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We tested the prognostic performance of different scores for the identification of subjects with acute respiratory failure by COVID-19, at risk of in-hospital mortality and NIV failure. We conducted a retrospective study, in the Medical High-Dependency Unit of the University-Hospital Careggi. We included all subjects with COVID-19 and ARF requiring non-invasive ventilation (NIV) between March 2020 and January 2021. Clinical parameters, the HACOR score (Heart rate, Acidosis, Consciousness, Oxygenation, Respiratory Rate) and ROX index ((SpO2/FiO2)/respiratory rate) were collected 3 (-3) and 1 day (-1) before the NIV initiation, the first day of treatment (Day0) and after 1 (+1), 2 (+2), 5 (+5), 8 (+8) and 11 (+11) of treatment. The primary outcomes were in-hospital mortality and NIV failure. We included 135 subjects, mean age 69±13 years, 69% male. Patients, who needed mechanical ventilation, showed a higher HACOR score (Day0: 6 [5-7] vs 6 [6-7], p=.057; Day+2: 6 [6-6] vs 6 [4-6], p=.013) and a lower ROX index (Day0: 4.2±2.3 vs 5.1±2.3, p=.055; Day+2: 4.4±1.2.vs 5.5±1.3, p=.001) than those with successful NIV. An HACOR score >5 was more frequent among nonsurvivors (Day0: 82% vs 58%; Day2: 82% vs 48%, all p<0.01) and it was associated with in-hospital mortality (Day0: RR 5.88, 95%CI 2.01-17.22; Day2: RR 4.33, 95%CI 1.64-11.41) independent to age and Charlson index. In conclusion, in subjects treated with NIV for ARF caused by COVID19, respiratory parameters collected after the beginning of NIV allowed to identify those at risk of an adverse outcome. An HACOR score >5 was independently associated with increased mortality rate., (© 2022. The Author(s).)

COVID-19 has been associated with a broad range of long-term sequelae, commonly referred to as "long-COVID" or "post-COVID-19" syndrome. Despite an increasing body of literature, long COVID remains poorly characterized. We retrospectively analysed data from electronic medical records of patients admitted to the post-COVID-19 outpatient service of the Infectious and Tropical Diseases Unit, Careggi University Hospital, Florence, Italy, between June 2020 and June 2021, 4-12 weeks after hospital discharge. A total of 428 patients, 41% women, median age 64 years, underwent a follow-up visit a median 53 days after hospital discharge. Overall, 76% patients reported at least one persistent symptom, including dyspnoea (37%), chronic fatigue (36%), insomnia (16%), visual disorders (13%) and brain fog (13%). Increasing oxygen support (OR 1.4, 95% CI 1.1-1.8), use of immunosuppressants (OR 6.4, 95% CI 1.5-28) and female sex (OR 1.8, 95% CI 1.1-2.9) were associated with a higher risk of long COVID symptoms. Comparison between symptomatic patients infected in the period March-December 2020 (prevalent circulation of wild-type SARS-CoV-2) with those infected in the period January-April 2021 (prevalent circulation of B.1.1.7 Alpha variant) showed a significant modification in the pattern of symptoms belonging to the neurological and cognitive/emotional categories. Our findings confirmed shortness of breath and chronic fatigue as the most frequent long COVID manifestations, while female sex and severe COVID-19 course were the main risk factors for developing lingering symptoms. SARS-CoV-2 variants may induce different long COVID phenotypes, possibly due to changes in cell tropism and differences in viral-host interaction.

Background: Switching inhaler regimens can be driven by poor disease control but also by nonclinical factors, such as cost and environmental impact. The consequences of switching for nonclinical reasons are largely unclear., Objective: To systematically review the real-world consequences of switching inhaler regimens for nonclinical reasons in asthma and/or chronic obstructive pulmonary disease patients., Methods: Embase, MEDLINE, EBM Reviews, and EconLit were searched to November 21, 2020. Conference searches and reference checking were also performed. Real-world studies of asthma and/or chronic obstructive pulmonary disease patients undergoing a switch in inhaler regimen for any reason apart from clinical need were included. Two reviewers screened and extracted data. Key outcomes included symptom control, exacerbations, and patient-doctor relationships., Results: A total of 8,958 records were screened and 21 studies included. Higher-quality (matched comparative) studies were prioritized. Five matched studies (6 datasets) reported on symptom control: 5 datasets (n = 7,530) with unclear patient consent reported improved disease control following switching, and 1 dataset (n = 1,648) with non-consented patients reported significantly worsened disease control. Three matched studies (5 datasets, n = 10,084) reported on exacerbation rate ratios; results were heterogeneous depending on the definition used. Two studies (n = 137) reported that switching inhaler regimens could have a negative impact on the doctor-patient relationship, especially when the switches were non-consented. Study quality was generally low., Conclusions: Switching inhaler regimens is a complex issue that can have variable clinical consequences and can harm the patient-doctor relationship. Limited high-quality evidence was identified, and study designs were heterogeneous. A robust framework is needed to guide the personalized switching of inhalers., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The prevalence of asthma in Italy is estimated to be around 4%; it affects approximately 2,000,000 citizens, and up to 80-90% of patients have mild-to-moderate asthma. Despite the clinical relevance of mild-to-moderate asthma, longitudinal observational data are very limited, including data on disease progression (worsening vs. improvement), the response to treatment, and prognosis. Studies are needed to develop long-term, observational, real-life research in large cohorts. The primary outcomes of this study will be based on prospective observation and the epidemiological evolution of mild and moderate asthma. Secondary outcomes will include patient-reported outcomes, treatments over time, disease-related functional and inflammatory patterns, and environmental and life-style influences., Methods: This study, called the Mild/Moderate Asthma Network of Italy (MANI), is a research initiative launched by the Italian Respiratory Society and the Italian Society of Allergology, Asthma and Clinical Immunology. MANI is a cluster-based, real world, cross-sectional, prospective, observational cohort study that includes 20,000 patients with mild-to-moderate asthma. (ClinicalTrials.gov Identifier: NCT04796844)., Results and Conclusion: Despite advances in asthma care, several research gaps remain to be addressed through clinical research. This study will add important new knowledge about long-term disease history, the transferability of clinical research results to daily practice, the efficacy of currently recommended strategies, and their impact on the burden and evolution of the disease., Abbreviations: MANI:Mild/Moderate Asthma Network of ItalySANI:Severe Asthma Network ItalyGINA:Global Initiative for AsthmaSABA:short acting β2-agonistsICS:inhaled corticosteroidsCRF:Case Report Form.

