Microbial Dysregulation of the Gut-Lung Axis in Bronchiectasis.

Rationale: Emerging data support the existence of a microbial "gut-lung" axis that remains unexplored in bronchiectasis. Methods: Prospective and concurrent sampling of gut (stool) and lung (sputum) was performed in a cohort of n = 57 individuals with bronchiectasis and subjected to bacteriome (16S rRNA) and mycobiome (18S Internal Transcribed Spacer) sequencing (total, 228 microbiomes). Shotgun metagenomics was performed in a subset (n = 15; 30 microbiomes). Data from gut and lung compartments were integrated by weighted similarity network fusion, clustered, and subjected to co-occurrence analysis to evaluate gut-lung networks. Murine experiments were undertaken to validate specific Pseudomonas-driven gut-lung interactions. Results: Microbial communities in stable bronchiectasis demonstrate a significant gut-lung interaction. Multibiome integration followed by unsupervised clustering reveals two patient clusters, differing by gut-lung interactions and with contrasting clinical phenotypes. A high gut-lung interaction cluster, characterized by lung Pseudomonas, gut Bacteroides, and gut Saccharomyces, is associated with increased exacerbations and greater radiological and overall bronchiectasis severity, whereas the low gut-lung interaction cluster demonstrates an overrepresentation of lung commensals, including Prevotella, Fusobacterium, and Porphyromonas with gut Candida. The lung Pseudomonas-gut Bacteroides relationship, observed in the high gut-lung interaction bronchiectasis cluster, was validated in a murine model of lung Pseudomonas aeruginosa infection. This interaction was abrogated after antibiotic (imipenem) pretreatment in mice confirming the relevance and therapeutic potential of targeting the gut microbiome to influence the gut-lung axis. Metagenomics in a subset of individuals with bronchiectasis corroborated our findings from targeted analyses. Conclusions: A dysregulated gut-lung axis, driven by lung Pseudomonas, associates with poorer clinical outcomes in bronchiectasis.

Heterogeneity of weight gain after initiation of Elexacaftor/Tezacaftor/Ivacaftor in people with cystic fibrosis.

BACKGROUND: The introduction of the novel therapy, Elexacaftor/Tezacaftor/Ivacaftor (ETI) has been effective in improving weight gain in both clinical trials and real-world studies. However, the magnitude of this effect appears to be heterogeneous across patient subgroups. This study aims to identify potential determinants of heterogeneity in weight gain following 6-month ETI therapy. METHODS: We conducted a multicenter, prospective cohort study enrolling 92 adults with CF at two major CF centers in Italy with follow-up visit at one month and six months from ETI initiation. The treatment's effect on weight changes was evaluated using mixed effect regression models that included subject-specific random intercepts and fixed effects for potential predictors of treatment response, time and a predictor-by-time interaction term. RESULTS: The mean weight gain at six months from the start of treatment was 4.6 kg (95% CI: 2.3-6.9) for the 10 patients with underweight, 3.2 kg (95% CI: 2.3-4.0) for the 72 patients with normal weight, and 0.7 kg (95% CI: -1.6-3.0) for the 10 patients with overweight. After six months of ETI treatment, 8 (80%) of the patients with underweight transitioned to the normal weight category, while 11 (15.3%) of the normal-weight patients became overweight. The major determinants of heterogeneity in weight gain were the baseline BMI and the presence of at least one CFTR residual function mutation, explaining 13% and 8% of the variability, respectively. CONCLUSIONS: Our results indicate that ETI is highly effective in improving weight gain in underweight subjects with CF. However, our data also suggests the need for close monitoring of excess weight gain to prevent potential cardiometabolic complications.

Walking the path of treatable traits in interstitial lung diseases.

Interstitial lung diseases (ILDs) are complex and heterogeneous diseases. The use of traditional diagnostic classification in ILD can lead to suboptimal management, which is worsened by not considering the molecular pathways, biological complexity, and disease phenotypes. The identification of specific "treatable traits" in ILDs, which are clinically relevant and modifiable disease characteristics, may improve patient's outcomes. Treatable traits in ILDs may be classified into four different domains (pulmonary, aetiological, comorbidities, and lifestyle), which will facilitate identification of related assessment tools, treatment options, and expected benefits. A multidisciplinary care team model is a potential way to implement a "treatable traits" strategy into clinical practice with the aim of improving patients' outcomes. Multidisciplinary models of care, international registries, and the use of artificial intelligence may facilitate the implementation of the "treatable traits" approach into clinical practice. Prospective studies are needed to test potential therapies for a variety of treatable traits to further advance care of patients with ILD.

