RESUMEN
OBJECTIVE: Previous studies suggested that distinct phenotypes of eosinophilic granulomatosis with polyangiitis (EGPA; formerly known as Churg-Strauss syndrome) could be determined by the presence or absence of antineutrophil cytoplasmic antibodies (ANCA), reflecting predominant vasculitic or eosinophilic processes, respectively. This study explored whether ANCA-based clusters or other clusters can be identified in EGPA. METHODS: This study used standardized data of 15 European centers for patients with EGPA fulfilling widely accepted classification criteria. We used multiple correspondence analysis, hierarchical cluster analysis, and a decision tree model. The main model included 10 clinical variables (musculoskeletal [MSK], mucocutaneous, ophthalmological, ENT, cardiovascular, pulmonary, gastrointestinal, renal, central, or peripheral neurological involvement); a second model also included ANCA results. RESULTS: The analyses included 489 patients diagnosed between 1984 and 2015. ANCA were detected in 37.2% of patients, mostly perinuclear ANCA (85.4%) and/or antimyeloperoxidase (87%). Compared with ANCA-negative patients, those with ANCA had more renal (P < 0.001) and peripheral neurological involvement (P = 0.04), fewer cardiovascular signs (P < 0.001), and fewer biopsies with eosinophilic tissue infiltrates (P = 0.001). The cluster analyses generated 4 (model without ANCA) and 5 clusters (model with ANCA). Both models identified 3 identical clusters of 34, 39, and 40 patients according to the presence or absence of ENT, central nervous system, and ophthalmological involvement. Peripheral neurological and cardiovascular involvement were not predictive characteristics. CONCLUSION: Although reinforcing the known association of ANCA status with clinical manifestations, cluster analysis does not support a complete separation of EGPA in ANCA-positive and -negative subsets. Collectively, these data indicate that EGPA should be regarded as a phenotypic spectrum rather than a dichotomous disease.
Asunto(s)
Síndrome de Churg-Strauss , Granulomatosis con Poliangitis , Humanos , Síndrome de Churg-Strauss/diagnóstico , Granulomatosis con Poliangitis/diagnóstico , Anticuerpos Anticitoplasma de Neutrófilos , Fenotipo , Análisis por ConglomeradosRESUMEN
Airway remodeling is accepted to be a determining component within the natural history of asthma. It is a phenomenon characterized by changes in the airways structures that marches in parallel with and can be influenced by airway inflammation, floating at the interface between both natural and adaptive immunity and physical and mechanical cells behavior. In this review we aimed to highlight the comprehensive, yet not exhaustive, evidences of how immune cells induce, regulate and adapt to the recognized markers of airway remodeling. Mucous cell hyperplasia, epithelial dysfunction and mesenchymal transition, extracellular matrix protein synthesis and restructuration, fibroblast to myofibroblast transition, airway smooth muscle proliferation, bioactive and contractile properties, and vascular remodeling encompass complex physiopathological mechanisms that can be induced, suppressed or regulated by different cellular and molecular pathways. Growth factors, cytokines, chemokines and adhesion molecules expressed or derived either from the immune network of cells infiltrating the asthmatic airways and involving T helper lymphocytes, immune lymphoid cells, dendritic cells, eosinophils, neutrophils, mast cells or by the structural components such as epithelial cells, fibroblasts, myocytes, airway smooth muscle cells concur with protein cellular matrix component and metalloproteases in modifying the airway structure in a detrimental way. The consequences in lung function decline, fixed airway obstruction and clinical severity of the disease suggest the possibility of identify among the immune molecular pathway of remodeling some biological parameters or signal pathway to be either a good tracer for monitoring the disease evolution or a target for hypothetical phenotypes and endotypes. In the era of personalized medicine, a biomarker of remodeling might predict a response to small-molecule inhibitors or biologicals potentially targeting a fundamental aspect of asthma pathogenesis that impacts on the low responsiveness to airway inflammation directed treatments.
