Search

Introduction: Eosinophilic granulomatosis with polyangiitis (EGPA) is a multisystemic, immune-mediated disease that occurs in patients with asthma and eosinophilia. It is characterized by inflammation of small and medium-caliber blood vessels., Case Report: In this report we present an unusual clinical case of EGPA with positive anti-neutrophil cytoplasmic antibodies who manifested bilateral pleural effusion. The diagnosis was confirmed through laboratory assessments and bronchial biopsies. The patient was treated with methylprednisolone showing improvement in symptoms., Conclusions: our case appears interesting considering the limited evidence of pleural effusion in patients with EGPA documented in the literature.

Chronic obstructive pulmonary disease (COPD) ranks as the third leading cause of global illness and mortality. It is commonly triggered by exposure to respiratory irritants like cigarette smoke or biofuel pollutants. This multifaceted condition manifests through an array of symptoms and lung irregularities, characterized by chronic inflammation and reduced lung function. Present therapies primarily rely on maintenance medications to alleviate symptoms, but fall short in impeding disease advancement. COPD's diverse nature, influenced by various phenotypes, complicates diagnosis, necessitating precise molecular characterization. Omics-driven methodologies, including biomarker identification and therapeutic target exploration, offer a promising avenue for addressing COPD's complexity. This analysis underscores the critical necessity of improving molecular profiling to deepen our comprehension of COPD and identify potential therapeutic targets. Moreover, it advocates for tailoring treatment strategies to individual phenotypes. Through comprehensive exploration-based molecular characterization and the adoption of personalized methodologies, innovative treatments may emerge that are capable of altering the trajectory of COPD, instilling optimism for efficacious disease-modifying interventions.

Autophagy is a complex physiological pathway mediating homeostasis and survival of cells degrading damaged organelles and regulating their recycling. Physiologic autophagy can maintain normal lung function, decrease lung cellular senescence, and inhibit myofibroblast differentiation. It is well known that autophagy is activated in several chronic inflammatory diseases; however, its role in the pathogenesis of chronic obstructive pulmonary disease (COPD) and the expression of autophagy-related genes (ATGs) in lower airways of COPD patients is still controversial. The expression and localization of all ATG proteins that represented key components of the autophagic machinery modulating elongation, closure, and maturation of autophagosome membranes were retrospectively measured in peripheral lungs of patients with stable COPD ( n = 10), control smokers with normal lung function ( n = 10), and control nonsmoking subjects ( n = 8) using immunohistochemical analysis. These results show an increased expression of ATG4 protein in alveolar septa and bronchiolar epithelium of stable COPD patients compared to smokers with normal lung function and non-smoker subjects. In particular, the genes in the ATG4 protein family (including ATG4A, ATG4B, ATG4C, and ATG4D) that have a key role in the modulation of the physiological autophagic machinery are the most important ATGs increased in the compartment of lower airways of stable COPD patients, suggesting that the alteration shown in COPD patients can be also correlated to impaired modulation of autophagic machinery modulating elongation, closure, and maturation of autophagosomes membranes. Statistical analysis was performed by the Kruskal-Wallis test and the Mann-Whitney U test for comparison between groups. A statistically significant increased expression of ATG4A ( p = 0.0047), ATG4D ( p = 0.018), and ATG5 ( p = 0.019) was documented in the bronchiolar epithelium as well in alveolar lining for ATG4A ( p = 0.0036), ATG4B ( p = 0.0054), ATG4C ( p = 0.0064), ATG4D ( p = 0.0084), ATG5 ( p = 0.0088), and ATG7 ( p = 0.018) in patients with stable COPD compared to control groups. The ATG4 isoforms may be considered as additional potential targets for the development of new drugs in COPD.

IL-33 is a multifaceted cytokine, plays a pivotal role in various biological processes, making it a subject of extensive research and intrigue in the field of immunology. This cytokine acts as a key regulator, effectively putting the brakes on proinflammatory nuclear factor-kappa B (NF-κB), thereby modulating chromatin compaction by promoting nucleosome-to-nucleosome interactions. IL-33's influence extends to the realm of innate and acquired immunity through its binding to the membrane-bound ST2 molecule (ST2L) of the IL-33R complex, which is expressed on various immune cells, such as Th2 cells, mast cells, natural killer cells, myeloid cells, and dendritic cells. IL-33's role in inflammation is far from one-dimensional, as it has been found to have a dual role in inflammatory disorders. In the quest to understand the origins of IL-33, immunohistochemical examination of lung tissue samples from patients with adenocarcinoma could shed light on its presence in bronchial epithelial and vascular endothelial cells, in lung tissue cancerous lesions. For this reason, we conducted a pilot study about the immunohistochemical expression of IL-33 in surgical specimens of stage 1 o 2 lung adenocarcinoma received after lung resection surgery.Our results demonstrated that patients had nuclear IL-33 immunopositivity in the alveolar pneumocytes of the normal lung tissue at the periphery of lung adenocarcinoma specimen. Note the evident negativity of the neoplastic adenocarcinoma cells. Other data showed IL-33 nuclear immunoexpression in endothelial cells of intratumoral vascular structures.This finding could indicate that IL-33 might be involved in regulating blood vessel formation and maintenance within the tumor, which is a critical factor in tumor growth and progression.The presence of IL-33 in normal lung tissue and intratumoral vascular structures may be related to its physiological functions in these contexts, while its absence in neoplastic adenocarcinoma cells could indicate a potential loss of regulatory control, which might have implications for the development and progression of the tumor., Competing Interests: Declaration of Competing Interest All the authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Poxviridae family includes several viruses that infecting humans usually causes skin lesions only, but in some cases their clinical course is complicated by viral pneumonia (with or without bacterial superinfections). Historically variola virus has been the poxviridae most frequently associated with the development of pneumonia with many large outbreaks worldwide before its eradication in 1980. It is still considered a biological threat for its potential in biological warfare and bioterrorism. Smallpox pneumonia can be severe with the onset of acute respiratory distress syndrome (ARDS) and death. Vaccinia virus, used for vaccination against smallpox exceptionally, in immunocompromised patients, can induce generalized (with also lung involvement) severe disease after vaccination. MPXV virus occasionally can cause pneumonia particularly in immunocompromised patients. The pathophysiology of poxviridae pneumonia is still an area of active research; however, in animal models these viruses can cause both direct damage to the lower airways epithelium and a hyperinflammatory syndrome, like a cytokine storm. Multiple mechanisms of immune evasion have also been described. The treatment of poxviridae pneumonia is mainly based on careful supportive care. Despite the absence of randomized clinical trials in patients with poxviridae pneumonia there are antiviral drugs, such as tecovirimat, cidofovir and brincidofovir, FDA-approved for use in smallpox and also available under an expanded access protocol for treatment of MPXV. There are 2 (replication-deficient modified vaccinia Ankara and replication-competent vaccinia virus) smallpox vaccines FDA-approved with the first one also approved for prevention of MPXV in adults that are at high risk of infection., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Chronic obstructive pulmonary disease (COPD) represents an independent risk factor for lung cancer development. Accelerated cell senescence, induced by oxidative stress and inflammation, is a common pathogenic determinant of both COPD and lung cancer. The post transcriptional regulation of genes involved in these processes is finely regulated by RNA-binding proteins (RBPs), which regulate mRNA turnover, subcellular localization, splicing and translation. Multiple pro-inflammatory mediators (including cytokines, chemokines, proteins, growth factors and others), responsible of lung microenvironment alteration, are regulated by RBPs. Several mouse models have shown the implication of RBPs in multiple mechanisms that sustain chronic inflammation and neoplastic transformation. However, further studies are required to clarify the role of RBPs in the pathogenic mechanisms shared by lung cancer and COPD, in order to identify novel biomarkers and therapeutic targets. This review will therefore focus on the studies collectively indicating the role of RBPs in oxidative stress and chronic inflammation as common pathogenic mechanisms shared by lung cancer and COPD.

