Chronic obstructive pulmonary disease's eosinophilic phenotype: Clinical characteristics, biomarkers and biotherapy.

COPD is a chronic, heterogeneous inflammatory disorder of the airways with persistent and poorly reversible airflow limitation, causing symptoms such as cough, shortness of breath, and sputum production. Despite optimal treatment, some patients remain symptomatic due to the disease's heterogeneity, manifesting in various phenotypes. One notable phenotype involves eosinophilic inflammation, with a variable prevalence. Identifying eosinophilic phenotypes is crucial for tailored therapeutic strategies, as they respond favorably to corticosteroids and potentially biologics. Recent advances in both clinical trials and spontaneous research have helped understand the biological and clinical characteristics of this phenotype, although no universal consensus has been reached yet on the definition of the cut-off values of the eosinophil peripheral blood count. Moreover, there is evidence of novel emerging biomarkers which might go beyond the sole eosinophil count, while significant advancements in terms of pharmacological treatment have been made, with dupilumab being the first biological drug being licensed for COPD patients with elevated circulating eosinophils in the stable phase. In light of the above, although several papers have been written on the relationship between eosinophils and COPD, in the present work we endeavored to summarize and discuss the pivotal literature findings regarding the eosinophilic COPD in order to help define the biological and clinical features of this peculiar phenotype, with particular attention to the use of established and emerging biomarkers, as well as current and future therapeutic perspectives.

A Comparison of GOLD and STAR Severity Stages in Individuals with Chronic Obstructive Pulmonary Disease Undergoing Pulmonary Rehabilitation.

BACKGROUND: Alongside the recognized Global Initiative for Obstructive Lung Disease (GOLD) classification, the STaging of Airflow obstruction by Ratio (STAR) severity scheme has been proposed for categorizing chronic obstructive pulmonary disease (COPD). STUDY QUESTION: What is the agreement and utility of the GOLD and STAR classifications in severe COPD patients entering the rehabilitation setting? STUDY DESIGN AND METHODS: Medical records were reviewed in this multicenter retrospective study, examining key functional variables and their changes in a large cohort of COPD patients undergoing pulmonary rehabilitation (PR). RESULTS: A total of 1,516 participants (33.7% females, median age 72.0 years) were included in the analysis. Compared to GOLD, the use of the STAR classification resulted in a different disease severity category for 53.4% of patients. An unweighted Cohen's κ of 0.25 and a Bangdiwala B value of 0.24 revealed a fair agreement between the two classifications. Higher weighted agreement measures (0.47 and 0.78, respectively) suggested that discrepancies between the classifications mainly occurred for contiguous stages. GOLD demonstrated superior discrimination between stages for chronic respiratory failure, while STAR exhibited better performance in detecting hyperinflation. In terms of their application within PR settings, GOLD exhibited superior performance compared to STAR in identifying the minimal clinically important difference (MCID) in 6-minute walking distance and modified Medical Research Council (mMRC) score. Accordingly, GOLD but not STAR acted as an independent predictor for achieving a MCID in mMRC (OR: 1.48; 95% CI: 1.12-1.94; P=0.005) and also independently predicted changes in Braden score (ß=0.154; P=0.004). INTERPRETATION: STAR shows a more uniform gradation of disease severity and enhanced performance in detecting hyperinflation but our preliminary findings do not endorse its utilization in the rehabilitation setting.

Exploring the Impact of Inhaled Corticosteroids on Endothelial Function in Chronic Obstructive Pulmonary Disease Patients Undergoing Pulmonary Rehabilitation.

Background: Chronic obstructive pulmonary disease (COPD) is associated with subclinical atherosclerosis and endothelial dysfunction, which can be assessed non-invasively through flow-mediated dilation (FMD). In this study, we evaluated the potential impact of inhaled corticosteroid (ICS) therapy on FMD of COPD patients undergoing pulmonary rehabilitation (PR). Methods: Medical records of COPD patients undergoing FMD assessment upon admission to our Pulmonary Rehabilitation Unit were reviewed in this retrospective post hoc analysis. Results: A total of 46 patients with COPD (median age 71.5 years, 28.3% postmenopausal females) were included in the final analysis. Among these, 27 participants were currently receiving ICS therapy, while 19 were not. At baseline, the two groups showed no difference in the main clinical and functional variables. Similarly, no significant difference was observed in vascular reactivity parameters, with a median FMD of 3.12% (IQR: 2.23-4.45) in ICS users and 3.39% (IQR: 2.45-4.08) in ICS nonusers (p = 0.544). After PR, a significant improvement in the main rehabilitation and patient-reported outcomes was observed in all groups, with a significant improvement in FMD documented in both patients treated with steroids (from 3.12%; IQR: 2.23-4.45 to 4.77%; IQR: 3.25-5.63, p = 0.022) and in those who were not (from 3.39%; IQR: 2.45-4.08 to 5.04%; IQR: 3.98-6.06, p = 0.005). FMD changes were of comparable magnitude among groups. Conclusions: Our preliminary findings do not indicate a significant impact of medications containing ICS on the endothelial function of COPD patients, suggesting that the potential beneficial effect of PR on this surrogate marker of cardiovascular risk is independent of inhaled therapy.

