Urticaria and Anaphylaxis

Discovering the cause of idiopathic urticaria or anaphylaxis demands a thorough history and evaluation. The articles selected for discussion are just a few of those in the allergy literature showing that one must do a meticulous history and evaluation of the contents of materials to which patients are exposed before one can conclude that the anaphylaxis or urticaria truly is idiopathic.

Although urticaria is, of course, not life-threatening, it does present a major difficulty for patients in terms of severe itching, inability to sleep, and, if angioedema is present, even disfigurement. The condition is often frustrating for the primary care physician, who wants to avoid using steroids in these patients but often feels compelled to refer the patient to an allergist—only to see the patient return with a regimen of steroids and an antihistamine. Treatment during the evaluation process is important because the evaluation often requires several visits to a physician, whether generalist or specialist.

Urticaria itself is generally a straightforward diagnosis, but two caveats are important. First, the presence of angioedema with urticaria has essentially the same clinical meaning as uncomplicated urticaria itself. However, angioedema without urticaria is a separate syndrome; the two most common causes are angiotensin-converting enzyme inhibitors and hereditary angioedema. Second, urticaria can look much like erythema multiforme, which is a vasculitic process. What differentiates these conditions is that urticaria does not leave the pigment after it recedes, whereas the lesions of erythema multiforme leave hyperpigmented areas.

Some Causes of Acute Urticaria and Anaphylaxis Took Extra Work To Find

The approach to effective diagnosis and management of urticaria depends on establishing the time of the onset of rash. Acute intermittent urticaria develops within minutes of exposure to the antigen and lasts for several hours. A common cause is aspirin, and most causes can be identified during an initial interview. As the following studies show, however, establishing the cause can sometimes be extremely difficult, requiring painstaking and meticulous interviews and testing of numerous possible antigens.

Beaudouin E, Kanny G, Lambert H, Fremont S, Moneret-Vautrin DA. Food anaphylaxis following ingestion of carmine. Ann Allergy Asthma Immunol. 1996; 74:427-30.

This case report describes a patient who had an anaphylactic reaction after consuming yogurt. The cause of the reaction was found to be carmine, a natural dye that is extracted from dried female insects and is present in such foodstuffs as candy, ice cream, cookies, and pastries; syrups, liquors, and vinegar; cheese, butter, and yogurt; delicatessen meat and sausage casing; bouillon; and jams and caviar.

This report shows that the physician needs to see the labels from potentially antigenic foodstuffs. A three-visit approach is often helpful. At the first visit, the patient presents with the urticarial or anaphylactic syndrome and the physician can establish this diagnosis. At the second visit, the patient brings in labels from all products used shortly before the onset of symptoms. The third visit occurs after the physician contacts the manufacturers of the products to uncover reports of antigenicity.

Kanny G, Fremont S, Talhouarne G, Nicolas JP, Moneret-Vautrin DA. Anaphylaxis to mustard as a masked allergen in chicken dips. Ann Allergy Asthma Immunol. 1995; 75:340-2.

An increasing number of cases of anaphylaxis are due to spices. The patient in this case report had an anaphylactic reaction 20 minutes after consuming "chicken dips" (various sauces into which chicken is dipped) in a fast food restaurant. The patient had had similar reactions on several previous occasions, all of which could be explained by ingestion of mustard.

To many physicians, allergy testing seems to be a complicated clinical procedure, and radioallergosorbent tests were done in all of the case reports summarized in this Update. However, any physician can do simple testing after narrowing the range of potential allergens. In this patient, for example, a simple skin test could have been done by having the patient bring in the suspected mustard antigen. The mustard could have been placed on the skin, and a skin prick done through the mustard would have shown a local weal and flare reaction.

If a patient has a positive reaction, appropriate controls are necessary to distinguish an irritant (not mediated by IgE) response from an allergic (mediated by IgE) response. This process consists of doing skin tests on a person who can eat mustard without ill effects. A dilution of mustard that causes no reaction in the nonsensitive person should be determined. If this dilution causes a reaction in the sensitive person, an IgE-mediated reaction is confirmed.