Toll-like receptor 7 (TLR7) is known for eliciting immunity against single-stranded RNA viruses, and is increased in both human and cigarette smoke (CS)-induced, experimental chronic obstructive pulmonary disease (COPD). Here we show that the severity of CS-induced emphysema and COPD is reduced in TLR7-deficient mice, while inhalation of imiquimod, a TLR7-agonist, induces emphysema without CS exposure. This imiquimod-induced emphysema is reduced in mice deficient in mast cell protease-6, or when wild-type mice are treated with the mast cell stabilizer, cromolyn. Furthermore, therapeutic treatment with anti-TLR7 monoclonal antibody suppresses CS-induced emphysema, experimental COPD and accumulation of pulmonary mast cells in mice. Lastly, TLR7 mRNA is increased in pre-existing datasets from patients with COPD, while TLR7 + mast cells are increased in COPD lungs and associated with severity of COPD. Our results thus support roles for TLR7 in mediating emphysema and COPD through mast cell activity, and may implicate TLR7 as a potential therapeutic target., (© 2023. Crown.)

Primary lung carcinoma or lung cancer (LC) is classified into small-cell or non-small-cell (NSCLC) lung carcinoma. Lung squamous cell carcinoma (LSCC) is the second most common subtype of NSCLC responsible for 30% of all LCs, and its survival remains low with only 24% of patients living for five years or longer post-diagnosis primarily due to the advanced stage of tumors at the time of diagnosis. The pathogenesis of LSCC is still poorly understood and has hampered the development of effective diagnostics and therapies. This review highlights the known risk factors, genetic and epigenetic alterations, miRNA biomarkers linked to the development and diagnosis of LSCC and the lack of therapeutic strategies to target specifically LSCC. We will also discuss existing animal models of LSCC including carcinogen induced, transgenic and xenograft mouse models, and their advantages and limitations along with the chemopreventive studies and molecular studies conducted using them. The importance of developing new and improved mouse models will also be discussed that will provide further insights into the initiation and progression of LSCC, and enable the identification of new biomarkers and therapeutic targets., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sahu, Donovan, Paudel, Pickles, Chimankar, Kim, Horvart, Dua, Ieni, Nucera, Bielefeldt-Ohmann, Mazilli, Caramori, Lyons and Hansbro.)

Background: Pulmonary arterial hypertension (PAH) encompasses a group of diseases characterized by raised pulmonary vascular resistance, resulting from vascular remodelling and inflammation. Bromodomain and extra-terminal (BET) proteins are required for the expression of a subset of NF-κB-induced inflammatory genes which can be inhibited by the BET mimic JQ1+. We hypothesised that JQ+ would supress TNFα-driven inflammatory responses in human pulmonary vascular cells from PAH patients., Methods: Immunohistochemical staining of human peripheral lung tissue (N = 14 PAH and N = 12 non-PAH) was performed for the BET proteins BRD2 and 4. Human pulmonary microvascular endothelial cells (HPMEC) and pulmonary artery smooth muscle cells (HPASMC) from PAH patients (N = 4) and non-PAH controls (N = 4) were stimulated with TNFα in presence or absence of JQ1+ or its inactive isomer JQ1-. IL-6 and -8 mRNA was measured by RT-qPCR and protein levels by ELISA. Chromatin immunoprecipitation analysis was performed using EZ-ChIP™ and NF-κB p65 activation determined using a TransAm kit. MTT assay was used to measure cell viability., Results: Nuclear staining of BRD2 and BRD4 was significantly (p < 0.0001) increased in the lung vascular endothelial and smooth muscle cells from PAH patients compared to controls with normal lung function. TNFα-driven IL-6 release from both HPMECs and HPASMCs was greater in PAH cells than control cells. Levels of CXCL8/IL-8 protein release was higher in PAH HPASMCs than in control cells with similar release observed in HPMECs. TNFα-induced recruitment of activated NF-κB p65 to the IL-6 and CXCL8/IL-8 promoters were similar in both cell types and between subject groups. JQ1+ suppressed TNFα-induced IL-6 and CXCL8/IL-8 release and mRNA expression to a comparable extent in control and PAH HPMECs and HPASMCs. JQ1 had a greater efficacy on IL-6 release in HPMEC and on CXCL8/IL-8 release in HPASMC., Conclusion: BET inhibition decreases TNFα driven inflammation in primary pulmonary vascular cells. The anti-inflammatory actions of JQ1 suggests distinct cell-specific regulatory control of these genes. BET proteins could be a target for future therapies for PAH., (© 2023. The Author(s).)

Background Empiric antimicrobial therapy with azithromycin is highly used in patients admitted to the hospital with COVID-19, despite prior research suggesting that azithromycin may be associated with increased risk of cardiovascular events. Methods and Results This study was conducted using data from the ISACS-COVID-19 (International Survey of Acute Coronavirus Syndromes-COVID-19) registry. Patients with a confirmed diagnosis of SARS-CoV-2 infection were eligible for inclusion. The study included 793 patients exposed to azithromycin within 24 hours from hospital admission and 2141 patients who received only standard care. The primary exposure was cardiovascular disease (CVD). Main outcome measures were 30-day mortality and acute heart failure (AHF). Among 2934 patients, 1066 (36.4%) had preexisting CVD. A total of 617 (21.0%) died, and 253 (8.6%) had AHF. Azithromycin therapy was consistently associated with an increased risk of AHF in patients with preexisting CVD (risk ratio [RR], 1.48 [95% CI, 1.06-2.06]). Receiving azithromycin versus standard care was not significantly associated with death (RR, 0.94 [95% CI, 0.69-1.28]). By contrast, we found significantly reduced odds of death (RR, 0.57 [95% CI, 0.42-0.79]) and no significant increase in AHF (RR, 1.23 [95% CI, 0.75-2.04]) in patients without prior CVD. The relative risks of death from the 2 subgroups were significantly different from each other ( P interaction =0.01). Statistically significant association was observed between AHF and death (odds ratio, 2.28 [95% CI, 1.34-3.90]). Conclusions These findings suggest that azithromycin use in patients with COVID-19 and prior history of CVD is significantly associated with an increased risk of AHF and all-cause 30-day mortality. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT05188612.

Introduction: The RNA-binding protein AU-rich-element factor-1 (AUF-1) participates to posttranscriptional regulation of genes involved in inflammation and cellular senescence, two pathogenic mechanisms of chronic obstructive pulmonary disease (COPD). Decreased AUF-1 expression was described in bronchiolar epithelium of COPD patients versus controls and in vitro cytokine- and cigarette smoke-challenged human airway epithelial cells, prompting the identification of epithelial AUF-1-targeted transcripts and function, and investigation on the mechanism of its loss., Results: RNA immunoprecipitation-sequencing (RIP-Seq) identified, in the human airway epithelial cell line BEAS-2B, 494 AUF-1-bound mRNAs enriched in their 3'-untranslated regions for a Guanine-Cytosine (GC)-rich binding motif. AUF-1 association with selected transcripts and with a synthetic GC-rich motif were validated by biotin pulldown. AUF-1-targets' steady-state levels were equally affected by partial or near-total AUF-1 loss induced by cytomix (TNFα/IL1β/IFNγ/10 nM each) and siRNA, respectively, with differential transcript decay rates. Cytomix-mediated decrease in AUF-1 levels in BEAS-2B and primary human small-airways epithelium (HSAEC) was replicated by treatment with the senescence- inducer compound etoposide and associated with readouts of cell-cycle arrest, increase in lysosomal damage and senescence-associated secretory phenotype (SASP) factors, and with AUF-1 transfer in extracellular vesicles, detected by transmission electron microscopy and immunoblotting. Extensive in-silico and genome ontology analysis found, consistent with AUF-1 functions, enriched RIP-Seq-derived AUF-1-targets in COPD-related pathways involved in inflammation, senescence, gene regulation and also in the public SASP proteome atlas; AUF-1 target signature was also significantly represented in multiple transcriptomic COPD databases generated from primary HSAEC, from lung tissue and from single-cell RNA-sequencing, displaying a predominant downregulation of expression., Discussion: Loss of intracellular AUF-1 may alter posttranscriptional regulation of targets particularly relevant for protection of genomic integrity and gene regulation, thus concurring to airway epithelial inflammatory responses related to oxidative stress and accelerated aging. Exosomal-associated AUF-1 may in turn preserve bound RNA targets and sustain their function, participating to spreading of inflammation and senescence to neighbouring cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Salvato, Ricciardi, Dal Col, Nigro, Giurato, Memoli, Sellitto, Lamparelli, Crescenzi, Vitale, Vatrella, Nucera, Brun, Caicci, Dama, Stiff, Castellano, Idrees, Johansen, Faiz, Wark, Hansbro, Adcock, Caramori and Stellato.)