Asunto(s)
Remodelación de las Vías Aéreas (Respiratorias)/inmunología , Asma/inmunología , Fibroblastos/fisiología , Inflamación/inmunología , Miocitos del Músculo Liso/metabolismo , Mucosa Respiratoria/fisiología , Obstrucción de las Vías Aéreas , Animales , Humanos , Transducción de SeñalRESUMEN
BACKGROUND: Severe asthma is a disease with a heavy socio-economic burden and a relevant impact on the life of patients. Mepolizumab (MEP) was recently introduced in practice. The previous data were favourable as efficacy and safety are concerned. Nowadays, we can report the clinical data after more than one year of use of MEP in the real-life setting. OBJECTIVE: To evaluate the efficacy and safety of MEP in a real life framework, mainly concerning asthma exacerbations, steroid dependence, effects on respiratory function and adverse events. METHODS: This retrospective analysis was performed on 138 patients, treated with MEP for at least 12 months, and referred to eleven severe asthma clinics in Italy. All patients met the criteria for severe uncontrolled asthma according to ATS/ERS guidelines and prescribing MEP conditions according to the Italian Drug Agency (AIFA). RESULTS: We could observe 138 patients (78 female, age 58⯱â¯10 years). The average age of onset of asthma was 34⯱â¯16 years. The blood eosinophil count decreased from 822⯱â¯491/µL at baseline to 117⯱â¯96/µL (pâ¯<â¯.0001) after 12 months of therapy. Exacerbations decreased from 3.8/year to 0.7/year (-81%; pâ¯<â¯.0001). Steroid-dependent patients before MEP (80%) with a daily dose of 10.1⯱â¯9.4â¯mg prednisone decrease at 28% after 12 months with a mean of 2.0⯱â¯4.2â¯mg/day (pâ¯<â¯.0001). The occurrence of adverse events was overall low. CONCLUSIONS & CLINICAL RELEVANCE: In this real-life setting, MEP confirmed its efficacy and safety profile, already shown in clinical trials. This was apparent concerning exacerbation rate, systemic steroids intake and safety.
Asunto(s)
Antiasmáticos/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Asma/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/efectos adversos , Progresión de la Enfermedad , Eosinófilos/efectos de los fármacos , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Humanos , Italia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
OBJECTIVES: We conducted a systematic macroscopic and microscopic examination of occlusal and para-occlusal wear in a large dental sample (n = 3,014) from 217 individuals dated to the Early Bronze age site of Gricignano d'Aversa, Italy. We used macroscopic and microscopic techniques to document nondietary occlusal and para-occlusal wear and to analyze calculus inclusions in some of the teeth. In combining an analysis of the wear with the calculus inclusions we linked the specific wear to the likely fiber that was involved in producing it. MATERIALS AND METHODS: Teeth and their high resolution epoxy casts were analyzed through SEM and reflected light microscopes. Nineteen individuals (fifteen with activity induced dental modifications and four as a control sample) were examined for the presence of calculus inclusions. RESULTS: Activity induced dental modifications (AIDMs), notches, grooves and micro-striations, were found in the 62.2% of the adult females, in 21.2% of the adults of unknown sex and in a single male. We found the full spectrum of dental manipulations from very minor nonocclusal wear in some young individuals to severe attrition at the other extreme. The width of the striations and grooves, mostly on the upper incisors, suggests a craft activity involving fibers and thread production and manipulation. From the dental calculus of two females with grooves and striations, we extracted three fragments of fibers, identified as hemp (Cannabis, sp.). Previously from Gricignano woven hemp fibers were found on both surfaces of a metal blade associated with a male burial. DISCUSSION: This study found the co-occurrence of tooth AIDMs and the actual fibers preserved in the dental calculus. As more work is done analyzing dental calculus in a variety of humans, it is apparent that this biological material holds rich resources documenting non-dietary habits.
