The Role of Galectins in Asthma Pathophysiology: A Comprehensive Review.

Galectins are a group of ß-galactoside-binding proteins with several roles in immune response, cellular adhesion, and inflammation development. Current evidence suggest that these proteins could play a crucial role in many respiratory diseases such as pulmonary fibrosis, lung cancer, and respiratory infections. From this standpoint, an increasing body of evidence have recognized galectins as potential biomarkers involved in several aspects of asthma pathophysiology. Among them, galectin-3 (Gal-3), galectin-9 (Gal-9), and galectin-10 (Gal-10) are the most extensively studied in human and animal asthma models. These galectins can affect T helper 2 (Th2) and non-Th2 inflammation, mucus production, airway responsiveness, and bronchial remodeling. Nevertheless, while higher Gal-3 and Gal-9 concentrations are associated with a stronger degree of Th-2 phlogosis, Gal-10, which forms Charcot-Leyden Crystals (CLCs), correlates with sputum eosinophilic count, interleukin-5 (IL-5) production, and immunoglobulin E (IgE) secretion. Finally, several galectins have shown potential in clinical response monitoring after inhaled corticosteroids (ICS) and biologic therapies, confirming their potential role as reliable biomarkers in patients with asthma.

Pioneering role of machine learning in unveiling intensive care unit-acquired weakness.

In the research published in the World Journal of Clinical Cases, Wang and Long conducted a quantitative analysis to delineate the risk factors for intensive care unit-acquired weakness (ICU-AW) utilizing advanced machine learning methodologies. The study employed a multilayer perceptron neural network to accurately predict the incidence of ICU-AW, focusing on critical variables such as ICU stay duration and mechanical ventilation. This research marks a significant advancement in applying machine learning to clinical diagnostics, offering a new paradigm for predictive medicine in critical care. It underscores the importance of integrating artificial intelligence technologies in clinical practice to enhance patient management strategies and calls for interdisciplinary collaboration to drive innovation in healthcare.

Managing Small Airway Disease in Patients with Severe Asthma: Transitioning from the "Silent Zone" to Achieving "Quiet Asthma".

Background/Objectives: Several studies have demonstrated the positive clinical and functional impact of adding Long-Acting Muscarinic Antagonist (LAMA) to Inhaled Corticosteroids (ICS) and Long-Acting Beta-Agonists (LABA) therapy in the treatment of severe asthma. Aim and objectives: To demonstrate that treating Small Airways Disease (SAD) in severe asthma patients who are candidates for biologics can improve respiratory symptoms, lung function, and airways inflammation, potentially avoiding or delaying the use of biological therapy. Methods: Thirty-two severe asthma patients with SAD were transitioned from separate inhalers for ICS/LABA and LAMA to extrafine single-inhaler beclomethasone, formoterol, and glycopyrronium. None of these patients underwent biological therapy before the study. Follow-up evaluations were conducted at baseline (T0) and three months after initiation (T3). Assessments included clinical evaluations, spirometry, oscillometry, and inflammation markers. Results: Transitioning to single-inhaler triple therapy from T0 to T3 resulted in significant improvements in Asthma Control Test (ACT) and SAD parameters, including increased Forced Expiratory Volume in the mid-range of lung capacity and improved airway resistance and reactance measurements using impulse oscillometry. A significant reduction in airway inflammation was evidenced by lower levels of Fractional Exhaled Nitric Oxide 350 (FeNO 350) (p < 0.001 for all). Conclusions: Adopting a single-inhaler triple therapy notably enhanced clinical control and small airway function in patients with severe asthma and SAD, supporting the positive impact of target-therapy for the achievement of a stable state termed "Quiet Asthma".

Can Galectin-3 be a reliable predictive biomarker for post-COVID syndrome development?

