Spontaneous Ventilation Thoracoscopic Lung Biopsy in Undetermined Interstitial Lung Disease: Systematic Review and Meta-Analysis.

Thoracoscopic surgical biopsy has shown excellent histological characterization of undetermined interstitial lung diseases, although the morbidity rates reported are not negligible. In delicate patients, interstitial lung disease and restrictive ventilatory impairment morbidity are thought to be due at least in part to tracheal intubation with single-lung mechanical ventilation; therefore, spontaneous ventilation thoracoscopic lung biopsy (SVTLB) has been proposed as a potentially less invasive surgical option. This systematic review summarizes the results of SVTLB, focusing on diagnostic yield and operative morbidity. A systematic search for original studies regarding SVTLB published between 2010 to 2023 was performed. In addition, articles comparing SVTLB to mechanical ventilation thoracoscopic lung biopsy (MVTLB) were selected for a meta-analysis. Overall, 13 studies (two before 2017 and eleven between 2018 and 2023) entailing 675 patients were included. Diagnostic yield ranged from 84.6% to 100%. There were 64 (9.5%) complications, most of which were minor. There was no 30-day operative mortality. When comparing SVTLB to MVTLB, the former group showed a significantly lower risk of complications (p < 0.001), whereas no differences were found in diagnostic accuracy. The results of this review suggest that SVTLB is being increasingly adopted worldwide and has proven to be a safe procedure with excellent diagnostic accuracy.

Expert guidance on the management and challenges of long-COVID syndrome: a systematic review.

INTRODUCTION: Long-COVID is a condition characterized by the permanence of symptoms beyond 4 weeks after an initial infection. It affects 1 out of 5 people and is loosely related to the severity of acute infection and pathological mechanisms, which are yet to be understood. AREAS COVERED: This article looks at currently available and under-studied therapies for long-COVID syndrome. It particularly gives focus to ongoing trials and reviews the underlying mechanisms. A comprehensive literature search was performed on PubMed and clincaltrial.gov of clinical trials concerning the management of long-COVID syndrome. EXPERT OPINION: 'Long-COVID' syndrome is a new emergency characterized by several symptoms such as fatigue, dyspnea, cognitive and attention disorders, sleep disorders, post-traumatic stress disorder, muscle pain, and concentration problems. Despite the many guidelines available to date, there are no established treatments of long-COVID. Pharmacological research is studying known drugs that act on the reduction or modulation of systemic inflammation, or innovative drugs used in similar pathologies. Rehabilitation now seems to be the safest treatment to offer, whereas we will have to wait for the pharmacological research trials in progress as well as plan new trials based on a better understanding of the pathogenic mechanisms.

Synergy across the drugs approved for the treatment of asthma.

INTRODUCTION: Inhaled corticosteroids are the cornerstone for the treatment of stable asthma, however, when disease severity increases, escalating therapy to combinations of drugs acting on distinct signalling pathways is required. It is advantageous to providing evidence of a synergistic interaction across drug combinations, as it allows optimizing bronchodilation while lowering the dose of single agents. In the respiratory pharmacology field, two statistical models are accepted as gold standard to characterize drug interactions, namely the Bliss Independence criterion and the Unified Theory. In this review, pharmacological interactions across drugs approved for the treatment of asthma have been systematically assessed. EVIDENCE ACQUISITION: A comprehensive literature search was performed in MEDLINE for studies that used a validated pharmacological method for assessing drug interaction. The results were extracted and reported via qualitative synthesis. EVIDENCE SYNTHESIS: Overall, 45 studies were identified from literature search and 5 met the inclusion criteria. Current evidence coming from ex-vivo models of asthma indicates that drug combinations modulating bronchial contractility induce a synergistic bronchorelaxant effect. In murine models of lung inflammation, the combination between inhaled corticosteroids and ß2-adrenoceptor agonists synergistically improve lung function and the inflammatory profile. CONCLUSIONS: There is still limited knowledge regarding the mechanistic basis underlying pharmacological interactions across drugs approved for asthma. The synergism elicited by combined agents is an effect of class. Specifically designed clinical trials are needed to confirm the results coming from preclinical evidence, but also to establish the minimal dose for combined agents to induce a synergistic interaction and maximize bronchodilation.

