory radioallergosorbent tests.³ Many physical and contact urticaria can be confirmed by a challenge of the offending agent. An initial baseline investigation with a complete blood count and erythrocyte sedimentation rate should be taken in more severe cases to identify any internal disease or raise the possibility of urticarial vasculitis.¹⁷ Of note, a biopsy is more sensitive and specific for ruling out urticarial vasculitis than are a complete blood count and erythrocyte sedimentation rate.

A search for thyroid autoantibodies is appropriate for all chronic urticaria not responding to first-line therapies with antihistamines, especially when autoimmune urticaria is suspected.² Further investigations are guided by clinical suspicion, which may include a skin biopsy, autoimmune screening, urinalysis, serum cryoglobulins, and hepatitis B and C serology.³¹ The only available test to screen for autoantibodies against the IgE receptor is the autologous serum skin test. This test should be performed with care because infections could be transmitted, particularly if, by mistake, patients were not injected with their own serum.³¹ Measurement of C4 is indicated only in patients who present with angioedema alone and should be followed by a determination of the levels and function of C1 inhibitor, if C4 is below reference range.²⁹

Management and Treatment

Management of urticaria depends on its cause. Aggravating factors should be identified from the history, and triggering stimuli for physical urticaria should be avoided. Simple cooling lotions such as menthol 1% or 2% in an aqueous cream often are useful.³² Aspirin and NSAIDs should be avoided because they aggravate symptoms in 30% of patients.³³ Patients taking low-dose aspirin for its antithrombotic properties usually can continue regular treatment. Avoiding codeine and other opiates also is recommended because an enhanced skin test reaction may be found in chronic urticaria.³⁴ Avoiding dietary pseudoallergens, such as food coloring and natural salicylates, is controversial.^14,35 This generally has only a small role unless proven by a double-blinded placebo-controlled challenge.²

The mainstays for treatment of urticaria are oral antihistamines, as they reduce pruritus and wheal duration and numbers. Oral antihistamines have been reported to produce moderate or good response in 44% to 91% of patients with all types of urticaria.^36,37 Antihistamines can be grouped into first-generation (sedating), second generation (minimally sedating), third-generation (nonsedating), and H₂ antagonists.¹⁷ The physiologic and pathologic actions of histamine are mediated through 4 histamine receptor subtypes: H₁, H₂, H₃, and H₄.³⁸ The erythema, wheal formation, and itching associated with urticaria are mainly due to activation of H₁ receptors and the less contributory role of H₂ receptors.³⁸ Histamine H₃ receptors are located presynaptically on postganglionic sympathetic norepinephric nerves, including sympathetics innervating the heart and blood vessels. The contribution of H₃ receptors to skin responses mediated by histamine has not been fully elucidated. However, in a recent experimental study, the authors reported that the combination of H1 and H3 antagonists might be a novel approach for the treatment of urticaria.³⁸

Initially, a minimally sedating second- or third-generation antihistamine, such as loratadine,³⁹ fexofenadine hydrochloride,⁴⁰ and cetirizine hydrochloride,^41-44 should be given at a once-daily oral dosing. When one antihistamine is not helpful, it is usually worth trying a different one, and some physicians combine 2 or more antihistamines at the same time.³ It is common practice to exceed the licensed dose in severely affected patients.³¹ High doses of antihistamines have effects beyond the blockade of histamine receptors, and actions that are not due to antagonism of H₁ receptors may account for the efficacy of older antihistamines.⁴⁵ As a general rule, antihistamines are safe and have few substantial adverse effects; drug interactions are rare. If possible, it is best to avoid all antihistamines in pregnancy, though none have been proven teratogenic. If one is used, the consensus is that chlorpheniramine maleate is among the safest.⁴⁶

Addition of a sedating first-generation antihistamine such as hydroxyzine at night can be helpful, especially if nocturnal pruritus prevents sleep. The use of a sedating antihistamine as monotherapy is less desirable because of impairment of cognitive function, including driving performance and concentration. The addition of a H₂ antagonist to conventional H₁ antihistamines may be helpful in some patients.^3,47 Doxepin hydrochloride at low doses (10–50 mg) is used for its potent H1 and H2 receptor antagonist properties. Doxepin hydrochloride is highly sedative and especially suitable for patients with associated depression.⁴⁸

Oral corticosteroids given in short reducing courses may be needed for severe exacerbations not responding to full-dose antihistamines. Relatively high doses of up to 40 to 60 mg of prednisone may be needed for disease control. Alternate-day ste-roids may be used for patients with severe disease.⁶ Long-term administration should be avoided.¹

Many patients feel reassured by carrying an epinephrine pen for self-administration if they are prone to severe attacks. Leukotriene antagonists (zafirlukast and montelukast sodium) have been shown to be superior to placebo in the treatment of patients with chronic urticaria.^49,50 Nifedipine has a small effect in chronic urticaria and often is used for patients with concomitant hypertension. Thyroxine recently was reported to suppress CIU symptoms associated with antithyroid autoantibodies in some patients.⁵¹

Given the role of the immune system in a subset of patients, immunosuppressive therapy is considered for patients with a severe disabling course. Cyclosporine at 2.5 to 5 mg/kg per day is of proven value in autoantibody-positive chronic urticaria⁵² but also is effective in most cases of severe autoantibody-negative disease.¹⁵ Tacrolimus also has shown promise in a recent trial.⁵³ Other options include plasmapheresis⁵⁴ and intravenous immunoglobulin.^55,56 Optimal treatment protocols have yet to be confirmed. Treatments for CIU with only limited or anecdotal supportive evidence include sulfasalazine, methotrexate, rofecoxib, colchicine, dapsone, and cyclophosphamide.³

Future treatment may involve development of selective immunotherapy targeting the IgE receptor or vaccinations to down-regulate and induce tolerance to the IgE receptor. Other potential strategies include blocking formation of C5a and use of therapeutic antibodies such as anti-IgE, anti–tumor necrosis factor α, and anti–interleukin 5.²

Conclusion

There is no single way to manage urticaria and angioedema. Most patients are treated successfully with antihistamines. However, patients with severe antihistamine-resistant urticaria may be very disabled by their disease, and the treatment can pose a major challenge to the physician.

Urticaria has been recognized since the days of Hippocrates. The name of the condition dates back to the 18th century, when the burning and edema of the skin was likened to that caused by contact with nettles (Urtica dioica). Urticaria affects 10% to 25% of the population worldwide at some point in their lives.¹ The condition is characterized by short-lived edema of the skin, mouth, and genitalia related to a transient leakage of plasma from small blood vessels into the surrounding connective tissues. Urticaria may present with superficial edema of the dermis (wheals) or deeper edema of the dermal, subcutaneous, or submucosal tissues (angioedema).² Wheals typically are itchy with a pale center, maturing into pink superficial plaques. Areas of angioedema tend to be pale and painful; last longer than wheals; and may involve the mouth and rarely the bowel.

Case Report

A 40-year-old woman in otherwise good health presented with a 5-year history of recurrent pruritic light red lesions on her chest and back. She reported that individual lesions would last up to 24 hours in one area before disappearing, while other new crops of lesions would develop in other areas of her body. She had no associated facial edema or lip or throat involvement, and she denied taking any medications. Her history failed to reveal any potential triggers for the eruptions. On physical examination, multiple elevated superficial erythematous papules and plaques were noted, with shapes varying from annular to circinate, areas of central clearing, and targetlike lesions on the trunk and extremities. The lesions blanched with pressure (Figure). The woman had no mucosal involvement, scars, or change in pigmentation. Results from the remainder of the physical examination were unremarkable.

PLEASE REFER TO THE PDF TO VIEW THE FIGURE

Because of the extent of involvement and the erythematous to violaceous aspect of certain lesions, a 3-mm punch biopsy was performed to rule out urticarial vasculitis. Histology results were consistent with urticaria with red blood extravasation but without vasculitis. Our patient initially was treated with topical clobetasol propionate ointment, 10 mg of cetirizine hydrochloride, and topical calamine lotion. At follow-up one week later, she mentioned that she had improved after 5 days of treatment but began developing new lesions 2 days prior to her second visit. Given the severity of pruritus and after a discussion of the role of corticosteroids for acute urticaria, a taper dose of prednisone was prescribed at 40 mg/d, in addition to 60 mg of fexofenadine hydrochloride twice daily. The patient was lesion- and symptom-free after 7 days of treatment, with no recurrence one month later.

Comment

Urticaria may be acute or chronic. Acute urticaria is idiopathic in more than 50% of patients but can occur as a type 1 hypersensitivity reaction to food or wasp or bee stings; an immunologic response to blood products, infection, or febrile illness; or an adverse effect of drug therapy by various mechanisms, such as penicillin or angiotensin-converting enzyme inhibitors.³ As opposed to acute urticaria, chronic urticaria is defined by recurrent episodes occurring at least twice weekly for 6 weeks.² Urticaria occurring less frequently than this, over a long period, is more accurately termed episodic because it is more likely to have an identifiable environmental trigger. All chronic urticaria implicitly go through an acute stage (<6 weeks). Although many classification systems of chronic urticaria exist, a concise clinical classification is included in the Table.² Urticarial vasculitis is a small vessel vasculitis but is included in the classification because it is clinically indistinguishable from other urticarial lesions.

PLEASE REFER TO THE PDF TO VIEW THE TABLE

Urticarial lesions in chronic urticaria typically last 4 to 36 hours and can occur in individuals of any age (though it is most common in women), usually with few systemic symptoms.⁴ Pruritus is nearly always severe, especially at night, and may prevent sleep. Fifty percent of cases resolve spontaneously by 6 months, but of those that do not, 40% still have symptoms of urticaria 10 years later.⁴ The severe effect of chronic urticaria on quality of life often is underestimated.⁵

Ordinary Urticaria

Patients previously classified as having chronic idiopathic or "ordinary" urticaria are now divided into 2 groups: 50% to 60% of these patients have chronic idiopathic urticaria (CIU), and the remainder have chronic autoimmune urticaria (CAU).⁶ Results from a study in children demonstrated that autoimmune urticaria occurs in children in as many as 30% of chronic cases.⁷ CAU is caused by an immunoglobulin (Ig) G antibody to the α subunit of the IgE receptor (35%–40% of cases) or to IgE (5%–10% of cases).⁶ The IgG subclasses that appear to be pathogenic are IgG1; IgG3; and, to a lesser degree, IgG4 (though not IgG2).⁶ Complement activation augments histamine secretion by release of C5a.⁸ CAU has been reported to be associated with antithyroid antibodies (27% of cases)^6,9; autoimmune conditions such as vitiligo, rheumatoid arthritis, and pernicious anemia; and low vitamin B₁₂ levels.¹⁰ Patients with demonstrable histamine-releasing autoantibodies have a very strong association with HLA-DR4 and its associated allele HLA-DQ8.¹¹

Histologically, the 2 groups of urticaria are indistinguishable.6 Advanced techniques show a perivascular nonnecrotizing infiltrate of CD4⁺ lymphocytes consisting of a mixture of T_H1 and T_H2 subtypes, plus monocytes, neutrophils, eosinophils, and basophils. These cells are recruited because of interactions with C5a, cell priming cytokines, chemokines, and adhesion molecules.⁶ A recent study also found inflammatory cells and mediator up-regulation in uninvolved CIU skin as a sign of prolonged and widespread "urticarial status."¹²

Physical Urticaria

Physical urticaria are classified and induced by a physical stimulus. Most physical urticaria occur within minutes of provocation and resolve within 2 hours, with the exception of delayed pressure urticaria, which may persist for 24 hours or longer.¹³ Angioedema may occur in all physical urticaria except dermographism. Overlap between groups is common, and physical urticaria often occur as an added feature of chronic urticaria.

The most common type of physical urticaria is simple immediate dermographism, presenting with linear wheals at sites of scratching or friction. It occurs in about 1.4% to 5% of the population worldwide¹⁴ and may be viewed as an exaggerated physiologic response. On average, dermographism runs a course of 2 to 3 years before usually resolving spontaneously.¹⁵

Delayed-pressure urticaria is a response to sustained pressure to the skin, presenting with deep erythematous edema after a delay of unknown cause lasting 30 minutes to 12 hours.^14,16 An increased level of interleukin 6 has been found in suction blister fluid over induced lesions.^2,15 The edema tends to be deeper, pruritic, and painful, and it may persist for days. Systemic features such as malaise, flulike symptoms, and arthralgia may occur. The prognosis is variable, but the mean duration is 6 to 9 years.¹⁷ The response to antihistamines often is poor, and oral corticosteroids may be needed for disease control.²

Cholinergic urticaria usually presents with multiple, transient, pruritic, small, red macules or papules on the neck, trunk, forearms, wrists, and thighs in response to heat, often surrounded by an obvious flare. It mainly affects young adults, with an overall prevalence of 11% in this group.¹⁸ Fifty percent of patients are atopic.¹⁵ Angioedema and systemic manifestations such as headache, palpitations, abdominal pain, wheezing, and syncope may occur. The cholinergic sympathetic innervation of sweat glands is involved because the eruption can be blocked by topical anticholinergic drugs,¹⁹ but how this leads to urticaria is unclear. The routine treatment is with low-sedation H₁-type antihistamines, with or without an anxiolytic such as oral propranolol. In severe cases, the anabolic steroid stanazolol has been used.¹⁵

Cold urticaria is a heterogeneous condition in which whealing occurs within minutes in response to cold exposure, most frequently in children and young adults. Wheals usually arise at the site of localized cooling but may be generalized following lowering of the body temperature.¹⁶ Diagnosis may be confirmed by applying an ice cube for 5 to 15 minutes to the skin, allowing an interval for skin rewarming, and observing the development of whealing that occurs on skin rewarming. Systemic symptoms such as flushing, headache, abdominal pain, and syncope can occur if large areas are affected. The cause is unknown, but a serum factor, possibly IgM or IgE, has been implicated.²⁰ A heterozygous deficiency of the protease inhibitor α1-antichymotrypsin has been demonstrated and may be etiologically important in some patients.²¹ The prognosis is good, with spontaneous improvement in an average of 2 to 3 years.¹⁵ Ninety-six percent of cases of cold urticaria are primary.²² The diagnosis of secondary acquired cold urticaria depends on being able to demonstrate cryoglobulins, cold agglutinins, or possibly cryofibrinogens.¹⁷ These findings should, in turn, lead to investigations for an underlying cause, such as hepatitis B or C infection, lymphoproliferative disease, or infectious mononucleosis.¹⁵

Other uncommon forms of physical urticaria include adrenergic urticaria, which develops during phases of stress and has been associated with an increase in the plasma concentrations of norepinephrine, epinephrine, and prolactin.²³ Aquagenic urticaria is precipitated by skin contact with water of any temperature.³ Exercise-induced anaphylaxis involves urticaria, respiratory distress, or hypotension after exercise. In localized heat urticaria, wheals occur on skin in direct contact with warm objects. Solar urticaria is a rare condition that occurs within minutes of exposure to UV light waves ranging from 280 to 760 nm¹⁴; it usually disappears in less than one hour. Vibratory urticaria occurs after a vibratory stimulus and can be a hereditary autosomaldominant disorder or an acquired sporadic disease.²⁴

Urticarial Vasculitis

Urticarial vasculitis describes a distinct entity in which the gross cutaneous lesions resemble urticaria and histologically show features of a vasculitis. The diagnosis is suggested clinically by wheals lasting more than 24 hours and residual bruising.²⁵ Although the clinical lesions may present as typical urticaria, pathophysiologically, it is a different disease caused by deposition of antigen-antibody complexes in vessel walls, a type 3 reaction causing vascular damage.¹⁷ Lesions often occur at pressure points and may resolve with residual purpura. Extracutaneous manifestations include transient and migratory arthralgia (50%); gastrointestinal symptoms (20%); and pulmonary obstructive disease (20%), particularly in smokers and patients with renal disease (5%–10%).¹⁷ Normocomplementemic urticarial vasculitis usually is idiopathic, but hypocomplementemic urticarial vasculitis may be associated with underlying systemic lupus erythematosus, Sjögren syndrome, or cryoglobulinemia.² Primary urticarial vasculitis can occasionally evolve into systemic lupus erythematosus.²⁶ Patients with urticarial vasculitis often improve on nonsteroidal anti-inflammatory drugs (NSAIDs), but some patients may need immunosuppressive therapy.

Contact Urticaria

Contact urticaria develops at the site(s) of contact of an urticant and can be divided into an allergic subgroup caused by an IgE-allergen interaction and a nonallergic subgroup that is IgE independent. The allergic form typically is seen in children with atopic dermatitis sensitized to environmental allergens such as grass, animals, food, or latex, and it may be complicated by anaphylaxis. Natural rubber latex is one of the most important causes today.²⁷ This type appears within minutes, fades within 2 hours, and is partially inhibited by antihistamines. Nonallergic contact urticaria is caused by the direct effect of the urticant on blood vessels and includes irritants such as benzoic acid and cinnamic aldehyde in cosmetics. It may take 45 minutes for lesions to appear and urticaria is partially inhibited by NSAIDs.

