Contribution of Alpha-gal in Pathologies Other than Alpha-gal Syndrome: Focusing on Chronic Spontaneous Urticaria

BACKGROUND: Chronic urticaria is a skin disease characterized by the appearance of itchy weals and/or angioedema for 6 or more weeks. Chronic urticaria is subdivided into chronic spontaneous urticaria, which occurs due to an unknown cause, and chronic inducible urticaria, which occurs as a result of exposure to various physical factors (water, cold, heat, pressure, mechanical irritation), can occur simultaneously or independently of each other. Omalizumab, anti-IgE monoclonal antibody, is approved for the treatment of patients with chronic spontaneous urticaria and is the second choice in cases of resistance to antihistamine treatment. In patients with a combination of chronic spontaneous urticaria and chronic inducible urticaria, the effectiveness of treatment with omalizumab has been little studied.
 AIM: compare the effectiveness of omalizumab treatment in patients with chronic spontaneous urticaria and patients with a combination of chronic spontaneous and chronic induced urticaria.
 MATERIALS AND METHODS: Under supervision there were 30 patients with chronic spontaneous urticaria and combined chronic spontaneous and inducible urticaria (15 patients in each group). Evaluation of the effectiveness of treatment was carried out according to the results of the questionnaires DLQI (dermatological index of quality of life), CU-Q2oL (questionnaire for quality of life in chronic urticaria), UCT (urticaria control test), UAS (urticaria activity scale), HADS (Hospital Anxiety and Depression Scale) and provocation tests in dynamics before and during treatment.
 RESULTS: All patients received omalizumab 300 mg subcutaneously once a month for 6 to 12 months. After the first injection of omalizumab, we noted a decrease in the severity of urticaria, an increase in the level of disease control and quality of life when comparing parameters before and during treatment in more than 90% of patients. Improved performance remained at this level throughout all subsequent months of treatment.
 CONCLUSION: Omalizumab is equally effective in patients with an isolated form of chronic spontaneous urticaria and in patients with a combined form of chronic spontaneous and inducible urticaria. The use of omalizumab allows you to control the symptoms of chronic spontaneous and inducible urticaria, even with prolonged use.

Decoding the Enigma of Urticaria and Angioedema

IntroductionDelayed allergy to red meat, also termed alpha-gal syndrome, is increasingly reported in adults and African communities, while pediatric cases remain rare.Case presentationHere, we report on a 7-year-old Caucasian boy presenting with recurrent wheals since the age of 5 years old. Episodes with hives occurred around every 3 weeks, mainly in the evening. One of these episodes was also associated with angioedema. No clear trigger was identified. At the first visit, after excluding an infection and autoimmune thyroiditis, chronic spontaneous urticaria was suspected and symptomatic treatment with antihistamines was prescribed. Six months later, the boy presented at the emergency room with generalized urticaria, dyspnoea, and emesis. Symptoms resolved after administration of epinephrine and antihistamines. A detailed medical history after this event revealed that he had eaten three sausages as well as jelly beans containing gelatine several hours prior to this episode. More precisely, after eating the sausages and jelly beans during the day, he had shown some hives before going to bed, and later developed the other symptoms in the middle of the night, suggesting alpha-gal syndrome. In his history, several tick bites are reported. Immunoglobulin E levels for alpha-gal were clearly elevated, confirming the diagnosis of a delayed-appearing immunoglobulin E-mediated allergic reaction to alpha-gal. Emergency medication was prescribed and avoidance of red meat and gelatine-containing foods was recommended. Under this exclusion diet, the boy remained asymptomatic, with the exception of two accidents in the follow up of 3 years, one developing during a barbecue and the second after exceptionally eating marshmallows.ConclusionA detailed clinical history led to the diagnosis of alpha-gal syndrome. Although alpha-gal syndrome is typically seen in adults, our case illustrates that children can also present with this potentially life-threatening allergy. Since alpha-gal syndrome is rare in Europe, the disease is not well known and often overlooked for several years, especially in children.

