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Abstract Introduction Chronic obstructive pulmonary disease (COPD) is a frequent cause of morbidity and mortality. Dysregulated and enhanced immune-inflammatory responses have been described in COPD. Recent data showed impaired immune responses and, in particular, of interferon (IFNs) signaling pathway in these patients. Aim To evaluate in peripheral lung of COPD patients, the expression of some of the less investigated key components of the innate immune responses leading to IFN productions including: IFN-receptors (IFNAR1/IFNAR2), IRF-3 and MDA-5. Correlations with clinical traits and with the inflammatory cell profile have been assessed. Methods Lung specimens were collected from 58 subjects undergoing thoracic surgery: 22 COPD patients, 21 smokers with normal lung function (SC) and 15 non-smoker controls (nSC). The expression of IFNAR1, IFNAR2, IRF-3 and MDA-5, of eosinophils and activated NK cells (NKp46+) were quantified in the peripheral lung by immunohistochemistry. Results A significant increase of IRF-3 + alveolar macrophages were observed in COPD and SC compared with nSC subjects. However, in COPD patients, the lower the levels of IRF-3 + alveolar macrophages the lower the FEV1 and the higher the exacerbation rate. The presence of chronic bronchitis (CB) was also associated with low levels of IRF-3 + alveolar macrophages. NKp46 + cells, but not eosinophils, were increased in COPD patients compared to nSC patients (p

Background: Despite the well-known efficacy of anti-COVID-19 vaccines in preventing morbidity and mortality, several vaccinated individuals are diagnosed with SARS-CoV-2 breakthrough infection, which might require hospitalisation. This multicentre, observational, and retrospective study aimed to investigate the clinical characteristics and outcomes of vaccinated vs. non-vaccinated patients, both hospitalised with SARS-CoV-2 infection in 3 major hospitals in Northern Italy. Methods: Data collection was retrospective, and paper and electronic medical records of adult patients with a diagnosed SARS-CoV-2 infection were pseudo-anonymised and analysed. Vaccinated and non-vaccinated individuals were manually paired, using a predetermined matching criterion (similar age, gender, and date of hospitalisation). Demographic, clinical, treatment, and outcome data were compared between groups differing by vaccination status using Pearson’s Chi-square and Mann-Whitney tests. Moreover, multiple logistic regression analyses were performed to assess the impact of vaccination status on ICU admission or intra-hospital mortality. Results: Data from 360 patients were collected. Vaccinated patients presented with a higher prevalence of relevant comorbidities, like kidney replacement therapy or haematological malignancy, despite a milder clinical presentation at the first evaluation. Non-vaccinated patients required intensive care more often than their vaccinated counterparts (8.8% vs. 1.7%, p = 0.002). Contrariwise, no difference in intra-hospital mortality was observed between the two groups (19% vs. 20%, p = 0.853). These results were confirmed by multivariable logistic regressions, which showed that vaccination was significantly associated with decreased risk of ICU admission (aOR=0.172, 95%CI: 0.039–0.542, p = 0.007), but not of intra-hospital mortality (aOR=0.996, 95%CI: 0.582–1.703, p = 0.987). Conclusions: This study provides real-world data on vaccinated patients hospitalised with COVID-19 in Northern Italy. Our results suggest that COVID-19 vaccination has a protective role in individuals with higher risk profiles, especially regarding the need for ICU admission. These findings contribute to our understanding of SARS-CoV-2 infection outcomes among vaccinated individuals and emphasise the importance of vaccination in preventing severe disease, particularly in those countries with lower first-booster uptake rates.

A panel of 24 international experts met in July 2022 to discuss challenges associated with pertussis detection, monitoring, and vaccination in adults; conclusions from this meeting are presented. There has been a shift in the epidemiology of pertussis toward older children and adults. This shift has been attributed to the waning of infection- or vaccine-induced immunity, newer detection techniques causing detection bias, and possibly the replacement of whole-cell pertussis with acellular vaccines in high-income countries, which may lead to immunity waning more quickly. The burden of adult pertussis is still likely under-ascertained due to widespread under-recognition by healthcare professionals (HCPs), under-diagnosis, and under-reporting in this age group. Non-standardized testing guidance and varied case definitions have contributed to under-reporting. Key barriers to HCP engagement with the tetanus, diphtheria, and pertussis (Tdap) vaccine include low awareness, lack of time/funding, and lack of motivation due to low prioritization of Tdap.

ABSTRACTPertussis has several notable consequences, causing economic burden, increased strain on healthcare facilities, and reductions in quality of life. Recent years have seen a trend toward an increase in pertussis cases affecting older children and adults. To boost immunity, and protect vulnerable populations, an enduring approach to vaccination has been proposed, but gaps remain in the evidence surrounding adult vaccination that are needed to inform such a policy. Gaps include: the true incidence of pertussis and its complications in adults; regional variations in disease recognition and reporting; and incidence of severe disease, hospitalizations, and deaths in older adults. Better data on the efficacy/effectiveness of pertussis vaccination in adults, duration of protection, and factors leading to poor vaccine uptake are needed. Addressing the critical evidence gaps will help highlight important areas of unmet need and justify the importance of adult pertussis vaccination to healthcare professionals, policymakers, and payers.

Abstract Rationale It is unclear how each individual asthma symptom is associated with asthma diagnosis or control. Objectives To assess the performance of individual asthma symptoms in the identification of patients with asthma and their association with asthma control. Methods In this cross‐sectional study, we assessed real‐world data using the MASK‐air® app. We compared the frequency of occurrence of five asthma symptoms (dyspnea, wheezing, chest tightness, fatigue and night symptoms, as assessed by the Control of Allergic Rhinitis and Asthma Test [CARAT] questionnaire) in patients with probable, possible or no current asthma. We calculated the sensitivity, specificity and predictive values of each symptom, and assessed the association between each symptom and asthma control (measured using the e‐DASTHMA score). Results were validated in a sample of patients with a physician‐established diagnosis of asthma. Measurement and Main Results We included 951 patients (2153 CARAT assessments), with 468 having probable asthma, 166 possible asthma and 317 no evidence of asthma. Wheezing displayed the highest specificity (90.5%) and positive predictive value (90.8%). In patients with probable asthma, dyspnea and chest tightness were more strongly associated with asthma control than other symptoms. Dyspnea was the symptom with the highest sensitivity (76.1%) and the one consistently associated with the control of asthma as assessed by e‐DASTHMA. Consistent results were observed when assessing patients with a physician‐made diagnosis of asthma. Conclusions Wheezing and chest tightness were the asthma symptoms with the highest specificity for asthma diagnosis, while dyspnea displayed the highest sensitivity and strongest association with asthma control.

Background Asthma is a heterogeneous disease with a prevalence and severity that differs between male and female patients.Question What are differences between male and female patients with asthma with regard to asthma control, lung function, inflammation and exacerbations?Methods We performed a post hoc analysis in the ATLANTIS (Assessment of Small Airways Involvement in Asthma) study, an observational cohort study including patients with asthma from nine countries with a follow-up of 1 year during which patients were characterised with measures of large and small airway function, questionnaires, inflammation and imaging. We compared differences in baseline characteristics and longitudinal outcomes between male and female patients with asthma.Results 773 patients were enrolled; 450 (58%) of these were female. At baseline, female patients with asthma were in higher Global Initiative for Asthma (GINA) steps (p=0.042), had higher Asthma Control Questionnaire 6 (F: 0.83; M: 0.66, p

Background: The relationships between spirometric assessment of lung function and symptoms (including exacerbations) in patients with asthma and/or chronic obstructive pulmonary disease (COPD) in a real-life setting are uncertain. Objectives: To assess the relationships between baseline post-bronchodilator (post-BD) spirometry measures of lung function and symptoms and exacerbations in patients with a physician-assigned diagnosis of asthma and/or COPD. Design: The NOVEL observational longiTudinal studY (NOVELTY) is a global, prospective, 3-year observational study. Methods: Logistic regression analysis was used to evaluate relationships. Spirometry measures were assessed as percent predicted (%pred). Symptoms were assessed at baseline, and exacerbations were assessed at baseline and Year 1. Results: A total of 11,181 patients in NOVELTY had spirometry data (asthma, n = 5903; COPD, n = 3881; asthma + COPD, n = 1397). A 10% lower post-BD %pred forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity (FVC) – adjusted for age and sex – were significantly associated with dyspnea (modified Medical Research Council ⩾ grade 2), frequent breathlessness [St George’s Respiratory Questionnaire (SGRQ)], frequent wheeze attacks (SGRQ), nocturnal awakening (Respiratory Symptoms Questionnaire; ⩾1 night/week), and frequent productive cough (SGRQ). Lower post-BD %pred FEV 1 and, to a lesser extent, lower post-BD %pred FVC were significantly associated with ⩾1 physician-reported exacerbation at baseline or Year 1. This association was stronger in patients with COPD than in those with asthma. Conclusion: In a real-life setting, reduced lung function is consistently associated with symptoms in patients with asthma, COPD, or asthma + COPD. The relationship with exacerbations is stronger in COPD only than in asthma. Trail registration: clinicaltrials.gov identifier: NCT02760329 ( www.clinicaltrials.gov ).