Revealing the gap: fractional exhaled nitric oxide and clinical responsiveness to biological therapy in severe asthma - a retrospective study.

A proportion of patients with severe asthma treated with biological drugs undergoes a significant decline in F ENO. However, variations in F ENO are largely independent of the clinical efficacy of the biological drug therapy. https://bit.ly/3xWszYJ.

Exhaled breath condensate (EBC) in respiratory diseases: recent advances and future perspectives in the age of omic sciences.

Exhaled breath condensate (EBC) is used as a promising noninvasive diagnostic tool in the field of respiratory medicine. EBC is achieved by cooling exhaled air, which contains aerosolized particles and volatile compounds present in the breath. This method provides useful information on the biochemical and inflammatory state of the airways. In respiratory diseases such as asthma, chronic obstructive pulmonary disease and cystic fibrosis, EBC analysis can reveal elevated levels of biomarkers such as hydrogen peroxide, nitric oxide and various cytokines, which correlate with oxidative stress and inflammation. Furthermore, the presence of certain volatile organic compounds in EBC has been linked to specific respiratory conditions, potentially serving as disease-specific fingerprints. The noninvasive nature of EBC sampling makes it particularly useful for repeated measures and for use in vulnerable populations, including children and the elderly. Despite its potential, the standardization of collection methods, analytical techniques and interpretation of results currently limits its use in clinical practice. Nonetheless, EBC holds significant promise for improving the diagnosis, monitoring and therapy of respiratory diseases. In this tutorial we will present the latest advances in EBC research in airway diseases and future prospects for clinical applications of EBC analysis, including the application of the Omic sciences for its analysis.

Corrigendum: Evidence for a genetic contribution to the ossification of spinal ligaments in ossification of posterior longitudinal ligament and diffuse idiopathic skeletal hyperostosis: a narrative review.

[This corrects the article DOI: 10.3389/fgene.2022.987867.].

Endotyping Chronic Respiratory Diseases: T2 Inflammation in the United Airways Model.

Over the past 15 years, the paradigm of viewing the upper and lower airways as a unified system has progressively shifted the approach to chronic respiratory diseases (CRDs). As the global prevalence of CRDs continues to increase, it becomes evident that acknowledging the presence of airway pathology as an integrated entity could profoundly impact healthcare resource allocation and guide the implementation of pharmacological and rehabilitation strategies. In the era of precision medicine, endotyping has emerged as another novel approach to CRDs, whereby pathologies are categorized into distinct subtypes based on specific molecular mechanisms. This has contributed to the growing acknowledgment of a group of conditions that, in both the upper and lower airways, share a common type 2 (T2) inflammatory signature. These diverse pathologies, ranging from allergic rhinitis to severe asthma, frequently coexist and share diagnostic and prognostic biomarkers, as well as therapeutic strategies targeting common molecular pathways. Thus, T2 inflammation may serve as a unifying endotypic trait for the upper and lower airways, reinforcing the practical significance of the united airways model. This review aims to summarize the literature on the role of T2 inflammation in major CRDs, emphasizing the value of common biomarkers and integrated treatment strategies targeting shared molecular mechanisms.

Serum parathormone, vitamin D and cardiovascular risk factors and markers: A pilot study.