Audicana MT, Fernandez de Corres L, Munoz D, Fernandez E, Navarro JA, del Pozo MD. Recurrent anaphylaxis caused by Anisakis simplex parasitizing fish. J Allergy Clin Immunol. 1995; 96:558-60.

Sometimes, a food allergy is not caused by foods or additives themselves but by contaminating parasites. The patient in this case report had periodic severe anaphylactic reactions to consumption of fish. The types of fish species varied, and reactions were not consistent. Work-up of this patient showed the patient to be allergic to Anisakis simplex, an organism that commonly parasitizes fish in the North Sea. Fish should be deep-frozen and cooked at temperatures higher than 60 °C for 10 minutes to protect against infection with live parasites, but these techniques do not alter the antigenicity of the parasite.

Schwartz HJ. Latex: a potential hidden food allergen in fast food restaurants. J Allergy Clin Immunol. 1995; 95:139-40.

A clinician dealing with a patient who developed urticaria at a restaurant should recall that allergens can be added to food during its preparation. This case report describes two patients with known latex allergy who had anaphylactic reactions in fast food restaurants. After thorough interviews and testing, the patients' reactions were found to have been caused by latex from the gloves worn by food handlers that had contaminated the food. Both patients later ate the same food from the restaurant; this food had not been handled by workers with latex gloves, and the patients had no reactions.

This report also suggests how "informal" allergy testing can be done. When a food is associated with an immediate reaction, patients can bring the food to the physician's office and ingest it there. The range of possible causes can be narrowed under such controlled circumstances.

Tarlo SM, Dolovich J, Listgarten C. Anaphylaxis to carrageenan: a pseudo-latex allergy. J Allergy Clin Immunol. 1995; 95:933-6.

This case report describes a patient who developed anaphylaxis during a barium enema. The allergy was first presumed to have been caused by the latex tip of the rectal introducer. However, after results of skin testing of latex were negative, the cause of the reaction was found to be carrageenan, an additive to the barium solution. Carrageenan is an emulsifying and suspending agent found in many pharmaceutical agents and in some food products, cosmetics, and shoe polishes.

The barium enema had been ordered because of the patient's 8-month history of nausea, vomiting, abdominal bloating, and diarrhea. These symptoms had been attributed to the irritable bowel syndrome. When this patient avoided materials containing carrageenan, her gastrointestinal symptoms resolved. Such an observation raises the question of whether a subset of patients who have symptoms of the irritable bowel syndrome are actually having allergic reactions.

Anaphylaxis is a life-threatening illness, and urticaria is a serious imposition on patients. Latex is a common allergen, as are aspirin and several foodstuffs (for example, cod, peanuts, soy, egg white, almonds, walnuts, and lobster). Given the hidden nature of the materials that cause anaphylaxis, all patients who have had serious reactions should carry injectable epinephrine with them, especially when eating in restaurants.

Chronic Urticaria Was Associated with Autoimmunity

Rumbyrt JS, Katz JL, Schocket AL. Resolution of chronic urticaria in patients with thyroid autoimmunity. J Allergy Clin Immunol. 1995; 96:901-5.

Chronic urticaria is manifested as a long-term rash that waxes and wanes. Unlike the causes of acute urticaria and anaphylaxis, the causes of chronic urticaria have heretofore been notoriously difficult to uncover. Moreover, the diagnosis itself is less obvious because serum sickness and the vasculitis syndromes can mimic chronic urticaria; the latter, however, is usually accompanied by fever and arthralgias.

In previous studies, the cause of chronic urticaria was found in only 10% to 20% of cases. However, recent studies have found that one common cause is Helicobacter pylori infection. It was observed that when some patients with chronic urticaria and H. pylori-positive ulcers were treated with antibiotics for the ulcers, urticarial episodes also disappeared.