Acute effect of oxygen therapy on exercise tolerance and dyspnea perception in ILD patients.

Ambulatory oxygen therapy (AOT) is commonly prescribed in interstitial lung disease (ILD) patients, with the aim of reducing dyspnea and increasing exercise tolerance. Despite its frequent use and a reasonable physiological rationale, there is a lack of evidence supporting the effect of AOT on improving dyspnea during exercise. Moreover, dyspnea encompasses distinct sensory (intensity, quality) and affective (anxiety, fear) components with different underlying neurophysiological mechanisms. The aim of this study was to evaluate the effect of oxygen supplementation on exercise tolerance and dyspnea in ILD patients with exercise induced hypoxia (EIH). Forty-seven ILD patients performed a six-minute walk test (6MWT) on room air (RA) and with oxygen supplementation (Ox). The 6MWT distance (6MWD) was significantly greater with oxygen supplementation (RA: 242±143 m vs Ox: 345±106 m p<0,01). With oxygen supplementation, the overall dyspnea and anxiety significantly decreased both at rest [1.1±1.4 Borg Unit (BU)] vs 0.4±0.9BU, p.<0.01, and 1.1±1.6BU vs 0.5±1.3 BU, p.<0.05, respectively) and at the end of exercise (5.1±2.6 BU vs 3.7±2.5 BU, p<0.001 and 3.4 ±2.9 vs 2.5±2.8, p.<0.01, respectively) despite a greater walked distance. In ILD patients with EIH, oxygen supplementation increases the exercise tolerance and reduces overall dyspnea perception and the anxiety component of breathlessness.

Impact of long-acting muscarinic antagonists on small airways in asthma and COPD: A systematic review.

Small airway disease is recognized as a cardinal pathological process of chronic obstructive pulmonary disease (COPD), and recently small airways have been recognized as a major site of airflow obstruction also in asthmatic patients. The transversal involvement of small airways in COPD and asthma has warranted research efforts to identify therapeutic strategies able to unlock the small airway compartment. The mainstay of COPD treatment is represented by long-acting ß2-adrenoceptor agonists (LABAs) and long-acting muscarinic antagonists (LAMAs). In asthma, the efficacy of LAMAs administered add-on to inhaled corticosteroids (ICSs) or ICS/LABA combinations has been investigated only in recent years. The aim of this systematic review was to examine the current literature concerning the impact of LAMAs on small airways and their lung deposition in both COPD and asthma. LAMAs administered either alone or in combination induced an effective bronchorelaxant effect of small airways, however the effectiveness of respiratory medications not only relies on the selected drug, but also on the employed inhalation device and patient's adherence. Tiotropium delivered via Respimat® SMI achieved a superior drug deposition in the peripheral lung compared to HandiHaler® dry powder inhaler and metered-dose inhalers (MDIs). The use of co-suspension™ delivery technology for MDIs and the introduction of the eFlow® nebulizer to deliver glycopyrronium improved aerosol drug delivery to the peripheral lung, by achieving uniform distribution of drug particles. This systematic review provides a synthesis of current literature concerning the impact of LAMAs on small airways and an insight on LAMAs distribution within the lung.

Efficacy and safety of triple combination therapy for treating chronic obstructive pulmonary disease: an expert review.

Introduction: The current recommendations of chronic obstructive pulmonary disease (COPD) suggest to escalate from inhaled corticosteroid/long-acting ß2-adrenoceptor agonist (ICS/LABA) treatment to triple therapy in patients experiencing persistent breathlessness, exercise limitation, or exacerbation. The addition of an ICS to LABA/long-acting muscarinic antagonist (LAMA) combination is recommended for frequently exacerbating patients with high levels of blood eosinophils. Nowadays, three triple therapies have been approved as fixed-dose combinations (FDCs) for the treatment of COPD: beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FOR/GLY), fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI), and budesonide/glycopyrronium bromide/formoterol fumarate (BUD/GLY/FOR).Areas covered: This narrative review evaluates the efficacy and safety profile of triple FDC therapy for the treatment of COPD, by evaluating the data originating from pivotal randomized-controlled trials (RCTs).Expert opinion: The currently approved triple FDCs exert a protective effect against the risk of COPD exacerbation compared to ICS/LABA and LABA/LAMA, with some concerns regarding the risk of pneumonia for some specific FDCs. Since the assessed RCTs were characterized by important confounders, the obtained results should be interpreted with caution. Indeed, FDCs provide advantages in terms of improved adherence to treatment and lower errors in COPD management; however, direct head-to-head comparisons are needed to establish real differences between the currently approved triple FDCs.

