ALLERGY ROUNDS
Chronic urticaria Macy I. Levine,
M.D.
Pittsburgh, Pa.
In l!G4, Sheldon, l~ovell, and Mathews’ characterized the attitude of many physicians toward urticaria in the title of their review, “The Vetiw Urticaria Problem.” TTnger” rcflectcd a similar posture in his article, “Chronic Urticaria. 1. Approach to an ISnigma.” ln 1964, an unidentified cynic said, “I should rather SW a tiger come into my ofice than a patient with chronic urticaria.“” These gloomy viewpoints would be fortified by Fromer’s4 comment that “The nlanagenlent of patients with (Bhronic urticaria depends largely on the ability of the clinician to find a cause,” and the finding of Green, Koelsche, and Kicrlantl” that 70 per cent of bhcir caseshad an undetermined cause. Now, after twenty years, MathcwsC has reversed this position by pointing out that patients with chronic urticaria can usually be controlled clven without identification of the cause. I should like to add another optimistic point of view in the following CBSCdiscussion and present some of t.he experiences gained in this clinic in the past two tlecades. PRESENTATION
OF CASE
This 51.yenr-old white housewife and registerad nurse was first wcn on April 2, 1970, I~~:ause of hivw of 11 months’ duration. She developed gcnoralizcd, pruritic urticarinl lesions onck day after she broke her high-protein weight reduction diet. The hives occurred almost cbvery day, mostly at night rind whrn the patient felt wnrm or tried to relax. In l!W~runry. 1970, thus hives flared up following ndministrat,ion of penicillin for a “virus.” There was no wrrrlation with nny othw factor. In Kovembw, 1969, an nllwgist I)erformcd 12 allergy tests ant1 wportetl a positiw rcwtion only to cat. JJc considered tension to hc :L wnsative factor :~nd advised the- patirn! to get rid of the wt, calcan the: hour thoroughly, and takr hytlroxyr,irw. Thr patient followvrcl this advice without betwfit. She then restrirtrd 1lc.r diet, avoiding nuts, eggs, nntl c!hoc:olnt~~, which she, thought, were aggravating the hives, but noted no change. She used epinephrinc and nntihistnminow with somc~ relief and steroid drugs without apparent wlic~f. At, the :I~C of 27, the paticwt, had caonsultcbd another allergist twcaust! of naual symptoms and wns administered some allergy tcaats and then immunothwapy. I&h year since 1962 she had ~ufferetl with wnsonel rhinitis from April to dune. She received injections of emulsified grnss and dust extrwts in May, 1969, just 4 tlnys prior to the onset of thr urticarin. The patient complained of occasional lwadaches, lightheadedneaq, bloating, frequent epi-
of hfcdicirw, IJ;Cvernity of Pittsburgh School of Medicine. Xupported in pnrt by a grant from the Pennsylvania Allsrgy A.swciation. Hcreived for publicntion June 4, 1974. Heprint requests to: Macy I. Lcvinc, M.D., 3347 Forbes Ave., Pittsburgh, Vol.
5.5, No.
4, pp.
676-685
Pa.,
15813.
VOLUME NUMBER
55 4
Chronic
urticaria
277
sodes of diarrhea, and discomfort in her knees, ankles, and feet. She felt very tense and frustrated, but did not associate these symptoms with her hives. She frequently spoke about her husband, a hardworking steel company executive who had been divorced twice before this marriage, and who drank heavily and always criticized the patient. The husband had had congestive failure and impotence. On one occasion the patient left him, only to return because she could not manage financially. The family history revealed that the mother and two children of the patient had seasonal allergic rhinitis. The past history revealed many surgical procedures: tonsillectomy, appendectomy, hemorrhoideetomy, salpingo-oophorectomy, and excision of a cyst from the thigh. In 1958, left carotid ligation was performed for intracranial bleeding and diphenylhydantoin therapy was instituted. In August, 1969, primidone was substituted for diphenylhydantoin because it was thought possible that the latter drug might be causing the hives, but there was no change. About 1966, the patient had all of her teeth extracted and then had much ditTiculty getting used to dentures. Physicial examination revealed an obese female weighing 168 pounds and 5 feet, 4% inches in height. The blood pressure was 140/78. The left eye showed a cataract. The mouth was edentulous. Healed scars were noted on the left side of the neck and on the abdomen. Urticarial lesions were observed on the body and extremities. No other abnormalities were noted. Intradermal testing with 23 allergens, Mecholyl, 1: 10,000, and acetylcholine, 1 :lO,OOO, gave negative results. Histamine, l:lO,OOO, produced a 10 x 9 mm. wheal and 18 x 19 mm. erythema. Bradykinin, 1: 10,000, produced a 9 x 8 mm. wheal and 11 x 9 mm. erythema. Treatment included epinephrine, ephedrine, pseudoephedrine, carbinoxamine, methdilazine, and ehlordiazepoxide. However, the hives recurred almost daily. Neither hives nor diarrhea occurred when the patient fasted. Because of the persistence of symptoms the patient was hospitalized at Montefiore Hospital, Pittsburgh, in November, 1970. The patient complained of left shoulder pain, which was diagnosed due to periarthritis and treated with a local triamcinolone injection and physical therapy. She also complained of pain in the coccygeal area as the result of a fall. There were no new physical abnormalities. The weight was 178 pounds. The following laboratory tests were normal or negative: complete blood count, urinalysis, VDRL, electrocardiogram, sedimentation rate, lupus erythematosus preparation, antinuclear antibody, two stool specimens for ova and parasites, fasting