Atopy and Response to Omalizumab Treatment in Chronic Spontaneous Urticaria.

INTRODUCTION: The possible influence of sensitization to aeroallergens on omalizumab response in chronic spontaneous urticaria (CSU) has been insufficiently investigated. This study's aim was to investigate atopy's influence on omalizumab response in CSU patients. METHOD: Retrospective study of CSU patients followed at a Portuguese Urticaria Center of Reference and Excellence (UCARE), treated with omalizumab for at least 6 months, between 2015 and 2022. At T0, all patients underwent quantification of specific immunoglobulin E (IgE) for total extract of most prevalent aeroallergens (ImmunoCAP Thermo Fisher Scientific®) and were divided in 2 groups, according to their response to omalizumab during the first 16 weeks of treatment: responders (R) (UAS7 <7) versus partial (PR) (UAS7 = 7-15) and nonresponders (UAS7 >15). R were further classified as fast (FR) (4-6 weeks) and slow responders (SR) (12-16 weeks). Total serum IgE, circulating eosinophil, and basophil counts were compared between groups at T0. p < 0.05 was considered statistically significant (SPSS® v25.0). RESULTS: Ninety-six patients (80% female) were studied, mean age 49 ± 14 years. Median CSU duration pre-omalizumab was 3 (0.6-20) years and mean omalizumab treatment duration was 3.7 ± 2.3 years. 38 (40%) had concomitant chronic inducible urticaria and 72 (75%) angioedema. Based on positive results of the specific IgE assay, 35 patients (36%) were considered atopic. Most patients (n = 30; 86%) were sensitized to house dust mites (HDM) (Dermatophagoides farinae = 28, Dermatophagoides pteronyssinus = 27, Blomia tropicalis = 19, Lepidoglyphus destructor = 17), followed by pollens (n = 12; 34%) (mixture of grasses = 10, Olea europaea = 7, Parietaria officinalis = 6), epithelia (n = 9; 26%) (dog = 8, cat = 7), and fungi (Alternaria alternata = 4; 11%). Eight patients (23%) were monosensitized to HDM and 4 (11%) to pollens. No significant association was found between aeroallergen sensitization and CSU duration, concomitant chronic inducible urticaria, or angioedema. Atopic patients featured significantly higher levels of baseline total serum IgE than nonatopic (469 vs. 94 U/mL, respectively; p = 0.0009). Mean baseline counts of eosinophils and basophils were not significantly different between atopic and non-atopic, respectively: eosinophils (128 vs. 121/mm3) and basophils (26 vs. 28/mm3). Regarding response to omalizumab, most patients (58; 60%) were responders: FR - 46 (79%); SR - 12 (21%). There was no significant association between aeroallergen sensitization and omalizumab response or speed of response. CONCLUSIONS: As far as we know, this is the first study exploring the influence of atopy sensitization pattern on omalizumab response in CSU. According to our results, presence of atopy/sensitization pattern does not influence omalizumab response in CSU patients.

Risk factors for systemic reactions in typical cold urticaria: Results from the COLD-CE study.

BACKGROUND: Cold urticaria (ColdU), that is, the occurrence of wheals or angioedema in response to cold exposure, is classified into typical and atypical forms. The diagnosis of typical ColdU relies on whealing in response to local cold stimulation testing (CST). It can also manifest with cold-induced anaphylaxis (ColdA). We aimed to determine risk factors for ColdA in typical ColdU. METHODS: An international, cross-sectional study COLD-CE was carried out at 32 urticaria centers of reference and excellence (UCAREs). Detailed history was taken and CST with an ice cube and/or TempTest® performed. ColdA was defined as an acute cold-induced involvement of the skin and/or visible mucosal tissue and at least one of: cardiovascular manifestations, difficulty breathing, or gastrointestinal symptoms. RESULTS: Of 551 ColdU patients, 75% (n = 412) had a positive CST and ColdA occurred in 37% (n = 151) of the latter. Cold-induced generalized wheals, angioedema, acral swelling, oropharyngeal/laryngeal symptoms, and itch of earlobes were identified as signs/symptoms of severe disease. ColdA was most commonly provoked by complete cold water immersion and ColdA caused by cold air was more common in countries with a warmer climate. Ten percent (n = 40) of typical ColdU patients had a concomitant chronic spontaneous urticaria (CSU). They had a lower frequency of ColdA than those without CSU (4% vs. 39%, p = .003). We identified the following risk factors for cardiovascular manifestations: previous systemic reaction to a Hymenoptera sting, angioedema, oropharyngeal/laryngeal symptoms, and itchy earlobes. CONCLUSION: ColdA is common in typical ColdU. High-risk patients require education about their condition and how to use an adrenaline autoinjector.