Are there pulmonary sequelae in patients recovering from COVID-19?

It has been recently hypothesized that infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may lead to fibrotic sequelae in patients recovering from coronavirus disease 2019 (COVID-19). In this observational study, hospitalized patients with COVID-19 had a HRCT of the chest performed to detect the extension of fibrotic abnormalities via Hounsfield Units (HU). At follow-up, the lung density significantly improved in both lungs and in each lobe of all patients, being in the normal range (- 950 to - 700 HU). This study provides preliminary evidence that hospitalized patients with mild-to-moderate forms of COVID-19 are not at risk of developing pulmonary fibrosis.

Experimental Glucocorticoid Receptor Agonists for the Treatment of Asthma: A Systematic Review.

Inhaled corticosteroids (ICSs) are considered the cornerstone of asthma treatment. Despite the solid evidence documenting the efficacy and safety of ICSs at the level of the airways, their use can be affected by pulmonary and systemic adverse events (AEs) when administered chronically and/or at high doses. Thus, there is a pharmacological and medical need for new glucocorticoid (GC) receptor (GR) ligands with a more favorable therapeutic index, in order to overcome the shortcomings of currently available ICSs. The therapeutic profile of GCs can be improved by enhancing genomic mechanisms mediated by transrepression, which is assumed to be responsible for several anti-inflammatory and immunomodulatory actions, rather than transactivation, which causes most of the GC-associated AEs. It was assumed that an independent modulation of the molecular mechanisms underlying transactivation and transrepression could translate into the dissociation of beneficial effects from AEs. Therefore, current research is looking for GCs that are able to elicit prevalently transrepression with negligible transactivating activity. These compounds are known as selective glucocorticoid receptor agonists (SEGRAs). In this review, experimental GR agonists currently in pre-clinical and clinical development for the treatment of asthma have been systematically assessed. Several compounds are currently under pre-clinical development, but only three novel experimental GR agonists (GW870086X, AZD5423, AZD7594) seem to have some potential therapeutic relevance and have entered clinical trials for the treatment of asthma. Since data from pre-clinical studies have not always been confirmed in clinical investigations, well-designed randomized controlled trials are needed in asthmatic patients to confirm the potentially positive benefit/risk ratio of each specific SEGRA and to optimize the development strategy of these agents in respiratory medicine.

Dyspnea perception and neurological symptoms in non-severe COVID-19 patients.

INTRODUCTION: The relationship between dyspnea and COVID-19 is unknown. In COVID-19 patients, the higher prevalence of neurological symptoms and the lack of dyspnea may suggest common underlying pathogenetic mechanisms. The aim of this preliminary study is to address whether there is a lack of dyspnea in COVID-19 patients and if there is a relationship between neurological symptoms and the perception of dyspnea. METHODS: A structured interview regarding the occurrence of subjective neurological symptoms was performed and coupled with a questionnaire about the intensity and qualities of dyspnea. Respiratory rate (RR) and an arterial blood gas on room air were concurrently evaluated. RESULTS: Twenty-two patients (age 68.4 ± 13.9 years, 13 males and 9 females) were included and divided into two groups according to the Borg dyspnea scale: dyspneic patients BU ≥ 1(DYSP) and non-dyspneic patients BU < 1 (NDYSP). The prevalence of dyspnea overall was 31.8%. The prevalence of neurological symptoms, dyspnea descriptors, RR, pH, PaCO2, PaO2, or lactate was similar between groups. CONCLUSION: This study confirms that the prevalence of dyspnea is low in non-severe COVID-19 patients, but contrary to our hypothesis of a relationship between shortness of breath and neurological symptoms, we have not been able to find any evidence of an impairment in dyspnea perception, either in the DYSP or NDYSP group.