blood sugar, blood urea nitrogen, serum electrophoretic pattern, chest roentgenogram, and barium enema. Cholesterol was 354. The biochemical profile was otherwise normal. Leukocyte alkaline phosphatase was 53. C’3 was 250. (Normal values: cholesterol, 150-250 mg./lOO ml.; C’3, 145 ?: 22 mg./lOO ml. ; leukocyte alkaline phosphatase, 15-100.) A high-speed drill punch biopsy of the skin was performed without anesthesia and with the patient off all medication for 10 hours. One specimen was obtained from a wheal on the left thigh for examination by light microscopy. Another specimen was obtained from a wheal in the left deltoid area for examination by electron microscopy. A control specimen was obtained from unaffected skin in the left deltoid area. Under light microscopy the epidermis of the wheal was normal. The dermis showed some dilated capillaries and perivascular infiltration with leukocytes, mainly polymorphonuclear cells. An occasional eosinophil and a rare mast cell were seen. Under electron microscopy, 7 the control site with its mast cells (Fig. 1) appeared normal. The electron microscopic picture of the wheal revealed no dramatic changes except for the mast cells, which showed a reduction in density of the granules (Fig. 2). The cytoplasm of these cells consistently contained membrane-bounded fat droplets. Up to seven droplets were counted in a single section of a cell. During the hospital stay the diet was limited to six foods (lamb, lettuce, pears, rice, rye, tea) that seldom cause allergic reactions. Primidone was discontinued and diphenylhydantoin was reinstituted. Methdilazine and ephedrine were continued. The patient avoided use of her dentures for 3 days, but observed no change in her hives during this period. The patient was advised ahout the results of her studies, advised that she had no sign of cancer or other serious illness, and given much opportunity to ventilate her feelings. She was discharged after 9 days with instructions to add the restricted foods to the diet and continue the same medica-
278
Levine
J. ALLERGY
CLIN.
IMMUNOL. AF’t?ft lW5
FIG. 1. Mast cell from an unaffected skin area showing granules and well-developed villous processes (Pr). Each mast cell granule is surrounded by a membrane (m) and consists of an outer zone of poorly developed lamellar element (lam) and an inner core (c) of fine or coarse grainy material. The granules vary in size, shape, and density. Skin from the deltoid region. (x22,000.)
t ions. Although 3hr uxs still Ilitving hives, they tended to 1~2 ~mallrr and IRYY pruritic. The patient returnrd to the office I month later and reported freedom from hives for 3 weeks. She had added the restricted foods to the diet and felt less nervous and more energetic. She had lost weight to 159 pounds and had obtained new dentures. She was not seen again but she did respond to an inquiry from me with a letter dated April Ii, 1974, in which she recorded continued freedom from hives and other illness. She had had herpes xoster in August, l!K3, and periodic diarrhea and abdominal discomfort, but upper gastrointestinal and barium enema x-ray examinations showed no abnormality in August, 1972. DISCUSSION
It is quite clear from the history and inspection of the skin lesions that this patient has chronic urticaria. The diagnosis of this condition is usually straightforward, but occasionally the patient exhibits erythematous ma&w and targetshaped wheala that suggest erythema multiforme. This question in ditEerentia1 diagnosis may ultimately be resolved by skin biopsy. According to various authors, the time period required for hives to be considered chronic varies from 1 to 6 months. Unless one includes some intermediate category, T think that 1 month is sufficient time for urticaria to be considered chronic because there doea not ap-
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55 4
FIG. 2. Part cell granules the cytoplasm encountered
Chronic
of a mast cell from the wheal showing some as compared with the cells fram the adjacent of the mast cell contains membrane-bounded in the control cells. (~22,000.)
urticaria
279
reduction in density of mast unaffected skin. In addition, fat droplets (F) not usually
pear to be any significant clinical difference between the patient with hives for 1 month and the one with hives lasting over 6 months. The designation, chronic intractable urticaria, may be used for the patient with hives that persist for more than 2 years. Another question deals with what constitutes chronicity. This has not been defined in the literature. It would seem to me that the occurrence of hives to some degree on most days and without free intervals longer than 5 days would constitute chronicity, and would give some basis for distinguishing acute recurrent urticaria. ETIOLOGY
Our patient shows no good evidence for an allergic basis for her urticaria, except for the flare-up following penicillin therapy. It is possible that the emulsified allergy extracts she received 4 days prior to the onset of the hives were responsible for initiating the attack, but not for its persistence. The failure of the patient to have seasonal rhinitis in 1970 and the negative intradermal tests with dust and grass pollens cast doubt on this possibility. Although a psychiatric appraisal was not obtained, much information about emotional conflicts and disturbed feelings was easily elicited. The patient had much anxiety, frustration, and resentment. She was obese and had several nonspecific complaints. Her
280
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CLIN.