BACKGROUND AND OBJECTIVES: Reliable biomarkers able to predict post-COVID syndrome development are still lacking. The aim of the study was to evaluate the relationship between Galectin-3 blood concentrations and the development of post-COVID syndrome. METHODS: We performed a single-center, prospective, observational study, enrolling 437 consecutive patients attending our outpatient clinic for the post-COVID assessment. For each patient, we recorded the main clinical, functional and radiological findings. We also dosed several blood biomarkers which have been related to COVID-19 disease, including Galectin-3. We performed Receiver Operating Characteristic (ROC) and multivariate regression analysis to evaluate the predictive performance of Galectin-3 for post-COVID syndrome development. RESULTS: Among the blood biomarkers tested, Galectin-3 resulted the only one correlated with the outcome, although the insufficient performance of the Cox regression model from a statistical standpoint. Correlation coefficients and ROC curves analysis revealed the close relationship between Galectin-3 levels and the time passed from the acute phase of COVID-19 disease, suggesting a possible predictive role for this biomarker when dosed from 60 to 120 days after the infection. CONCLUSIONS: Galectin-3 could play an important role as predictive biomarker for COVID-19 sequelae, but its evaluation must be carefully planned along the follow up to avoid misinterpretations.

Advancing Care in Severe Asthma: The Art of Switching Biologics.

Biologics targeting IgE, IL-5, IL-4/IL-13, and TSLP are crucial in severe asthma treatment. Research, including randomized controlled trials and real-world studies, has been conducted to assess their efficacy and identify patient characteristics that may predict positive responses. The effectiveness of switching biologics, especially given overlaps in treatment eligibility, and the clinical outcomes post-cessation are critical areas of investigation. This work reviews the effects of switching between these biologics and the indicators of treatment success or failure. Insights are primarily derived from real-world experiences, focusing on patients transitioning from one monoclonal antibody to another. Moreover, this review aims to provide insights into the effectiveness, safety, and broader implications of switching biologics, enhancing understanding for clinicians to optimize severe asthma management. The article underlines the importance of a patient-centered approach, biomarker assessment, and the evolving nature of asthma treatment in making informed decisions about biologic therapy.

Can single-inhaler Beclometasone Dipropionate/Formoterol Fumarate/Glycopyrronium therapy postpone or save biologics for severe asthma?

Inhaled corticosteroids, along with beta2-agonists and anti-muscarinics, represent the cornerstone of asthma treatment. Although the advent of monoclonal antibodies has dramatically changed severe asthma management, there are still patients ineligible or with poor response to biologics. Moreover, high costs associated with monoclonal antibodies prescription are still an open issue, leading clinicians to carefully assess cost-benefit ratio before their administration. From this perspective, the use of single-inhaler Beclometasone Dipropionate/Formoterol Fumarate/Glycopyrronium in patients with severe asthma could not only improve their clinical and functional performance, but also postpone biologic prescription, with positive repercussions on healthcare costs.

The Predictors of Long COVID in Southeastern Italy.

INTRODUCTION: Long COVID is now recognized as a common consequence of the SARS-CoV-2 infection, but we are still far from fully understanding its pathogenesis and predictive factors. Many pathophysiological factors have been studied, including ethnicity. To our knowledge, the risk factors for Long COVID have not been studied in Southeastern Italy. AIMS: The aim of this study was to evaluate the predictive factors of Long COVID in a cohort of patients from Southeastern Italy. METHODS: We conducted a retrospective longitudinal study, enrolling inpatients and outpatients diagnosed with COVID-19 from June 2021 to March 2022. A total of 436 subjects were evaluated in an outpatient setting 12 weeks after a SARS-CoV-2 infection, recording comorbidities, symptoms, therapy, and clinical information. Univariate and multivariate binomial logistic regression analyses were performed on different risk factors to define the probability of developing Long COVID. RESULTS: A total of 71.8% of patients (313) developed Long COVID, while the remaining 123 (28.3%) had a complete remission of symptoms 3 months after acute infection. During the acute phase of COVID-19, 68.3% of patients experienced respiratory failure and 81.4% received corticosteroid therapy. In a multivariate analysis, the female sex (SEX M ODD 0.513) and corticosteroids (ODD 2.25) were maintained as predictive values. CONCLUSIONS: From our data and in line with other studies, the female sex emerges as a risk factor for Long COVID in the population of Southeastern Italy. Corticosteroid therapy administered in the acute phase also appears to be associated with an increased risk of Long COVID. Although indications for the prescription of corticosteroid therapy in the acute phase were indicated by the presence of pneumonia complicated by respiratory insufficiency, there was an over-prescription of corticosteroid therapy in the real life of our cohort, with 64% of patients having respiratory insufficiency and 81% having corticosteroid therapy. We hypothesize that a synergistic link between viral infection and the side effects of corticosteroid therapy may arise in selected cases.

