- Urticaria - 12/12/2005 RE: Chronic urticaria in a 10 year old child I am a physician's assistant, but my question pertains to my own daughter. She is 10 years old. She developed hives for no apparent reason in late August 2005. They started on her buttocks, then gradually spread to other parts of her body each day thereafter, to the point where she has now had chronic hives every morning over her entire body since early September. She is being followed by an allergist in the Kaiser system. He ran the various blood tests, stool sample, and urinalysis. She has had her thyroid levels checked, liver panel, allergy testing (with the exception of food allergy panel), ANA, sedimentation rate, and even had a biopsy of one of the hives. Everything has come back normal. Her pattern when it comes to the occurrence of hives is she wakes with them in the morning. She will have hives on every part of her body. As the day progresses, the hives will fade, but not until later afternoon. By the time she is ready for bed, most have disappeared, with just a few very light ones still present. When she wakes in the morning, she has them all over her body again, including her face, which is the difficult part for her because she cannot hide them from her classmates as she can the others on her body under her clothes. The allergist does not think this is related to an allergy and I agree, mainly because of their pattern. She also lives at he Dad's house 50% of the time. We are divorced and share joint custody. We use different types of soaps, have different clothes for her, different environments, but she has the same problem at his house as she does at mine. There is no stress in our relationship. We still do things together as a family. We have been divorced for over 3 years as well, so it is not like it is a new situation for her. The hives just suddenly appeared one morning. Her doctor seems to think the triggering of the hives is related to her just starting puberty, since the hives came about right around the same time she developed underarm odor for the first time. The problem with her is that she is not responding to any of the antihistamines. She has even been tried on Doxepin with 20 mg at night and 20 mg in the morning, and it does not decrease the hives or the itch either. She has been tried on the combination of H1 and H2 receptors as well, and that did nothing as well. She has been tried on Zyrtec, and had no response to that either. Before the Doxepin and Zyrtec, she was tried on the other antihistamines, such as Atarax, Claritin, Allegra, etc. The only thing that ever made the hives go away for any period of time was when they placed her on prednisone. However, the hives returned 2-3 days after the prednisone was stopped. She was put on this, 3 separate times. However, I understand that the potential side effects of this medication outweigh the benefits, so we do not want her to be placed on steroids. I have read through all of the literature on your website regarding UC. I have yet to come across anything that relates UC with hormones or puberty. Obviously there is something going on inside of her body when she is sleeping that is triggering the hives. Do you know of any literature or cases similar to hers. I have also read over the studies and literature regarding thyroid autoimmunity and the autologuos serum test. I am not sure if the thryoid antibody levels were checked, but I know the autologous serum test was not done. Should I have these tests ran? I am not sure if it is worth running these studies, because my understanding is that there really is not much in the way of treatment for this, or at least treatment that has been studied and found safe for children in her age group. Any information you might be able to add to her case would be most appreciated. If you have any recommendations for another avenue of treatment we could try, that would be appreciated as well. I think we have all pretty much accepted the fact that she's going to be stuck with these for quite some time, since we can't seem to find a cause. So our main focus right now is finding a medication or treatment other than steroids that can help reduce the occurrence or appearance of the hives, along with the itch, without having to use steroids. The clinical picture you describe is often frustrating to the patient, parents and those treating her. I have enclosed below excerpts from my response to another Ask the Expert question about chronic urticaria (CU) in a child. Some of the points discussed may well apply to your daughter as well. I should make some additional points: 1) When I wrote that response, it was unclear how often auto-immune reactivity against the high affinity IgE receptor (screened for by the autologous serum skin test or ASST) was positive in children with CU. A recent report found such reactivity in about the same percentage of children with CU as seen in adults with CU. Studies by several groups, including my own have shown no impressive differences between ASST-positive and ASST-negative patients in either their clinical manifestations or response to therapy. One exception to the latter is that a pioneering group in the investigation of CU found a impressive decrease in the hives for about 2-3 weeks in some of the patients treated with plasmapharesis (suggesting that these autoantibodies or something else in the plasma was playing a causal role). However, since the hives returned repeated pharesis would be needed, not a practical chronic approach. 2) The clinical relevance of the increased frequency of anti-thyroid antibodies in CU patients is still debated although some report improvement in the CU following cautious treatment with thyroxin (even when the baseline thyroid function is normal).Thus, I do not think there is a reason to assess such autoantibodies in your daughter until we know more about their practical clinical relevance. 3) In a number of patients the CU is worsened by aspirin ingestion, particularly in children with CU. So avoidance of chronic use of aspirin or NSAID agents is advisable. Triggering of CU by acetaminophen is much less common. 4) I am not aware of an impressive clustering of CU onset at the time of onset of menarche (when hormone levels are beginning to increase, as you mentioned). However, CU is more frequent in females, and the CU flares in some women monthly in the immediate pre-menstrual period. 5) With regards to therapy, the lack of impressive improvement with any medication trued (except steroids) suggests that an anti-inflammatory approach is needed. I agree that steroids should not be used chronically if at all possible. Some approaches to consider include: a) use of a leukotriene antagonist (such as Singulair ) along with a non-sedating antihistamine such as Allegra for a trial period of 3-4 weeks. b) if there is no improvement, consider a trial of colchicine 0.6 mg once daily. If there is no improvement in 3-4 weeks, consider a trial of Plaquenil. If there is improvement with Plaquenil treatment, the eyes should be checked every 6 months for the occasional eye toxicity of Plaquenil. Excerpt from previous response: Chronic urticaria (CU) without obvious relationship to certain environmental exposures is often a difficult diagnostic problem in both children and adults. Some of the questions/approaches to such CU in children which bear consideration are these: 1) In most cases of CU, anything that raises the body temperature and/or dilates skin blood vessels has the potential for worsening the urticaria. However, there is a particular type of CU called cholinergic urticaria, characterized by very small, itchy wheals surrounded by a large area of erythema (redness) . These are usually triggered by body overheating and/or emotional stress. 2) In some children, CU is associated with chronic viral infections and/or aspirin treatment. If aspirin is being taken frequently a trial of withholding such medication should be made. Reactions to acetaminophen are a much less frequent cause of CU. Of course, reactions to any medications taken chronically by the child may be suspect and a trial of withholding such medication should be considered. 3) Certain systemic diseases may include CU in the presentation. a) It is important to determine whether the individual hive lesions last more than 24 hours and/or leaves a residual pigmented area in the skin. If this is the case, a punch biopsy of a fresh hive should be obtained to look for a possible cutaneous vasculitis as the cause (see enclosed abstract). b) In adults, about 20% of CU patients have evidence of thyroid autoimmunity when screened by appropriate antibody tests. It is less clear how often this occurs in children with CU, but worth investigating. You mentioned thyroid tests were normal without specifying which tests. One has to measure levels of anti-thyroid antibodies. c) A form of systemic mastocytosis called urticaria pigmentosa may look superficially like CU. In this condition there are somewhat tan small skin lesions which become hive-like in appearance when rubbed d) Some congenital conditions such as the Muckle-Wells syndrome may be first manifest as CU-like condition in childhood. There are often systemic manifestations as well d) f) A recent report described an association with Celiac Disease (detected by specific ant-endomysial antibody tests) in about 5% of a group of children with severe CU. The significance of this finding is increased by their observation that the CU cleared within 10 days of starting a gluten-free diet in the children with CU and evidence of Celiac disease. Allergy. 2005 Sep;60(9):1174-7.      Related Articles, Links Hypersensitivity reactions to paracetamol in children: a study of 25 cases. Boussetta K, Ponvert C, Karila C, Bourgeois ML, Blic J, Scheinmann P. Service de Medecine Infantile B, Hopital d'Enfants de Tunis, Tunis, Tunisie. BACKGROUND: Allergic-like reactions to paracetamol (acetaminophen) are rare. Paracetamol allergic and non allergic hypersensitivity (HS) has been diagnosed in a few patients with skin and/or respiratory symptoms, immediate and accelerated urticaria, and angioedema especially. Most patients with HS to paracetamol were also hypersensitive to anti-inflammatory drugs (i.e. acetylsalicylic acid, ASA), suggesting that their reactions resulted from a non allergic HS. However, anaphylactic reactions, and potentially harmful toxidermias, such as acute generalized exanthematic pustulosis and toxic epidermal necrolysis, have been related to specific paracetamol allergic HS, with tolerance to anti-inflammatory drugs. PATIENTS AND METHODS: We report the results of a study performed in 25 children with suspected paracetamol HS. Diagnosis of paracetamol HS was based on a suggestive clinical history and a positive response in an oral challenge (OC) test. RESULTS: Paracetamol HS was diagnosed in only one child (4%). In this child, a positive response to an OC with ASA diagnosed HS to anti-inflammatory drugs. CONCLUSIONS: Our results in children agree with those of the literature, showing that paracetamol HS is rare, and is associated with HS to anti-inflammatory drugs in most patients.   Isr Med Assoc J. 2005 May;7(5):320-2.         Related Articles, Links Pediatric cutaneous mastocytosis: a review of 180 patients. Ben-Amitai D, Metzker A, Cohen HA. Schneider Children's Medical Center of Israel, Petah Tiqva, Israel. BACKGROUND: Mastocytosis is a heterogeneous group of diseases characterized by the abnormal infiltration of mast cells in the skin and, sometimes, other organs. Some patients may experience symptoms related to mast cell mediator release. OBJECTIVE: To analyze the clinical features of cutaneous mastocytosis in a large series of children. METHODS: We conducted a file review of all children clinically diagnosed with cutaneous mastocytosis in our department over the last 20 years. We evaluated gender, age at onset, character and distribution of the lesions, associated symptoms, and course of the disease. RESULTS: Altogether, 180 patients with cutaneous mastocytosis were identified. The male to female ratio was 1.5:1. About one-third of patients had a mastocytoma, which was present at birth in over 40% and appeared during the first year of life in most of the remainder. Urticaria pigmentosa was noted in 65% of the patients, presenting at birth in 20% and during the first year in most of the remainder. The majority of lesions was distributed over the trunk and limbs. Different kinds of associated symptoms were noted. Prognosis in general was good. Only 11% of the cases, all urticaria pigmentosa, were familial. CONCLUSIONS: Most cases of pediatric mastocytosis are sporadic and appear during the first 2 years of life, especially on the trunk. Urticaria pigmentosa is the most frequent variant. The prognosis of pediatric mastocytosis, in general, is good. J Dermatol. 2001 Nov;28(11):632-4.      