Abstract Background Asthma is stratified into type 2-high and type 2-low inflammatory phenotypes. Limited success has been achieved in developing drugs that target type 2-low inflammation. Previous studies have linked IL-6 signaling to severe asthma. IL-6 cooperates with soluble-IL-6Rα to activate cell signaling in airway epithelium. Objective We sought to study the role of sIL-6Rα amplified IL-6 signaling in airway epithelium and to develop an IL-6+ sIL-6Rα gene signature that may be used to select asthma patients who potentially respond to anti-IL-6 therapy. Methods Human airway epithelial cells were stimulated with combinations of IL-6, sIL-6Rα, and inhibitors, sgp130 (Olamkicept), and anti-IL-6R (Tocilizumab), to assess effects on pathway activation, epithelial barrier integrity, and gene expression. A gene signature was generated to identify IL-6 high patients using bronchial biopsies and nasal brushes. Results Soluble-IL-6Rα amplified the activation of the IL-6 pathway, shown by the increase of STAT3 phosphorylation and stronger gene induction in airway epithelial cells compared to IL-6 alone. Olamkicept and Tocilizumab inhibited the effect of IL-6 + sIL-6Rα on gene expression. We developed an IL-6 + sIL-6Rα gene signature and observed enrichment of this signature in bronchial biopsies but not nasal brushes from asthma patients compared to healthy controls. An IL-6 + sIL-6Rα gene signature score was associated with lower levels of sputum eosinophils in asthma. Conclusion sIL-6Rα amplifies IL-6 signaling in bronchial epithelial cells. Higher local airway IL-6 + sIL-6Rα signaling is observed in asthma patients with low sputum eosinophils.

What is this summary about? This summary describes the results of a clinical study called MANDALA that was published in the New England Journal of Medicine in 2022. In the MANDALA study, researchers looked at a new asthma rescue inhaler that contains both albuterol and budesonide in a single inhaler (known as albuterol–budesonide , AIRSUPRA™). This summary describes the results for people aged 18 yearsand older who took part in the study.

Abstract Background The recent pandemic outbursts, due to SARS-CoV-2, have highlighted once more the central role of the inflammatory process in the propagation of viral infection. The main consequence of COVID-19 is the induction of a diffuse pro-inflammatory state, also defined as a cytokine storm, which affects different organs, but mostly the lungs. We aimed to prove the efficacy of cinnamaldehyde, the active compound of cinnamon, as an anti-inflammatory compound, able to reduce SARS-CoV-2 induced cytokine storm. Results We enrolled 53 COVID-19 patients hospitalized for respiratory failure. The cohort was composed by 39 males and 13 females, aged 65.0 ± 9.8 years. We reported that COVID-19 patients have significantly higher IL-1β and IL-6 plasma levels compared to non-COVID-19 pneumonia patients. In addition, human mononuclear cells (PBMCs) isolated from SARS-CoV-2 infected patients are significantly more prone to release pro-inflammatory cytokines upon stimuli. We demonstrated, using in vitro cell models, that macrophages are responsible for mediating the pro-inflammatory cytokine storm while lung cells support SARS-CoV-2 replication upon viral infection. In this context, cinnamaldehyde administration significantly reduces SARS-CoV-2-related inflammation by inhibiting NLRP3 mediated IL-1β release in both PBMCs and THP-1 macrophages, as well as viral replication in CaLu-3 epithelial cells. Lastly, aerosol-administered cinnamaldehyde was able to significantly reduce IL-1β release in an in vivo lung-inflammatory model. Conclusion The obtained results suggest the possible use of cinnamaldehyde as a co-adjuvant preventive treatment for COVID-19 disease together with vaccination, but also as a promising dietary supplement to reduce, more broadly, viral induced inflammation.

Objective: Chronic obstructive pulmonary disease (COPD) is one of the main causes of morbidity and mortality in the United States. Oxidative stress due to cigarette smoking seems to be one of the major driving mechanisms in COPD pathogenesis. Since the scavenger receptor B1 (SR-B1) appears to play a key role in med iating the uptake for ɑ-tocopherol and other antioxidants in lung tissue, we aimed to investigate its role in COPD pathogenesis. Methods: Lung tissue biopsies were obtained from 12 subjects; 6 of these had a diagnosis of COPD in a stable clinical state, the others 6 were current (n = 1) or ex-smokers (n = 5) with normal lung function (controls). 4-Hydroxynonenal (4-HNE)–SR-B1 adducts were detected by immunoprecipitation. ɑ-tocopherol concentration was determined by HPLC. Results: SR-B1 levels were lower in COPD patients and these results par allel with lower levels of vitamin E in lung tissue found in COPD patients . This effect can be the consequence of oxidative posttranslational modifications, confirmed by the binding of the peroxidation product 4-HNE to SR-B1 possibly leading to its degradation. Conclusions: The loss of SR-B1 may be involved in lung ɑ-tocopherol content decrease with the consequence of making lung tissue more susceptible to oxidative damage as suggested by the SR-B1–4-HNE adduct formation, and more prone to COPD development. Thus, our findings suggest a novel role of SR-B1 in pathomechani sms underlying COPD. Significance statement Chronic obstructive pulmonary disease (COPD) is one of the main causes of morbidity and mortality in the United States. Oxidative stress has been suggested to be the major driving mechanism in COPD pathogenesis. Loss of scavenger receptor BI (SR-B1) significantly decreases tocopherol lung content making lung tissue more susceptible to oxidative damage. The results of our study show that SR-B1 levels were lower in COPD patients and these results parallel with lower levels of vitamin E in lung tissue. Our findings suggest a novel role of SR- B1 in pathomechanisms underlying COPD.

Abstract 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

Abstract Background Pleural disease (PD), particularly malignant pleural effusion (MPE), is a common cause of hospital admission and its prevalence is rising worldwide. Recent advances in diagnostic and therapeutic options, such as Indwelling Pleural Catheters (IPCs), have simplified PD treatment, allowing an effective outpatients management. Therefore, dedicated pleural services can improve PD care, guaranteeing specialized management and optimizing time and cost. We aimed to provide an overview on MPE management in Italy, mainly focused on distribution and characteristics of pleural services and IPCs use. Methods A nationwide survey, endorsed by the Italian Thoracic Society, was distributed by email to members of selected subgroups in 2021. Results Ninety (23%) members replied, most of whom being pulmonologists (91%). MPE resulted the most common cause of pleural effusion and was managed with heterogenous approaches, including talc pleurodesis via slurry (43%), talc poudrage (31%), repeated thoracentesis (22%) and IPCs insertion (2%). The setting of IPC insertion was inpatient care in 48% of cases, with a predominance of draining frequency every other day. IPC management mainly relied on caregivers (42%). The presence of a pleural service was reported by 37% of respondents. Conclusions The present study provides an extensive overview of MPE management in Italy, showing a highly heterogeneous approach, a scarce prevalence of out-patient pleural services, and a still limited adoption of IPCs, mainly due to lack of dedicated community care systems. This survey emphasizes the need of promoting a higher spreading of pleural services and an innovative healthcare delivery with more favourable cost-benefit ratio.