Methodological Aspects of Induced Sputum.

We aimed to conduct a state-of-the-art review of the current literature and offer further insights into the methodological aspects concerning induced sputum. The increasing popularity of sputum induction as a non-invasive and cost-effective method for obtaining lower airway secretions from patients who cannot produce sputum naturally has led to extensive research and applications in respiratory conditions like asthma and COPD. This technique allows for analysis of the cellular and biochemical components of the sputum to take place, providing insights into airway inflammation, immune cells, and help in predicting treatment response. Furthermore, induced sputum enables various analyses, including microRNA and gene expression studies and immunophenotyping. The procedure is generally safe and well tolerated, even in patients with airflow limitations; however, monitoring lung function is essential, especially in those with airway hyperresponsiveness. Optimal saline solution concentration and inhalation duration have been investigated, recommending a 15-20 min induction with hypertonic saline. Expectoration involves coughing at the end of each inhalation time. Careful handling during sputum processing is necessary for obtaining accurate results in cell cytology, immunocytochemistry, and in situ hybridization. Overall, induced sputum offers significant advantages as a preferred alternative for large-scale and repeated airway sampling, despite some technical demands and limitations.

Exhaled volatile organic compounds for diagnosis and monitoring of asthma.

The asthmatic inflammatory process results in the generation of volatile organic compounds (VOCs), which are subsequently secreted by the airways. The study of these elements through gas chromatography-mass spectrometry (GC-MS), which can identify individual molecules with a discriminatory capacity of over 85%, and electronic-Nose (e-NOSE), which is able to perform a quick onboard pattern-recognition analysis of VOCs, has allowed new prospects for non-invasive analysis of the disease in an "omics" approach. In this review, we aim to collect and compare the progress made in VOCs analysis using the two methods and their instrumental characteristics. Studies have described the potential of GC-MS and e-NOSE in a multitude of relevant aspects of the disease in both children and adults, as well as differential diagnosis between asthma and other conditions such as wheezing, cystic fibrosis, COPD, allergic rhinitis and last but not least, the accuracy of these methods compared to other diagnostic tools such as lung function, FeNO and eosinophil count. Due to significant limitations of both methods, it is still necessary to improve and standardize techniques. Currently, e-NOSE appears to be the most promising aid in clinical practice, whereas GC-MS, as the gold standard for the structural analysis of molecules, remains an essential tool in terms of research for further studies on the pathophysiologic pathways of the asthmatic inflammatory process. In conclusion, the study of VOCs through GC-MS and e-NOSE appears to hold promise for the non-invasive diagnosis, assessment, and monitoring of asthma, as well as for further research studies on the disease.

Effect of Food Intake on Exhaled Volatile Organic Compounds Profile Analyzed by an Electronic Nose.

Exhaled breath analysis using an e-nose is a groundbreaking tool for exhaled volatile organic compound (VOC) analysis, which has already shown its applicability in several respiratory and systemic diseases. It is still unclear whether food intake can be considered a confounder when analyzing the VOC-profile. We aimed to assess whether an e-nose can discriminate exhaled breath before and after predefined food intake at different time periods. We enrolled 28 healthy non-smoking adults and collected their exhaled breath as follows: (a) before food intake, (b) within 5 min after food consumption, (c) within 1 h after eating, and (d) within 2 h after eating. Exhaled breath was collected by a formerly validated method and analyzed by an e-nose (Cyranose 320). By principal component analysis, significant variations in the exhaled VOC-profile were shown for principal component 1 (capturing 63.4% of total variance) when comparing baseline vs. 5 min and vs. 1 h after food intake (both p < 0.05). No significance was shown in the comparison between baseline and 2 h after food intake. Therefore, the exhaled VOC-profile seems to be influenced by very recent food intake. Interestingly, two hours might be sufficient to avoid food induced alterations of exhaled VOC-spectrum when sampling for research protocols.

Assessment of Five Questionnaires for Chronic Obstructive Pulmonary Disease in a Southern Italian Population: A Proof-of-Concept Study.