Chronic spontaneous urticaria (CSU) in children is mostly spontaneous in onset (57%). Treatment comprises long-term antihistaminic therapy without need for elaborate investigations. A subset of such patients don't respond to conventional treatment and novel therapies to help reduce pill burden is the need of the hour. To determine the efficacy and safety of autologous serum therapy (AST) in pediatric patients with chronic spontaneous urticaria. All pediatric patients, aged between 6-16 years, attended to our OPD from March 2019 to March 2020 were recruited. Clinico-demographic data and baseline investigations of all patients were performed. Two-weekly AST therapy was given for 8 visits with levocetrizine tablet 5mg on an on-demand basis. Urticaria activity score (UAS) sheet was provided to record and return every 2 weeks. Statistical analysis was done using the IBM SPSS 26 software package. Autologous serum skin test (ASST) was positive in 63% patients. Both the ASST positive and ASST negative group showed significant reduction in UAS7 score at week 14 compared to baseline. The reduction in mean UAS7 score was associated with a decreased pill burden and positive response in the patient and physician global assessment scale. No statistically significant difference between the two groups in terms of mean UAS7 reduction was found. This study has explored the efficacy and safety of autologous serum therapy in the pediatric CSU patients. Both ASST positive and ASST negative group respond to AST therapy.

Sex differences in the pathogenesis of chronic urticaria

Clinical utility of the Chronic Urticaria Index

Objective To investigate the role of erythrocyte complement receptor type 1 (CR1) in the pathogenesis of chronic urticaria.Methods Venous blood samples were collected from 59 patients with chronic urticaria (including 14 cases of dermatographism and 45 chronic idiopathic urticaria) and 29 healthy human controls.Flow cytometry was carried out to quantify the expression level of CR1,and double-antibody sandwich enzyme-linked immunosorbent assay to determine the serum level of immunoglobulin E (IgE),complement C3,C4 and 50％ complement hemolytic activity (CH50).Differences in these parameters were analyzed by one-way ANOVA and independent samples t-test,and correlation between these paramenters by Pearson correlation analysis.Results The expression level (expressed as mean fluorescence intensity per 10 000 erythrocytes) of CR1 was significantly higher in patients with dermatographism and chronic idiopathic urticaria than in the healthy controls (35.06 ± 2.06 and 29.17 ± 1.53 vs.20.46 ± 2.57,t =4.20 and 3.33,both P ＜ 0.05),while no statistical difference was observed between the patients with dermatographism and chronic idiopathic urticaria (P ＞ 0.05).Increased total serum IgE levels were observed in patients with dermatographism and chronic idiopathic urticaria compared with the healthy controls ((769.89 ± 123.0) μg/L and (340.09 ± 29.74) μg/L vs.(107.63 ± 88.79) μg/L,t =5.58,5.85,both P ＜ 0.05),and in patients with dermatographism compared with those with chronic idiopathic urticaria (t =3.49,P ＜ 0.05).For patients with chronic urticaria,there was a statistical difference in the expression level of CR1 between individuals (n=22) with total serum IgE levels ranging from 0 to 240 μg/L and those (n =17) higher than 500 μg/L (24.45 ± 10.83 vs.33.09 ± 11.86,t =3.33,P＜ 0.05).The total serum IgE levels were positively correlated with the level of CR1 (r =0.27,P ＜ 0.05),but uncorrelated with that of complement C3 (r =0.16,P ＞ 0.05) or C4 (r =-0.08,P＞ 0.05).The level of complement C3 was positively correlated with that of C4 (r =0.54,P ＜ 0.01).One-way ANOVA revealed no significant difference in the serum levels of complement C3,C4,or CH50 between the patients with dermatographism,patients with chronic idiopathic urticaria and healthy controls (all P ＞ 0.05).Conclusion CR1 is abnormally expressed in patients with chronic urticaria. Key words: Urticaria; Receptors, complement; Complement C3; Complement C4; Immunoglobulin E