Background The diagnosis of COPD requires the demonstration of non-fully reversible airflow limitation by spirometry in the appropriate clinical context. Yet, there are patients with symptoms and relevant exposures suggestive of COPD with either normal spirometry (pre-COPD) or preserved ratio but impaired spirometry (PRISm). Their prevalence, clinical characteristics and associated outcomes in a real-life setting are unclear. Methods To investigate them, we studied 3183 patients diagnosed with COPD by their attending physician included in the NOVELTY study (clinicaltrials.gov identifier NCT02760329), a global, 3-year, observational, real-life cohort that included patients recruited from both primary and specialist care clinics in 18 countries. Results We found that 1) approximately a quarter of patients diagnosed with (and treated for) COPD in real life did not fulfil the spirometric diagnostic criteria recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD), and could be instead categorised as pre-COPD (13%) or PRISm (14%); 2) disease burden (symptoms and exacerbations) was highest in GOLD 3–4 patients (exacerbations per person-year (PPY) 0.82) and lower but similar in those in GOLD 1–2, pre-COPD and PRISm (exacerbations range 0.27–0.43 PPY); 3) lung function decline was highest in pre-COPD and GOLD 1–2, and much less pronounced in PRISm and GOLD 3-4; 4) PRISm and pre-COPD were not stable diagnostic categories and change substantially over time; and 5) all-cause mortality was highest in GOLD 3–4, lowest in pre-COPD, and intermediate and similar in GOLD 1–2 and PRISm. Conclusions Patients diagnosed COPD in a real-life clinical setting present great diversity in symptom burden, progression and survival, warranting medical attention.

The treatable traits approach represents a strategy for patient management. It is based on the identification of characteristics susceptible to treatments or predictive of treatment response in each individual patient. With the objective of accelerating progress in research and clinical practice relating to such a treatable traits approach, the Portraits event was convened in Barcelona, Spain, in November 2022. Here, while reporting the key concepts that emerged from the discussions during the meeting, we review the current state of the art related to treatable traits and chronic respiratory diseases management, and we describe the possible actions that clinicians can take in clinical practice to implement the treatable traits framework. Furthermore, we explore the new concept of GETomics and the new models of research in the field of COPD.

Objetivos: O vírus sincicial respiratório (VSR) pode causar doença respiratória grave em adultos mais velhos com problemas cardiorrespiratórios. Em um estudo controlado por placebo de fase 3 em andamento (NCT04886596), a eficácia da vacina (VE) RSVPreF3 OA durante a primeira temporada de VSR foi de 82,6% contra doenças do trato respiratório inferior relacionadas ao VSR (RSV-LRTD), e 71,7% contra doenças respiratórias agudas relacionadas ao VSR (RSV-ARI) em adultos com ≥60 anos de idade. Apresentamos a VE em participantes com condições cardiorrespiratórias coexistentes de interesse associadas a um risco maior de desfechos graves da doença por VSR. Métodos: Adultos com ≥60 anos foram randomizados 1:1 e receberam 1 dose de vacina RSVPreF3 OA ou placebo. A VE foi avalida contra primeiros episódios de RSV-LRTD e RSV-ARI em subgrupos de interesse específico. Resultados: Dos 12.467 pacientes que receberam a vacina RSVPreF3 OA e 12.499 pacientes que receberam placebo, um total de 20,0% e 19,4%, respectivamente, tinham ≥ 1 condição cardiorrespiratória de interesse. As taxas de incidência de RSV-LRTD e RSV-ARI foram maiores no grupo placebo com ≥1 condição cardiorrespiratória de interesse versus aqueles sem nenhuma condição médica de interesse. A VE foi de 92,1% para prevenir RSV-LRTD, e 88,1% para RSV-ARI. Conclusões: RSVPreF3 OA foi eficaz contra RSV-LRTD e RSV-ARI em adultos com ≥ 60 anos de idade com condições cardiorrespiratórias de interesse, sendo essa provavelmente a população que mais pode se beneficiar da proteção contra VSR. ENCORE: este é um ENCORE de um resumo apresentado na ERS 2023.

Background The stepwise approach to long-term asthma management, which traditionally incorporates short-acting β2-agonist reliever therapy, has been a core feature of asthma guidelines for over 30 years. There have been no studies, however, directly investigating the use of an entire guideline-recommended track. Recently, inhaled corticosteroid–formoterol has been recommended as the preferred reliever therapy in adult asthma, in accordance with a stepwise “Anti-Inflammatory Reliever” (AIR) treatment track. Objective The aim of this study was to evaluate the AIR stepwise approach recommended by the New Zealand adolescent and adult asthma guidelines, in combination with a novel algorithm for transitioning between treatment steps. Methods This 52-week, open-label, single-group study will recruit 100 adults aged 18 to 75 years with mild, moderate and moderate–severe asthma (ACTRN12620001010987). Participants will be allocated to budesonide–formoterol 200/6 µg, one actuation as needed (Step 1), one actuation twice daily and as needed (Step 2), or two actuations twice daily and one as needed (Step 3). Treatment steps will be adjusted throughout the study, in response to reliever use and asthma attacks, according to a stepwise AIR algorithm. Following a 26-week period of investigator-led transitions, participants will adjust their own treatment step. The primary outcome is participant satisfaction as measured by the Global Satisfaction score of the Treatment Satisfaction Questionnaire for Medication. Secondary outcomes will assess efficacy and safety, and describe patterns of medication use and participant flow through the treatment steps. Conclusion This is the first trial to assess the AIR treatment track and algorithm. The results will provide knowledge to guide the clinical use of this approach.

Abstract Background Dyspnea is common after COVID-19 pneumonia and can be characterized by a defective CO2 diffusion (DLCO) despite normal pulmonary function tests (PFT). Nevertheless, DLCO impairment tends to normalize at 1 year, with no dyspnea regression. The altered regional distribution of ventilation and a dysfunction of the peripheral lung may characterize dyspnea at 1 year after COVID-19 pneumonia. We aimed at assessing the pattern of airway resistance and inflammation and the regional ventilation inhomogeneity in COVID-19 pneumonia survivors at 12-months after hospital discharge. Methods We followed up at 1-year patients previously admitted to the respiratory units (intensive care or sub-intensive care unit) for COVID-19 acute respiratory failure at 1-year after hospital discharge. PFT (spirometry, DLCO), impulse oscillometry (IOS), measurements of the exhaled nitric oxide (FENO) and Electrical Impedance Tomography (EIT) were used to evaluate lung volumes, CO2 diffusion capacity, peripheral lung inflammation/resistances and the regional inhomogeneity of ventilation distribution. A full medical examination was conducted, and symptoms of new onset (not present before COVID-19) were recorded. Patients were therefore divided into two groups based on the presence/absence of dyspnea (defined as mMRC ≥1) compared to evaluate differences in the respiratory function derived parameters. Results Sixty-seven patients were admitted between October and December 2020. Of them, 42/67 (63%) patients were discharged alive and 33 were evaluated during the follow up. Their mean age was 64 ± 11 years and 24/33 (73%) were males. Their maximum respiratory support was in 7/33 (21%) oxygen, in 4/33 (12%) HFNC, in 14/33 (42%) NIV/CPAP and in 8/33 (24%) invasive mechanical ventilation. During the clinical examination, 15/33 (45%) reported dyspnea. When comparing the two groups, no significant differences were found in PFT, in the peripheral airway inflammation (FENO) or mechanical properties (IOS). However, EIT showed a significantly higher regional inhomogeneity in patients with dyspnea both during resting breathing (0.98[0.96–1] vs 1.1[1–1.1], p = 0.012) and during forced expiration (0.96[0.94–1] vs 1 [0.98–1.1], p = 0.045). Conclusions New onset dyspnea characterizes 45% of patients 1 year after COVID-19 pneumonia. In these patients, despite pulmonary function test may be normal, EIT shows a higher regional inhomogeneity both during quiet and forced breathing which may contribute to dyspnea. Clinical trial registration Clinicaltrials.gov NCT04343053, registration date 13/04/2020.

IntroductionThe pathophysiology of the Corona Virus Disease 2019 (COVID-19) is incompletely known. A robust inflammatory response caused by viral replication is a main cause of the acute lung and multiorgan injury observed in critical patients. Inflammasomes are likely players in COVID-19 pathogenesis. The P2X7 receptor (P2X7R), a plasma membrane ATP-gated ion channel, is a main activator of the NLRP3 inflammasome, of the ensuing release of inflammatory cytokines and of cell death by pyroptosis. The P2X7R has been implicated in COVID-19-dependent hyperinflammation and in the associated multiorgan damage. Shed P2X7R (sP2X7R) and shed NLRP3 (sNLRP3) have been detected in plasma and other body fluids, especially during infection and inflammation.MethodsBlood samples from 96 patients with confirmed SARS-CoV-2 infection with various degrees of disease severity were tested at the time of diagnosis at hospital admission. Standard haematological parameters and IL-6, IL-10, IL-1β, sP2X7R and sNLRP3 levels were measured, compared to reference values, statistically validated, and correlated to clinical outcome. ResultsMost COVID-19 patients included in this study had lymphopenia, eosinopenia, neutrophilia, increased inflammatory and coagulation indexes, and augmented sNLRP3, IL-6 and IL-10 levels. Blood concentration of sP2X7R was also increased, and significantly positively correlated with lymphopenia, procalcitonin (PCT), IL-10, and alanine transaminase (ALT). Patients with increased sP2X7R levels at diagnosis also showed fever and respiratory symptoms, were more often transferred to Pneumology division, required mechanical ventilation, and had a higher likelihood to die during hospitalization. ConclusionBlood sP2X7R was elevated in the early phases of COVID-19 and predicted an adverse clinical outcome. It is suggested that sP2X7R might be a useful marker of disease progression.