Aims: Previous analyses on sex differences in case fatality rates at population-level data had limited adjustment for key patient clinical characteristics thought to be associated with coronavirus disease 2019 (COVID-19) outcomes. We aimed to estimate the risk of specific organ dysfunctions and mortality in women and men., Methods and Results: This retrospective cross-sectional study included 17 hospitals within 5 European countries participating in the International Survey of Acute Coronavirus Syndromes COVID-19 (NCT05188612). Participants were individuals hospitalized with positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from March 2020 to February 2022. Risk-adjusted ratios (RRs) of in-hospital mortality, acute respiratory failure (ARF), acute heart failure (AHF), and acute kidney injury (AKI) were calculated for women vs. men. Estimates were evaluated by inverse probability weighting and logistic regression models. The overall care cohort included 4499 patients with COVID-19-associated hospitalizations. Of these, 1524 (33.9%) were admitted to intensive care unit (ICU), and 1117 (24.8%) died during hospitalization. Compared with men, women were less likely to be admitted to ICU [RR: 0.80; 95% confidence interval (CI): 0.71-0.91]. In general wards (GWs) and ICU cohorts, the adjusted women-to-men RRs for in-hospital mortality were of 1.13 (95% CI: 0.90-1.42) and 0.86 (95% CI: 0.70-1.05; pinteraction = 0.04). Development of AHF, AKI, and ARF was associated with increased mortality risk (odds ratios: 2.27, 95% CI: 1.73-2.98; 3.85, 95% CI: 3.21-4.63; and 3.95, 95% CI: 3.04-5.14, respectively). The adjusted RRs for AKI and ARF were comparable among women and men regardless of intensity of care. In contrast, female sex was associated with higher odds for AHF in GW, but not in ICU (RRs: 1.25; 95% CI: 0.94-1.67 vs. 0.83; 95% CI: 0.59-1.16, pinteraction = 0.04)., Conclusions: Women in GW were at increased risk of AHF and in-hospital mortality for COVID-19 compared with men. For patients receiving ICU care, fatal complications including AHF and mortality appeared to be independent of sex. Equitable access to COVID-19 ICU care is needed to minimize the unfavourable outcome of women presenting with COVID-19-related complications., Competing Interests: Conflicts of interests: The authors declare that they have no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection can be asymptomatic or cause a disease (COVID-19) characterized by different levels of severity. The main cause of severe COVID-19 and death is represented by acute (or acute on chronic) respiratory failure and acute respiratory distress syndrome (ARDS), often requiring hospital admission and ventilator support.The molecular pathogenesis of COVID-19-related ARDS (by now termed c-ARDS) is still poorly understood. In this review we will discuss the genetic susceptibility to COVID-19, the pathogenesis and the local and systemic biomarkers correlated with c-ARDS and the therapeutic options that target the cell signalling pathways of c-ARDS., (© 2023. The Author(s).)

Background: COPD is the third leading cause of death worldwide. Cigarette smoke (CS)-induced chronic inflammation inducing airway remodelling, emphysema and impaired lung function is the primary cause. Effective therapies are urgently needed. Human chymase (hCMA)1 and its orthologue mCMA1/mouse mast cell protease (mMCP)5 are exocytosed from activated mast cells and have adverse roles in numerous disorders, but their role in COPD is unknown., Methods: We evaluated hCMA1 levels in lung tissues of COPD patients. We used mmcp5 -deficient ( -/- ) mice to evaluate this protease's role and potential for therapeutic targeting in CS-induced experimental COPD. In addition, we used ex vivo/in vitro studies to define mechanisms., Results: The levels of hCMA1 mRNA and CMA1 + mast cells were increased in lung tissues from severe compared to early/mild COPD patients, non-COPD smokers and healthy controls. Degranulated mast cell numbers and mMCP5 protein were increased in lung tissues of wild-type mice with experimental COPD. mmcp5 -/- mice were protected against CS-induced inflammation and macrophage accumulation, airway remodelling, emphysema and impaired lung function in experimental COPD. CS extract challenge of co-cultures of mast cells from wild-type, but not mmcp5 -/- mice with wild-type lung macrophages increased in tumour necrosis factor (TNF)-α release. It also caused the release of CMA1 from human mast cells, and recombinant hCMA-1 induced TNF-α release from human macrophages. Treatment with CMA1 inhibitor potently suppressed these hallmark features of experimental COPD., Conclusion: CMA1/mMCP5 promotes the pathogenesis of COPD, in part, by inducing TNF-α expression and release from lung macrophages. Inhibiting hCMA1 may be a novel treatment for COPD., Competing Interests: Conflict of interest: M. Fricker reports grants from GlaxoSmithKline, outside the submitted work. P.M. Hansbro reports grants from National Health and Medical Research Council, grants from Australian Research Council, during the conduct of the study. The remaining authors disclose no potential conflicts of interest., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)

Proinflammatory monocytes play a preponderant role in the development of a cytokine storm causing fatal consequences in coronavirus disease 2019 (COVID-19) patients, highlighting the importance of analyzing in more detail monocyte distribution in these patients. In this study, we identified an atypical monocyte subpopulation expressing CD56 molecules that showed a low level of HLA-DR and high level of l-selectin. They released higher amounts of TNF-α and IL-6 and expressed genes associated with an excessive inflammatory process. Remarkably, the frequency of CD56 + monocytes inversely correlated with that of CD16 + monocytes and a high CD56 + /CD16 + monocyte ratio was associated with both disease severity and mortality, as well as with serum concentration of type I IFN, a factor able to induce the appearance of CD56 + monocytes. In conclusion, severe COVID-19 is characterized by the abundance of hyperinflammatory CD56 + monocytes, which could represent a novel marker with prognostic significance and, possibly, a therapeutic target for controlling the inflammatory process occurring during COVID-19., (Copyright © 2022 by The American Association of Immunologists, Inc.)

Background: Identification of COPD patients with a rapid decline in FEV1 is of particular interest for prognostic and therapeutic reasons., Objective: To determine the expression of markers of inflammation in COPD patients with rapid functional decline in comparison to slow or no decliners., Methods: In COPD patients monitored for at least 3 years (mean ± SD: 5.8 ± 3 years) for lung functional decline, the expression and localization of inflammatory markers was measured in bronchial biopsies of patients with no lung functional decline (FEV1% + 30 ± 43 ml/year, n = 21), slow (FEV1% ml/year, - 40 ± 19, n = 14) and rapid decline (FEV1% ml/year, - 112 ± 53, n = 15) using immunohistochemistry. ELISA test was used for polymeric immunoglobulin receptor (pIgR) quantitation "in vitro"., Results: The expression of secretory IgA was significantly reduced in bronchial epithelium (p = 0.011) and plasma cell numbers was significantly reduced in the bronchial lamina propria (p = 0.017) of rapid decliners compared to no decliners. Bronchial inflammatory cell infiltration, CD4, CD8, CD68, CD20, NK, neutrophils, eosinophils, mast cells, pIgR, was not changed in epithelium and lamina propria of rapid decliners compared to other groups. Plasma cells/mm 2 correlated positively with scored total IgA in lamina propria of all patients. "In vitro" stimulation of 16HBE cells with LPS (10 μg/ml) and IL-8 (10 ng/ml) induced a significant increase while H 2 O 2 (100 μM) significantly decreased pIgR epithelial expression., Conclusion: These data show an impaired humoral immune response in rapid decliners with COPD, marked by reduced epithelial secretory IgA and plasma cell numbers in the bronchial lamina propria. These findings may help in the prognostic stratification and treatment of COPD., (© 2022. The Author(s).)

The characteristic features of chronic obstructive pulmonary disease (COPD) include inflammation and remodeling of the lower airways and lung parenchyma together with activation of inflammatory and immune processes. Due to the increasing habit of cigarette smoking worldwide COPD prevalence is increasing globally. Current therapies are unable to prevent COPD progression in many patients or target many of its hallmark characteristics which may reflect the lack of adequate biomarkers to detect the heterogeneous clinical and molecular nature of COPD. In this chapter we review recent molecular data that may indicate novel pathways that underpin COPD subphenotypes and indicate potential improvements in the classes of drugs currently used to treat COPD. We also highlight the evidence for new drugs or approaches to treat COPD identified using molecular and other approaches including kinase inhibitors, cytokine- and chemokine-directed biologicals and small molecules, anti-oxidants and redox signaling pathway inhibitors, inhaled anti-infectious agents and senolytics. It is important to consider the phenotypes/molecular endotypes of COPD patients together with specific outcome measures to target new therapies to particular COPD subtypes. This will require greater understanding of COPD molecular pathologies and a focus on biomarkers of predicting disease subsets and responder/non-responder populations.