Asunto(s)
Cálculos Dentales , Desgaste de los Dientes , Adolescente , Adulto , Antropología Física , Cannabis , Cementerios , Niño , Preescolar , Cálculos Dentales/etnología , Cálculos Dentales/historia , Cálculos Dentales/patología , Femenino , Historia Antigua , Humanos , Italia/etnología , Masculino , Persona de Mediana Edad , Textiles/historia , Diente/patología , Desgaste de los Dientes/etnología , Desgaste de los Dientes/historia , Desgaste de los Dientes/patología , Adulto JovenRESUMEN
OBJECTIVE: Increasing asthma incidence may be due to an overall increase in asthma awareness by physicians, potentially resulting in overdiagnosis. One of the unique features of asthma is bronchial hyperresponsiveness, which can be assessed by methacholine bronchial challenge (MBC). Overdiagnosis may result in over- or mistreatment. The aims of this study were to describe the prevalence of the over-/misdiagnosis of asthma and the use of anti-asthmatic drugs in patients with asthma-like symptoms who had not yet undergone a respiratory function assessment to confirm the diagnosis of asthma. METHODS: This was a retrospective study analyzing all MBCs performed by our Outpatient Allergy Clinic in a two-year period to confirm/exclude the diagnosis of asthma in patients referred by general practitioners and complaining of asthma-like symptoms. Anti-asthmatic medications used by the patients until the MBC date were recorded. RESULTS: 43.8% of the reviewed MBCs were positive and 37.4% of the patients with a positive MBC were previously taking anti-asthmatic drugs (568.8 ± 76.4 mcg mean beclomethasone equivalents), compared to 51.2% of those patients with a negative MBC (464.8 ± 57.8 mcg). No differences were found in the daily doses of inhaled corticosteroids or other anti-asthmatic drugs, or in the duration of treatment before the assessment of bronchial hyperresponsiveness. CONCLUSIONS: A sizeable percentage of subjects who reported physician-diagnosed asthma had a negative MBC. Nevertheless, a greater proportion of negative MBC patients were taking anti-asthmatic drugs compared to those with a confirmed diagnosis of asthma, illustrating that the overdiagnosis of asthma may lead to over- and mistreatment of respiratory symptoms.
Asunto(s)
Antiasmáticos/uso terapéutico , Asma/diagnóstico , Asma/tratamiento farmacológico , Errores Diagnósticos/estadística & datos numéricos , Utilización de Medicamentos/estadística & datos numéricos , Adulto , Antiasmáticos/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Derivación y Consulta/estadística & datos numéricos , Pruebas de Función Respiratoria , Estudios RetrospectivosRESUMEN
In eosinophilic granulomatosis with polyangiitis (EGPA) clonally expanded T cells might concur in granuloma formation and vascular injury. The TCR ß-variable (BV) chain repertoire and third complementarity determining region (CDR3) of peripheral CD4+ and CD8+ cells in EGPA patients and age-matched controls and the expression of cytokines and chemokine receptors were investigated. The CD8+ lymphocytes of EGPA patients showed an increased frequency of BV expansions with a skewed profile of BV CDR3 lengths, increased CCR5 and CXCR3 expression and increased INFγ and TNFα production. In two patients, the TCR CDR3 cDNA sequences of the expanded BV family were identified. The CD4+ lymphocytes of EGPA patients revealed a higher expression of CRTH2 and increased production of IL-5. In conclusion, CD4+ T cells display a Th2 profile and CD8+ T cells are clonally expanded in EGPA and have a proinflammatory phenotype, suggesting their pathogenic role in vasculitic damage.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Síndrome de Churg-Strauss/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores , Células Cultivadas , Síndrome de Churg-Strauss/sangre , Regiones Determinantes de Complementariedad , Femenino , Granuloma/inmunología , Humanos , Cambio de Clase de Inmunoglobulina/inmunología , Inflamación/inmunología , Interferón gamma/biosíntesis , Interleucina-5/biosíntesis , Masculino , Persona de Mediana Edad , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores CCR5/biosíntesis , Receptores CXCR3/biosíntesis , Receptores Inmunológicos/biosíntesis , Receptores de Prostaglandina/biosíntesis , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