Chronic urticaria (CU) comes as chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIndU).1 Across its types and subtypes, CU is a heterogeneous disease that has different phenotypes with distinct clinical characteristics and different endotypes with distinct underlying pathophysiological mechanisms.2, 3 It may be possible that subtypes of CU patients exhibit distinct phenotypic disease signatures that can point to differences in what drives their condition and in their response to treatments. Cluster analysis is a popular unsupervised machine learning (ML) method for discovering previously undetected data patterns.4 ML-based cluster analysis has been used in several diseases for the identification and characterization of patient subgroups.5, 6 As of now, no study has attempted to identify CU subtypes with this method. Here, we performed a proof-of-concept study to test whether cluster analysis using ML algorithms can identify subgroups of CU patients based on clinical and routine laboratory characteristics. We retrospectively analyzed the medical charts of a cohort of 431 CU patients. Institutional review board was obtained, and due to retrospective nature of the study, patient consent was not required. ML-based k-means clustering with principal component silhouette analyses (PCA) and use of the elbow method of dimensionally reduced data showed 4 clusters of CU patients, with a homogeneous balance between the clusters and the selected evaluation metrics (methods are provided in supplementary material) (Figure S3). Clustering analyses with PCA resulted in more meaningful clusters than without and supported the positive impact of reduced dimensions, and cluster number identified. Cluster characteristics and comparisons identified clinically distinct patient subgroups (Table 1). Cluster 1 (The “CIndU only” cluster) was the smallest cluster and consisted of all and only CIndU patients who did not have comorbid CSU. Of all clusters, cluster 1 patients had the highest age [median 42 (28–51) years], the shortest duration of disease [12 (5–96) months], and the lowest IgE levels [74.6 (35.1–188.5) IU/ml]. Cluster 2 (The “high IgE” cluster) was the largest cluster. All patients had CSU, and half of them had comorbid CIndU. Cluster 2 patients, on average, had the highest IgE levels [132 (56.4–271.5) IU/ml], the highest rate of comorbid atopic dermatitis (7.7%), and the lowest rate of ANA and IgG-anti-TPO positivity (1.4% and 4.2%, respectively). Cluster 3 (The “autoimmune” cluster) had the highest percentage of women (92%) in all clusters. All patients had CSU, and more than half also had CIndU (56.3%). Three of four patients (77.3%) had angioedema, the highest percentage of any cluster. Cluster 3 patients also had the second-lowest IgE levels (84.2 IU/ml) of any CSU cluster and the highest rates of IgG-anti-TPO and ANA positivity across all clusters (39.8% and 52.3%, respectively). Cluster 4 (The “high comorbidity” cluster) consisted only of CSU patients, and comorbid CIndU was rare (14.3%). The defining characteristics of patients in this cluster, the high comorbidity cluster, were their high rates of hypertension (74%), diabetes mellitus (62%), and hypothyroidism (38%), each at least twice as high as in any other cluster. The results of our study provide proof of concept that the use of unsupervised ML algorithms can identify meaningful and distinct groups of patients with CU and cluster CU into four different and distinct subtypes. Three of these four clusters are remarkably similar to how patients with CU are classified in real life, that is, as having CIndU or CSU as their primary form of CU and, in the latter, as having autoimmune or autoallergic CSU (Figure 1). This suggests that ML-based algorithms can be used to establish patient signatures, which may then be used to better characterize relevant and distinct pathomechanisms of CU subgroups. This, in turn, will allow us to better manage CU, by optimizing the use of available treatments and guiding the development of new and better ones. This project benefitted from the support (non-financial) of the GA2LEN network of urticaria centers of reference and excellence (UCARE, www.ga2len-ucare.com). MT has no relevant conflict of interest in relation to this work. Outside of it, MT is or recently was a speaker and/or advisor for Novartis. RE has no relevant conflict of interest in relation to this work. Outside of it, RE is or recently was a speaker and/or advisor for Novartis. EZ, YT, MA, and AG have no conflict of interest. MM has no relevant conflicts of interest in relation to this work. Outside of it, MM is or recently was a speaker and/or advisor for and/or has received research funding from Allakos, Amgen, Aralez, ArgenX, AstraZeneca, Celldex, Centogene, CSL Behring, FAES, Genentech, GIInnovation, Innate Pharma, Kyowa Kirin, Leo Pharma, Lilly, Menarini, Moxie, Novartis, Roche, Sanofi/Regeneron, Third HarmonicBio, UCB, and Uriach. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Objective To explore the association of genome methylation with the pathogenesis of chronic urticaria by detecting genome methylation level of chronic idiopathic urticaria and autoimmune urticaria. Methods 45 patients with chronic urticaria were divided into chronic idiopathic urticaria group and autoimmune urticaria group using ASST method. Serum TgAb, TPOAb, ANA, SAM, and SAH were detected. Results The positive rate of ASST was 46.7% in patients with chronic urticaria, as compared with 0% in control group. There was a statistical significance between the two groups. The positive rates of TgAb, TPOAb, and ANA were 23.80%, 14.29%, and 14.29% in autoimmune urticaria group, 4.16%, 4.16%, and 0 in chronic idiopathic urticaria group, and 5%, 0%, and 0% in the control group. TgAb differed significantly between autoimmune urticaria group and the other two groups, but not between chronic idiopathic urticaria group and the control group. TPOAb and ANA did not differ statistically between the two groups. SAM, SAH, and SAM/SAH did not differ significantly. Conclusions Autoimmune urticaria accounts for 46.7% in patients with chronic urticaria. TGAb is significantly higher in autoimmune urticaria patients than in those with chronic idiopathic urticaria. Further research should be done to confirm whether TGAb can be a kind of valuable clinical detection index of autoimmune urticaria. There is no statistical significance in SAM, SAH, and SAM/SAH between the two groups, which is likely to suggest that methylation is not involved in the pathogenesis of autoimmune urticaria. But this conclusion needs to be confirmed by bigger samples. Key words: Urticaria; DNA methylation; S-adenosylmethionine; S-adenosylhomosysteine

