Unmasking Carcinoid Syndrome in a Chronic Obstructive Pulmonary Disease (COPD) Patient: A Rare Presentation with Wheezing and Angioedema.

Carcinoid syndrome is a rare condition resulting from neuroendocrine tumors (NETs) that secrete vasoactive substances like serotonin. This report describes the case of a 61-year-old man with a history of chronic obstructive pulmonary disease (COPD) and hypertension who presented with new-onset angioedema, loss of consciousness, and a fall. He had been treated for COPD exacerbations during ER visits without improvement and was unaware of a prior mesenteric carcinoid tumor diagnosis from 2012. The next emergency evaluation revealed significant airway and facial edema necessitating intubation. Imaging and biopsy identified a well-differentiated grade 1 NET with extensive liver metastases. Laboratory tests showed elevated levels of serum serotonin, chromogranin A, and 24-hour urine 5-hydroxyindoleacetic acid (5-HIAA). Post-discharge, a PET scan confirmed metastatic lesions primarily in the liver and small bowel, with an unresectable mesenteric mass. The patient was treated with lanreotide and became symptom-free. This case underscores the need to consider carcinoid syndrome in patients with COPD presenting with unexplained respiratory symptoms, as timely diagnosis and treatment can significantly enhance patient outcomes.

Chronic Spontaneous Urticaria: Quality of Life and Economic Impacts.

This study focuses on quality of life (QoL) assessment in chronic urticaria, delving into tools, disease-specific measures, and its profound impact. With expanding therapeutic options, understanding QoL becomes crucial. QoL measures often involve comparisons of patient-reported outcomes in addition to quantitative measures of disease control. Emerging tools include the Urticaria Activity and Impact Measure, which may provide a balanced evaluation. In addition to discussions of the various QoL measures, the psychological impact of chronic urticaria are highlighted, covering emotional burden, stress, and psychiatric comorbidities. Finally, the economic impacts reveal escalating health care costs and cost-effectiveness considerations of therapies like omalizumab.

The Definition, Classification, and History of Urticaria.

The term "urticaria" was first introduced by William Cullen in the eighteenth century. Urticaria is a common mast cell-mediated cutaneous disease presenting with pruritic wheals, angioedema, or both. It is classified as acute (≤6 weeks) or chronic (>6 weeks) and as spontaneous (no definite triggers) or inducible (definite and subtype-specific triggers). The international urticaria guideline on the definition, classification, diagnosis, and management of urticaria is revised every 4 years. The global network of Urticaria Centers of Reference and Excellence, the biggest and most active consortium of urticaria specialists, offers physicians and patients several research, educational, and digital care initiatives.

Classification, Diagnosis, and Pathology of Angioedema Without Hives.

A clear disease classification schema coupled with an understanding of the specific mechanisms involved in the different types of angioedema without hives informs the diagnostic assessment. The recommended approach involves several key steps. Foremost is the recognizing of the clinical clues which allow for the differentiation of mast cell-mediated disorders from bradykinin-mediated angioedema. Enhanced vascular permeability related to bradykinin is of critical importance to identify given the implications for disease morbidity and risk of mortality. The ability to efficiently categorize and diagnose all forms of angioedema results in improved patient outcomes.

Contact System Activation and Bradykinin Generation in Angioedema: Laboratory Assessment and Biomarker Utilization.

The role of contact system activation has been clearly established in the pathogenesis of hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH). C1 inhibitor (C1INH)-protease complexes, levels of functional C1INH, plasma kallikrein activation, and cleavage of high-molecular-weight kininogen have each been associated with disease activity. More recently, HAE with normal levels of C1INH (HAE-nl-C1INH) has been recognized. Six genetic mutations have been identified which are linked to HAE-nl-C1INH phenotypes. The majority of individuals with HAE-nl-C1INH fall into the unknown category. There is substantial evidence that bradykinin generation underlies the recurrent attacks of swelling in some of these cohorts.

Current and Emerging Therapeutics in Hereditary Angioedema.

