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The Natural History of Chronic Urticaria in Childhood
S102 Abstracts
J ALLERGY CLIN IMMUNOL FEBRUARY 2009
SUNDAY
383
The Natural History of Chronic Urticaria in Childhood S. Chansakulporn, S. Pongpreuksa, P. Sangacharoenkit, P. Pacharn, N. Visitsunthorn, P. Vichyanond, O. Jirapongsananurak; Mahidol University, Bangkok, Thailand. RATIONALE: Information on the natural course of chronic urticaria (CU) in childhood is limited. This study was aimed to examine the natural history of CU and identify predictors for CU remission. METHODS: Children 4-15 years of age with CU were investigated for CBC, ESR, ANA, CH50, free-T4, TSH, anti-thyroglobulin, anti-microsomal antibody, autologous serum skin test (ASST), skin prick tests (SPT) to foods, food challenges, and stool examination for parasites. The patients were followed every 3-6 months and patients without symptoms for 12 months were considered remission. RESULTS: Ninety children (54% females) with the mean age and duration of follow up of 8.8 6 3.2 and 4.2 6 1.6 years were recruited. Elevated ESR, ANA, and eosinophilia were found in 13%, 22%, 24%, respectively. None of these patients had clinical features of urticarial vasculitis, abnormal CH50, TSH or free-T4. Anti-thyroglobulin and anti-microsomal antibodies were not detected. Chronic autoimmune urticaria (CAU), which determined by positive ASST, was identified in 38.9% of children. SPT to foods were positive in 30% and 9% had positive food challenges. After diet elimination, 5/8 patients had CU remission. Parasitic infestations were found in 5.6% without clinical correlation. CU remission at 1, 3, 5 years after the onset of symptoms were 18.9%, 40%, 68.6%, respectively. Patients with CAU did not have different remission rate, compared to nonCAU patients (p 5 0.510). Demographic data and all investigations could not predict CU remission. CONCLUSIONS: CU in children had a favorable outcome. Patients with CAU did not demonstrate a recalcitrant disease and there was no predictor for CU remission.
Infusion of C1 Inhibitor as Therapy for Swelling in Hereditary Angioedema Patients Reverses Abnormalities of the Plasma Bradykinin-forming Pathway and Fibrinolysis K. Joseph, T. E. Tholanikunnel, A. P. Kaplan; Medical University of South Carolina, Charleston, SC. RATIONALE: Hereditary angioedema (HAE) is typically due to a deficiency of C1 inhibitor (C1INH) with gene defects that lead to diminished plasma levels or production of a dysfunctional protein. Replacement therapy with C1INH has been shown to be effective in ameliorating acute episodes of swelling. We have reported elevated baseline levels of bradykinin, C4a, and plasmin-a2 antiplasmin complexes in HAE plasma compared to normal plasma, and production of Hageman factor fragment (HFf) upon in vitro activation of HAE plasma (Annals Allergy Asthma Immunol, In Press). We reassessed these parameters after treatment of episodes of swelling with intravenous C1INH. METHODS: We obtained samples of plasma (Lev Pharmaceuticals Inc.) from nine HAE patients at a quiescent period (baseline), during an attack of swelling, and at 1 hr, 4 hr and 12 hr after termination of an infusion of C1INH. Factor XIIa, kallikrein and plasmin were each measured by cleavage of synthetic substrates specific for each. RESULTS: Each enzyme was strikingly elevated at baseline compared to a control plasma and there was a progressive decline of activity to normal for factor XIIa and plasmin. Kallikrein decreased in 7/9 patients at 1 hr, and then decreased in all patients. Bradykinin levels were elevated at the outset in all patients, increased prominently during an attack of swelling, decreased to baseline after 1 hr, and then decreased to normal by 4 hr and 12 hr. CONCLUSIONS: The data indicate that C1INH infusion reverses all parameters of plasma activation, particularly factor XIIa, the initiating enzyme, plasmin and bradykinin, the mediator of the swelling.