Subjective neurological symptoms frequently occur in patients with SARS-CoV2 infection.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) represents a novel pneumonia leading to severe acute respiratory syndrome (SARS). Recent studies documented that SARS-Coronavirus2 (SARS-CoV2), responsible for COVID-19, can affect the nervous system. The aim of the present observational study was to prospectively assess subjective neurological symptoms (sNS) in patients with SARS-CoV2 infection. METHODS: We included patients hospitalized at the University Hospital of Rome "Tor Vergata", medical center dedicated to the treatment of patients with COVID-19 diagnosis, who underwent an anamnestic interview about sNS consisting of 13 items, each related to a specific symptom, requiring a dichotomized answer. RESULTS: We included 103 patients with SARS-CoV2 infection. Ninety-four patients (91.3%) reported at least one sNS. Sleep impairment was the most frequent symptom, followed by dysgeusia, headache, hyposmia, and depression. Women more frequently complained hyposmia, dysgeusia, dizziness, numbeness/paresthesias, daytime sleepiness, and muscle ache. Moreover, muscle ache and daytime sleepiness were more frequent in the first 2 days after admission. Conversely, sleep impairment was more frequent in patients with more than 7 days of hospitalization. In these patients we also documented higher white blood cells and lower C-reactive protein levels. These laboratory findings correlated with the occurrence of hyposmia, dysgeusia, headache, daytime sleepiness, and depression. CONCLUSIONS: Patients with SARS-CoV2 infection frequently present with sNS. These symptoms are present from the early phases of the disease. The possibly intrinsic neurotropic properties of SARS-CoV2 may justify the very high frequency of sNS. Further studies targeted at investigating the consequences of SARS-CoV2 infection on the CNS should be planned.

Diagnostic Performance and Safety of Bronchoalveolar Lavage in Thrombocytopenic Haematological Patients for Invasive Fungal Infections Diagnosis: A Monocentric, Retrospective Experience.

BACKGROUND: Although bronchoalveolar lavage (BAL) measurements of galactomannan antigen (GM) seems to be more sensitive than serum testing to detect invasive fungal infection (IFI), a consensus on the most appropriate diagnostic threshold of the BAL GM test is still unclear. Moreover, there is uncertainty as to whether BAL is a safe procedure in patients with hematological malignancies (HM) and thrombocytopenia. OBJECTIVES: Based on this background, 102 adult patients with HM and associated thrombocytopenia were retrospectively analyzed with the dual aim of 1) determining whether BAL is a safe and feasible procedure; and, 2) identifying the most appropriate threshold for GM positivity in the diagnosis of IFI. PATIENTS/METHODS: each BAL was considered as one case/patient. One hundred twelve BALs were carried out in 102 HM patients: at the time of the BAL, the median platelet count (PLTs) in all patients was 47×109/L (1-476), and 31 patients (27%) had PLTs< 20×109/L. RESULTS: complications from the BAL were infrequent (3.5%) and mild. No bleeding was reported. The BAL GM cut off of >0.8 was associated with the best diagnostic accuracy (sensitivity 72.97% and specificity 80%). Antifungal treatment of patients with BAL GM >0.8 resulted in a clinical-radiological improvement in 35/41 patients (85%). CONCLUSIONS: BAL was a safe procedure also in thrombocytopenic patients, permitting an IFI diagnosis not otherwise identifiable using EORTC/MSG criteria. Our data suggest that a BAL GM value of>0.8 represents the most useful cut-off in terms of sensibility and specificity. Further prospective studies on a more significant number of patients are needed to confirm these results.

Efficacy and cardiovascular safety profile of dual bronchodilation therapy in chronic obstructive pulmonary disease: A bidimensional comparative analysis across fixed-dose combinations.