Related Articles, Links Unusual urticarias. Black AK. St John's Institute of Dermatology, Kings College, St. Thomas Hospital, London, UK. Typical urticarial lesions are transient cutaneous swellings of sudden onset, often itchy, persisting for less than 24 hours and resolving to leave normal appearing skin. Angioedema lesions are similar subcutaneous lesions. Atypical urticarias persist for longer than 24 hours, may be painful and bruised in appearance and accompanied with severe systemic symptoms. Conditions where prolonged weals are present include delayed pressure urticaria and urticarial vasculitis. These conditions do not respond well to antihistamine therapy. In delayed pressure urticaria, weals appear after a delay of hours at sites of sustained pressure on the skin and occur in association with ordinary chronic 'idiopathic' urticaria. Weals of urticarial vasculitis show histological features of venulitis, and can be accompanied by arthralgia and abdominal pain. Rarely, the condition is due to infective or autoimmune disease. Urticarial diseases, sometimes with features of urticarial vasculitis, and with associated systemic features include Schnitzler's Syndrome, Still's disease and Muckle-Wells syndrome. The latter syndrome is linked with chromosome 1q44, as is autosomal dominant cold urticaria, an unusual physical urticaria. Persistent cholinergic erythema, a variant of cholinergic urticaria, has been mistaken for a drug eruption or cutaneous mastocytosis. Rarely, food and exercise induced urticaria and anaphylaxis occur when exercise follows a specific food or any meal within a few hours. The early stages of inflammatory disease may be mistaken for urticaria and angioedema, but lesions usually persist for longer than 48 hours and are accompanied by epidermal changes. 1: Clin Exp Allergy. 2004 Sep;34(9):1401-7.      Related Articles, Links Desloratadine in combination with montelukast in the treatment of chronic urticaria: a randomized, double-blind, placebo-controlled study. Nettis E, Colanardi MC, Paradiso MT, Ferrannini A. Department of Medical Clinic, Immunology and Infectious Diseases, Section of Allergy and Clinical Immunology, University of Bari, Bari, Italy. BACKGROUND: Chronic urticaria (CU) is a common skin condition. It is frequently a disabling disease due to the persistency of clinical symptoms, the unpredictable course and negative influence on the quality of life. OBJECTIVE: The aim of this study is to determine whether montelukast, a LTD4 receptor antagonist, plus desloratadine, is more efficacious than desloratadine alone in the treatment of chronic urticaria. MATERIALS: A randomized, double-blind, placebo-controlled study was conducted on 81 patients with a diagnosis of CU. A 1-week single-blind placebo run-in period (baseline) was followed by a 6-weeks double blind active treatment period. The patients were randomized to receive the following treatment once daily: (a) oral desloratadine (5 mg) plus placebo; (b) desloratadine (5 mg) plus montelukast (10 mg); (c) oral placebo alone. The study ended after another 1-week single-blind placebo washout period. RESULTS: The evaluable population thus consisted of 76 patients. Both desloratadine alone and desloratadine plus montelukast administered once daily yielded improvements with respect to the baseline assessment as regards pruritus, number of separate episodes, size and number of weals, visual analogue score and patients' quality of life and with respect to the placebo group both in the active treatment period and in the run-out period. However, desloratadine plus montelukast was shown to improve the symptoms and patients' quality of life significantly more than desloratadine alone, although it did not have a significant effect on the number of urticarial episodes. CONCLUSION: The combination of desloratadine plus montelukast is effective in the treatment of CU. It may therefore be a valid alternative in patients with relatively mild CU, in view of its efficacy and the lack of adverse events. 12/7/05 re: Cyclosporin I am an allergist in Denver, CO. I would like to know the guidelines regarding 1. Indication. 2. Patient selection criteria. 3. Use/doses. 4. Monitoring need. For cyclosporin in chronic persistent urticaria. To my knowledge, there are no published national guidelines for the treatment of chronic idiopathic urticaria (CIU) with cyclosporin A (CsA), likely because there has not yet been sufficient experience in enough medical centers with this treatment modality in CIU. I have enclosed below an abstract of a report by Greaves' group in the UK (likely the first sizable controlled study in this area). Also enclosed is an abstract of a report from Italy of a more recent controlled study. I do not have extensive personal experience with CsA treatment of CIU. However, I will attempt to answer your questions based on my impressions from published reports and my conversations with individuals carrying out such treatment. 1) Indications - severe CIU not adequately controlled by a variety of antihistamines, leukotriene antagonists and sometimes requiring treatment with sizable daily doses of corticosteroids. The literature suggests a significant improvement (not necessarily complete remission) in 50-75% of such patients during CsA treatment. 2) Contra-indications - chronic renal disease, possibly uncontrolled hypertension, lack of responsible patient reliability in taking meds, getting follow-up evaluations, etc (CsA is a potent treatment!) 3) Dosing - most groups use 4 mg/kg/day CsAto start after obtaining baseline chemistry panel. If the patient has baseline muscle symptoms check serum level of muscle enzymes and exclude patient if significantly increased. Most reports describe a duration of 4-8 week therapy. One report claims no better clinical improvement when treating for more than 4 weeks 4) Evaluation - For clinical improvement assessment, try to use a scale of urticaria severity/ extent on the body analogous to that used in atopic dermatitis (see enclosed abstract by Grattan et al). This will give you a better idea if the improvement is partial. For adverse effect evaluation, check BUN/creatinine/urinalaysis weekly x2, then every 2 weeks. If onset of muscle symptoms, check levels of muscle enzymes. Although not reported in CIU treatment, some groups treating transplant patients claim that serum CsA levels are more reliable predictors of adverse effects (there is apparently significant patient to patient variability in the rate of metabolism of CsA). Incidentally, a recent study by Kaplan's group suggests that at least part of the beneficial effects of CsA in CIU may be due to direct inhibition of mediator release from basophils and mast cells. Br J Dermatol. 2000 Aug;143(2):365-72. Randomized double-blind study of cyclosporin in chronic 'idiopathic' urticaria. Grattan CE, O'Donnell BF, Francis DM, Niimi N, Barlow RJ, Seed PT, Kobza Black A, Greaves MW. Dermatology Centre, West Norwich Hospital , Norwich NR2 3TU, UK. BACKGROUND: Histamine-releasing activity (HRA) is detectable in up to 50% of patients with chronic ordinary urticaria. OBJECTIVES: To determine the effect of cyclosporin on clinical features and HRA in patients with chronic urticaria. METHODS: Thirty patients with severe unremitting disease, responding poorly to antihistamines and showing a positive autologous serum skin test (ASST) as a marker of HRA, were randomized to 4 mg kg-1 daily of cyclosporin (Sandimmun, n = 20) or placebo (n = 10) for 4 weeks. Non-responders were offered open-label cyclosporin for 4 weeks. All were followed for up to 20 weeks or until clinical relapse; all took cetirizine 20 mg daily throughout the study. The primary measure of efficacy was a daily urticaria activity score (UAS) of weal numbers and itch (maximum score 42 per week). A positive response was defined as a reduction to < 25% of baseline weekly UAS and relapse as a return to > 75%. The effect of cyclosporin on serum HRA was assessed by in vitro basophil histamine release assays and ASSTs before and after treatment. RESULTS: Twenty-nine patients (19 active, 10 controls) completed the randomized trial medication. Eight of 19 on active treatment but none on placebo had responded at 4 weeks (P < 0.05). Three others on active drug met the criterion for response at 2 weeks but not at 4 weeks. Mean reduction in UAS between weeks 0 and 4 was 12.7 (95% confidence interval, CI 6.6-18.8) for active and 2.3 (95% CI - 3.3-7.9) for placebo (P = 0.005). Seventeen non-responders (seven randomized to active and 10 to placebo) chose open-label cyclosporin and 11 responded after 4 weeks. Six of the eight randomized active drug responders relapsed within 6 weeks. Of the 19 responders to randomized and open-label cyclosporin, five (26%) had not relapsed by the study end-point. Mean in vitro serum HRA fell from 36% (95% CI 22-49%) to 5% (95% CI 1-8%) after cyclosporin treatment (n = 11, P < 0.0001). The ASST response to post-treatment serum was also reduced (P < 0.05). CONCLUSIONS: This study shows that cyclosporin is effective for chronic urticaria and provides further evidence for a role of histamine-releasing autoantibodies in the pathogenesis of this chronic 'idiopathic' disease. Allergy Asthma Proc. 2003 Jul-Aug;24(4):285-90. Related Articles, Links Treatment of chronic idiopathic urticaria and positive autologous serum skin test with cyclosporine: clinical and immunological evaluation. Di Gioacchino M, Di Stefano F, Cavallucci E, Verna N, Ramondo S, Paolini F, Caruso R, Schiavone C, Masci S, Santucci B, Paganelli R, Conti P. IRCCS San Gallicano, Roma, Italy. This study evaluates the effectiveness and safety of cyclosporine (CsA) in the treatment of patients with chronic idiopathic urticaria with a positive autologous serum skin test (ASST), who fail to respond to conventional therapy, and requiring long-term oral steroid treatment. In a double-blind study, 40 adults were assigned randomly to receive CsA (5 mg/kg per day for 8 weeks and then 4 mg/kg per day for 8 weeks) or cetirizine (10 mg/day) and then they were followed up for 9 months. After 2 weeks, the study was opened because 16 patients (40%) had daily severe relapses requiring systemic steroids treatment. All of these patients had been receiving antihistamines and, therefore, all patients also were assigned to the CsA treatment regimen (5 mg/kg per day for 8 weeks and then 4 mg/kg per day for 8 weeks). The ASST and clinical severity score were evaluated before and after treatment. All of the 40 patients completed the 16-week CsA course without dropping out because of relevant side effects. In three patients, CsA was reduced by 0.5 mg/kg per day after the 1st month of treatment for a mild and reversible increase in serum creatinine. During CsA treatment, 20 patients had relapses resolving spontaneously (8 patients) or with antihistamines (12 patients). During the 9-month follow-up period, 22 patients had relapses resolving spontaneously (10 patients) or with antihistamines (12 patients). Only two patients failed to complete the study because of severe symptoms occurring after 4 and 7 days of follow-up and requiring long-term steroid treatment. After 9 months of follow-up, 16 patients were still in full remission. The clinical severity score of chronic idiopathic urticaria dropped significantly by the end of the 4th month of treatment (p = 0.002) as well as by the completion of follow-up (p = 0.007). The ASST was negative in 13 patients and positive in 3 of 16 patients, with total remission of symptoms. Significant score reduction also was observed in patients experiencing relapses that resolved spontaneously (p = 0.005) or with antihistamines (p = 0.03). These results show the long-term efficacy and tolerability of CsA in patients with severe chronic idiopathic urticaria, unresponsive to conventional treatments. 12/2/05 re: Treatment of chronic urticaria I am a fifty year old female pharmacist who needs some advice regarding my current outbreak of chronic urticaria. I also have Hashimoto's thyroiditis with positive antithyroid antibodies. There are no other health concerns except for the abundance of weight gained with an underactive thyroid (now supplemented) and inability to exercise because the heat of working out exacerbates the hive outbreaks and wheezing. Since my first episode in my teens, I have endured six episodes of chronic urticaria ranging in length from 6 to 12 months, with the current episode now at 18 months duration. I have experienced angioedema on several occasions, most commonly after ingestion of aspirin (to which I am allergic only during episodes of CU) or foods containing salicylate, such as tomatoes, eggplant, cranberry, etc although I have been frustrated by the apparent inconsistencies of any salicylate containing food lists I have been able to obtain. There have been occasions where I've noticed a correlation between the hives and soda or Crystal Light consumption, so I have eliminated offending drinks with preservatives and dyes as well. When my immune system is behaving I have no food allergies at all. A naturopath recommended an anti allergy/anti-inflammatory diet which eliminated the foods known to be a problem, plus wheat, corn, dairy, beef, and eggs. I followed the diet for a month but found it incredibly restrictive and stopped. Since then the hives are worse than ever. My question to you is: Is there evidence that food choices/eliminations can calm the chaos of CU or am I driving myself crazy trying to find and eliminate the offending foods for no benefit? I feel like short of not eating at all, I've tried everything and still my immune system rages. The current episode is significant in that in addition to the hives that come and go regularly from my torso arms and legs and occasionally face, I have what may be the vasculitis you describe in your replies to other providers on this website. I put in a ten hour day on my feet at work and the long lasting hives on my feet and lower legs are leaving behind painful bruised looking outlines and pink shadows that persist for days. My current meds include: Levoxyl 50 mcg 2QD Zyrtec 10-20 mg HS Singulair 10 mg HS Paroxetine 10 mg QD I also tried the addition of H2 blockers which didn't seem to make a difference. I am desperate to find a specialist who can evaluate me. I have seen an endocrinologist, a dermatologist, an allergist, my primary and at her urging, a