IMMUNOL. APRIL 1975
which providctl iiltcsnsivcb stucl?-, ill improvement followed the hospitalization, tention, and much opportunity to talk about herself and her feelings. In addition, her fears about cancer and other diseases were dispelled. Subsc~clucnt ly. shcl felt less anxious, had more energy, and lost weight. 1Vit.h this history a11t1 thca absence of other factors, it seems rcasonablc to consider the urticaria l)s!cliogc-ic in origin. Xost authors reporting investigations of patients with cahronic urticuria havcl found psychogenic factors responsible for some proportion of thc~ir (WSW. varying from 10 to 68 per cent.“? “-lo This proportion mavY be related to the oricntafion 01 the physician and his interest and understanding of emotional factors in disease. which is related to the amount of information lcarncd about the psychologic milieu of the patient. What constitutes evidence for causation is largclp a matter of opinion in any case. In an earlier multidisciplinary investigation of 40 (::LSW of chronic urticaria,14 we considered chronic nrticarin to be a psychosomatic disease with the hives occurring as the regressive, physiologic expression or nnconscious conflict when the usual defense mechanisms become inadequate. Although 11 per cent of patients with chronic urticaria tlcvelop hives I’ollowing ingestion of aspirin,‘” this drug is not the primary cause of thcl tliseasc> in these patients. There arc isolated reports that allergy to other tlrllgs, I’oods. molds, and other allergens arc’ responsible for the condition. I’awsitic: infcctioll. focal infection, neoplasms, and autoimmune diWilWS IIilvC INWl listctl as C;lWWS of chronic urticaria, but there is no well-documcntt>(l c~vitl~~nccthat, ;IIIJ’ of thcsc are responsible for anything other than a chance association. Thus, from the ctiologic viewpoint. paticlnts with c.hronicaurticdaria fall into three caategorics: one group in whom no cansativo f;ztor WII 1~: itlcnt ifietl, one in whom emotional factors appear to IW implicatc~l. ~114 one srn;~ll groul) in whom an allergic basis is suspected. LABORATORY
INVESTIGATiON
Our patient had clxt,cnsivct laboratory studies without abnormalit\. c~sc:~pt for an unrelated cholesterol elevation. This is the usual ospcriencac with thrsc patients; one accumulates a mass of negative laboratory data. Asel and Anderson”’ found an elevation ol’ leukocyte alkaline phosphatasc activity in all of 12 cases studied. In 11 of our easesof chronic urticaria. the leukocyte alkalinci phosphatase acativity ranged from 13 to 129. with ii n1w11 of 59 atIt only 3 (xX’s above 100. Thus, we could not confirm this finding. Cohen and (Iricp” prcscntcd evidence that amebiasis played it role in thr etiology of urticaria. With Dr. Raymond CypesP I have studied 50 patients with urticaria, including 18 with acute and 32 with chronic, urticaria. These represented 75 per (lent of all patients seen with urticaria during the?20 month period of the study. In no case were ova and parasites found in the stools, and in none of 40 sera from these patients was there a positive test, for antibodies to Entccnroeba histolvtica or trichinella. Thus, parasitic infection does not appear to be a cause of urticaria, and stool examination for ova and parasites is not a worthwhile routine procedure in urticaria, at least in this part of the country. Intradermal allergy testing gave negative results in our patient as in most
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patients. I have never seen a patient in whom allergy testing itself led to the ctiologic diagnosis. Therefore, allergy testing should not be a routine procedure in the investigation of the patient with chronic urticaria. Such testing has limited value in confirming a specific sensitivity suggested by the history. PATHOLOGY
MontgomerP’ stated that the urticarial wheal is characterized histologically by edema, particularly in the upper dermis and in the connective tissue, with the presence of histiocytes and polymorphonuclear and lymphocytic cells and fibrin deposition in the dermis. In chronic urticaria there is a greater cellular infiltration and vacuolation of t.he basal cells of the epidermis. There have been no reports on this subject using electron microscopy. The light microscopic finding in the case presented here are not those described above but more like the description of I~ever,Zuwho reported edema, particularly of the upper dermis, and collagen bundles, and some perivascular lymphocytic infiltration. The electron microscopic findings are of interest in that there is an absence of mast cell degranulation, but there is evidence of mast cell activity as deduced by the presence of fat droplets. The significance of the reduced density of the mast cell granules is not known but may reflect a discharge of chemical mediators from the cell. PROGNOSIS
There are no published reports dealing with the natural course of chronic urticaria. However, in 1966 we conducted a long-term follow-up study of 88 patients with chronic urticaria seen at least 3 years prior to the onset of the study.Z’ We were able to contact 68, or 77 per cent, of the patients by personal interview, telephone, or mail, with an average follow-up period of 71,$ years. There were 23 patients who continued to have hives. Of these only 4 were severe, 5 were in the care of a physician, and 11 required medication. Two patients had died, 1 of Hodgkin’s disease and 1 of a heart attack. The remainder had recovered completely. In no other case did the patient develop any significant disease or complication, such as neoplasm, collagen disease, or focal infection. Thus, chronic urticaria is a benign diseasewith a good prognosis. MANAGEMENT
The diagnostic management of the patient with urticaria begins with a thorough history and physical examination. Whether any laboratory investigation is needed depends on the information obtained. It may be desirable to perform specific tests to confirm or eliminate clues elicited in the history. There is no basis at the present time to recommend any test as part of the routine evaluation of the patient with urticaria. Certainly, there is no good evidence to believe that allergy testing will identify the cause, When the patient suspects that some food or drug produces hives, that substance should be avoided for a period of time, after which it may be tried in order to see if symptoms appear. Trial diets may be used for a few weeks or a month but not much longer if there is no improvement. Aspirin should be avoided and other drugs should be prescribed with discretion, particularly those
282
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J. ALLERGY
ClIN.