BACKGROUND AND AIMS: Vitamin D deficiency is a common cause of secondary hyperparathyroidism, particularly in elderly people. The aim of this study was to evaluate the associations of serum vitamin D and parathormone (PTH) concentrations with blood pressure values and hypertension-mediated target organ damage (HMOD), including left ventricular (LV) hypertrophy and carotid plaque (CP). METHODS AND RESULTS: We enrolled consecutive patients admitted to the Hypertension Center of Federico II University Hospital in Naples, Italy. All patients underwent carotid doppler ultrasound and echocardiography, measurement of vitamin D and PTH levels and main clinical and laboratory parameters. A total of 126 patients (mean age 54 years, 68% males) were enrolled. Pearson's correlation analysis indicated that PTH levels directly correlated with age, diabetes, dyslipidemia, hypertension, fasting glucose, and LV mass, and inversely with glomerular filtration rate, LDL cholesterol, and vitamin D. Vitamin D levels correlated inversely with PTH, diabetes and CP. Multivariate regression models indicated that an increased LV mass was associated with the presence of obesity (ß = 0.342; P = 0.001). Maximal intima-media thickness was significantly associated with older age (ß = 0.303; P = 0.033). Combined presence of low vitamin D/high PTH levels were associated with more than 4-fold increased risk of having CP in both univariate (OR = 4.77, p = 0.0001) and multivariate regression analysis (OR = 4.52, p = 0.014). CONCLUSION: In a population at high cardiovascular risk, vitamin D and PTH levels were not directly associated with blood pressure values and HMOD. Secondary hyperparathyroidism due to vitamin D deficiency is associated with carotid atherosclerosis independently of other common cardiovascular risk factors.

Autoimmunity against Nucleus Ambiguous Is Putatively Possible in Both Long-COVID-19 and Vaccinated Subjects: Scientific Evidence and Working Hypothesis.

As reported by the World Health Organization (WHO), about 10-20% of people have experienced mid- to long-term effects following SARS-CoV-2 infection, collectively referred to as post-COVID-19 condition or long-COVID, including some neurovegetative symptoms. Numerous findings have suggested that the onset of these neurovegetative symptoms upon viral infection may be caused by the production of autoantibodies through molecular mimicry phenomena. Accordingly, we had previously demonstrated that 22 of the human proteins sharing putatively immunogenic peptides with SARS-CoV-2 proteins are expressed in the dorsal motor nucleus and nucleus ambiguous. Therefore, if molecular mimicry occurs following severe forms of COVID-19, there could be transitory or permanent damage in some vagal structures, resulting in a lower vagal tone and all the related clinical signs. We investigated the presence of autoantibodies against two proteins of vagal nuclei sharing a peptide with SARS-CoV-2 spike glycoprotein using an immunoassay test on blood obtained from patients with cardiorespiratory symptoms in patients affected by ongoing symptomatic COVID-19 (long-COVID), subjects vaccinated without a history of SARS-CoV-2 infection, and subjects not vaccinated without a history of SARS-CoV-2 infection. Interestingly, putative autoantibodies were present in both long-COVID-19 and vaccinated groups, opening interesting questions about pathogenic mechanisms of the disease.

The Beneficial Impact of Pulmonary Rehabilitation in Idiopathic Pulmonary Fibrosis: A Review of the Current Literature.

Idiopathic pulmonary fibrosis (IPF) is a chronic and irreversible fibrotic disease whose natural history is characterised by a progressive worsening of the pulmonary function, exertional dyspnoea, exercise intolerance, reduced physical activity, and health-related quality of life (HRQOL) impairment. Pulmonary rehabilitation (PR) is a comprehensive, multi-disciplinary programme that uses a combination of strength training, teaching, counselling, and behaviour modification techniques to reduce symptoms and optimise functional capacity in patients with chronic lung disease. Based on the well-documented effectiveness of PR in chronic obstructive pulmonary disease (COPD), over the years supportive evidence of its benefits for other respiratory diseases has been emerging. Although the latest rehabilitation guidelines recognised PR's efficacy for interstitial lung disease (ILD) and IPF in particular, this comprehensive approach remains underused and under-resourced. In this review, we will discuss the advantages and beneficial effects of PR on IPF, analysing its impact on exercise capacity, disease-related symptoms, cardiovascular outcomes, body composition, and HRQOL.

Exploring novel perspectives on eosinophilic inflammation in severe asthma.

Two recent articles by the same research group documented that patients with severe eosinophilic asthma exhibit an increased proportion of a subtype of eosinophils, namely CD62Llow inflammatory eosinophils (iEos) and identified an intriguing correlation between such iEos and asthma control scores. Moreover, CD62Llow iEos were reduced after treatment with the anti-IL-5 monoclonal antibody mepolizumab. In the future, we believe that eosinophil subtypes could represent a useful biomarker in severe eosinophilic asthma, helping clinicians characterize patient endotypes and monitoring the response to biological drugs.