384
386
Hereditary Angioedema Due to Missense Mutations in the Factor XII Gene: Clinical Features, Trigger Factors, and Therapy K. Bork1, K. Wulff2, J. Hardt3, G. Witzke1, P. Staubach1; 1Department of Dermatology, University of Mainz, Mainz, Germany, 2Institute of Human Genetics, University of Greifswald, Greifswald, Germany, 3Department of Psychosomatic Medicine and Psychotherapy, University of Mainz, Mainz, Germany. RATIONALE: Hereditary angioedema due to mutations in the factor XII gene is a recently described disease entity occurring mainly in women and differs from hereditary angioedema due to C1 inhibitor deficiency. To assess the clinical symptoms, factors triggering acute attacks, and treatment of this molecularly defined disease. METHODS: 35 patients, all women, with hereditary angioedema and with the factor XII mutations Thr309Lys and Thr309Arg coming from 13 families were studied. The observation period was 8.4 years on average. RESULTS: Recurrent facial swellings occurred in all patients, skin swellings at other sites, abdominal pain attacks, tongue swellings, laryngeal edema and edema of the soft palate were less frequent. The mean frequency of angioedema attacks was 12.7 1/2 7.9 per year. Factors triggering angiodema attacks included trauma, pressure, and emotional stress. Clinical symptoms started mainly after intake of oral contraceptives (17 women) or onset of pregnancy (3 women). Exacerbation of the symptoms occurred after oral contraceptives (8 women), pregnancy (7 women), hormonal replacement therapy (3 women), intake of angiotensin-converting enzyme inhibitors (2 women) and an angiotensin1 receptor blocker (one woman). C1 inhibitor activity was normal in the plasma of most patients, in others slightly decreased. Effective treatment included C1 inhibitor concentrate for angioedema attacks (6 women), and, for prophylaxis, progesterone (8 women), danazol (2 women), and tranexamic acid (one woman). CONCLUSIONS: Facial swelling is a cardinal symptom of this condition. The influence of estrogens may be high but is highly variable. Different treatment options are available.
385
Potential Role for Eosinophil-derived Tissue Factor in the Activation of Coagulation in Patients with Chronic Urticaria M. Cugno1,2, A. V. Marzano2, A. Tedeschi2, D. Fanoni2, L. Venegoni1, D. Spinelli2, R. Asero3; 1University of Milan, Milan, Italy, 2IRCCS Maggiore Hospital, Milan, Italy, 3Clinica San Carlo, Paderno Dugnano-Milan, Italy. RATIONALE: Although chronic urticaria (CU) often recognizes an autoimmune mechanism related to histamine-releasing autoantibodies, an activation of blood coagulation via tissue factor (TF) and a strong expression of TF in lesional skin have been described. Eosinophils have recently been demonstrated as the major source of TF in human blood, thus we assessed whether eosinophils are the cellular source of TF in CU skin lesions. METHODS: Twenty patients with severe CU were studied. Skin biopsy specimens were taken from wheals lasting from 3 to 12 hours. The control group consisted of specimens of perilesional normal skin from different types of skin tumors (10) and various skin disorders with non-eosinophilic infiltrates, including leukocytoclastic vasculitis (7), lichen planus (8) and mastocytosis (3). TF expression was evaluated by immunohistochemical methods using an anti-TF monoclonal antibody. Co-localization of TF and eosinophil cationic protein, a classic cell marker of eosinophils, was investigated by double-staining studies using 2 specific monoclonal antibodies in the 4 specimens showing the highest TF reactivity scores. RESULTS: All specimens from patients with CU clearly showed TF expression that was absent in all normal control specimens (p 5 0.0001) and in the skin disorders with non-eosinophilic infiltrates (p 5 0.0010.0001). The double-staining experiments for TF and eosinophil cationic protein showed that the TF-positive cells were eosinophils. CONCLUSIONS: Eosinophils are the main source of TF in CU lesional skin. This finding highlights the role of these cells as potential activators of coagulation in CU.