IMMUNOL. APRIL 1975
that commonly produce hives. Food dyes have been implicated recently in the ~ansatiol\ of nrticaria. Trial diets may help identify this source of difficulty. Any specific factor that products or aggravates the urticaria should hc ;t\oicl~d. This includes animals, insects, clothing, scratching the skin or pressure’ on the skin. in atlclition to foods and drugs. Although the primary cause may by unknown, the paticbnt may have c~xac~crbationn due’ to specific sensitivities that. (‘a?1 1W recognisctl. At. the first visit the patient should be advised that the diagnosis is clear, ww if the c~ausr is not, that his condition is not contagious, serious. crippling, or a sign of (*ariver or other major disease, and that the outlook is good. Meanwhile, hc will bc given medication to help him fcrl hetter and control his symptoms. Symptomatic therapy inpludcs antihistaminic agents and sympathomimetic drugs. One can init.iatc t.hcrap\r with earbinoxamine, 4 mg. four times daily, alternating with hydroxyaine, “5 mg. three times a day. Other a.ntihistamines may bc substituted if necessary and ephedrine or pseudoephedrine added for additional relief or to minimize the sedativr side effects. Epinephrine may by usefnl in acute attacks. Steroid therapy should be reserved for patients who fail to respond to the above program, even though this modality has not been greatly cficctivr in chronic urticaria. Sedatives, tranquilizers, and other types of drugs should he used for t,hc relief of specific. symptoms or special problems. Patients with chronic urticaria have usually experienced trying times, have had much advice and treatment, and have had little relief. They require patience. kindness, and attention. The patient often knows better than anyone else what his prohlcm is, and his voice must bc heard. A comprehensive, well-directed treatment program will generally help control the urticaria, if not relieve it entirely. REFERENCES 1 Sheldon, J. M., Mathews, K. P., and Lovell, R. G.: The vexing urticaria problem: present. concepts of etiology urld mnnrcaemctnt,J. A~.I.ER~Y 26: 525, 1954. 2 Ungcar, h. ET.: Chronic urticnria. T. Approach to an enigma, Texas State J. Med. 56: 347, 1960. 3 ‘I’as, J.: Chronic urticarin, Derm:~tologicn 136: 90, 1967. 4 Fronwr, .J. I..: Atopic urticaria rind &+oneurotic edema, in (‘ricp, I,. H., editor: Dermatologic allergy : 1 mmunolopy, diagnosis, mamlgemrnt, Philadelphia, 1967, IV. R. Saunders (‘onlpany, pp. 279-297. 5 Gwen, G. R., Koolsche, G. A., and Kierland, R. B.: Etiology and pathogtwesis of chronic urticxria, Ann. Allergy 23: 30, 1965. 6 Mathews, K. I’.: A current view of urticaria, Med. Clin. North Am. 68: 186, 19il. 7 Caunn, N., und Levinr, M. I.: Unpublished obaetvati,ons. 8 Eisenberg, B. C.: Mnnagement of chronic urticaria, .T. A. M. A. 169: 14, 1959. 9 Hnlpern, S. H.: Chronic hives in children: An analysis of 75 eases, Ann. Allergy 23: 689, 1965. 10 Mitchell, J. H., Smith, D. L., and Mayers, R. A.: Is chronic urticaria an allergic diaorderl Ann. Allergy 16: 128, 1957. 11 Rces, L.: An aetiological study of chronic urticaria and angioneurotic edema, .J. Psychosom. Hes. 2: 172, 1957. 12 Steinhnrdt, M. a.: erticaria and angioedemn. Statistical survey of 500 caees, Ann. Allergy 12: 659, 1954. 13 Miller, I). A., Freeman, G. L., and Akers, W. A.: Chronic urticaria. A clinical study of 50 patients, Am. J. Med. 44: 68, 1968.
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14 Shoemaker, R. J., Levine, M. I., Shipman, W. G., and Mally, M. A.: A search for the affective determinants of chronic urticaria, Am. J. Psychiatry 119: 358, 1962. (Abst.) 15 J:~nws, .T., an(l \Varin, H. P. : Chronic urtisarin : The effect of aspirin, Br. J. Dermatol. 82: 204, 19io. 16 Easel, N. D., and Anderson, P. C.: Disproportionate leukocyte alkaline phosphatase elevation due to urticarin, J. Invest. Dermatol. 43: 535, 1964. and angio-edema in association vvith amebiasis, 17 Cohen, S. G., and Criep, L. H.: Urticaria Am. Pratt. Dig. Treat. 1: 246, 1950. 18 Levine, RI. I., and Cypess, R. H.: Unpublished observations. 19 Montgomery, H.: Dermatopathology, New York, 1967, Harper & Row, Publishers, chap. 8, pp. iii-li8. 20 Lever, W. F. : Histopathology of the skin, ed. 3, Philadelphia, 1961, J. B. Lippincott Company, p. 114. 21 Bauschard, F. D., Ebken, R. K., and Levine, M. I.: Clinical course of chronic urticaris. J. ALLERGY 37: 105, 1966. (Abst.)
Erratum In Abstract No. 110, “Effect of beta-adrenergic reactivity to histamine,” which appeared on page JOURNAL, the fourth line in the second paragraph wheal size in both groups.
stimulation and blockade on cutaneous 113 of the February, 1975, issue of the should read: (3) Isoproterenol deareased
Chronic urticaria Macy I. Levine,
M.D.