Angioedema is characterized by transient movement of fluid from the vasculature into the interstitial space leading to subcutaneous or submucosal non-pitting edema. Current evidence suggests that most angioedema conditions can be grouped into 2 categories: mast cell-mediated (previously termed histaminergic) or bradykinin-mediated angioedema. Although effective therapies for mast cell-mediated angioedema have existed for decades, specific therapies for bradykinin-mediated angioedema have more recently been developed. In recent years, rigorous studies of these therapies in treating hereditary angioedema (HAE) have led to regulatory approvals of medication for HAE management thereby greatly expanding HAE treatment options.

Clinical features and potential markers of disease in idiopathic non-histaminergic angioedema, a real-life study.

Idiopathic non-histaminergic acquired angioedema (InH-AAE) is a rare disease, with unknown etiology and pathogenesis, characterized by recurrent clinical manifestations and resistance to antihistamines and corticosteroids. We aim to evaluate clinical features and potential markers of disease in an Italian cohort of patients with InH-AAE. We enrolled 26 patients diagnosed with InH-AAE. Information about clinical features, treatments, routine laboratory investigations, immunological and genetic tests were collected. We assessed plasma levels of complement components, angiogenic and lymphangiogenic mediators, proinflammatory cytokines and chemokines, and activity of phospholipases A2. Finally, patients underwent nailfold videocapillaroscopy (NVC); both quantitative and qualitative capillaroscopic parameters were analyzed. Plasma levels of VEGFs were similar in healthy controls and in InH-AAE patients. ANGPT1 was decreased in InH-AAE patients compared to controls while ANGPT2 was similar to controls. Interestingly, the ANGPT2/ANGPT1 ratio (an index of vascular permeability) was increased in InH-AAE patients compared to controls. sPLA2 activity, elevated in patients with C1-INH-HAE, showed differences also when measured in InH-AAE patients. TNF-α concentration was higher in InH-AAE patients than in healthy controls, conversely, the levels of CXCL8, and IL-6 were similar in both groups. At the NVC, the capillary loops mainly appeared short and tortuous in InH-AAE patients. InH-AAE represents a diagnostic challenge. Due to the potential life-threatening character of this condition, a prompt identification of the potentially bradykinin-mediated forms is crucial. A better comprehension of the mechanism involved in InH-AAE would also lead to the development of new therapeutic approaches to improve life quality of patients affected by this disabling disease.

Quantification of C1 inhibitor activity using a chromogenic automated assay: analytical and clinical performances.

OBJECTIVES: The quantification of functional C1 inhibitor activity (fC1-INH) is an important tool to diagnose bradykinin-mediated angioedema (AE), whether hereditary or acquired. For that an accurate assay is necessary, therefore we evaluated the analytical performances of a fC1-INH chromogenic assay (Berichrom®, Siemens) performed utilizing an Optilite turbidimeter (Binding Site). METHODS: fC1-INH was quantified by means of the chromogenic assay Berichrom®. Internal quality controls were used to determine the precision of the assay. Stability under various storage and matrix conditions, uncertainty, linearity, interference (of hemolysis, lipemia, and icterus), agreement with the manual Technochrom® assay, and diagnostic performances were further evaluated on samples from patients and healthy donors. RESULTS: The fC1-INH Berichrom® assay presented good performances regarding intra- and inter-assay precision (CV: 1.3-4.5 % and 3.0-6.0 %, respectively), expanded uncertainty (5.5 % at normal level and 12.5 % at the clinical threshold) and linearity (rho2>0.99: range 7-130 % activity). Addition of interfering substances (hemoglobin <16 g/L, intralipid® <12 g/L, and bilirubin <1 g/L) did not affect fC1-INH quantification. fC1-INH activity from healthy donors remained stable in citrate whole blood until 4 days at room temperature, and 7 days when plasma was collected. Agreement between the automated Berichrom® assay and the manual Technochrom® assay (n=47) was excellent as obtained with both quantitative (Deming regression and Bland-Altman difference plot) and qualitative (Kappa index=1) analyses. Finally, the diagnostic performance of the quantification of fC1-INH for AE evaluated on 81 patients revealed a sensitivity of 100 %, a specificity of 97.2 %, a positive predictive value of 83.3 % and a negative predictive value of 100 %. CONCLUSIONS: The automated fC1-INH Berichrom® assay showed good performance, both at the analytical and diagnostic/clinical levels that allowed its usage in a clinical laboratory for C1-INH-dependent bradykinin-mediated AE research in combination with quantitative C1-INH and C4 determinations.