Adrenaline autoinjector is under-prescribed in typical cold urticaria patients living in tropical climate countries.

Background: The diagnosis of typical cold urticaria (ColdU) relies on whealing in response to local cold stimulation testing (CST). It can also manifest with cold-induced anaphylaxis (ColdA). Till date, it is largely unclear how often patients with ColdU receive adrenaline treatment and are provided with an adrenaline autoinjector (AAI). Methods: An international, cross-sectional study, COLD-CE (i.e., comprehensive evaluation of ColdU and other cold-induced reactions), was carried out at 32 UCAREs. Detailed histories were taken and CST with an ice cube and/or TempTest® performed. ColdA was defined as an acute cold-induced (i.e., by cold water, air, or surfaces) involvement of the skin and/or visible mucosal tissue and at least one of the symptoms (cardiovascular manifestations, difficulty breathing, or gastrointestinal symptoms). Results: Of the 551 ColdU patients, 75% (n = 412) had a positive CST. Of them, concomitant chronic spontaneous urticaria was diagnosed in 10%. Of 372 patients with stand-alone ColdU, 69% were women and 91% adults. Their median age was 36 (IQR 26 - 48) years. Patients were also categorized into residents of countries with a tropical (n = 33), temperate (n = 264), or cold (n = 75) climate (Table 1: R13C1, R17C1, R21C1). AAI was more often prescribed to residents of temperate than tropical countries (30% vs. 12%, p = .038; Table 1: R31C1), although the frequency of ColdA did not significantly differ between these countries (44% vs. 42%, p = 1.000; R29C2). Residents of tropical countries had a higher frequency of ColdA induced by cold air than residents of temperate (36% vs. 12%, p = .001; R29C4) or cold (36% vs. 12%, p = .007; R25C4) countries. Cardiovascular manifestations induced by cold air were diagnosed in 33% (n = 11) of residents of tropical countries, but only 18% (n = 2) and 36% (n = 4) of them had received adrenaline and AAI, respectively (R13 - 15C7). Furthermore, hypotension and/or loss of consciousness induced by cold air occurred in 18% (n = 6) of patients, but only 17% (n = 1) received adrenaline (R13 - 14C10). ColdA was induced by complete cold water immersion in 9% (n = 3) of patients, and none of them received adrenaline treatment nor AAI (R13 - 15C3). Conclusion: Our findings suggest that ColdA is undertreated and call for changes in ColdU management.

Rapid desensitization to antineoplastic drugs in an outpatient immunoallergology clinic: Outcomes and risk factors.

BACKGROUND: Hypersensitivity reactions to antineoplastic agents may lead to discontinuation of first-line treatments. Rapid drug desensitization (RDD) allows for a safe reintroduction in patients who are allergic to them. OBJECTIVE: To evaluate the safety and efficacy of the Brigham and Women's Hospital's 12-step RDD in a Portuguese patient population with cancer and to identify markers associated with breakthrough reactions (BTRs) to platins. METHODS: We conducted a retrospective review of desensitizations undertaken at the Immunoallergology Day-Care Unit of the Santa Maria Hospital in Lisbon, Portugal, from July 2008 to July 2019. Adult patients with cancer and with immediate hypersensitivity reactions were included. Skin testing was performed to platins, trastuzumab, and cetuximab. The 12-step protocol was used for most patients, and a shorter protocol was used in 9 patients who were taxane-reactive to resume regular infusions. RESULTS: A total of 1471 RDDs were performed in 272 patients to 136 platins, 124 taxanes, 13 monoclonal antibodies, and 10 other drugs. Skin test results were positive in 127 of patients who were platin-reactive (95.3%) and negative in patients who were cetuximab- and trastuzumab-reactive. There were 141 BTRs during RDD (9.6% of infusions), 79.4% induced by platins with the majority having mild reactions (68.8%). There were 8 patients who were paclitaxel-reactive, and who completed a shorter protocol and resumed regular infusions successfully. Multiple platin infusions (cutoff: ≥10) and total immunoglobulin E greater than or equal to 100 U/mL were identified as independent risk factors for BTRs in patients who were platin-reactive. CONCLUSION: This large single-center study confirmed the safety and efficacy of the 12-step RDD protocol in a diverse cancer population, providing evidence of its universal applications. Total immunoglobulin E is a potentially useful biomarker to identify high-risk patients who are platin-reactive.