Chronic urticaria (CU) is a debilitating mast cell-driven disease, often refractory to standard therapy (ie, antihistamines). Lirentelimab, an anti-sialic acid-binding immunoglobulin-like lectin 8 mAb, selectively inhibits mast cells and depletes eosinophils. We sought to determine safety and efficacy of lirentelimab in patients with CU. This phase 2a study enrolled patients with CU refractory to up to 4-fold H1-antihistamine doses. Patients received 6 monthly intravenous doses of lirentelimab (0.3, 1, and up to 3 mg/kg). Primary efficacy end point was change in Urticaria Control Test score at week 22. Urticaria Activity Score weekly average (UAS7) was assessed in patients with chronic spontaneous urticaria (CSU), and Cholinergic UAS7 was used for patients with cholinergic urticaria (CholU). A total of 45 patients were enrolled in 4 cohorts (n= 13 omalizumab-naive CSU, n= 11 omalizumab-refractory CSU, n= 11 CholU, n= 10 symptomatic dermographism). Urticaria Control Test scores increased with lirentelimab across cohorts, with mean changes at week 22 of 11.1± 4.1, 4.8± 7.0, 6.5± 6.2, and 3.4± 4.1 and complete response rates (Urticaria Control Test score≥ 12) of 92%, 36%, 82%, and 40%, respectively. In omalizumab-naive and omalizumab-refractory patients with CSU, disease activity decreased at week 22 (mean UAS7 change, -73% and -47%, respectively), with UAS7 response rates (≥50% reduction) of 77% and 45%, respectively. In patients with symptomatic dermographism, 50% (5 of 10) and 40% (4 of 10) had complete itch and hive resolution by FricTest, respectively, and 100% (7 of 7) evaluable patients with CholU had negative responses to Pulse-Controlled Ergometry exercise test. Most common adverse events included infusion-related reactions (43%; all mild/moderate and transient), nasopharyngitis (21%), and headache (19%). No treatment-related serious adverse events occurred. Lirentelimab demonstrated activity across 3 forms of antihistamine-refractory CU.