naturopath, and all agree, hives are difficult, but thus far, haven't gotten them under control. I am going out of my mind with the itching painful legs, not to mention that just about my whole body is covered except my head. Are you or any of the colleagues you mention in your responses close to Boston, MA? Or do you know a specialist familiar with chronic urticaria in the New England area whom you could recommend? I live in Southern New Hampshire but would consider travel if necessary. I have enclosed below abstracts of two recent review articles by Dr. Sheikh of the Beth Israel/Deaconess Med Center in Boston who has a particular interest in chronic urticaria. You may wish to set up an appointment to see Dr. Sheikh for another opinion re evaluation and treatment, if feasible. As pointed out by Dr. Sheikh, an external cause is found for chronic urticaria in adults in only a small minority of cases, even when extensively investigated. Hence the name chronic idiopathic urticaria (CIU) is commonly applied. Recent studies suggest that an auto-immune reaction against the high-affinity IgE receptor (present on basophils and mast cells) may be responsible for about 40% of CIU cases. In about 20% of CIU cases there is evidence of thyroid auto-immunity but the pathogenic significance of this is still uncertain. I gather that your CIU did not improve with thyroid replacement therapy. It is not unusual for aspirin ingestion to aggravate CIU when the disease is already active. There is no evidence that this is due to an anti-aspirin allergy. A biochemical effect of the aspirin is more likely. That is likely why aspirin ingestion does not cause problems when your CIU is quiescent to begin with. Dr. S. Lockey in Lancaster, PA proposed years ago that salicylates in foods caused problems when aspirin ingestion worsened the CIU. However, more recent studies have not supported and even countered that theory. Therefore I think that it is not productive to eliminate this or that food to see what affect it has on your CIU. If you want convincing evidence whether something you have been ingesting is playing a role, the best approach I know (assuming that you are having urticaria daily) is to try an elemental diet agent such as Tolerex as your sole food for 7-10 days, recording intensity of rash daily before and during this diet. Then return to your regular diet and see whether the rash worsens. If you see a pattern of impressively decreased rash while on the Tolerex trial with worsening after returning to a regular diet, you should try Tolerex for another 7-10 day period. I should mention that Tolerex is nutritionally sufficient. If your skin lesions leave discolored and/or tender skin areas, then a punch biopsy of a fresh lesion is indicated looking for cutaneous vasculitis. The reading/interpretation of such biopsies should be made by an experience dermatopathologist. Therefore, it may be advisable to defer such a biopsy until you are evaluated by Dr. Sheikh with the resources of a major medical center. If cutaneous vasculitis is present, other blood tests and treatments may be indicated. In the meantime, you may want to try doxipen at bedtime. It is a very potent antihistamine (and has other actions as well). However, it is quite sedating. I generally have patients start with a low dose to start (10-20 mg), increasing as tolerated. Curr Opin Allergy Clin Immunol. 2005 Oct;5(5):403-7. Autoantibodies to the high-affinity IgE receptor in chronic urticaria: how important are they? Sheikh J. Harvard Medical School and Division of Allergy and Inflammation, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA. PURPOSE OF REVIEW: Eighty to 90% of patients with chronic urticaria have no specific external cause for their disease, which is therefore labeled 'chronic idiopathic urticaria.' We now know, however, that as many as 30-50% of patients have evidence of an autoantibody to the high-affinity receptor for IgE (FcepsilonRI), which may be pathogenic. The exact prevalence and role of these autoantibodies is still under investigation. RECENT FINDINGS: The frequency of autoantibodies to FcepsilonRI in chronic urticaria has been estimated at 30-50%, but extensive epidemiological studies have not been done. Recent work has confirmed that autoantibodies to FcepsilonRI can be functional, meaning that they can cause histamine release from basophils in vitro. Evidence increasingly suggests that such autoantibodies are also functional in vivo, but conclusive evidence is still lacking. Approximately 50% of cases of urticaria still have no known cause, but recent studies have demonstrated that some of these patients may have intrinsic abnormalities of basophils or mast cells. SUMMARY: The recent evidence that is discussed in this review helps to clarify the role of autoantibodies in some cases of urticaria, but also points towards other non-autoimmune mechanisms that might be pathogenic. Further investigation in these areas will help us to understand the cause of urticaria in cases that are still classified as 'idiopathic.' : Immunol Allergy Clin North Am. 2004 May;24(2):317-34, vii-viii. Related Articles, Links Advances in the treatment of chronic urticaria. Sheikh J. Division of Allergy and Inflammation, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. There have been a number of exciting developments in the treatment of allergic diseases in recent years, but the development of new treatments for urticaria has lagged behind. The standard treatment for chronic urticaria (CU) involves the use of H1 antagonists. A number of small but promising studies have found potential benefit with medications that are used less often. This article reviews the established therapies for CU and the experimental evidence for the use of nonstandard and relatively unknown therapies. The potential usefulness of some of the new allergy medications for the treatment of CU also is discussed. 11/8/05 re: Clinical value of Raji cell assay I am currently following two patients with chronic urticaria, episodic angioedema who both have elevated Raji Cell Immune Complex, but normal C1q Binding Immune Complex levels. I'm wondering what the significance is of this one positive test and if there are any disease processes that are likely correlated. The first patient is a 22 yo female with CU/recurrent angioedema. She has FH of autoimmune disease, and herself has endometriosis, vitiligo, and elevated anti-thyroglublin antibodies. Normal labs have included negative H. pylori, serum tryptase, latex Rast (she's an OB delivery nurse), CBC, ESR, C3 and C4, biopsy of lesion which showed nonspecific urticaria. She is controlling symptoms with bid Zyrtec, Singulair, Ranitidine, Levoxyl. She also had negative autologous serum testing. The 2nd patient is a 52 yo female with history of suspected chronic urticaria, who is presenting with recurrence of CU and episodic AE. This patient has not yet had a biopsy of lesion (pending). She has normal CBC, CMETA, ESR, C3, C4, H. pylori. She is on Levoxyl for her thyroid disease (she has elevated anti-TPO ab, and thyroglobulin ab). She did have elevated LDH, which upon recheck was borderline (about 177). Should the Raji Cell immune complex elevation be attributed to their disease processes present, or do I need to go searching further? Is Rheumatology consultation advisable? There has been much less enthusiasm for the use of the Raji cell assay for circulating immune complexes in recent years. Evidence for this feeling is the fact that there are much less publications in recent years of studies employing the Raji cell assay. I believe that this reduced use is because of the great "sensitivity" and non-specificity of the Raji cell assay. For example, the presence of certain anti-lymphocyte antibodies in the serum can give a "false positive" Raji cell result. The normal complement and C1q binding results you described would suggest to me that circulating immune complexes are not the cause of the chronic urticaria (CU) in your patients, particularly if there is also no evidence of vasculitis in the skin biopsy of your second patient. CU is sometimes seen in those with conditions such as lupus. However, if there are no clinical manifestations to suggest a connective tissue inflammatory disease, I think that an extensive laboratory search for related autoantibodies and a Rheumatology consult would have a low yield. As you likely know, serum anti-thyroid antibodies are present in15-20% of patients with idiopathic CU; abnormal thyroid function is found in about 50% of those with such anti-thyroid antibodies and CU. Alan Schocket's group in Denver has reported a significant decrease in the CU in about 50% of those treated with L-thyroxine, even when the patient was euthyroid before the L-thyroxine treatment was started. Varying results have been reported subsequently by other groups trying this approach in CU. 10/25/05 re: Corticosteroid treatment in chronic urticaria I would like to get some advice on the management of a patient with type1 diabtetes and initial episode of angioedema about 6 months ago, followed by periodic recurrence of urticaria. He is on Zyrtec 10 mghs as needed , Allegra 10 mg/d, Zantac 150 mg bid and Singulair 10 mg hs. however on this regimen he gets break-thrus not responding to prn Benadryl. I am starting him on Doxipen, but wanted to find out which steroid could be given with the least likelihood of increasing his blood sugars. He is on an insulin pump and requires high boluses of Humalog to control his sugars and in the interim he feels very fatigued. He was on Lisinopril, but that has been stopped. Any other thoughts on managing this patient. To my knowledge, there is no difference in the potential for aggravating diabetes among doses of different corticosteroid (CS) agents with equivalent anti-inflammatory effects. I could also find no reference to such differences in a brief Medline search. Therefore, I would search very hard for other types of therapy that would control the chronic idiopathic urticaria (CIU) or at least allow reduction of the CS dose required for control of the CIU. I have listed below some suggestions: 1) Is there any temporal relationship between onset of the CIU and start of the Humalog? One would not expect an urticarial allergic reactions to a human insulin prep, but such have been occasionally reported 2) Does the patient have auto-immune thyroid disease? Anti-thyroid antibodies are present in about 20% of those with CIU (vs about 3% in normals). I would check for anti-thyroid peroxidase and anti-thyroglobulin antibodies as well as thyroid function. If the patient is hyperthyroid, this could be aggravating the hyperglycemia. 3) Do individual urticarial lesions last more than 24 hours and/or leave pigmented areas in the site? If so, I would obtain a punch biopsy of a fresh urticarial lesion looking for vasculitis. A skin biopsy may also be indicated when the CIU is not controlled by intensive antihistamine/anti-leukotriene therapy. One is looking for “neutrophilic urticaria” characterized by prominent neutrophil accumulation in the lesions. Such urticaria may be better controlled by colchicine. 4) I have found doxepin to be helpful occasionally. However, it can be quite sedating, so I have generally prescribed full doses only at bedtime. If prescribed for daytime use, I generally start with 10 mg/day for average-sized adults, increasing the dose gradually as tolerated and needed. 5) Some studies, mainly in Europe, have reported that H. pylori infection is causal in CIU with improvement following treatment of H. pylori 6) Other medications reported occasionally to be helpful in controlling CIU have included hydroxychloroquine, azulfidine analogs (usually used in inflammatory bowel disease) and even coumadin. Cyclosporine has been reported to control CIU uncontrolled by other meds. However, the potential for adverse effects generally limits such treatment to quite severe CIU. 10/17/05 re: Diagnosis of delayed pressure urticaria Can you please advise us on how to properly code for an in house challenge to confirm the diagnosis of delayed pressure urticaria/angioedema. Patient was weighted with 15lb weights and ambulated in the office for 15 minutes. He will return in four and eight hour intervals for evaluation. We are also searching for the ICD-9 code for this particular diagnosis. As pointed out in a recent review of delayed pressure urticaria (DPU) by Lawlor and Black , very experienced investigators of urticaria (Immunology and Allergy Clinics of North America 2004;24:247-58), there is no standardized diagnostic method for doing blunt pressure challenges to diagnose DPU. Unfortunately, I was unable to download this article to send to you. Therefore, I suggest that you obtain the article to see different approaches reported by different investigators. A relatively simple approach described in that review involves hanging a 15 pound weight hanging at the end of bandage type material looped over the collarbone area while the patient sits for at least 15 minutes (depending on the tolerance of the hanging weight). The site over the collarbone is then inspected immediately after removal of the weight and at 6 and 8 hours later. I have used a somewhat approach in my practice. I am not expert in ICD-9 coding. However, if you contact the Joint Council on Allergy, Asthma and Immunology (JCAAI) Their website is available as a link in the "Other Links" section of this AADMC website. Once in the JCAAI website, contact them asking for your question about the ICD-9 code for DPU to be referred to Dr. Donald Aaronson for input. 