Antifouling Napyradiomycins from Marine-Derived Actinomycetes Streptomyces aculeolatus.

The undesired attachment of micro and macroorganisms on water-immersed surfaces, known as marine biofouling, results in severe prevention and maintenance costs (billions €/year) for aquaculture, shipping and other industries that rely on coastal and off-shore infrastructures. To date, there are no sustainable, cost-effective and environmentally safe solutions to address this challenging phenomenon. Therefore, we investigated the antifouling activity of napyradiomycin derivatives that were isolated from actinomycetes from ocean sediments collected off the Madeira Archipelago. Our results revealed that napyradiomycins inhibited ≥80% of the marine biofilm-forming bacteria assayed, as well as the settlement of Mytilus galloprovincialis larvae (EC50 < 5 µg/ml and LC50/EC50 >15), without viability impairment. In silico prediction of toxicity end points are of the same order of magnitude of standard approved drugs and biocides. Altogether, napyradiomycins disclosed bioactivity against marine micro and macrofouling organisms, and non-toxic effects towards the studied species, displaying potential to be used in the development of antifouling products.

Intra-clade metabolomic profiling of MAR4 Streptomyces from the Macaronesia Atlantic region reveals a source of anti-biofilm metabolites.

The search for new and effective strategies to reduce bacterial biofilm formation is of utmost importance as bacterial resistance to antibiotics continues to emerge. The use of anti-biofilm agents that can disrupt recalcitrant bacterial communities can be an advantageous alternative to antimicrobials, as their use does not lead to the development of resistance mechanisms. Six MAR4 Streptomyces strains isolated from the Madeira Archipelago, at the unexplored Macaronesia Atlantic ecoregion, were used to study the chemical diversity of produced hybrid isoprenoids. These marine actinomycetes were investigated by analysing their crude extracts using LC-MS/MS and their metabolomic profiles were compared using multivariate statistical analysis (principal component analysis), showing a separation trend closely related to their phylogeny. Molecular networking unveiled the presence of a class of metabolites not previously described from MAR4 strains and new chemical derivatives belonging to the napyradiomycin and marinone classes. Furthermore, these MAR4 strains produce metabolites that inhibit biofilm formation of Staphylococcus aureus and Marinobacter hydrocarbonoclasticus. The anti-biofilm activity of napyradiomycin SF2415B3 (1) against S. aureus was confirmed.

Omalizumab in Chronic Spontaneous Urticaria (CSU): Real-Life Experience in Dose/Interval Adjustments and Treatment Discontinuation.