Introduction: Chronic urticaria (CU) is a common skin condition that can be divided into chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIndU). Omalizumab is one treatment option for CU, but currently there are limited clinical studies of omalizumab’s efficacy for treating CU in Chinese patients. This study sought to investigate the efficacy and safety of omalizumab treatment for CU patients in a Chinese patient population. Specifically, we aimed to compare the differential efficacy of omalizumab for CSU and CIndU patients and predict risk factors for recurrence. Methods: We completed a retrospective clinical data review of 130 CU patients who received omalizumab treatment from August 2020 to May 2022, with a maximum follow-up period of 18 months. Results: A total of 108 CSU patients and 22 CIndU patients were included in the study. After treatment with omalizumab, the response rate in the CSU group was higher than that in the CIndU group (93.5% vs. 68.2%), and CSU patients accounted for a higher proportion of responders and early responders (responders: 87.1% vs. 12.9%, p < 0.001; early responders: 95.7% vs. 4.3%, p = 0.001). Nonresponders had lower total immunoglobulin E (IgE) levels (75.0 vs. 167.5 IU/mL, p = 0.046) and a relatively shorter duration of treatment (1.0 vs. 3.0 months, p = 0.009) compared to responders. Early responders had shorter disease duration (1.0 vs. 3.0 years, p = 0.028), higher baseline UCT (4.0 vs. 2.0, p = 0.034), lower baseline DLQI (18.0 vs. 18.5, p = 0.026), and shorter total treatment time (2.0 vs. 4.0 months, p < 0.001) compared to late responders. All adverse events reported during treatment were mild. Seventy-four patients with CU discontinued the drug after achieving complete disease control, of which 26 (35.1%) relapsed for 2.0 months (interquartile range: 1.0–3.0 months). Compared with nonrelapsed patients, relapsed patients often had other allergic diseases (42.3% vs. 18.8%, p = 0.029), higher basal levels of total IgE (263.0 vs. 140.0 IU/mL, p = 0.033), and longer disease duration (4.2 vs. 1.0 years, p = 0.002). Relapsed patients could still achieve good disease control after restarting omalizumab therapy. Conclusion: Omalizumab was effective and safe for CSU and CIndU patients. Patients with CSU responded more quickly to omalizumab and showed a relatively better treatment effect. However, there was a possibility of relapse after discontinuation of omalizumab after complete control of CU, and in these cases, restarting omalizumab treatment after relapse was effective.

Omalizumab has emerged as a novel and effective treatment option for patients with antihistamine-resistant chronic urticaria. It is unclear whether patients with recurrent urticaria symptoms after discontinuation of omalizumab treatment can benefit from retreatment. To assess the response of patients with chronic urticaria who receive omalizumab retreatment. Retrospective analyses were conducted of outpatients treated at an urticaria specialist center of a university hospital. Participants included 25 consecutive patients (aged 18-74 years; 18 women) with chronic spontaneous urticaria, chronic inducible urticaria, or both who showed complete response to omalizumab treatment, experienced relapse after discontinuation of treatment, and received retreatment with omalizumab. Subcutaneous treatment with omalizumab (150-600 mg/mo). Response after retreatment was assessed by the urticaria activity score in patients with chronic spontaneous urticaria and by trigger threshold testing (in patients with cold urticaria or symptomatic dermographism) and/or a carefully determined history (in patients with cholinergic urticaria, solar urticaria, or pressure urticaria). Adverse events were documented. All patients experienced complete response after retreatment. None of the patients reported relevant adverse events during omalizumab treatment and retreatment. Omalizumab retreatment is effective and safe in patients with chronic urticaria who have benefited from initial omalizumab treatment.