Chronic inhalation of cigarette smoke is a prominent cause of chronic obstructive pulmonary disease (COPD) and provides an important source of exogenous oxidants. In addition, several inflammatory and structural cells are a source of endogenous oxidants in the lower airways of COPD patients, even in former smokers. This suggests that oxidants play a key role in the pathogenesis of COPD. This oxidative stress is counterbalanced by the protective effects of the various endogenous antioxidant defenses of the lower airways. A large amount of data from animal models and patients with COPD have shown that both the stable phase of the disease, and during exacerbations, have increased oxidative stress in the lower airways compared with age-matched smokers with normal lung function. Thus, counteracting the increased oxidative stress may produce clinical benefits in COPD patients. Smoking cessation is currently the most effective treatment of COPD patients and reduces oxidative stress in the lower airways. In addition, many drugs used to treat COPD have some antioxidant effects, however, it is still unclear if their clinical efficacy is related to pharmacological modulation of the oxidant/antioxidant balance. Several new antioxidant compounds are in development for the treatment of COPD.

Inhaled glucocorticoids (GCs) are drugs widely used as treatment for asthma patients. They prevent the recruitment and activation of lung immune and inflammatory cells and, moreover, have profound effects on airway structural cells to reverse the effects of disease on airway inflammation. GCs bind to a specific receptor, the glucocorticoid receptor (GR), which is a member of the nuclear receptor superfamily and modulates pro- and anti-inflammatory gene transcription through a number of distinct and complementary mechanisms. Targets genes include many pro-inflammatory mediators such as chemokines, cytokines, growth factors and their receptors. Inhaled GCs are very effective for most asthma patients with little, if any, systemic side effects depending upon the dose. However, some patients show poor asthma control even after the administration of high doses of topical or even systemic GCs. Several mechanisms relating to inflammation have been considered to be responsible for the onset of the relative GC resistance observed in these patients. In these patients, the side-effect profile of GCs prevent continued use of high doses and new drugs are needed. Targeting the defective pathways associated with GC function in these patients may also reactivate GC responsiveness., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

There is no justification for a therapeutic nihilism in clinical practice because current management (pharmacological and non-pharmacological) of the patients with chronic obstructive pulmonary disease according to treatable traits is effective in decreasing their respiratory symptoms, increasing their exercise tolerance and capacity, improving their quality of life, preventing (and treating) many of their exacerbations and decreasing their mortality.

In chronic obstructive pulmonary disease (COPD) patients, bacterial and viral infections play a relevant role in worsening lung function and, therefore, favour disease progression. The inflammatory response to lung infections may become a specific indication of the bacterial and viral infections. We here review data on the bacterial-viral infections and related airways and lung parenchyma inflammation in stable and exacerbated COPD, focussing our attention on the prevalent molecular pathways in these different clinical conditions. The roles of macrophages, autophagy and NETosis are also briefly discussed in the context of lung infections in COPD. Controlling their combined response may restore a balanced lung homeostasis, reducing the risk of lung function decline. KEY MESSAGE Bacteria and viruses can influence the responses of the innate and adaptive immune system in the lung of chronic obstructive pulmonary disease (COPD) patients. The relationship between viruses and bacterial colonization, and the consequences of the imbalance of these components can modulate the inflammatory state of the COPD lung. The complex actions involving immune trigger cells, which activate innate and cell-mediated inflammatory responses, could be responsible for the clinical consequences of irreversible airflow limitation, lung remodelling and emphysema in COPD patients.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of morbidity and death worldwide. Inhalation of cigarette smoke (CS) is the major cause in developed countries. Current therapies have limited efficacy in controlling disease or halting its progression. Aberrant expression of microRNAs (miRNAs) is associated with lung disease, including COPD. We performed miRNA microarray analyses of the lungs of mice with CS-induced experimental COPD. miR-21 was the second highest up-regulated miRNA, particularly in airway epithelium and lung macrophages. Its expression in human lung tissue correlated with reduced lung function in COPD. Prophylactic and therapeutic treatment with a specific miR-21 inhibitor (Ant-21) inhibited CS-induced lung miR-21 expression in mice; suppressed airway macrophages, neutrophils, and lymphocytes; and improved lung function, as evidenced by decreased lung hysteresis, transpulmonary resistance, and tissue damping in mouse models of COPD. In silico analyses identified a potential miR-21/special AT-rich sequence–binding protein 1 (SATB1)/S100 calcium binding protein A9 (S100A9)/nuclear factor κB (NF-κB) axis, which was further investigated. CS exposure reduced lung SATB1 in a mouse model of COPD, whereas Ant-21 treatment restored SATB1 and reduced S100A9 expression and NF-κB activity. The beneficial effects of Ant-21 in mice were reversed by treatment with SATB1-targeting small interfering RNA. We have identified a pathogenic role for a miR-21/SATB1/S100A9/NF-κB axis in COPD and defined miR-21 as a therapeutic target for this disease.

Background: The global prevalence of chronic obstructive pulmonary disease (COPD) has increased markedly in recent decades. Given the scarcity of resources available to address global health challenges and respiratory medicine being relatively under-invested in, it is important to define research priorities for COPD globally. In this paper, we aim to identify a ranked set of COPD research priorities that need to be addressed in the next 10 years to substantially reduce the global impact of COPD., Methods: We adapted the Child Health and Nutrition Research Initiative (CHNRI) methodology to identify global COPD research priorities., Results: 62 experts contributed 230 research ideas, which were scored by 34 researchers according to six pre-defined criteria: answerability, effectiveness, feasibility, deliverability, burden reduction, and equity. The top-ranked research priority was the need for new effective strategies to support smoking cessation. Of the top 20 overall research priorities, six were focused on feasible and cost-effective pulmonary rehabilitation delivery and access, particularly in primary/community care and low-resource settings. Three of the top 10 overall priorities called for research on improved screening and accurate diagnostic methods for COPD in low-resource primary care settings. Further ideas that drew support involved a better understanding of risk factors for COPD, development of effective training programmes for health workers and physicians in low resource settings, and evaluation of novel interventions to encourage physical activity., Conclusions: The experts agreed that the most pressing feasible research questions to address in the next decade for COPD reduction were on prevention, diagnosis and rehabilitation of COPD, especially in low resource settings. The largest gains should be expected in low- and middle-income countries (LMIC) settings, as the large majority of COPD deaths occur in those settings. Research priorities identified by this systematic international process should inform and motivate policymakers, funders, and researchers to support and conduct research to reduce the global burden of COPD., Competing Interests: Competing interests: The authors completed the ICMJE Unified Competing Interest form (available upon request from the corresponding author), and declare no conflicts of interest. Igor Rudan and Harry Campbell are the Co-Editor in Chief of the Journal of Global Health. To ensure that any possible conflict of interest relevant to the journal has been addressed, this article was reviewed according to best practice guidelines of international editorial organisations., (Copyright © 2021 by the Journal of Global Health. All rights reserved.)

Glucocorticoids are anti-inflammatory drugs used in combination with inhaled bronchodilators, such as β2-agonists and antimuscarinics, for the treatment of stable chronic obstructive pulmonary disease (COPD), to improve respiratory symptoms, such as exertional dyspnoea, and to decrease the risk of future COPD exacerbations. However, it remains controversial whether their regular long-term use increases the risk of developing diabetes mellitus. The objective of this narrative review is therefore to analyse all the randomized controlled trials performed in patients with stable COPD to identify the risk of new onset diabetes mellitus during a long-term (at least 52 weeks) regular treatment with inhaled glucocorticoids alone compared to placebo. From a literature search on PubMed, 19 studies fulfilling these criteria have been identified. The inhaled glucocorticoids administered were: fluticasone propionate (7 studies), budesonide (6 studies), mometasone furoate (3 studies), beclomethasone dipropionate (1 study), triamcinolone acetonide (1 study), and fluticasone furoate (1 study) respectively. Only 3 out of the 19 trials identified in our narrative review reported data on diabetes mellitus, and in these the incidence of diabetes mellitus was not significantly different in both treatment arms (inhaled glucocorticoids and placebo), regardless of the type of glucocorticoid used.