Background and Objectives: Chronic obstructive pulmonary disease (COPD) is a growing burden to society, and remains underdiagnosed in Italy. This study aimed at evaluating five validated screening questionnaires to consider which one was the most accurate, and the optimal cut-off score for each to be considered for the Southern Italian population. Materials and Methods: A total of 144 patients were recruited in the study. The age range was 46-85 years. All subjects underwent spirometry, and completed the five questionnaires: CDQ, LFQ, COPD-PS, COPD-SQ, and CAPTURE. Receiver-operator curves (ROC) were drawn for each questionnaire. The area under the curve (AUC), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), values for the optimal cut-off score and previously recommended score were calculated and compared. Results: Of the questionnaires, the CDQ, LFQ, and COPD-SQ had significant differences between COPD (n = 86) and non-COPD (n = 52) groups. The AUCs for each questionnaire with (95%CI) were: CAPTURE, 0.602 (0.431-0.773); CDQ, 0.714 (0.555-0.872); LFQ, 0.331 (0.183-0.479; COPD-PS, 0.652 (0.497-0.807); and COPD-SQ, 0.679 (0.520-0.837). Only the CDQ and COPD-SQ had significant AUC screening characteristics. The optimal cut-off values for the CDQ, LFQ, and COPD-PS were modified to 22, 10, and 4, respectively. The COPD-SQ remained at 17. Conclusion: The CDQ and COPD-SQ can discriminate between individuals with and without COPD in the Italian population. The CDQ has a moderate screening accuracy, and the COPD-PS and COPD-SQ have low accuracy, when the optimal cut-off scores are used. Of the five questionnaires assessed, the CDQ and COPD-SQ questionnaires could be used for screening for COPD in the Southern Italian population.

Severe asthma clinical remission after biologic treatment with anti-IL4/IL13: A real-life experience.

INTRODUCTION: Dupilumab, a fully human anti-interleukin-4/interleukin-13 monoclonal antibody, has shown efficacy in many aspects of Type-2 severe asthma management. Currently, we lack real-life studies addressing the achievment of clinical remission in patients treated with this biologic. MATERIALS AND METHODS: We performed a prospective study enrolling 18 patients with severe asthma treated with Dupilumab. We assessed main clinical, functional and biological severe asthma features at baseline (T0) and after a 1-year course of treatment (T12). Clinical remission was defined at T12 in patients without asthma exacerbations, no oral corticosteroid (OCS) use, ACT ≥ 20 and FEV1 improvement ≥ 100 ml from baseline. RESULTS: Among total population, 38.9% of patients achieved clinical remission at T12. Anti IL-4/IL-13 treatment significantly reduced asthma exacerbations and OCS use in the overall cohort, with a more pronounced ACT improvement in the remission group. Patients achieving clinical remission went through a step down of the inhalation therapy, suspending long-acting anti-muscarinics administration at T12. CONCLUSIONS: Treatment with anti-IL4/IL13 can induce clinical remission in patients with T2 severe asthma.

Asthma and Fixed Airways Obstruction: Real Life Aspects.

We aimed to evaluate asthmatic patients with fixed airways obstruction (FAO) and to verify the impact of follow-up in an asthma-dedicated outpatient clinic on symptoms control and spirometry compared to asthmatics without FAO. We enrolled 20 asthmatic FAO+ patients and 20 FAO- asthmatics at baseline (T0) and at a one-year follow-up visit (T1). FAO+ and FAO- groups were compared for anamnesis, FEV1, asthma control test (ACT) and their ΔT0-T1. FAO+ and FAO- groups did not differ for age, BMI, pack-years, allergy, T0 blood eosinophils, comorbidities or GINA therapy step at T0 and T1, whereas, in the FAO+ group, we found more patients with a delay >5 years between symptoms onset and correct asthma diagnosis (p < 0.05). ACT at T0 and ΔT0-T1, FEV1 at ΔT0-T1 and number of exacerbations at T0 and ΔT0-T1 did not differ between groups. Despite a widespread perception of FAO, per se, as a severity factor for asthma, we found similar severity profiles and amelioration after one year of treatment in the FAO+ and FAO- groups. The only factor linked to FAO development in our population was a delay in asthma diagnosis from respiratory symptoms onset, which may have led to airway remodeling. Physicians should characterize patients with FAO for avoiding misdiagnosis between asthma and other respiratory diseases and for establishing the appropriate therapy.