Fire gilding and silvering are age-old mercury-based processes used to coat thesurface of less precious substrates with thin layers of gold or silver. In ancient times, these methods were used to produce and decorate different types of artefacts, such as jewels, statues, amulets, and commonly-used objects. Gilders performed these processes not only to decorate objects but also to simulate the appearance of gold or silver, sometimes fraudulently. From a technological point of view, the aim of these workmen over 2000 years ago was to make the precious metal coatings as thin and adherent as possible. This was in order to save expensive metals and to improve the resistance to the wear caused by continued use and circulation. Without knowledge about the chemical-physical processes, the ancient crafts-men systematically manipulated these metals to create functional and decorative artistic objects. The mercury-based methods were also fraudulently used in ancient times to produce objects such as jewels and coins that looked like they were made of silver or gold but actually had a less precious core. These coins were minted by counterfeiters but also by the official issuing authorities. The latter was probably because of a lack of precious metals, reflecting periods of severe economic conditions. In this Account, we discuss some representative cases of gold- and silver-coatedobjects, focusing on unique and valuable Roman and Dark Ages period works of art, such as the St. Ambrogio's altar (825 AD), and commonly used objects. We carried out the investigations using surface analytical methods, such as selected area X-ray photoelectron spectroscopy and scanning electron microscopy combined with energy-dispersive spectroscopy. We used these methods to investigate the surface and subsurface chemical features of these important examples of art and technology, interpreting some aspects of the manufacturing methods and of disclosing degradation agents and mechanisms. These findings may contribute to cultural heritage preservation, thus extending the applicability of the surface analytical techniques.
RESUMEN
Background: Indirect comparison among biologics in severe asthma (SA) is a challenging but desirable goal for clinicians in real life. The aim of the study is to define characteristics of a biologic-treated T2-driven-SA population and to evaluate the effectiveness of biologic treatments in a real-world setting by variation in intra/inter-biologic parameters in an up to 4-year follow-up. Methods: Demographic, clinical, functional, and biological characteristics were evaluated retrospectively in 104 patients recruited until July 2022 at baseline (T0) and over a maximum of 4 years (T4) of biologic therapy (omalizumab/OmaG = 41, from T0 to T4, mepolizumab/MepoG = 26, from T0 to T4, benralizumab/BenraG = 18, from T0 to T2, and dupilumab/DupiG = 19, from T0 to T1). Variations of parameters using means of paired Delta were assessed. Results: At baseline, patients had high prevalence of T2-driven comorbidities, low asthma control test (ACT mean 17.65 ± 4.41), impaired pulmonary function (FEV1 65 ± 18 %pred), frequent exacerbations/year (AEs 3.5 ± 3), and OCS dependence (60%). DupiG had lower T2 biomarkers/comorbidities and AEs, and worse FEV1 (57 ± 19 %pred) compared to other biologics (p < 0.05). All biologics improved ACT, FEV1%, FVC%, AEs rate, and OCS use. FEV1% improved in MepoG and BenraG over the minimal clinically important difference and was sustained over 4 years in OmaG and MepoG. A significant RV reduction in OmaG (T4) and DupiG (T1), and BenraG normalization (T2) of airflow limitation were found. We observed through inter-biologic parameters pair delta variation comparison a significant nocturnal awakenings reduction in BenraG vs. OmaG/MepoG, and neutrophils reduction in BenraG/DupiG vs. OmaG. Conclusions: Indirect comparison among biologics unveils clinical and functional improvements that may mark a different effectiveness. These results may highlight the preference of a single biologic compared to another with regard to specific treatable traits.
