Asian Pacific Journal of Allergy and Immunology (1995) 13: 29 - 35

Cold Urticaria in Thai Children: Comparison between Cyproheptadine and ketotifen in the Treatment

Nualanong Visitsunthorn, Montri Tuchinda, and Pakit Vichyanond

Cold urticaria syndromes are SUMMARY: The study was performed In 6 Thai children with primary acquired characterized by the development of cold urticaria_ They all suffered from generalized urticaria and two of them aiso urticaria and/or angioedema after cold had angioedema. All of them had normal erythrocyte sedimentation rate, exposure. l In Thai children with complement 3 and negative VORL, TPHA, hepatitis B screen and cold agglutinin urticaria, 1.4% developed symptoms titer. Cryoglobulin was checked in 3 cases and showed negative results A double-blind cross-over study to compare the effectiveness of cyproheptadine after cold exposure.2 The diagnosis of and ketotifen demonstrated that the efficacy of cyproheptadine and ketotifen on cold urticaria is based on history of clinical symptoms and Ice cube test was not significantly different (p>O.05). Both symptoms after cold exposure. Ice cube of them showed good results in the treatment of cold urticaria with mild side test is a simple and easy investigation effects. During the follow up, 5 cases showed complete recovery while the other to confirm diagnosis ofcold urticaria. 3,4 one developed one or two exacerbations per year upon cold exposure. However, Cyproheptadine is one of the H 1 an­ the symptoms were mild and subsided on administration of one or two doses of tagonist which is effective in the treat­ H, antihistamine. Our data demonstrated that ketotifen was as effective as ment of cold urticaria 5-9 and can inhibit cyproheptadine in the treatment of cold urticaria in Thai children. wheal and flare from the ice cube test after 4 weeks of treatment.3 Long term use of antihistamine may be necessary also to compare the clinical symptoms, visit (week 0) as shown in the study in the treatment of cold urticaria so the ice cube score and side effects between protocol in Table 1. On the second visit medication should be harmless. the treatment with cyproheptadine and (week 0) complete blood count, differ­ Cyproheptadine can depress growth in ketotifen. ential white count, stool examination, long term use in childrenlO so other erythrocyte sedimentation rate (ESR), MATERJALS AND METHODS ), effective drugs should be used instead complement 3 (C3 VDRL, TPHA, of cyproheptadine. Ketoti fen is an The double blind cross-over hepatitis B screening (HBs Ag, HBs antihistamine that can prevent mast study was performed in six Thai chil­ Ab, HBcAb), cold agglutinin titer cell degranulation. ll,12 It has been dren with primary acquired cold urticaria shown to prevent clinical urticaria in who were referred to the Allergy Clinic, cold induced urticaria. ll,13-l6 Previous Department of Pediatrics, Faculty of From the Department of Pediatrics. Faculty studies showed lack of significant Medicine Siriraj Hospital, Mahidol of Medicine Siriraj Hospital, Mahidol Univer­ side effects after prolonged use of University, Bangkok, Thailand. On first sity. Bangkok 10700, Thailand. ketotifen. l7,l8 The aims of our study visit, history and physical examination Correspondence : Nualanong Visitsunthorn, were to evaluate the characteristics, included ice cube test were performed. Department of Pediatrics. Faculty of Medicine laboratory findings and clinical course All medications were stopped for a Siriraj Hospital, Mahidol University, Bangkok of Thai children with cold urticaria and week from first (week -1) to second 10700, Thailand_ 30 VISITSUNTHORN, ET AL.

throughout the study. A positive ice Table 1. The study protocol. cube test is shown in Fig. l. The clinical score was recorded Group I cyproheptadine ketotifen as percent of improvement (0-100%). The clinical scores recorded were frequency of urticarial attack, size of Group II ketotifen I cyproheptadine '----~ urticarial rash, pruritus, swelling and other systemic symptoms associated with cold exposure. * * * * * * * I I I I I I I The side effects such as drowsi­

-1 o 2 4 6 8 10weeks ness, dry lips, increased appetite and dizziness were scored as tHows: *= follow up and perform ice cube test. o = no side effect 1 == mild side effect (no distur­ bance to normal acti,:,ity) and cryoglobulin were done. The patients were randomly devided into 2 groups (3 patients in each group). Group I: cyproheptadine (0.25 mg/kg/ day divided twice daily) was started at week 0 and continued to week 4 then stopped for 2 weeks as a washed­ out period. At week 6, ketotifen R (Zaditen , Sandoz, dose < 35 kg:0.5 mg bid; ~ 35 kg: 1 mg bid) was started and continued to week 10. Group II: ketotifen was administered first on week 0 to 4 then 2 week washed-out and 4 weeks of cyproheptadine therapy. Every visit the ice cube test was done. The clinical improvement score and side effect score were informed by the patients and their par­ ents.