The interplay of type-2 inflammation and antiviral immunity underpins asthma exacerbation pathogenesis. Virus infection induces type-2 inflammation-promoting chemokines CCL17 and CCL22 in asthma; however, mechanisms regulating induction are poorly understood. By using a human rhinovirus (RV) challenge model in human airway epithelial cells in vitro and mice in vivo, we assessed mechanisms regulating CCL17 and CCL22 expression. Subjects with mild to moderate asthma and healthy volunteers were experimentally infected with RV and airway CCL17 and CCL22 protein quantified. In vitro airway epithelial cell- and mouse-RV infection models were then used to define STAT6- and NF-κB-mediated regulation of CCL17 and CCL22 expression. Following RV infection, CCL17 and CCL22 expression was higher in asthma, which differentially correlated with clinical and immunological parameters. Air-liquid interface-differentiated primary epithelial cells from donors with asthma also expressed higher levels of RV-induced CCL22. RV infection boosted type-2 cytokine-induced STAT6 activation. In epithelial cells, type-2 cytokines and STAT6 activation had differential effects on chemokine expression, increasing CCL17 and suppressing CCL22, whereas NF-κB promoted expression of both chemokines. In mice, RV infection activated pulmonary STAT6, which was required for CCL17 but not CCL22 expression. STAT6-knockout mice infected with RV expressed increased levels of NF-κB-regulated chemokines, which was associated with rapid viral clearance. Therefore, RV-induced upregulation of CCL17 and CCL22 was mediated by NF-κB activation, whereas expression was differentially regulated by STAT6. Together, these findings suggest that therapeutic targeting of type-2 STAT6 activation alone will not block all inflammatory pathways during RV infection in asthma.

Disproportionate systemic inflammation in chronic obstructive pulmonary disease (COPD) is associated with declining lung functions and comorbidities. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have emerged as valuable markers of the systemic inflammation in COPD. Adiponectin (Acpr30) circulates in serum as complexes of different molecular weight (HMW, MMW, LMW) with multifaceted metabolic and anti-inflammatory properties implicated in airway pathophysiology. We aimed to investigate the association between Acpr30 and its oligomers and the NLR and PLR in COPD patients. Seventy stable COPD patients were enrolled. Acrp30 serum levels and the HMW oligomers as well as hematological parameters and their ratio were evaluated. Both NLR and PLR are associated with lower BMI. Interestingly, total Acpr30 is negatively associated with NLR but not with PLR; after adjusting for age, BMI and FEV1, Acpr30 was independently associated with NLR. Conversely, HMW Acpr30 and HMW/Acpr30 ratio were positively correlated to NLR. The association of Acpr30, HMW Acpr30 and HMW/totalAcpr30 ratio with NLR but not with PLR in COPD patients indicates that Acrp30 oligomerization could represent a biological mechanism interfering with systemic inflammation in COPD. Further studies in larger cohorts of patients are required to confirm these results.

Chronic obstructive pulmonary disease (COPD) represents a heightened inflammatory response in the lung generally resulting from tobacco smoking-induced recruitment and activation of inflammatory cells and/or activation of lower airway structural cells. Several mediators can modulate activation and recruitment of these cells, particularly those belonging to the chemokines (conventional and atypical) family. There is emerging evidence for complex roles of atypical chemokines and their receptors (such as high mobility group box 1 (HMGB1), antimicrobial peptides, receptor for advanced glycosylation end products (RAGE) or toll-like receptors (TLRs)) in the pathogenesis of COPD, both in the stable disease and during exacerbations. Modulators of these pathways represent potential novel therapies for COPD and many are now in preclinical development. Inhibition of only a single atypical chemokine or receptor may not block inflammatory processes because there is redundancy in this network. However, there are many animal studies that encourage studies for modulating the atypical chemokine network in COPD. Thus, few pharmaceutical companies maintain a significant interest in developing agents that target these molecules as potential antiinflammatory drugs. Antibody-based (biological) and small molecule drug (SMD)-based therapies targeting atypical chemokines and/or their receptors are mostly at the preclinical stage and their progression to clinical trials is eagerly awaited. These agents will most likely enhance our knowledge about the role of atypical chemokines in COPD pathophysiology and thereby improve COPD management., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Therapeutic advances using targeted biologicals and small-molecule drugs have achieved significant success in the treatment of chronic allergic, autoimmune, and inflammatory diseases particularly for some patients with severe, treatment-resistant forms. This has been aided by improved identification of disease phenotypes. Despite these achievements, not all severe forms of chronic inflammatory and autoimmune diseases are successfully targeted, and current treatment options, besides allergen immunotherapy for selected allergic diseases, fail to change the disease course. T cell-based therapies aim to cure diseases through the selective induction of appropriate immune responses following the delivery of engineered, specific cytotoxic, or regulatory T cells (Tregs). Adoptive cell therapies (ACT) with genetically engineered T cells have revolutionized the oncology field, bringing curative treatment for leukemia and lymphoma, while therapies exploiting the suppressive functions of Tregs have been developed in nononcological settings, such as in transplantation and autoimmune diseases. ACT with Tregs are also being considered in nononcological settings such as cardiovascular disease, obesity, and chronic inflammatory disorders. After describing the general features of T cell-based approaches and current applications in autoimmune diseases, this position paper reviews the experimental models testing or supporting T cell-based approaches, especially Treg-based approaches, in severe IgE-mediated responses and chronic respiratory airway diseases, such as severe asthma and COPD. Along with an assessment of challenges and unmet needs facing the application of ACT in these settings, this article underscores the potential of ACT to offer curative options for patients with severe or treatment-resistant forms of these immune-driven disorders., (© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Introduction: Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by chronic bronchitis, emphysema, and remodeling. Its prevalence is increasing worldwide; however, there are few effective therapies, and none of the treatments currently available prevent the progression of the disease or target all of the hallmark features. The development and progression of COPD are heterogeneous, which has hampered the development of new therapies., Areas Covered: In this review, we cover the emergence of the improvement of existing classes of drugs including glucocorticoids, β2-adrenoceptor agonists, phosphodiesterase inhibitors, PDE4 selective inhibitors, PDE3/PDE4 inhibitors, protease inhibitors, recombinant α1-antitrypsin and neutrophil elastase inhibitors. We also highlight new compounds that target recently identified mechanisms of COPD, new dual-action muscarinic antagonists, and β2-agonists, kinase inhibitors, cytokine modifiers, chemokines modifiers, NF-κB inhibitors, senolytics, antioxidants, inhaled antiviral agents, anti-fibrotic compounds, and compounds stimulating lung regeneration., Expert Opinion: Given the myriad of potential therapeutic avenues that can be pursued, careful consideration of the phenotypes/endotypes of COPD patients will be important for personalized treatment options in the future, and a full understanding of disease mechanisms in patient subsets will ensure these emerging therapies are targeted appropriately.