Studies establish a link between autoimmune factors and chronic spontaneous urticaria (CSU). T cells are crucial in immune-mediated diseases like CSU, and T-cell receptor (TCR) diversity could be pivotal in autoimmune responses. The clinical relevance of TCR variations in CSU is unknown, but understanding them may offer insights into CSU's pathogenesis and treatment. This cross-sectional study included 132 chronic urticaria (CU) patients versus 100 age-matched healthy donors (HD), with subgroup analyses on CU type, angioedema, allergic comorbidities, and anti-IgE therapy efficacy. Peripheral TCRβ repertoires were analyzed by high-throughput sequencing. CSU patients showed reduced TCR diversity (lower D50) and increased large clone proportions than HD. Moreover, TCR diversity in CSU patients was significantly lower than in those with Chronic Inducible Urticaria (ClndU). There were also differences in variable (V) and joining (J) gene usage between CU and HD groups as well as CSU and ClndU groups. However, in subgroup analyses regarding angioedema, allergic comorbidities, and the efficacy of anti-IgE treatment, no significant differences were found in TCR diversity or large TCRβ clones. Notably, patients with treatment relapse or poor response to anti-IgE therapy had a higher proportion of positively charged CDR3. Additionally, age affected TCR diversity, but TIgE value, EOS counts, CU duration, and UAS7 score did not associate significantly with D50. CSU patients exhibit reduced TCR diversity and increased large clone proportions, indicating abnormal T cell activation. The TCR diversity differences and distinct V and J gene usage between CSU and ClndU may indicate different mechanisms in T lymphocyte-associated immune responses for these two subtypes of CU. The higher positive charge in CDR3 of relapsed or poorly responsive patients to anti-IGE treatment may indicate more antigen charge involvement. These findings provide new insights into the pathogenesis of CSU and potential future treatments.

Chronic urticaria (CU), characterized by daily wheals and/or angioedema lasting more than 6 weeks, is a common skin disease. CU is classified as spontaneous or inducible. Because of Coronavirus Disease-19 (COVID-19) pandemic, face-to-face visits were reduced, and many centers started remote consultations to minimize hospital admissions and risk for viral diffusion. Telemedicine became a valuable tool for evaluating and monitoring patients with chronic diseases, such as CU. This study aims to evaluate the effectiveness of telemedicine as a means for the follow-up of patients with chronic spontaneous urticaria (CSU) during the COVID-19 pandemic. In particular, we collected data related to CSU evolution and treatment by remote consultation. Moreover, we specifically investigated the impact of SARS-CoV-2 infection or vaccination on CSU in relapsing or worsening of such a disease. The electronic charts were reviewed for patients diagnosed with CSU, who were referred to the allergy unit of Meyer Children's Hospital, Florence. For each patient, a review of demographic characteristics, diagnostic workup, efficacy, and tolerability of the treatment was performed. Patients with a physical agent triggering CU were excluded from the study. Disease activity was monitored using the Urticaria Activity Score (UAS7). In addition, when the COVID-19 pandemic started, follow-up continued through telemedicine after an initial face-to-face visit when possible. Approximately 1 year after the diagnosis of CSU, patients were recontacted to investigate whether they had experienced a relapse or worsening of urticaria during a possible COVID-19 or immediately after receiving a COVID-19 vaccine. From January 2020 to March 2021, 84 cases of CSU were identified, with 71 (84.5%) of these being evaluated via televisit (remote consultation). During the remote follow-up period, 38/71 (53.5%) patients who were evaluated via televisit recovered completely from CSU, while 24 (33.8%) made therapy adjustments, and 9 (12.7%) had to discontinue follow-up through remote visits and return to face-to-face visits. In February 2022, we recontacted the 71 patients with CSU, and 50 (70.4%) of them answered by phone call interview. Four (19.2%) of the 26 patients who had COVID-19 showed CSU relapse, while 1 (3.8%) had a CSU worsening. Instead, 1 (3.8%) patient of the 26 who were vaccinated had a relapse of CSU, and 1 (3.8%) had a worsening of CSU, both after the first dose. Our data showed that telemedicine can be an effective tool for the follow-up of patients with CSU. Moreover, COVID-19, as well as COVID-19 vaccination, may trigger CSU relapse or worsening, but both are unspecific triggers, and urticaria shows a very short duration in most cases.