Despite several long-acting ß2-adrenoceptor agonist (LABA)/long-acting muscarinic antagonist (LAMA) fixed-dose combinations (FDCs) are currently approved for the treatment of chronic obstructive pulmonary disease (COPD), there are limited findings concerning the direct comparison across the different LABA/LAMA FDCs. The aim of this study was to compare the efficacy/safety profile of approved LABA/LAMA FDCs in COPD. A network meta-analysis was performed by linking the efficacy (forced expiratory volume in 1 s, St' George Respiratory Questionnaire, transitional dyspnea index) and safety (cardiovascular serious adverse events) outcomes resulting from randomized controlled trials that directly compared LABA/LAMA FDCs with placebo and/or each other. The Surface Under the Cumulative Ranking Curve Analysis (SUCRA) was performed for each single outcome (SUCRA: 1 = best, 0 = worst). The combined efficacy/safety profile was reported via the novel Improved Bidimensional SUCRA score (IBiS: the higher the value the better the treatment). Data obtained from 12,136 COPD patients (79.50% LABA/LAMA FDCs vs. placebo; 20.50% direct comparison between different LABA/LAMA FDCs) were extracted from 22 studies published between 2013 and 2019. The IBiS score showed the following rank of efficacy/safety profile: tiotropium/olodaterol 5/5 µg (area 66.83%) ¼ glycopyrronium/indacaterol 15.6/27.5 µg (area 40.43%)  >  umeclidinium/vilanterol 62.5/25 µg (area 30.48%)  ≈  aclidinium/formoterol 400/12 µg (area 28.44%)  >  glycopyrronium/indacaterol 50/110 µg (area 19.95%)  >  glycopyrronium/formoterol 14.4/9.6 µg (area 11.50%). Each available LABA/LAMA FDC has a specific efficacy/safety profile that needs to be considered for personalized therapy in COPD. Head-to-head studies aimed to assess the impact of different LABA/LAMA FDCs on the risk of COPD exacerbation are needed to further improve the information provided by this quantitative synthesis.

Evolving Concepts in Chronic Obstructive Pulmonary Disease Blood-Based Biomarkers.

In recent years, there has been a great deal of interest in the identification and validation of blood-based biomarkers for clinical use in chronic obstructive pulmonary disease (COPD). We now have panels of blood biomarkers that potentially hold great promise as they show statistically significant associations with COPD, but biomarkers for the diagnosis of COPD remain elusive. In fact, they are yet to demonstrate sufficient accuracy to be accepted in clinical use, and many are not specific to COPD but more related to inflammation (e.g. interleukin-6) or associated with other chronic diseases such as diabetes (e.g. soluble receptor for advanced glycation endproducts [sRAGE]). Although no single blood-based biomarker has demonstrated clinical utility for either the diagnosis or progression of COPD, it has been suggested that combinations of individual markers may provide important diagnostic or prognostic information; however, the interpretation of COPD biomarker results still requires thought and many questions remain unanswered.

A potential role of triple therapy for asthma patients.

Introduction: The use of LAMAs in asthma is now supported by pharmacological and clinical evidence, whereas the effectiveness of therapy with ICS/LABA/LAMA fixed dose combinations in patients with asthma still remains to be determined. Areas covered: The pharmacological rationale that explains why it is possible to use triple therapy in asthma and the results of clinical studies that have explored the effects of this therapy in asthmatics is critically examined. A systematic search was conducted on 10 August 2019, and included six electronic databases: EMBASE, MEDLINE, Scopus, The Cochrane Library, Web of Science, and Google Scholar. Expert opinion: The real role of single inhaler triple therapy in asthma will be demonstrated when the various trials that are currently ongoing or are scheduled will be completed. We believe that it is appropriate to treat with triple therapy asthmatic patients who have smoked and remain symptomatic or suffer from frequent exacerbations despite initial inhaler therapy with ICS/LABA. However, we must establish when to step up or mainly step down triple therapy especially in patients who are well controlled, and what will be the cost of these combinations in the management of asthma.

Efficacy and safety profile of mucolytic/antioxidant agents in chronic obstructive pulmonary disease: a comparative analysis across erdosteine, carbocysteine, and N-acetylcysteine.