Ice cube test method One-cubic-inch ice cube was gen­ tly placed without pressure on the ven­ tral surface of forearm for 5 minutes. The result of ice cube test was checked at 10 minutes after the ice cube was removed and score was recorded Fig.1. A positive ice cube test on the forearm of a cold urticaria patient. (Table 2) by the same investigator

2 == modrate side effect (mild Table 2. Determination of ice cube test. disturbance to normal ac­ tivity) Ice cube Findings 3 severe side effect (definite disturbance to normal ac­ o none tivity) 1 red, very little edema The clinical and side effect scores 2 some wheal, slight raise between cyproheptadine and ketoti fen 3 definite wheal were compared at 4 weeks after treat­ 4 large wheal, 1/8 inch height ment. Ice cube scores between cypro­ COLD URTICARIA TREATMENT IN CHILDREN 31

heptadine and ketotifen were compared on the beginning of the treatment, at 2 Table 3. Characteristics of six Thai children with cold urticaria. and 4 weeks after treatment. An cases were followed up for Patient No. more than 5 years to study the course of cold urticaria and occurrence of other 1 2 3 4 5 6 allergic disorders. Age (years) 9 7 8 7 4 7 Sex· M F M M F M Statistical analysis Duration of cold 3 2 3 6 2 6 The results were analyzed by urticaria (months) non-parametric analysis. A p value < Severity of G G G G,A G G,A 0.05 was considered statistically symptoms- significant. Allergic history*** 0 AR 0 Asthma IE Asthma Familial allergic*** RESULTS history AR Urt Urt Urt 0 AR Characteristics of six Thai chil­ Area of cold skin, skin skin skin skin skin, dren with cold urticaria are shown in exposure oral oral Table 3. Mean age of the patients mucosa mucosa was 7 years. Four of them were male . M= male, F= female and two were female. All of the cases - G= generalized, A= angioedema suffered from urticaria for more than *** AR= allergic rhinitis 6 weeks. Mean duration of urticaria IE= Infantile eczema before the study was 3.6 months. all Urt= urticaria of the cases had generalized urticaria 0= none while two of them also suffered from angioedema. Area of cold exposure in all of the cases was skin. Two cases also experienced cold urticaria after Table 4. Laboratory findings in cold urticaria children. oral mucosa exposure to cold (ice and ice cream ingestion). None of them had Patient No. history or dermographism, cholinergic urticaria, aspirin-induced urticaria or 2 3 4 5 6 familial history of cold urticaria. Labo­ Ice cube score 4 2 3 2 3 4 ratory findings of the patients are Total blood eosinophils 410 952 0 603 0 396 shown in Table 4. Only two cases (cells!cu mm) had blood eosinophil counts of more Stool examination Giardia N N N N N than 500 cells/mm3. Stool examination cyst was positive for Giardia fambfia cysts ESR WNL WNL WNL WNL WNL WNL in one case who had blood eosinophil VORL N N N 1: 1 N N 410 cells/mm3. He was treated with Cold agglutinin < 1: 64 1: 4 < 1: 4 < 1: 4 < 1: 4 < 1: 4 metronidazole before the study Hepatitis screening N N N N N N started. Cryoglobulin was done in 3 C3 WNL WNL WNL WNL WNL WNL cases and all were negative. IgG,lgA,lgM WNL WNL WNL WNL WNL WNL Cryoglobulin N N N Comparison between the results of cyproheptadine and ketotifen on N negative clinical improvement is shown in WNL within normal limits Fig. 2. The mean percent of clinical not done improvement of cyproheptadine was 85 ± 6 and ketotifen was 88 ± 6 which were not significantly different heptadine and ketotifen before, at 2 were 3, 2.6 and 0.66 and of ketotifen (p>0.05). Comparison between ice and 4 weeks after treatment were were 3, 2.4 and 0.66, respectively. cube scores after cyproheptadine and not significantly different (p>0.05). Comparison between the mean ketotifen treatment is shown in Fig. 3. The mean ice cube scores of cypro­ side effect scores after cyproheptadine The mean ice cube scores of cypro- heptadine before, at 2 and 4 weeks and ketotifen in Fig. 4 showed trend 32 VISITSUNTHORN, ET AL.