Omalizumab is a recombinant monoclonal antibody, targeting the epsilon 3 domain of free serum IgE antibodies, and thus preventing their attachment to the cognate high-affinity receptor on mast cells and reducing the number of cell-bound receptors. It represents the first ‘biological’ that has been studied in allergy and was registered several years ago for the treatment of severe allergic asthma in adults and children by the FDA and the EMA. About one year ago, omalizumab was registered for adult patients with chronic spontaneous urticaria – with or without angioedema – which is insufficiently controlled by standard treatment, including high-dose antihistamines. During the last years, international guidelines have profoundly changed our therapeutic approaches to chronic urticarial patients in which, instead of a previously recommended combination treatment with different histamine receptor antagonists, an increase of non-sedating H-1 receptor antagonists of the second generation up to a quadruple dose of the standard recommended regimen is now the general rule (1,2,3,4). These new recommendations have led to a remarkable improvement of response rates seen in urticarial patients; however, by far not all adult patients with chronic spontaneous urticaria are sufficiently controlled even by high doses of antihistamines. The application of omalizumab as a third-line option has demonstrated an unexpected additional benefit and leads to a complete relief of symptom in almost all treated patients. All three of the pivotal phase III studies in adults have led to a recommended dose of 300 mg omalizumab in 4 weeks, which differs from dose regimens for allergic asthma, where the patient's body weight and the total serum IgE levels determine the omalizumab dose. It seems that with the novel treatment option the vast majority of all adult patients with chronic spontaneous urticaria are adequately controlled without major safety problems, which is a remarkable step forward in the long-term treatment of urticaria. The problems of chronic urticaria in childhood seem to be inadequately perceived, which may be due to its low prevalence compared to adults. Until recently, the natural course of CU has not really been studied in large cohorts of children. A recent prospective study from Thailand suggests that chronic urticaria in children has a more favorable outcome than in adults, with a remission rate of 18.5% after one year and 54% after 3 years 5. Like adults, more than 30% of the children with a chronic spontaneous urticaria were found to have autoantibodies to the alpha subunit of the high-affinity IgE receptor (Fc-epsilon-R 1) and/or anti-IgE antibodies. The presence of these autoantibodies may be screened for by performing the autologous serum skin test (ASST). Up to now, the intervention with the recombinant monoclonal antibody omalizumab has been studied in childhood only for severe asthma as well as in rhinitis. In most parts of the world, it is registered for the treatment of uncontrolled severe asthma after the age of six. A systematic review on the use of omalizumab in children, which appears in this issue, indicates that the addition of omalizumab in patients with uncontrolled allergic asthma can be considered as effective and safe 6. Up to now, there is not a single randomized controlled trial in children with urticaria. Therefore, the different case reports presented in this issue reporting a beneficial effect in refractory solar urticaria, and in spontaneous and physical urticaria are very encouraging and of high interest (7,8,9). Although very severe clinical cases of uncontrollable chronic urticaria compared to adults seem to be rare and the outcome may be more favorable in childhood, the information presented here strongly suggests that the pathophysiologic mechanism leading to chronic urticaria in childhood may be similar. It appears that the time has come to ask for randomized controlled trials with omalizumab and possibly other biologics for an apparently forgotten disorder in childhood which may deserve more attention and consideration than given in the past.