The study by Rumbyrt and colleagues suggests that for a subset of patients, chronic urticaria has an autoimmune cause. Leznoff and colleagues [1] had previously found that some patients with chronic urticaria also have high levels of antithyroid antibody. These patients, however, also had clinical thyroid disease. In Rumbyrt and colleagues' study, patients in a chronic urticaria clinic who were euthyroid but had antithyroid antibodies were investigated to assess the effect of thyroid autoimmunity on urticaria.

Ten euthyroid patients with refractory urticaria were treated with thyroxine: seven patients who had elevated antithyroid antibody levels at baseline and three controls who had no antithyroid antibodies. Thyroid function and antimicrosomal and antithyroglobulin antibody levels were monitored during treatment. If the urticaria clinically responded, thyroxine therapy was discontinued; therapy was restarted if symptoms recurred.

While receiving thyroxine, the seven patients reported resolution of symptoms within 4 weeks. The three controls did not respond to thyroxine. In five patients, symptoms recurred after treatment was stopped; these symptoms again resolved after treatment was restarted. Thyroid-stimulating hormone levels decreased in all patients who had a clinical response, but clinical resolution of urticaria was not correlated with antithyroid antibody levels.

Thus, it now appears that thyroid autoimmunity may be associated with chronic urticaria in some euthyroid patients and that treatment with thyroid hormone can result in clinical remission of urticaria. The antithyroid antibodies are an indicator of autoimmunity, but their levels do not correlate with disease activity. However, a decrease in thyroid-stimulating hormone levels caused by treatment did correlate with a beneficial response, raising the possibility that chronic thyroid stimulation of a thyroid gland inflamed by an autoimmune mechanism may release products from inflammatory cells in the thyroid that cause the urticaria.

With the discovery of the H. pylori and autoimmune associations, the work-up of a patient with chronic urticaria may now uncover as many as 50% of the causes of the syndrome.

Anaphylaxis Was a Somatoform Disorder

Choy AC, Patterson R, Patterson DR, Grammer LC, Greenberger PA, McGrath KG, et al. Undifferentiated somatoform idiopathic anaphylaxis: nonorganic symptoms mimicking idiopathic anaphylaxis. J Allergy Clin Immunol. 1995; 96:893-900.

Not all anaphylactoid reactions are true anaphylaxis. Idiopathic anaphylaxis is a syndrome of urticaria or angioedema accompanied by one of the following events: collapse, shock, bronchospasm, and severe gastrointestinal symptoms. In this study, Choy and colleagues evaluated and treated patients with somatic symptoms that mimic idiopathic anaphylaxis.

The authors had previously evaluated and treated 350 patients with idiopathic anaphylaxis. They used an established classification system [2] that included patients with idiopathic anaphylaxis variant. In this latter group of patients, histories were compatible with idiopathic anaphylaxis but the diagnosis had been excluded. Exclusion was based on the lack of objective physical findings and no response to therapy. Since the publication of Wong and colleagues' report [2], which included 9 patients with idiopathic anaphylaxis variant, 11 additional patients have been studied.

The 20 patients with idiopathic anaphylaxis variant did not have correlating objective physical findings and did not respond to the therapeutic regimen for idiopathic anaphylaxis. They met the Diagnostic and Statistical Manual of Mental Disorders criteria for undifferentiated somatoform disorders.

In two patients, symptoms resolved after somatoform disorder was diagnosed. One patient with vocal cord dysfunction was referred to speech therapy, which controlled symptoms. Nine patients were offered psychiatric consultation. Three of the nine accepted and had beneficial responses. One patient who had been referred to a psychiatrist refused follow-up. Five patients refused psychiatric evaluation and continued to have anaphylactic symptoms that prompted recurrent visits to the emergency department.

The cost of the previous evaluation of these patients ranged from $3000 to $150 000 per patient (mean, $30 545 per patient). Somatoform disorder was strongly suggested by a failure to respond to treatment with prednisone, 60 mg each morning; hydroxyzine, 25 mg three times daily; albuterol, 2 mg three times daily; and epinephrine injection. When possible, patients with a somatoform disorder should be discussed with an appropriate expert colleague to obtain concurrence as to the diagnosis.