Summary: Background: Validated questionnaires are used to assess asthma control over the past 1–4 weeks from reporting. However, they do not adequately capture asthma control in patients with fluctuating symptoms. Using the Mobile Airways Sentinel Network for airway diseases (MASK-air) app, we developed and validated an electronic daily asthma control score (e-DASTHMA). Methods: We used MASK-air data (freely available to users in 27 countries) to develop and assess different daily control scores for asthma. Data-driven control scores were developed based on asthma symptoms reported by a visual analogue scale (VAS) and self-reported asthma medication use. We included the daily monitoring data from all MASK-air users aged 16–90 years (or older than 13 years to 90 years in countries with a lower age of digital consent) who had used the app in at least 3 different calendar months and had reported at least 1 day of asthma medication use. For each score, we assessed construct validity, test–retest reliability, responsiveness, and accuracy. We used VASs on dyspnoea and work disturbance, EQ-5D-VAS, Control of Allergic Rhinitis and Asthma Test (CARAT), CARAT asthma, and Work Productivity and Activity Impairment: Allergy Specific (WPAI:AS) questionnaires as comparators. We performed an internal validation using MASK-air data from Jan 1 to Oct 12, 2022, and an external validation using a cohort of patients with physician-diagnosed asthma (the INSPIRERS cohort) who had had their diagnosis and control (Global Initiative for Asthma [GINA] classification) of asthma ascertained by a physician. Findings: We studied 135 635 days of MASK-air data from 1662 users from May 21, 2015, to Dec 31, 2021. The scores were strongly correlated with VAS dyspnoea (Spearman correlation coefficient range 0·68–0·82) and moderately correlated with work comparators and quality-of-life-related comparators (for WPAI:AS work, we observed Spearman correlation coefficients of 0·59–0·68). They also displayed high test–retest reliability (intraclass correlation coefficients range 0·79–0·95) and moderate-to-high responsiveness (correlation coefficient range 0·69–0·79; effect size measures range 0·57–0·99 in the comparison with VAS dyspnoea). The best-performing score displayed a strong correlation with the effect of asthma on work and school activities in the INSPIRERS cohort (Spearman correlation coefficients 0·70; 95% CI 0·61–0·78) and good accuracy for the identification of patients with uncontrolled or partly controlled asthma according to GINA (area under the receiver operating curve 0·73; 95% CI 0·68–0·78). Interpretation: e-DASTHMA is a good tool for the daily assessment of asthma control. This tool can be used as an endpoint in clinical trials as well as in clinical practice to assess fluctuations in asthma control and guide treatment optimisation. Funding: None.

Vaccines against SARS-CoV-2 ameliorate infection and adverse outcomes from SARS-CoV-2. Elicitation of high affinity and durable protective antibody responses is a hallmark of a successful humoral immune response to vaccination. To assess the relevance of serum levels of SARS-CoV-2 specific antibodies and to further characterize the immune response to SARS-CoV-2 vaccines, we report i) the levels of spike-binding and neutralizing antibodies to SARS-COV-2 in the sera of 30 healthy volunteers at nine months after the second vaccination dose of mRNA vaccine and one month after the booster dose; ii) the levels of IFN-γ production by blood T cells exposed to SARS-CoV-2 spike antigen (Wuhan, Alpha B.1.1.7, Delta B.1.617.2, and Omicron B1.1.529 variants); and iii) the specific phenotype of T cells related with exposure to SARS-CoV-2 spike antigen. We observed that the booster dose induced increased humoral and adaptive immune responses and led to early activation of the memory CD8+ T subset.

Recent data support the existence of a distinctive ‘vascular’ phenotype with the involvement of both pulmonary parenchyma and its circulation in COVID‐19 pneumonia. Its prompt identification is important for the accurate management of COVID‐19 patients. The aim is to analyse the pro and contra of the different modalities to identify the ‘vascular’ phenotype. Chest computed tomography scan and angiogram may quantify both parenchyma and vascular damage, but the presence of thrombosis of pulmonary microcirculation may be missed. Increased d‐dimer concentration confirms a thrombotic state, but it cannot localize the thrombus. An elevation of troponin concentration non‐specifically reflects cardiac injury. Echocardiogram and electrocardiogram provide specific signs of right ventricular pressure overload. This is particularly relevant for the ‘vascular’ phenotype, which does not necessarily represent the result of thrombo‐embolic venous complications, but more frequently, it is the result of pulmonary microcirculation thrombosis in situ and needs immediate therapeutic action. Condensed abstract Despite diagnosis of the ‘vascular’ phenotype of COVID‐19 pneumonia may be subtle, the evidence indicates a reasonable possibility of identifying it already in the initial stage of the infection. Chest computed tomography scan and angiogram, increased d‐dimer concentration, and elevation of troponin concentration may be not sufficient to identify ‘vascular’ phenotype. Echocardiogram and electrocardiogram provide specific signs of right ventricular pressure overload. This is particularly relevant for the ‘vascular’ phenotype, which does not necessarily represent the result of thrombo‐embolic venous complications, but more frequently, it is the result of pulmonary microcirculation thrombosis in situ and needs immediate therapeutic action.

ABSTRACTBackground: Treatment guidelines for asthma management are derived almost exclusively from the results of controlled clinical trials undertaken in carefully selected patient populations; meaning that their outcomes may not reflect the true performance of treatments when used in general daily medical practice. The aim of this meta-analysis was to combine the results of observational studies investigating the fluticasone propionate/formoterol (FP/FORM) fixed-dose combination in real-world asthma patients. Methods: A systemic literature review was completed in March 2019 using the PubMed database. We identified 394 studies. Five studies, which included a total of 4756 patients treated with FP/FORM, were judged eligible and included in the meta-analysis. Results: The estimated severe asthma exacerbation rate was 11.47% (95% CI, 5.8 to 18.72%), calculated from the random effect model. A sensitivity analysis excluding 2 studies (one was an outlier, and the exacerbation rate for the studied treatment alone could not be determined in the other) showed a 7.04% rate of severe asthma exacerbations. The estimated relative risk of the incidence of severe asthma exacerbations was 0.323 (95% CI, 0.159 to 0.658). The estimated asthma control rate was 60.6% (95% CI, 55.7% to 65.6%). The odds of achieving asthma control significantly increased by FP/FORM compared with pre-study conditions (estimated odds ratio: 2.214 [95% CI, 1.292 to 3.795]; p

Background: The infection and negative effects of the SARS-CoV-2 (severe acute respiratory syndrome coronavirus) virus are mitigated by vaccines. It is unknown whether vaccination has worked by eliciting robust protective innate immune responses with high affinity. Methods: Twenty healthy volunteers received three doses of Comirnaty (Pfizer Australia Pty Ltd.) and were evaluated 9 months after the second vaccination and 1 month after the booster dose. The exclusion criteria were the presence of adverse effects following the vaccination, a history of smoking, and heterologous immunization. The inclusion criteria were the absence of prior Coronavirus Disease (COVID)-19 history, the absence of adverse effects, and the absence of comorbidities. Specific phenotype and levels of CD107a and granzyme production by blood NK (natural killer) cells were analyzed after exposure to SARS-CoV-2 spike antigen (Wuhan, Alpha B.1.1.7, Delta B.1.617.2, and Omicron B1.1.529 variants), and related with anti-SARS-CoV-2 antibody production. Results: The booster dose caused early NK CD56dim subset activation and memory-like phenotype. Conclusions: We report the relevance of the innate immune response, especially NK cells, to SARS-CoV-2 vaccines to guarantee efficient protection against the infection following a booster dose.