In patients with chronic cough and age-matched control subjects, we attempted to evoke coughing and/or an urge to cough (UTC) by finger pressure along the sternocleidomastoid and sternum, on the lower cervical or first dorsal vertebrae, the jugular notch as well as with maximum neck extension and flexion These mechanical actions were ineffective in controls but reproducibly evoked coughing or UTC in about 50% of chronic coughers; sternal and spinal responses were abolished temporarily by local cooling. The results may disclose a novel paradigm of cough sensitisation possibly involving central convergence of somatic and visceral neural stimuli., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Inhaled medications are central to treating asthma and chronic obstructive pulmonary disease (COPD), yet critical inhaler technique errors are made by up to 90% of patients. In the clinical research setting, recruitment of subjects with poor inhaler technique may give a false impression of both the benefits and the necessity of add-on treatments such as biologic therapies., Objective: To assess the frequency with which inhaler technique is assessed and reliably optimized before and during patient enrollment into randomized controlled trials (RCTs) addressing the efficacy of topical therapy, and the escalation of therapy for asthma and COPD., Methods: Systematic searches were conducted of PubMed and Embase for RCTs published in the past 10 years involving patients with a diagnosis of asthma or COPD undergoing escalation of baseline inhaled therapy (stepping up, changing, adding, switching, increasing, etc) or the introduction of biologic agents., Results: Searches highlighted 1,014 studies, 118 of which were eligible after the removal of duplicates as well as screening and full text review. Of these, only 14 (11.9%) included accessible information in the methods section or referred to such information in online supplements or protocols concerning assessment of participants' inhaler technique. We therefore developed the proposed Best Practice Inhaler Technique Assessment and Reporting Checklist., Conclusions: Our study identifies a concerning lack of checking and correcting inhaler technique, or at least reporting that this was undertaken, before enrollment in asthma and COPD RCTs, which may affect the conclusions drawn. Mandating the use of a standardized checklist in RCT protocols and ensuring all published RCTs report checking and correcting inhaler technique before enrollment are important next steps., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The study aimed to determine the associations of Peak Inspiratory Flow (PIF), inhalation technique and adherence with health status and exacerbations in participants with COPD using DPI maintenance therapy. This cross-sectional multi-country observational real-world study included COPD participants aged ≥40 years using a DPI for maintenance therapy. PIF was measured three times with the In-Check DIAL G16: (1) typical PIF at resistance of participant's inhaler, (2) maximal PIF at resistance of participant's inhaler, (3) maximal PIF at low resistance. Suboptimal PIF (sPIF) was defined as PIF lower than required for the device. Participants completed questionnaires on health status (Clinical COPD Questionnaire (CCQ)), adherence (Test of Adherence to Inhalers (TAI)) and exacerbations. Inhalation technique was assessed by standardised evaluation of video recordings. Complete data were available from 1434 participants (50.1% female, mean age 69.2 years). GOLD stage was available for 801 participants: GOLD stage I (23.6%), II (54.9%), III (17.4%) and IV (4.1%)). Of all participants, 29% had a sPIF, and 16% were shown able to generate an optimal PIF but failed to do so. sPIF was significantly associated with worse health status (0.226 (95% CI 0.107-0.346), worse units on CCQ; p = 0.001). The errors 'teeth and lips sealed around mouthpiece', 'breathe in', and 'breathe out calmly after inhalation' were related to health status. Adherence was not associated with health status. After correcting for multiple testing, no significant association was found with moderate or severe exacerbations in the last 12 months. To conclude, sPIF is associated with poorer health status. This study demonstrates the importance of PIF assessment in DPI inhalation therapy. Healthcare professionals should consider selecting appropriate inhalers in cases of sPIF., (© 2022. The Author(s).)