Angioedema Without Wheals

It is useful to classify angioedema occurring without wheals as a separate entity because its etiology may be associated with hereditary angioedema, which must be excluded. The condition usually is idiopathic or caused by a drug reaction to angiotensin-converting enzyme inhibitors, aspirin, or NSAIDs. Hereditary angioedema is a rare autosomal-dominant condition with a prevalence between 1:10,000 and 1:150,000 in the general population and is caused by a deficiency (type 1, 85%) or dysfunction (type 2, 15%) of C1 inhibitor.²⁸ A low level of C4 in the serum is a constant and diagnostic feature. A third type affecting primarily women and exacerbated by estrogens recently has been described.²⁸ Patients have lifelong episodic angioedema and may experience colicky abdominal pain. Laryngeal involvement can be life threatening. Treatment is difficult and involves fluid replacement and purified C1 inhibitor concentrate for acute attacks (not approved in the United States) and prophylactic treatment with anabolic androgens and antifibrinolytics.²⁸

Diagnosis

The diagnosis of urticaria is primarily clinical; extensive laboratory tests are very rarely needed—only when indicated by the patient history.³ Some authors argue that laboratory investigations are unnecessary for mild ordinary urticaria responding to antihistamines.²⁹ Taking a thorough patient history has been found to be almost as effective in identifying a cause as a complete diagnostic evaluation.³⁰ In acute urticaria, if the history indicates a type 1 hypersensitivity reaction, confirmation is possible by a prick test or laboratory radioallergosorbent tests.³ Many physical and contact urticaria can be confirmed by a challenge of the offending agent. An initial baseline investigation with a complete blood count and erythrocyte sedimentation rate should be taken in more severe cases to identify any internal disease or raise the possibility of urticarial vasculitis.¹⁷ Of note, a biopsy is more sensitive and specific for ruling out urticarial vasculitis than are a complete blood count and erythrocyte sedimentation rate.

A search for thyroid autoantibodies is appropriate for all chronic urticaria not responding to first-line therapies with antihistamines, especially when autoimmune urticaria is suspected.² Further investigations are guided by clinical suspicion, which may include a skin biopsy, autoimmune screening, urinalysis, serum cryoglobulins, and hepatitis B and C serology.³¹ The only available test to screen for autoantibodies against the IgE receptor is the autologous serum skin test. This test should be performed with care because infections could be transmitted, particularly if, by mistake, patients were not injected with their own serum.³¹ Measurement of C4 is indicated only in patients who present with angioedema alone and should be followed by a determination of the levels and function of C1 inhibitor, if C4 is below reference range.²⁹

Management and Treatment

Management of urticaria depends on its cause. Aggravating factors should be identified from the history, and triggering stimuli for physical urticaria should be avoided. Simple cooling lotions such as menthol 1% or 2% in an aqueous cream often are useful.³² Aspirin and NSAIDs should be avoided because they aggravate symptoms in 30% of patients.³³ Patients taking low-dose aspirin for its antithrombotic properties usually can continue regular treatment. Avoiding codeine and other opiates also is recommended because an enhanced skin test reaction may be found in chronic urticaria.³⁴ Avoiding dietary pseudoallergens, such as food coloring and natural salicylates, is controversial.^14,35 This generally has only a small role unless proven by a double-blinded placebo-controlled challenge.²

The mainstays for treatment of urticaria are oral antihistamines, as they reduce pruritus and wheal duration and numbers. Oral antihistamines have been reported to produce moderate or good response in 44% to 91% of patients with all types of urticaria.^36,37 Antihistamines can be grouped into first-generation (sedating), second generation (minimally sedating), third-generation (nonsedating), and H₂ antagonists.¹⁷ The physiologic and pathologic actions of histamine are mediated through 4 histamine receptor subtypes: H₁, H₂, H₃, and H₄.³⁸ The erythema, wheal formation, and itching associated with urticaria are mainly due to activation of H₁ receptors and the less contributory role of H₂ receptors.³⁸ Histamine H₃ receptors are located presynaptically on postganglionic sympathetic norepinephric nerves, including sympathetics innervating the heart and blood vessels. The contribution of H₃ receptors to skin responses mediated by histamine has not been fully elucidated. However, in a recent experimental study, the authors reported that the combination of H1 and H3 antagonists might be a novel approach for the treatment of urticaria.³⁸

Initially, a minimally sedating second- or third-generation antihistamine, such as loratadine,³⁹ fexofenadine hydrochloride,⁴⁰ and cetirizine hydrochloride,^41-44 should be given at a once-daily oral dosing. When one antihistamine is not helpful, it is usually worth trying a different one, and some physicians combine 2 or more antihistamines at the same time.³ It is common practice to exceed the licensed dose in severely affected patients.³¹ High doses of antihistamines have effects beyond the blockade of histamine receptors, and actions that are not due to antagonism of H₁ receptors may account for the efficacy of older antihistamines.⁴⁵ As a general rule, antihistamines are safe and have few substantial adverse effects; drug interactions are rare. If possible, it is best to avoid all antihistamines in pregnancy, though none have been proven teratogenic. If one is used, the consensus is that chlorpheniramine maleate is among the safest.⁴⁶

Addition of a sedating first-generation antihistamine such as hydroxyzine at night can be helpful, especially if nocturnal pruritus prevents sleep. The use of a sedating antihistamine as monotherapy is less desirable because of impairment of cognitive function, including driving performance and concentration. The addition of a H₂ antagonist to conventional H₁ antihistamines may be helpful in some patients.^3,47 Doxepin hydrochloride at low doses (10–50 mg) is used for its potent H1 and H2 receptor antagonist properties. Doxepin hydrochloride is highly sedative and especially suitable for patients with associated depression.⁴⁸

Oral corticosteroids given in short reducing courses may be needed for severe exacerbations not responding to full-dose antihistamines. Relatively high doses of up to 40 to 60 mg of prednisone may be needed for disease control. Alternate-day ste-roids may be used for patients with severe disease.⁶ Long-term administration should be avoided.¹

Many patients feel reassured by carrying an epinephrine pen for self-administration if they are prone to severe attacks. Leukotriene antagonists (zafirlukast and montelukast sodium) have been shown to be superior to placebo in the treatment of patients with chronic urticaria.^49,50 Nifedipine has a small effect in chronic urticaria and often is used for patients with concomitant hypertension. Thyroxine recently was reported to suppress CIU symptoms associated with antithyroid autoantibodies in some patients.⁵¹

Given the role of the immune system in a subset of patients, immunosuppressive therapy is considered for patients with a severe disabling course. Cyclosporine at 2.5 to 5 mg/kg per day is of proven value in autoantibody-positive chronic urticaria⁵² but also is effective in most cases of severe autoantibody-negative disease.¹⁵ Tacrolimus also has shown promise in a recent trial.⁵³ Other options include plasmapheresis⁵⁴ and intravenous immunoglobulin.^55,56 Optimal treatment protocols have yet to be confirmed. Treatments for CIU with only limited or anecdotal supportive evidence include sulfasalazine, methotrexate, rofecoxib, colchicine, dapsone, and cyclophosphamide.³

Future treatment may involve development of selective immunotherapy targeting the IgE receptor or vaccinations to down-regulate and induce tolerance to the IgE receptor. Other potential strategies include blocking formation of C5a and use of therapeutic antibodies such as anti-IgE, anti–tumor necrosis factor α, and anti–interleukin 5.²

Conclusion

There is no single way to manage urticaria and angioedema. Most patients are treated successfully with antihistamines. However, patients with severe antihistamine-resistant urticaria may be very disabled by their disease, and the treatment can pose a major challenge to the physician.

Case Report

An otherwise healthy 9-year-old Filipino girl presented with a complaint of urticaria precipitated by cold exposure over the preceding 5 weeks. She had no recent illnesses and normal results of a school physical examination performed 2 weeks prior to symptom onset. The patient's medical history was significant only for cat allergy; however, she noted that on multiple occasions, erythema and pruritus appeared on her arms and face after walking through the freezer aisle of a grocery store. Urticaria subsequently developed on regions where she scratched and spontaneously resolved 2 to 3 hours later. On one occasion, urticaria appeared diffusely on the patient while she showered after swimming; it resolved within a few hours after she was given diphenhydramine by her mother. Three days prior to presentation, the patient experienced upper lip angioedema with erythema, globus sensation, and difficulty swallowing after drinking a strawberry slushy. She denied having respiratory complaints at that time, and her symptoms again resolved spontaneously. A day later, the patient tolerated ice cream with no complaints. Her family history was significant for a maternal history of seasonal allergies.

On physical examination, the patient appeared to be well. She had 2 to 3 discrete urticarial lesions on the distal posterior aspect of each calf that, according to her mother, recently began appearing on "cold and rainy" days. The mother attributed them to her daughter's lower legs being exposed because of the length of her pants. Results of the remainder of the examination were unremarkable, and dermatographism was absent.

Laboratory evaluation consisted of a strawberry radioallergosorbent test and cryoglobulins test, both of which had negative results. An ice cube wrapped in plastic was applied to the volar surface of the patient's right forearm for 5 minutes. A 9X6-cm wheal was noted 3 minutes after ice removal (Figure).

PLEASE REFER TO THE PDF TO VIEW THE FIGURE

A diagnosis of cold urticaria with associated angioedema was made. The patient's mother opted for her daughter to use only diphenhydramine as needed; additionally, an epinephrine autoinjector was dispensed. By 3 months after symptom onset, the patient's only complaint was pruritus of her hands if they became too cold. No urticaria was noted. At 6-month follow-up, the patient denied having had symptoms for the preceding 2 months, and the results of an ice cube test were negative. 

Comment

Cold urticaria is a form of physical urticaria that is notable for the development of urticaria and/or angioedema after cold exposure.¹ Cold urticaria syndromes were first described in the 19th century² and are uncommon. However, it has been observed that approximately one third of adult³ and pediatric⁴ patients with cold urticaria have systemic reactions that are mostly hypotensive episodes associated with aquatic activities. Thus, identification of these patients should be a priority.

The prevalence of cold urticaria is not well defined. Cold urticaria is most commonly noted in young adults, with only 11% of cases noted in children under 10 years of age.³ Most forms of cold urticaria are idiopathic (Table); however, some forms can be secondary to underlying conditions such as malignancies, vasculitides, and infectious diseases.⁸ Cryoglobulinemia (primary and secondary to malignancy) often is cited as a cause of secondary cold urticaria.^3,8-11 Mounting evidence indicates that a possible autoimmune mechanism underlies the idiopathic form of this disorder in many patients.¹²

PLEASE REFER TO THE PDF TO VIEW THE TABLE

Although most forms of cold urticaria are considered to be acquired, familial forms have been described,^7,13 some of which have been classified within the hereditary periodic fever syndromes.¹² Diagnosis of cold urticaria primarily is made by evaluating the patient's clinical history; the diagnosis may be confirmed by applying a cold stimulus, most commonly an ice cube wrapped in plastic and applied to the volar aspect of the patient's forearm. A positive reaction is noted by the formation of a wheal during rewarming of the skin. The length of time that a cold stimulus is applied is not standardized; commonly, 3-, 5-, and 10-minute applications are used. Visitsuntorn et al¹⁴ observed the effectiveness of 3- or 5-minute applications in children who had not taken antihistamines for at least 5 days prior. The authors also noted that false-positive results (defined as reddening of the skin and minimal edema) were possible with 10- and 20-minute applications in patients with chronic urticaria not induced by cold. Other studies have observed that the length of time necessary for a cold stimulus to induce wheal formation inversely may be related to the patient's risk of having a systemic reaction.^1,8,12 Specifically, patients who demonstrated wheal formation after the application of a cold stimulus for 3 minutes or less were noted to experience cold-induced hypotension more frequently. Regardless, it should be recognized that all patients with cold urticaria are at risk for hypotensive reactions.

Approximately 20% of patients with cold urticaria lack an immediate response to cold stimulus with an ice cube; these patients have so-called atypical acquired cold urticaria syndromes^1,12 (eg, cold-dependant dermatographism, delayed cold urticaria, systemic cold urticaria). Other forms of cold stimulus testing that can be considered include partially immersing a limb of the patient's in cold water³ or placing the patient in a cold room¹⁵; however, these forms of cold stimulus may put the patient at increased risk for a systemic reaction. Finally, scratching the skin prior to cooling or during cooling also may be of diagnostic value in cases of cold-dependant dermatographism.^9,15

Additional testing should be guided by a patient's history. To determine if a secondary cause is responsible for the clinical presentation of cold urticaria, laboratory studies could include complete blood count, erythrocyte sedimentation rate, antinuclear antibodies titer, infectious mononucleosis serology, syphilis serology, rheumatoid factor, total complement, cold agglutinins, cold hemolysin, cryofibrinogen, and cryoglobulin.¹² Of note, approximately 4% of patients with cold urticaria have been observed to have cryoglobulinemia. Thus, testing for cryoglobulinemia is the most likely laboratory study to yield positive results.^1,16 Beyond evaluation for cryoprecipitates, however, an extensive search for etiology is not indicated unless additional clinical findings warrant investigation.¹⁶

Treatment of patients with cold urticaria can be difficult. Patients and their families should be counseled on the risks of aquatic activities and should be instructed on the proper use of an epinephrine autoinjector. In severe cases, patients may elect to move to warmer climates. Antihistamines sometimes provide benefit, especially at high doses and/or with the more potent formulations, such as doxepin. Cyproheptadine has been shown to be more effective than chlorpheniramine.¹⁷ Second-generation antihistamines also may be considered to minimize sedation. Cetirizine, loratadine, and desloratadine have been shown to be effective and well-tolerated options for treatment.^18,19 Additionally, leukotriene receptor antagonists may have a role in treatment.⁵ Bonadonna et al⁶ demonstrated that cetirizine and zafirlukast in combination are more effective than either drug alone. Adjusting the level of medication so that the patient requires more than 3 minutes of cold stimulus testing before having a wheal response is a recommended goal of therapy that is aimed at minimizing the patient's risk of having a hypotensive reaction.¹²

Cold urticaria is an uncommon disorder that can put patients at significant risk. Taking a thorough history and confirming the condition through the use of cold stimulation tests can lead to a diagnosis in most cases. Although most forms of cold urticaria are idiopathic and acquired, familial and secondary forms also must be kept in mind when considering this diagnosis. In addition to antihistamine therapy, an epinephrine autoinjector and preventive measures play an important role in treating patients with cold urticaria. 

Case Report

An otherwise healthy 9-year-old Filipino girl presented with a complaint of urticaria precipitated by cold exposure over the preceding 5 weeks. She had no recent illnesses and normal results of a school physical examination performed 2 weeks prior to symptom onset. The patient's medical history was significant only for cat allergy; however, she noted that on multiple occasions, erythema and pruritus appeared on her arms and face after walking through the freezer aisle of a grocery store. Urticaria subsequently developed on regions where she scratched and spontaneously resolved 2 to 3 hours later. On one occasion, urticaria appeared diffusely on the patient while she showered after swimming; it resolved within a few hours after she was given diphenhydramine by her mother. Three days prior to presentation, the patient experienced upper lip angioedema with erythema, globus sensation, and difficulty swallowing after drinking a strawberry slushy. She denied having respiratory complaints at that time, and her symptoms again resolved spontaneously. A day later, the patient tolerated ice cream with no complaints. Her family history was significant for a maternal history of seasonal allergies.

On physical examination, the patient appeared to be well. She had 2 to 3 discrete urticarial lesions on the distal posterior aspect of each calf that, according to her mother, recently began appearing on "cold and rainy" days. The mother attributed them to her daughter's lower legs being exposed because of the length of her pants. Results of the remainder of the examination were unremarkable, and dermatographism was absent.

Laboratory evaluation consisted of a strawberry radioallergosorbent test and cryoglobulins test, both of which had negative results. An ice cube wrapped in plastic was applied to the volar surface of the patient's right forearm for 5 minutes. A 9X6-cm wheal was noted 3 minutes after ice removal (Figure).

PLEASE REFER TO THE PDF TO VIEW THE FIGURE

A diagnosis of cold urticaria with associated angioedema was made. The patient's mother opted for her daughter to use only diphenhydramine as needed; additionally, an epinephrine autoinjector was dispensed. By 3 months after symptom onset, the patient's only complaint was pruritus of her hands if they became too cold. No urticaria was noted. At 6-month follow-up, the patient denied having had symptoms for the preceding 2 months, and the results of an ice cube test were negative. 

Comment

Cold urticaria is a form of physical urticaria that is notable for the development of urticaria and/or angioedema after cold exposure.¹ Cold urticaria syndromes were first described in the 19th century² and are uncommon. However, it has been observed that approximately one third of adult³ and pediatric⁴ patients with cold urticaria have systemic reactions that are mostly hypotensive episodes associated with aquatic activities. Thus, identification of these patients should be a priority.

The prevalence of cold urticaria is not well defined. Cold urticaria is most commonly noted in young adults, with only 11% of cases noted in children under 10 years of age.³ Most forms of cold urticaria are idiopathic (Table); however, some forms can be secondary to underlying conditions such as malignancies, vasculitides, and infectious diseases.⁸ Cryoglobulinemia (primary and secondary to malignancy) often is cited as a cause of secondary cold urticaria.^3,8-11 Mounting evidence indicates that a possible autoimmune mechanism underlies the idiopathic form of this disorder in many patients.¹²

PLEASE REFER TO THE PDF TO VIEW THE TABLE

Although most forms of cold urticaria are considered to be acquired, familial forms have been described,^7,13 some of which have been classified within the hereditary periodic fever syndromes.¹² Diagnosis of cold urticaria primarily is made by evaluating the patient's clinical history; the diagnosis may be confirmed by applying a cold stimulus, most commonly an ice cube wrapped in plastic and applied to the volar aspect of the patient's forearm. A positive reaction is noted by the formation of a wheal during rewarming of the skin. The length of time that a cold stimulus is applied is not standardized; commonly, 3-, 5-, and 10-minute applications are used. Visitsuntorn et al¹⁴ observed the effectiveness of 3- or 5-minute applications in children who had not taken antihistamines for at least 5 days prior. The authors also noted that false-positive results (defined as reddening of the skin and minimal edema) were possible with 10- and 20-minute applications in patients with chronic urticaria not induced by cold. Other studies have observed that the length of time necessary for a cold stimulus to induce wheal formation inversely may be related to the patient's risk of having a systemic reaction.^1,8,12 Specifically, patients who demonstrated wheal formation after the application of a cold stimulus for 3 minutes or less were noted to experience cold-induced hypotension more frequently. Regardless, it should be recognized that all patients with cold urticaria are at risk for hypotensive reactions.