Background In randomised controlled trials, as-needed inhaled corticosteroid (ICS)-formoterol reliever therapy reduces severe exacerbation risk compared with maintenance ICS plus short-acting beta2-agonist (SABA) reliever in adolescent and adult asthma, but results in slightly worse control of asthma symptoms, as measured by mean Asthma Control Questionnaire-5 (ACQ-5) score.Objective To assess the levels and changes in asthma control for as-needed budesonide–formoterol versus maintenance budesonide plus SABA in post hoc analyses from the Novel START and PRACTICAL clinical trials.Methods The number and proportion of participants at study end in each ACQ-5 category (‘well-controlled’, ‘partly controlled’ or ‘inadequately controlled’ symptoms), and in each responder category based on the minimal clinically important difference for ACQ-5 of 0.5 (improved, no change and worse) with as-needed budesonide–formoterol and maintenance budesonide plus SABA treatment were calculated.Results With last observation carried forwards, 189/214 (88.3%) and 354/434 (81.6%) of patients in the budesonide–formoterol group had ‘well-controlled’ or ‘partly controlled’ symptoms at the end of the study, vs 183/214 (85.5%) and 358/431 (83.1%) in the budesonide maintenance group, for Novel START and PRACTICAL, respectively. The proportion of patients whose symptom control was either improved or unchanged from baseline was 190/214 (88.8%) and 368/434 (84.8%) for budesonide–formoterol, vs 185/214 (86.4%) and 376/431 (87.2%) for maintenance budesonide, in Novel START and PRACTICAL respectively.Conclusions There were no clinically important differences in the proportions of patients with ‘well-controlled’ or ‘partly controlled’ asthma symptoms, or proportions who improved or maintained their level of control, with as-needed budesonide–formoterol versus maintenance budesonide plus SABA.

The aim of this study (NCT04343053) is to investigate the relationship between platelet activation, myocardial injury, and mortality in patients affected by Coronavirus disease 2019 (COVID-19). Fifty-four patients with respiratory failure due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were enrolled as cases. Eleven patients with the same clinical presentation, but negative for SARS-CoV-2 infection, were included as controls. Blood samples were collected at three different time points (inclusion [T1], after 7 ± 2 days [T2] and 14 ± 2 days [T3]). Platelet aggregation by light transmittance aggregometry and the circulating levels of soluble CD40 ligand (sCD40L) and P-selectin were measured. Platelet biomarkers did not differ between cases and controls, except for sCD40L which was higher in COVID-19 patients (p = .003). In COVID-19 patients, P-selectin and sCD40L levels decreased from T1 to T3 and were higher in cases requiring admission to intensive care unit (p = .004 and p = .008, respectively). Patients with myocardial injury (37%), as well as those who died (30%), had higher values of all biomarkers of platelet activation (p

Abstract Background Asthma is a chronic disease characterized by airway hyperresponsiveness, inflammation and mucus production. In Type 2 asthma, two phenotypic components are often co-expressed (eosinophilic and allergic). Elevated biomarker levels, such as eosinophils (EOS), fraction of exhaled nitric oxide (FeNO) and immunoglobulin E (IgE), are key clinical indicators of Type 2 inflammation. Dupilumab has been recently approved for the treatment of uncontrolled severe Type 2 asthma. Type 2 asthma includes allergic and/or eosinophilic phenotypes. The aim of this analysis was to estimate the dupilumab-eligible population in Italy and characterize it by expected biomarker status. Methods A 4-step approach was carried out to calculate dupilumab-eligible population. The approach consisted in: (1) estimating the total number of asthma patients in Italy (using 2016–2017 Italian-adapted Global Initiative for Asthma -GINA- guidelines); (2) estimating the number of severe asthma patients with poorly controlled or uncontrolled disease (using the findings of two recent administrative claim analyses conducted in Italy); (3) stratifying the severe uncontrolled population by biomarker levels (EOS, FeNO and IgE) according to the outcomes of the QUEST trial (a clinical study assessing the efficacy of dupilumab in patients with uncontrolled moderate-to-severe asthma; NCT02414854); (4) identifying the sub-populations of severe uncontrolled asthma patients characterised by raised blood EOS and/or FeNO level (thus indicated to receive dupilumab). Results According to these estimates, about 3.3 million asthmatic patients live in Italy (6.10% of the population). Of them, almost 20 thousand (N = 19,960) have uncontrolled severe asthma. Dupilumab-eligible patients would be N = 15,988, corresponding to 80.1% of the total uncontrolled severe population. Most of these patients (89.3%; N = 14,271) have at least an increase of EOS level, while slightly more than half (51.9%; N = 8,303) have raised levels of both biomarkers. Increased FeNO levels without increased EOS are observed less frequently (N = 1,717; 10.7% of the eligible population). Conclusions There is a strong rationale for testing all asthma biomarkers during diagnosis and disease follow-up. Given the large availability and the limited costs, these tests are cost-effective tools to detect severe Type 2 asthma, stratify patients by phenotype, and drive appropriate treatment decisions.

Abstract Chronic obstructive pulmonary disease (COPD) treatment guidelines do not currently include recommendations for escalation directly from monotherapy to triple therapy. This 12-week, double-blind, double-dummy study randomized 800 symptomatic moderate-to-very-severe COPD patients receiving tiotropium (TIO) for ≥3 months to once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 mcg via ELLIPTA (n = 400) or TIO 18 mcg via HandiHaler (n = 400) plus matched placebo. Study endpoints included change from baseline in trough forced expiratory volume in 1 s (FEV1) at Days 85 (primary), 28 and 84 (secondary), health status (St George’s Respiratory Questionnaire [SGRQ] and COPD Assessment Test [CAT]) and safety. FF/UMEC/VI significantly improved trough FEV1 at all timepoints (Day 85 treatment difference [95% CI] 95 mL [62–128]; P

Abstract Background A single-inhaler extrafine triple combination of beclometasone dipropionate (BDP), formoterol fumarate (FF) and glycopyrronium (G) has been developed for maintenance therapy of chronic obstructive pulmonary disease (COPD). This study evaluated the efficacy and safety of BDP/FF/G in patients in three eastern Asian areas: China, Republic of Korea and Taiwan. Methods TRIVERSYTI was a double-blind, randomised, active-controlled, parallel-group study in patients with COPD, post-bronchodilator forced expiratory volume in 1 s (FEV1)

Abstract Background Biomarkers can be used to detect the presence of endothelial and/or alveolar epithelial injuries in case of ARDS. Angiopoietin-2 (Ang-2), soluble intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion protein-1 (VCAM-1), P-selectin and E-selectin are biomarkers of endothelial injury, whereas the receptor for advanced glycation end-products (RAGE) reflects alveolar epithelial injury. The aims of this study were to evaluate whether the plasma concentration of the above-mentioned biomarkers was different 1) in survivors and non-survivors of COVID-19-related ARDS and 2) in COVID-19-related and classical ARDS. Methods This prospective study was performed in two COVID-19-dedicated Intensive Care Units (ICU) and one non-COVID-19 ICU at Ferrara University Hospital. A cohort of 31 mechanically ventilated patients with COVID-19 ARDS and a cohort of 11 patients with classical ARDS were enrolled. Ang-2, ICAM-1, VCAM-1, P-selectin, E-selectin and RAGE were determined with a bead-based multiplex immunoassay at three time points: inclusion in the study (T1), after 7 ± 2 days (T2) and 14 ± 2 days (T3). The primary outcome was to evaluate the plasma trend of the biomarker levels in survivors and non-survivors. The secondary outcome was to evaluate the differences in respiratory mechanics variables and gas exchanges between survivors and non-survivors. Furthermore, we compared the plasma levels of the biomarkers at T1 in patients with COVID-19-related ARDS and classical ARDS. Results In COVID-19-related ARDS, the plasma levels of Ang-2 and ICAM-1 at T1 were statistically higher in non-survivors than survivors, (p = 0.04 and p = 0.03, respectively), whereas those of P-selectin, E-selectin and RAGE did not differ. Ang-2 and ICAM-1 at T1 were predictors of mortality (AUROC 0.650 and 0.717, respectively). At T1, RAGE and P-selectin levels were higher in classical ARDS than in COVID-19-related ARDS. Ang-2, ICAM-1 and E-selectin were lower in classical ARDS than in COVID-19-related ARDS (all p