Treatable traits and challenges in the clinical management of non-tuberculous mycobacteria lung disease in people with cystic fibrosis.

INTRODUCTION: Over the last ten years an increasing prevalence and incidence of non-tuberculous mycobacteria (NTM) has been reported among patients with cystic fibrosis (CF) Viviani (J Cyst Fibros, 15(5):619-623, 2016). NTM pulmonary disease has been associated with negative clinical outcomes and often requires pharmacological treatment. Although specific guidelines help clinicians in the process of diagnosis and clinical management, the focus on the multidimensional assessment of concomitant problems is still scarce. MAIN BODY: This review aims to identify the treatable traits of NTM pulmonary disease in people with CF and discuss the importance of a multidisciplinary approach in order to detect and manage all the clinical and behavioral aspects of the disease. The multidisciplinary complexity of NTM pulmonary disease in CF requires careful management of respiratory and extra-respiratory, including control of comorbidities, drug interactions and behavioral factors as adherence to therapies. CONCLUSIONS: The treatable trait strategy can help to optimize clinical management through systematic assessment of all the aspects of the disease, providing a holistic treatment for such a multi-systemic and complex condition.

Glucocorticoid Therapy in COVID-19.

Coronavirus disease 2019 (COVID-19) pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in significant mortality in pandemic proportions. Inflammation in response to the infection contributes to the pathogenesis of pneumonia. This review will discuss prior studies on the use of glucocorticoids to treat respiratory infections, the rationale for the use glucocorticoids in COVID-19, and review of existing data. We will also highlight outstanding research questions for future studies.

Efficacy of Pirfenidone and Nintedanib in Interstitial Lung Diseases Other than Idiopathic Pulmonary Fibrosis: A Systematic Review.

Pirfenidone and nintedanib are antifibrotic medications approved for idiopathic pulmonary fibrosis treatment by regulatory agencies and available for clinical use worldwide. These drugs have been shown to reduce the rate of decline in forced vital capacity and the risk of acute exacerbation among patients with idiopathic pulmonary fibrosis. Recent data suggest that different interstitial lung diseases with a progressive pulmonary fibrosis phenotype can share similar pathogenetic and biological pathways and could be amenable to antifibrotic therapies. Indeed, historical management strategies in interstitial lung disease have failed to identify potential treatments once progression has occurred despite available drugs. In this systematic review, we summarized data on the efficacy of pirfenidone and nintedanib in interstitial lung diseases other than idiopathic pulmonary fibrosis as well as ongoing and upcoming clinical trials. We identify two well-designed trials regarding nintedanib demonstrating the efficacy of this drug in slowing disease progression in patients with interstitial lung diseases other than idiopathic pulmonary fibrosis. On the other hand, results on the use of pirfenidone in interstitial lung diseases other than idiopathic pulmonary fibrosis should be interpreted with more caution on the basis of trial limitations. Several randomized control trials are underway to improve the quality of evidence in the interstitial lung disease field.

Community-acquired pneumonia.

Community-acquired pneumonia is not usually considered a high-priority problem by the public, although it is responsible for substantial mortality, with a third of patients dying within 1 year after being discharged from hospital for pneumoniae. Although up to 18% of patients with community-acquired pneumonia who were hospitalised (admitted to hospital and treated there) have at least one risk factor for immunosuppression worldwide, strong evidence on community-acquired pneumonia management in this population is scarce. Several features of clinical management for community-acquired pneumonia should be addressed to reduce mortality, morbidity, and complications related to community-acquired pneumonia in patients who are immunocompetent and patients who are immunocompromised. These features include rapid diagnosis, microbiological investigation, prevention and management of complications (eg, respiratory failure, sepsis, and multiorgan failure), empirical antibiotic therapy in accordance with patient's risk factors and local microbiological epidemiology, individualised antibiotic therapy according to microbiological data, appropriate outcomes for therapeutic switch from parenteral to oral antibiotics, discharge planning, and long-term follow-up. This Seminar offers an updated view on community-acquired pneumonia in adults, with suggestions for clinical and translational research.

Pro-resolving and pro-inflammatory fatty acid-derived mediators in sputum of stable state bronchiectasis patients.