Approximately 20% of patients with cold urticaria lack an immediate response to cold stimulus with an ice cube; these patients have so-called atypical acquired cold urticaria syndromes^1,12 (eg, cold-dependant dermatographism, delayed cold urticaria, systemic cold urticaria). Other forms of cold stimulus testing that can be considered include partially immersing a limb of the patient's in cold water³ or placing the patient in a cold room¹⁵; however, these forms of cold stimulus may put the patient at increased risk for a systemic reaction. Finally, scratching the skin prior to cooling or during cooling also may be of diagnostic value in cases of cold-dependant dermatographism.^9,15

Additional testing should be guided by a patient's history. To determine if a secondary cause is responsible for the clinical presentation of cold urticaria, laboratory studies could include complete blood count, erythrocyte sedimentation rate, antinuclear antibodies titer, infectious mononucleosis serology, syphilis serology, rheumatoid factor, total complement, cold agglutinins, cold hemolysin, cryofibrinogen, and cryoglobulin.¹² Of note, approximately 4% of patients with cold urticaria have been observed to have cryoglobulinemia. Thus, testing for cryoglobulinemia is the most likely laboratory study to yield positive results.^1,16 Beyond evaluation for cryoprecipitates, however, an extensive search for etiology is not indicated unless additional clinical findings warrant investigation.¹⁶

Treatment of patients with cold urticaria can be difficult. Patients and their families should be counseled on the risks of aquatic activities and should be instructed on the proper use of an epinephrine autoinjector. In severe cases, patients may elect to move to warmer climates. Antihistamines sometimes provide benefit, especially at high doses and/or with the more potent formulations, such as doxepin. Cyproheptadine has been shown to be more effective than chlorpheniramine.¹⁷ Second-generation antihistamines also may be considered to minimize sedation. Cetirizine, loratadine, and desloratadine have been shown to be effective and well-tolerated options for treatment.^18,19 Additionally, leukotriene receptor antagonists may have a role in treatment.⁵ Bonadonna et al⁶ demonstrated that cetirizine and zafirlukast in combination are more effective than either drug alone. Adjusting the level of medication so that the patient requires more than 3 minutes of cold stimulus testing before having a wheal response is a recommended goal of therapy that is aimed at minimizing the patient's risk of having a hypotensive reaction.¹²

Cold urticaria is an uncommon disorder that can put patients at significant risk. Taking a thorough history and confirming the condition through the use of cold stimulation tests can lead to a diagnosis in most cases. Although most forms of cold urticaria are idiopathic and acquired, familial and secondary forms also must be kept in mind when considering this diagnosis. In addition to antihistamine therapy, an epinephrine autoinjector and preventive measures play an important role in treating patients with cold urticaria. 

Case Report

An otherwise healthy 9-year-old Filipino girl presented with a complaint of urticaria precipitated by cold exposure over the preceding 5 weeks. She had no recent illnesses and normal results of a school physical examination performed 2 weeks prior to symptom onset. The patient's medical history was significant only for cat allergy; however, she noted that on multiple occasions, erythema and pruritus appeared on her arms and face after walking through the freezer aisle of a grocery store. Urticaria subsequently developed on regions where she scratched and spontaneously resolved 2 to 3 hours later. On one occasion, urticaria appeared diffusely on the patient while she showered after swimming; it resolved within a few hours after she was given diphenhydramine by her mother. Three days prior to presentation, the patient experienced upper lip angioedema with erythema, globus sensation, and difficulty swallowing after drinking a strawberry slushy. She denied having respiratory complaints at that time, and her symptoms again resolved spontaneously. A day later, the patient tolerated ice cream with no complaints. Her family history was significant for a maternal history of seasonal allergies.

On physical examination, the patient appeared to be well. She had 2 to 3 discrete urticarial lesions on the distal posterior aspect of each calf that, according to her mother, recently began appearing on "cold and rainy" days. The mother attributed them to her daughter's lower legs being exposed because of the length of her pants. Results of the remainder of the examination were unremarkable, and dermatographism was absent.

Laboratory evaluation consisted of a strawberry radioallergosorbent test and cryoglobulins test, both of which had negative results. An ice cube wrapped in plastic was applied to the volar surface of the patient's right forearm for 5 minutes. A 9X6-cm wheal was noted 3 minutes after ice removal (Figure).

PLEASE REFER TO THE PDF TO VIEW THE FIGURE

A diagnosis of cold urticaria with associated angioedema was made. The patient's mother opted for her daughter to use only diphenhydramine as needed; additionally, an epinephrine autoinjector was dispensed. By 3 months after symptom onset, the patient's only complaint was pruritus of her hands if they became too cold. No urticaria was noted. At 6-month follow-up, the patient denied having had symptoms for the preceding 2 months, and the results of an ice cube test were negative. 

Comment

Cold urticaria is a form of physical urticaria that is notable for the development of urticaria and/or angioedema after cold exposure.¹ Cold urticaria syndromes were first described in the 19th century² and are uncommon. However, it has been observed that approximately one third of adult³ and pediatric⁴ patients with cold urticaria have systemic reactions that are mostly hypotensive episodes associated with aquatic activities. Thus, identification of these patients should be a priority.

The prevalence of cold urticaria is not well defined. Cold urticaria is most commonly noted in young adults, with only 11% of cases noted in children under 10 years of age.³ Most forms of cold urticaria are idiopathic (Table); however, some forms can be secondary to underlying conditions such as malignancies, vasculitides, and infectious diseases.⁸ Cryoglobulinemia (primary and secondary to malignancy) often is cited as a cause of secondary cold urticaria.^3,8-11 Mounting evidence indicates that a possible autoimmune mechanism underlies the idiopathic form of this disorder in many patients.¹²

PLEASE REFER TO THE PDF TO VIEW THE TABLE

Although most forms of cold urticaria are considered to be acquired, familial forms have been described,^7,13 some of which have been classified within the hereditary periodic fever syndromes.¹² Diagnosis of cold urticaria primarily is made by evaluating the patient's clinical history; the diagnosis may be confirmed by applying a cold stimulus, most commonly an ice cube wrapped in plastic and applied to the volar aspect of the patient's forearm. A positive reaction is noted by the formation of a wheal during rewarming of the skin. The length of time that a cold stimulus is applied is not standardized; commonly, 3-, 5-, and 10-minute applications are used. Visitsuntorn et al¹⁴ observed the effectiveness of 3- or 5-minute applications in children who had not taken antihistamines for at least 5 days prior. The authors also noted that false-positive results (defined as reddening of the skin and minimal edema) were possible with 10- and 20-minute applications in patients with chronic urticaria not induced by cold. Other studies have observed that the length of time necessary for a cold stimulus to induce wheal formation inversely may be related to the patient's risk of having a systemic reaction.^1,8,12 Specifically, patients who demonstrated wheal formation after the application of a cold stimulus for 3 minutes or less were noted to experience cold-induced hypotension more frequently. Regardless, it should be recognized that all patients with cold urticaria are at risk for hypotensive reactions.

Approximately 20% of patients with cold urticaria lack an immediate response to cold stimulus with an ice cube; these patients have so-called atypical acquired cold urticaria syndromes^1,12 (eg, cold-dependant dermatographism, delayed cold urticaria, systemic cold urticaria). Other forms of cold stimulus testing that can be considered include partially immersing a limb of the patient's in cold water³ or placing the patient in a cold room¹⁵; however, these forms of cold stimulus may put the patient at increased risk for a systemic reaction. Finally, scratching the skin prior to cooling or during cooling also may be of diagnostic value in cases of cold-dependant dermatographism.^9,15

Additional testing should be guided by a patient's history. To determine if a secondary cause is responsible for the clinical presentation of cold urticaria, laboratory studies could include complete blood count, erythrocyte sedimentation rate, antinuclear antibodies titer, infectious mononucleosis serology, syphilis serology, rheumatoid factor, total complement, cold agglutinins, cold hemolysin, cryofibrinogen, and cryoglobulin.¹² Of note, approximately 4% of patients with cold urticaria have been observed to have cryoglobulinemia. Thus, testing for cryoglobulinemia is the most likely laboratory study to yield positive results.^1,16 Beyond evaluation for cryoprecipitates, however, an extensive search for etiology is not indicated unless additional clinical findings warrant investigation.¹⁶

Treatment of patients with cold urticaria can be difficult. Patients and their families should be counseled on the risks of aquatic activities and should be instructed on the proper use of an epinephrine autoinjector. In severe cases, patients may elect to move to warmer climates. Antihistamines sometimes provide benefit, especially at high doses and/or with the more potent formulations, such as doxepin. Cyproheptadine has been shown to be more effective than chlorpheniramine.¹⁷ Second-generation antihistamines also may be considered to minimize sedation. Cetirizine, loratadine, and desloratadine have been shown to be effective and well-tolerated options for treatment.^18,19 Additionally, leukotriene receptor antagonists may have a role in treatment.⁵ Bonadonna et al⁶ demonstrated that cetirizine and zafirlukast in combination are more effective than either drug alone. Adjusting the level of medication so that the patient requires more than 3 minutes of cold stimulus testing before having a wheal response is a recommended goal of therapy that is aimed at minimizing the patient's risk of having a hypotensive reaction.¹²

Cold urticaria is an uncommon disorder that can put patients at significant risk. Taking a thorough history and confirming the condition through the use of cold stimulation tests can lead to a diagnosis in most cases. Although most forms of cold urticaria are idiopathic and acquired, familial and secondary forms also must be kept in mind when considering this diagnosis. In addition to antihistamine therapy, an epinephrine autoinjector and preventive measures play an important role in treating patients with cold urticaria. 

How idiopathic is chronic idiopathic urticaria (CIU)? With the fast pace of scientific and medical discovery, it is anomalous that diseases with no known cause remain. However, despite the fact that CIU is less well understood than many other diseases, recent findings have partially illuminated this condition's etiology. At least 2 subgroups of patients with CIU exist. One group is composed of 30% to 50% of patients with CIU with autoimmune chronic urticaria caused by autoantibodies against either the high-affinity immunoglobulin E (IgE) receptor FcεRI or, less commonly, IgE.1,2 Patients in this subgroup have an increased likelihood of thyroid autoimmunity; thyroid autoantibodies, Hashimoto thyroiditis, and Graves disease are recognized as being associated with CIU.3 Indeed, 27% of patients with CIU have high-titre antithyroglobulin, antithyroid peroxidase autoantibodies, or both, and 19% have abnormal thyroid function.3 However, the remaining 50% to 70% of patients with CIU are truly idiopathic, because there is no known cause for the disease.1 In keeping with the illusive nature of CIU, the prevalence of the disease has not been firmly established.4 Most recent estimates suggest that 15% to 20% of the US population experience at least one episode of urticaria in their lifetime, and up to 3% of the population are diagnosed with CIU.5,6 Interestingly, middle-aged women are more likely to experience the condition than other groups7; also, women are approximately 3 times more likely than men to acquire any autoimmune disease during their lifetime,⁸ supporting the notion that CIU is often an autoimmune disease.

Quality of Life
The impact of a disease extends beyond physical signs and symptoms; health-related quality of life (QOL) also should play a pivotal role in the evaluation of the effect of a disease or its treatment. This parameter is particularly pertinent to CIU, as evidenced by O'Donnell et al9 whose analysis of a disease-specific, purpose-designed questionnaire and the Nottingham Health Profile demonstrated that patients with chronic urticaria experienced considerable disability, handicap, and reduced QOL. Part 1 of the health profile showed that patients were restricted in areas of mobility, sleep, and energy and experienced pain, social isolation, and altered emotional reactions. Part 2 showed that patients experienced problems in relation to work, home management, social life, relationships, sex life, hobbies, and holidays. Interestingly, patients in this survey had almost identical scores for part 1 of the health profile as did patients with coronary artery disease; both groups experienced lack of energy, feelings of social isolation, and emotional upset.9 Perhaps because skin diseases are so visible and thus potentially stigmatizing, dermatology patients can be impacted significantly in terms of QOL; however, the effect of CIU appears to be particularly acute. Using the validated Dermatology Life Quality Index (DLQI), a survey of 170 consecutive patients had results that showed that patients with CIU experienced greater QOL impairment than outpatients with either psoriasis, acne, or vitiligo and experienced a comparable level of impairment to patients with severe atopic dermatitis.10 Because of CIU's devastating effect on health-related QOL and the discomfort of CIU, appropriate treatment selection is crucial. The ideal treatment for CIU would not only rid the patient of the wheals, edema, and pruritus that characterize the condition but also improve QOL. This review outlines the treatment options available, focusing on oral H1 antihistamines, and offers a means of differentiating this class of agent. 

Antihistamines in the Treatment of CIU
It is well established that elevated tissue levels of histamine are found in the skin of patients with different forms of chronic urticaria.11-13 Although more subclasses of histamine receptors have been identified, those initially isolated—H1 and H2—are involved in the cutaneous responses seen in urticaria. Specifically, the binding of histamine to the H1 receptor causes erythema (by vasodilation), edema (by increasing vascular permeability), and itching. The same responses, with the exception of itching, are caused by histamine binding to the H2 receptor. In 30% to 50% of patients diagnosed with CIU, histamine release from mast cells leads to wheal formation because of an autoimmune process. In contrast, patients with CIU without this autoimmune response experience the same effects of mast cell degranulation and subsequent release of histamine by a process yet to be elucidated. The sentinel involvement of histamine in CIU is, therefore, unequivocal; irrespective of etiology, the appropriate use of H1 antihistamines—which stabilize an active conformation of the H1 receptor and thus prevent activation by histamine—remains the basis of treatment.14 However, for patients unresponsive to conventional H1-antihistamine monotherapy, adjunctive treatments often are prescribed including a combination of H1 antihistamines (either 2 different newer-generation agents concurrently or a newer-generation agent plus a first-generation agent at night), H2 antihistamines, tricyclic antidepressants (principally doxepin), antileukotriene therapy, and intermittent pulses of corticosteroids.15 In the event of inadequate symptom control after these therapies have been explored, immunomodulatory agents such as cyclosporine have been used to treat patients refractory to conventional therapy.14 The method of activity for the adjunctive treatments is based on the following approaches: blocking H1 and H2 receptors, blocking nonhistamine mediators of urticaria, and blocking the cellular and inflammatory components of the urticarial reaction. In summary, because H1 antihistamines are first-line therapy for CIU, and for many patients remain the only option available, the selection of the optimal antihistamine is of vital importance. 

Selection of Antihistamines
The first antihistamine was developed in 1937; in the 1940s, phenbenzamine became the first commercially available antihistamine, followed by similar H1-receptor antagonists such as chlorpheniramine, brompheniramine, and diphenhydramine. Despite its relative antiquity, diphenhydramine remains the most widely used antihistamine in the United States.16 These first-generation H1-receptor antagonists, though effective in the treatment of urticaria and allergic rhinitis, were shown to cause undesired side effects for 2 distinct reasons: their lack of selectivity for the H1 receptor and their propensity to cross the blood-brain barrier and affect the central nervous system.17 As a result of their lack of selectivity, older-generation agents cause anticholinergic effects such as dry mouth, headache, and urinary retention.18-20 Furthermore, at supraclinical doses, some antihistamines are toxic¹⁶ and have been shown to cause sinus tachycardia.21 Children have been known to experience severe toxic reactions and even death following overdose of older-generation antihistamines because of the drug's lack of selectivity.22-25 Because older-generation antihistamines can bind to H1 receptors in the brain and histamine in the brain plays a role in central nervous system arousal and alertness, these agents also are associated with sedation and cognitive impairment (eg, impaired sensorimotor coordination and decreases in attention span, memory function, ability to process information, and psychomotor performance16,26,27). The binding of first-generation antihistamines to cerebral H1 receptors has been demonstrated in many studies employing objective psychometric tests and also by the relatively new technique of positron emission tomographic imaging.28-30

Newer-Generation Antihistamines
Newer-generation antihistamines were developed in the early 1980s with the aim of being more specific for the H1 receptor, as well as of overcoming the adverse events observed with older agents. As testament to achieving this goal, allergists agree that newer-generation antihistamines are preferred to first-generation agents because of their more favorable efficacy:safety ratio.16,18 Although there is no such formal consensus among dermatologists and those specifically treating CIU, it is likely the same logic would apply if equivalent efficacy between old and new antihistamines can be established for CIU. This review explores the newer-generation antihistamines available in the United States for the treatment of CIU: fexofenadine, loratadine, desloratadine, and cetirizine. An evidence-based analysis of the efficacy of these agents and an analysis of the therapeutic window of these antihistamines, with particular focus on their sedation and cognitive impairment potential, are emphasized (Table).