RESUMEN
PURPOSE OF REVIEW: Exhaled nitric oxide (FENO) is a noninvasive marker of eosinophilic airway inflammation, therefore, highly informative in asthma. Although FENO measurement is a potentially accessible tool to many physicians, recommendations regarding its clinical utility in diagnosing or tailoring treatment have not reached the expected diffusion. More recently FENO emerged as a biomarker for type-2 asthma phenotyping and a predictor of response to biologics. RECENT FINDINGS: The physiological discoveries and relevant acquisitions in clinical practice regarding FENO in asthma are presented. The FENO story draw a wavy path, characterized by promising findings, exciting confirmations and periods of low visibility. FENO emerged as a tool to increase the probability of asthma diagnosis. FENO predicts response to inhaled glucocorticoids (ICS), favoring the development of tailored treatment strategies and unrevealing nonadherence to ICS in difficult-to-treat or uncontrolled asthma. Finally, FENO was associated with a more severe phenotype and became a consolidated biomarker of type-2 inflammation. SUMMARY: FENO demonstrated to be a noninvasive and very reproducible test, encompassing many applications in the field of asthma management. Its routinely use, according to international guidelines, may improve the quality of patient assistance, from difficult-to-treat cases to biologic monitoring.
Asunto(s)
Asma , Óxido Nítrico , Humanos , Pruebas Respiratorias , Asma/diagnóstico , Asma/tratamiento farmacológico , Glucocorticoides/uso terapéutico , Biomarcadores , EspiraciónRESUMEN
The heterogeneity of asthma makes it challenging to unravel the pathophysiologic mechanisms of the disease. Despite the wealth of research identifying diverse phenotypes, many gaps still remain in our knowledge of the disease's complexity. A crucial aspect is the impact of airborne factors over a lifetime, which often results in a complex overlap of phenotypes associated with type 2 (T2), non-T2 and mixed inflammation. Evidence now shows overlaps between the phenotypes associated with T2, non-T2 and mixed T2/non-T2 inflammation. These interconnections could be induced by different determinants such as recurrent infections, environmental factors, T-helper plasticity and comorbidities, collectively resulting in a complex network of distinct pathways generally considered as mutually exclusive. In this scenario, we need to abandon the concept of asthma as a disease characterised by distinct traits grouped into static segregated categories. It is now evident that there are multiple interplays between the various physiologic, cellular and molecular features of asthma, and the overlap of phenotypes cannot be ignored.
Asunto(s)
Asma , Humanos , Asma/diagnóstico , Asma/genética , Fenotipo , Comorbilidad , InflamaciónRESUMEN
Patients with severe asthma perceive beneficial effects of biologics and good self-reported adherence to treatment, even when self-administered at home https://bit.ly/48vP70w.
RESUMEN
Background: High total IgE levels are weak predictors of T2High and have been reported in nonallergic asthma. Therefore, the role of total serum IgE (IgE) in the T2High phenotype is still debated. Objective: This study investigated the reliability of stratifying asthmatics into IgEHigh and IgELow within the T2High and T2Low phenotypes. Methods: This cross-sectional single-center study investigated the association of clinical, functional, and bio-humoral parameters in a large asthmatic population stratified by IgE ≥ 100 kU/L, allergen sensitization, B-EOS ≥ 300/µL, and FENO ≥ 30 ppb. Results: Combining T2 biomarkers and IgE identifies (1) T2Low-IgELow (15.5%); (2) T2Low-IgEHigh (5.1%); (3) T2High-IgELow (33.6%); and T2High-IgEHigh (45.7%). T2Low-IgELow patients have more frequent cardiovascular and metabolic comorbidities, a higher prevalence of emphysema, and higher LAMA use than the two T2High subgroups. Higher exacerbation rates, rhinitis, and anxiety/depression syndrome characterize the T2Low-IgEHigh phenotype vs. the T2Low-IgELow phenotype. Within the T2High, low IgE was associated with female sex, obesity, and anxiety/depression. Conclusions: High IgE in T2Low patients is associated with a peculiar clinical phenotype, similar to T2High in terms of disease severity and nasal comorbidities, while retaining the T2Low features. IgE may represent an additional biomarker for clustering asthma in both T2High and T2Low phenotypes rather than a predictor of T2High asthma "per se".