Predictive model to differentiate chronic histaminergic angioedema and chronic spontaneous urticaria with angioedema.

Background: Chronic histaminergic angioedema (CHA) may be classified as a separate acquired angioedema (AE) or as an endotype of chronic spontaneous urticaria (CSU). A recent study suggested them to be independent pathologies. Objective: We carried out an exhaustive analysis between CHA and AE-CSU to explore the possible differentiation between them on the bases of a series of predictors. Methods: An observational, retrospective, cross-sectional, and exploratory study was designed. Fifty-six CHA and 40 AE-CSU patients were included. Data were extracted from the year before and year after time of diagnosis. A predictive model was generated by logistic regression, and its discriminatory power was assessed using the area under the receiver operating characteristic curve. Results: The average frequency of AE attacks per year turned out to be higher in the AE-CSU group than in the CHA group, both before (median [interquartile range] 12 [43] vs 8 [16]) and after (24.3 [51.2] vs 2 [4.25]) diagnosis, respectively. The uvula was more frequently affected in CHA. No other differences were found. However, using 7 clinical characteristics of the patients, a multiple logistic regression model was able to predict, with a specificity of 86.4%, a sensitivity of 92.3%, and an area under the curve of 95.1% (P = .024), that CHA and AE-CSU behaved differently. Conclusion: CHA has similar characteristics to AE-CSU, although they slightly differed in the frequency of attacks and their location. Despite its similarities, a multiple logistic regression model that used clinical and evolutionary characteristics allowed the differentiation of both pathologies and supports the idea that these 2 entities are independent.

[Clinical development of anti-FXII therapeutics as a target in thrombo-inflammation]. / Développement clinique des thérapeutiques anti-facteur XII ciblant la thrombo-inflammation.

The history of anticoagulation has evolved considerably, from non-specific drugs to molecules that directly target specific coagulation factors, such as direct oral anticoagulants (DOACs). Since last decade, DOACs are widely used in clinical practice because of their ease to use with favorable pharmacological profile and not requiring monitoring. New therapeutics targeting the contact phase of coagulation are currently under development, and could make it possible to prevent thrombotic risk without altering hemostasis, thereby reducing the risk of bleeding. Factor XII, being at the crossroads between hemostasis and inflammation, appears to be an interesting target that could limit thrombo-inflammation without increasing bleeding risk. The aim of this article is to summarize the main information concerning FXII inhibitors and to review the results of various clinical trials available to date, focusing on applications beyond hemostasis, such as in the management of hereditary angioedema.

Unveiling therapeutic frontiers: DON/DRP-104 as innovative Plasma kallikrein inhibitors against carcinoma-associated hereditary angioedema shocks - a comprehensive molecular dynamics exploration.

Human plasma kallikrein (PKa) is a member of the serine protease family and serves as a key mediator of the kallikrein-kinin system (KKS), which is known for its regulatory roles in inflammation, vasodilation, blood pressure, and coagulation. Genetic dysregulation of KKS leads to Hereditary Angioedema (HAE), which is characterized by spontaneous, painful swelling in various body regions. Importantly, HAE frequently coexists with various cancers. Despite substantial efforts towards the development of PKa inhibitors for HAE, there remains a need for bifunctional agents addressing both anti-cancer and anti-HAE aspects, especially against carcinoma-associated comorbid HAE conditions. Consequently, we investigated the therapeutic potential of the anti-glutamine prodrug, isopropyl(S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)-propanamido)-6-diazo-5-oxo-hexanoate (DRP-104), and its active form, 6-Diazo-5-oxo-l-norleucine (DON), recognized for their anti-cancer properties, as novel PKa inhibitors. Utilizing structure-based in silico methods, we conducted a comparative analysis with berotralstat, a clinically approved HAE prophylactic, and sebetralstat, an investigational HAE therapeutic agent, in Phase 3 clinical trials. Inhibiting PKa with DON resulted in relatively heightened structural stability, rigidity, restricted protein folding, and solvent-accessible loop exposure, contributing to increased intra-atomic hydrogen bond formation. Conversely, PKa inhibition with DRP-104 induced restricted residue flexibility and significantly disrupted the critical SER195-HIS57 arrangement in the catalytic triad. Both DON and DRP-104, along with the reference drugs, induced strong cooperative intra-residue motion and bidirectional displacement in the PKa architecture. The results revealed favorable binding kinetics of DON/DRP-104, showing thermodynamic profiles that were either superior or comparable to those of the reference drugs. These findings support their consideration for clinical investigations into the management of carcinoma-associated HAE.