Efficacy of Newer-Generation Antihistamines
Numerous randomized double-blind clinical studies have demonstrated the efficacy of fexofenadine,31-34 loratadine,35,36 desloratadine,37,38 and cetirizine39,40 in relieving the symptoms of CIU. Fexofenadine—The safety and efficacy of various doses of fexofenadine at relieving the symptoms of CIU has been established in several large randomized controlled clinical trials. Two similar CIU studies investigated the efficacy of fexofenadine HCl using doses of 20, 60, 120, and 240 mg twice daily (BID). In both studies, doses of 60 mg or more BID were shown to reduce severity of pruritus, number of wheals, and interference with sleep and normal daily activities compared with placebo.33,34 Furthermore, studies in Japanese and Thai patients have indicated that the effectiveness of fexofenadine 60 mg BID is not limited by ethnicity or genotype.41,42 Although many studies have examined some QOL parameters as secondary endpoints as a component of efficacy studies, fexofenadine has been studied using the validated DLQI and Work Productivity and Activity Impairment questionnaires.⁴³ Two identically designed 4-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group trials examined the effects of 60 mg BID on patients aged 12 to 65 years with moderate to severe CIU. Fexofenadine treatment significantly improved overall DLQI score compared with placebo (P≤.0002), and also significantly increased work productivity (P≤.014). In addition, a trend toward increased classroom productivity and significant improvements in 5 of the 6 individual DLQI domains were observed.43 The efficacy and safety of a range of once-daily (QD) doses of fexofenadine have been evaluated in a large, multicenter, double-blind, placebo-controlled, parallel-group, dose-ranging study.31 Adults (N=222) were randomized to receive either fexofenadine HCl 60, 120, 180, or 240 mg QD or placebo QD for 6 weeks. The combined fexofenadine groups showed a significant reduction in mean total symptom score (pruritus score and number of wheals) compared with placebo (P=.0019). The study suggested that 180 mg QD is the optimal dose for the treatment of CIU because this dose alone significantly reduced the number of wheals compared with placebo (P=.0064) and significantly improved mean total symptom score consistently over the 6-week study period (P<.05).31 Supporting the efficacy of this once-daily dose, a recent double-blind placebo-controlled study of fexofenadine HCl 180 mg QD was shown to produce a beneficial effect on urticaria.32
Loratadine—The relative efficacy of loratadine and the first-generation antihistamine hydroxyzine has been established in a large 4-week (optional 12-week) trial comparing the 2 compounds with placebo in 172 patients with CIU. Patients were randomized to receive either: 10 mg loratadine QD and placebo BID; hydroxyzine 3 times daily; or placebo 3 times daily. As measured by all efficacy evaluations (physician and patient evaluations of the effect of treatment at each visit plus patient daily diary cards), loratadine and hydroxyzine were found to be more effective than placebo and clinically comparable to each other.35
In the only placebo-controlled comparative study between 2 newer-generation antihistamines in the treatment of CIU, Guerra et al44 showed that loratadine was more effective than cetirizine in some aspects of controlling the symptoms of CIU. In this double-blind study, 116 patients with CIU were randomly assigned loratadine 10 mg, cetirizine 10 mg, or placebo QD for 28 days. Both active drugs significantly reduced global clinical symptoms (P<.05), but loratadine was more rapid in developing its activity than cetirizine (P<.01 at day 3) and also appeared to be safer when the frequency of treatment-emergent side effects were compared.44
Desloratadine—Desloratadine is the major active metabolite of loratadine, which has been available in the United States since 2002 for the treatment of CIU. The efficacy of the drug has been evaluated in 2 major randomized controlled clinical trials.37,38
Ring et al37 reported that desloratadine exhibited superior efficacy compared with placebo in a multicenter, randomized, double-blind trial of 190 patients with a history of CIU. Patients were assigned to receive either desloratadine 5 mg QD or placebo QD for 6 weeks. The active treatment was superior to placebo at reducing pruritus and overall symptoms after the first dose and throughout the 6-week study.37 Similarly, therapeutic response and global CIU status, as well as QOL measures such as interference with sleep, were improved with desloratadine compared with placebo throughout the study period.37 Using the same dose (5 mg QD), a further 6-week placebo-controlled study of desloratadine indicated the effectiveness of this agent at relieving CIU symptoms.38 Over the study period, the mean total CIU symptom score was significantly improved compared with placebo, as were the individual scores of pruritus, number of hives, and the size of the largest hive. Interference with sleep was reduced and performance of daily activities was improved with desloratadine. These statistically and clinically significant improvements were seen within the first 24 hours of treatment and were sustained throughout the 6-week treatment period.38
Cetirizine—As with loratadine, cetirizine has been shown to be as effective as first-generation hydroxyzine at relieving the symptoms of CIU.40 For example, a 4-week, multicenter, randomized, double-blind, double-dummy trial investigated the efficacy and safety of cetirizine 10 mg QD and hydroxyzine 25 mg 3 times daily compared with placebo in patients with CIU. Patients in the cetirizine and hydroxyzine groups showed significant reductions during weeks 1, 2, 3, and 4 in the number and size of lesions and in the severity of pruritus compared with patients who received placebo. In addition, physician and patient evaluations at the end of week 4 revealed an improvement in urticarial symptoms for the cetirizine and hydroxyzine groups compared with the placebo group.40
All 4 newer-generation H1 antihistamines (fexofenadine, loratadine, desloratadine, and cetirizine) have been shown to be superior to placebo at treating the symptoms of CIU, and both loratadine and cetirizine have been proven to be as effective as first-generation hydroxyzine.35,40 Although no trials have evaluated fexofenadine and desloratadine compared with hydroxyzine, comparisons demonstrating equivalence have been made with their parent compounds (loratadine35 and terfenadine45).
There are few controlled studies in which newer-generation antihistamines have been directly compared, and there is no evidence-based data demonstrating statistical superiority of one second-generation agent over another in the treatment of CIU. For example, although a recent trial compared the efficacy of cetirizine with fexofenadine, the results are weakened by the study design. Patients with CIU were randomized to either cetirizine 10 mg (n=52) or fexofenadine 180 mg (n=45); at 28 days, 51.9% (27) and 4.4% (2) of cetirizine and fexofenadine patients, respectively, were symptom free (P=.00001), while partial improvement was experienced by 36.5% (19) of cetirizine patients and 42.2% (19) of fexofenadine patients.46 However, there was no control group, baseline symptom severity data were not provided, and the authors did not describe how the patients’ symptoms were assessed.46 Therefore, a definitive assessment of the relative efficacy of newer-generation antihistamines cannot be achieved by reviewing published trials alone.Anti-inflammatory Properties
Due to the absence of well-designed placebo-controlled comparisons of newer-generation antihistamines, other properties have been examined to aid treatment comparisons. For example, it has been suggested that some H1-receptor antagonists may achieve anti-inflammatory effects in a clinical context, which could prove advantageous in the treatment of CIU because the disease is characterized by tissue inflammation.47
To investigate the anti-inflammatory activity of fexofenadine, an immunohistochemical evaluation of the agent was undertaken in patients with CIU.48 Twenty patients received fexofenadine HCl 180 mg QD for 4 weeks; the expression of adhesion molecules, mast cell proteases, and proinflammatory cytokines were evaluated before and after treatment, as were the patients’ assessments of urticarial symptoms. After treatment with fexofenadine, significant decreases in the expression of endothelial leukocyte adhesion molecule-1 (P=.02), vascular cell adhesion molecule-1 (P=.04), and tryptase (P=.04) were observed, confirming the hypothesis that fexofenadine has some anti-inflammatory properties.
This study in humans must be put into context with the numerous in vitro, ex vivo, and animal studies that have been conducted in this area. A review of such data suggests that all newer-generation antihistamines inhibit the release or generation of multiple inflammatory mediators, including IL-4, IL-6, IL-8, IL-13, prostaglandin D3, leukotriene C, tryptase, histamine, and the tumor necrosis factor α­induced chemokine regulated upon activation normal T cell expressed and secreted, in addition to eosinophil chemotaxis and adhesion molecules.47 For example, both loratadine and desloratadine (10 μmol/L) significantly inhibited the expression of intercellular adhesion molecule-1 and class II HLA antigen (HLA-DE) in nasal epithelial cells in vitro.49 However, many of these anti-inflammatory effects have only been observed at high drug concentrations.47 For example, an in vitro study of cetirizine assessing the inhibition of IL-5­ dependent eosinophil survival revealed a concentration of 100 μmol/L was required to achieve significant inhibition—much higher than that used clinically.47,50
Clearly, if clinical anti-inflammatory effects necessitate doses higher than those recommended for allergic diseases, drugs that can be used at higher doses without causing unwanted side effects such as sedation and cognitive impairment may be of the greatest utility in the treatment of CIU. This is a particularly pertinent point because patients with CIU may be prescribed much higher doses than recommended to manage symptoms effectively.17
The Therapeutic Window—Because of the lack of rigorously designed clinical trials comparing the efficacy of second-generation antihistamines and the putative anti-inflammatory activities of these agents that may occur at higher-than-recommended dosing levels, the relative safety of agents may direct the selection of the optimum antihistamine for the treatment of CIU. Ideally, an agent would be effective at a wide range of doses without causing unwanted side effects. This is because a wide therapeutic window permits the physician to optimize treatment to the individual. The safety of the newer-generation antihistamines has been assessed in numerous clinical trials, usually as secondary analyses to efficacy parameters; indeed, all of the efficacy studies described here indicated a good safety and tolerability profile for each of the antihistamines.
Clinical trials, however, do not always reflect the reality of clinical practice. Patients taking antihistamines frequently overcomply with their medication,51 particularly if they do not experience immediate relief. Furthermore, as previously mentioned, it is occasionally necessary for dermatologists to prescribe high doses of antihistamines for patients who do not respond to standard-dose first-line therapy.17 Thus, it is valid to examine the safety of the different antihistamines at high doses to obtain a true picture of how drugs may be affecting patients.
Sedation and Impairment—A number of studies using objective psychometric tests have indicated that newer-generation antihistamines generally have better sedative profiles than first-generation agents; however, at higher doses, sedation and impairment become evident.
Two meta-analyses of published data on antihistamines report that newer drugs had lower impairment/nonimpairment ratios than older agents.28,29 That is, proportionally more studies indicated nonimpairment versus impairment with the newer agents compared with their predecessors. However, the same meta-analyses revealed that both loratadine and cetirizine were associated with sedation/impairment in a number of tests, often when they were used at higher-than-recommended doses. In contrast, fexofenadine, even at doses of up to 360 mg, was not associated with any sedation or impairment and had an impairment:nonimpairment ratio of zero.28,29
A study by Mann et al52 corroborates the finding that different newer-generation antihistamines have the potential to cause sedation, with fexofenadine being the least likely of those studied to do so. This prescription-event monitoring study showed that the odds ratios for the incidence of sedation were 0.63 for fexofenadine and 5.53 for cetirizine compared with loratadine.52 Higher-than-recommended doses of loratadine53 and desloratadine54 also can cause sedation.
A recent approach to the question of blood-brain barrier penetration involves the use of positron emission tomography. This technique has been used to study the binding of antihistamines to cerebral H1 receptors. Tashiro et al30 used positron emission tomographic imaging to compare fexofenadine with cetirizine by examining relative H1 receptor occupancy in the brain. Quantitative analysis showed that fexofenadine did not occupy H1 receptors in the cerebral cortex, while cetirizine occupied between 20% to 50% of the H1 receptors, depending on the brain region.30 These findings support evidence from comparative trials that indicate that although cetirizine is less sedating than older antihistamines, it causes more sedation and impairment of performance than other second-generation antihistamines. As a result, the US Food and Drug Administration has classified cetirizine as sedating rather than nonsedating, and the product carries the full sedation precaution.
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Comment
Antihistamines can be used effectively to control the symptoms of CIU; newer-generation antihistamines have been shown to be as effective as their predecessors at relieving patients of their symptoms35,40 and improving their QOL.43 However, there is a paucity of well-designed placebo-controlled comparative clinical trials; the data available indicate that agents are effective and safe, but they do not provide a means to assess which agent is the safest and most effective. Instead, we must examine alternative sources of evidence to help us select the optimum antihistamine for the treatment of CIU.
Evidence from pharmacologic studies indicates that newer agents demonstrate some anti-inflammatory activity, which could provide additional therapeutic benefit. However, these studies have largely been limited to in vitro tests and animal modeling and do not yet provide the means to differentiate agents.
Newer-generation antihistamines vary in their propensity to cause sedation and cognitive impairment, with cetirizine representing the most impairing of the class, as recognized by its sedating description by the US Food and Drug Administration. At recommended doses, fexofenadine, loratadine, and desloratadine have not been found to cause significant impairment and are labeled as nonsedating by the US Food and Drug Administration. However, patients with urticaria are known to take above-recommended doses51 and physicians occasionally prescribe off-label doses to achieve the desired level of symptom control. The risk of sedation caused by these 2 factors should be considered in practice when selecting an antihistamine.
Sedation and impairment affect QOL and manifest as decreased classroom learning ability and decreased work productivity.28 Furthermore, it has been suggested that cerebral H1-receptor blockade is associated with falls in the elderly and cognitive slowing, and is a contributing factor in traffic accidents.27
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Conclusion
In controlled clinical studies of CIU, the second-generation H1-antihistamines have been proven to be clinically comparable to the most potent of the first-generation antihistamines, such as hydroxyzine. Clinical studies comparing these agents are few and have shown no statistically significant differences in efficacy.
If sedation and cognitive impairment are to be considered relevant to the choice of therapy for CIU because of their impact on QOL and safety, then newer-generation agents should be selected over older-generation antihistamines.37,40 Furthermore, of the new agents, those that are labeled nonsedating at recommended doses (fexofenadine, loratadine, and desloratadine) should be selected over cetirizine. However, in cases where the physician judges that a higher-than-recommended dose should be prescribed or when the patient is likely to take a higher dose, fexofenadine should be considered. In addition to its proven efficacy in treating the symptoms of CIU,31,33,34 fexofenadine is the only antihistamine that is nonsedating, even at doses 2 to 4 times above the recommended levels.

How idiopathic is chronic idiopathic urticaria (CIU)? With the fast pace of scientific and medical discovery, it is anomalous that diseases with no known cause remain. However, despite the fact that CIU is less well understood than many other diseases, recent findings have partially illuminated this condition's etiology. At least 2 subgroups of patients with CIU exist. One group is composed of 30% to 50% of patients with CIU with autoimmune chronic urticaria caused by autoantibodies against either the high-affinity immunoglobulin E (IgE) receptor FcεRI or, less commonly, IgE.1,2 Patients in this subgroup have an increased likelihood of thyroid autoimmunity; thyroid autoantibodies, Hashimoto thyroiditis, and Graves disease are recognized as being associated with CIU.3 Indeed, 27% of patients with CIU have high-titre antithyroglobulin, antithyroid peroxidase autoantibodies, or both, and 19% have abnormal thyroid function.3 However, the remaining 50% to 70% of patients with CIU are truly idiopathic, because there is no known cause for the disease.1 In keeping with the illusive nature of CIU, the prevalence of the disease has not been firmly established.4 Most recent estimates suggest that 15% to 20% of the US population experience at least one episode of urticaria in their lifetime, and up to 3% of the population are diagnosed with CIU.5,6 Interestingly, middle-aged women are more likely to experience the condition than other groups7; also, women are approximately 3 times more likely than men to acquire any autoimmune disease during their lifetime,⁸ supporting the notion that CIU is often an autoimmune disease.

Quality of Life
The impact of a disease extends beyond physical signs and symptoms; health-related quality of life (QOL) also should play a pivotal role in the evaluation of the effect of a disease or its treatment. This parameter is particularly pertinent to CIU, as evidenced by O'Donnell et al9 whose analysis of a disease-specific, purpose-designed questionnaire and the Nottingham Health Profile demonstrated that patients with chronic urticaria experienced considerable disability, handicap, and reduced QOL. Part 1 of the health profile showed that patients were restricted in areas of mobility, sleep, and energy and experienced pain, social isolation, and altered emotional reactions. Part 2 showed that patients experienced problems in relation to work, home management, social life, relationships, sex life, hobbies, and holidays. Interestingly, patients in this survey had almost identical scores for part 1 of the health profile as did patients with coronary artery disease; both groups experienced lack of energy, feelings of social isolation, and emotional upset.9 Perhaps because skin diseases are so visible and thus potentially stigmatizing, dermatology patients can be impacted significantly in terms of QOL; however, the effect of CIU appears to be particularly acute. Using the validated Dermatology Life Quality Index (DLQI), a survey of 170 consecutive patients had results that showed that patients with CIU experienced greater QOL impairment than outpatients with either psoriasis, acne, or vitiligo and experienced a comparable level of impairment to patients with severe atopic dermatitis.10 Because of CIU's devastating effect on health-related QOL and the discomfort of CIU, appropriate treatment selection is crucial. The ideal treatment for CIU would not only rid the patient of the wheals, edema, and pruritus that characterize the condition but also improve QOL. This review outlines the treatment options available, focusing on oral H1 antihistamines, and offers a means of differentiating this class of agent. 

Antihistamines in the Treatment of CIU
It is well established that elevated tissue levels of histamine are found in the skin of patients with different forms of chronic urticaria.11-13 Although more subclasses of histamine receptors have been identified, those initially isolated—H1 and H2—are involved in the cutaneous responses seen in urticaria. Specifically, the binding of histamine to the H1 receptor causes erythema (by vasodilation), edema (by increasing vascular permeability), and itching. The same responses, with the exception of itching, are caused by histamine binding to the H2 receptor. In 30% to 50% of patients diagnosed with CIU, histamine release from mast cells leads to wheal formation because of an autoimmune process. In contrast, patients with CIU without this autoimmune response experience the same effects of mast cell degranulation and subsequent release of histamine by a process yet to be elucidated. The sentinel involvement of histamine in CIU is, therefore, unequivocal; irrespective of etiology, the appropriate use of H1 antihistamines—which stabilize an active conformation of the H1 receptor and thus prevent activation by histamine—remains the basis of treatment.14 However, for patients unresponsive to conventional H1-antihistamine monotherapy, adjunctive treatments often are prescribed including a combination of H1 antihistamines (either 2 different newer-generation agents concurrently or a newer-generation agent plus a first-generation agent at night), H2 antihistamines, tricyclic antidepressants (principally doxepin), antileukotriene therapy, and intermittent pulses of corticosteroids.15 In the event of inadequate symptom control after these therapies have been explored, immunomodulatory agents such as cyclosporine have been used to treat patients refractory to conventional therapy.14 The method of activity for the adjunctive treatments is based on the following approaches: blocking H1 and H2 receptors, blocking nonhistamine mediators of urticaria, and blocking the cellular and inflammatory components of the urticarial reaction. In summary, because H1 antihistamines are first-line therapy for CIU, and for many patients remain the only option available, the selection of the optimal antihistamine is of vital importance. 