Rationale: Lung biopsy (LBx) has a relevant role in the prediction of prognosis of interstitial lung diseases (ILDs), but its impact on the clinical management of patients remains unexplored. Objectives: This study evaluates whether LBx may change the therapeutic strategy and assesses the effect of diagnostic reclassification after LBx on long-term prognosis. Methods: We evaluated the LBx of 426 consecutive patients with ILDs, without a definite usual interstitial pneumonia pattern on high-resolution computed tomographic imaging. A total of 266 patients underwent transbronchial lung cryobiopsy (TBLC), and 160 patients underwent surgical lung biopsy (SLB). The multidisciplinary team (MDT) determined a diagnosis with high or low confidence, and a management strategy, both before and after the LBx data. Results: Final MDT diagnoses were 189 idiopathic pulmonary fibrosis (IPF), 143 non-IPF fibrotic ILDs, and 94 nonfibrotic ILDs. LBx data changed the management strategy in 145 cases (34%), with similar results for TBLC and SLB (the treatment strategy changed in 31.5% of TBLC cases, 84/266, P  < 0.001, and in 38% of SLB, 61/160, P  < 0.001). After LBx, the MDT was less inclined to "wait and see" (from 15% to 4% of cases, P  < 0.001) or to prescribe steroids only (from 54% to 37%, P  < 0.001) and was more confident to treat with antifibrotics (from 23% to 44%, P  < 0.001) or immunosuppressive drugs (from 7% to 14%, P  < 0.001). The therapeutic strategy changed in 70% of reclassified cases (60/85) and in 59% of cases in which LBx increased the MDT confidence (84/142). Reclassification significantly impacted the outcome. The cases classified as non-IPF by clinician and radiologist and then reclassified to be IPF after LBx showed a significantly worse survival compared with non-IPF confirmed cases (adjusted hazard ratio [HR], 3.8; 95% confidence interval [CI], 1.75-8.3); P  = 0.001. Cases initially classified as IPF and then reclassified as non-IPF after LBx showed a better prognosis compared with IPF confirmed cases (HR, 0.41; 95% CI, 0.18-0.94; P  = 0.03). Conclusions: Reclassification of cases with LBx data increased diagnostic confidence and changed the therapeutic strategy in one-third of cases. Pathologic reclassification of cases refined prognosis prediction. Patients classified as non-IPF by clinician and radiologist and then reclassified IPF after LBx had worse prognosis compared with the non-IPF confirmed cases.

Objective: The aim of this study was to identify the main CT features that may help in distinguishing a progression of interstitial lung disease (ILD) secondary to SSc from COVID-19 pneumonia., Methods: This multicentric study included 22 international readers grouped into a radiologist group (RADs) and a non-radiologist group (nRADs). A total of 99 patients, 52 with COVID-19 and 47 with SSc-ILD, were included in the study., Results: Fibrosis inside focal ground-glass opacities (GGOs) in the upper lobes; fibrosis in the lower lobe GGOs; reticulations in lower lobes (especially if bilateral and symmetrical or associated with signs of fibrosis) were the CT features most frequently associated with SSc-ILD. The CT features most frequently associated with COVID- 19 pneumonia were: consolidation (CONS) in the lower lobes, CONS with peripheral (both central/peripheral or patchy distributions), anterior and posterior CONS and rounded-shaped GGOs in the lower lobes. After multivariate analysis, the presence of CONs in the lower lobes (P < 0.0001) and signs of fibrosis in GGOs in the lower lobes (P < 0.0001) remained independently associated with COVID-19 pneumonia and SSc-ILD, respectively. A predictive score was created that was positively associated with COVID-19 diagnosis (96.1% sensitivity and 83.3% specificity)., Conclusion: CT diagnosis differentiating between COVID-19 pneumonia and SSc-ILD is possible through a combination of the proposed score and radiologic expertise. The presence of consolidation in the lower lobes may suggest COVID-19 pneumonia, while the presence of fibrosis inside GGOs may indicate SSc-ILD., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To investigate the persistence of symptoms compatible with COVID-19 in a real-file prospective cohort of patients at 12 months from hospital discharge., Methods: Longitudinal, prospective, single-center, cohort telephone follow-up (FU) study in a Tertiary Care Hospital. All consecutive patients >18 years admitted for COVID-19 were prospectively enrolled in a telephone FU program aimed at monitoring symptoms after 1,3,6,9 and 12 months from hospital discharge. The survey screened for somatic (fatigue, dyspnea, dyspnea, palpitations, cough, chest pain, abdominal pain, ageusia, anosmia, bowel symptoms) and emotional symptoms (insomnia, confusion, altered sense of reality, loss of appetite, fear, and depression) and frailty. Only patients with 12 months FU data were analyzed (N=254). Prevalence and factors associated with symptoms were the main outcomes. Frailty was defined by the presence of ≥3 indicators: weakness, slowness/impaired mobility, weight-loss, low physical activity, and exhaustion., Results: At 12 months, 40.5% of patients reported at least one symptom. The most common somatic ones were fatigue, exertional dyspnea, cough, bowel complaints while the most common psycho-emotional were insomnia, confusion, fear, and depression. Age, gender, gender, frailty, multiple symptoms at baseline and chronic obstructive pulmonary disease (COPD) were associated with symptoms persistence. Furthermore, frailty, COPD and multiple symptoms at baseline were associated with increased risk of somatic symptoms at 12 months, while age and gender were associated with emotional ones., Conclusions: Burden of the long COVID-19 symptoms decreased over time but remained as high as 40% at 12 months with important gender and functional differences, highlighting potential patient categories who may benefit from specific follow up strategies., (Copyright © 2021 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Asthma and chronic obstructive pulmonary disease (COPD) are major causes of morbidity and mortality worldwide. Optimal control of these conditions is a constant challenge for both physicians and patients. Poor inhaler practice is widespread and is a substantial contributing factor to the suboptimal clinical control of both conditions. The practicality, dependability, and acceptability of different inhalers influence the overall effectiveness and success of inhalation therapy. In this paper, experts from various European countries (Finland, Germany, Hungary, Italy, Poland, Spain, and Sweden) address inhaler selection with special focus on the Easyhaler ® device, a high- or medium-high resistance dry-powder inhaler (DPI). The evidence examined indicates that use of the Easyhaler is associated with effective control of asthma or COPD, as shown by the generally accepted indicators of treatment success. Moreover, the Easyhaler is widely accepted by patients, is reported to be easy to learn and teach, and is associated with patient adherence. These advantages help patient education regarding correct inhaler use and the rational selection of drugs and devices. We conclude that switching inhaler device to the Easyhaler may improve asthma and COPD control without causing any additional risks. In an era of climate change, switching from pressurized metered-dose inhalers to DPIs is also a cost-effective way to reduce emissions of greenhouse gases. Enhanced feature (slides, video, animation) (MP4 43768 kb)., (© 2021. The Author(s).)