J ALLERGY CLIN IMMUNOL FEBRUARY 2009
SUNDAY
383
The Natural History of Chronic Urticaria in Childhood S. Chansakulporn, S. Pongpreuksa, P. Sangacharoenkit, P. Pacharn, N. Visitsunthorn, P. Vichyanond, O. Jirapongsananurak; Mahidol University, Bangkok, Thailand. RATIONALE: Information on the natural course of chronic urticaria (CU) in childhood is limited. This study was aimed to examine the natural history of CU and identify predictors for CU remission. METHODS: Children 4-15 years of age with CU were investigated for CBC, ESR, ANA, CH50, free-T4, TSH, anti-thyroglobulin, anti-microsomal antibody, autologous serum skin test (ASST), skin prick tests (SPT) to foods, food challenges, and stool examination for parasites. The patients were followed every 3-6 months and patients without symptoms for 12 months were considered remission. RESULTS: Ninety children (54% females) with the mean age and duration of follow up of 8.8 6 3.2 and 4.2 6 1.6 years were recruited. Elevated ESR, ANA, and eosinophilia were found in 13%, 22%, 24%, respectively. None of these patients had clinical features of urticarial vasculitis, abnormal CH50, TSH or free-T4. Anti-thyroglobulin and anti-microsomal antibodies were not detected. Chronic autoimmune urticaria (CAU), which determined by positive ASST, was identified in 38.9% of children. SPT to foods were positive in 30% and 9% had positive food challenges. After diet elimination, 5/8 patients had CU remission. Parasitic infestations were found in 5.6% without clinical correlation. CU remission at 1, 3, 5 years after the onset of symptoms were 18.9%, 40%, 68.6%, respectively. Patients with CAU did not have different remission rate, compared to nonCAU patients (p 5 0.510). Demographic data and all investigations could not predict CU remission. CONCLUSIONS: CU in children had a favorable outcome. Patients with CAU did not demonstrate a recalcitrant disease and there was no predictor for CU remission.
Infusion of C1 Inhibitor as Therapy for Swelling in Hereditary Angioedema Patients Reverses Abnormalities of the Plasma Bradykinin-forming Pathway and Fibrinolysis K. Joseph, T. E. Tholanikunnel, A. P. Kaplan; Medical University of South Carolina, Charleston, SC. RATIONALE: Hereditary angioedema (HAE) is typically due to a deficiency of C1 inhibitor (C1INH) with gene defects that lead to diminished plasma levels or production of a dysfunctional protein. Replacement therapy with C1INH has been shown to be effective in ameliorating acute episodes of swelling. We have reported elevated baseline levels of bradykinin, C4a, and plasmin-a2 antiplasmin complexes in HAE plasma compared to normal plasma, and production of Hageman factor fragment (HFf) upon in vitro activation of HAE plasma (Annals Allergy Asthma Immunol, In Press). We reassessed these parameters after treatment of episodes of swelling with intravenous C1INH. METHODS: We obtained samples of plasma (Lev Pharmaceuticals Inc.) from nine HAE patients at a quiescent period (baseline), during an attack of swelling, and at 1 hr, 4 hr and 12 hr after termination of an infusion of C1INH. Factor XIIa, kallikrein and plasmin were each measured by cleavage of synthetic substrates specific for each. RESULTS: Each enzyme was strikingly elevated at baseline compared to a control plasma and there was a progressive decline of activity to normal for factor XIIa and plasmin. Kallikrein decreased in 7/9 patients at 1 hr, and then decreased in all patients. Bradykinin levels were elevated at the outset in all patients, increased prominently during an attack of swelling, decreased to baseline after 1 hr, and then decreased to normal by 4 hr and 12 hr. CONCLUSIONS: The data indicate that C1INH infusion reverses all parameters of plasma activation, particularly factor XIIa, the initiating enzyme, plasmin and bradykinin, the mediator of the swelling.