Selection of Antihistamines
The first antihistamine was developed in 1937; in the 1940s, phenbenzamine became the first commercially available antihistamine, followed by similar H1-receptor antagonists such as chlorpheniramine, brompheniramine, and diphenhydramine. Despite its relative antiquity, diphenhydramine remains the most widely used antihistamine in the United States.16 These first-generation H1-receptor antagonists, though effective in the treatment of urticaria and allergic rhinitis, were shown to cause undesired side effects for 2 distinct reasons: their lack of selectivity for the H1 receptor and their propensity to cross the blood-brain barrier and affect the central nervous system.17 As a result of their lack of selectivity, older-generation agents cause anticholinergic effects such as dry mouth, headache, and urinary retention.18-20 Furthermore, at supraclinical doses, some antihistamines are toxic¹⁶ and have been shown to cause sinus tachycardia.21 Children have been known to experience severe toxic reactions and even death following overdose of older-generation antihistamines because of the drug's lack of selectivity.22-25 Because older-generation antihistamines can bind to H1 receptors in the brain and histamine in the brain plays a role in central nervous system arousal and alertness, these agents also are associated with sedation and cognitive impairment (eg, impaired sensorimotor coordination and decreases in attention span, memory function, ability to process information, and psychomotor performance16,26,27). The binding of first-generation antihistamines to cerebral H1 receptors has been demonstrated in many studies employing objective psychometric tests and also by the relatively new technique of positron emission tomographic imaging.28-30

Newer-Generation Antihistamines
Newer-generation antihistamines were developed in the early 1980s with the aim of being more specific for the H1 receptor, as well as of overcoming the adverse events observed with older agents. As testament to achieving this goal, allergists agree that newer-generation antihistamines are preferred to first-generation agents because of their more favorable efficacy:safety ratio.16,18 Although there is no such formal consensus among dermatologists and those specifically treating CIU, it is likely the same logic would apply if equivalent efficacy between old and new antihistamines can be established for CIU. This review explores the newer-generation antihistamines available in the United States for the treatment of CIU: fexofenadine, loratadine, desloratadine, and cetirizine. An evidence-based analysis of the efficacy of these agents and an analysis of the therapeutic window of these antihistamines, with particular focus on their sedation and cognitive impairment potential, are emphasized (Table).

Efficacy of Newer-Generation Antihistamines
Numerous randomized double-blind clinical studies have demonstrated the efficacy of fexofenadine,31-34 loratadine,35,36 desloratadine,37,38 and cetirizine39,40 in relieving the symptoms of CIU. Fexofenadine—The safety and efficacy of various doses of fexofenadine at relieving the symptoms of CIU has been established in several large randomized controlled clinical trials. Two similar CIU studies investigated the efficacy of fexofenadine HCl using doses of 20, 60, 120, and 240 mg twice daily (BID). In both studies, doses of 60 mg or more BID were shown to reduce severity of pruritus, number of wheals, and interference with sleep and normal daily activities compared with placebo.33,34 Furthermore, studies in Japanese and Thai patients have indicated that the effectiveness of fexofenadine 60 mg BID is not limited by ethnicity or genotype.41,42 Although many studies have examined some QOL parameters as secondary endpoints as a component of efficacy studies, fexofenadine has been studied using the validated DLQI and Work Productivity and Activity Impairment questionnaires.⁴³ Two identically designed 4-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group trials examined the effects of 60 mg BID on patients aged 12 to 65 years with moderate to severe CIU. Fexofenadine treatment significantly improved overall DLQI score compared with placebo (P≤.0002), and also significantly increased work productivity (P≤.014). In addition, a trend toward increased classroom productivity and significant improvements in 5 of the 6 individual DLQI domains were observed.43 The efficacy and safety of a range of once-daily (QD) doses of fexofenadine have been evaluated in a large, multicenter, double-blind, placebo-controlled, parallel-group, dose-ranging study.31 Adults (N=222) were randomized to receive either fexofenadine HCl 60, 120, 180, or 240 mg QD or placebo QD for 6 weeks. The combined fexofenadine groups showed a significant reduction in mean total symptom score (pruritus score and number of wheals) compared with placebo (P=.0019). The study suggested that 180 mg QD is the optimal dose for the treatment of CIU because this dose alone significantly reduced the number of wheals compared with placebo (P=.0064) and significantly improved mean total symptom score consistently over the 6-week study period (P<.05).31 Supporting the efficacy of this once-daily dose, a recent double-blind placebo-controlled study of fexofenadine HCl 180 mg QD was shown to produce a beneficial effect on urticaria.32
Loratadine—The relative efficacy of loratadine and the first-generation antihistamine hydroxyzine has been established in a large 4-week (optional 12-week) trial comparing the 2 compounds with placebo in 172 patients with CIU. Patients were randomized to receive either: 10 mg loratadine QD and placebo BID; hydroxyzine 3 times daily; or placebo 3 times daily. As measured by all efficacy evaluations (physician and patient evaluations of the effect of treatment at each visit plus patient daily diary cards), loratadine and hydroxyzine were found to be more effective than placebo and clinically comparable to each other.35
In the only placebo-controlled comparative study between 2 newer-generation antihistamines in the treatment of CIU, Guerra et al44 showed that loratadine was more effective than cetirizine in some aspects of controlling the symptoms of CIU. In this double-blind study, 116 patients with CIU were randomly assigned loratadine 10 mg, cetirizine 10 mg, or placebo QD for 28 days. Both active drugs significantly reduced global clinical symptoms (P<.05), but loratadine was more rapid in developing its activity than cetirizine (P<.01 at day 3) and also appeared to be safer when the frequency of treatment-emergent side effects were compared.44
Desloratadine—Desloratadine is the major active metabolite of loratadine, which has been available in the United States since 2002 for the treatment of CIU. The efficacy of the drug has been evaluated in 2 major randomized controlled clinical trials.37,38
Ring et al37 reported that desloratadine exhibited superior efficacy compared with placebo in a multicenter, randomized, double-blind trial of 190 patients with a history of CIU. Patients were assigned to receive either desloratadine 5 mg QD or placebo QD for 6 weeks. The active treatment was superior to placebo at reducing pruritus and overall symptoms after the first dose and throughout the 6-week study.37 Similarly, therapeutic response and global CIU status, as well as QOL measures such as interference with sleep, were improved with desloratadine compared with placebo throughout the study period.37 Using the same dose (5 mg QD), a further 6-week placebo-controlled study of desloratadine indicated the effectiveness of this agent at relieving CIU symptoms.38 Over the study period, the mean total CIU symptom score was significantly improved compared with placebo, as were the individual scores of pruritus, number of hives, and the size of the largest hive. Interference with sleep was reduced and performance of daily activities was improved with desloratadine. These statistically and clinically significant improvements were seen within the first 24 hours of treatment and were sustained throughout the 6-week treatment period.38
Cetirizine—As with loratadine, cetirizine has been shown to be as effective as first-generation hydroxyzine at relieving the symptoms of CIU.40 For example, a 4-week, multicenter, randomized, double-blind, double-dummy trial investigated the efficacy and safety of cetirizine 10 mg QD and hydroxyzine 25 mg 3 times daily compared with placebo in patients with CIU. Patients in the cetirizine and hydroxyzine groups showed significant reductions during weeks 1, 2, 3, and 4 in the number and size of lesions and in the severity of pruritus compared with patients who received placebo. In addition, physician and patient evaluations at the end of week 4 revealed an improvement in urticarial symptoms for the cetirizine and hydroxyzine groups compared with the placebo group.40
All 4 newer-generation H1 antihistamines (fexofenadine, loratadine, desloratadine, and cetirizine) have been shown to be superior to placebo at treating the symptoms of CIU, and both loratadine and cetirizine have been proven to be as effective as first-generation hydroxyzine.35,40 Although no trials have evaluated fexofenadine and desloratadine compared with hydroxyzine, comparisons demonstrating equivalence have been made with their parent compounds (loratadine35 and terfenadine45).
There are few controlled studies in which newer-generation antihistamines have been directly compared, and there is no evidence-based data demonstrating statistical superiority of one second-generation agent over another in the treatment of CIU. For example, although a recent trial compared the efficacy of cetirizine with fexofenadine, the results are weakened by the study design. Patients with CIU were randomized to either cetirizine 10 mg (n=52) or fexofenadine 180 mg (n=45); at 28 days, 51.9% (27) and 4.4% (2) of cetirizine and fexofenadine patients, respectively, were symptom free (P=.00001), while partial improvement was experienced by 36.5% (19) of cetirizine patients and 42.2% (19) of fexofenadine patients.46 However, there was no control group, baseline symptom severity data were not provided, and the authors did not describe how the patients’ symptoms were assessed.46 Therefore, a definitive assessment of the relative efficacy of newer-generation antihistamines cannot be achieved by reviewing published trials alone.Anti-inflammatory Properties
Due to the absence of well-designed placebo-controlled comparisons of newer-generation antihistamines, other properties have been examined to aid treatment comparisons. For example, it has been suggested that some H1-receptor antagonists may achieve anti-inflammatory effects in a clinical context, which could prove advantageous in the treatment of CIU because the disease is characterized by tissue inflammation.47
To investigate the anti-inflammatory activity of fexofenadine, an immunohistochemical evaluation of the agent was undertaken in patients with CIU.48 Twenty patients received fexofenadine HCl 180 mg QD for 4 weeks; the expression of adhesion molecules, mast cell proteases, and proinflammatory cytokines were evaluated before and after treatment, as were the patients’ assessments of urticarial symptoms. After treatment with fexofenadine, significant decreases in the expression of endothelial leukocyte adhesion molecule-1 (P=.02), vascular cell adhesion molecule-1 (P=.04), and tryptase (P=.04) were observed, confirming the hypothesis that fexofenadine has some anti-inflammatory properties.
This study in humans must be put into context with the numerous in vitro, ex vivo, and animal studies that have been conducted in this area. A review of such data suggests that all newer-generation antihistamines inhibit the release or generation of multiple inflammatory mediators, including IL-4, IL-6, IL-8, IL-13, prostaglandin D3, leukotriene C, tryptase, histamine, and the tumor necrosis factor α­induced chemokine regulated upon activation normal T cell expressed and secreted, in addition to eosinophil chemotaxis and adhesion molecules.47 For example, both loratadine and desloratadine (10 μmol/L) significantly inhibited the expression of intercellular adhesion molecule-1 and class II HLA antigen (HLA-DE) in nasal epithelial cells in vitro.49 However, many of these anti-inflammatory effects have only been observed at high drug concentrations.47 For example, an in vitro study of cetirizine assessing the inhibition of IL-5­ dependent eosinophil survival revealed a concentration of 100 μmol/L was required to achieve significant inhibition—much higher than that used clinically.47,50
Clearly, if clinical anti-inflammatory effects necessitate doses higher than those recommended for allergic diseases, drugs that can be used at higher doses without causing unwanted side effects such as sedation and cognitive impairment may be of the greatest utility in the treatment of CIU. This is a particularly pertinent point because patients with CIU may be prescribed much higher doses than recommended to manage symptoms effectively.17
The Therapeutic Window—Because of the lack of rigorously designed clinical trials comparing the efficacy of second-generation antihistamines and the putative anti-inflammatory activities of these agents that may occur at higher-than-recommended dosing levels, the relative safety of agents may direct the selection of the optimum antihistamine for the treatment of CIU. Ideally, an agent would be effective at a wide range of doses without causing unwanted side effects. This is because a wide therapeutic window permits the physician to optimize treatment to the individual. The safety of the newer-generation antihistamines has been assessed in numerous clinical trials, usually as secondary analyses to efficacy parameters; indeed, all of the efficacy studies described here indicated a good safety and tolerability profile for each of the antihistamines.
Clinical trials, however, do not always reflect the reality of clinical practice. Patients taking antihistamines frequently overcomply with their medication,51 particularly if they do not experience immediate relief. Furthermore, as previously mentioned, it is occasionally necessary for dermatologists to prescribe high doses of antihistamines for patients who do not respond to standard-dose first-line therapy.17 Thus, it is valid to examine the safety of the different antihistamines at high doses to obtain a true picture of how drugs may be affecting patients.
Sedation and Impairment—A number of studies using objective psychometric tests have indicated that newer-generation antihistamines generally have better sedative profiles than first-generation agents; however, at higher doses, sedation and impairment become evident.
Two meta-analyses of published data on antihistamines report that newer drugs had lower impairment/nonimpairment ratios than older agents.28,29 That is, proportionally more studies indicated nonimpairment versus impairment with the newer agents compared with their predecessors. However, the same meta-analyses revealed that both loratadine and cetirizine were associated with sedation/impairment in a number of tests, often when they were used at higher-than-recommended doses. In contrast, fexofenadine, even at doses of up to 360 mg, was not associated with any sedation or impairment and had an impairment:nonimpairment ratio of zero.28,29
A study by Mann et al52 corroborates the finding that different newer-generation antihistamines have the potential to cause sedation, with fexofenadine being the least likely of those studied to do so. This prescription-event monitoring study showed that the odds ratios for the incidence of sedation were 0.63 for fexofenadine and 5.53 for cetirizine compared with loratadine.52 Higher-than-recommended doses of loratadine53 and desloratadine54 also can cause sedation.
A recent approach to the question of blood-brain barrier penetration involves the use of positron emission tomography. This technique has been used to study the binding of antihistamines to cerebral H1 receptors. Tashiro et al30 used positron emission tomographic imaging to compare fexofenadine with cetirizine by examining relative H1 receptor occupancy in the brain. Quantitative analysis showed that fexofenadine did not occupy H1 receptors in the cerebral cortex, while cetirizine occupied between 20% to 50% of the H1 receptors, depending on the brain region.30 These findings support evidence from comparative trials that indicate that although cetirizine is less sedating than older antihistamines, it causes more sedation and impairment of performance than other second-generation antihistamines. As a result, the US Food and Drug Administration has classified cetirizine as sedating rather than nonsedating, and the product carries the full sedation precaution.
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Comment
Antihistamines can be used effectively to control the symptoms of CIU; newer-generation antihistamines have been shown to be as effective as their predecessors at relieving patients of their symptoms35,40 and improving their QOL.43 However, there is a paucity of well-designed placebo-controlled comparative clinical trials; the data available indicate that agents are effective and safe, but they do not provide a means to assess which agent is the safest and most effective. Instead, we must examine alternative sources of evidence to help us select the optimum antihistamine for the treatment of CIU.
Evidence from pharmacologic studies indicates that newer agents demonstrate some anti-inflammatory activity, which could provide additional therapeutic benefit. However, these studies have largely been limited to in vitro tests and animal modeling and do not yet provide the means to differentiate agents.
Newer-generation antihistamines vary in their propensity to cause sedation and cognitive impairment, with cetirizine representing the most impairing of the class, as recognized by its sedating description by the US Food and Drug Administration. At recommended doses, fexofenadine, loratadine, and desloratadine have not been found to cause significant impairment and are labeled as nonsedating by the US Food and Drug Administration. However, patients with urticaria are known to take above-recommended doses51 and physicians occasionally prescribe off-label doses to achieve the desired level of symptom control. The risk of sedation caused by these 2 factors should be considered in practice when selecting an antihistamine.
Sedation and impairment affect QOL and manifest as decreased classroom learning ability and decreased work productivity.28 Furthermore, it has been suggested that cerebral H1-receptor blockade is associated with falls in the elderly and cognitive slowing, and is a contributing factor in traffic accidents.27
back to top
Conclusion
In controlled clinical studies of CIU, the second-generation H1-antihistamines have been proven to be clinically comparable to the most potent of the first-generation antihistamines, such as hydroxyzine. Clinical studies comparing these agents are few and have shown no statistically significant differences in efficacy.
If sedation and cognitive impairment are to be considered relevant to the choice of therapy for CIU because of their impact on QOL and safety, then newer-generation agents should be selected over older-generation antihistamines.37,40 Furthermore, of the new agents, those that are labeled nonsedating at recommended doses (fexofenadine, loratadine, and desloratadine) should be selected over cetirizine. However, in cases where the physician judges that a higher-than-recommended dose should be prescribed or when the patient is likely to take a higher dose, fexofenadine should be considered. In addition to its proven efficacy in treating the symptoms of CIU,31,33,34 fexofenadine is the only antihistamine that is nonsedating, even at doses 2 to 4 times above the recommended levels.

How idiopathic is chronic idiopathic urticaria (CIU)? With the fast pace of scientific and medical discovery, it is anomalous that diseases with no known cause remain. However, despite the fact that CIU is less well understood than many other diseases, recent findings have partially illuminated this condition's etiology. At least 2 subgroups of patients with CIU exist. One group is composed of 30% to 50% of patients with CIU with autoimmune chronic urticaria caused by autoantibodies against either the high-affinity immunoglobulin E (IgE) receptor FcεRI or, less commonly, IgE.1,2 Patients in this subgroup have an increased likelihood of thyroid autoimmunity; thyroid autoantibodies, Hashimoto thyroiditis, and Graves disease are recognized as being associated with CIU.3 Indeed, 27% of patients with CIU have high-titre antithyroglobulin, antithyroid peroxidase autoantibodies, or both, and 19% have abnormal thyroid function.3 However, the remaining 50% to 70% of patients with CIU are truly idiopathic, because there is no known cause for the disease.1 In keeping with the illusive nature of CIU, the prevalence of the disease has not been firmly established.4 Most recent estimates suggest that 15% to 20% of the US population experience at least one episode of urticaria in their lifetime, and up to 3% of the population are diagnosed with CIU.5,6 Interestingly, middle-aged women are more likely to experience the condition than other groups7; also, women are approximately 3 times more likely than men to acquire any autoimmune disease during their lifetime,⁸ supporting the notion that CIU is often an autoimmune disease.