BACKGROUND: Bronchiectasis is characterized by neutrophilic inflammation and frequent exacerbations often associated with infections. Lipid mediators play critical roles in the inflammatory response, and the balance between anti-inflammatory and pro-inflammatory mediators could drive to chronic inflammation. The aim of this study was to evaluate the metabolites of docosahexaenoic acid and arachidonic acid in sputum of adults with bronchiectasis defining their associations with clinical data, bacterial load and neutrophil elastase. METHODS: An observational, cross-sectional study was conducted at the bronchiectasis program of the Policlinico Hospital in Milan, Italy, where patients were enrolled. Active neutrophil elastase was measured by enzyme-linked immunosorbent assay, pro-resolving and pro-inflammatory fatty acid-derived mediators were evaluated by mass spectrometry and respiratory pathogens were assessed by real-time PCR. Analysis were performed on sputum collected during stable state and clinical data were also collected. RESULTS: Levels of pro-inflammatory mediators derived from arachidonic acid metabolism showed association with neutrophil elastase, were proportional to Pseudomonas aeruginosa identifications and were linked with radiological gravity index, while the concentrations of pro-resolution mediators derived from docosahexaenoic acid were associated with a better health status, highlighted by the inverse correlation with radiological gravity index, bacterial infections and sputum volume production. CONCLUSION: Pro-inflammatory mediators derived from FA metabolisms are associated with severity of bronchiectasis while DHA-derived metabolites are inversely associated with severity of the disease, which may be used for personized treatment of bronchiectasis.

Lung Microbiome in Idiopathic Pulmonary Fibrosis and Other Interstitial Lung Diseases.

Interstitial lung diseases represent a heterogeneous and wide group of diseases in which factors leading to disease initiation and progression are not fully understood. Recent evidence suggests that the lung microbiome might influence the pathogenesis and progression of interstitial lung diseases. In recent years, the utilization of culture-independent methodologies has allowed the identification of complex and dynamic communities of microbes, in patients with interstitial lung diseases. However, the potential mechanisms by which these changes may drive disease pathogenesis and progression are largely unknown. The aim of this review is to discuss the role of the altered lung microbiome in several interstitial lung diseases. Untangling the host-microbiome interaction in the lung and airway of interstitial lung disease patients is a research priority. Thus, lung dysbiosis is a potentially treatable trait across several interstitial lung diseases, and its proper characterization and treatment might be crucial to change the natural history of these diseases and improve outcomes.

Prognostic parameters of in-hospital mortality in COVID-19 patients-An Italian experience.

Background During COVID-19 outbreak, Italy was the first country in Europe to be heavily affected with an intensive care unit mortality of 26%. In order to reduce this percentage, physicians should establish clear and objective criteria to stratify COVID-19 patients at high risk of in-hospital death. Thus, the aim has been to test a large spectrum of variables ranging from clinical evaluation to laboratory biomarkers to identify which parameter would best predict all-cause in-hospital mortality in COVID-19 patients. Design observational study. Results Multivariate Cox regression analysis showed that each 5 years of increase in age corresponded to a hazard ratio (HR) of 1.28 (95% CI 1.00-1.65, P = .050); each increment of 803 ng/L of N-terminal pro-B-type natriuretic peptide (NT-proBNP) corresponded to a HR of 1.24 (95% CI 1.11-1.39, P < .001); each increment of 58 ng/L of interleukin (IL)-6 corresponded to a HR of 1.23 (95% CI 1.09-1.40, P < .001), and each increment of 250 U/L of lactate dehydrogenase (LDH) corresponded to a HR of 1.23 (95% CI 1.10-1.37, P < .001). According to the calculated cut-points for age (≥70 years), NT-proBNP (≥803 ng/L), IL-6 (≥58 ng/L) and LDH (≥371 U/L) when 2 out of these 4 were overcome, the HR was 2.96 (95% CI 1.97-4.45, P < .001). Conclusion In COVID-19 patients, besides age, the evaluation of three biochemical parameters, available in few hours after hospital admission can predict in-hospital mortality regardless of other comorbidities.

Switching to nebulised short acting bronchodilators does not increase the risk of arrhythmia in patients hospitalized with a COPD exacerbation.