Abstract Background Inhaled corticosteroids (ICS) are indicated for prevention of exacerbations in patients with COPD, but they are frequently overprescribed. ICS withdrawal has been recommended by international guidelines in order to prevent side effects in patients in whom ICS are not indicated. Method Observational comparative effectiveness study aimed to evaluate the effect of ICS withdrawal versus continuation of triple therapy (TT) in COPD patients in primary care. Data were obtained from the Optimum Patient Care Research Database (OPCRD) in the UK. Results A total of 1046 patients who withdrew ICS were matched 1:4 by time on TT to 4184 patients who continued with TT. Up to 76.1% of the total population had 0 or 1 exacerbation the previous year. After controlling for confounders, patients who discontinued ICS did not have an increased risk of moderate or severe exacerbations (adjusted HR: 1.04, 95% confidence interval (CI) 0.94–1.15; p = 0.441). However, rates of exacerbations managed in primary care (incidence rate ratio (IRR) 1.33, 95% CI 1.10–1.60; p = 0.003) or in hospital (IRR 1.72, 95% CI 1.03–2.86; p = 0.036) were higher in the cessation group. Unsuccessful ICS withdrawal was significantly and independently associated with more frequent courses of oral corticosteroids the previous year and with a blood eosinophil count ≥ 300 cells/μL. Conclusions In this primary care population of patients with COPD, composed mostly of infrequent exacerbators, discontinuation of ICS from TT was not associated with an increased risk of exacerbation; however, the subgroup of patients with more frequent courses of oral corticosteroids and high blood eosinophil counts should not be withdrawn from ICS. Trial registration European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (EUPAS30851).

Abstract Background The treatment with short-acting beta-2 agonists (SABA) alone is no longer recommended due to safety issues. Instead, the current Global Initiative for Asthma (GINA) Report recommends the use of the combination of inhaled corticosteroids (ICS) with the rapid/long-acting beta-2 agonist formoterol, although the use in steps 1 and 2 is still off-label in the EU and in many countries. It is important to understand clinicians’ knowledge and opinions on the issue with the ultimate goal to encourage the implementation of the new approach in clinical practice. Methods We performed an international survey, directed to pulmonologists interested in the management of patients with asthma. Results Most participants reported that SABA alone should not be used in GINA Step 1 asthma treatment. As-needed low-dose ICS/formoterol combination to patients in step 1, and as-needed low-dose ICS/formoterol as reliever therapy in any step were found to be of current use prescribed in their real-life settings. SABA alone was still prescribed to a proportion of patients, although the pulmonologists’ opinion was that it should no longer be used. Conclusions Most specialists are up to date and understand the relevance of the changes in GINA reports from 2019. Nevertheless, dissemination and implementation of GINA novel management strategy is still needed.

Abstract Background Mepolizumab and benralizumab are clinically effective biological treatments for severe eosinophilic asthmatic patients by hampering eosinophilic inflammation. The effects of these compound on the immunoglobulin (Ig)E T2 component are virtually unknown. Objectives To evaluate the change in total IgE levels at 4 ± 2 months after initiation of the mepolizumab (primary outcome) or benralizumab. When available, the changes of blood inflammatory cell counts, lung function and asthma control test (ACT) were also assessed and correlated with changes in total IgE levels. Methods Observational, retrospective, multicentre, cohort study. Severe eosinophilic atopic asthmatic patients treated with mepolizumab or benralizumab were included in the analysis. Results Three‐month treatment (on average) with mepolizumab (n = 104) or benralizumab (n = 82) resulted in significantly higher reduction of blood eosinophil and basophil levels in patients treated with benralizumab compared to mepolizumab. Mepolizumab did not significantly modified the levels of blood total IgE during the study period, whereas benralizumab significantly reduced (−35%, p

Abstract Background In asthma, persistent airflow limitation (PAL) is associated with poorer control, lung function decline and exacerbations. Using post‐hoc analyses we evaluated: the relationship between post‐salbutamol PAL at screening, airflow limitation (AL) during 52 weeks treatment with extrafine beclometasone dipropionate/formoterol fumarate/glycopyrronium (BDP/FF/G) versus BDP/FF and the risk of moderate/severe asthma exacerbations. Methods TRIMARAN and TRIGGER were double‐blind studies comparing BDP/FF/G with BDP/FF (TRIMARAN medium‐dose ICS; TRIGGER high‐dose) in adults with uncontrolled asthma. Patients were subgrouped according to post‐salbutamol PAL status at screening, and AL over the 52‐week treatment period. Results Most patients with post‐salbutamol PAL at screening had AL at all on‐treatment visits (TRIMARAN 62.8%; TRIGGER 66.8%). A significantly higher proportion of patients had normalised airflow on ≥1 follow‐up visit when receiving BDP/FF/G than BDP/FF (TRIMARAN 44.1 vs. 33.1% [p = 0.003]; TRIGGER 40.1 vs. 26.0% [p

Abstract Background A number of single-inhaler triple therapies are being developed for asthma, including the extrafine formulation of beclometasone dipropionate (BDP), formoterol fumarate (FF), and glycopyrronium (G). Given asthma is a heterogenous disease, we investigated whether the clinical response to the addition of the long-acting muscarinic antagonist component within inhaled triple therapy was impacted by a range of clinical characteristics. Methods These were pre-specified and post-hoc sub-group analyses of TRIMARAN and TRIGGER, which were double-blind, 52-week studies comparing medium-strength (100/6/10 µg; TRIMARAN) and high-strength (200/6/10 µg; TRIGGER) BDP/FF/G with the respective BDP/FF strengths in adults with uncontrolled asthma and a history of ≥ 1 exacerbation. Co-primary endpoints were pre-dose forced expiratory volume in 1 s (FEV1) at Week 26 and the rate of moderate-to-severe exacerbations over 52 weeks. Key secondary endpoints: peak FEV1 at Week 26 and average morning peak expiratory flow over the first 26 weeks in each study, and severe exacerbation rate over 52 weeks (pooled data). Results Baseline clinical characteristics (pre-specified analyses) had no consistent effect on the lung function improvements with BDP/FF/G. For the exacerbation endpoints, sub-groups with higher reversibility gained greatest relative benefit from BDP/FF/G versus BDP/FF. In post-hoc analyses with patients sub-grouped by screening blood eosinophil values, in TRIMARAN the greatest relative effect of BDP/FF/G versus BDP/FF on the lung function endpoints was in the ≤ 300 cells/µL group; in TRIGGER, eosinophil levels did not markedly influence the relative efficacy of BDP/FF/G versus BDP/FF. Eosinophil levels did not influence relative efficacy on moderate-to-severe or severe exacerbations. Conclusion Overall, the relative efficacy of extrafine BDP/FF/G versus BDP/FF was not influenced by a range of clinical characteristics. However, some patient sub-groups gained additional benefit from BDP/FF/G for certain endpoints. In particular, for exacerbations the relative efficacy of BDP/FF/G was greater in more reversible patients. Trial registration ClinicalTrials.gov: TRIMARAN, NCT02676076 (registered February 8, 2016, https://clinicaltrials.gov/ct2/show/NCT02676076?term=NCT02676076&draw=2&rank=1 ,); TRIGGER, NCT02676089 (registered February 8, 2016, https://clinicaltrials.gov/ct2/show/NCT02676089?term=NCT02676089&draw=2&rank=1 )

Cytopathological analyses of bronchial washings (BWs) collected during fibre‐optic bronchoscopy are often inconclusive for lung cancer diagnosis. To address this issue, we assessed the suitability of conducting molecular analyses on BWs, with the aim to improve the diagnosis and outcome prediction of lung cancer. The methylation status of RASSF1A, CDH1, DLC1 and PRPH was analysed in BW samples from 91 lung cancer patients and 31 controls, using a novel two‐colour droplet digital methylation‐specific PCR (ddMSP) technique. Mutations in ALK, BRAF, EGFR, ERBB2, KRAS, MAP2K1, MET, NRAS, PIK3CA, ROS1 and TP53 and gene fusions of ALK, RET and ROS1 were also investigated, using next‐generation sequencing on 73 lung cancer patients and 14 tumour‐free individuals. Our four‐gene methylation panel had significant diagnostic power, with 97% sensitivity and 74% specificity (relative risk, 7.3; odds ratio, 6.1; 95% confidence interval, 12.7–127). In contrast, gene mutation analysis had a remarkable value for predictive, but not for diagnostic, purposes. Actionable mutations in EGFR, HER2 and ROS1 as well as in other cancer genes (KRAS, PIK3CA and TP53) were detected. Concordance with gene mutations uncovered in tumour biopsies was higher than 90%. In addition, bronchial‐washing analyses permitted complete patient coverage and the detection of additional actionable mutations. In conclusion, BWs are a useful material on which to perform molecular tests based on gene panels: aberrant gene methylation and mutation analyses could be performed as approaches accompanying current diagnostic and predictive assays during the initial workup phase. This study establishes the grounds for further prospective investigation.