Pittsburgh, Pa.
In l!G4, Sheldon, l~ovell, and Mathews’ characterized the attitude of many physicians toward urticaria in the title of their review, “The Vetiw Urticaria Problem.” TTnger” rcflectcd a similar posture in his article, “Chronic Urticaria. 1. Approach to an ISnigma.” ln 1964, an unidentified cynic said, “I should rather SW a tiger come into my ofice than a patient with chronic urticaria.“” These gloomy viewpoints would be fortified by Fromer’s4 comment that “The nlanagenlent of patients with (Bhronic urticaria depends largely on the ability of the clinician to find a cause,” and the finding of Green, Koelsche, and Kicrlantl” that 70 per cent of bhcir caseshad an undetermined cause. Now, after twenty years, MathcwsC has reversed this position by pointing out that patients with chronic urticaria can usually be controlled clven without identification of the cause. I should like to add another optimistic point of view in the following CBSCdiscussion and present some of t.he experiences gained in this clinic in the past two tlecades. PRESENTATION
OF CASE
This 51.yenr-old white housewife and registerad nurse was first wcn on April 2, 1970, I~~:ause of hivw of 11 months’ duration. She developed gcnoralizcd, pruritic urticarinl lesions onck day after she broke her high-protein weight reduction diet. The hives occurred almost cbvery day, mostly at night rind whrn the patient felt wnrm or tried to relax. In l!W~runry. 1970, thus hives flared up following ndministrat,ion of penicillin for a “virus.” There was no wrrrlation with nny othw factor. In Kovembw, 1969, an nllwgist I)erformcd 12 allergy tests ant1 wportetl a positiw rcwtion only to cat. JJc considered tension to hc :L wnsative factor :~nd advised the- patirn! to get rid of the wt, calcan the: hour thoroughly, and takr hytlroxyr,irw. Thr patient followvrcl this advice without betwfit. She then restrirtrd 1lc.r diet, avoiding nuts, eggs, nntl c!hoc:olnt~~, which she, thought, were aggravating the hives, but noted no change. She used epinephrinc and nntihistnminow with somc~ relief and steroid drugs without apparent wlic~f. At, the :I~C of 27, the paticwt, had caonsultcbd another allergist twcaust! of naual symptoms and wns administered some allergy tcaats and then immunothwapy. I&h year since 1962 she had ~ufferetl with wnsonel rhinitis from April to dune. She received injections of emulsified grnss and dust extrwts in May, 1969, just 4 tlnys prior to the onset of thr urticarin. The patient complained of occasional lwadaches, lightheadedneaq, bloating, frequent epi-
of hfcdicirw, IJ;Cvernity of Pittsburgh School of Medicine. Xupported in pnrt by a grant from the Pennsylvania Allsrgy A.swciation. Hcreived for publicntion June 4, 1974. Heprint requests to: Macy I. Lcvinc, M.D., 3347 Forbes Ave., Pittsburgh, Vol.
5.5, No.
4, pp.
676-685
Pa.,
15813.
VOLUME NUMBER
55 4
Chronic
urticaria
277
sodes of diarrhea, and discomfort in her knees, ankles, and feet. She felt very tense and frustrated, but did not associate these symptoms with her hives. She frequently spoke about her husband, a hardworking steel company executive who had been divorced twice before this marriage, and who drank heavily and always criticized the patient. The husband had had congestive failure and impotence. On one occasion the patient left him, only to return because she could not manage financially. The family history revealed that the mother and two children of the patient had seasonal allergic rhinitis. The past history revealed many surgical procedures: tonsillectomy, appendectomy, hemorrhoideetomy, salpingo-oophorectomy, and excision of a cyst from the thigh. In 1958, left carotid ligation was performed for intracranial bleeding and diphenylhydantoin therapy was instituted. In August, 1969, primidone was substituted for diphenylhydantoin because it was thought possible that the latter drug might be causing the hives, but there was no change. About 1966, the patient had all of her teeth extracted and then had much ditTiculty getting used to dentures. Physicial examination revealed an obese female weighing 168 pounds and 5 feet, 4% inches in height. The blood pressure was 140/78. The left eye showed a cataract. The mouth was edentulous. Healed scars were noted on the left side of the neck and on the abdomen. Urticarial lesions were observed on the body and extremities. No other abnormalities were noted. Intradermal testing with 23 allergens, Mecholyl, 1: 10,000, and acetylcholine, 1 :lO,OOO, gave negative results. Histamine, l:lO,OOO, produced a 10 x 9 mm. wheal and 18 x 19 mm. erythema. Bradykinin, 1: 10,000, produced a 9 x 8 mm. wheal and 11 x 9 mm. erythema. Treatment included epinephrine, ephedrine, pseudoephedrine, carbinoxamine, methdilazine, and ehlordiazepoxide. However, the hives recurred