Effects of benralizumab in a population of patients affected by severe eosinophilic asthma and chronic rhinosinusitis with nasal polyps: a real life study.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a frequent comorbidity in severe eosinophilic asthma (SEA), which may contribute to the loss of asthma control. CRSwNP and SEA share a T2-mediated mechanism and the use of some anti-asthma monoclonal antibodies has recently been extended to CRSwNP. Unlike dupilumab and omalizumab, benralizumab approval for CRSwNP is ongoing. We aimed to evaluate the efficacy of benralizumab efficacy on SEA and on CRSwNP in patients affected by both pathologies in a real life setting. METHODS: 17 patients affected by both SEA and CRSwNP participated to our study. At baseline (T0) and at one year after benralizumab initiation (T1), all participants underwent  spirometry, exhaled nitric oxide (FeNO), Asthma Control Test (ACT), nasal endoscopy with Nasal Polyp Score (NPS), nasal cytology and Sino-Nasal Outcome Test 22 (SNOT 22).The continuous oral corticosteroid therapy (OCS), the number of year exacerbations and the need for sinus surgery were also evaluated  for each patient. RESULTS: At T1, a marked reduction of SNOT-22, NPS, nasal eosinophils and neutrophils count were shown compared to T0. Moreover, at T1 ACT was significantly increased and FeNO, exacerbations/year and mean OCS dosage were significantly reduced compared to T0. CONCLUSIONS: Our real-life study demonstrates the efficacy of benralizumab not only on SEA but also on nasal cytology and on nasal polyposis, confirming that patients affected by both SEA and CRSwNP may receive a considerable benefit from anti-IL5 receptor, treating both the comorbidities at once.

High Level of Blood Eosinophils and Localization of Bronchiectasis in Patients with Severe Asthma: A Pilot Study.

Background. Severe asthma and bronchiectasis are heterogeneous diseases that frequently coexist. The location of bronchiectasis is generally determined by specific underlying pathophysiological mechanisms. The aim of this study was to determine whether in a population suffering from both severe asthma and bronchiectasis there was a correlation between eosinophilic inflammation and localization of bronchiectasis. Methods. We enrolled 41 patients with coexisting bronchiectasis from eight different severe asthma center outpatient clinics and collected the following data: baseline characteristics, Asthma Control Test, Asthma Control Questionnaire, IgE level, blood count, high-resolution computed tomography and bronchiectasis-related parameters, skin prick test, FeNO50 and flow-volume spirometry. The study was retrospectively registered. Results. The presence of eosinophils > 1000 cells/µL was related to distribution of lower pulmonary bronchiectasis (9.1% upper lobes vs. 53.3% lower lobes, p = 0.014). Indeed, the presence of eosinophilic counts > 1000 increased the probability of lower localization of bronchiectasis compared to upper lobes (ODD 0.088 (0.010−0.772), p = 0.028). Conclusions. An increase in blood eosinophils > 1000 cells/µL seems to be associated with lower preferential localization of bronchiectasis with sparing of the upper lung lobes. This could represent a new potential radiological phenotype that could have a dedicated therapeutic strategy in the future.

Super-Responders to Biologic Treatment in Type 2-High Severe Asthma: Passing Fad or a Meaningful Phenotype?

Defining super-response to biologic treatment is a major concern in severe asthma. Although many definitions have been proposed, there is still a gap between the clinical perception of the super-response and a standardized classification. The current definition of super-response mainly relies on several clinical features, while many aspects of severe asthma inflammation and lung function are still poorly considered. Furthermore, many criteria of severe asthma super-response overlap with those of the clinical remission, leaving room for possible misclassifications. In this context, identifying the correct trajectory linking these 2 aspects of type 2-high severe asthma could help clinicians to understand which factors can predict a greater response to biologic therapies. In this paper, we review various aspects of super-response assessment, proposing some new criteria for its definition as well as new perspectives on its relationship with severe asthma clinical remission.

The Role of Gut Bacteriome in Asthma, Chronic Obstructive Pulmonary Disease and Obstructive Sleep Apnoea.