BACKGROUND: To date there are no head-to-head studies comparing different mucolytic/antioxidant agents. Considering the inconsistent evidence resulting from the pivotal studies on mucolytic/antioxidant agents tested in chronic obstructive pulmonary disease (COPD), and the recent publication of Reducing Exacerbations and Symptoms by Treatment with ORal Erdosteine in COPD (RESTORE) study, we have performed a meta-analysis to compare the efficacy and safety of erdosteine 600 mg/day, carbocysteine 1500 mg/day, and N-acetylcysteine (NAC) 1200 mg/day in COPD. METHODS: A pairwise and network meta-analyses were performed to assess the efficacy of erdosteine, carbocysteine, and NAC on acute exacerbation of COPD (AECOPD), duration of AECOPD, and hospitalization. The frequency of adverse events (AEs) was also investigated. RESULTS: Data obtained from 2753 COPD patients were extracted from 7 RCTs published between 2004 and 2017. In the pairwise meta-analysis mucolytic/antioxidant agents significantly reduced the risk of AECOPD (RR 0.74 95%CI 0.68-0.80). The network meta-analysis provided the following rank of effectiveness: erdosteine>carbocysteine>NAC. Only erdosteine reduced the risk of experiencing at least one AECOPD (P < 0.01) and the risk of hospitalization due to AECOPD (P < 0.05). Erdosteine and NAC both significantly reduced the duration of AECOPD (P < 0.01). The AEs induced by erdosteine, carbocysteine, and NAC were mild in severity and generally well tolerated. The quality of evidence of this quantitative synthesis is moderate. CONCLUSIONS: The overall efficacy/safety profile of erdosteine is superior to that of both carbocysteine and NAC. Future head-to-head studies performed on the same COPD populations are needed to definitely confirm the results of this meta-analysis. TRIAL REGISTRATION: CRD42016053762 .

The prognostic role of Gender-Age-Physiology system in idiopathic pulmonary fibrosis patients treated with pirfenidone.

INTRODUCTION: Gender, age, physiology (GAP) system have proven to be an easy tool for predicting disease stages and survival in idiopathic pulmonary fibrosis (IPF) patients. OBJECTIVE: To validate mortality risk as determined by the GAP system in a real-life multicentre IPF population treated with pirfenidone. METHODS: The study included patients who received pirfenidone for at least 6 months. The GAP calculator and the GAP index were determined. The primary outcome was all-cause mortality. The prognostic accuracy of the GAP system was evaluated with respect to calibration and discrimination. RESULTS AND CONCLUSION: Sixty-eight IPF patients were enrolled in the study. The median follow-up was 2.4 years (range 0.1-7.4 years). A total of 22 deaths as first event (32%) and of 10 lung transplantation (15%) were recorded. The cumulative incidence of mortality at 1, 2 and 3 years was 10.4%, 22.4% and 38.4%, respectively. The differences between the predicted and observed mortality were not significant for the GAP index while the observed mortality become comparable to that predicted by the GAP calculator only in the third year of follow-up. The C-index for the GAP index was 0.74 (95% CI 0.57-0.93) while the C-statistic value for the GAP calculator was 0.77 (95% CI 0.59-0.95).

Emerging biological therapies for treating chronic obstructive pulmonary disease: A pairwise and network meta-analysis.

Inflammation in chronic obstructive pulmonary disease (COPD) is often corticosteroid resistant and, thus, alternative anti-inflammatory approaches are needed. Since it is still not clear whether blocking specific pro-inflammatory factors may provide clinical benefit in COPD, we have performed a meta-analysis to quantify the impact of monoclonal antibodies (mABs) targeting the cytokine/chemokine-mediated inflammation in COPD. A pairwise and network meta-analyses were performed by extracting data from randomized clicnial trials on COPD concerning the impact of mABs vs. placebo on the risk of exacerbation, forced expiratory volume in 1 s (FEV1), and St. George's Respiratory Questionnaire (SGRQ). Data on the interleukin (IL)-1ß antagonist canakinumab, IL-1R1 antagonist MEDI8986, IL-5 antagonist mepolizumab, IL-5R antagonist benralizumab, IL-8 antagonist ABX-IL8, and TNF-α antagonist infliximab were found. Overall, mAB therapy had a moderate impact on the risk exacerbation, but not on FEV1 and SGRQ. The pairwise meta-analysis performed in eosinophilic patients, and the network approach, indicated that mepolizumab elicited a beneficial effect against the risk of exacerbation, whereas benralizumab was more effective in improving both FEV1 and SGRQ. This study demonstrates that targeting the pathway activated by IL-5 may have a beneficial impact in eosinophilic COPD patients.