Introduction: Dry powder inhalers (DPIs), a commonly prescribed inhaler type for respiratory diseases, require patients to generate sufficient peak inspiratory flow (PIF) to ensure optimal drug delivery to the airways. Effectiveness of therapy also requires a good inhalation technique and adequate medication adherence. For patients with chronic obstructive pulmonary disease (COPD), recent studies conducted in tertiary care suggest that DPI users with suboptimal PIF have poorer COPD-related health status and increased exacerbation risk versus those with optimal PIF. The PIFotal study will investigate the impact of PIF, inhalation technique and medication adherence on patient-reported outcomes in patients with COPD in primary care using a DPI for their maintenance therapy., Methods and Analysis: This cross-sectional observational study will assess 1200 patients (aged ≥ 40 years, diagnosed with COPD and using a DPI for COPD maintenance therapy for ≥ 3 months) from the Netherlands, Spain, Portugal, Poland, Greece and Australia. Assessments will consist of (1) PIF measurements (usual patient inhalation manoeuvre, maximal PIF against resistance of own inhaler, and maximal PIF against low resistance); (2) Clinical COPD Questionnaire (CCQ), COPD Assessment Test and Test of Adherence to Inhalers scores; and (3) video recordings of patient inhalation technique. Dependent variables include health status (CCQ score), number of self-reported exacerbations in previous 12 months, and healthcare resource utilisation in previous 6 months. Independent variables include PIF values, inhalation technique errors, medication adherence, and demographic and clinical characteristics. In the primary analysis, the mean difference in CCQ score between patients (1) with optimal/suboptimal PIF, (2) exhibiting/not exhibiting inhalation technique errors, and (3) adhering/not adhering to medication will be examined in a multivariable linear mixed model., Ethics: The study protocol was approved by ethics committees/institutional review boards of all participating sites prior to enrolment; written informed consent was obtained from all study participants., Trial Registration Number: ClinicalTrials.gov: NCT04532853., (© 2021. The Author(s).)

Pulmonary drug delivery is currently the focus of research and development because of its potential to produce maximum therapeutic benefit to patients by directing the drug straight to the lung disease site. Among all the available delivery options, one popular, proven and convenient inhaler device is the capsule-based dry powder inhaler (cDPI) for the treatment of an increasingly diverse range of diseases. cDPIs use a hard capsule that contains a powder formulation which consists of a mixture of a micronized drug and a carrier usually the lactose, known for its good lung tolerance. The capsule is either inserted into the device during manufacturer or by the patient prior to use. After perforating, opening or cut the capsule in the device, patients take a deep and rapid breath to inhale the powder, using air as the vector of drug displacement. The system is simple, relatively cheap and characterized by a lower carbon footprint than that of pressurized metered dose inhalers. This article reviews cDPI technology, focusing particularly on the importance of capsule characteristics and their function as a drug reservoir in cDPIs.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes CoronaVirus Disease 2019 (COVID-19), has resulted in a worldwide pandemic and currently represents a major public health crisis. It has caused outbreaks of illness through person-to-person transmission of the virus mainly via close contacts, and droplets produced by an infected person's cough or sneeze. Aerosolised inhaled therapy is the mainstay for treating obstructive airway diseases at home and in healthcare settings, but there is heightened particular concern about the potential risk for transmission of SARS-CoV-2 in the form of aerosolised respiratory droplets during the nebulised treatment of patients with COVID-19. As a consequence of this concern, the use of hand-held inhalers, especially pressurised metered dose inhalers, has risen considerably as an alternative to nebulisers, and this switch has led to inadequate supplies of inhalers in some countries. However, there is no evidence supporting an increased risk of viral transmission during nebulisation in COVID-19 patients. Furthermore, some patients may be unable to adequately use their new device and may not benefit fully from the switch to treatment via hand-held inhalers. Thus, there is no compelling reason to alter aerosol delivery devices for patients with established nebuliser-based regimens. The purpose of this paper is to discuss the current evidence and understanding of the use of aerosolised inhaled therapies during the SARS-CoV-2 pandemic and to provide some guidance on the measures to be taken to minimise the risk of transmitting infection, if any, during aerosol therapies., (© 2021. Società Italiana di Medicina Interna (SIMI).)