The Antiphospholipid Antibody Syndrome

In the past, the work-up and referral of patients suspected of having the antiphospholipid antibody syndrome reflected how little was known about the syndrome. Depending on which symptoms and signs are most prominent, patients are referred to neurologists, hematologists, rheumatologists, or allergists.

Recurrent thromboembolic events, which can be arterial, venous, or even mixed-vessel thrombi, are a hallmark of the syndrome. They can cause stroke, pulmonary embolism, and recurrent spontaneous abortion. Livedo reticularis is common and represents thrombi in postcapillary venules. Oddly, platelet levels are often decreased. "Vasomotor" symptoms include migraine headaches, the Raynaud syndrome, and transient ischemic attacks.

At present, the laboratory work-up of a patient suspected of having the antiphospholipid antibody syndrome comprises three tests. The diagnosis is confirmed by positive results on one or more of the following: First, anticardiolipin antibody IgG levels may be elevated (although they can also be elevated in syphilis, human immunodeficiency virus infection, and other infections). Second, results of the lupus anticoagulant test may be positive. Third, the activated partial thromboplastin time may be prolonged because of the inactive phospholipid in the serum. The antiphospholipid antibody syndrome was first associated with systemic lupus erythematosus (thus its original name—lupus anticoagulant), but it is now clear that it occurs more commonly as a primary syndrome.

Antibodies to a Protein May Be Responsible for the Antiphospholipid Antibody Syndrome

Cabiedes J, Cabral AR, Alarcon-Segovia D. Clinical manifestations of the antiphospholipid syndrome in patients with system lupus erythematosus associate more strongly with anti-ß₂-glycoprotein-1 than with antiphospholipid antibodies. J Rheumatol. 1995; 22:1899-906.

A protein found in normal human serum (ß₂-glycoprotein-1) behaves as a cofactor for binding antiphospholipid antibodies to the anionic phospholipids found in patients with systemic lupus erythematosus and the antiphospholipid antibody syndrome. In contrast, this protein does not seem to be required for the reactivity of anticardiolipin antibodies in syphilis sera.

Cabiedes and colleagues studied the presence and clinical significance of antibodies to phospholipid-free ß₂-glycoprotein-1 in the serum of 94 patients with systemic lupus erythematosus (group 1). Twenty-one of these patients had the antiphospholipid antibody syndrome according to clinical and serologic criteria. Eighteen patients (group 2) met the clinical criteria for the syndrome but had no serum antiphospholipid antibodies, and 33 patients (group 3) had no clinical features or serologic findings typical of the syndrome. Twenty-two patients (group 4) were positive for antiphospholipid antibodies but had no related clinical manifestations.

Thirty-five of 39 patients (groups 1 and 2) with systemic lupus erythematosus and clinical manifestations of the antiphospholipid antibody syndrome but only 2 of 55 patients (groups 3 and 4) with systemic lupus erythematosus and no clinical manifestations of the syndrome had antibodies to ß₂-glycoprotein-1 (P < 0.001). Positivity for ß₂-glycoprotein-1 was seen in 16 patients (group 2) who had systemic lupus erythematosus and clinical manifestations of the antiphospholipid antibody syndrome and were negative for antibodies to phospholipids. All 35 patients with systemic lupus erythematosus and vascular complications were positive for ß (₂-glycoprotein-1), but these antibodies were present in only 4 of 55 patients with lupus but no vascular manifestations (P < 0.001). These findings indicate that the clinical manifestations of the antiphospholipid antibody syndrome are strongly associated with antibodies to phospholipid-free ß₂-glycoprotein-1.

Antibody Level Was Correlated with Disease Activity

Cabral AR, Cabiedes J, Alarcon-Segovia D. Antibodies to phospholipid-free ß₂-glycoprotein-1 in patients with primary antiphospholipid syndrome. J Rheumatol. 1995; 22:1894-8.

After the study described in the preceding section suggested a strong association between the antiphospholipid antibody syndrome and phospholipid-free ß₂-glycoprotein-1, the same researchers investigated serum antibodies to this protein and their relation to clinical manifestations of primary (not associated with systemic lupus erythematosus) antiphospholipid antibody syndrome.