Introduction: Cigarette smoking and oxidative stress are common risk factors for the multi-morbidities associated with chronic obstructive pulmonary disease (COPD). Elevated levels of advanced glycation endproducts (AGE) increase the risk of cardiovascular disease (CVD) comorbidity and mortality. The enzyme fructosamine-3-kinase (FN3K) reduces this risk by lowering AGE levels., Methods: The distribution and expression of FN3K protein in lung tissues from stable COPD and control subjects, as well as an animal model of COPD, was assessed by immunohistochemistry. Serum FN3K protein and AGE levels were assessed by ELISA in patients with COPD exacerbations receiving metformin. Genetic variants within the FN3K and FN3K-RP genes were evaluated for associations with cardiorespiratory function in the Subpopulations and Intermediate Outcome Measures in COPD Study cohort., Results: This pilot study demonstrates that FN3K expression in the blood and human lung epithelium is distributed at either high or low levels irrespective of disease status. The percentage of lung epithelial cells expressing FN3K was higher in control smokers with normal lung function, but this induction was not observed in COPD patients nor in a smoking model of COPD. The top five nominal FN3K polymorphisms with possible association to decreased cardiorespiratory function (p<0.008-0.02), all failed to reach the threshold (p<0.0028) to be considered highly significant following multi-comparison analysis. Metformin enhanced systemic levels of FN3K in COPD subjects independent of their high-expression or low-expression status., Discussion: The data highlight that low and high FN3K expressors exist within our study cohort and metformin induces FN3K levels, highlighting a potential mechanism to reduce the risk of CVD comorbidity and mortality., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Posttranscriptional gene regulation (PTGR) contributes to inflammation through alterations in messenger RNA (mRNA) turnover and translation rates. RNA-binding proteins (RBPs) coordinate these processes but their role in lung inflammatory diseases is ill-defined. We evaluated the expression of a curated list of mRNA-binding RBPs (mRBPs) in selected Gene Expression Omnibus (GEO) transcriptomic databases of airway epithelium isolated from chronic obstructive pulmonary disease (COPD), severe asthma (SA) and matched control subjects, hypothesizing that global changes in mRBPs expression could be used to infer their pathogenetic roles and identify novel disease-related regulatory networks. Methods: A published list of 692 mRBPs [Nat Rev Genet 2014] was searched in GEO datasets originated from bronchial brushings of stable COPD patients (C), smokers (S), non-smokers (NS) controls with normal lung function ( n = 6/12/12) (GEO ID: GSE5058) and of (SA) and healthy control (HC) ( n = 6/12) (GSE63142). Fluorescence intensity data were extracted and normalized on the medians for fold change (FC) comparisons. FCs were set at ≥ |1.5| with a false discovery rate (FDR) of ≤ 0.05. Pearson correlation maps and heatmaps were generated using tMEV tools v4&#95;9&#95;0.45. DNA sequence motifs were searched using PScan-ChIP. Gene Ontology (GO) was performed with Ingenuity Pathway Analysis (IPA) tool. Results: Significant mRBP expression changes were detected for S/NS, COPD/NS and COPD/S ( n = 41, 391, 382, respectively). Of those, 32% of genes changed by FC ≥ |1.5| in S/NS but more than 60% in COPD/NS and COPD/S ( n = 13, 267, 257, respectively). Genes were predominantly downregulated in COPD/NS ( n = 194, 73%) and COPD/S ( n = 202, 79%), less so in S/NS ( n = 4, 31%). Unsupervised cluster analysis identified in 4 out of 12 S the same mRBP pattern seen in C, postulating subclinical COPD. Significant DNA motifs enrichment for transcriptional regulation was found for downregulated RBPs. Correlation analysis identified five clusters of co-expressed mRBPs. GO analysis revealed significant enrichments in canonical pathways both specific and shared among comparisons. Unexpectedly, no significant mRBPs modulation was found in SA compared to controls. Conclusions: Airway epithelial mRBPs profiling reveals a COPD-specific global downregulation of RBPs shared by a subset of control smokers, the potential of functional cooperation by coexpressed RBPs and significant impact on relevant pathogenetic pathways in COPD. Elucidation of PTGR in COPD could identify disease biomarkers or pathways for therapeutic targeting., (Copyright © 2020 Ricciardi, Giurato, Memoli, Pietrafesa, Dal Col, Salvato, Nigro, Vatrella, Caramori, Casolaro and Stellato.)

Recent advances in cancer immunotherapy have clearly shown that checkpoint-based immunotherapy is effective in a small subgroup of cancer patients. However, no effective predictive biomarker has been identified so far. The major histocompatibility complex, better known in humans as human leukocyte antigen (HLA), is a very polymorphic gene complex consisting of more than 200 genes. It has a crucial role in activating an appropriate host immune response against pathogens and tumor cells by discriminating self and non-self peptides. Several lines of evidence have shown that down-regulation of expression of HLA class I antigen derived peptide complexes by cancer cells is a mechanism of tumor immune escape and is often associated to poor prognosis in cancer patients. In addition, it has also been shown that HLA class I and II antigen expression, as well as defects in the antigen processing machinery complex, may predict tumor responses in cancer immunotherapy. Nevertheless, the role of HLA in predicting tumor responses to checkpoint-based immunotherapy is still debated. In this review, firstly, we will describe the structure and function of the HLA system. Secondly, we will summarize the HLA defects and their clinical significance in cancer patients. Thirdly, we will review the potential role of the HLA as a predictive biomarker for checkpoint-based immunotherapy in cancer patients. Lastly, we will discuss the potential strategies that may restore HLA function to implement novel therapeutic strategies in cancer patients., Competing Interests: The authors declare no conflict of interest.

The MUC5B promoter variant rs35705950 is associated with idiopathic pulmonary fibrosis (IPF). MUC5B glycoprotein is overexpressed in IPF lungs. We examined immunohistochemical expression of MUC5B in different interstitial lung disease patterns according to rs35705950 T-allele carriage. We observed increased expression of MUC5B in T-allele carriers in both distal airways and honeycomb cysts in patients with IPF (n=23), but no difference in MUC5B expression according to T-carrier status in the distal airways of patients with idiopathic non-specific interstitial pneumonitis (n=17), in scleroderma-associated non-specific interstitial pneumonitis (n=15) or in control lungs (n=20), suggesting that tissue overexpression in MUC5B rs35705950 T-carriers is specific to IPF., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: The aim of this study was to measure gender differences among COPD patients' quality of care (QOC) before and after two educational interventions in Southern Italy., Methods: In this prospective cohort study, COPD patients were identified from primary care electronic medical records (EMRs). Twelve process indicators concerning diagnosis, preventative measures and therapeutic processes were developed as a measure of QOC. Educational interventions consisted of clinical seminars and audits on COPD QOC at baseline, and at 12 and 24 months. QOC indicators were stratified by gender: odds ratios (ORs) (males as reference group) of having a good QOC indicator were calculated at baseline, 12 and 24 months, with 95% confidence intervals (CIs) using hierarchical generalised linear models., Results: Of 46 326 people registered in the EMRs, 1463 COPD patients (3.1%) were identified, of which 37% were women. QOC indicators reflecting best practice 24 months after the educational programme were generally not different to baseline, often favouring men. On the other hand, the composite global QOC indicator suggested that while a good overall QOC at baseline was significantly higher in men than women (OR: 0.74; 95% CI: 0.57-0.96), it became nonsignificant at 24 months (OR: 0.96; 95% CI: 0.72-1.29)., Conclusions: Specific QOC indicators among COPD patients often favoured men. However, several gender disparities seen at baseline disappeared at 24 months, suggesting that even general educational interventions which do not target gender can improve the gender disparity in QOC., Competing Interests: Conflict of interest: V. Isgrò has nothing to disclose. Conflict of interest: J. Sultana has nothing to disclose. Conflict of interest: A. Fontana has nothing to disclose. Conflict of interest: V. Ientile has nothing to disclose. Conflict of interest: U. Alecci has nothing to disclose. Conflict of interest: R. Scoglio has nothing to disclose. Conflict of interest: F. Magliozzo has nothing to disclose. Conflict of interest: S. Scondotto has nothing to disclose. Conflict of interest: G. Caramori has nothing to disclose. Conflict of interest: M. Cazzola reports participation in courses sponsored by Almirall, AstraZeneca, Biofutura, Boehringer Ingelheim, Chiesi Farmaceutici, Cipla, Edmond Pharma, GlaxoSmithKline, Lallemand, Menarini Group, Mundipharma, Novartis, Pfizer, Teva, Verona Pharma and Zambon; and consultancy for ABC Farmaceutici, AstraZeneca, Chiesi Farmaceutici, Edmond Pharma, Lallemand, Novartis, Ockham Biotech, Verona Pharma and Zambon, all outside the submitted work. Conflict of interest: G. Trifirò reports an unconditional grant from Novartis and a pharmacovigilance grant (Evaluating the appropriate use and safety of drugs used for chronic obstructive pulmonary disease in a Sicilian primary care setting) from the Italian Drug Agency/Sicilian Regional during the conduct of the study; participation on advisory boards for Sandoz, Hospira, Sanofi, Biogen, Ibsen and Shire, consultancy for Otsuka, acting as the principal investigator of studies funded by Amgen, AstraZeneca, Daiichi Sankyo and IBSA, and coordinator of a master's degree that received unconditional grants from several pharmaceutical companies, outside the submitted work., (Copyright ©ERS 2020.)