For more than 50 years, small airways disease has been considered a key feature of chronic obstructive pulmonary disease (COPD) and a major cause of airway obstruction. Both preventable and treatable, small airways disease has important clinical consequences if left unchecked. Small airways disease is associated with poor spirometry results, increased lung hyperinflation, and poor health status, making the small airways an important treatment target in COPD. The early detection of small airways disease remains the key barrier; if detected early, treatments designed to target small airways may help reduce symptoms and allow patients to maintain their activities. Studies are needed to evaluate the possible role of new drugs and novel drug formulations, inhalers, and inhalation devices for treating small airways disease. These developments will help to improve our management of small airways disease in patients with COPD., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To assess the association of pre-morbid functional status [Barthel Index (BI)] and frailty [modified Frailty Index (mFI)] with in-hospital mortality and a risk scoring system developed for COVID-19 in patients ≥75 years diagnosed with COVID-19., Design: Retrospective bicentric observational study., Setting and Participants: Data on consecutive patients aged ≥75 years admitted with COVID-19 at 2 Italian tertiary care centers were collected from February 22 to May 30, 2020., Methods: Overall, 221 consecutive patients with COVID-19 aged ≥75 years were admitted to 2 hospitals in the study period and were included in the analysis. Clinical, functional (BI), frailty (mFI), laboratory, and imaging data were collected. Mortality risk on admission was assessed with the COVID-19 Mortality Risk Score (COVID-19 MRS), a dedicated score developed for hospital triage., Results: Ninety-seven (43.9%) patients died. BI, frailty, age, dementia, respiratory rate, Pao 2 /Fio 2 ratio, creatinine, and platelet count were associated with mortality. Analysis of the area under the receiver operating characteristic (AUC) indicated that the predictivity of age was modest and the combination of BI, mFI, and COVID-19 MRS yielded the highest prediction accuracy (AUC COVID-19MRS+BI+mFI vs AUC Age : 0.87 vs 0.59; difference: +0.28, lower bound-upper bound: 0.17-0.34, P < .001)., Conclusions and Implications: Premorbid BI and mFI are associated with mortality and improved the accuracy of the COVID-19 MRS. Functional status may prove useful to guide clinical management of older individuals., (Copyright © 2021 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: Hyponatremia is the most common electrolyte disorder in hospitalized patients and occurs in about 30% of patients with pneumonia. Hyponatremia has been associated with a worse outcome in several pathologic conditions The main objective of this study was to determine whether serum sodium alterations may be independent predictors of the outcome of hospitalized COVID-19 patients., Design and Methods: In this observational study, data from 441 laboratory-confirmed COVID-19 patients admitted to a University Hospital were collected. After excluding 61 patients (no serum sodium at admission available, saline solution infusion before sodium assessment, transfer from another hospital), data from 380 patients were analyzed., Results: 274 (72.1%) patients had normonatremia at admission, 87 (22.9%) patients had hyponatremia and 19 (5%) patients had hypernatremia. We found an inverse correlation between serum sodium and IL-6, whereas a direct correlation between serum sodium and PaO2/FiO2 ratio was observed. Patients with hyponatremia had a higher prevalence of non-invasive ventilation and ICU transfer than those with normonatremia or hypernatremia. Hyponatremia was an independent predictor of in-hospital mortality (2.7-fold increase vs normonatremia) and each mEq/L of serum sodium reduction was associated with a 14.4% increased risk of death., Conclusions: These results suggest that serum sodium at admission may be considered as an early prognostic marker of disease severity in hospitalized COVID-19 patients.

We evaluated 100 postacute coronavirus disease 2019 (COVID-19) patients a median (interquartile range) of 60 (48-67) days after discharge from the Careggi University Hospital, Italy. Eighty-four (84%) had at least 1 persistent symptom, irrespective of COVID-19 severity. A considerable number of hospital readmissions (10%) and/or infectious diseases (14%) during the postdischarge period were reported., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The current pandemic emergence of novel coronavirus disease (COVID-19) poses a relevant threat to global health. SARS-CoV-2 infection is characterized by a wide range of clinical manifestations, ranging from absence of symptoms to severe forms that need intensive care treatment. Here, plasma-EDTA samples of 30 patients compared with age- and sex-matched controls were analyzed via untargeted nuclear magnetic resonance (NMR)-based metabolomics and lipidomics. With the same approach, the effect of tocilizumab administration was evaluated in a subset of patients. Despite the heterogeneity of the clinical symptoms, COVID-19 patients are characterized by common plasma metabolomic and lipidomic signatures (91.7% and 87.5% accuracy, respectively, when compared to controls). Tocilizumab treatment resulted in at least partial reversion of the metabolic alterations due to SARS-CoV-2 infection. In conclusion, NMR-based metabolomic and lipidomic profiling provides novel insights into the pathophysiological mechanism of human response to SARS-CoV-2 infection and to monitor treatment outcomes., Competing Interests: The authors have declared that no competing interests exist.

Background: Idiopathic pulmonary fibrosis (IPF) is a severe progressive interstitial lung disease. At 5-year follow-up, 15% of IPF patients develop lung cancer, which significantly reduces the survival rate. Here we review the literature on the clinical role of oncomarkers in IPF progression, and describe the trend of routine oncomarkers in IPF patients over the longest follow-up yet reported., Materials and Methods: A systematic search of the literature in PubMed was performed to find relevant studies published up to 24 September 2020. The most common oncomarkers were chosen to select papers related to pulmonary fibrosis. Then, 24 IPF patients and 25 non-IPF patients, followed at Careggi ILD Referral Centre and Siena Regional Referral Centre for ILD, were enrolled consecutively., Results: A few studies reported an association between serum oncomarkers and severity of IPF. NSE, CEA, Ca19.9, and Ca125 were higher in the IPF, than in the non-IPF, group at every follow-up ( p < 0.05). Ca15.3 concentrations were higher in the IPF, than the non-IPF, group at t3 ( p = 0.0080) and t4 ( p = 0.0168). To improve the specificity and sensitivity of Ca15.3, a panel of biomarkers was analyzed, with the IPF group as dependent variable, and chitotriosidase, Cyfra 21.1, Ca15.3, Ca125, and Ca19.9 as independent variables., Conclusions: This study focused on the discovery of multiple biomarker signatures, such as combinations of oncomarkers, that are widely and routinely available in biochemistry laboratories. The combination of clinical parameters and biological markers could help achieve more accurate results regarding prognosis and response to treatment in IPF. Our results could pave the way for a more "personalized" medical approach to patients affected by IPF.