year upon cold exposure, However, the symptoms was mild and subsided Clinical improvement (%) on administration of one or two doses of cyproheptadine or ketotifen. The 100 clinical course of six cold urticaria chil­ dren is shown in Table 5, Three of the 90 cases have had no other allergic problems while the others suffered ,",";1 t,:·,: ;::;.-:;.~:;.: from asthma and allergic rhinitis, 80 f- "."'."...... ". "."'...... ".... "0"0"0""0"'...... • "."."0"0'"...... DISCUSSION "."'0"'0"'0"­ 70 ".".".",."...... Cold urticaria is a common form "."0"0"0""...... "0"0"'0"'0"'...... • of physical urticaria, Incidence of cold "."."."."...... 60 "0"0"0"'."...... urticaria is 2.5% of urticaria patients at "0"0"0"0"'­...... "0"0"0"'0"'...... "."0"0./'0"'0...... all age groups and 74% of physical 50 o!:.!:.!::'::.'::-::-::-::-::-:: urticaria,19 Primary acquired or idiopathic cold urticaria is the most Cyproheptadine Ketotifen common form of cold urticaria,2U Our study included six children with Fig.2. Comparison between the result of cyproheptadine and ketotifen on clinical primary acquired cold urticaria aged symptoms, 4 to 9 years old. Four of them were male. Previous studies have shown the controversy between sex distribution which may be due to the selection of the patients,20-22 Cold urticaria may start at any age range from 1 to 74 years 20 but most of them develop the Ice cube score symptoms in young adult. ~ cyproheptadine Symptoms of cold urticaria can 4 be localized, generalized, angioedema [] ketotifen or systemic such as tireness, headache, 3 dyspnea, tachycardia, collapse and even anaphylactic shock20,22 In our re­ 2 port, four of the six patients had only generalized lesions while two of them 1 also had angioedema. Cold urticaria usually appears after expsure to a cold, humid, windy climate or to cold 024 water. 22 Swimming in cold water week oftreatment may cause life-threatening cold urticaria22 Mucosal exposure such as ice-cream ingestion may cause Flg.3. Comparison between the result of cyproheptadine and ketotifen on ice cube oral mucosal swelling and genera­ test. lized urticaria or angioedema.23 I n our study, two of the patients had cold that ketotifen had less freCfJency of high as 2, These side effects were urticaria after both skin and oral side effect (4/6) compared with drowsiness, dry lips and dizziness. mucosa exposure while the others cyproheptadine (2/6). The mean side One patient complained of increasing had lesions only after skin exposure. effect scores between these two drugs the appetite after both medications. A previous study found that 25% of (observed along the course) after 4 After five years of follow up, 5 cold urticaria had atopic disease2U weeks of treatment were 0.66 and cases had complete recovery. The other which was nearly the same as in the 0.5 which were not significantly one showed improvement in clinical normal population in Finland24 Four different (p>0.05). Only one in each symptoms but still developed one or of the patients in our study had a drug treatment group had score as two episodes of cold urticaria per history of atopy and five had a COLD URTICARIA TREATMENT IN CHILDREN 33

of inclusion and no history of such Side effect score diseases just before the symptoms occurred. The previous study showed that 12% of primary acquired cold 3 urticaria associated with dermographism and 8% associated with cholinergic urticaria.20 None of the patients from 2 o our study had history of cholinergic urticaria or dermographism. Symptoms of cold urticaria may 1 develop months or years be fore the 000 patients are first evaluated.22 Sponta­ o neous recovery of primary acquired cold urticaria occurs within one and o 00 a half to two years after onset of symptoms.22 However, the symptoms may be present from a few months to Cyproheptadine 9 Ketotifen 20 years or longer .1 ,22 The previous study showed that 25% of patients Flg.4. Comparison between the side effects of cyproheptadine and ketotifen. became asymptom;ltic in 1.6 years. The symptoms last more than 10 years in twenty percent of cases while in 55% of cases, the symptoms decreased 25 Table 5. Clinical course of six cold urticaria children. and were less harmful. The other study showed that 50% of cases were Patient No. free from lesions within one year while 25% of cases had episodes 2 3 4 5 6 more than 20 years.l <) I n our study the patients developed symptoms 2 Present status· CR CR CR CR CR 1*** to 6 months before the first evalua­ Total duration of 12 14 39 30 8 > 66 tion. The duration of cold urticaria in cold urticaria our patients lasted 8 to more than 66 (months) months. One of the cases still has Present allergic" 0 AR 0 Asthma 0 Asthma urticaria once or twice a year after disorder exposure to cold but the symptom is • CR= complete recovery, 1= improved mild and subsides after antihistamine .. 0= none. AR= allergic rhinitis administration. This patient also has *** The patient developed one or two exacerbations of cold urticaria per year. had moderate asthma since the time cold urticaria was diagnosed. There familial history of atopy. that cold urticaria appears. These fac­ is currently no definitive method to The term secondary acquired tors are infections such as measles, predict the duration of symptoms of cold urticaria is used if cold urticaria chicken pox, scarlet fever, infectious cold urticaria. is associated with cryoglobulins, cryofi­ mononucleosis, ascaritic infection The definitive pathophysiology brinogen, cold agglutinin, paroxysmal and respiratory viral infections.25 -30 of cold urticaria is unknown. Degra­ hemoglobinuria, chronic lymphocytic Complement fixing antibody titers to nulation of mast cells and release of leukemia, lymphosarcoma cold hemo­ measles virus, cytomegalovirus, herpes histamine during attacks of cold urti ­ 11 lysin or syphilis4, 25 while primary simplex virus and Mycoplasma caria have been demonstrated. acquired cold urticaria is used if cold pneumoniae were significantly higher Histamine has been s hown to be the urticaria is not associated with these in cold urticaria patients than in con­ main mediators for immediate edema diseases. Almost 20% of primary trols30 VORL, TPHA, cold agglutinin, and vasodilatation in cold urticaria acquired cold urticaria patients hepatitis screening and cryoglobulin after cold exposure8 ,32 It is also experience some possible triggering in our patients from the study were not demonstrated that other vasoactive factors or factors that can induce symp­ significantly abnormal. There were no factors and PG O2 would be possible toms just before or at the same time associated viral infections at the time candidate to have a role in cold­ 34 VISITSUNTHORN, ET AL.

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