Angiotensin-Converting Enzyme (ACE) Inhibitor-Induced Angioedema in an African American Male With Coronavirus Disease 2019 (COVID-19).

Angioedema is a condition characterized by non-pitting swelling of the subcutaneous or submucosal tissues in particular the face, lips, and oral cavity. Angiotensin-converting enzyme (ACE) inhibitors are known to contribute to the development of angioedema by increasing the levels of bradykinin and its active metabolites. Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is hypothesized to contribute to the development of angioedema by modifying ACE II levels and further increasing the level of bradykinin in patients taking ACE inhibitors. African Americans may be at particular risk of developing angioedema with concomitant SARS-CoV-2 infection and ACE inhibitor use. This case involves a 31-year-old African American male diagnosed with coronavirus disease 2019 (COVID-19) who developed angioedema while taking an ACE inhibitor.

DAB2IP associates with hereditary angioedema: Insights into the role of VEGF signaling in HAE pathophysiology.

BACKGROUND: In the recent years, there was an important improvement in the understanding of the pathogenesis of hereditary angioedema (HAE). Notwithstanding, in a large portion of patients with unknown mutation (HAE-UNK) the genetic cause remains to be identified. OBJECTIVES: To identify new genetic targets associated with HAE, a large Argentine family with HAE-UNK spanning 3 generations was studied. METHODS: Whole exome sequencing was performed on affected family members to identify potential genetic variants associated with HAE-UNK. In silico analyses and experimental studies were applied to assess the role of the identified gene variant. RESULTS: A missense variant (p.D239N) in DAB2IP was identified. The variant occurred in the C2-domain, the region interacting with vascular endothelial growth factor receptor 2 (VEGFR2). It was found to be rare, and predicted to have a detrimental effect on the functionality of DAB2IP. Protein structure modeling predicted changes in the mutant p.D239N protein structure, impacting protein stability. The p.D239N variant affected the subcellular localization of VEGFR2. Cells transfected with the DAB2IP-239N transcript exhibited an intracellular distribution, and VEGFR2 remained associated with the cell membrane. The altered localization pattern indicated reduced colocalization of the mutant protein with VEGFR2, suggesting a diminished ability of VEGFR2 binding. CONCLUSIONS: The study identified a novel missense variant (p.D239N) in DAB2IP in a family with HAE-UNK and highlighted the role of dysregulated VEGF-mediated signaling in altered endothelial permeability. DAB2IP loss-of-function pathogenic variants lead to the impairment of the endothelial VEGF/VEGFR2 ligand system and represent a new pathophysiologic cause of HAE-UNK.

An international survey assessing the effects of the duration of attack-free period on health-related quality of life for patients with hereditary angioedema.