Lung microbiota (LM) is an interesting new way to consider and redesign pathogenesis and possible therapeutic approach to many lung diseases, such as idiopathic pulmonary fibrosis (IPF), which is an interstitial pneumonia with bad prognosis. Chronic inflammation is the basis but probably not the only cause of lung fibrosis and although the risk factors are not completely clear, endogenous factors (e.g. gastroesophageal reflux) and environmental factors like cigarette smoking, industrial dusts, and precisely microbial agents could contribute to the IPF development. It is well demonstrated that many bacteria can cause epithelial cell injuries in the airways through induction of a host immune response or by activating flogosis mediators following a chronic, low-level antigenic stimulus. This persistent host response could influence fibroblast responsiveness suggesting that LM may play a role in repetitive alveolar injury in IPF. We reviewed literature regarding not only bacteria but also the role of virome and mycobiome in IPF. In fact, some viruses such as hepatitis C virus or certain fungi could be etiological agents or co-factors in the IPF progress. We aim to illustrate how the cross-talk between different local microbiotas throughout specific axis and immune modulation governed by microorganisms could be at the basis of lung dysfunctions and IPF development. Finally, since the future direction of medicine will be personalized, we suggest that the analysis of LM could be a goal to research new therapies also in IPF., Competing Interests: the study was founded by University of Florence Amedeiex60%the authors declare no confict of interest related to the present manuscript., (Copyright: © 2021 SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES.)

As of October 2020 management of Coronavirus disease 2019 (COVID-19) is based on supportive care and off-label or compassionate-use therapies. On March 2020 tocilizumab - an anti-IL-6 receptor monoclonal antibody - was suggested as immunomodulatory treatment in severe COVID-19 because hyperinflammatory syndrome occurs in many patients similarly to the cytokine release syndrome that develops after CAR-T cell therapy. In our retrospective observational study, 20 severe COVID-19 patients requiring intensive care were treated with tocilizumab in addition to standard-of-care therapy (SOC) and compared with 13 COVID-19 patients receiving only SOC. Clinical respiratory status, inflammatory markers and vascular radiologic score improved after one week from tocilizumab administration. On the contrary, these parameters were stable or worsened in patients receiving only SOC. Despite major study limitations, improvement of alveolar-arterial oxygen gradient as well as vascular radiologic score after one week may account for improved pulmonary vascular perfusion and could explain the more rapid recovery of COVID-19 patients receiving tocilizumab compared to controls., (Copyright © 2020 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)

Objectives: Several physiological abnormalities that develop during COVID-19 are associated with increased mortality. In the present study, we aimed to develop a clinical risk score to predict the in-hospital mortality in COVID-19 patients, based on a set of variables available soon after the hospitalisation triage., Setting: Retrospective cohort study of 516 patients consecutively admitted for COVID-19 to two Italian tertiary hospitals located in Northern and Central Italy were collected from 22 February 2020 (date of first admission) to 10 April 2020., Participants: Consecutive patients≥18 years admitted for COVID-19., Main Outcome Measures: Simple clinical and laboratory findings readily available after triage were compared by patients' survival status ('dead' vs 'alive'), with the objective of identifying baseline variables associated with mortality. These were used to build a COVID-19 in-hospital mortality risk score (COVID-19MRS)., Results: Mean age was 67±13 years (mean±SD), and 66.9% were male. Using Cox regression analysis, tertiles of increasing age (≥75, upper vs <62 years, lower: HR 7.92; p<0.001) and number of chronic diseases (≥4 vs 0-1: HR 2.09; p=0.007), respiratory rate (HR 1.04 per unit increase; p=0.001), PaO 2 /FiO 2 (HR 0.995 per unit increase; p<0.001), serum creatinine (HR 1.34 per unit increase; p<0.001) and platelet count (HR 0.995 per unit increase; p=0.001) were predictors of mortality. All six predictors were used to build the COVID-19MRS (Area Under the Curve 0.90, 95% CI 0.87 to 0.93), which proved to be highly accurate in stratifying patients at low, intermediate and high risk of in-hospital death (p<0.001)., Conclusions: The COVID-19MRS is a rapid, operator-independent and inexpensive clinical tool that objectively predicts mortality in patients with COVID-19. The score could be helpful from triage to guide earlier assignment of COVID-19 patients to the most appropriate level of care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: There is currently a lack of clinical data on the novel beta-coronavirus infection [caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)] and concomitant primary lung cancer. Our goal was to report our experiences with 5 patients treated for lung cancer while infected with SARS-CoV-2., Methods: We retrospectively evaluated 5 adult patients infected with SARS-CoV-2 who were admitted to our thoracic surgery unit between 29 January 2020 and 4 March 2020 for surgical treatment of a primary lung cancer. Clinical data and outcomes are reported., Results: All patients were men with a mean age of 74.0 years (range 67-80). Four of the 5 patients (80%) reported chronic comorbidities. Surgery comprised minimally invasive lobectomy (2 patients) and segmentectomy (1 patient), lobectomy with en bloc chest wall resection (1 patient) and pneumonectomy (1 patient). Mean chest drain duration was 12.4 days (range 8-22); mean hospital stay was 33.8 days (range 21-60). SARS-CoV-2-related symptoms were fever (3 patients), persistent cough (3 patients), diarrhoea (2 patients) and syncope (2 patients); 1 patient reported no symptoms. Morbidity related to surgery was 60%; 30-day mortality was 40%. Two patients (1 with a right pneumonectomy, 74 years old; 1 with a lobectomy with chest wall resection and reconstruction, 70 years old), developed SARS-CoV-2-related lung failure leading to death 60 and 32 days after surgery, respectively., Conclusions: Lung cancer surgery may represent a high-risk factor for developing a severe case of coronavirus disease 2019, particularly in patients with advanced stages of lung cancer. Additional strategies are needed to reduce the risk of morbidity and mortality from SARS-CoV-2 infection during treatment for lung cancer., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