almost daily. Neither hives nor diarrhea occurred when the patient fasted. Because of the persistence of symptoms the patient was hospitalized at Montefiore Hospital, Pittsburgh, in November, 1970. The patient complained of left shoulder pain, which was diagnosed due to periarthritis and treated with a local triamcinolone injection and physical therapy. She also complained of pain in the coccygeal area as the result of a fall. There were no new physical abnormalities. The weight was 178 pounds. The following laboratory tests were normal or negative: complete blood count, urinalysis, VDRL, electrocardiogram, sedimentation rate, lupus erythematosus preparation, antinuclear antibody, two stool specimens for ova and parasites, fasting blood sugar, blood urea nitrogen, serum electrophoretic pattern, chest roentgenogram, and barium enema. Cholesterol was 354. The biochemical profile was otherwise normal. Leukocyte alkaline phosphatase was 53. C’3 was 250. (Normal values: cholesterol, 150-250 mg./lOO ml.; C’3, 145 ?: 22 mg./lOO ml. ; leukocyte alkaline phosphatase, 15-100.) A high-speed drill punch biopsy of the skin was performed without anesthesia and with the patient off all medication for 10 hours. One specimen was obtained from a wheal on the left thigh for examination by light microscopy. Another specimen was obtained from a wheal in the left deltoid area for examination by electron microscopy. A control specimen was obtained from unaffected skin in the left deltoid area. Under light microscopy the epidermis of the wheal was normal. The dermis showed some dilated capillaries and perivascular infiltration with leukocytes, mainly polymorphonuclear cells. An occasional eosinophil and a rare mast cell were seen. Under electron microscopy, 7 the control site with its mast cells (Fig. 1) appeared normal. The electron microscopic picture of the wheal revealed no dramatic changes except for the mast cells, which showed a reduction in density of the granules (Fig. 2). The cytoplasm of these cells consistently contained membrane-bounded fat droplets. Up to seven droplets were counted in a single section of a cell. During the hospital stay the diet was limited to six foods (lamb, lettuce, pears, rice, rye, tea) that seldom cause allergic reactions. Primidone was discontinued and diphenylhydantoin was reinstituted. Methdilazine and ephedrine were continued. The patient avoided use of her dentures for 3 days, but observed no change in her hives during this period. The patient was advised ahout the results of her studies, advised that she had no sign of cancer or other serious illness, and given much opportunity to ventilate her feelings. She was discharged after 9 days with instructions to add the restricted foods to the diet and continue the same medica-
278
Levine
J. ALLERGY
CLIN.
IMMUNOL. AF’t?ft lW5
FIG. 1. Mast cell from an unaffected skin area showing granules and well-developed villous processes (Pr). Each mast cell granule is surrounded by a membrane (m) and consists of an outer zone of poorly developed lamellar element (lam) and an inner core (c) of fine or coarse grainy material. The granules vary in size, shape, and density. Skin from the deltoid region. (x22,000.)
t ions. Although 3hr uxs still Ilitving hives, they tended to 1~2 ~mallrr and IRYY pruritic. The patient returnrd to the office I month later and reported freedom from hives for 3 weeks. She had added the restricted foods to the diet and felt less nervous and more energetic. She had lost weight to 159 pounds and had obtained new dentures. She was not seen again but she did respond to an inquiry from me with a letter dated April Ii, 1974, in which she recorded continued freedom from hives and other illness. She had had herpes xoster in August, l!K3, and periodic diarrhea and abdominal discomfort, but upper gastrointestinal and barium enema x-ray examinations showed no abnormality in August, 1972. DISCUSSION
It is quite clear from the history and inspection of the skin lesions that this patient has chronic urticaria. The diagnosis of this condition is usually straightforward, but occasionally the patient exhibits erythematous ma&w and targetshaped wheala that suggest erythema multiforme. This question in ditEerentia1 diagnosis may ultimately be resolved by skin biopsy. According to various authors, the time period required for hives to be considered chronic varies from 1 to 6 months. Unless one includes some intermediate category, T think that 1 month is sufficient time for urticaria to be considered chronic because there doea not ap-
VOLUME NUMBER
55 4
FIG. 2. Part cell granules the cytoplasm encountered
Chronic
of a mast cell from the wheal showing some as compared with the cells fram the adjacent of the mast cell contains membrane-bounded in the control cells. (~22,000.)