Quality of Life
The impact of a disease extends beyond physical signs and symptoms; health-related quality of life (QOL) also should play a pivotal role in the evaluation of the effect of a disease or its treatment. This parameter is particularly pertinent to CIU, as evidenced by O'Donnell et al9 whose analysis of a disease-specific, purpose-designed questionnaire and the Nottingham Health Profile demonstrated that patients with chronic urticaria experienced considerable disability, handicap, and reduced QOL. Part 1 of the health profile showed that patients were restricted in areas of mobility, sleep, and energy and experienced pain, social isolation, and altered emotional reactions. Part 2 showed that patients experienced problems in relation to work, home management, social life, relationships, sex life, hobbies, and holidays. Interestingly, patients in this survey had almost identical scores for part 1 of the health profile as did patients with coronary artery disease; both groups experienced lack of energy, feelings of social isolation, and emotional upset.9 Perhaps because skin diseases are so visible and thus potentially stigmatizing, dermatology patients can be impacted significantly in terms of QOL; however, the effect of CIU appears to be particularly acute. Using the validated Dermatology Life Quality Index (DLQI), a survey of 170 consecutive patients had results that showed that patients with CIU experienced greater QOL impairment than outpatients with either psoriasis, acne, or vitiligo and experienced a comparable level of impairment to patients with severe atopic dermatitis.10 Because of CIU's devastating effect on health-related QOL and the discomfort of CIU, appropriate treatment selection is crucial. The ideal treatment for CIU would not only rid the patient of the wheals, edema, and pruritus that characterize the condition but also improve QOL. This review outlines the treatment options available, focusing on oral H1 antihistamines, and offers a means of differentiating this class of agent. 

Antihistamines in the Treatment of CIU
It is well established that elevated tissue levels of histamine are found in the skin of patients with different forms of chronic urticaria.11-13 Although more subclasses of histamine receptors have been identified, those initially isolated—H1 and H2—are involved in the cutaneous responses seen in urticaria. Specifically, the binding of histamine to the H1 receptor causes erythema (by vasodilation), edema (by increasing vascular permeability), and itching. The same responses, with the exception of itching, are caused by histamine binding to the H2 receptor. In 30% to 50% of patients diagnosed with CIU, histamine release from mast cells leads to wheal formation because of an autoimmune process. In contrast, patients with CIU without this autoimmune response experience the same effects of mast cell degranulation and subsequent release of histamine by a process yet to be elucidated. The sentinel involvement of histamine in CIU is, therefore, unequivocal; irrespective of etiology, the appropriate use of H1 antihistamines—which stabilize an active conformation of the H1 receptor and thus prevent activation by histamine—remains the basis of treatment.14 However, for patients unresponsive to conventional H1-antihistamine monotherapy, adjunctive treatments often are prescribed including a combination of H1 antihistamines (either 2 different newer-generation agents concurrently or a newer-generation agent plus a first-generation agent at night), H2 antihistamines, tricyclic antidepressants (principally doxepin), antileukotriene therapy, and intermittent pulses of corticosteroids.15 In the event of inadequate symptom control after these therapies have been explored, immunomodulatory agents such as cyclosporine have been used to treat patients refractory to conventional therapy.14 The method of activity for the adjunctive treatments is based on the following approaches: blocking H1 and H2 receptors, blocking nonhistamine mediators of urticaria, and blocking the cellular and inflammatory components of the urticarial reaction. In summary, because H1 antihistamines are first-line therapy for CIU, and for many patients remain the only option available, the selection of the optimal antihistamine is of vital importance. 

Selection of Antihistamines
The first antihistamine was developed in 1937; in the 1940s, phenbenzamine became the first commercially available antihistamine, followed by similar H1-receptor antagonists such as chlorpheniramine, brompheniramine, and diphenhydramine. Despite its relative antiquity, diphenhydramine remains the most widely used antihistamine in the United States.16 These first-generation H1-receptor antagonists, though effective in the treatment of urticaria and allergic rhinitis, were shown to cause undesired side effects for 2 distinct reasons: their lack of selectivity for the H1 receptor and their propensity to cross the blood-brain barrier and affect the central nervous system.17 As a result of their lack of selectivity, older-generation agents cause anticholinergic effects such as dry mouth, headache, and urinary retention.18-20 Furthermore, at supraclinical doses, some antihistamines are toxic¹⁶ and have been shown to cause sinus tachycardia.21 Children have been known to experience severe toxic reactions and even death following overdose of older-generation antihistamines because of the drug's lack of selectivity.22-25 Because older-generation antihistamines can bind to H1 receptors in the brain and histamine in the brain plays a role in central nervous system arousal and alertness, these agents also are associated with sedation and cognitive impairment (eg, impaired sensorimotor coordination and decreases in attention span, memory function, ability to process information, and psychomotor performance16,26,27). The binding of first-generation antihistamines to cerebral H1 receptors has been demonstrated in many studies employing objective psychometric tests and also by the relatively new technique of positron emission tomographic imaging.28-30

Newer-Generation Antihistamines
Newer-generation antihistamines were developed in the early 1980s with the aim of being more specific for the H1 receptor, as well as of overcoming the adverse events observed with older agents. As testament to achieving this goal, allergists agree that newer-generation antihistamines are preferred to first-generation agents because of their more favorable efficacy:safety ratio.16,18 Although there is no such formal consensus among dermatologists and those specifically treating CIU, it is likely the same logic would apply if equivalent efficacy between old and new antihistamines can be established for CIU. This review explores the newer-generation antihistamines available in the United States for the treatment of CIU: fexofenadine, loratadine, desloratadine, and cetirizine. An evidence-based analysis of the efficacy of these agents and an analysis of the therapeutic window of these antihistamines, with particular focus on their sedation and cognitive impairment potential, are emphasized (Table).

Efficacy of Newer-Generation Antihistamines
Numerous randomized double-blind clinical studies have demonstrated the efficacy of fexofenadine,31-34 loratadine,35,36 desloratadine,37,38 and cetirizine39,40 in relieving the symptoms of CIU. Fexofenadine—The safety and efficacy of various doses of fexofenadine at relieving the symptoms of CIU has been established in several large randomized controlled clinical trials. Two similar CIU studies investigated the efficacy of fexofenadine HCl using doses of 20, 60, 120, and 240 mg twice daily (BID). In both studies, doses of 60 mg or more BID were shown to reduce severity of pruritus, number of wheals, and interference with sleep and normal daily activities compared with placebo.33,34 Furthermore, studies in Japanese and Thai patients have indicated that the effectiveness of fexofenadine 60 mg BID is not limited by ethnicity or genotype.41,42 Although many studies have examined some QOL parameters as secondary endpoints as a component of efficacy studies, fexofenadine has been studied using the validated DLQI and Work Productivity and Activity Impairment questionnaires.⁴³ Two identically designed 4-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group trials examined the effects of 60 mg BID on patients aged 12 to 65 years with moderate to severe CIU. Fexofenadine treatment significantly improved overall DLQI score compared with placebo (P≤.0002), and also significantly increased work productivity (P≤.014). In addition, a trend toward increased classroom productivity and significant improvements in 5 of the 6 individual DLQI domains were observed.43 The efficacy and safety of a range of once-daily (QD) doses of fexofenadine have been evaluated in a large, multicenter, double-blind, placebo-controlled, parallel-group, dose-ranging study.31 Adults (N=222) were randomized to receive either fexofenadine HCl 60, 120, 180, or 240 mg QD or placebo QD for 6 weeks. The combined fexofenadine groups showed a significant reduction in mean total symptom score (pruritus score and number of wheals) compared with placebo (P=.0019). The study suggested that 180 mg QD is the optimal dose for the treatment of CIU because this dose alone significantly reduced the number of wheals compared with placebo (P=.0064) and significantly improved mean total symptom score consistently over the 6-week study period (P<.05).31 Supporting the efficacy of this once-daily dose, a recent double-blind placebo-controlled study of fexofenadine HCl 180 mg QD was shown to produce a beneficial effect on urticaria.32
Loratadine—The relative efficacy of loratadine and the first-generation antihistamine hydroxyzine has been established in a large 4-week (optional 12-week) trial comparing the 2 compounds with placebo in 172 patients with CIU. Patients were randomized to receive either: 10 mg loratadine QD and placebo BID; hydroxyzine 3 times daily; or placebo 3 times daily. As measured by all efficacy evaluations (physician and patient evaluations of the effect of treatment at each visit plus patient daily diary cards), loratadine and hydroxyzine were found to be more effective than placebo and clinically comparable to each other.35
In the only placebo-controlled comparative study between 2 newer-generation antihistamines in the treatment of CIU, Guerra et al44 showed that loratadine was more effective than cetirizine in some aspects of controlling the symptoms of CIU. In this double-blind study, 116 patients with CIU were randomly assigned loratadine 10 mg, cetirizine 10 mg, or placebo QD for 28 days. Both active drugs significantly reduced global clinical symptoms (P<.05), but loratadine was more rapid in developing its activity than cetirizine (P<.01 at day 3) and also appeared to be safer when the frequency of treatment-emergent side effects were compared.44
Desloratadine—Desloratadine is the major active metabolite of loratadine, which has been available in the United States since 2002 for the treatment of CIU. The efficacy of the drug has been evaluated in 2 major randomized controlled clinical trials.37,38
Ring et al37 reported that desloratadine exhibited superior efficacy compared with placebo in a multicenter, randomized, double-blind trial of 190 patients with a history of CIU. Patients were assigned to receive either desloratadine 5 mg QD or placebo QD for 6 weeks. The active treatment was superior to placebo at reducing pruritus and overall symptoms after the first dose and throughout the 6-week study.37 Similarly, therapeutic response and global CIU status, as well as QOL measures such as interference with sleep, were improved with desloratadine compared with placebo throughout the study period.37 Using the same dose (5 mg QD), a further 6-week placebo-controlled study of desloratadine indicated the effectiveness of this agent at relieving CIU symptoms.38 Over the study period, the mean total CIU symptom score was significantly improved compared with placebo, as were the individual scores of pruritus, number of hives, and the size of the largest hive. Interference with sleep was reduced and performance of daily activities was improved with desloratadine. These statistically and clinically significant improvements were seen within the first 24 hours of treatment and were sustained throughout the 6-week treatment period.38
Cetirizine—As with loratadine, cetirizine has been shown to be as effective as first-generation hydroxyzine at relieving the symptoms of CIU.40 For example, a 4-week, multicenter, randomized, double-blind, double-dummy trial investigated the efficacy and safety of cetirizine 10 mg QD and hydroxyzine 25 mg 3 times daily compared with placebo in patients with CIU. Patients in the cetirizine and hydroxyzine groups showed significant reductions during weeks 1, 2, 3, and 4 in the number and size of lesions and in the severity of pruritus compared with patients who received placebo. In addition, physician and patient evaluations at the end of week 4 revealed an improvement in urticarial symptoms for the cetirizine and hydroxyzine groups compared with the placebo group.40
All 4 newer-generation H1 antihistamines (fexofenadine, loratadine, desloratadine, and cetirizine) have been shown to be superior to placebo at treating the symptoms of CIU, and both loratadine and cetirizine have been proven to be as effective as first-generation hydroxyzine.35,40 Although no trials have evaluated fexofenadine and desloratadine compared with hydroxyzine, comparisons demonstrating equivalence have been made with their parent compounds (loratadine35 and terfenadine45).
There are few controlled studies in which newer-generation antihistamines have been directly compared, and there is no evidence-based data demonstrating statistical superiority of one second-generation agent over another in the treatment of CIU. For example, although a recent trial compared the efficacy of cetirizine with fexofenadine, the results are weakened by the study design. Patients with CIU were randomized to either cetirizine 10 mg (n=52) or fexofenadine 180 mg (n=45); at 28 days, 51.9% (27) and 4.4% (2) of cetirizine and fexofenadine patients, respectively, were symptom free (P=.00001), while partial improvement was experienced by 36.5% (19) of cetirizine patients and 42.2% (19) of fexofenadine patients.46 However, there was no control group, baseline symptom severity data were not provided, and the authors did not describe how the patients’ symptoms were assessed.46 Therefore, a definitive assessment of the relative efficacy of newer-generation antihistamines cannot be achieved by reviewing published trials alone.Anti-inflammatory Properties
Due to the absence of well-designed placebo-controlled comparisons of newer-generation antihistamines, other properties have been examined to aid treatment comparisons. For example, it has been suggested that some H1-receptor antagonists may achieve anti-inflammatory effects in a clinical context, which could prove advantageous in the treatment of CIU because the disease is characterized by tissue inflammation.47
To investigate the anti-inflammatory activity of fexofenadine, an immunohistochemical evaluation of the agent was undertaken in patients with CIU.48 Twenty patients received fexofenadine HCl 180 mg QD for 4 weeks; the expression of adhesion molecules, mast cell proteases, and proinflammatory cytokines were evaluated before and after treatment, as were the patients’ assessments of urticarial symptoms. After treatment with fexofenadine, significant decreases in the expression of endothelial leukocyte adhesion molecule-1 (P=.02), vascular cell adhesion molecule-1 (P=.04), and tryptase (P=.04) were observed, confirming the hypothesis that fexofenadine has some anti-inflammatory properties.
This study in humans must be put into context with the numerous in vitro, ex vivo, and animal studies that have been conducted in this area. A review of such data suggests that all newer-generation antihistamines inhibit the release or generation of multiple inflammatory mediators, including IL-4, IL-6, IL-8, IL-13, prostaglandin D3, leukotriene C, tryptase, histamine, and the tumor necrosis factor α­induced chemokine regulated upon activation normal T cell expressed and secreted, in addition to eosinophil chemotaxis and adhesion molecules.47 For example, both loratadine and desloratadine (10 μmol/L) significantly inhibited the expression of intercellular adhesion molecule-1 and class II HLA antigen (HLA-DE) in nasal epithelial cells in vitro.49 However, many of these anti-inflammatory effects have only been observed at high drug concentrations.47 For example, an in vitro study of cetirizine assessing the inhibition of IL-5­ dependent eosinophil survival revealed a concentration of 100 μmol/L was required to achieve significant inhibition—much higher than that used clinically.47,50
Clearly, if clinical anti-inflammatory effects necessitate doses higher than those recommended for allergic diseases, drugs that can be used at higher doses without causing unwanted side effects such as sedation and cognitive impairment may be of the greatest utility in the treatment of CIU. This is a particularly pertinent point because patients with CIU may be prescribed much higher doses than recommended to manage symptoms effectively.17
The Therapeutic Window—Because of the lack of rigorously designed clinical trials comparing the efficacy of second-generation antihistamines and the putative anti-inflammatory activities of these agents that may occur at higher-than-recommended dosing levels, the relative safety of agents may direct the selection of the optimum antihistamine for the treatment of CIU. Ideally, an agent would be effective at a wide range of doses without causing unwanted side effects. This is because a wide therapeutic window permits the physician to optimize treatment to the individual. The safety of the newer-generation antihistamines has been assessed in numerous clinical trials, usually as secondary analyses to efficacy parameters; indeed, all of the efficacy studies described here indicated a good safety and tolerability profile for each of the antihistamines.
Clinical trials, however, do not always reflect the reality of clinical practice. Patients taking antihistamines frequently overcomply with their medication,51 particularly if they do not experience immediate relief. Furthermore, as previously mentioned, it is occasionally necessary for dermatologists to prescribe high doses of antihistamines for patients who do not respond to standard-dose first-line therapy.17 Thus, it is valid to examine the safety of the different antihistamines at high doses to obtain a true picture of how drugs may be affecting patients.
Sedation and Impairment—A number of studies using objective psychometric tests have indicated that newer-generation antihistamines generally have better sedative profiles than first-generation agents; however, at higher doses, sedation and impairment become evident.
Two meta-analyses of published data on antihistamines report that newer drugs had lower impairment/nonimpairment ratios than older agents.28,29 That is, proportionally more studies indicated nonimpairment versus impairment with the newer agents compared with their predecessors. However, the same meta-analyses revealed that both loratadine and cetirizine were associated with sedation/impairment in a number of tests, often when they were used at higher-than-recommended doses. In contrast, fexofenadine, even at doses of up to 360 mg, was not associated with any sedation or impairment and had an impairment:nonimpairment ratio of zero.28,29
A study by Mann et al52 corroborates the finding that different newer-generation antihistamines have the potential to cause sedation, with fexofenadine being the least likely of those studied to do so. This prescription-event monitoring study showed that the odds ratios for the incidence of sedation were 0.63 for fexofenadine and 5.53 for cetirizine compared with loratadine.52 Higher-than-recommended doses of loratadine53 and desloratadine54 also can cause sedation.
A recent approach to the question of blood-brain barrier penetration involves the use of positron emission tomography. This technique has been used to study the binding of antihistamines to cerebral H1 receptors. Tashiro et al30 used positron emission tomographic imaging to compare fexofenadine with cetirizine by examining relative H1 receptor occupancy in the brain. Quantitative analysis showed that fexofenadine did not occupy H1 receptors in the cerebral cortex, while cetirizine occupied between 20% to 50% of the H1 receptors, depending on the brain region.30 These findings support evidence from comparative trials that indicate that although cetirizine is less sedating than older antihistamines, it causes more sedation and impairment of performance than other second-generation antihistamines. As a result, the US Food and Drug Administration has classified cetirizine as sedating rather than nonsedating, and the product carries the full sedation precaution.
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Comment
Antihistamines can be used effectively to control the symptoms of CIU; newer-generation antihistamines have been shown to be as effective as their predecessors at relieving patients of their symptoms35,40 and improving their QOL.43 However, there is a paucity of well-designed placebo-controlled comparative clinical trials; the data available indicate that agents are effective and safe, but they do not provide a means to assess which agent is the safest and most effective. Instead, we must examine alternative sources of evidence to help us select the optimum antihistamine for the treatment of CIU.
Evidence from pharmacologic studies indicates that newer agents demonstrate some anti-inflammatory activity, which could provide additional therapeutic benefit. However, these studies have largely been limited to in vitro tests and animal modeling and do not yet provide the means to differentiate agents.
Newer-generation antihistamines vary in their propensity to cause sedation and cognitive impairment, with cetirizine representing the most impairing of the class, as recognized by its sedating description by the US Food and Drug Administration. At recommended doses, fexofenadine, loratadine, and desloratadine have not been found to cause significant impairment and are labeled as nonsedating by the US Food and Drug Administration. However, patients with urticaria are known to take above-recommended doses51 and physicians occasionally prescribe off-label doses to achieve the desired level of symptom control. The risk of sedation caused by these 2 factors should be considered in practice when selecting an antihistamine.
Sedation and impairment affect QOL and manifest as decreased classroom learning ability and decreased work productivity.28 Furthermore, it has been suggested that cerebral H1-receptor blockade is associated with falls in the elderly and cognitive slowing, and is a contributing factor in traffic accidents.27
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Conclusion
In controlled clinical studies of CIU, the second-generation H1-antihistamines have been proven to be clinically comparable to the most potent of the first-generation antihistamines, such as hydroxyzine. Clinical studies comparing these agents are few and have shown no statistically significant differences in efficacy.
If sedation and cognitive impairment are to be considered relevant to the choice of therapy for CIU because of their impact on QOL and safety, then newer-generation agents should be selected over older-generation antihistamines.37,40 Furthermore, of the new agents, those that are labeled nonsedating at recommended doses (fexofenadine, loratadine, and desloratadine) should be selected over cetirizine. However, in cases where the physician judges that a higher-than-recommended dose should be prescribed or when the patient is likely to take a higher dose, fexofenadine should be considered. In addition to its proven efficacy in treating the symptoms of CIU,31,33,34 fexofenadine is the only antihistamine that is nonsedating, even at doses 2 to 4 times above the recommended levels.