9/28/05 re: Chronic urticaria in 5 year old child I am a licensed health care worker(physical therapist) and my daughter has had chronic urticaria for 8 months now. She has seen an allergist and naturopathic doctors but nothing seems to help rid this problem. The allergist did blood work and all that came up was a sed rate of 20. Two months later, the sed rate was normal. All other blood work was negative(ANA, thyroid ect). She gets the hives on a daily basis and they appear to exacerbate with heat and friction. They also get very severe with fever. Antihistamines are ineffective and I am reluctant to put her on higher and higher doses which are what her allergist wants to do. Any suggestions would be most appreciated (ie any additional tests that should be done). Chronic urticaria (CU) without obvious relationship to certain environmental exposures is often a difficult diagnostic problem in both children and adults. Some of the questions/approaches to such CU in children which bear consideration are these: 1) In most cases of CU, anything that raises the body temperature and/or dilates skin blood vessels has the potential for worsening the urticaria. However, there is a particular type of CU called cholinergic urticaria, characterized by very small, itchy wheals surrounded by a large area of erythema (redness) . These are usually triggered by body overheating and/or emotional stress. 2) In some children, CU is associated with chronic viral infections and/or aspirin treatment. If aspirin is being taken frequently a trial of withholding such medication should be made. Reactions to acetaminophen are a much less frequent cause of CU. Of course, reactions to any medications taken chronically by the child may be suspect and a trial of withholding such medication should be considered. 3) Certain systemic diseases may include CU in the presentation. a) It is important to determine whether the individual hive lesions last more than 24 hours and/or leaves a residual pigmented area in the skin. If this is the case, a punch biopsy of a fresh hive should be obtained to look for a possible cutaneous vasculitis as the cause (see enclosed abstract) b) In adults, about 20% of CU patients have evidence of thyroid autoimmunity when screened by appropriate antibody tests. It is less clear how often this occurs in children with CU, but worth investigating. You mentioned thyroid tests were normal without specifying which tests. One has to measure levels of anti-thyroid antibodies. c) A form of systemic mastocytosis called urticaria pigmentosa may look superficially like CU. In this condition there are somewhat tan small skin lesions which become hive-like in appearance when rubbed d) Some congenital conditions such as the Muckle-Wells syndrome may be first manifest as CU-like condition in childhood. There are often systemic manifestations as well (see enclosed abstract). e) It is now believed that many cases of CU (in adults at least) are due to an auto-immune reaction causing histamine release. It is not yet clear how often this occurs in children (see enclosed abstract). f) A recent report described an association with Celiac Disease (detected by specific ant-endomysial antibody tests) in about 5% of a group of children with severe CU. The significance of this finding is increased by their observation that the CU cleared within 10 days of starting a gluten-free diet in the children with CU and evidence of Celiac disease. 4) Food allergies are an infrequent cause of CU but should be considered in a 5 year old. I assume that the blood studies obtained by your allergist included tests for IgE anti-food antibodies. Occasionally, food allergies may be present in the presence of negative food antibody tests. Another way of investigating this is to put the child on an allergen free (elemental) diet with no other foods for 5 days, observing whether there is a significant reduction in the CU. Then, resume the usual diet and see whether the CU returns to its usual intensity. If the findings are suggestive of a relationship, try the elimination/normal diet cycle again. If still impressive differences in CU with the elimination diet, try more selective alterations. Your allergist should be able to help you with this approach 5) I assume that your allergist asked and there is no relationship of the CU lesions to exposure to physical stimuli (e.g.-cold, local heat, sun, deep pressure, etc.) Insofar as medication to control the symptoms of CU when the usual antihistamines are ineffective, some recent studies have suggested that combination therapy with a non-sedating antihistamine (such as Allegra) and Singulair, 5 mg (a leukotriene antagonist) may be helpful. I do not know of anyone in Arizona with a particular expertise in CU occurring in children. The senior dermatologist in a large Children's Hospital in your area should have considerable experience in treating CU. I have enclosed several abstracts (below) related to my comments. Allergy. 2005 Sep;60(9):1174-7. Related Articles, Links Hypersensitivity reactions to paracetamol in children: a study of 25 cases. Boussetta K, Ponvert C, Karila C, Bourgeois ML, Blic J, Scheinmann P. Service de Medecine Infantile B, Hopital d'Enfants de Tunis, Tunis, Tunisie. BACKGROUND: Allergic-like reactions to paracetamol (acetaminophen) are rare. Paracetamol allergic and nonallergic hypersensitivity (HS) has been diagnosed in a few patients with skin and/or respiratory symptoms, immediate and accelerated urticaria, and angioedema especially. Most patients with HS to paracetamol were also hypersensitive to anti-inflammatory drugs (i.e. acetylsalicylic acid, ASA), suggesting that their reactions resulted from a nonallergic HS. However, anaphylactic reactions, and potentially harmful toxidermias, such as acute generalized exanthematic pustulosis and toxic epidermal necrolysis, have been related to specific paracetamol allergic HS, with tolerance to anti-inflammatory drugs. PATIENTS AND METHODS: We report the results of a study performed in 25 children with suspected paracetamol HS. Diagnosis of paracetamol HS was based on a suggestive clinical history and a positive response in an oral challenge (OC) test. RESULTS: Paracetamol HS was diagnosed in only one child (4%). In this child, a positive response to an OC with ASA diagnosed HS to anti-inflammatory drugs. CONCLUSIONS: Our results in children agree with those of the literature, showing that paracetamol HS is rare, and is associated with HS to anti-inflammatory drugs in most patients. Isr Med Assoc J. 2005 May;7(5):320-2. Related Articles, Links Pediatric cutaneous mastocytosis: a review of 180 patients. Ben-Amitai D, Metzker A, Cohen HA. Schneider Children's Medical Center of Israel, Petah Tiqva, Israel. BACKGROUND: Mastocytosis is a heterogeneous group of diseases characterized by the abnormal infiltration of mast cells in the skin and, sometimes, other organs. Some patients may experience symptoms related to mast cell mediator release. OBJECTIVE: To analyze the clinical features of cutaneous mastocytosis in a large series of children. METHODS: We conducted a file review of all children clinically diagnosed with cutaneous mastocytosis in our department over the last 20 years. We evaluated gender, age at onset, character and distribution of the lesions, associated symptoms, and course of the disease. RESULTS: Altogether, 180 patients with cutaneous mastocytosis were identified. The male to female ratio was 1.5:1. About one-third of patients had a mastocytoma, which was present at birth in over 40% and appeared during the first year of life in most of the remainder. Urticaria pigmentosa was noted in 65% of the patients, presenting at birth in 20% and during the first year in most of the remainder. The majority of lesions were distributed over the trunk and limbs. Different kinds of associated symptoms were noted. Prognosis in general was good. Only 11% of the cases, all urticaria pigmentosa, were familial. CONCLUSIONS: Most cases of pediatric mastocytosis are sporadic and appear during the first 2 years of life, especially on the trunk. Urticaria pigmentosa is the most frequent variant. The prognosis of pediatric mastocytosis, in general, is good. J Investig Allergol Clin Immunol. 2004;14(4):343-5. Related Articles, Links Chronic autoreactive urticaria at six years of age. Asero R, Lorini M, Tedeschi A. Clinica San Carlo, Paderno Dugnano (Milano), Italy. A case of chronic urticaria in a child 6 years old is described. The strong skin reactivity upon intradermal injection of autologous serum suggested an autoreactive pathogenesis; however, patient's serum was unable to induce histamine release from basophils in-vitro, indicating the presence of a histamine-releasing factor specific for mast cells, and possibly other than an anti-FcepsilonRI or anti-IgE antibody. Intradermal test with autologous serum may be useful in revealing the autoreactive nature of chronic urticaria and can avoid a frustrating search for other causes of the disease. In children presenting with chronic or recurrent urticaria the diagnostic workup should include the autologous serum skin test. J Dermatol. 2001 Nov;28(11):632-4. Related Articles, Links Unusual urticarias. Black AK. St John's Institute of Dermatology, Kings College, St. Thomas' Hospital, London, UK. Typical urticarial lesions are transient cutaneous swellings of sudden onset, often itchy, persisting for less than 24 hours and resolving to leave normal appearing skin. Angioedema lesions are similar subcutaneous lesions. Atypical urticarias persist for longer than 24 hours, may be painful and bruised in appearance and accompanied with severe systemic symptoms. Conditions where prolonged weals are present include delayed pressure urticaria and urticarial vasculitis. These conditions do not respond well to antihistamine therapy. In delayed pressure urticaria, weals appear after a delay of hours at sites of sustained pressure on the skin and occur in association with ordinary chronic 'idiopathic' urticaria. Weals of urticarial vasculitis show histological features of venulitis, and can be accompanied by arthralgia and abdominal pain. Rarely, the condition is due to infective or autoimmune disease. Urticarial diseases, sometimes with features of urticarial vasculitis, and with associated systemic features include Schnitzler's Syndrome, Still's disease and Muckle-Wells syndrome. The latter syndrome is linked with chromosome 1q44, as is autosomal dominant cold urticaria, an unusual physical urticaria. Persistent cholinergic erythema, a variant of cholinergic urticaria, has been mistaken for a drug eruption or cutaneous mastocytosis. Rarely, food and exercise induced urticaria and anaphylaxis occur when exercise follows a specific food or any meal within a few hours. The early stages of inflammatory disease may be mistaken for urticaria and angioedema, but lesions usually persist for longer than 48 hours and are accompanied by epidermal changes. 8/5/05 re: Treatment of chronic idiopathic urticaria with thyroxin I have a question regarding a patient with type 1 dm, who also has CIU. She is currently being tx with Prednisone, Doxepin, Allegra, Zyrtec, Gastrochrome, and Singulair. Hives were previously controlled for 3 months on this med regime, and Prednisone was able to be d/c for one month. She also has Hashimoto's Thyroiditis, but currently thyroid fx is normal, and she has not begun any thyroid replacement tx. What is your experience treating difficult to control people using Thyroid therapy? Is the addition of a thyroid supplement helpful in CIU? Another med suggested by her allergist is Ketotifen. Would appreciate your input, as this patient would greatly benefit from the ability to dc the Prednisone. Most investigators are convinced that there is an association between thyroid auto-immunity and chronic idiopathic urticaria (CIU). However, there is considerable debate about the value of thyroxin therapy in CIU with thyroid auto-immunity and normal thyroid function. I have enclosed below a section of a review article by me that deals with the matter of thyroid autoimmunity and CIU. It sounds as if your patient has had severe CIU requiring chronic prednisone therapy (with potential for adverse effects, particularly in someone with pre-existent diabetes). Therefore, if one wishes to try thyroxin therapy in a patient such as you described, I would make these suggestions:1) Obtain written informed consent of the patient in advance, since thyroxin therapy is not considered a standard treatment of CIU; 2) start with a very low dose of thyroxine gradually increasing the dose (as tolerated) until a decrease in the CIU or the usual daily thyroxin dose is reached. Shocket's group in Denver (with perhaps one of the largest experiences with thyroxin treatment in CIU) has reported success in about 50% of those treated, generally starting within several weeks after therapy is initiated; 3) monitor thyroid function regularly during and after thyroxin treatment. It may be advisable to have the patient seen periodically by an endocrinologist to make sure no adverse effects of thyroxin therapy have occurred. I have had only limited experience trying oral ketotifen in CIU since this agent is not generally available in the USA. There was no impressive improvement in the two patients for which I tried ketotifen. A review published in France in 2003 concluded that ketotifen was no more successful than H1 antihistamines (see enclosed abstract). Other medications have been tried in cases such as yours. There have been case reports/small series describing encouraging results with agents such as warfarin and sulfasalazine, but these findings remain to be