urticaria
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reduction in density of mast unaffected skin. In addition, fat droplets (F) not usually
pear to be any significant clinical difference between the patient with hives for 1 month and the one with hives lasting over 6 months. The designation, chronic intractable urticaria, may be used for the patient with hives that persist for more than 2 years. Another question deals with what constitutes chronicity. This has not been defined in the literature. It would seem to me that the occurrence of hives to some degree on most days and without free intervals longer than 5 days would constitute chronicity, and would give some basis for distinguishing acute recurrent urticaria. ETIOLOGY
Our patient shows no good evidence for an allergic basis for her urticaria, except for the flare-up following penicillin therapy. It is possible that the emulsified allergy extracts she received 4 days prior to the onset of the hives were responsible for initiating the attack, but not for its persistence. The failure of the patient to have seasonal rhinitis in 1970 and the negative intradermal tests with dust and grass pollens cast doubt on this possibility. Although a psychiatric appraisal was not obtained, much information about emotional conflicts and disturbed feelings was easily elicited. The patient had much anxiety, frustration, and resentment. She was obese and had several nonspecific complaints. Her
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which providctl iiltcsnsivcb stucl?-, ill improvement followed the hospitalization, tention, and much opportunity to talk about herself and her feelings. In addition, her fears about cancer and other diseases were dispelled. Subsc~clucnt ly. shcl felt less anxious, had more energy, and lost weight. 1Vit.h this history a11t1 thca absence of other factors, it seems rcasonablc to consider the urticaria l)s!cliogc-ic in origin. Xost authors reporting investigations of patients with cahronic urticuria havcl found psychogenic factors responsible for some proportion of thc~ir (WSW. varying from 10 to 68 per cent.“? “-lo This proportion mavY be related to the oricntafion 01 the physician and his interest and understanding of emotional factors in disease. which is related to the amount of information lcarncd about the psychologic milieu of the patient. What constitutes evidence for causation is largclp a matter of opinion in any case. In an earlier multidisciplinary investigation of 40 (::LSW of chronic urticaria,14 we considered chronic nrticarin to be a psychosomatic disease with the hives occurring as the regressive, physiologic expression or nnconscious conflict when the usual defense mechanisms become inadequate. Although 11 per cent of patients with chronic urticaria tlcvelop hives I’ollowing ingestion of aspirin,‘” this drug is not the primary cause of thcl tliseasc> in these patients. There arc isolated reports that allergy to other tlrllgs, I’oods. molds, and other allergens arc’ responsible for the condition. I’awsitic: infcctioll. focal infection, neoplasms, and autoimmune diWilWS IIilvC INWl listctl as C;lWWS of chronic urticaria, but there is no well-documcntt>(l c~vitl~~nccthat, ;IIIJ’ of thcsc are responsible for anything other than a chance association. Thus, from the ctiologic viewpoint. paticlnts with c.hronicaurticdaria fall into three caategorics: one group in whom no cansativo f;ztor WII 1~: itlcnt ifietl, one in whom emotional factors appear to IW implicatc~l. ~114 one srn;~ll groul) in whom an allergic basis is suspected. LABORATORY
INVESTIGATiON
Our patient had clxt,cnsivct laboratory studies without abnormalit\. c~sc:~pt for an unrelated cholesterol elevation. This is the usual ospcriencac with thrsc patients; one accumulates a mass of negative laboratory data. Asel and Anderson”’ found an elevation ol’ leukocyte alkaline phosphatasc activity in all of 12 cases studied. In 11 of our easesof chronic urticaria. the leukocyte alkalinci phosphatase acativity ranged from 13 to 129. with ii n1w11 of 59 atIt only 3 (xX’s above 100. Thus, we could not confirm this finding. Cohen and (Iricp” prcscntcd evidence that amebiasis played it role in thr etiology of urticaria. With Dr. Raymond CypesP I have studied 50 patients with urticaria, including 18 with acute and 32 with chronic, urticaria. These represented 75 per (lent of all patients seen with urticaria during the?20 month period of the study. In no case were ova and parasites found in the stools, and in none of 40 sera from these patients was there a positive test, for antibodies to Entccnroeba histolvtica or trichinella. Thus, parasitic infection does not appear to be a cause of urticaria, and stool examination for ova and parasites is not a worthwhile routine procedure in urticaria, at least in this part of the country. Intradermal allergy testing gave negative results in our patient as in most
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patients. I have never seen a patient in whom allergy testing itself led to the ctiologic diagnosis. Therefore, allergy testing should not be a routine procedure in the investigation of the patient with chronic urticaria. Such testing has limited value in confirming a specific sensitivity suggested by the history. PATHOLOGY
MontgomerP’ stated that the urticarial wheal is characterized histologically by edema, particularly in the upper dermis and in the connective tissue, with the presence of histiocytes and polymorphonuclear and lymphocytic cells and fibrin deposition in the dermis. In chronic urticaria there is a greater cellular infiltration and vacuolation of t.he basal cells of the epidermis. There have been no reports on this subject using electron microscopy. The light microscopic finding in the case presented here are not those described above but more like the description of I~ever,Zuwho reported edema, particularly of the upper dermis, and collagen bundles, and some perivascular lymphocytic infiltration. The electron microscopic findings are of interest in that there is an absence of mast cell degranulation, but there is evidence of mast cell activity as deduced by the presence of fat droplets. The significance of the reduced density of the mast cell granules is not known but may reflect a discharge of chemical mediators from the cell. PROGNOSIS
