T HE JOURNAL OF INVESTIGATIVE DERMATOLOGY 67:327-332, 1976 Vol. 67, No.3 Copyright © 1976 by The Williams & Wilkins Co. Printed in U.S.A . IN VIVO STUDIES OF THE PATHOGENESIS OF COLD URTICARIA, B CHOLINERGIC URTICARIA, AND VIBRATION-INDUCED SWELLING ALLEN P. KAPLAN, M.D., AND MICHAEL A. BEAVEN, PH.D. Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, and Pulmonary Branch, National Heart and Lung Institute, National Institutes of Health, Bethesda, Maryland, U. S. A. The disorders generally classified as physical normally subsides during the next 5 min. The urticarias include cold urticaria, local and general­ patient with cold urticaria usually complains of ized (cholinergic) heat urticaria, dermographism, pruritus in the area between 2 and 4 min after pressure urticaria, and vibration-induced angio­ removal of the ice cube and develops a large hive edema. These diseases have the" common property the size of the ice cube within 10 min. Figure 1 of being reproducibly induced by physical stimuli shows the result of a positive ice cube test demon­ and are not associated with an increased incidence strating swelling which encompasses the area of allergic disorders such as hay fever or extrinsic where the ice cube was placed as well as the area asthma in which offending allergens are identifia­ where ice water dripped down the patient's arm. ble. Studies of these diseases have involved at­ In order to identify the mediators released in tempts to identify circulating antibodies that cold urticaria, patients were studied in the follow­ might be responsible for the observed sensitivity or ing manner. An intravenous catheter was placed in to determine the release of vasoactive principles in the brachial vein and 5% dextrose in water was response to the inciting stimulus. In this paper we slowly infused. Baseline samples were obtained will summarize studies of mediator release and the and the intravenous line was flushed with normal mechanism by which such release occurs in cold saline containing 15 U/ ml heparin in order to urticaria, cholinergic urticaria, and vibration­ prevent local coagulation. The hand was then induced angioedema. lowered into a bucket of ice water (O DC) and submerged to about 2 inches above the wrist for 4 min. The hand was removed; a second sample was COLD URTICARIA drawn; and subsequent samples were obtained Cold urticaria is characterized by the rapid after 2, 5, 8, 12, 15, and 20 min. A 5-ml sample was development of hives and swelling after exposure discarded immediately before each sample was to a cold stimulus. It can occur in any age group , collected in order to eliminate any intravenous has no predilection for either sex, and is not fluid present in the catheter; the catheter was then associated with other allergic disorders. The typi­ flushed with heparinized saline. Samples for hista­ cal patient may become symptomatic while walk­ mine and serotonin determinations were drawn ing outside in the winter; however, pruritus and into 12-ml plastic syringes containing 100 U hepa­ swelling are often most prominent when the person rin (0.1 ml of a 1,000 U/ml solution). Ten milliliters comes indoors and begins to warm. Only exposed of blood were drawn and spun for 20 min at 900 g, portions of the body such as the face and hands are and the plasma was separated with Pasteur affected. Although cold foods such as ice cream pipettes. Samples for bradykinin determinations may lead to swelling of the lips or tongue, pharyn­ were collected into ethylenediamine tetraacetate geal or laryngeal edema are exceedingly rare and (9 mg/10 ml blood) and hexadimethrine bromide gastrointestinal symptoms are not seen. However, (3.6 mg/lO ml blood). ge neralized exposure, for example while swim­ Six patients with cold-induced urticaria were ming, can lead to such massive mediator release studied. Each had a positive ice cube test while that hypotension, fainting, and drownings can tests for cryoglobulins, cold agglutinins, cryofi­ result [1] . brinogen, and serology for syphilis were negative. A simple diagnostic test which reproduces this The patients had a normal protein electrophoretic l-i henomenon is to place an ice cube on the patient's pattern and a normal serum IgE level. Samples i!)rearm for 5 min and then wait 10 min for any were assayed for histamine by the radioenzymic 12action to occur. Although everyone has evidence procedure described by Beaven et al [2], while r,f redness after the ice cube is removed, this serotonin was determined by a double isotopic assay [3] based on the procedure of Saavadra et al. [4]. Bradykinin was assayed by radioimmunoassay Reprint requests to: Dr. A. P. Kaplan, Allergic Dis­ ases Section, Laboratory of Clinical Investigation, [5.1 , HAID, National Institutes