confirmed. The lack of confirmatory reports in the recent literature make me wonder how applicable those reported findings are to usual clinical practice. Several reports have concluded that cyclosporine A (CsA) treatment can be very beneficial in severe CIU not controlled by other therapy. However, as you know, CsA is a potent immunosuppressive agent which has to be used carefully, monitoring closely for dose-dependent adverse effects on the kidneys and muscles. If CsA therapy is being considered, I suggest getting someone with considerable experience using CsA involved in the case. I have enclosed below my review (for this AADMC website) of a recent report about CsA therapy in CIU. from Zweiman, B CHRONIC URTICARIA AND SYSTEMIC DISEASES Current Allergy and Asthma Reports 2003;3:455-57 Anti-thyroid autoimmunity. For about 20 years it has been noted by most, but not all groups, that there is an increased prevalence (generally 10-30%) of IgG anti-thyroid antibodies in the sera of CIU patients when compared to a 3-5% prevalence of such antibodies in age and gender matched controls without CU (4). These antibodies are directed most commonly against a specific peroxidase present in thyroid microsomes (TPO). Antibodies against thyroglobulin and the thyrotrophin (thyroid stimulating) receptor have also been found in some CU sera (4,5). Some investigators have found an equal prevalence of anti-thyroid antibodies in CU of both reportedly defined etiology and 3. ICU, predominantly in females (5). A variable (0-47) percentage of CIU with reported anti-thyroid antibodies have had evidence of thyroid disease and/or thyroid dysfunction, most commonly Hashimoto's thyroiditis; there is less common association of CU with Graves disease (reviewed in5).It is unclear whether these anti-thyroid antibodies are pathogenic in CU. They are almost always of the IgG isotype; with question whether they may also be of the IgE type. One group has reported that these anti-thyroid antibodies can induce increased histamine release (21). Perhaps the most controversial evidence linking thyroid autoimmunity to the pathogenesis of CIU comes from trials of L-thyroxine in patients with CIU and thyroid autoimmunity, some of whom were euthyroid. Some, but not all, groups have reported a significant reduction in CIU manifestations in a majority of patients treated with L-thyroxine, with recurrence of the CU following discontinuation of the L-thyroxine therapy (6). Such clinical responses to L-thyroxine were seen only in those CU patients who had anti-thyroid antibodies One group reporting good clinical responses to L-thyroxine treatment in 15 of 18 patients with CIU and thyroid autoimmunity found no post-treatment change in serum anti-thyroid antibody levels, but a decrease in the frequency of positive autologous serum skin test responses (7). Thus, the exact relationship between CIU and the associated thyroid autoimmunity requires further clarification.It does appear to me that there is an increased prevalence of thyroid auto-immunity in CIU patients. However this thyroid autoimmunity does not appear to be a reflection of generalized autoimmunity. One group reported increased serum levels of anti-thyroid antibodies, but not auto-antibodies directed against other organ components, anti-nuclear antibodies, or anti-cardiolipin, anti-myeloperoxidase or anti-proteinase 3 antibodies in a group of CU patients. (8)   Ann Dermatol Venereol. 2003 May;130 Spec No 1:1S129-44. [Treatment of chronic idiopathic urticaria unresponsive to type 1 antihistamines in monotherapy] [Article in French] Mateus C. Service de Dermatologie-Venereologie, Hopital Tarnier, 89, rue d'Assas, 75006 Paris. The chronic idiopathic urticaria treatment is a difficult and often frustrating problem for physicians. Due to the lack of definitive medical therapeutic programs to relieve the symptoms and prevent their recurrence, several pharmacologic approaches to the management of chronic idiopathic urticaria are proposed. The chronic urticaria pharmacologic therapy is therefore fit to abrogate effects of histamine and other mediators on cutaneous vasculature and inflammatory cells that participate in the pathogenesis of the urticaria. The most common approach is to avoid all aggravating factors and to block histamine. The mainstay therapy is the H1 antihistamines. A significant number of patients may remain unresponsive even after an increase in the dose or a change in the type of H1 antihistaminic drug. In these cases, several therapies can be associated: combinations of H1 antihistamines, nonsedating one tablet (morning) and one sedating (evening), this approach is very usual but no study has confirmed it rational; addition an H2 antagonist to the previous treatment for some patients may improve control of their symptoms; alternatively, the tricyclic antidepressant, Doxepin is usually prescribed. The results of other drugs reported in the literature is unpredictable, to include them in a strategy therapy. The results with Beta adrenergic agents, nifedipine, ketotifen, leukotriene antagonists and tranexamic acid are variable and don't appear better than those with H1 antagonists. The efficiency of danazol has to be confirmed by other controlled studies. Warfarin, sulfasalazine and ultraviolet radiation have been used apparently successfully, but no controlled study has been published. Only when the above treatments have failed then immunosuppresive therapies, intravenous immunoglobulin and plasmapheresis can be proposed for chronic idiopathic urticaria . Cyclosporin therapy of chronic idiopathic urticaria SUMMARY Background - Chronic idiopathic urticaria (CIU) is sometimes difficult to treat with little or no improvement during use of antihistamines (AH) and usual anti-inflammatory agents. There have been previous small studies of cyclosporin (CsA) therapy in severe CIU. Findings - Baskan et al of the Uludag University Hospital in Bursa, Turkey evaluated the response to treatment with CsA (4 mg/kg/day) for 4 or 12 weeks in 20 adults with CIU unresponsive to AH and a positive autologous serum skin test (ASST). They found a marked decrease in wheal numbers and itching during the first 4 weeks of therapy with no additional or more persistent benefit when the CsA treatment was continued past the first month. REFERENCE - J Dermatol Treat 2004;15:164-8 EDITOR'S COMMENTS These findings are not novel, with similar effects of CsA therapy previous reported by Greaves' group in a limited number of those with severe CIU unresponsive to AH. However, this current preliminary study does suggest that continuation of CsA therapy for more than 4 weeks confers no additional benefit. This is both surprising and helpful information since a concern about CsA treatment in this dose range would be cumulative adverse effects, particularly on renal function. It would be important to know what a more prolonged follow-up evaluation after a 4 week CsA treatment period would show in this study. 4/28/05 re: Urticaria and asthma I have a question about urticaria and asthma.If a patient presents with a simple urticarial rash (no signs of angioedema, airway compromise, wheezing, etc...), but has a history of asthma, do they need to be sent to the hospital for admission/observation? Or, if it is the rash only, can they be managed as an outpatient with benadryl, prednisone? Or, do they need to be observed for a few hours? We work in an urban setting, with a large portion of people with asthma. The question is what do we do with them when they develop your basic allergic rash only. If an episode of urticaria occurs without evidence of oropharyngeal angioedema or worsening of asthma in someone with underlying asthma, such urticaria can generally be treated on an outpatient basis without the need for hospitalization or other prolonged observation. It is true that an acute anaphylactic reaction can be manifest as both urticaria and asthma (sometimes with accompanying laryngeal edema). However, in such situations, the asthma is already present within a short period of time after onset of the reaction and would not be expected to become manifest hours later. I should comment about your proposed use of Benadryl for the urticaria. I would suggest using a non-sedating antihistamine such as fexofenadine instead of Benadryl, particularly if the patient has to drive in the succeeding hours, Fexofenadine is about as effective as Benadryl (diphenhydramine) in urticaria without the potential for sedation and other inhibition of cognitive capacity (including driving performance). 4/19/05 re: Urticaria decreased by pregnancy/O.C. use I just saw a 24 year old female patient with history of hives since January 03. She was evaluated by a dermatologist and an allergist in the past. RAST testing was done at that time due to extensive hives which was negative. Biopsy of the lesions was not significant. Basic blood work and also for complements, cryoglobulins was normal except for TSH at 5.2 with normal upper limit being 5.0. It has been followed as per the patient and has been normal. Patient got pregnant in April 03 and hives diappeared in a few weeks. They recurred after her pregnancy. She has tried Atarax, Zyrtec, Allegra, Claritin, Singulair, Benadryl, Zantac which have not helped. The only thing that controls the hives is oral contraceptive pills. The patient wants to get pregnant and wants to stop the OCP but is afraid that she will have recurrence. Skin testing for foods and inhalants was negative. I have thought about putting her on Doxepin but that is in Category C for pregnancy and patient does not want to take it. I have heard of hives to Depo-provera and hypersensitivity injections but have not heard cases that are controlled by OCP. I would appreciate your feed back. I have not observed the improvement of chronic idiopathic urticaria (CIU) with the use of oral contraceptive agents (OC) or consistently with pregnancy. I could not find any reference to such improvement in a Medline search. Therefore, I obtained input from Dr. Michael Schatz of the Kaiser-Permanente Group (and immediate Past-President of the AAAAI). As you may know, Dr. Schatz is an expert in the effects of pregnancy on allergies and asthma. Dr. Schatz kindly responded immediately to my request for input with comments enclosed below. An outside possibility is that the CIU in your patient may be related somehow to autoimmune thyroid disease. You mentioned a transiently slightly elevated TSH level. As you know, there are increased serum levels of antibodies against thyroid antigens (most commonly microsomal antigen, now identified as thyroid peroxidase) in about 20% of CIU patients, as compared to about a 3% incidence in normal females of your patient's age. If such thyroid auto-immunity does play a causal role in the CIU (not yet proven), it is conceivable that some hormonal effect of pregnancy/OC use could suppress the pathogenic mechanism. Therefore, it may be worth checking for serum levels of anti-thyroid antibodies, even if the patient is eutthyroid. Dr. Schatz's comments: This is very interesting case, but, like you, I have seen nothing like it clinically or in the literature. I don't really have any specific suggestions. If the patient desires another pregnancy, it seems like the most reasonable approach would be to stop the BC pills and treat with the most pregnancy-friendly medications (loratadine or cetrizine, ranitidine, and possibly terbutaline) to try to provide at least some control until pregnancy supervenes and hopefully improves the situation. I'm sorry I don't have anything better to suggest. 4/12/05 re: Lanolin contact allergy I have seen a 14 year old girl with a history that at age 3 she developed a probable urticarial rash on her arms after the application of suncream containing lanolin. She has now within 2 months had 2 episodes where,on the first occasion she developed a widespread urticarial rash over her body with facial oedema, lip swelling but no respiratory distress or angioedema. She was at a sleep over and her friend had sprayed the sheets with a perfume containing lanolin. She required an antihistamine and was given oral steroids. The second episode involved showering using a tablet of new, ingredient unavailable, soap. Within minutes she developed periorbital oedema and required oral antihistamine with no further symptoms .She uses various make-ups, some contain lanolin. Is a lanolin allergy unlikely in view of this? How common is lanolin allergy? As you may have surmised, the subject of contact allergy to lanolin is somewhat controversial. Some leaders in the Dermatology field feel that lanolin is a rare, if any, cause of contact allergy, while others claim that lanolin may cause reactions, but at a very low frequency (see enclosed abstracts). Yet others argue that lanolin may sensitize when it is a component of topical medications applied to already diseased skin while lanolin in cosmetics rarely causes problems on healthy skin (see enclosed abstract).Some authors claim that the lanolin reagent used in "standard" patch testing trays elicit too many false positive or false negative responses (see enclosed abstract). There is even less reported about contact urticaria attributed to topical lanolin use. Therefore, I think that a useful approach in your patient would be to do patch testing with each of the suspect agents themselves. I recommend that this be done by a physician with considerable experience in carrying out and interpreting such patch tests. Because the reaction reported by the patient was apparently urticarial, the patch test sites should be examined within 2 hours after application as well as the traditional examination of the sites at 48 and 96 hours. Contact Dermatitis. 