Patients with severe eosinophilic asthma (SEA) have an increased proportion of a subtype of eosinophils, CD62L^low inflammatory eosinophils (iEos), which are reduced after mepolizumab treatment. iEos might represent a novel useful biomarker in SEA.

Novel Strategies in Diagnosing Heart Failure with Preserved Ejection Fraction: A Comprehensive Literature Review.

Heart failure (HF) with preserved ejection fraction (HFpEF) is a prevalent global condition affecting approximately 50% of the HF population. With the aging of the worldwide population, its incidence and prevalence are expected to rise even further. Unfortunately, until recently, no effective medications were available to reduce the high mortality and hospitalization rates associated with HFpEF, making it a significant unmet need in cardiovascular medicine. Although HFpEF is commonly defined as HF with normal ejection fraction and elevated left ventricular filling pressure, performing invasive hemodynamic assessments on every individual suspected of having HFpEF is neither feasible nor practical. Consequently, several clinical criteria and diagnostic tools have been proposed to aid in diagnosing HFpEF. Overall, these criteria and tools are designed to assist healthcare professionals in identifying and evaluating patients who may have HFpEF based on a combination of signs, symptoms, biomarkers, and non-invasive imaging findings. By employing these non-invasive diagnostic approaches, clinicians can make informed decisions regarding the best pharmacological and rehabilitation strategies for individuals with suspected HFpEF. This literature review aims to provide an overview of all currently available methods for diagnosing and monitoring this disabling condition.

Visual vertical neglect in acquired brain injury: a systematic review.

Vertical neglect represents a visuospatial deficit occurring as a possible consequence of acquired brain injury (ABI). Differently from unilateral spatial neglect on horizontal space, vertical neglect is poorly studied in the literature and rarely assessed in clinical practice. In the available studies, the terms "radial," "vertical," and "altitudinal" neglect are often used interchangeably, although they do not describe the same spatial dimension. "Altitudinal" and "vertical" refer to the sagittal plane, whereas "radial" refers to the transverse plane. The term "vertical" is sometimes used interchangeably with respect to both axes. The aim of this systematic review was to identify the main characteristics of vertical neglect after ABI, the diagnostic tools used, and the treatment options. We also proposed a clarification of the manifestations and characteristics of vertical and radial neglect. The 23 articles reviewed, showed that the vertical neglect occurred more frequently on the lower space than on the upper space, that its presence was associated with horizontal neglect, and that it could also occur with compromise of the radial space, with the near radial being more common. The most frequent etiology associated with vertical neglect is vascular, particularly ischaemic. The lesions side are very heterogeneous and include both cortical and subcortical areas and all lobes, although the temporal lobe is most affected. With regard to the assessment tools, paper and pencil tasks are the most commonly used diagnostic tools to identify vertical neglect, although in recent years the use of computer-based tasks increased. Taken together, our results suggest that vertical neglect may be underestimated in patients with right hemisphere lesions and should always be assessed, especially in cases where the patient shows signs of horizontal neglect. The clinical assessment of vertical neglect is very important since it can lead to important functional limitations in everyday life, such as poor wheelchair handling, stumbling over unnoticed obstacles located below (or above), walking down stairs, taking off shoes.

The biomarkers' landscape of post-COVID-19 patients can suggest selective clinical interventions.

In COVID-19 clinical symptoms can persist even after negativization also in individuals who have had mild or moderate disease. We here investigated the biomarkers that define the post-COVID-19 clinical state analyzing the exhaled breath condensate (EBC) of 38 post COVID-19 patients and 38 sex and age-matched healthy controls via nuclear magnetic resonance (NMR)-based metabolomics. Predicted gene-modulated microRNAs (miRNAs) related to COVID-19 were quantified from EBC of 10 patients and 10 controls. Finally, clinical parameters from all post-COVID-19 patients were correlated with metabolomic data. Post-COVID-19 patients and controls showed different metabolic phenotype ("metabotype"). From the metabolites, by using enrichment analysis we identified miRNAs that resulted up-regulated (hsa-miR146a-5p) and down-regulated (hsa-miR-126-3p and hsa-miR-223-3p) in post-COVID-19. Taken together, our multiomics data indicate that post-COVID-19 patients before rehabilitation are characterized by persistent inflammation, dysregulation of liver, endovascular thrombotic and pulmonary processes, and physical impairment, which should be the primary clinical targets to contrast the post-acute sequelae of COVID-19.