The global COVID-19 pandemic has led to a race to find medications that can improve the prognosis of the disease. Azithromycin, in association with hydroxychloroquine or chloroquine, has been proposed as one such medication. The aim of this review is to describe the pharmacological mechanism, clinical evidence and prescribing guidelines concerning azithromycin in COVID-19 patients. There is weak evidence on the antiviral and immunomodulating effects of azithromycin, which in addition is not based on results from COVID-19 patients specifically. Therefore, this antibacterial should be considered only as empirical treatment of community-acquired pneumonia (CAP), although not all current treatment guidelines are in agreement. After the initial expectations raised by a small trial, more recent evidence has raised serious safety concerns on the use of hydroxychloroquine or chloroquine with azithromycin to treat COVID-19 patients, as all these drugs have arrhythmogenic potential. The World Health Organization has not made recommendations suggesting the use of azithromycin with hydroxychloroquine or chloroquine as treatment for COVID-19, but some national organisations have taken a different position, recommending this as first-line treatment. Several scientific societies, including the American College of Cardiology, have cautioned about the risks of this treatment in view of the lack of evidence concerning its benefits.

Introduction: Late-Onset Pompe Disease (LOPD) is characterized by progressive limb-girdle muscle weakness and respiratory dysfunction. Diaphragm is the most impaired muscle in LOPD and its dysfunction cause major respiratory symptoms. The aim of this study was to evaluate the correlation between diaphragm thickness and mobility assessed by ultrasonography and respiratory function and muscle strength tests in patients with LOPD., Methods: 17 patients with LOPD (9 female, 47 ± 15 years) and 17 age and gender-matched healthy controls underwent spirometry, muscle strength testing, and ultrasound evaluation of diaphragm excursion and thickness., Results: The following parameters were significantly reduced in LOPD patients versus controls (all p < 0.001): forced vital capacity (FVC) in seated and supine position, maximum inspiratory and expiratory pressure (MIP and MEP), diaphragm excursion, thickness at functional residual capacity (FRC) and total lung capacity (TLC), and thickness fraction (TF). Ultrasound studies of diaphragm thickness at FRC correlated with MIP (r = 0.74; p < 0.0001) and seated FVC(r = 0.73; p < 0.05). Diaphragm thickness at TLC correlated with MIP (r = 0.85; p < 0.0001) and FVC in both seated (r = 0.77; p < 0.0001) and supine position (r = 0.68; p < 0.05). TF correlated significantly with MIP (r = 0.80; p < 0.001), FVC in both seated (r = 0.66; p < 0,005) and supine position (r = 0.61; p < 0.05). Interestingly diaphragm thickness at FRC correlated with disease duration (years) in LOPD patients (r = -0.53; p < 0,05). Ultrasound diaphragm mobility correlated with diaphragm thickness at TLC(r = 0.87; p < 0.0001), FRC (r = 0.84; p < 0.005) and TF (r = 0.73; p < 0.05). Moreover diaphragm mobility correlated with FVC in seated(r = 0.79; p < 0.005) and supine position(r = 0.74; p < 0.05) and MIP (r = 0.81; p < 0.005)., Conclusion: Diaphragm ultrasonography is a simple and reproducible technique for manage respiratory dysfunction in LOPD patients.

Severe asthma is an important topic in respiratory diseases, due to its high impact on morbidity and mortality as well as on health-care resources. The many challenges that still exist in the management of the most difficult-to-treat forms of the disease, and the acknowledgement of the existence of unexplored areas in the pathophysiological mechanisms and the therapeutic targets represent an opportunity to gather experts in the field with the immediate goals to summarize current understanding about the natural history of severe asthma and to identify gaps in knowledge and research opportunities, with the aim to contribute to improved medical care and health outcomes. This article is a consensus document from the "International Course on Severe Asthma" that took place in Palermo, Italy, on May 10-11, 2019. Emerging topics in severe asthma were addressed and discussed among experts, with special focus on patient's needs and research opportunities, with the aim to highlight the unanswered questions in the diagnostic process and therapeutic approach.

Diffuse alveolar hemorrhage (DAH) is an acute often life-threatening condition characterized by a variable combination of hemoptysis, dyspnoea, diffuse and bilateral ground glass pulmonary opacities, anemia and hypoxemia, that can be induced by different causes, including several drugs. We report here the case of a 25-year-old woman who has been admitted to our pulmonary clinic for the onset of chest pain, cough and haemoptysis, started one week after her first treatment with alemtuzumab for multiple sclerosis. Computed tomography (CT) scan of the chest at the admission showed diffuse and bilateral ground glass pulmonary opacities. Her symptoms resolved completely without any treatment, after the interruption of alemtuzumab, and CT scan of the chest performed one month later showed total disappearance of the pulmonary opacities.

Background: Little is known about the innate immune response to viral infections in stable Chronic Obstructive Pulmonary Disease (COPD). Objectives: To evaluate the innate immune mediators related to respiratory viruses in the bronchial biopsies and lung parenchyma of stable COPD patients. Methods: We evaluated the immunohistochemical (IHC) expression of Toll-like receptors 3-7-8-9 (TLR-3-7-8-9), TIR domain-containing adaptor inducing IFNβ (TRIF), Interferon regulatory factor 3 (IRF3), Phospho interferon regulatory factor 3&nbsp; ( pIRF3), Interferon regulatory factor 7 (IRF7), Phospho interferon regulatory factor 7 (pIRF7), retinoic acid-inducible gene I (RIG1), melanoma differentiation-associated protein 5 (MDA5), Probable ATP-dependent RNA helicase DHX58 ( LGP2), Mitochondrial antiviral-signaling protein (MAVS), Stimulator of interferon genes (STING), DNA-dependent activator of IFN regulatory factors (DAI), forkhead box protein A3(FOXA3), Interferon alfa (IFNα), and Interferon beta (IFNβ) in the bronchial mucosa of patients with mild/moderate ( n = 16), severe/very severe ( n = 18) stable COPD, control smokers (CS) ( n = 12), and control non-smokers (CNS) ( n = 12). We performed similar IHC analyses in peripheral lung from COPD ( n = 12) and CS ( n = 12). IFNα and IFNβ were assessed in bronchoalveolar lavage (BAL) supernatant from CNS ( n = 8), CS ( n = 9) and mild/moderate COPD ( n = 12). Viral load, including adenovirus-B, -C, Bocavirus, Respiratory syncytial Virus (RSV),Human Rhinovirus (HRV), Coronavirus, Influenza virus A (FLU-A), Influenza virus B (FLU-B), and Parainfluenzae-1 were measured in bronchial rings and lung parenchyma of COPD patients and the related control group (CS). Results: Among the viral-related innate immune mediators, RIG1, LGP2, MAVS, STING, and DAI resulted well expressed in the bronchial and lung tissues of COPD patients, although not in a significantly different mode from control groups. Compared to CS, COPD patients showed no significant differences of viral load in bronchial rings and lung parenchyma. Conclusions: Some virus-related molecules are well-expressed in the lung tissue and bronchi of stable COPD patients independently of the disease severity, suggesting a "primed" tissue environment capable of sensing the potential viral infections occurring in these patients.

Introduction : Evidence accumulated in the last decade has started to reveal the enormous complexity in the expression, interactions and functions of the large number of different mucins present in the different compartments of the human lower airways. This occurs both in normal subjects and in COPD patients in different clinical phases and stages of severity. Areas covered : We review the known physiological mechanisms that regulate mucin production in human lower airways of normal subjects, the changes in mucin synthesis/secretion in COPD patients and the clinical efficacy of drugs that modulate mucin synthesis/secretion. Expert opinion : It is evident that the old simplistic concept that mucus hypersecretion in COPD patients is associated with negative clinical outcomes is not valid and that the therapeutic potential of 'mucolytic drugs' is under-appreciated due to the complexity of the associated molecular network(s). Likewise, our current knowledge of the effects of the drugs already available on the market that target mucin synthesis/secretion/structure in the lower airways is extremely limited and often indirect and more well-controlled clinical trials are needed in this area.