RESUMEN
The efficacy mepolizumab in severe asthmatic patients is proven in the literature. Primarily to study the effect of mepolizumab on exacerbations, steroid dependence, and the continuation of efficacy in the long term. Secondarily to evaluate the effect of the drug on nasal polyps. Analyzing data from SANI (Severe Asthma Network Italy) clinics, we observed severe asthmatic patients treated with mepolizumab 100 mg/4 weeks, for a period of 3 years. 157 patients were observed. Exacerbations were reduced from the first year (-84.6%) and progressively to 90 and 95% in the second and third ones. Steroid-dependent patients decreased from 54% to 21% and subsequently to 11% in the second year and 6% in the third year. Patients with concomitant nasal polyps, assessed by SNOT-22, showed a 49% reduction in value from baseline to the third year. The study demonstrated the long-term efficacy of mepolizumab in a real-life setting.
RESUMEN
Severe asthma affects about 10% of the population with asthma and is characterized by low lung function and a high count of blood leukocytes, mainly eosinophils. Various definitions are used in clinical practice and in the literature to identify asthma remission: clinical remission, inflammatory remission, and complete remission. This work highlights a consensus for asthma remission using a Delphi method. In the context of the Severe Asthma Network Italy, which accounts for 57 severe asthma centers and more than 2,200 patients, a board of six experts drafted a list of candidate statements in a questionnaire, which has been revised to minimize redundancies and ensure clear and consistent wording for the first round (R1) of the analysis. Thirty-two statements were included in the R1 questionnaire and then submitted to a panel of 80 experts, which used a 5-point Likert scale to measure agreement regarding each statement. Then, an interim analysis of R1 data was performed, and items were discussed and considered to produce a consistent questionnaire for round 2 (R2) of the analysis. Then, the board set the R2 questionnaire, which included only important topics. Panelists were asked to vote on the statements in the R2 questionnaire afterward. During R2, the criteria of complete clinical remission (the absence of the need for oral corticosteroids, symptoms, exacerbations or attacks, and pulmonary function stability) and those of partial clinical remission (the absence of the need for oral corticosteroids, and two of three criteria: the absence of symptoms, exacerbations or attacks, and pulmonary stability) were confirmed. This Severe Asthma Network Italy Delphi analysis defined a valuable and independent tool that is easy to use, to test the efficacy of different treatments in patients with severe asthma enrolled into the SANI registry.
Asunto(s)
Asma , Humanos , Técnica Delphi , Consenso , Asma/tratamiento farmacológico , Italia/epidemiología , Corticoesteroides/uso terapéuticoRESUMEN
OBJECTIVES: PTPN22 is involved in T-cell activation and its R620W single-nucleotide polymorphism (SNP) has been shown to predispose to different autoimmune diseases. The aims of this study were to investigate the role of the PTPN22 R620W SNP in conferring susceptibility to the ANCA-associated vasculitides (AAVs), and to explore potential associations between the PTPN22 genotype and the disease manifestations. METHODS: PTPN22 R620W SNP was genotyped in a cohort of 344 AAV patients [143 with granulomatosis with polyangiitis (Wegener's) (GPA), 102 with microscopic polyangiitis (MPA) and 99 with Churg-Strauss syndrome (CSS)] and in 945 healthy controls. RESULTS: The frequency of the minor allele (620W) was significantly higher in GPA patients than in controls [P = 0.005, χ(2 )= 7.858, odds ratio (OR) = 1.91], while no statistically significant association was found with MPA or CSS. Among GPA patients, the 620W allele was particularly enriched in ANCA-positive patients as compared with controls (P = 0.00012, χ(2 )= 14.73, OR = 2.31); a particularly marked association was also found with ENT involvement (P = 0.0071, χ(2 )= 7.258, OR = 1.98), lung involvement (P = 0.0060, χ(2 )= 7.541, OR = 2.07) and skin manifestations of all kinds (P = 0.000047, χ(2 )= 16.567, OR = 3.73). CONCLUSION: The PTPN22 620W allele confers susceptibility to the development of GPA (but not of MPA or CSS), and particularly of its ANCA-positive subset.