The Clinical Application of Established and Emerging Biomarkers for Chronic Respiratory Diseases.

Biomarkers are indicators of a pathological or physiological state, and they are essential for facilitating the diagnosis of a subclinical condition, understanding the origin or progression of a disease, stratifying the risk, and assessing the response to a specific therapeutic approach [...].

Flow-mediated dilation as a marker of endothelial dysfunction in pulmonary diseases: A narrative review.

The endothelium is an active and crucial component of vessels and produces several key regulatory factors for the homeostasis of the entire organism. Endothelial function can be investigated invasively or non-invasively, both in the coronary and peripheral circulation. A widely accepted method for the assessment of endothelial function is measurement of flow-mediated dilation (FMD), which evaluates the vascular response to changes in blood flow. In this current review, we describe FMD applications in the clinical setting of different respiratory diseases: acute SARS-COV2 infection, pulmonary embolism; post-acute SARS-COV2 infection, Chronic Obstructive Pulmonary Disease, Obstructive Sleep Apneas Syndrome, Pulmonary Hypertension, Interstitial Lung Diseases. Emerging evidence shows that FMD might be an effective tool to assess the cardiovascular risk in patients suffering from the undermentioned respiratory diseases as well as an independent predictive factor of disease severity and/or recovery.

Cardiovascular Risk Associated with Alpha-1 Antitrypsin Deficiency (AATD) Genotypes: A Meta-Analysis with Meta-Regressions.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) can result in severe liver and respiratory disorders. The uninhibited elastase activity on the elastic tissue of arterial walls suggests that AATD may also impact vascular health. Thus, we performed a meta-analysis of the studies evaluating cardiovascular risk in individuals with AATD and non-AATD controls. METHODS: A systematic literature search was conducted in the main scientific databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Differences between cases and controls were expressed as odds ratios (OR) with 95% confidence intervals (95%CI). The protocol was registered on PROSPERO under the identification number CRD42023429756. RESULTS: The analysis of eight studies showed that, with a prevented fraction of disease of 15.0% and a corresponding OR of 0.779 (95%CI: 0.665-0.912; p = 0.002), a total of 24,428 individuals with AATD exhibited a significantly lower risk of ischemic heart disease compared to 534,654 non-AATD controls. Accordingly, given a prevented fraction of disease of 19.5%, a lower risk of acute myocardial infarction was documented when analyzing four studies on 21,741 cases and 513,733 controls (OR: 0.774; 95%CI: 0.599-0.999; p = 0.049). Sensitivity and subgroup analyses substantially confirmed results. Meta-regression models suggested that these findings were not influenced by AATD genotypes or prevalence of chronic obstructive pulmonary disease (COPD) among cases and controls, while higher differences in the prevalence of male sex (Z-score: 3.40; p < 0.001), hypertension (Z-score: 2.31; p = 0.021), and diabetes (Z-score: 4.25; p < 0.001) were associated with a lower effect size. CONCLUSIONS: Individuals with AATD may exhibit a reduced risk of ischemic heart disease, even in the presence of mild deficiency of the serine protease inhibitor. Although caution is warranted due to the observational nature of the data, future pharmacological and rehabilitation strategies should also take this controversial relationship into account.

Clinical Applications of Nasal Nitric Oxide in Allergic Rhinitis: A Review of the Literature.

Allergic rhinitis, a common allergic disease affecting a significant number of individuals worldwide, is observed in 25% of children and 40% of adults, with its highest occurrence between the ages of 20 and 40. Its pathogenesis, like other allergic diseases, involves innate and adaptive immune responses, characterized by immunologic hypersensitivity to environmental substances. This response is mediated by type 2 immunity. Within type 2 allergic diseases, certain molecules have been identified as clinical biomarkers that contribute to diagnosis, prognosis, and therapy monitoring. Among these biomarkers, nitric oxide has shown to play a key role in various physiological and pathological processes, including neurotransmission, immunity, inflammation, regulation of mucus and cilia, inhibition of microorganisms, and tumor cell growth. Therefore, measurement of nasal nitric oxide has been proposed as an objective method for monitoring airway obstruction and inflammation in different settings (community, hospital, rehabilitation) and in various clinical conditions, including upper airways diseases of the nose and paranasal sinuses. The purpose of this review is to analyze the potential mechanisms contributing to the production of nasal nitric oxide in allergic rhinitis and other related health issues. Additionally, this review aims to identify potential implications for future research, treatment strategies, and long-term management of symptoms.