Background: Airway inflammation may drive the progression of chronic obstructive pulmonary disease (COPD) associated with alpha-1 antitrypsin deficiency (AATD), but the relationship between airway microbiota and inflammation has not been investigated., Methods: We studied 21 non-treated AATD (AATD-noT) patients, 20 AATD-COPD patients under augmentation therapy (AATD-AT), 20 cigarette smoke-associated COPD patients, 20 control healthy smokers (CS) and 21 non-smokers (CON) with normal lung function. We quantified sputum inflammatory cells and inflammatory markers (IL-27, CCL3, CCL5, CXCL8, LTB 4 , MPO) by ELISA, total bacterial load (16S) and pathogenic bacteria by qRT-PCR., Results: AATD-AT patients were younger but had similar spirometric and DLCO values compared to cigarette smoke-associated COPD, despite a lower burden of smoking history. Compared to cigarette smoke-associated COPD, AATD-noT and AATD-AT patients had lower sputum neutrophil levels ( p =0.0446, p =0.0135), total bacterial load (16S) ( p =0.0081, p =0.0223), M. catarrhalis ( p =0.0115, p =0.0127) and S. pneumoniae ( p =0.0013, p =0.0001). Sputum IL-27 was significantly elevated in CS and cigarette smoke-associated COPD. AATD-AT, but not AATD-noT patients, had IL-27 sputum levels (pg/ml) significantly lower than COPD ( p =0.0297) and these positively correlated with FEV 1 % predicted values ( r =0.578, p =0.0307)., Conclusions: Compared to cigarette smoke-associated COPD, AATD-AT (COPD) patients have a distinct airway inflammatory and microbiological profile. The decreased sputum bacterial load and IL-27 levels in AATD-AT patients suggests that augmentation therapy play a role in these changes., Competing Interests: This study was funded by Istituti Clinici Scientifici Maugeri, IRCCS and by Grifols Inc. Grifols Inc. with a two-year grant. Grifols funding included laboratory supplies, travel expenses for collecting samples around the Country and a fellowship for a Ph.D. The authors report no other conflicts of interest in this work., (© 2019 Balbi et al.)

Chronic obstructive pulmonary disease (COPD) is the third leading cause of morbidity and death globally. The lack of effective treatments results from an incomplete understanding of the underlying mechanisms driving COPD pathogenesis.Interleukin (IL)-22 has been implicated in airway inflammation and is increased in COPD patients. However, its roles in the pathogenesis of COPD is poorly understood. Here, we investigated the role of IL-22 in human COPD and in cigarette smoke (CS)-induced experimental COPD.IL-22 and IL-22 receptor mRNA expression and protein levels were increased in COPD patients compared to healthy smoking or non-smoking controls. IL-22 and IL-22 receptor levels were increased in the lungs of mice with experimental COPD compared to controls and the cellular source of IL-22 included CD4 + T-helper cells, γδ T-cells, natural killer T-cells and group 3 innate lymphoid cells. CS-induced pulmonary neutrophils were reduced in IL-22-deficient ( Il22 -/- ) mice. CS-induced airway remodelling and emphysema-like alveolar enlargement did not occur in Il22 -/- mice. Il22 -/- mice had improved lung function in terms of airway resistance, total lung capacity, inspiratory capacity, forced vital capacity and compliance.These data highlight important roles for IL-22 and its receptors in human COPD and CS-induced experimental COPD., Competing Interests: Conflict of interest: M.R. Starkey has nothing to disclose. Conflict of interest: M.W. Plank is a full-time employee of GlaxoSmithKline. Conflict of interest: P. Casolari has nothing to disclose. Conflict of interest: A. Papi reports board membership, consultancy, payment for lectures, grants for research and travel expenses reimbursement from Chiesi, AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Mundipharma and TEVA, payment for lectures and travel expenses reimbursement from Menarini, Novartis, Zambon and Sanofi, outside the submitted work. Conflict of interest: S. Pavlidis has nothing to disclose. Conflict of interest: Y Guo has nothing to disclose. Conflict of interest: G.J.M. Cameron has nothing to disclose. Conflict of interest: T.J. Haw has nothing to disclose. Conflict of interest: A. Tam has nothing to disclose. Conflict of interest: M. Obeidat has nothing to disclose. Conflict of interest: C. Donovan has nothing to disclose. Conflict of interest: N.G. Hansbro has nothing to disclose. Conflict of interest: D.H. Nguyen has nothing to disclose. Conflict of interest: P.M. Nair has nothing to disclose. Conflict of interest: R.Y. Kim has nothing to disclose. Conflict of interest: J.C. Horvat has nothing to disclose. Conflict of interest: G.E. Kaiko has nothing to disclose. Conflict of interest: S.K. Durum has nothing to disclose. Conflict of interest: P.A. Wark has nothing to disclose. Conflict of interest: D.D. Sin reports grants from Merck, personal fees for advisory board work from Sanofi-Aventis and Regeneron, grants and personal fees from Boehringer Ingelheim, grants and personal fees for lecturing and advisory board work from AstraZeneca, personal fees for lecturing and advisory board work from Novartis, outside the submitted work. Conflict of interest: G. Caramori has nothing to disclose. Conflict of interest: I.M. Adcock has nothing to disclose. Conflict of interest: P.S. Foster has nothing to disclose. Conflict of interest: P.M. Hansbro reports funding/consultancies from Pharmaxis, AstraZeneca, Sanofi, Pharmakea, Ausbio, and Allakos outside the submitted work., (The content of this work is not subject to copyright. Design and branding are copyright ©ERS 2019.)

Inflammation is a central feature of asthma and chronic obstructive pulmonary disease (COPD). Despite recent advances in the knowledge of the pathogenesis of asthma and COPD, much more research on the molecular mechanisms of asthma and COPD are needed to aid the logical development of new therapies for these common and important diseases, particularly in COPD where no new effective treatments currently exist. In the future the role of the activation/repression of different transcription factors and the genetic regulation of their expression in asthma and COPD may be an increasingly important aspect of research, as this may be one of the critical mechanisms regulating the expression of different clinical phenotypes and their responsiveness to therapy, particularly to anti-inflammatory drugs., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: COPD and lung cancer are leading causes of morbidity and mortality worldwide, and they share a common environmental risk factor in cigarette smoke exposure and a genetic predisposition represented by their incidence in only a fraction of smokers. This reflects the ability of cigarette smoke to induce an inflammatory response in the airways of susceptible smokers. Moreover, COPD could be a driving factor in lung cancer, by increasing oxidative stress and the resulting DNA damage and repression of the DNA repair mechanisms, chronic exposure to pro-inflammatory cytokines, repression of innate immunity and increased cellular proliferation. Areas covered: We have focused our review on the potential pathogenic molecular links between tobacco smoking-related COPD and lung cancer and the potential molecular targets for new drug development by understanding the common signaling pathways involved in COPD and lung cancer. Expert commentary: Research in this field is mostly limited to animal models or small clinical trials. Large clinical trials are needed but mostly combined models of COPD and lung cancer are necessary to investigate the processes caused by chronic inflammation, including genetic and epigenetic alteration, and the expression of inflammatory mediators that link COPD and lung cancer, to identify new molecular therapeutic targets.

Patients with chronic obstructive pulmonary disease (COPD) demonstrate a greater osteoporosis prevalence than the general population. This osteoporosis risk may be enhanced by treatment with inhaled corticosteroids (ICSs), which are recommended for COPD management when combined with long-acting bronchodilators, but may also be associated with reduced bone mineral density (BMD). We conducted a narrative literature review reporting results of randomized controlled trials (RCTs) of an ICS versus placebo over a treatment period of at least 12 months, with the aim of providing further insight into the link between bone fractures and ICS therapy. As of 16 October 2017, we identified 17 RCTs for inclusion. The ICSs studied were budesonide (six studies), fluticasone propionate (five studies), mometasone furoate (three studies), beclomethasone dipropionate, triamcinolone acetonide, and fluticasone furoate (one each). We found no difference in the number of bone fractures among patients receiving ICSs versus placebo across the six identified RCTs reporting fracture data. BMD data were available for subsets of patients in few studies, and baseline BMD data were rare; where these data were given, they were reported for treatment groups without stratification for factors known to affect BMD. Risk factors for reduced BMD and fractures, such as smoking and physical activity, were also often not reported. Furthermore, a standardized definition of the term "fracture" was not employed across these studies. The exact relationship between long-term ICS use and bone fracture incidence in patients with stable COPD remains unclear in light of our review. We have, however, identified several limiting factors in existing studies that may form the basis of future RCTs designed specifically to explore this relationship., Competing Interests: FA is an employee of GSK and owns stock in GSK. LS was an employee of GSK at the time of preparation of the manuscript. GC reports grants, personal fees, and non-financial support from Astra Zeneca, Boehringer Ingelheim, GSK, and Menarini Group, and grants from AlfaSigma, outside the submitted work. The authors report no other conflicts of interest in this work.