Fifteen patients with primary antiphospholipid antibody syndrome and high titers of IgG and IgM anticardiolipin antibodies were studied and compared with 13 anticardiolipin antibody-positive patients with syphilis and 76 healthy controls.

Twelve patients with primary antiphospholipid antibody syndrome but no patients with syphilis and no controls had IgG antibodies to phospholipid-free ß (₂-glycoprotein-1) (P < 0.001). Five patients with high IgM anticardiolipin titers were positive for IgG against ß₂-glycoprotein-1. Three patients had IgG or IgM anticardiolipin antibodies but no detectable ß₂-glycoprotein-1 antibodies. Other findings included patients with a negative lupus anticoagulant test result and positive anti-ß₂-glycoprotein-1 test result and three patients with a positive lupus anticoagulant test result and negative anti-ß₂-glycoprotein-1 antibody test result. No patients with syphilis and no controls had antibodies to ß₂-glycoprotein-1.

Antibodies to ß₂-glycoprotein-1 in patients with primary antiphospholipid antibody syndrome correlate well with disease activity. Other antibodies must be associated with clinical activity; these antibodies may be the phospholipid-bound ß₂-glycoprotein-1, not just the ß₂-glycoprotein-1 in serum samples that was studied. The anticardiolipin antibody test is a screening test, and either IgG or IgM anticardiolipin antibodies are associated with clinical manifestations. The lupus anticoagulant appears to be a distinct antibody. More than one thrombotic mechanism may be involved in the pathogenesis of the antiphospholipid antibody syndrome.

The major clinical questions are when to test for the syndrome and what the test results can tell us. Testing should be done in patients who have had stroke at an early age without other obvious causes and in patients with unusual embolic phenomena, pulmonary emboli without obvious risk factors, and recurrent fetal loss. Because treatment has now been shown to be effective, it might also be appropriate to test patients with unusual clusters of such symptoms as migraine headache with livedo reticularis or the Raynaud syndrome.

Warfarin Was Most Effective in the Secondary Prevention of Thrombosis

Khamashta MA, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ, Hughes GR. The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med. 1995; 332:993-7.

Until recently, the optimal approach for treating the antiphospholipid antibody syndrome was unclear because it is difficult to define the disease, few patients are known to have it, and it is difficult to follow patients during a long period. Khamashta and colleagues assessed the efficacy of warfarin, low-dose aspirin, or both in the secondary prevention of thrombosis in patients with the antiphospholipid antibody syndrome. A total of 147 patients (124 women) with the syndrome and a history of thrombosis were studied retrospectively. The syndrome was primary in 62 patients, associated with systemic lupus erythematosus in 66 patients, and lupus-like in 19 patients. Table 1 shows the types of antithrombotic treatments received by the patients.

Thrombosis recurred in 101 patients (69%) who had a total of 186 thrombi. Treatment with high-intensity warfarin (producing an international normalized ratio > 3.0) with or without low-dose aspirin (75 mg/d) was significantly more effective in preventing further thrombotic events than either treatment with low-intensity warfarin (international normalized ratio < 3.0) with or without low-dose aspirin or treatment with aspirin alone. The rate of recurring thrombosis was highest during the first 6 months after the cessation of warfarin therapy. Bleeding complications occurred in 29 patients receiving warfarin therapy and were severe in 7.

The risk for recurrent thrombosis in patients with the antiphospholipid antibody syndrome is high. (Table 1). Long-term anticoagulation therapy in which the international normalized ratio is maintained at or above 3.0 is advisable in these patients, but bleeding complications are a major concern. The question not answered by this study—and still uncertain—is how long therapy should be continued.

Asthma

The optimal treatment of asthma has largely depended on the relation between the acute reactive airways disease and the late-phase inflammatory response. The former is most effectively treated with ß-agonists, whereas the latter responds best to antiinflammatory agents. A simple way to assess the relative amount of each component of the disease is to assess lung function using spirometry and a ß-agonist. Spirometry is done once and then repeated after treatment with a rapid-acting ß-agonist inhaler. The improvement over the baseline spirogram is interpreted as reactive airways disease, and the remaining deficit is considered inflammatory disease.