BACKGROUND: Hereditary angioedema (HAE) is characterized by unpredictable and often severe cutaneous and mucosal swelling that affects the extremities, face, larynx, gastrointestinal tract, or genitourinary area. Introduction of novel long-term prophylactic treatment options (lanadelumab, berotralstat, and C1-esterase inhibitor SC [human]) into the treatment armamentarium has substantially reduced HAE attacks, allowing patients to be attack free for longer with improvements to their quality of life. Using data drawn from a wide-ranging survey of patients with HAE, we examined the relationship between duration of time attack free and health-related quality of life (HRQoL), exploring the possibility that there is an association between observed improvement in HRQoL and attack-free duration. METHODS: A survey among patients with HAE on long-term prophylaxis (LTP) in six countries (the US, Australia, Canada, UK, Germany, and Japan) assessed the relationship between attack-free duration and mean Angioedema Quality of Life (AE-QoL) scores, quality of life benefits, and rescue medication used. Analysis of covariance (ANCOVA) was used to assess the roles of LTP and attack-free period (< 1 month, 1- < 6 months, ≥ 6 months) on total AE-QoL scores. Results include descriptive p-values for strength of association, without control for multiplicity. Descriptive statistics were used to show the relationship between time attack free and quality of life benefits. RESULTS: Longer durations of time for which participants reported being attack free at the time of the survey correlated with better AE-QoL scores and less use of rescue medication. The mean total AE-QoL scores were 51.8, 33.2, and 19.9 for those who reported having been attack free for < 1 month, 1- < 6 months, and ≥ 6 months, respectively, with higher scores reflecting more impairment. The ANCOVA results showed a strong association between attack-free duration and AE-QoL total score. CONCLUSION: This study shows that longer attack-free duration has an influential role for better HRQoL in patients receiving LTP. Prolonging the attack-free period is an important goal of therapy and recent advances in LTP have increased attack-free duration. However, opportunities exist for new treatments to further increase attack-free duration and improve HRQoL for all patients with HAE.

Splenectomy allows remission of angioedema with acquired C1-INH deficiency associated with splenic marginal zone lymphoma.

Splenectomy may be considered as an alternative to rituximab in selected cases of acquired angioedema associated with splenic marginal zone lymphoma.

Angioedema After Use of Recombinant Tissue-Type Plasminogen Activators in Stroke.

Angioedema without concomitant urticaria is a well-known complication of treatment with the recombinant tissue-type plasminogen activator (r-tPA) alteplase and its genetically modified variant tenecteplase. It is potentially lethal when causing airway obstruction and can require intubation. The latest guideline for the early management of patients with acute ischemic stroke from the American Heart Association/American Stroke Association advises to treat this complication initially by interfering with the histamine pathway. This article aims to clarify the pathophysiological mechanism of r-tPA-induced angioedema and provides several arguments that this condition is primarily bradykinin-mediated and hence should be treated initially by intervening with the bradykinin pathway. Second, other-less frequently reported-adverse symptoms after r-tPA therapy and their proposed pathophysiological mechanisms leading to specific treatment are described. This manuscript describes the need for an update of the section "3.5 IV alteplase" from the American Heart Association/American Stroke Association guideline to treat this r-tPA-induced angioedema adequately and prevent potentially fatal outcomes.

A Practical Approach to Diagnosing and Managing Chronic Spontaneous Urticaria.

Chronic spontaneous urticaria (CSU) is an unpredictable inflammatory skin condition characterized by the spontaneous onset of itchy wheals, angioedema, or both, which occurs for longer than 6 weeks overall. Despite the relatively straightforward diagnostic algorithm for CSU, relying primarily on a detailed medical history and only limited laboratory tests, patients often wait years to be diagnosed, with many cycling through different healthcare practitioners before a diagnosis is made. Even then, current treatment options for CSU are limited, with approximately half of patients resistant to standard-of-care second-generation antihistamines at standard or higher doses. As such, there is an unmet need for improved, streamlined management for patients with CSU. Here, we review the evidence-based diagnostic algorithm for CSU, consider the required steps of the diagnostic workup, and provide practical, real-world advice on the management of CSU to improve the timely diagnosis and care of patients with this debilitating disease.

The role of the environment in allergic skin disease.

PURPOSE OF REVIEW: This paper explores how environmental factors influence allergic skin diseases, including atopic dermatitis (AD), contact dermatitis (CD), urticaria, angioedema, and reactions to drugs and insect bites. RECENT FINDINGS: Research indicates a significant impact of environmental elements on allergic skin diseases. High air pollution levels exacerbate symptoms, while climate change contributes to increased skin barrier dysfunction, particularly affecting AD. Allergen prevalence is influenced by climate and pollution. Irritants, like those in detergents and cosmetics, play a major role in CD. Plants also contribute, causing various skin reactions. Understanding the interplay between environmental factors and allergic skin diseases is crucial for effective management. Physicians must address these factors to support patient well-being and promote skin health amidst environmental changes.