BACKGROUND: Data on real-life experience with omalizumab dose/interval adjustments are still limited, as well as on omalizumab discontinuation. OBJECTIVE: To evaluate efficacy and safety of omalizumab dose/interval adjustment in a Portuguese cohort of patients with chronic spontaneous urticaria (CSU) and to characterize those who discontinued omalizumab. METHODS: A retrospective study of patients who started omalizumab for CSU at a Portuguese Urticaria Center of Reference and Excellence (UCARE) was conducted between 2009 and 2021. Response criteria were based on a weekly Urticaria Activity Score (UAS7) <7 points (partial: UAS7 7-15 points; nonresponders: UAS7 >15 points) and minimal important difference >10 points. RESULTS: A total of 138 patients were enrolled in the study; 83% of them were women, and the median age was 49 years (interquartile range: 40-58 years). On 300 mg q4 weeks, 96 (70%) patients were responders, 29 (21%) partial responders, and 13 (9%) nonresponders. After dose/interval adjustments (up to 600 mg q2 weeks), 108 (78%) were responders, 27 (20%) partial responders, and 3 (2%) nonresponders. No adverse events were reported. Updosing was more frequent in patients with angioedema, body mass index >30 kg/m2, positive basophil activation test, and autologous serum test. A total of 71 (51%) patients lengthened interval, presenting higher median pre-omalizumab D-dimer (0.2 vs 0 mcg/mL, P = .038) and C-reactive protein (0.3 vs 0.1 mg/dL, P = .030) values than those with a standard dose. In total, 37 patients (27%) stopped omalizumab, but 14 (38%) of them needed retreatment on average 11 months after discontinuation. Patients with angioedema and a longer omalizumab duration had higher chance of relapse. CONCLUSIONS: Omalizumab dose and/or interval adjustment is effective and safe and should be implemented in partial/nonresponders for response improvement and in responders for further discontinuation. A protocol for regimen adjustments is proposed.

Angioedema hereditário inaugural na idade pediátrica / Hereditary angioedema in a child with no family history of disease

O angioedema hereditário por défice de C1-inibidor é uma doença rara autossômica dominante com uma prevalência estimada em 1:50.000. Habitualmente a história familiar aponta para este diagnóstico. No entanto, a apresentação atípica com história familiar negativa pode atrasar o diagnóstico de meses a anos. Os autores apresentam o caso de uma criança de 6 anos sem antecedentes pessoais ou familiares relevantes que recorreu ao Serviço de Urgência pediátrico por edema, calor e rubor do cotovelo, joelho e maléolos direitos com 12h de evolução, sem fatores associados. Ao exame objetivo: edema do cotovelo, joelho e maléolos direitos, exantema não pruriginoso maleolar homolateral com discreto desconforto à palpação. Sem elevação dos parâmetros infeciosos ou inflamatórios. Foi iniciada corticoterapia sistêmica, com melhoria lenta do quadro. Teve alta, referenciada à consulta de Imunoalergologia. Na anamnese foram apurados quatro episódios de edema periarticular nos doze meses prévios. A avaliação analítica da criança revelou C1 inibidor 62 mg/dL, C1 inibidor funcional 29%, confirmada em duas determinações, e a dos pais e dos dois irmãos foi normal. No estudo genético não foram identificadas mutações nos genes SERPING. O angioedema hereditário por défice de função do C1-inibidor - tipo II - representa 15 a 20% dos casos. Embora a história familiar seja o maior sinal de alerta para o diagnóstico desta patologia, em 20-25% dos casos ocorre mutação espontânea. Nestes casos um elevado grau de suspeição é necessário e um atraso no diagnóstico pode levar a consequências graves. As opções terapêuticas em crianças menores de 12 anos são ainda limitadas.

Hereditary angioedema with C1-inhibitor deficiency is a rare autosomal dominant disease with an estimated prevalence of 1:50 000. Usually, family history points to this diagnosis. However, atypical presentation with negative family history may delay diagnosis in months to years. The authors describe the case of a 6-year-old girl with apparently no significant family or past medical history, presenting to the emergency department for edema, warmth, and redness of the right elbow, knee, and ankle, which started 12 hours earlier, without associated factors. On physical examination, edema of the right elbow, knee, and ankle, and nonpruritic rash on the right ankle with a slight discomfort on palpation were found. Laboratory infection or inflammation markers were not elevated. Systemic corticosteroids were started, with slow improvement. She was discharged and referred to an immunoallergology outpatient clinic. On medical history taking, four episodes of periarticular edema in the past 12 months were identified. Laboratory evaluation revealed C1-inhibitor at 62 mg/dL and functional C1-inhibitor at 29%, confirmed in two samples; the parents and two siblings were normal. On genetic testing, there were no mutations on the SERPING genes. Hereditary angioedema with C1-inhibitor deficiency ­ ie, type II ­ accounts for 15 to 20% of cases. Even though family history is the major indicator for diagnosis of this condition, a de novo mutation occurs in 20 to 25% of cases. In these cases, a high suspicion is necessary, and a delayed diagnosis could have severe implications. Therapeutic options in children under the age of 12 are limited.