of Health, Bethesda, Mary­ The results of the assay for histamine release in 5 'and 20014. patients are shown in Figure 2. Within 10 min after Abbreviations: the ice water challenge, a wave of histamine was ECF -A: eosinophil chemotactic factor of anaphylaxis PAF: Platelet activating factor obtained, the peak values ranging from 10 to 36 SRS-A: slow reacting substance of anaphylaxis ng/ml. Patients complained of warmth and ·pruri- 327 328 KAPLAN AND BEAVEN VoL. 67, No.3 hypothesis was confirmed by passing the patient's serum over immunoadsorbents prepared with anti­ sera against myeloma proteins of the IgG, IgM, IgA, IgD, and IgE classes of immunoglobulin. Only the anti-IgE immunoadsorbent removed the activ­ ity from the patient's serum. CHOLINERGIC URTICARIA Cholinergic urticaria or generalized heat urti­ caria is induced by an increase in body tempera- 40 -,-;;- 36 '\·i:/ • ,"I"",. ... , '1' ~"' . ":j" 32 .~ . ;..~"'> E ~ 28 E. UJ In < 24 UJ ....I a:::UJ UJ 20 ~ :::liE < ~ 16 !:!? :z: 12 8 4 FIG. 1. Photograph of an ice cube test performed on a patient with cold urticaria. -4 o 4 8 12 16 20 24 28 TIME (min) tus at about 2 min after removing the hand from FIG. 2. Study of histamine release after ice water the ice water. Swelling was observed between 2 and challenge in 6 patients with cold urticaria. 6 min, and peak histamine levels were obtained between 4 and 8 min. A single patient had a history of repeated episodes of hypotension caused by 240 wading in the ocean up to his knees for a period of 220 about 5 min. Such immersion caused flushing and light headedness that sometimes progressed to 200 episodes of fainting. The assay for histamine release in this patient is shown in Figure 3. Four 180 minutes after ice water challenge, the venous 160 160 effluent from his hand contained 260 ng/ml hista­ E mine. Also shown are the blood pressure recordings ';;0 140 140 E. obtained during this period; between 2 and 5 min 1&1 z 120 after challenge the patient flushed, was mildly i 120 c( ~ UJ diaphoretic, complained of tightness in his chest, VI 0: 100 100 :J :E VI and had a transient drop in diastolic blood pres­ VI 1&1 0: sure of 50 points. Assays of the same samples in all 80 80 Il. 0 6 patients contained no detectable serotonin or 0 0 60 60 -J bradykinin. CD Passive transfer studies in cold urticaria were performed by injecting 0.1 ml of serum into each of 40 40 two skin sites of the recipient and then challenging 20 20 the sites with an ice cube 2 and 48 hr later as described above. All sera were prescreened to be 0 -4 0 4 8 12 16 20 24 28 sure they were Australia antigen-negative and free TIME (min) from bacterial contamination. Only lout of the 6 FIG. 3. Histamine release (6) and blood pressure (e) patients studied had a positive test at 2 hr and at recording in a cold urticaria patient who had a history of 48 hr, suggesting an IgE-mediated reaction. This cold-induced hypotension. Sept. 1976 PATHOGENESIS OF URTICARIA 329 ture associated with exposure to a hot stimulus or with satellite lesions and, after exercise challenge, as a consequence of exercise or psychic stimuli [6, had markedly pruritic wheals over the entire body, 7]. Each of these challenges appears to initiate a many of which became confluent. After 5 min of neuroreflex which results in the elaboration of exercise, an increase in plasma histamine was acetylcholine from parasympathetic and/or sym­ observed. It then rose abruptly to 25 ng/ml after 7 pathetic neurons followed by pruritus and urti­ to 8 min and gradually declined over the next half caria. The lesions are characterized by small punc­ hour. In 2 of 4 other patients with milder symp­ tate wheals surrounded by considerable erythema toms, a positive mecholyl skin test without satel­ which tend to first appear over the upper thorax lite lesions was observed and a similar histamine and neck. Patients appear to be "hypersensitive" release curve was obtained. However the peak to cholinergic stimuli since intradermal injection of levels reached were 3 ng/ml and 4 ng/ml, respec­ mecholyl or acetylcholine produces a positive tively, while their baseline values were less than 1 wheal and flare reaction often surrounded by ng/m!. In the other 2 patients no elevation of smaller satellite lesions. This reactivity can be plasma histamine was detected. The sixth patient, used as a test for cholinergic urticaria; it is reported previously [9], had an atypical presenta­ diagnostic when satellite lesions are seen and is tion because the lesions were not pruritic and no suggestive of the disorder if a wheal appears. erythema was seen, but prominent wheals covered Figure 4 summarizes the neuroreflex pathway the entire body and the mecholyl skin test was thought to mediate cholinergic urticaria.