Abstract Asthma is a common chronic disease characterized by episodic or persistent respiratory symptoms and airflow limitation. Asthma treatment is based on a stepwise and control-based approach that involves an iterative cycle of assessment, adjustment of the treatment and review of the response aimed to minimize symptom burden and risk of exacerbations. Anti-inflammatory treatment is the mainstay of asthma management. In this review we will discuss the rationale and barriers to the treatment of asthma that may result in poor outcomes. The benefits of currently available treatments and the possible strategies to overcome the barriers that limit the achievement of asthma control in real-life conditions and how these led to the GINA 2019 guidelines for asthma treatment and prevention will also be discussed.

Abstract Background Patients with chronic obstructive pulmonary disease (COPD) are at risk of exacerbations and pneumonia; how the risk factors interact is unclear. Methods This post-hoc, pooled analysis included studies of COPD patients treated with inhaled corticosteroid (ICS)/long-acting β2 agonist (LABA) combinations and comparator arms of ICS, LABA, and/or placebo. Backward elimination via Cox’s proportional hazards regression modelling evaluated which combination of risk factors best predicts time to first (a) pneumonia, and (b) moderate/severe COPD exacerbation. Results Five studies contributed: NCT01009463, NCT01017952, NCT00144911, NCT00115492, and NCT00268216. Low body mass index (BMI), exacerbation history, worsening lung function (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage), and ICS treatment were identified as factors increasing pneumonia risk. BMI was the only pneumonia risk factor influenced by ICS treatment, with ICS further increasing risk for those with BMI

Abstract Background and objective The dose-response relationship of inhaled corticosteroid (ICS)/fast-onset long acting beta agonist (LABA) reliever therapy has not been formally addressed. The objective of this retrospective analysis is to ascertain from the available evidence whether ICS/fast-onset LABA administered as reliever therapy has a different dose-response relationship than maintenance fixed dose ICS/fast-onset LABA therapy in reducing risk of severe exacerbations. Methods A systematic literature review was undertaken to identify randomised controlled trials (RCTs) in which randomised treatments included either i) budesonide/formoterol reliever monotherapy versus budesonide/formoterol fixed dose maintenance with short acting beta agonist (SABA) reliever therapy, or ii) budesonide/formoterol reliever therapy in addition to budesonide/formoterol maintenance versus higher fixed dose maintenance budesonide/formoterol with SABA as reliever therapy. Eligible studies were reviewed to allow determination of the relative potency and efficacy of the comparator regimens to reduce the risk of a severe exacerbation. Results The one RCT of budesonide/formoterol reliever monotherapy showed a 4.6-fold (95% CI 2.9 to 7.3) greater potency than budesonide/formoterol fixed dose maintenance plus SABA reliever therapy in reducing the risk of severe exacerbations. In the one RCT that compared budesonide/formoterol maintenance and reliever therapy with higher fixed dose maintenance budesonide/formoterol plus SABA reliever therapy, there was an additional 26% (95% CI 4 to 42%) reduction in severe exacerbation risk with the addition of budesonide/formoterol reliever therapy to maintenance budesonide/formoterol, despite a 25% lower total budesonide/formoterol dose. Conclusion The limited available evidence suggests that budesonide/formoterol reliever therapy has greater potency and efficacy than budesonide/formoterol fixed dose maintenance plus SABA reliever therapy in reducing the risk of a severe exacerbation. This is an important concept which has the potential to guide clinical practice in asthma, although the small number of studies available highlights the need for further research to better define these pharmacological properties.

Introduction Uncontrolled asthma is associated with substantial morbidity. While fast-acting bronchodilators provide quick relief from asthma symptoms, their use as rescue fails to address the underlying inflammation. Combining a short-acting beta2-agonist, such as albuterol (salbutamol), with an inhaled corticosteroid, such as budesonide, in a single inhaler as rescue therapy could help control both bronchoconstriction and inflammation, and reduce the risk of asthma exacerbations.Methods and analysis The Phase 3 MANDALA study was designed to determine the efficacy of albuterol in combination with budesonide (albuterol/budesonide 180/160 µg or 180/80 µg, two actuations of 90/80 µg or 90/40 µg, respectively) versus albuterol (180 µg, two actuations of 90 µg) as rescue therapy in adult, adolescent and paediatric patients with moderate-to-severe asthma. This event-driven study enrolled symptomatic patients (3000 adults/adolescents and 100 children aged 4–11 years) who experienced ≥1 severe asthma exacerbation in the previous year and were receiving maintenance therapy for ≥3 months prior to study entry. The primary efficacy endpoint was time-to-first severe asthma exacerbation.Ethics and dissemination The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use and Good Clinical Practice and the applicable regulatory requirements.Trial registration NCT03769090.

Chronic respiratory diseases are the third leading cause of death, behind cardiovascular diseases and cancer, affecting approximately 550 million of people all over the world. Most of the chronic respiratory diseases are attributable to asthma and chronic obstructive pulmonary disease (COPD) with this latter being the major cause of deaths. Despite differences in etiology and symptoms, a common feature of asthma and COPD is an underlying degree of airways inflammation. The nature and severity of this inflammation might differ between and within different respiratory conditions and pharmacological anti-inflammatory treatments are unlikely to be effective in all patients. A precision medicine approach is needed to selectively target patients to increase the chance of therapeutic success. Inhibitors of the phosphodiesterase 4 (PDE4) enzyme like the oral PDE4 inhibitor roflumilast have shown a potential to reduce inflammatory-mediated processes and the frequency of exacerbations in certain groups of COPD patients with a chronic bronchitis phenotype. However, roflumilast use is dampened by class related side effects as nausea, diarrhea, weight loss and abdominal pain, resulting in both substantial treatment discontinuation in clinical practice and withdrawal from clinical trials. This has prompted the search for PDE4 inhibitors to be given by inhalation to reduce the systemic exposure (and thus optimize the systemic safety) and maximize the therapeutic effect in the lung. Tanimilast (international non-proprietary name of CHF6001) is a novel highly potent and selective inhaled PDE4 inhibitor with proven anti-inflammatory properties in various inflammatory cells, including leukocytes derived from asthma and COPD patients, as well as in experimental rodent models of pulmonary inflammation. Inhaled tanimilast has reached phase III clinical development by showing promising pharmacodynamic results associated with a good tolerability and safety profile, with no evidence of PDE4 inhibitors class-related side effects. In this review we will discuss the main outcomes of preclinical and clinical studies conducted during tanimilast development, with particular emphasis on the characterization of the pharmacodynamic profile that led to the identification of target populations with increased therapeutic potential in inflammatory respiratory diseases.

IntroductionAir pollution is a risk factor for respiratory infections and asthma exacerbations. We previously reported impaired Type-I and Type-III interferons (IFN-β/λ) from airway epithelial cells of preschool children with asthma and/or atopy. In this study we analyzed the association between rhinovirus-induced IFN-β/λ epithelial expression and acute exposure to the principal outdoor air pollutants in the same cohort.MethodsWe studied 34 children (17asthmatics/17non-asthmatics) undergoing fiberoptic bronchoscopy for clinical indications. Bronchial epithelial cells were harvested by brushing, cultured and experimentally infected with Rhinovirus Type 16 (RV16). RV16-induced IFN-β and λ expression was measured by quantitative real time PCR, as was RV16vRNA. The association between IFNs and the mean exposure to PM10, SO2 and NO2 in the day preceding bronchoscopy was evaluated using a Generalized Linear Model (GLM) with Gamma distribution.ResultsAcute exposure to PM10 and NO2 was negatively associated to RV16-induced IFNβ mRNA. For each increase of 1ug/m3 of NO2 we found a significative decrease of 2.3x103 IFN-β mRNA copies and for each increase of 1ug/m3 of PM10 a significative decrease of 1x103 IFN-β mRNA copies. No significant associations were detected between IFN-λ mRNA and NO2 nor PM10. Increasing levels of NO2 (but not PM10) were found to be associated to increased RV16 replication.ConclusionsShort-term exposure to high levels of NO2 and PM10 is associated to a reduced IFN-β expression by the airway epithelium, which may lead to increased viral replication. These findings suggest a potential mechanism underlying the link between air pollution, viral infections and asthma exacerbations.