The October 2001 domestic anthrax attacks affected 22 people, resulting in 5 fatalities. The added global terrorist threats have created an increasing need for homeland protection, as well as protection of our widely deployed forces battling terrorism. It is now relevant for physicians to be familiar with both clinical anthrax and adverse vaccine-related events associated with the resumption of the anthrax vaccine program. Dermatologists played a lead role in the initial response to the anthrax attack. We must be the lead providers most familiar with the cutaneous reactions that may be seen with the preventive vaccination. This article reviews the latest recommended evaluation and management of anthrax vaccine adverse events.

Case Reports Patient 1—A 36-year-old white male active duty military fighter pilot developed recurrent, localized urticaria after receiving his sixth anthrax vaccination (Figure 1). Results of a skin biopsy showed a superficial perivascular dermatitis with eosinophils consistent with urticaria. The urticaria continues to recur 21/2 years after his last vaccination and remains localized to the vaccinated arm.

Patient 2—A 33-year-old black male military member developed erythema multiforme one day after receiving his fifth anthrax vaccination. He had been treated for pharyngitis with a 10-day course of oral penicillin, which had been completed 2 days prior to receiving the vaccination. Target lesions were present on both arms and hands but were more prominent on the arm that received the vaccination (Figure 2). Results of a skin biopsy revealed a superficial perivascular and interface lymphocytic dermatitis, with vacuolar changes along the dermoepidermal junction compatible with erythema multiforme.

Patient 3—A 28-year-old white male military member presented with a pruritic rash that had developed on his face approximately 12 hours after receiving his fifth anthrax vaccination. The rash had spread to his torso (Figure 3) and lower extremities. Results of a punch biopsy revealed a superficial and deep lymphocytic infiltrate with interface changes and some extravasated red blood cells, findings felt to be consistent with an erythema multiforme reaction (Figure 4). The patient was treated with a 2-week course of prednisone and intramuscular diphenhydramine (Benadryl®), and clearing of symptoms was noted within 10 days.

Comment

The threat of anthrax is deadly and real, as shown by the domestic attacks via the US Postal Service in October 2001. In all, there were 11 confirmed cases of inhalation anthrax, resulting in 5 fatalities. In addition, there were 7 confirmed cases and 4 suspected cases of cutaneous anthrax. Twenty of the 22 cases were unquestionably linked to mail contaminated with a single strain of Bacillus anthracis.1 Anthrax is easy and cheap to produce and can be stored for prolonged periods, with spores survivable for decades in ambient conditions.2 The spores are resistant to dryness, heat, UV light, gamma radiation, and many disinfectants.3 In addition, anthrax is odorless, colorless, tasteless, and difficult to detect, thus making it a likely choice for future biological attacks. After the first gulf war, Iraq admitted to producing and deploying weaponized anthrax in missiles.4 The Sverdlovsk anthrax outbreak in the former Soviet Union occurred after the accidental release of aerosolized anthrax spores from a bioweapons facility and resulted in as many as 250 cases with 100 deaths.2 Fortunately, we have a vaccine that has been judged safe and effective by the US Food and Drug Administration (FDA), Centers for Disease Control and Prevention, and National Academy of Sciences. Protecting the health of US military forces who defend our vital interests is a national obligation.5 The trade-off for force protection of our military personnel involves a small incidence of vaccine-related adverse events (AEs), the most common being local type injection site reactions or skin reactions.

Natural cutaneous anthrax manifests within a few days as a painless, pruritic papule that progresses to a blister and evolves to a painless ulcer, with a black central eschar and surrounding local edema. In contrast, vaccine-related events manifest differently, and the vaccine cannot cause clinical anthrax infections. An algorithm for the evaluation of suspected cutaneous anthrax has been published by the American Academy of Dermatology Ad Hoc Task Force on Bioterrorism.6 Additional guidelines for clinical and laboratory diagnoses, specimen handling, and postexposure prophylaxis are available from the US Centers for Disease Control and Prevention.7

The vaccine itself is made from a noninfectious, cell-free sterile filtrate of an attenuated, nonencapsulated, nonproteolytic strain of B anthracis.8 It is considered an inactivated vaccine and is unable to cause infection. The anthrax vaccine has been approved by the FDA since 1970 and is safely administered to veterinarians, laboratory workers, woolen mill workers, and livestock handlers.8 In 1997, it was mandated that all US military personnel receive it. Full protection requires a schedule of 6 injections over 18 months (specifically, at 0, 2, and 4 weeks and 6, 12, and 18 months), with an annual booster thereafter. In the event of anthrax exposure, the vaccine also can be offered as postexposure prophylaxis with 3 doses at 2-week intervals, along with postexposure antibiotics.2 Contraindications to the anthrax vaccine include hypersensitivity reaction to a prior dose or vaccine component, human immunodeficiency virus positivity or immune suppression (active corticosteroid or other immunosuppressive treatment), any active infection or acute illness, pregnancy (confirmed or suspected), and age younger than 18 years or older than 65 years. 

Efficacy and Safety

The vaccine's efficacy against aerosolized anthrax was shown in studies on nonhuman primates. Sixty-two (95%) of the 65 primates vaccinated with the anthrax vaccine adsorbed (AVA) survived a lethal aerosol challenge, whereas all 18 unvaccinated controls died.8 In actively monitored studies on the safety of AVA, mild local reactions occurred in 3% to 20% of doses, moderate reactions in 1% to 3% of doses, and severe reactions in less than 1% of doses.8 Acute systemic reactions were reported in 0.06% of doses and consisted of transient symptoms of fever, chills, nausea, and general body aches.8

The current system for reporting AEs is the Vaccine Adverse Event Reporting System (VAERS), and the FDA reviews 100% of these reports. In addition, a US Department of Defense directive requires its military providers to initiate a report for any event following AVA that results in hospitalization, any loss of duty of more than 24 hours, or for suspected vaccine contamination.9 Reporting of other reactions suspected because of vaccination is encouraged, especially those that are clinically significant or unusual. The form can be obtained on the Web at http://www.vaers.org or via telephone at 800-822-7967. Electronic reporting is available on the Web at http://secure.vaers.org/VaersDataEntryintro.htm. The VAERS is a passive surveillance system, and determining causal associations between vaccines and AEs is not always possible.10 Other concurrent infections or exposures may precipitate a given symptom that may simply coincide with the receipt of a vaccine.11 For example, patient 2 may have had vaccine-associated erythema multiforme but because he had recently completed a course of penicillin, we cannot exclude the possibility of a concurrent antibiotic association.

The Anthrax Vaccine Expert Committee reviewed 602 VAERS reports filed from 1998 through 1999.12 Nearly one half of reports noted a local injection site AE, 33% of which were noted to be moderate to large. A subcutaneous nodule was cited in 5.3% of reports. Although three fourths of reports noted a "systemic" AE, these covered a broad spectrum, with 34 types cited at a frequency of more than 1%. The most common AEs, in declining order of incidence, were flulike symptoms, 20.8%; malaise, 13.3%; rash, 14.2%; arthralgia, 12%; headache, 10.1%; with the remainder of AEs all affecting fewer than 10% of patients. Among the reported 45 total "serious or medically important AEs," one report of each of the following was noted: systemic lupus erythematosus, angioedema, anaphylactoid reaction, and toxic epidermal necrolysis. None of these AEs were judged to be causally (defined as likely, certain, or probable) related to the vaccine itself.12 According to Friedlander et al,8 the "FDA continues to view the anthrax vaccine as safe and effective for individuals at risk of exposure to anthrax."

Management of Adverse Events

Adverse reactions after vaccination can be divided into local and systemic.

Cutaneous Reactions—The cutaneous manifestations and the latest recommendations from the Walter Reed National Vaccine healthcare center network9 are summarized partially in Tables 1 and 2.

Local reactions involve the injection site or have contiguous spread and are graded based on the measured size of the local redness or swelling (Table 1). Most local anthrax vaccine reactions require no treatment and resolve within 72 hours, though topical or oral steroids and oral antihistamines can be used to help manage symptoms. Unless the local reaction is very large or complicated, the patient can usually proceed with subsequent doses. Although some of these reactions may mimic cellulitis, antibiotic therapy for postvaccination inflammation is not warranted. Allergy consultation is recommended for a large or complicated reaction, especially if this occurs after the second dose. In this instance, the patient may be immune (a hyperresponder) and may not require further series (with the exception of the yearly booster).9 When a significant local type reaction has occurred, pretreatment to help prevent future large local reactions is indicated.

Systemic Reactions—These commonly include flulike symptoms, such as fever, anorexia, nausea, arthralgia, myalgia, or malaise. Treatment of mild to moderate systemic events is symptomatic (Table 2). Pretreatment also may be given with the next vaccine in patients who have had these symptoms on prior AVA vaccinations. If symptoms are clinically consistent with serum sickness or are severe and prolonged, the patient may benefit from a short course of oral prednisone. Vaccine-related AEs may warrant temporary delay from the schedule. When resumed, this does not require starting over but rather simply continuing from the last dose.9

For a generalized maculopapular rash or target lesions, a skin biopsy should be performed, especially if the rash is suggestive of early erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis. In these cases, temporary exemption from further vaccinations and VAERS reporting are indicated. The possibility exists that additional doses may result in a more serious skin reaction and should be given with caution only after expert evaluation and consideration of the risk:benefit ratio. The dermatologist should provide a clinical histopathologic diagnosis to help the allergist or expert in the vaccination program decide the best course for continuation or exemption from the full anthrax series. These cases may warrant permanent exemption from further vaccination series. No apparent safety data for challenge dosing or desensitization in these potentially life-threatening skin reactions exist. In patient 2 with erythema multiforme, further vaccinations for anthrax were waived permanently. Similarly, deferral from further anthrax vaccinations was recommended in patient 3.

In those cases of severe urticaria or angioedema, temporary exemption may be granted while requesting allergy consultation. Additional doses should be given with caution only after expert evaluation and consideration of the risk:benefit ratio. Permanent exemption may be required for those with anaphylaxis or sudden onset angioedema. In patient 1 with recurrent localized urticaria, the allergist recommended that a formal skin-prick test to future vaccine lots be performed before he received any further vaccine in the series. Although this local allergic-type reaction may be due to some component of the vaccine, we are unable to define the specific cause at this time. This is a rather unusual manifestation, with recurrence of the urticaria still persisting 21/2 years later and restricted only to the vaccinated arm. 

Conclusion

There are ongoing studies to evaluate whether a reduced number of anthrax vaccinations will provide the same immunity. In addition, other ongoing studies are comparing intramuscular administration versus the current usual subcutaneous route. Preliminary reports have shown that local reactions are less common in patients who received the vaccine via the intramuscular route than in those who received the vaccine via the subcutaneous route.13 This change in route of administration could reduce the number of adverse cutaneous reactions in the future. For further expert advice or clinical consultations, contact the Walter Reed National Vaccine Healthcare Center via telephone: 202-782-0411; fax: 202-782-4658; or e-mail: [email protected].

Since the domestic anthrax attacks in October 2001 and in the presence of continued worldwide threats to our armed forces, force protection remains a top priority. As dermatologists, we should be familiar with the current anthrax vaccine
program and be able to recognize and treat anthrax vaccine–related AEs.

The October 2001 domestic anthrax attacks affected 22 people, resulting in 5 fatalities. The added global terrorist threats have created an increasing need for homeland protection, as well as protection of our widely deployed forces battling terrorism. It is now relevant for physicians to be familiar with both clinical anthrax and adverse vaccine-related events associated with the resumption of the anthrax vaccine program. Dermatologists played a lead role in the initial response to the anthrax attack. We must be the lead providers most familiar with the cutaneous reactions that may be seen with the preventive vaccination. This article reviews the latest recommended evaluation and management of anthrax vaccine adverse events.

Case Reports Patient 1—A 36-year-old white male active duty military fighter pilot developed recurrent, localized urticaria after receiving his sixth anthrax vaccination (Figure 1). Results of a skin biopsy showed a superficial perivascular dermatitis with eosinophils consistent with urticaria. The urticaria continues to recur 21/2 years after his last vaccination and remains localized to the vaccinated arm.

Patient 2—A 33-year-old black male military member developed erythema multiforme one day after receiving his fifth anthrax vaccination. He had been treated for pharyngitis with a 10-day course of oral penicillin, which had been completed 2 days prior to receiving the vaccination. Target lesions were present on both arms and hands but were more prominent on the arm that received the vaccination (Figure 2). Results of a skin biopsy revealed a superficial perivascular and interface lymphocytic dermatitis, with vacuolar changes along the dermoepidermal junction compatible with erythema multiforme.

Patient 3—A 28-year-old white male military member presented with a pruritic rash that had developed on his face approximately 12 hours after receiving his fifth anthrax vaccination. The rash had spread to his torso (Figure 3) and lower extremities. Results of a punch biopsy revealed a superficial and deep lymphocytic infiltrate with interface changes and some extravasated red blood cells, findings felt to be consistent with an erythema multiforme reaction (Figure 4). The patient was treated with a 2-week course of prednisone and intramuscular diphenhydramine (Benadryl®), and clearing of symptoms was noted within 10 days.

Comment

The threat of anthrax is deadly and real, as shown by the domestic attacks via the US Postal Service in October 2001. In all, there were 11 confirmed cases of inhalation anthrax, resulting in 5 fatalities. In addition, there were 7 confirmed cases and 4 suspected cases of cutaneous anthrax. Twenty of the 22 cases were unquestionably linked to mail contaminated with a single strain of Bacillus anthracis.1 Anthrax is easy and cheap to produce and can be stored for prolonged periods, with spores survivable for decades in ambient conditions.2 The spores are resistant to dryness, heat, UV light, gamma radiation, and many disinfectants.3 In addition, anthrax is odorless, colorless, tasteless, and difficult to detect, thus making it a likely choice for future biological attacks. After the first gulf war, Iraq admitted to producing and deploying weaponized anthrax in missiles.4 The Sverdlovsk anthrax outbreak in the former Soviet Union occurred after the accidental release of aerosolized anthrax spores from a bioweapons facility and resulted in as many as 250 cases with 100 deaths.2 Fortunately, we have a vaccine that has been judged safe and effective by the US Food and Drug Administration (FDA), Centers for Disease Control and Prevention, and National Academy of Sciences. Protecting the health of US military forces who defend our vital interests is a national obligation.5 The trade-off for force protection of our military personnel involves a small incidence of vaccine-related adverse events (AEs), the most common being local type injection site reactions or skin reactions.

Natural cutaneous anthrax manifests within a few days as a painless, pruritic papule that progresses to a blister and evolves to a painless ulcer, with a black central eschar and surrounding local edema. In contrast, vaccine-related events manifest differently, and the vaccine cannot cause clinical anthrax infections. An algorithm for the evaluation of suspected cutaneous anthrax has been published by the American Academy of Dermatology Ad Hoc Task Force on Bioterrorism.6 Additional guidelines for clinical and laboratory diagnoses, specimen handling, and postexposure prophylaxis are available from the US Centers for Disease Control and Prevention.7

The vaccine itself is made from a noninfectious, cell-free sterile filtrate of an attenuated, nonencapsulated, nonproteolytic strain of B anthracis.8 It is considered an inactivated vaccine and is unable to cause infection. The anthrax vaccine has been approved by the FDA since 1970 and is safely administered to veterinarians, laboratory workers, woolen mill workers, and livestock handlers.8 In 1997, it was mandated that all US military personnel receive it. Full protection requires a schedule of 6 injections over 18 months (specifically, at 0, 2, and 4 weeks and 6, 12, and 18 months), with an annual booster thereafter. In the event of anthrax exposure, the vaccine also can be offered as postexposure prophylaxis with 3 doses at 2-week intervals, along with postexposure antibiotics.2 Contraindications to the anthrax vaccine include hypersensitivity reaction to a prior dose or vaccine component, human immunodeficiency virus positivity or immune suppression (active corticosteroid or other immunosuppressive treatment), any active infection or acute illness, pregnancy (confirmed or suspected), and age younger than 18 years or older than 65 years. 