BACKGROUNDCoronavirus disease 19 (COVID-19) is an emerging infectious disease caused by SARS-CoV-2. Antiviral immune response is crucial to achieve pathogen clearance; however, in some patients an excessive and aberrant host immune response can lead to an acute respiratory distress syndrome. The comprehension of the mechanisms that regulate pathogen elimination, immunity, and pathology is essential to better characterize disease progression and widen the spectrum of therapeutic options.METHODSWe performed a flow cytometric characterization of immune cell subsets from 30 patients with COVID-19 and correlated these data with clinical outcomes.RESULTSPatients with COVID-19 showed decreased numbers of circulating T, B, and NK cells and exhibited a skewing of CD8+ T cells toward a terminally differentiated/senescent phenotype. In agreement, CD4+ T and CD8+ T, but also NK cells, displayed reduced antiviral cytokine production capability. Moreover, a reduced cytotoxic potential was identified in patients with COVID-19, particularly in those who required intensive care. The latter group of patients also showed increased serum IL-6 levels that inversely correlated to the frequency of granzyme A-expressing NK cells. Off-label treatment with tocilizumab restored the cytotoxic potential of NK cells.CONCLUSIONThe association between IL-6 serum levels and the impairment of cytotoxic activity suggests the possibility that targeting this cytokine may restore antiviral mechanisms.FUNDINGThis study was supported by funds from the Department of Experimental and Clinical Medicine of University of Florence (the ex-60% fund and the "Excellence Departments 2018-2022 Project") derived from Ministero dell'Istruzione, dell'Università e della Ricerca (Italy).

Objective: To prospectively investigate whether differences in pulmonary vasculature exist in systemic sclerosis (SSc) and how they are distributed in patients with different pulmonary function., Methods: Seventy-four patients with SSc undergoing chest CT scan for interstitial lung disease (ILD) screening or follow-up were prospectively enrolled. A thorough clinical, laboratory and functional evaluation was performed the same day. Chest CT was spirometry gated at total lung capacity and images were analysed by two automated software programs to quantify emphysema, ILD patterns (ground-glass, reticular, honeycombing), and pulmonary vascular volume (PVV). Patients were divided in restricted (FVC% <80, DLco%<80), isolated DLco% reduction (iDLco- FVC%≥80, DLco%<80) and normals (FVC%≥80, DLco%≥80). Spearman ρ, Mann-Whitney tests and logistic regressions were used to assess for correlations, differences among groups and relationships between continuous variables., Results: Absolute and lung volume normalised PVV (PVV/LV) correlated inversely with functional parameters and positively with all ILD patterns (ρ=0.75 with ground glass, ρ=0.68 with reticular). PVV/LV was the only predictor of DLco at multivariate analysis (p=0.007). Meanwhile, the reticular pattern prevailed in peripheral regions and lower lung thirds, PVV/LV prevailed in central regions and middle lung thirds. iDLco group had a significantly higher PVV/LV (2.2%) than normal (1.6%), but lower than restricted ones (3.8%)., Conclusions: Chest CT in SSc detects a progressive increase in PVV/LV as DLco decreases. Redistribution of perfusion to less affected lung regions rather than angiogenesis nearby fibrotic lung may explain the results. Further studies to ascertain whether the increase in PVV/LV reflects a real increase in blood volume are needed., Competing Interests: Competing interests: MO reports grants from Gruppo Italiano Lotta Sclerodermia (GILS), grants from Fondazione Italiana Ricerca Artrite (FIRA), during the conduct of the study; grants from Menarini Foundation, personal fees from Novartis, outside the submitted work. CB and DG report personal fees from Actelion, outside the submitted work. MM-C reports grants from FIRA, grants from GILS, during the conduct of the study; grants and personal fees from Actelion, personal fees from Biogen, personal fees from Bayer, personal fees from Boehringer Ingelheim, personal fees from CSL Behring, personal fees from Eli-Lilly, outside the submitted work. ST reports grants and personal fees from Roche, personal fees from Boehringer-Ingelheim, outside the submitted work. GCa, GCi, GCu, AF, SC, SB-R, AB, MB and FL have no COI disclosures., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Transbronchial lung cryobiopsy (TBLC) has been introduced recently in the diagnosis of interstitial lung diseases. We aimed to evaluate the prognostic significance of the distinction between idiopathic pulmonary fibrosis and other interstitial lung diseases with the use of TBLC data in multidisciplinary team (MDT) diagnosis., Methods: In this single-centre, retrospective, investigator-initiated comparative study, we evaluated consecutive patients without a definite usual interstitial pneumonia pattern on high-resolution CT, who presented to the GB Morgagni Hospital (Forlì, Italy), and who underwent TBLC (Jan 1, 2011, to Dec 31, 2014) or surgical lung biopsy (SLB; Jan 1, 2002, to Dec 31, 2016). Three pathologists reviewed the specimens, masked to clinical information. MDT evaluation was done before and after biopsy. The primary endpoint was the prognostic significance of the MDT diagnostic separation between idiopathic pulmonary fibrosis and other interstitial lung diseases in patients undergoing TBLC. Mortality was evaluated by means of Cox regression analysis., Findings: We evaluated 500 consecutive cases, 426 of which were included: 266 had TBLC and 160 had SLB. 189 patients had idiopathic pulmonary fibrosis, 143 had other fibrotic interstitial lung diseases, and 94 had non-fibrotic interstitial lung diseases. Patients undergoing TBLC had more comorbidities and better preserved lung function compared with those undergoing SLB; among patients with a final MDT diagnosis of idiopathic pulmonary fibrosis, patients undergoing TBLC were older, had more comorbidities, and had a different post-biopsy treatment profile than those who received SLB. The distinction between idiopathic pulmonary fibrosis and other interstitial lung diseases made by MDT diagnosis on the basis of TBLC biopsy had clear prognostic significance, with a 5-year transplant-free survival of 68% (95% CI 57-76) in patients with an MDT idiopathic pulmonary fibrosis diagnosis based on TBLC compared with 93% (87-96) in patients without an idiopathic pulmonary fibrosis diagnosis based on TBLC (hazard ratio 5·28, 95% CI 2·72-10·04; p<0·0001). This distinction remained statistically significant in a multivariate analysis controlling for age, sex, smoking status, comorbidities, pulmonary function, and high-resolution CT patterns (p=0·02)., Interpretation: TBLC makes an important diagnostic contribution in interstitial lung disease, on the basis of the prognostic distinction between idiopathic pulmonary fibrosis and other interstitial lung diseases when TBLC findings are included in multidisciplinary diagnosis., Funding: None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Standard spirometry cannot identify the predominant mechanism underlying airflow obstruction in COPD, namely emphysema or airway disease. We aimed at validating a previously developed methodology to detect emphysema by mathematical analysis of the maximal expiratory flow-volume (MEFV) curve in standard spirometry., Methods: From the COPDGene population we selected those 5930 subjects with MEFV curve and inspiratory-expiratory CT obtained on the same day. The MEFV curve descending limb was fit real-time using forced vital capacity (FVC), peak expiratory flow, and forced expiratory flows at 25, 50 and 75% of FVC to derive an emphysema severity index (ESI), expressed as a continuous positive numeric parameter ranging from 0 to 10. According to inspiratory CT percent lung attenuation area below - 950 HU we defined three emphysema severity subgroups (%LAA -950insp  < 6, 6-14, ≥14). By co-registration of inspiratory-expiratory CT we quantified persistent (%pLDA) and functional (%fLDA) low-density areas as CT metrics of emphysema and airway disease, respectively., Results: ESI differentiated CT emphysema severity subgroups increasing in parallel with GOLD stages (p < .001), but with high variability within each stage. ESI had significantly higher correlations (p < .001) with emphysema than with airway disease CT metrics, explaining 67% of %pLDA variability. Conversely, standard spirometric variables (FEV 1 , FEV 1 /FVC) had significantly lower correlations than ESI with emphysema CT metrics and did not differentiate between emphysema and airways CT metrics., Conclusions: ESI adds to standard spirometry the power to discriminate whether emphysema is the predominant mechanism of airway obstruction. ESI methodology has been validated in the large multiethnic population of smokers of the COPDGene study and therefore it could be applied for clinical and research purposes in the general population of smokers, using a readily available online website.