If short acting ß2-agonists and muscarinic antagonists (SABA/SAMA) may have proarrhythmic effects during acute COPD exacerbations (AECOPD) is still unknown. The primary objective of the study was to investigate the incidence of new onset arrhythmias in hospitalized patients shifted to SABA/SAMA during an AECOPD compared with continuing chronic inhaled therapy. Secondary objectives were to assess the clinical characteristics of patients shifted to SABA/SAMA and risk factors for arrhythmia. This was a retrospective, observational, study enrolling consecutive patients hospitalized with an AECOPD. Incidence of arrhythmias was obtained reviewing digital records. Patients with chronic arrhythmias or home-treated with SABA/SAMA were excluded. 235 patients (63.8% males) were included, and 10/182 patients shifted to SABA/SAMA experienced arrhythmias, while no events were observed in patients on chronic inhaled therapy (p = 0.122). Shifted patients had a more severe AECOPD and history of paroxysmal atrial fibrillation was an independent risk factor for arrhythmia (OR 14.010, IC95%: 2.983-65.800; p = 0.001). In conclusion, shifting patients to SABA/SAMA appears not to increase the risk for arrhythmia during severe AECOPD. However, the pharmacological approach in patients with a history of paroxysmal arrhythmia should be carefully evaluated and monitored.

COVID-19 in Immunocompromised Patients: A Systematic Review.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was first identified as a novel coronavirus in Wuhan, Hubei province, central China, in December 2019, and is responsible for the 2019-to-present pandemic. According to the most recent data released by the World Health Organization, more than 200 million people have been infected by SARS-CoV-2 so far, and more than 4 million people died worldwide. Although our knowledge on SARS-CoV-2 and COVID-19 is constantly growing, data on COVID-19 in immunocompromised patients are still limited. The aim of the present systematic review is to describe clinical picture, disease severity, proposed treatment regimen, and response to vaccination in patients with different types and severity of immunosuppression.

Diagnosis and Initial Investigation of Bronchiectasis.

Bronchiectasis refers to both the name of a disease and a single radiological appearance that may, or may not, be associated with disease. As chronic respiratory disease, bronchiectasis is characterized by a variable range of signs and symptoms that may overlap with other chronic respiratory conditions. The proper identification of bronchiectasis as a disease in both primary and secondary care is of paramount importance. However, a standardized definition of radiologically and clinically significant bronchiectasis is still missing. Disease heterogeneity is a hallmark of bronchiectasis and applies not only to radiological features and clinical manifestations but also to other aspects of the disease, including the etiological and microbiological diagnosis as well as the evaluation of pulmonary function. Although the guidelines suggest a "minimum bundle" of tests, the diagnostic approach to bronchiectasis is challenging and may be driven by the "treatable traits" approach based on endotypes and biological characteristics. A broad spectrum of diagnostic tests could be used to investigate the etiology of bronchiectasis as well as other pulmonary, extrapulmonary, and environmental traits. Individualizing bronchiectasis workup according to the site of care (e.g., primary, secondary, and tertiary care) could help optimize patients' management and reduce healthcare costs.

Protease-Antiprotease Imbalance in Bronchiectasis.

Airway inflammation plays a central role in bronchiectasis. Protease-antiprotease balance is crucial in bronchiectasis pathophysiology and increased presence of unopposed proteases activity may contribute to bronchiectasis onset and progression. Proteases' over-reactivity and antiprotease deficiency may have a role in increasing inflammation in bronchiectasis airways and may lead to extracellular matrix degradation and tissue damage. Imbalances in serine proteases and matrix-metallo proteinases (MMPs) have been associated to bronchiectasis. Active neutrophil elastase has been associated with disease severity and poor long-term outcomes in this disease. Moreover, high levels of MMPs have been associated with radiological and disease severity. Finally, severe deficiency of α1-antitrypsin (AAT), as PiSZ and PiZZ (proteinase inhibitor SZ and ZZ) phenotype, have been associated with bronchiectasis development. Several treatments are under study to reduce protease activity in lungs. Molecules to inhibit neutrophil elastase activity have been developed in both oral or inhaled form, along with compounds inhibiting dipeptydil-peptidase 1, enzyme responsible for the activation of serine proteases. Finally, supplementation with AAT is in use for patients with severe deficiency. The identification of different targets of therapy within the protease-antiprotease balance contributes to a precision medicine approach in bronchiectasis and eventually interrupts and disrupts the vicious vortex which characterizes the disease.

COVID-19 multidisciplinary high dependency unit: the Milan model.

COVID-19 is a complex and heterogeneous disease. The pathogenesis and the complications of the disease are not fully elucidated, and increasing evidence shows that SARS-CoV-2 causes a systemic inflammatory disease rather than a pulmonary disease. The management of hospitalized patients in COVID-19 dedicated units is advisable for segregation purpose as well as for infection control. In this article we present the standard operating procedures of our COVID-19 high dependency unit of the Policlinico Hospital, in Milan. Our high dependency unit is based on a multidisciplinary approach. We think that the multidisciplinary involvement of several figures can better identify treatable traits of COVID-19 disease, early identify patients who can quickly deteriorate, particularly patients with multiple comorbidities, and better manage complications related to off-label treatments. Although no generalizable to other hospitals and different healthcare settings, we think that our experience and our point of view can be helpful for countries and hospitals that are now starting to face the COVID-19 outbreak.