Molecular sensitization profile of patients with lipid transfer protein syndrome and associated clinical characteristics / Perfil de sensibilização molecular de doentes com síndrome de proteínas de transferência lipídica e associação com características clínicas

Introduction: Lipid transfer proteins (LTPs) can cause a diversity of food allergy phenotypes, broadly defined as LTP syndrome. Objective: The aims of this study were to characterize the molecular profile of patients with this syndrome and to evaluate any possible association with clinical phenotypes. Methods: Retrospective study of patients followed up from April 2011 to April 2019. Patients with LTP syndrome and sensitization to Pru p 3, diagnosed by ImmunoCAP ISAC® (Phadia, Thermo Fisher Scientific, Sweden), were selected. Statistical analysis was conducted in IBM SPSS® v20. Results: One hundred patients were assessed, 64% of which were females, with a mean age 27.2±11.8 years (15% pediatric). Mean age at first reaction was 19.9±10 years. According to clinical presentation, two groups were created: local reaction (LR) (n=28) and systemic reaction (SR) (n=72). The following parameters were analyzed in association with the SR group: LTP sensitization profile, co-sensitization to profilins or PR-10 proteins, presence of atopy, and gender. In univariate analysis, a positive association was found between the SR group, female sex (odds ratio [OR] 2.8, p=0.02), and presence of Jug r 3 (OR 2.6, p=0.03). There was a negative association between the SR group, the presence of Par j 2 (OR 0.16, p < 0.01), and co-sensitization to profilins (OR 0.11, p < 0.01). In multivariate analysis, only the presence of Par j 2 kept statistical significance (OR 0.023, p < 0.01). Conclusions: Molecular profile characterization may be useful as a predictor of disease expression in an individual, making a relevant contribution to improved follow-up of these patients. Sensitization to Par j 2 seems to provide protection for the occurrence of SR.

Introdução: As proteínas de transferência lipídicas (LTP) são causa de uma variedade de fenótipos de alergia alimentar globalmente definidos como síndrome LTP. Objetivo: O nosso objetivo é caracterizar o perfil molecular destes doentes e avaliar associação com os fenótipos clínicos. Metodologia: Estudo retrospectivo em que foram selecionados doentes com síndrome de LTP e sensibilização ao alergênio molecular pru p 3 em ImmunoCAP ISAC® (Phadia, Thermo Fisher Scientific, Suécia) realizados de abril de 2011 a abril de 2019. A análise estatística foi realizada através do software IBM SPSS® v20. Resultados: Cem doentes, 64% do sexo feminino, com média de idades à data do exame de 27,2±11,8 anos (idade pediátrica - 15%). A média de idades da primeira reação foi de 19,9±10 anos. Foram constituídos dois grupos com base na apresentação clínica à data da realização do exame: local (LR) n = 28; sistêmica (SR) n = 72. Os seguintes parâmetros foram avaliados em relação ao grupo SR: perfil de sensibilização a LTP, co-sensibilização com profilinas ou PR-10, presença de atopia e gênero. Na análise univariada foi encontrada associação positiva com grupo SR para sexo feminino (Odds ratio (OR) 2,8, p = 0,02) e presença de Jug r 3 (OR 2,60, p = 0,03). Associaram-se negativamente à doença sistêmica a presença de Par j 2 (OR 0,16, p < 0,01) e de profilinas (OR 0,11, p < 0,01). Na análise multivariada apenas manteve significado estatístico a presença de par j 2 (OR 0,023, p < 0,01). Conclusões: A caracterização do perfil molecular pode ser útil como preditos da expressão da doença, sendo uma importante ferramenta no seguimento destes doentes. A presença de Par j 2 parece ser fator protetor de reação grave.