1998 Sep;39(3):103-7. The myth of lanolin allergy. Kligman AM. University of Pennsylvania, School of Medicine, Department of Dermatology, Philadelphia 19104, USA. Lanolin has the reputation of being an important contact sensitizer. The marketplace abounds with products that are labeled "lanolin free". In fact, lanolin is at most a weak contact allergen. The supposed hazards of sensitization to lanolin products are a resultant of faulty science and failure to appreciate the limitations of patch testing. Lanolin allergy is a myth created mainly by overzealous professional patch testers. No one has succeeded in sensitizing animals or humans to lanolin or wool wax alcohols. Most of the case reports are due to false positive reactions on inflamed skin. Dermatology. 1996;192(3):198-202. The lanolin paradox. Wolf R. Maccabee Dermatologic Outpatient Clinic, Tel-Aviv University, Israel. Several puzzling aspects of the use of lanolin are discussed as 'lanolin paradoxes', in analogy with the 'paraben paradoxes'. Lanolin in topical therapeutic agents sensitizes a high proportion of patients, whereas the same lanolin is 'safe' in cosmetics so widely used by millions of individuals. Patients with an allergic contact dermatitis to lanolin in a medication applied to a stasis ulcer can nevertheless use lanolin-containing cosmetics and not experience a reaction. Lanolin-sensitive individuals often show false-negative patch test reactions to unaltered lanolin. Patch testing with 30% wool wax alcohols used in the standard patch test tray cannot be considered a reliable method for detecting and confirming lanolin allergies. There are too many false-positive and false-negative results using the standard patch test tray. Br J Dermatol. 2001 Jul;145(1):28-31. A retrospective analysis of contact allergy to lanolin. Wakelin SH, Smith H, White IR, Rycroft RJ, McFadden JP. St John's Institute of Dermatology, London, UK. BACKGROUND: Lanolin is often stated to be an important sensitizer but some of the available literature is based on the analysis of high-risk patients. OBJECTIVES: To analyse the frequency of contact allergy to lanolin (wool alcohols) in a central London teaching hospital patch-test population. METHODS: Review of 24,449 patients recorded on our database during 1982--96 who were tested with a standard series containing 30% wool alcohols. RESULTS: The mean annual rate of sensitivity to this allergen was 1.7%. The wool alcohols- allergic group contained a higher proportion of females (P < 0.05), and the mean age of both males and females (48.4 and 49.2 years) was higher than that of non- wool alcohols-allergic patients (41.4 and 35.9 years; P < 0.0005). There was no difference in atopic eczema status between these groups. The highest prevalence of allergy to wool alcohols was among patients with lower leg dermatitis (6.0%; 95% confidence interval, CI 4.46--7.54), followed by those with anogenital dermatitis (3.23%; 95% CI 1.81--4.65). There was an unexplained decline in the rate of positive patch tests to Amerchol L-101. However, some patients who reacted to this were negative with wool alcohols, so it may be a useful additional test reagent. The mean rates of allergy to Eucerin (0.65% per annum) and 50% hydrogenated lanolin in petrolatum (1% per annum) were low, and we no longer use these as test reagents. CONCLUSIONS: This study illustrates that lanolin sensitization has remained at a relatively low and constant rate even in a high-risk population (i.e. patients with recent or active eczema. 4/11/05 re: Antihistamine treatment of chronic urticaria I am a Pharmacy Intern working in Vista Health Plan in Sunrise Florida. I will like to know if there is any study using combinations of two antihistamines at same time (Fexofenadine 180mg QD AM and Cetirizine 10mg QD PM) for the treatment of idiophatic urticaria in adults (54 yo female). It is a good option? Could we use both? Antihistamine (AH) treatment is usually the first-line pharmacologic approach in chronic idiopathic urticaria (CIU). In studies comparing individual AH in the treatment of CIU, fexofenadine 180 mg and cetirizine 10 mg have about the same efficacy overall. However, the response to any particular AH agent is variable in individual patients. An approach using fexofenadine given in the morning and cetirizine hs is quite reasonable, considering that fexofenadine 180 has no greater sedating effect than placebo (2-3% incidence) while sedation has been reported in up to 14% of adults treated with 10 mg cetirizine. Dr. Allen Kaplan of the Medical Univ. of South Carolina, an expert in CIU, feels that diphenhydramine (usually in doses of 50-100 mg) is often more effective than the newer "non-sedating" AH (see enclosed abstract). Kaplan recognizes that sedation/inhibition of cognition occurs commonly during initial treatment with diphenhydramine. However, he claims that such sedative effects of diphenhydramine become less prominent with continued use. I am not sure that such sedative effects go away in the majority of cases. However, use of Benadyl 50 mg taken 1-2 hours prior to sleep may be more effective than Zyrtec treatment hs. without leaving a morning "hangover". If neither Zyrtec nor diphenhydramine is sufficient to prevent nocturnal manifestations of CIU, you might try doxepin 50-100 mg. Doxepin is a particularly potent AH as well as having beneficial effects in certain emotional problems. However, doxepin does sedate commonly. Some experts use doxepin hs in CIU not controlled by other AH J Allergy Clin Immunol. 2004 Sep;114(3):465-74; quiz 475. Chronic urticaria: pathogenesis and treatment. Kaplan AP. Department of Medicine, Division of Pulmonary and Critical Care Medicine, Allergy and Clinical Immunology, Medical University of South Carolina, Charleston, SC 92425, USA. kaplana@musc.edu Patients previously designated as having chronic idiopathic urticaria are now divided into 2 groups: 40% to 50% with chronic autoimmune urticaria, and the remainder with chronic idiopathic urticaria. Patients in both groups may have concomitant angioedema (approximately 40%). The autoimmune subgroup has an association with antithyroid antibodies and is caused by IgG antibody to the alpha subunit of the IgE receptor (35% to 40%), usually reactive with unoccupied IgE receptors, or IgG antibody to IgE (5% to 10%). Complement activation augments histamine secretion by release of C5a. The IgG subclasses that appear to be pathogenic are IgG(1), IgG(3), and, to a lesser degree, IgG(4), but not IgG(2). Histology of chronic urticaria (both subtypes) reveals a perivascular non- necrotizing infiltrate of CD4(+) lymphocytes consisting of a mixture of T(H)1 and T(H)2 subtypes, plus monocytes, neutrophils, eosinophils, and basophils. These cells are recruited as a result of interactions with C5a, cell priming cytokines, chemokines, and adhesion molecules. Suggested therapy for patients with severe disease involves the use of high-dose hydroxyzine or diphenhydramine when nonsedating antihistamines are ineffective, supplemented by H-2 antagonists and leukotriene antagonists. The most severe patient may require protracted treatment with low-dose alternate-day steroid or cyclosporine. Cyclosporine can be steroid-sparing when side effects are encountered or when use of steroids is relatively contraindicated. Careful monitoring of blood pressure, BUN, creatinine, and urinalysis is required. 3/7/05 re: Urticaria treatment in pregnant patients I am facing many cases of urticaria in the center of allergy and asthma, I am facing the problem of a delay in the response to the treatment and specially in pregnants, my hands are tied, is there any new protocols in management. Thanks a lot. To respond to your questions I have obtained input from Dr. Michael Schatz of the Kaiser-Permanente Medical Group in San Diego CA, one of the leading experts in the world in the treatment of allergies and asthma in pregnant subjects. Dr. Schatz's response is enclosed below. There are reassuring data for use during pregnancy of loratadine (1769 exposures) and cetirizine (917 exposures) from the Swedish Medical Birth Registry (Kallen B. Use of antihistamine drugs in early pregnancy and delivery outcome. J Mat Fet Neonat Med 2002; 11:146-52). Although animal studies have not been reassuring for hydroxyzine, human data have not confirmed an increased risk, although they are not definitively reassuring either (data is summarized in our Chapter in Middleton, p. 1308). Animal studies are reassuring for terbutaline, montelukast, and doxepin, but there are few or no human data for these drugs. Ranitidine is considered safe for use during pregnancy, based on the available animal and human data. Thus, I would probably suggest treatment in the following order: 1. Loratadine 2. Cetirizine 3. Hydroxyzine (ideally after the first trimester) 4. Consider addition of ranitidine, terbutaline, or montelukast 5. Oral prednisone in severe, recalcitrant cases 12/14/04 re: Relation of silicone implants to chronic urticaria I am seeing a 60 year old lady in Arizona with hives for the past 4-6 weeks. When I saw her for the first time she had them only for 2-3 weeks. I advised her symptomatic treatment for acute hives and that no workup was needed at this time, but she and her husband insisted on blood work which included CBC, ESR, liver panel, TSH and thyroid antibodies which were normal. She is now questioning if it could be her silicone breast implants, which she had several years ago or valley fever. Hives are responding to Cetirizine and Ranitadine. Should I look into these causes? She will be returning for follow up soon. Any suggestions? I assume that if your patient has had silicone gel breast implants inserted in the USA , these have been in place for over 10 years, since the FDA essentially banned almost all use of these products in 1992 (see material enclosed below). However, several large studies have found no significant association between use of such implants and any systemic diseases (see enclosed abstracts). I have not seen a specific reference to chronic urticaria (CU) in such reports but have not found any convincing reports of an association of silicone gel implants and CU either. I have also not found any evidence linking CU to cocci infection (valley fever) either. You also asked for any ideas concerning the etiology of CU in a 60 year woman. As you likely know, the etiology of most of such cases is not detected with current approaches. In about 1/3 of the cases there is evidence suggesting an auto- immune reaction to the high-affinity IgE receptor (less commonly the IgE molecule itself) which activates basophils/mast cells to release mediators thought to cause the CU lesions. As you suggested in your comments, evidence of thyroid auto-immunity is present in about 20-25% of cases. When the urticaria first presents at this older age it is very important to rule out a drug reaction, whether due to prescription or OTC preparations. In these days when up to 1/3 of patients take some form of alternative medicine approach, the patient should be questioned carefully about use of such products (particularly herbal extracts). I say this because some patients do not volunteer such info to physicians for fear of being considered "strange". As you likely know, food allergies are rarely found to be causes of CU starting in older adults. However, some patients are convinced that some "hidden" food offender is at fault. If the patient wants to investigate this, has been having daily CU lesions when off antihistamines, and is the sort that will follow the recommendations reliably, one can try this approach. For a period of 3-5 days ingestion by the patient of nothing but an "elemental" diet. If there is an impressive decrease in the CU followed by recurrence of the CU upon resumption of her regular diet, then the food allergy possibility should be explored further. It has been suggested that CU first appearing in older adults should raise the suspicion of malignancy or other systemic diseases. However, when I reviewed the relevant literature in that area not long ago, I could not find convincing evidence of such associations, particularly when there was no other manifestation suggesting the systemic disease. If there are skin lesions (sometimes not very impressive) which urticate on local rubbing, a biopsy of a non-rubbed lesion should be obtained looking for evidence of cutaneous mastocytosis. I have enclosed as an attachment FYI the manuscript of that review article written by me (.Chronic urticaria and systemic diseases. Current Allergy and Asthma Reports 2003; 3:455-57). Documentation information: In January of 1992, the Food and Drug Administration (FDA) implemented a voluntary but strongly urged moratorium on the sale and use of silicone breast implants pending a review of additional information.(1) By April of 1992, the FDA had converted this moratorium to what was essentially a ban. The continued use of the implants in post mastectomy reconstruction was allowed, as was their use in a small number of breast augmentation patients who were willing to enroll in long-term studies. Since 1992, many reports have appeared that refute the alleged association of silicone gel implants with a number of health problems ranging from cancer to autoimmune diseases. In 1993, the Council of Scientific Affairs of the American Medical Association issued a report urging the association to "support the position that women have the right to choose silicone gel-filled or saline-filled breast implants for both augmentation and reconstruction after being fully informed about the risks and benefits."