Single Dose of Inhaled Steroid at 3:00 p.m. Was Effective

Pincus DJ, Szefler SJ, Ackerson LM, Martin RJ. Chronotherapy of asthma with inhaled steroids: the effect of dosage timing on drug efficacy. J Allergy Clin Immunol. 1995; 95:1172-8.

Once a large degree of inflammation is encountered, steroid agents become important. One question patients commonly ask physicians is, "When is the best time of day to take my drugs?" Studies in patients with asthma who received systemic corticosteroids at 3 p.m. have shown that this treatment has a therapeutic benefit superior to that seen with dosing at other times. Pincus and colleagues compared the anti-asthma and systemic effects of 800 µg (8 puffs) of inhaled triamcinolone given once daily at 3 p.m. with those of 200 µg (2 puffs) given four times daily in asthmatic patients who received theophylline and ß-agonist before entering the study.

Outcome measures included FEV₁, peak expiratory flow rates, response to methacholine challenges, and use of ß-agonists. Systemic effects included blood eosinophil and cortisol levels, both of which were measured. In both groups, blood eosinophil levels decreased and the cortisol level measured in the morning remained the same.

The therapeutic outcomes were equal in the two treatment groups. The only differences were that the multidose group required more methacholine to reduce the FEV₁ by 20%. The systemic effects of the two regimens did not differ. Total eosinophil count decreased in both groups, and the degree of clinical improvement did not differ between groups.

This study shows that in this group of patients, 3-p.m. dosing of inhaled triamcinolone is as effective as four-times-a-day dosing. Because daily dosing is likely to be associated with better patient compliance, it can be considered as an alternative to standard regimens. Historical data suggest that receiving the daily dosage between 5 p.m. and 6 p.m. might produce equal results and further simplify the treatment regimen; 3 p.m. is often an inconvenient time for patients to take medicine.

The Chronic Fatigue Syndrome

Our understanding of the chronic fatigue syndrome has changed, but the symptoms Table 2 remain confusing. The syndrome was initially thought to be due to the Epstein-Barr virus, but various studies refuted that hypothesis. The lack of knowledge about mechanism is often frustrating for physicians trying to decide what therapy to offer patients with the symptoms now used by the Centers for Disease Control and Prevention to define the syndrome (Table 2).

Chronic Fatigue Was Associated with Hypotension

Bou-Holaigah I, Rowe PC, Kan J, Calkins H. The relationship between neurally mediated hypotension and the chronic fatigue syndrome. JAMA. 1995; 274:961-7.

Researchers at Johns Hopkins University made the clinical observation that many patients who had syncope subsequently had symptoms of chronic fatigue for several weeks. These researchers then studied young persons with fatigue and found a subgroup that showed hypotension during testing and whose fatigue decreased when salt or other hypertensive agents were administered.

These researchers then compared the clinical symptoms and response evoked by upright tilt-Table testing in 14 healthy persons and in a sample of 23 patients who met strict criteria for the chronic fatigue syndrome. Each participant had a three-stage upright tilt-Table test with isoproterenol. Patients were then offered therapy with fludrocortisone, ß-adrenergic blocking agents, and disopyramide, alone or in combination.

An abnormal response to upright tilt was seen in 22 of 23 patients with the chronic fatigue syndrome and in only 4 of 14 controls (P < 0.001). Sixteen patients with the chronic fatigue syndrome, but no controls, had an abnormal response during stage 1 of tilt testing (P < 0.001). Nine patients reported complete or nearly complete resolution of the symptoms of the chronic fatigue syndrome after receiving therapy directed at neurally mediated hypotension. Although this study was not blinded, it appears to show that at least a subset of patients with the chronic fatigue syndrome may have neurally mediated hypotension and that symptoms may be improved in this group of patients by therapy directed at this abnormal cardiovascular reflex.

Dr. Roberts (Series Editor): York Health System Medical Group, York, PA 17403.