The human body contains a very complex and dynamic ecosystem of bacteria. The bacteriome interacts with the host bi-directionally, and changes in either factor impact the entire system. It has long been known that chronic airway diseases are associated with disturbances in the lung bacteriome. However, less is known about the role of gut bacteriome in the most common respiratory diseases. Here, we aim to summarise the evidence concerning the role of the intestinal bacteriome in the pathogenesis and disease course of bronchial asthma, chronic obstructive pulmonary disease, and obstructive sleep apnea. Furthermore, we discuss the consequences of an altered gut bacteriome on the most common comorbidities of these lung diseases. Lastly, we also reflect on the therapeutic potential of influencing the gut microbiome to improve disease outcomes.

The impact of healthcare setting on post-COVID mood disorders: a single-centre perspective from Southern Italy Respiratory Intensive Care Unit.

BACKGROUND AND OBJECTIVES: Post-COVID syndrome includes several clinical identities, with both physical and mental alterations lasting several months from the acute phase of COVID-19 disease. However, to date, data concerning the relationship between healthcare settings during COVID-19 disease and post-COVID mood disorders are lacking. METHODS: We performed a prospective study enrolling 440 patients with post-COVID syndrome. Each patient underwent a complete clinical evaluation, along with blood and functional tests. Patients were divided according to the healthcare setting needed during COVID-19 disease. RESULTS: Patients admitted to RICU were more prone to develop mental alterations, even when compared to ICU-admitted patients. Other risk factors for mood disorders included female gender and some post-COVID symptoms. CONCLUSIONS: Healthcare needs during COVID-19 can explain the higher incidence of mood disorders in post-COVID syndrome. RICU arises as an important but underexplored risk factor for post-COVID psychic sequelae.

The Role of a Polymer-Based E-Nose in the Detection of Head and Neck Cancer from Exhaled Breath.

The aim of our study was to assess whether a polymer-based e-nose can distinguish head and neck cancer subjects from healthy controls, as well as from patients with allergic rhinitis. A total number of 45 subjects participated in this study. The first group was composed of 15 patients with histology confirmed diagnosis of head and neck cancer. The second group was made up of 15 patients with diagnoses of allergic rhinitis. The control group consisted of 15 subjects with a negative history of upper airways and/or chest symptoms. Exhaled breath was collected from all participants and sampled by a polymer-based e-nose (Cyranose 320, Sensigent, Pasadena, CA, USA). In the Principal Component Analysis plot, patients with head and neck cancer clustered distinctly from the controls as well as from patients with allergic rhinitis. Using canonical discriminant analysis, the three groups were discriminated, with a cross validated accuracy% of 75.1, p < 0.01. The area under the curve of the receiver operating characteristic curve for the discrimination between head and neck cancer patients and the other groups was 0.87. To conclude, e-nose technology has the potential for application in the diagnosis of head and neck cancer, being an easy, quick, non-invasive and cost-effective tool.

A glimpse in post-COVID pathophysiology: the role of exhaled breath condensate pH as an early marker of residual alveolar inflammation.

BACKGROUND: Residual alveolar inflammation seems to be paramount in post-COVID pathophysiology. Currently, we still lack a reliable marker to detect and track alveolar phlogosis in these patients. Exhaled Breath Condensate (EBC) pH has robust evidences highlighting its correlation with lung phlogosis in various diseases. We aim to define the reliability of alveolar and bronchial EBC pH in the assessment and in the follow up of post-COVID-related inflammation. RESEARCH DESIGN AND METHODS: We enrolled 10 patients previously hospitalized due to COVID-19 pneumonia. We performed a complete follow-up after 3 months and 6 months from discharge. Each visit included routine blood tests, arterial blood gas analysis, 6-minute walking test, spirometry, diffusing capacity and body plethysmography. Finally, bronchial and alveolar EBC were collected at the end of each visit. RESULTS: Alveolar EBC pH was significantly lower than bronchial EBC pH at T1, alveolar EBC pH tended to be more acid after 3 months from hospital discharge compared to the same sample 6 months later. Serum inflammatory biomarkers showed no significant differences from T1 to T2. Alveolar EBC pH was positively correlated with neutrophil-lymphocyte ratio. CONCLUSIONS: Collecting EBC pH could help to understand pathophysiologic mechanism as well as monitoring alveolar inflammation in the post-COVID syndrome.