COVID-19 in lung transplant recipients: A case series from Milan, Italy.

Limited data are currently available regarding the course of COVID-19 in lung and solid organ transplant recipients. We hereby present four cases of SARS-CoV-2 pneumonia in lung transplant recipients from our center, set in Milan, Italy. We reduced immunosuppressive regimen in all these patients, typically holding the antiproliferative agent and augmenting steroids; everybody received hydroxychloroquine, initial empiric antibiotic treatment with piperacillin/tazobactam, and high-dose low molecular weight heparin. Clinical course seemed favorable in three of our patients, but one of them deteriorated after 10 days of hospitalization, probably due to an acute form of graft dysfunction triggered both by COVID-19 and a nosocomial bacterial infection, and eventually died. Although short-term prognosis could be considered benign in the majority of our patients, we should carefully monitor these individuals in order to detect early sign of clinical deterioration and graft dysfunction in the next few months.

Emerging Resistance of Gram Negative Pathogens in Community-Acquired Pneumonia.

In recent decades, there has been a growing interest about the role of gram negative bacteria in community-acquired pneumonia (CAP), especially Pseudomonas aeruginosa, Enterobacteriaceae, and Acinetobacter baumannii. The prevalence of these pathogens differs largely according to the local ecology and the geographical location. Identifying gram negative bacteria, and in particular resistant gram negative bacteria, is of paramount importance in patients with CAP because these pathogens are associated with higher clinical severity and unfavorable outcomes. The use of individualized risk factors to predict each pathogen is a helpful strategy that needs to be locally validated. However, it should be taken into account that most of the risk factors identified in the literature are heterogeneously defined or lack consistency. New diagnostic techniques, such as molecular testing, are promising methods for early detection of these gram negative pathogens. The increasing mechanisms of resistance to antibiotics of these pathogens have limited our therapeutic approach. This narrative review focuses on the epidemiology, risk factors, diagnosis, and therapeutic options for the most relevant gram negative bacteria that cause CAP.

Neutrophil elastase in bronchiectasis.

The role of neutrophil elastase (NE) is poorly understood in bronchiectasis because of the lack of preclinical data and so most of the assumptions made about NE inhibitor potential benefit is based on data from CF. In this context, NE seems to be a predictor of long-term clinical outcomes and a possible target of treatment. In order to better evaluate the role of NE in bronchiectasis, a systematic search of scientific evidence was performed.Two investigators independently performed the search on PubMed and included studies published up to May 15, 2017 according to predefined criteria. A final pool of 31 studies was included in the systematic review, with a total of 2679 patients. For each paper data of interest were extracted and reported in table.In this review sputum NE has proved useful as an inflammatory marker both in stable state bronchiectasis and during exacerbations and local or systemic antibiotic treatment. NE has also been associated with risk of exacerbation, time to next exacerbation and all-cause mortality. This study reviews also the role of NE as a specific target of treatment in bronchiectasis. Inhibition of NE is at a very early stage and future interventional studies should evaluate safety and efficacy for new molecules and formulations.

Vasoactive drugs for the treatment of pulmonary hypertension associated with interstitial lung diseases: a systematic review.

OBJECTIVES: Vasoactive drugs have exhibited clinical efficacy in addressing pulmonary arterial hypertension, manifesting a significant reduction in morbidity and mortality. Pulmonary hypertension may complicate advanced interstitial lung disease (PH-ILD) and is associated with high rates of disability, hospitalisation due to cardiac and respiratory illnesses, and mortality. Prior management hinged on treating the underlying lung disease and comorbidities. However, the INCREASE trial of inhaled treprostinil in PH-ILD has demonstrated that PH-ILD can be effectively treated with vasoactive drugs. METHODS: This comprehensive systematic review examines the evidence for vasoactive drugs in the management of PH-ILD. RESULTS: A total of 1442 pubblications were screened, 11 RCTs were considered for quantitative synthesis. Unfortunately, the salient studies are limited by population heterogeneity, short-term follow-up and the selection of outcomes with uncertain clinical significance. CONCLUSIONS: This systematic review underscores the necessity of establishing a precision medicine-oriented strategy, directed at uncovering and addressing the intricate cellular and molecular mechanisms that underlie the pathophysiology of PH-ILD. PROSPERO REGISTRATION NUMBER: CRD42023457482.