(2) The American College of Rheumatology also issued a statement, saying that "there is no convincing evidence that these implants cause any generalized disease."(3) Most recently, on June 21, 1999, the Institute of Medicine (IOM) of the National Academy of Sciences reported the conclusions of a 2-year investigation on the possible role of silicone gel implants in systemic diseases. This report was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases and was created by a panel of 13 scientists under the auspices of the IOM, which is a private, nonprofit organization that provides governmental health policy advice. This investigation discovered no association between silicone gel implants and cancer, immunologic disease, or other systemic diseases; moreover, they reported that implants pose no risk for breast feeding or to unborn infants. 4-6 Nevertheless, the FDA's ban remains in effect. Plast Reconstr Surg. 1995 Dec;96(7):1521-33. Related Articles, Links The fate of breast implants: a critical analysis of complications and outcomes. Handel N. Jensen JA, Black Q, Waisman JR, Silverstein MJ. Complications and outcomes were monitored following the implantation of 1655 breast implants over a 15-year period. Smooth, polyurethane, and textured implants were used in a variety of clinical settings. The time course of capsular contracture was analyzed by the Kaplan-Meier method. Regardless of implant type or indication for surgery, the probability of contracture increased with time. Polyurethane-covered implants were associated with a significant reduction in the risk of contracture for at least 7 years following implantation. Smooth and textured silicone implants had contracture rates similar to each other, and the particular type of surface texturing (Biocel versus Siltex) was of no consequence. Contracture was more common following breast reconstruction and implant replacement than after augmentation mammaplasty and was not affected by filler material or implant size. Implant position did not alter the risk of contracture after augmentation; tissue expansion did not affect the risk of contracture after breast reconstruction. Infections were unusual but most common after reconstruction and unrelated to surface texture or filler material. Skin wrinkling was more frequent with saline implants and in the presence of surface texturing. Implant rupture was rare, with an incidence of 1 per 760 implant-years. Implant-associated connective-tissue disease was noted in only one individual, an incidence of 1 per 3801 implant-years N Engl J Med. 2000 Mar 16;342(11):781-90. Related Articles, Links Meta-analyses of the relation between silicone breast implants and the risk of connective-tissue diseases. Janowsky EC, Kupper LL, Hulka BS. Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, 27599, USA. esther_janowsky@unc.edu BACKGROUND: The postulated relation between silicone breast implants and the risk of connective-tissue and autoimmune diseases has generated intense medical and legal interest during the past decade. The salience of the issue persists, despite the fact that a great deal of research has been conducted on this subject. To provide a stronger quantitative basis for addressing the postulated relation, we applied several techniques of meta-analysis that combine, compare, and summarize the results of existing relevant studies. METHODS: We searched data bases and reviewed citations in relevant articles to identify studies that met prestated inclusion criteria. Nine cohort studies, nine case-control studies, and two cross-sectional studies were included in our meta-analyses. We conducted meta- analyses of the results of these studies, both with and without adjustment for confounding factors, and a separate analysis restricted to studies of silicone-gel- filled breast implants. Finally, we estimated the annual number of new cases of connective-tissue disease that could be attributed to breast implants. RESULTS: There was no evidence that breast implants were associated with a significant increase in the summary adjusted relative risk of individual connective-tissue diseases (rheumatoid arthritis, 1.04 [95 percent confidence interval, 0.72 to 1.51]; systemic lupus erythematosus, 0.65 [95 percent confidence interval, 0.35 to 1.23]; scleroderma or systemic sclerosis, 1.01 [95 percent confidence interval, 0.59 to 1.73]; and Sjogren's syndrome, 1.42 [95 percent confidence interval, 0.65 to 3.11]); all definite connective-tissue diseases combined (0.80; 95 percent confidence interval, 0.62 to 1.04); or other autoimmune or rheumatic conditions (0.96; 95 percent confidence interval, 0.74 to 1.25). Nor was there evidence of significantly increased risk in the unadjusted analyses or in the analysis restricted to silicone-gel-filled implants. CONCLUSIONS: On the basis of our meta-analyses, there was no evidence of an association between breast implants in general, or silicone-gel-filled breast implants specifically, and any of the individual connective-tissue diseases, all definite connective-tissue diseases combined, or other autoimmune or rheumatic conditions. From a public health perspective, breast implants appear to have a minimal effect on the number of women in whom connective-tissue diseases develop, and the elimination of implants would not be likely to reduce the incidence of connective-tissue diseases. 12/7/04 re: ACE inhibitor treatment I have a patient with diabetes and solar urticaria. Sun exposure causes erythema and swelling of large areas of legs and arms. She has no lip, tongue, eye or throat swelling. Is there any reason to avoid ACE inhibitor use in this patient? As you likely know, ACE inhibitor therapy is considered contra-indicated in conditions characterized by increased levels of bradykinin (such as HAE) because ACE also strongly catabolizes bradykinin (kininase activity). Inhibition of ACE would therefore potentially increase bradykinin levels further. Previous studies, including ones in which I participated (see enclosed abstract), have shown increased release of histamine in sites of induced solar urticaria lesions. However, to my knowledge, there has not been a reported increase in plasma bradykinin levels in such blood specimens draining solar urticaria lesions. I do not know how much this has been studied. A clue as to whether bradykinin release is playing a major role in the solar urticaria lesions in your patient may come from the duration of the urticaria lesions after sun exposure. If the urticaria remits within 1-2 hours after complete withdrawal of the patient from sun exposure, it would suggest that histamine is the major mediator with likely little contribution by bradykinin. However, if the lesions are of longer duration, there is a greater likelihood that more than histamine is involved, possibly bradykinin. If the question persists in your mind, you may be able to answer the question directly if there is a photo-related diseases group or lab in the Dermatology Dept of your institution. They could assess the response to a local solar challenge of your patient when she is not taking an ACE inhibitor drug and then a repeat challenge when she has taken the ACE inhibitor for a week or so. The amount of solar challenge exposure required to induce the urticaria and/or the extent of the urticaria lesion can be assessed in such challenges. The current winter period would be a good time to do such challenges when the patient is not exposed much to ambient sunlight . As an aside, you may wish to consider an attempt to induce tolerance to sunlight in this patient before next spring by graded solar exposures (see second abstract below). Br J Clin Pharmacol. 1980 Feb;9(2):183-6. Elevated blood histamine levels and mast cell degranulation in solar urticaria. Hawk JL, Eady RA, Challoner AV, Kobza-Black A, Keahey TM, Greaves MW. 1 Ultraviolet radiation (UVR)- induced wealing was studied in four patients with solar urticaria, whose measured action spectra were within the range 300 to 700 nm. 2 Elevated histamine levels were found in blood draining wealed skin in all four patients. 3 Histological and electron microscopial studies of the irradiated skin showed evidence of mast cell degranulation. 4 These findings demonstrate an association between histamine release from mast cells and wealing in solar urticaria, and should encourage evaluation of drugs which suppress histamine release in this disorder. Br J Dermatol. 1984 Mar;110(3):327-38. Studies on the mechanism of clinical tolerance in solar urticaria. Keahey TM, Lavker RM, Kaidbey KH, Atkins PC, Zweiman B. Tolerance to artificial ultraviolet radiation (UVR) was induced in three patients with solar urticaria by administering graded whole body exposures to long-wave ultraviolet radiation (UV-A, 320-400 nm) in a phototherapy cabinet. Plasma histamine levels, mast cell ultra structure and cutaneous responses to intradermally injected codeine and histamine were examined before and after the induction of tolerance. No evidence of serum complement activation could be demonstrated following exposure of serum samples to UVR in vitro. These studies suggest that the state of tolerance is due neither to mediator (histamine) depletion nor to a systemic effect induced by UV-A but may be due to an increase in the mast cell degranulation threshold. 11/4/04 re: Urticaria after ocean swimming One of my primary care physicians called me to ask if I had ever heard of urticaria apparently caused only when the patient swims in the ocean. I reviewed with the PCP aquagenic and cold urticaria, but the PCP told me that appropriate tests for these 2 diagnoses had already been done and were negative. The patient apparently does not have other allergic disease, and is otherwise healthy. Any suggestions for diagnostic workup? I assume from your lack of mentioning it that the patient in question does not exhibit a rash after swimming in equally cold lake water (or cold swimming pool water if that has been experienced). If so, then the possibility of "seabather's eruption" can be raised (see enclosed abstracts). As noted in these abstracts, this eruption has been reported mainly from "warm ocean" areas although occasional mini-epidemics occur in more northern latitudes such as Long Island, NY. As you can see, the rash is mainly pruritic papules although urticaria has also been reported. It would be worth exploring whether there were other cases of rash in individuals swimming in that part of the ocean at the same time. Another possibility is a contact urticaria due to contact with certain "algae blooms". The dinoflagellate-induced rash is generally accompanied by systemic symptoms. J Am Acad Dermatol. 1994 Mar;30(3):399-406. Seabather's eruption. Clinical, histologic, and immunologic features. Wong DE, Meinking TL, Rosen LB, Taplin D, Hogan DJ, Burnett JW. Department of Dermatology and Cutaneous Surgery, University of Miami, FL 33101. BACKGROUND: Seabather's eruption (SE) is a highly pruritic eruption under swimwear that occurs after bathing in the ocean. Its cause has been unknown. Few data have been collected since the classic description by Sams in 1949. OBJECTIVE: Our purpose was to describe the clinical and histopathologic findings in SE and to confirm the cause. METHODS: Patients with a pruritic eruption that developed after swimming were seen within 1 week of onset. Skin biopsy specimens and sera were obtained in selected cases. Water samples taken from areas of active SE outbreaks were examined for a causative organism. Sera were tested by enzyme-linked immunosorbent assay for reactivity to this organism. RESULTS: In southeast Florida, during a 4-month period, 70 patients with SE were seen. Inflammatory papules and pruritus were noted within hours of exposure. Eruptions were maximal in areas covered by a bathing suit. Children were more likely than adults to have systemic symptoms. The average duration of the eruption and pruritus was 12.5 days, with recurrences in 4.3% of patients. Histopathologic examination revealed a superficial and deep perivascular and interstitial infiltrate consisting of lymphocytes, neutrophils, and eosinophils. Water samples contained many cnidarian larvae, later grown to maturity and identified as Linuche unguiculata (thimble jellyfish). Enzyme-linked immunosorbent assay demonstrated in patients' sera high IgG levels specific for L. unguiculata. CONCLUSION: SE is a severely pruritic marine dermatosis that resolves spontaneously within 2 weeks. Therapy is symptomatic but often ineffective. Sera from affected persons showed specific reactivity to L. unguiculata. South Med J. 1995 Nov;88(11):1163-5. Seabather's eruption. Ubillos SS, Vuong D, Sinnott JT, Sakalosky PE. Division of Infectious Diseases and Tropical Medicine, University of South Florida College of Medicine, Tampa, USA. Seabather's eruption is an unusual rash that develops in individuals who have been swimming in the ocean. We report the case of a 25-year-old woman who had the rash in a typical bathing suit distribution. Several species of cnidarian larvae have been implicated in causing the disease. Symptomatic treatment is the mainstay of therapy for this self-limited rash. Preventive measures allow patients to avoid the disease altogether. N Engl J Med. 1993 Aug 19;329(8):542-4. Seabather's eruption. Freudenthal AR, Joseph PR. Office of Marine Ecology, Nassau County Department of Health, Mineola, N.Y. BACKGROUND. Seabather's eruption is an annoying pruritic dermatitis that appears on the areas covered by the bathing suit as an erythematous macular or popular dermatitis, with