The risks of overusing short-acting β 2 -agonists (SABA), including an increase in asthma-related deaths, are many and well known. The Global Initiative on Asthma (GINA) 2019 and 2020 updates recommend as-needed inhaled corticosteroid (ICS)/formoterol as the preferred rescue medication in mild asthma as monotherapy and also in moderate to severe asthma when the maintenance and reliever therapy (MART) strategy is used. Using SABA for symptom relief, however, was the standard of treatment for many years, and consequently this practice persists, particularly in patients not taking ICS regularly. Here, we examine the rationale for this shift from a long-standing recommendation for as-needed SABA treatment to the use of as-needed ICS/formoterol and consider clinical evidence on strategies for asthma treatment and patient management.

Two years after its spreading, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still responsible for more than 2000 deaths per day worldwide, despite vaccines and monoclonal antibody countermeasures. Therefore, there is a need to understand the immune–inflammatory pathways that prompt the manifestation of the disease to identify a novel potential target for pharmacological intervention. In this context, the characterization of the main players in the SARS-CoV-2-induced cytokine storm is mandatory. To date, the most characterized have been IL-6 and the class I and II interferons, while less is known about the proinflammatory cytokine IL-1β and class III interferons. Here, we report a preliminary study aimed at the characterization of the lung inflammatory context in COVID-19 patients, with a special focus on IFN-λ and IL-1β. By investigating IFN and inflammatory cytokine patterns by IHC in 10 deceased patients due to COVID-19 infection, compared to 10 control subjects, we reveal that while IFN-β production was increased in COVID-19 patients, IFN-λ was almost abolished. At the same time, the levels of IL-1β were dramatically improved, while IL-6 lung levels seem to be unaffected by the infection. Our findings highlight a central role of IL-1β in prompting lung inflammation after SARS-CoV-2 infection. Together, we show that IFN-λ is negatively affected by viral infection, supporting the idea that IFN-λ administration together with the pharmaceutical blockage of IL-1β represents a promising approach to revert the COVID-19-induced cytokine storm.

Background: Since December 2019, SARS-CoV-2 has been causing cases of severe pneumonia in China and has spread all over the world, putting great pressure on health systems. Nasopharyngeal swab (NPS) sensitivity is suboptimal. When the SARS-CoV-2 infection is suspected despite negative NPSs, other tests may help to rule out the infection. Objectives: To evaluate the yield of the lower respiratory tract (LRT) isolation of SARS-CoV-2. To evaluate the correlations between SARS-CoV-2 detection and clinical symptoms, and laboratory values and RSNA CT review scores in suspect patients after two negative NPSs. To assess the safety of bronchoscopy in this scenario. Method: A retrospective analysis of data from LRT sampling (blind nasotracheal aspiration or bronchial washing) for suspected COVID-19 after two negative NPS. Chest CT scans were reviewed by two radiologists using the RSNA imaging classification. Results: SARS-CoV-2 was detected in 14/99 patients (14.1%). A correlation was found between SARS-CoV2 detection on the LRT and the presence of a cough as well as with typical CT features. Typical CT resulted in 57.1% sensitivity, 80.8% accuracy and 92.3% NPV. Neither severe complications nor infections in the personnel were reported. Conclusions: In suspect cases after two negative swabs, CT scan revision can help to rule out COVID-19. In selected cases, with consistent CT features above all, LRT sampling can be of help in confirming COVID-19.

Thoracoscopy is commonly used minimally invasive procedure in the field of interventional pulmonology. While medical thoracoscopy is the widely preferred modality, modifications to the technique and expansion in the scope of its utility have always challenged the conventional approach. We describe a modified technique of medical thoracoscopy in absence of pleural effusion also known as dry thoracoscopy under sedation and local anaesthesia.

Abstract Background Patients with chronic obstructive pulmonary disease (COPD) have excess risk of developing pneumonia; however, no definitive biomarkers of risk have been established. We hypothesized that blood neutrophils would help predict pneumonia risk in COPD. Methods A meta-analysis of randomized, double-blind clinical trials of COPD patients meeting the following criteria were selected from the GlaxoSmithKline trial registry: ≥1 inhaled corticosteroid-containing (ICS) arm (fluticasone propionate/salmeterol or fluticasone furoate/vilanterol), a control arm (non-ICS), pre-randomization blood neutrophil counts, ≥24-week duration. The number of patients with pneumonia events and time to first event (Kaplan–Meier analysis) were evaluated (post-hoc), stratified by baseline blood neutrophil count and ICS use. A Cox proportional hazards model was used to calculate hazard ratios (HR), split by median baseline blood neutrophils. Results Ten studies (1998 to 2011) with 11,131 patients were identified. The ICS (n = 6735) and non-ICS (n = 4396) cohorts were well matched in neutrophil distributions and demographics. Increasing neutrophil count was associated with an increased proportion of patients with pneumonia events; patients below the median neutrophil count were at less risk of a pneumonia event (HR, 0.75 [95% confidence interval 0.61–0.92]), and had longer time to a first event, compared with those at/above the median. The increase in pneumonia risk by neutrophil count was similar between the two cohorts. Conclusions Increased blood neutrophils in COPD were associated with increased pneumonia risk, independent of ICS use. These data suggest blood neutrophils may be a useful marker in defining treatment pathways in COPD.

Abstract Background We assessed the efficacy of the licensed mepolizumab dose (100 mg subcutaneously [SC]) in patients with severe eosinophilic asthma according to body weight/body mass index (BMI). Methods This was a post hoc individual patient-level meta-analysis of data from the Phase 3 studies MENSA (MEA115588/NCT01691521) and MUSCA (200862/NCT02281318). Patients aged ≥12 years with severe eosinophilic asthma and a history of exacerbations were randomised to 4-weekly placebo, mepolizumab 75 mg intravenously (IV) or 100 mg SC (MENSA) or placebo or mepolizumab 100 mg SC (MUSCA) for 32 (MENSA) or 24 (MUSCA) weeks. The primary endpoint was the annual rate of clinically significant exacerbations; other outcomes included the proportion of patients with no exacerbations, lung function, St George’s Respiratory Questionnaire (SGRQ) and Asthma Control Questionnaire-5 (ACQ-5) scores and blood eosinophil counts. Analyses were performed by baseline body weight and BMI (≤60, > 60–75, > 75–90, > 90, 25–30, > 30, 90 kg; improvements in SGRQ and ACQ-5 scores were seen across all categories. Conclusions Mepolizumab 100 mg SC has consistent clinical benefits in patients with severe eosinophilic asthma across a range of body weights and BMIs. Data show that the fixed-dose regimen of mepolizumab is suitable, without the need for weight-based dosing. Trial registration This manuscript is a post hoc meta-analysis of data from the Phase 3 studies MENSA and MUSCA. ClinicalTrials.gov, NCT01691521 (MEA115588; MENSA). Registered September 24, 2012. ClinicalTrials.gov, NCT02281318 (200862; MUSCA). Registered November 3, 2014.

People with pre-existing lung diseases such as chronic obstructive pulmonary disease (COPD) are more likely to get very sick from SARS-CoV-2 disease 2019 (COVID-19). Still, an interrogation of the immune response to COVID-19 infection, spatially throughout the lung structure, is lacking in patients with COPD. For this study, we characterized the immune microenvironment of the lung parenchyma, airways, and vessels of never- and ever-smokers with or without COPD, all of whom died of COVID-19, using spatial transcriptomic and proteomic profiling. The parenchyma, airways, and vessels of COPD patients, compared to control lungs had (1) significant enrichment for lung-resident CD45RO+ memory CD4+ T cells; (2) downregulation of genes associated with T cell antigen priming and memory T cell differentiation; and (3) higher expression of proteins associated with SARS-CoV-2 entry and primary receptor ubiquitously across the ROIs and in particular the lung parenchyma, despite similar SARS-CoV-2 structural gene expression levels. In conclusion, the lung parenchyma, airways, and vessels of COPD patients have increased T-lymphocytes with a blunted memory CD4 T cell response and a more invasive SARS-CoV-2 infection pattern and may underlie the higher death toll observed with COVID-19.