There are no published reports dealing with the natural course of chronic urticaria. However, in 1966 we conducted a long-term follow-up study of 88 patients with chronic urticaria seen at least 3 years prior to the onset of the study.Z’ We were able to contact 68, or 77 per cent, of the patients by personal interview, telephone, or mail, with an average follow-up period of 71,$ years. There were 23 patients who continued to have hives. Of these only 4 were severe, 5 were in the care of a physician, and 11 required medication. Two patients had died, 1 of Hodgkin’s disease and 1 of a heart attack. The remainder had recovered completely. In no other case did the patient develop any significant disease or complication, such as neoplasm, collagen disease, or focal infection. Thus, chronic urticaria is a benign diseasewith a good prognosis. MANAGEMENT
The diagnostic management of the patient with urticaria begins with a thorough history and physical examination. Whether any laboratory investigation is needed depends on the information obtained. It may be desirable to perform specific tests to confirm or eliminate clues elicited in the history. There is no basis at the present time to recommend any test as part of the routine evaluation of the patient with urticaria. Certainly, there is no good evidence to believe that allergy testing will identify the cause, When the patient suspects that some food or drug produces hives, that substance should be avoided for a period of time, after which it may be tried in order to see if symptoms appear. Trial diets may be used for a few weeks or a month but not much longer if there is no improvement. Aspirin should be avoided and other drugs should be prescribed with discretion, particularly those
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that commonly produce hives. Food dyes have been implicated recently in the ~ansatiol\ of nrticaria. Trial diets may help identify this source of difficulty. Any specific factor that products or aggravates the urticaria should hc ;t\oicl~d. This includes animals, insects, clothing, scratching the skin or pressure’ on the skin. in atlclition to foods and drugs. Although the primary cause may by unknown, the paticbnt may have c~xac~crbationn due’ to specific sensitivities that. (‘a?1 1W recognisctl. At. the first visit the patient should be advised that the diagnosis is clear, ww if the c~ausr is not, that his condition is not contagious, serious. crippling, or a sign of (*ariver or other major disease, and that the outlook is good. Meanwhile, hc will bc given medication to help him fcrl hetter and control his symptoms. Symptomatic therapy inpludcs antihistaminic agents and sympathomimetic drugs. One can init.iatc t.hcrap\r with earbinoxamine, 4 mg. four times daily, alternating with hydroxyaine, “5 mg. three times a day. Other a.ntihistamines may bc substituted if necessary and ephedrine or pseudoephedrine added for additional relief or to minimize the sedativr side effects. Epinephrine may by usefnl in acute attacks. Steroid therapy should be reserved for patients who fail to respond to the above program, even though this modality has not been greatly cficctivr in chronic urticaria. Sedatives, tranquilizers, and other types of drugs should he used for t,hc relief of specific. symptoms or special problems. Patients with chronic urticaria have usually experienced trying times, have had much advice and treatment, and have had little relief. They require patience. kindness, and attention. The patient often knows better than anyone else what his prohlcm is, and his voice must bc heard. A comprehensive, well-directed treatment program will generally help control the urticaria, if not relieve it entirely. REFERENCES 1 Sheldon, J. M., Mathews, K. P., and Lovell, R. G.: The vexing urticaria problem: present. concepts of etiology urld mnnrcaemctnt,J. A~.I.ER~Y 26: 525, 1954. 2 Ungcar, h. ET.: Chronic urticnria. T. Approach to an enigma, Texas State J. Med. 56: 347, 1960. 3 ‘I’as, J.: Chronic urticarin, Derm:~tologicn 136: 90, 1967. 4 Fronwr, .J. I..: Atopic urticaria rind &+oneurotic edema, in (‘ricp, I,. H., editor: Dermatologic allergy : 1 mmunolopy, diagnosis, mamlgemrnt, Philadelphia, 1967, IV. R. Saunders (‘onlpany, pp. 279-297. 5 Gwen, G. R., Koolsche, G. A., and Kierland, R. B.: Etiology and pathogtwesis of chronic urticxria, Ann. Allergy 23: 30, 1965. 6 Mathews, K. I’.: A current view of urticaria, Med. Clin. North Am. 68: 186, 19il. 7 Caunn, N., und Levinr, M. I.: Unpublished obaetvati,ons. 8 Eisenberg, B. C.: Mnnagement of chronic urticaria, .T. A. M. A. 169: 14, 1959. 9 Hnlpern, S. H.: Chronic hives in children: An analysis of 75 eases, Ann. Allergy 23: 689, 1965. 10 Mitchell, J. H., Smith, D. L., and Mayers, R. A.: Is chronic urticaria an allergic diaorderl Ann. Allergy 16: 128, 1957. 11 Rces, L.: An aetiological study of chronic urticaria and angioneurotic edema, .J. Psychosom. Hes. 2: 172, 1957. 12 Steinhnrdt, M. a.: erticaria and angioedemn. Statistical survey of 500 caees, Ann. Allergy 12: 659, 1954. 13 Miller, I). A., Freeman, G. L., and Akers, W. A.: Chronic urticaria. A clinical study of 50 patients, Am. J. Med. 44: 68, 1968.
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14 Shoemaker, R. J., Levine, M. I., Shipman, W. G., and Mally, M. A.: A search for the affective determinants of chronic urticaria, Am. J. Psychiatry 119: 358, 1962. (Abst.) 15 J:~nws, .T., an(l \Varin, H. P. : Chronic urtisarin : The effect of aspirin, Br. J. Dermatol. 82: 204, 19io. 16 Easel, N. D., and Anderson, P. C.: Disproportionate leukocyte alkaline phosphatase elevation due to urticarin, J. Invest. Dermatol. 43: 535, 1964. and angio-edema in association vvith amebiasis, 17 Cohen, S. G., and Criep, L. H.: Urticaria Am. Pratt. Dig. Treat. 1: 246, 1950. 18 Levine, RI. I., and Cypess, R. H.: Unpublished observations. 19 Montgomery, H.: Dermatopathology, New York, 1967, Harper & Row, Publishers, chap. 8, pp. iii-li8. 20 Lever, W. F. : Histopathology of the skin, ed. 3, Philadelphia, 1961, J. B. Lippincott Company, p. 114. 21 Bauschard, F. D., Ebken, R. K., and Levine, M. I.: Clinical course of chronic urticaris. J. ALLERGY 37: 105, 1966. (Abst.)
Erratum In Abstract No. 110, “Effect of beta-adrenergic reactivity to histamine,” which appeared on page JOURNAL, the fourth line in the second paragraph wheal size in both groups.
stimulation and blockade on cutaneous 113 of the February, 1975, issue of the should read: (3) Isoproterenol deareased