384
386
Hereditary Angioedema Due to Missense Mutations in the Factor XII Gene: Clinical Features, Trigger Factors, and Therapy K. Bork1, K. Wulff2, J. Hardt3, G. Witzke1, P. Staubach1; 1Department of Dermatology, University of Mainz, Mainz, Germany, 2Institute of Human Genetics, University of Greifswald, Greifswald, Germany, 3Department of Psychosomatic Medicine and Psychotherapy, University of Mainz, Mainz, Germany. RATIONALE: Hereditary angioedema due to mutations in the factor XII gene is a recently described disease entity occurring mainly in women and differs from hereditary angioedema due to C1 inhibitor deficiency. To assess the clinical symptoms, factors triggering acute attacks, and treatment of this molecularly defined disease. METHODS: 35 patients, all women, with hereditary angioedema and with the factor XII mutations Thr309Lys and Thr309Arg coming from 13 families were studied. The observation period was 8.4 years on average. RESULTS: Recurrent facial swellings occurred in all patients, skin swellings at other sites, abdominal pain attacks, tongue swellings, laryngeal edema and edema of the soft palate were less frequent. The mean frequency of angioedema attacks was 12.7 1/2 7.9 per year. Factors triggering angiodema attacks included trauma, pressure, and emotional stress. Clinical symptoms started mainly after intake of oral contraceptives (17 women) or onset of pregnancy (3 women). Exacerbation of the symptoms occurred after oral contraceptives (8 women), pregnancy (7 women), hormonal replacement therapy (3 women), intake of angiotensin-converting enzyme inhibitors (2 women) and an angiotensin1 receptor blocker (one woman). C1 inhibitor activity was normal in the plasma of most patients, in others slightly decreased. Effective treatment included C1 inhibitor concentrate for angioedema attacks (6 women), and, for prophylaxis, progesterone (8 women), danazol (2 women), and tranexamic acid (one woman). CONCLUSIONS: Facial swelling is a cardinal symptom of this condition. The influence of estrogens may be high but is highly variable. Different treatment options are available.
385
Potential Role for Eosinophil-derived Tissue Factor in the Activation of Coagulation in Patients with Chronic Urticaria M. Cugno1,2, A. V. Marzano2, A. Tedeschi2, D. Fanoni2, L. Venegoni1, D. Spinelli2, R. Asero3; 1University of Milan, Milan, Italy, 2IRCCS Maggiore Hospital, Milan, Italy, 3Clinica San Carlo, Paderno Dugnano-Milan, Italy. RATIONALE: Although chronic urticaria (CU) often recognizes an autoimmune mechanism related to histamine-releasing autoantibodies, an activation of blood coagulation via tissue factor (TF) and a strong expression of TF in lesional skin have been described. Eosinophils have recently been demonstrated as the major source of TF in human blood, thus we assessed whether eosinophils are the cellular source of TF in CU skin lesions. METHODS: Twenty patients with severe CU were studied. Skin biopsy specimens were taken from wheals lasting from 3 to 12 hours. The control group consisted of specimens of perilesional normal skin from different types of skin tumors (10) and various skin disorders with non-eosinophilic infiltrates, including leukocytoclastic vasculitis (7), lichen planus (8) and mastocytosis (3). TF expression was evaluated by immunohistochemical methods using an anti-TF monoclonal antibody. Co-localization of TF and eosinophil cationic protein, a classic cell marker of eosinophils, was investigated by double-staining studies using 2 specific monoclonal antibodies in the 4 specimens showing the highest TF reactivity scores. RESULTS: All specimens from patients with CU clearly showed TF expression that was absent in all normal control specimens (p 5 0.0001) and in the skin disorders with non-eosinophilic infiltrates (p 5 0.0010.0001). The double-staining experiments for TF and eosinophil cationic protein showed that the TF-positive cells were eosinophils. CONCLUSIONS: Eosinophils are the main source of TF in CU lesional skin. This finding highlights the role of these cells as potential activators of coagulation in CU.