or without urticaria. It occurs sporadically in Florida, the Caribbean, and as far north as Bermuda. The cause is not known. METHODS. We collected information in Nassau County, Long Island, New York, about cases of all types of water-related dermatitis reported by beach personnel, health providers, and affected swimmers from 1970 through 1991. Concurrently, we surveyed all Nassau County swimming waters, especially during the summer season (June through September), for the presence of organisms capable of causing dermatitis. In 1980 a sudden epidemic of a severe, unfamiliar dermatitis in ocean bathers prompted increased surveillance of cases and waters. Planula larvae of the phylum Cnidaria were collected from the ocean and beaches and inside bathing suits. They were examined, photographed, tested on healthy subjects, and observed in the laboratory for metamorphosis. RESULTS. Three outbreaks of seabather's eruption have occurred on Long Island since 1975. The first, in August 1975, affected a small number of swimmers on the eastern end of Long Island. In 1980 there were thousands of cases along the entire south shore of the island, and in 1990 there were hundreds in the same area. In nonepidemic years, five or fewer cases have been reported yearly. Surveillance for larvae revealed them to be present during the swimming season in epidemic years, but in nonepidemic years they did not appear until autumn, after the swimming season. Applying larvae to the skin of healthy subjects produced a dermatitis indistinguishable from seabather's eruption. All larvae metamorphosed in the laboratory to the adult sea anemone Edwardsiella lineata. CONCLUSIONS. Seabather's eruption, previously reported only as sporadic cases in southern climates, has occurred sporadically and in outbreaks 1000 miles north of most previously described cases. These Long Island episodes were probably caused by the planula larvae of E. lineata. Public Health Rep. 1997 Jan-Feb;112(1):59-62. Risk factors for seabather's eruption: a prospective cohort study. Kumar S, Hlady WG, Malecki JM. Division of Epidemiology and Disease Control, Palm Beach County Public Health Department, Riviera Beach, FL 33404, USA. OBJECTIVE: A prospective cohort study was performed to identify risk factors for seabather's eruption. METHODS: Study participants were recruited at four beaches in Palm Beach County, Florida, during three weekends of May and June 1993. Participants were interviewed by telephone after 48 hours regarding medical history, beach activities, development of rashes, and use of possible preventive measures. RESULTS: Seabather's eruption, defined by the occurrence of a rash within two days of exposure to seawater, was reported by 114 (16%) of 735 respondents. The strongest predictor of seabather's eruption was a past history of the condition. Children less than 16 years of age were also at increased risk, as were surfers. Showering with one's bathing suit off was a useful protective measure. CONCLUSION: The study's findings suggest that when the seasonal risk of seabather's eruption is present, children, people with a history of seabather's eruption, and surfers are at greatest risk. During the sea lice season, seabathers can minimize their risk by showering with their bathing suits off after seabathing. Length of the time spent in water was not significantly associated with seabather's eruption. 9/27/04 re: Treatment of cold urticaria A 43 year old fireman with a history of systemic cold-induced urticaria x 3 years. He has recently had worsening symptoms - had one episode of hives, itching and chest tightness after returning from a fire where he was sweating, and changing in the air-conditioned firehouse. He was unable to tolerate cyproheptadine due to fatigue and Allegra 180 is not working. Any Suggestions? He is worried about being unable to continue as a firefighter and I think this is a valid concern. As you know most but not all patients with cold urticaria CU are benefited sufficiently by treatment with second/third generation antihistamines. In those not responsive, I would suggest: 1) Check for the presence of cryoglobulins, particularly if the serum complement levels are decreased. 2) Try a combination of cetirizine and montelukast (see enclosed abstract). You can assess the effect of this pre-treatment on the patient's local response to an ice cube challenge test. 3) Some authors describe a beneficial effect of calcium channel blocker meds in CU. However, I think that such agents help the Raynaud's symptoms but I am not convinced that they help CU. 4) I would advise your patient to not go directly into an air-conditioned environment after being in a very hot environment (allow time to "cool down" at warm but not hot temperature before going into a cool environment such as air-conditioned rooms). In some patients with CU it is the rate of cooling more than the absolute level of the cold temperature that determines how much the CU is expressed. J Am Acad Dermatol. 2003 Oct;49(4):714-6. Treatment of acquired cold urticaria with cetirizine and zafirlukast in combination. Bonadonna P, Lombardi C, Senna G, Canonica GW, Passalacqua G. Allergy Service, Verona General Hospital, Verona, Italy. Acquired cold urticaria is an infrequent physical urticaria that can provoke severe systemic reactions. Histamine is the primary mediator, but leukotrienes are also involved in the pathogenesis. H(1) antihistamines are recommended as first-choice treatment, but their efficacy is sometimes unsatisfactory. On the basis of pathogenic knowledge, it can be hypothesized that a combination therapy with antihistamines and leukotriene receptor antagonists is more effective than each drug given alone. We tested this hypothesis in 2 patients with severe systemic cold urticaria poorly responsive to conventional therapy. The patients underwent 3 consecutive treatment regimens (each of 2 weeks): cetirizine (10 mg once a day); zafirlukast (20 mg twice a day); and their combination. They were clinically evaluated, after each regimen, by means of a visual analog scale and ice-cube test. The combination therapy was superior to the 2 drugs given alone, as testified by subjective and objective evaluations. 9/8/04 re: Hives - etiology Patient is an 18 year old black male with a history of severe untreated allergic rhinitis and moderate persistent asthma who developed hives and swelling of his face, scalp chest and legs while at football practice. He also complained of occular pruritis and tightness in his chest. It was a very hot day and ragweed counts were in the very high range. He had been at practice every day for the past week with out any complaints. He did not eat beforehand and has played football for years. PMH also positive for lip swelling and vomiting with shrimp, but no history of anaphylaxis. He denies ever having been stung before and denies being stung at the time and denies ever having been stung before ever. He does report in the past trouble with occasional wheezing with vigorous exercise on hot humid days but no history of hives in the past with exercise. At the field with his reaction he used his albuterol 3 puff and was brought to the PCP where his O2 sat was 96-97 % on room air RR 16. FEV 1 in PCP office was 93% with a FEV1 84% of the FVC. He had wheezing on exam but no mention of hives or angioedema made in the PCP note, patient given prednisone and referred to me. Because of the severe presentation of the reaction at the field and as a resident, I had seen patient's in the ER with no recollection of being stung I Included RAST to venom. The Patient's RAST from QUEST came back as follows: Honey Bee < 0.35 Yellow Jacket 5.21 Yellow Hornet 15.9 White Faced Hornet 9.77 Wasp 7.42 Shrimp was >100 Ragweed 3.76 Dust Mite 68.9 I did read in the Boston Globe a few years ago of a football player dieing at the field and a stinger was found on autopsy and I wonder how common this is and perhaps if this is what happened here. The patient was placed on Clarinex and advair 100/50 bid and has since returned to practice symptom free. With no recollection of ever having been stung, what is the risk of this patient having a life threatening reaction if he is stung? Would you recommend VIT to this patient? Any other ideas of further evaluation? The clinical picture you describe did not suggest a clear-cut cause of the acute urticaria episode, in my opinion. To help respond to your question concerning the clinical significance of the anti-venom IgE antibody findings you described, I obtained input from Dr. Robert Reisman of the SUNY, Buffalo Med Center, one of the leading clinical investigators of hymenoptera stinging insect allergy in the USA. His response is enclosed below. As you can see, Dr. Reisman's extensive experience is that a sting injecting a sufficient amount of venom to induce a generalized allergic reaction should be felt locally by the person stung. The question remains as to the reason why such an individual has sizable levels of IgE anti-venom antibodies. It should be mentioned that a recent report by Golden et al of the AAAAI Insect Committee (JACI 2003;112:495-98) concluded that the in vitro (RAST type) tests for anti-venom antibodies are positive in the face of negative venom skin tests in about 10% of those with fairly convincing histories suggesting a previous systemic allergic reaction to a sting. They recommend likely undertaking venom IT if the history suggested a severe reaction. In cases such as your patient, where the history is not clear-cut, the usual recommendation would be for the patient to practice stinging insect avoidance, carry an Epi-Pen at all times when exposure is possible, but not venom IT. That would go along with Dr. Reisman's recommendations. Meanwhile, one might consider an exercise challenge sufficient to raise the body temperature without prior medication. If the patient, having been told about the antibody findings you described, is insistent on knowing whether he is tolerant to insect stings, one could consider referring him to one of the med centers carrying out such challenges in a carefully controlled environment. Dr. Reisman's comments: There are two issues raised by this case presentation, the etiology of the acute allergic reaction and the clinical relevance of the elevated levels of venom specific IgE. I believe the most likely diagnosis of the allergic reaction is exercise induced anaphylaxis. I do not believe the reaction was due to an insect sting. Insect stings always cause pain, in contrast to insect bites, and people always know when stung. The reported elevated titers of venom specific IgE [RAST], in absence of venom exposure, is very unusual and needs clarification. Venom skin tests should be done. I would expect these tests to be negative; if positive, prescribe an Epi Pen [which he should have anyway], but not venom immunotherapy. Would educate regarding exercise anaphylaxis. 9/8/04 re: Significance of low CH50 level I have a 40 year old female patient who had multiple episodes of facial edema over the past 10 years. In the past 1 year, she has developed chronic idiopathic urticaria. Skin biopsy confirmed urticaria, no vasculitis was evident. Since her urticaria was difficult to control, required oral steroids from past physicians, I did some bloodwork. CH50 was absent, C3 and C4 were normal. ANA, thyroid antibodies, liver function tests were normal. Is the CH50 related to her symptomatology, or is it a red herring? The first thing that comes to my mind when hearing about a very low CH50 level in the face of normal C3 and C4 levels is a technical problem in which the serum specimen stood too long at room temperature or was otherwise altered so as to inactivate the complement biologic activity. The C3 and C4 levels can remain normal in such specimens since they are usually assayed by an immunoassay. Such immunoassays measure the amount of C3 and C4 protein regardless of whether the biologic activity is decreased on prolonged standing of the serum specimen at room temperature. Therefore, I would obtain another blood specimen for CH50, C3 and C4 levels, making sure that the serum is removed promptly and frozen at -60 to -70 degrees C if it is not immediately transported to the lab for analysis. If the CH50 level is again very low with normal C3 and C4 levels, my next thought would be a deficiency of one of the late complement components (C5 through C8). The clinical pictures most commonly associated with such deficiencies are recurrent infections, generally selective such as the neisserial infections and occasional other disorders seen in those deficient in C6 (see enclosed abstract). I am not aware of chronic urticaria/angioedema as a manifestation of such deficiency. Facial edema and very low CH50 levels would be relatively common in hereditary angioedema (HAE) or one of its “acquired” variants. However, the serum C4 level should be decreased in these disorders, particularly if the serum was obtained at a time close to when the patient has angioedema episodes (see enclosed abstract). Also, chronic urticaria generally does not accompany the angioedema in HAE. You may still wish to obtain serum level of the C1 inhibitor if the CH50 is consistently very low. The Melkersson-Rosenthal syndrome is another consideration in recurrent facial edema without angioedema elsewhere (see enclosed abstract). I assume that the patient is not taking an ACE inhibitor, in which recurrent facial angioedema episodes occur in about 1% of treated individuals. If you wish further input after obtaining additional lab studies, please submit another Ask The Expert question at that time, including the addi