Efficacy and Safety

The vaccine's efficacy against aerosolized anthrax was shown in studies on nonhuman primates. Sixty-two (95%) of the 65 primates vaccinated with the anthrax vaccine adsorbed (AVA) survived a lethal aerosol challenge, whereas all 18 unvaccinated controls died.8 In actively monitored studies on the safety of AVA, mild local reactions occurred in 3% to 20% of doses, moderate reactions in 1% to 3% of doses, and severe reactions in less than 1% of doses.8 Acute systemic reactions were reported in 0.06% of doses and consisted of transient symptoms of fever, chills, nausea, and general body aches.8

The current system for reporting AEs is the Vaccine Adverse Event Reporting System (VAERS), and the FDA reviews 100% of these reports. In addition, a US Department of Defense directive requires its military providers to initiate a report for any event following AVA that results in hospitalization, any loss of duty of more than 24 hours, or for suspected vaccine contamination.9 Reporting of other reactions suspected because of vaccination is encouraged, especially those that are clinically significant or unusual. The form can be obtained on the Web at http://www.vaers.org or via telephone at 800-822-7967. Electronic reporting is available on the Web at http://secure.vaers.org/VaersDataEntryintro.htm. The VAERS is a passive surveillance system, and determining causal associations between vaccines and AEs is not always possible.10 Other concurrent infections or exposures may precipitate a given symptom that may simply coincide with the receipt of a vaccine.11 For example, patient 2 may have had vaccine-associated erythema multiforme but because he had recently completed a course of penicillin, we cannot exclude the possibility of a concurrent antibiotic association.

The Anthrax Vaccine Expert Committee reviewed 602 VAERS reports filed from 1998 through 1999.12 Nearly one half of reports noted a local injection site AE, 33% of which were noted to be moderate to large. A subcutaneous nodule was cited in 5.3% of reports. Although three fourths of reports noted a "systemic" AE, these covered a broad spectrum, with 34 types cited at a frequency of more than 1%. The most common AEs, in declining order of incidence, were flulike symptoms, 20.8%; malaise, 13.3%; rash, 14.2%; arthralgia, 12%; headache, 10.1%; with the remainder of AEs all affecting fewer than 10% of patients. Among the reported 45 total "serious or medically important AEs," one report of each of the following was noted: systemic lupus erythematosus, angioedema, anaphylactoid reaction, and toxic epidermal necrolysis. None of these AEs were judged to be causally (defined as likely, certain, or probable) related to the vaccine itself.12 According to Friedlander et al,8 the "FDA continues to view the anthrax vaccine as safe and effective for individuals at risk of exposure to anthrax."

Management of Adverse Events

Adverse reactions after vaccination can be divided into local and systemic.

Cutaneous Reactions—The cutaneous manifestations and the latest recommendations from the Walter Reed National Vaccine healthcare center network9 are summarized partially in Tables 1 and 2.

Local reactions involve the injection site or have contiguous spread and are graded based on the measured size of the local redness or swelling (Table 1). Most local anthrax vaccine reactions require no treatment and resolve within 72 hours, though topical or oral steroids and oral antihistamines can be used to help manage symptoms. Unless the local reaction is very large or complicated, the patient can usually proceed with subsequent doses. Although some of these reactions may mimic cellulitis, antibiotic therapy for postvaccination inflammation is not warranted. Allergy consultation is recommended for a large or complicated reaction, especially if this occurs after the second dose. In this instance, the patient may be immune (a hyperresponder) and may not require further series (with the exception of the yearly booster).9 When a significant local type reaction has occurred, pretreatment to help prevent future large local reactions is indicated.

Systemic Reactions—These commonly include flulike symptoms, such as fever, anorexia, nausea, arthralgia, myalgia, or malaise. Treatment of mild to moderate systemic events is symptomatic (Table 2). Pretreatment also may be given with the next vaccine in patients who have had these symptoms on prior AVA vaccinations. If symptoms are clinically consistent with serum sickness or are severe and prolonged, the patient may benefit from a short course of oral prednisone. Vaccine-related AEs may warrant temporary delay from the schedule. When resumed, this does not require starting over but rather simply continuing from the last dose.9

For a generalized maculopapular rash or target lesions, a skin biopsy should be performed, especially if the rash is suggestive of early erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis. In these cases, temporary exemption from further vaccinations and VAERS reporting are indicated. The possibility exists that additional doses may result in a more serious skin reaction and should be given with caution only after expert evaluation and consideration of the risk:benefit ratio. The dermatologist should provide a clinical histopathologic diagnosis to help the allergist or expert in the vaccination program decide the best course for continuation or exemption from the full anthrax series. These cases may warrant permanent exemption from further vaccination series. No apparent safety data for challenge dosing or desensitization in these potentially life-threatening skin reactions exist. In patient 2 with erythema multiforme, further vaccinations for anthrax were waived permanently. Similarly, deferral from further anthrax vaccinations was recommended in patient 3.

In those cases of severe urticaria or angioedema, temporary exemption may be granted while requesting allergy consultation. Additional doses should be given with caution only after expert evaluation and consideration of the risk:benefit ratio. Permanent exemption may be required for those with anaphylaxis or sudden onset angioedema. In patient 1 with recurrent localized urticaria, the allergist recommended that a formal skin-prick test to future vaccine lots be performed before he received any further vaccine in the series. Although this local allergic-type reaction may be due to some component of the vaccine, we are unable to define the specific cause at this time. This is a rather unusual manifestation, with recurrence of the urticaria still persisting 21/2 years later and restricted only to the vaccinated arm. 

Conclusion

There are ongoing studies to evaluate whether a reduced number of anthrax vaccinations will provide the same immunity. In addition, other ongoing studies are comparing intramuscular administration versus the current usual subcutaneous route. Preliminary reports have shown that local reactions are less common in patients who received the vaccine via the intramuscular route than in those who received the vaccine via the subcutaneous route.13 This change in route of administration could reduce the number of adverse cutaneous reactions in the future. For further expert advice or clinical consultations, contact the Walter Reed National Vaccine Healthcare Center via telephone: 202-782-0411; fax: 202-782-4658; or e-mail: [email protected].

Since the domestic anthrax attacks in October 2001 and in the presence of continued worldwide threats to our armed forces, force protection remains a top priority. As dermatologists, we should be familiar with the current anthrax vaccine
program and be able to recognize and treat anthrax vaccine–related AEs.

The October 2001 domestic anthrax attacks affected 22 people, resulting in 5 fatalities. The added global terrorist threats have created an increasing need for homeland protection, as well as protection of our widely deployed forces battling terrorism. It is now relevant for physicians to be familiar with both clinical anthrax and adverse vaccine-related events associated with the resumption of the anthrax vaccine program. Dermatologists played a lead role in the initial response to the anthrax attack. We must be the lead providers most familiar with the cutaneous reactions that may be seen with the preventive vaccination. This article reviews the latest recommended evaluation and management of anthrax vaccine adverse events.

Case Reports Patient 1—A 36-year-old white male active duty military fighter pilot developed recurrent, localized urticaria after receiving his sixth anthrax vaccination (Figure 1). Results of a skin biopsy showed a superficial perivascular dermatitis with eosinophils consistent with urticaria. The urticaria continues to recur 21/2 years after his last vaccination and remains localized to the vaccinated arm.

Patient 2—A 33-year-old black male military member developed erythema multiforme one day after receiving his fifth anthrax vaccination. He had been treated for pharyngitis with a 10-day course of oral penicillin, which had been completed 2 days prior to receiving the vaccination. Target lesions were present on both arms and hands but were more prominent on the arm that received the vaccination (Figure 2). Results of a skin biopsy revealed a superficial perivascular and interface lymphocytic dermatitis, with vacuolar changes along the dermoepidermal junction compatible with erythema multiforme.

Patient 3—A 28-year-old white male military member presented with a pruritic rash that had developed on his face approximately 12 hours after receiving his fifth anthrax vaccination. The rash had spread to his torso (Figure 3) and lower extremities. Results of a punch biopsy revealed a superficial and deep lymphocytic infiltrate with interface changes and some extravasated red blood cells, findings felt to be consistent with an erythema multiforme reaction (Figure 4). The patient was treated with a 2-week course of prednisone and intramuscular diphenhydramine (Benadryl®), and clearing of symptoms was noted within 10 days.

Comment

The threat of anthrax is deadly and real, as shown by the domestic attacks via the US Postal Service in October 2001. In all, there were 11 confirmed cases of inhalation anthrax, resulting in 5 fatalities. In addition, there were 7 confirmed cases and 4 suspected cases of cutaneous anthrax. Twenty of the 22 cases were unquestionably linked to mail contaminated with a single strain of Bacillus anthracis.1 Anthrax is easy and cheap to produce and can be stored for prolonged periods, with spores survivable for decades in ambient conditions.2 The spores are resistant to dryness, heat, UV light, gamma radiation, and many disinfectants.3 In addition, anthrax is odorless, colorless, tasteless, and difficult to detect, thus making it a likely choice for future biological attacks. After the first gulf war, Iraq admitted to producing and deploying weaponized anthrax in missiles.4 The Sverdlovsk anthrax outbreak in the former Soviet Union occurred after the accidental release of aerosolized anthrax spores from a bioweapons facility and resulted in as many as 250 cases with 100 deaths.2 Fortunately, we have a vaccine that has been judged safe and effective by the US Food and Drug Administration (FDA), Centers for Disease Control and Prevention, and National Academy of Sciences. Protecting the health of US military forces who defend our vital interests is a national obligation.5 The trade-off for force protection of our military personnel involves a small incidence of vaccine-related adverse events (AEs), the most common being local type injection site reactions or skin reactions.

Natural cutaneous anthrax manifests within a few days as a painless, pruritic papule that progresses to a blister and evolves to a painless ulcer, with a black central eschar and surrounding local edema. In contrast, vaccine-related events manifest differently, and the vaccine cannot cause clinical anthrax infections. An algorithm for the evaluation of suspected cutaneous anthrax has been published by the American Academy of Dermatology Ad Hoc Task Force on Bioterrorism.6 Additional guidelines for clinical and laboratory diagnoses, specimen handling, and postexposure prophylaxis are available from the US Centers for Disease Control and Prevention.7

The vaccine itself is made from a noninfectious, cell-free sterile filtrate of an attenuated, nonencapsulated, nonproteolytic strain of B anthracis.8 It is considered an inactivated vaccine and is unable to cause infection. The anthrax vaccine has been approved by the FDA since 1970 and is safely administered to veterinarians, laboratory workers, woolen mill workers, and livestock handlers.8 In 1997, it was mandated that all US military personnel receive it. Full protection requires a schedule of 6 injections over 18 months (specifically, at 0, 2, and 4 weeks and 6, 12, and 18 months), with an annual booster thereafter. In the event of anthrax exposure, the vaccine also can be offered as postexposure prophylaxis with 3 doses at 2-week intervals, along with postexposure antibiotics.2 Contraindications to the anthrax vaccine include hypersensitivity reaction to a prior dose or vaccine component, human immunodeficiency virus positivity or immune suppression (active corticosteroid or other immunosuppressive treatment), any active infection or acute illness, pregnancy (confirmed or suspected), and age younger than 18 years or older than 65 years. 

Efficacy and Safety

The vaccine's efficacy against aerosolized anthrax was shown in studies on nonhuman primates. Sixty-two (95%) of the 65 primates vaccinated with the anthrax vaccine adsorbed (AVA) survived a lethal aerosol challenge, whereas all 18 unvaccinated controls died.8 In actively monitored studies on the safety of AVA, mild local reactions occurred in 3% to 20% of doses, moderate reactions in 1% to 3% of doses, and severe reactions in less than 1% of doses.8 Acute systemic reactions were reported in 0.06% of doses and consisted of transient symptoms of fever, chills, nausea, and general body aches.8

The current system for reporting AEs is the Vaccine Adverse Event Reporting System (VAERS), and the FDA reviews 100% of these reports. In addition, a US Department of Defense directive requires its military providers to initiate a report for any event following AVA that results in hospitalization, any loss of duty of more than 24 hours, or for suspected vaccine contamination.9 Reporting of other reactions suspected because of vaccination is encouraged, especially those that are clinically significant or unusual. The form can be obtained on the Web at http://www.vaers.org or via telephone at 800-822-7967. Electronic reporting is available on the Web at http://secure.vaers.org/VaersDataEntryintro.htm. The VAERS is a passive surveillance system, and determining causal associations between vaccines and AEs is not always possible.10 Other concurrent infections or exposures may precipitate a given symptom that may simply coincide with the receipt of a vaccine.11 For example, patient 2 may have had vaccine-associated erythema multiforme but because he had recently completed a course of penicillin, we cannot exclude the possibility of a concurrent antibiotic association.

The Anthrax Vaccine Expert Committee reviewed 602 VAERS reports filed from 1998 through 1999.12 Nearly one half of reports noted a local injection site AE, 33% of which were noted to be moderate to large. A subcutaneous nodule was cited in 5.3% of reports. Although three fourths of reports noted a "systemic" AE, these covered a broad spectrum, with 34 types cited at a frequency of more than 1%. The most common AEs, in declining order of incidence, were flulike symptoms, 20.8%; malaise, 13.3%; rash, 14.2%; arthralgia, 12%; headache, 10.1%; with the remainder of AEs all affecting fewer than 10% of patients. Among the reported 45 total "serious or medically important AEs," one report of each of the following was noted: systemic lupus erythematosus, angioedema, anaphylactoid reaction, and toxic epidermal necrolysis. None of these AEs were judged to be causally (defined as likely, certain, or probable) related to the vaccine itself.12 According to Friedlander et al,8 the "FDA continues to view the anthrax vaccine as safe and effective for individuals at risk of exposure to anthrax."

Management of Adverse Events

Adverse reactions after vaccination can be divided into local and systemic.

Cutaneous Reactions—The cutaneous manifestations and the latest recommendations from the Walter Reed National Vaccine healthcare center network9 are summarized partially in Tables 1 and 2.

Local reactions involve the injection site or have contiguous spread and are graded based on the measured size of the local redness or swelling (Table 1). Most local anthrax vaccine reactions require no treatment and resolve within 72 hours, though topical or oral steroids and oral antihistamines can be used to help manage symptoms. Unless the local reaction is very large or complicated, the patient can usually proceed with subsequent doses. Although some of these reactions may mimic cellulitis, antibiotic therapy for postvaccination inflammation is not warranted. Allergy consultation is recommended for a large or complicated reaction, especially if this occurs after the second dose. In this instance, the patient may be immune (a hyperresponder) and may not require further series (with the exception of the yearly booster).9 When a significant local type reaction has occurred, pretreatment to help prevent future large local reactions is indicated.

Systemic Reactions—These commonly include flulike symptoms, such as fever, anorexia, nausea, arthralgia, myalgia, or malaise. Treatment of mild to moderate systemic events is symptomatic (Table 2). Pretreatment also may be given with the next vaccine in patients who have had these symptoms on prior AVA vaccinations. If symptoms are clinically consistent with serum sickness or are severe and prolonged, the patient may benefit from a short course of oral prednisone. Vaccine-related AEs may warrant temporary delay from the schedule. When resumed, this does not require starting over but rather simply continuing from the last dose.9

For a generalized maculopapular rash or target lesions, a skin biopsy should be performed, especially if the rash is suggestive of early erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis. In these cases, temporary exemption from further vaccinations and VAERS reporting are indicated. The possibility exists that additional doses may result in a more serious skin reaction and should be given with caution only after expert evaluation and consideration of the risk:benefit ratio. The dermatologist should provide a clinical histopathologic diagnosis to help the allergist or expert in the vaccination program decide the best course for continuation or exemption from the full anthrax series. These cases may warrant permanent exemption from further vaccination series. No apparent safety data for challenge dosing or desensitization in these potentially life-threatening skin reactions exist. In patient 2 with erythema multiforme, further vaccinations for anthrax were waived permanently. Similarly, deferral from further anthrax vaccinations was recommended in patient 3.

In those cases of severe urticaria or angioedema, temporary exemption may be granted while requesting allergy consultation. Additional doses should be given with caution only after expert evaluation and consideration of the risk:benefit ratio. Permanent exemption may be required for those with anaphylaxis or sudden onset angioedema. In patient 1 with recurrent localized urticaria, the allergist recommended that a formal skin-prick test to future vaccine lots be performed before he received any further vaccine in the series. Although this local allergic-type reaction may be due to some component of the vaccine, we are unable to define the specific cause at this time. This is a rather unusual manifestation, with recurrence of the urticaria still persisting 21/2 years later and restricted only to the vaccinated arm. 

Conclusion

There are ongoing studies to evaluate whether a reduced number of anthrax vaccinations will provide the same immunity. In addition, other ongoing studies are comparing intramuscular administration versus the current usual subcutaneous route. Preliminary reports have shown that local reactions are less common in patients who received the vaccine via the intramuscular route than in those who received the vaccine via the subcutaneous route.13 This change in route of administration could reduce the number of adverse cutaneous reactions in the future. For further expert advice or clinical consultations, contact the Walter Reed National Vaccine Healthcare Center via telephone: 202-782-0411; fax: 202-782-4658; or e-mail: [email protected].

Since the domestic anthrax attacks in October 2001 and in the presence of continued worldwide threats to our armed forces, force protection remains a top priority. As dermatologists, we should be familiar with the current anthrax vaccine
program and be able to recognize and treat anthrax vaccine–related AEs.