Spacers are pressurized metered-dose inhaler (pMDI) accessory devices developed to reduce problems of poor inhaler technique with pMDIs. Spacers that feature a 1-way inspiratory valve are termed valved holding chambers (VHCs); they act as aerosol reservoirs, allowing the user to actuate the pMDI device and then inhale the medication in a 2-step process that helps users overcome challenges in coordinating pMDI actuation with inhalation. Both spacers and VHCs have been shown to increase fine particle delivery to the lungs, decrease oropharyngeal deposition, and reduce corticosteroid-related side effects such as throat irritation, dysphonia, and oral candidiasis commonly seen with the use of pMDIs alone. Spacers and VHCs are not all the same, and also are not interchangeable: the performance may vary according to their size, shape, material of manufacture and propensity to become electrostatically charged, their mode of interface with the patient, and the presence or otherwise of valves and feedback devices. Thus, pairing of a pMDI plus a spacer or a VHC should be considered as a unique delivery system. In this Rostrum we discuss the risk potential for a patient getting switched to a spacer or VHC that delivers a reduced dose medication., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction : Inhaled therapies are likely to continue to dominate asthma and chronic obstructive pulmonary disease treatment. Dry powder inhalers (DPIs) have several advantages over pressurized metered-dose inhaler (pMDIs), that are most frequently marketed world-wide, but often difficult to use. This literature search focus on DPI features, with respect to Easyhaler, that may affect their use and patients' clinical benefit. Areas covered : DPIs are breath-actuated, easy to use, convenient to use, and more environmentally friendly. During inhalation, the formulation in a DPI is disaggregated by a turbulent airflow energy to generate particles with the greatest likelihood of deposition into the airways. The resistance among DPIs varies from low to high and those with high resistance are wrongly considered as difficult to use. Multidose reservoir-type DPIs have been developed to efficiently deliver a wide range of medications, including the fixed-dose combination of budesonide and formoterol. Easyhaler® shares a similar shape with pMDIs and, as other DPIs, its performance is unaffected by environmental and storage conditions. Due to Easyhaler internal design, dose emission is consistent irrespective of the inhalation flow used by each patient. Expert opinion : Easyhaler® may be considered one of the most convenient inhalers, for daily use, in patients with asthma or COPD.

Background: Chronic cough is a major health problem worldwide and patients are best managed in specialised tertiary centres. Little information is available on the characteristics of chronic cough patients in several European countries, including Italy., Aims: We report on the demographic, anthropometric and clinical features of a large Italian population of adult chronic cough outpatients (about 1200), who were referred to a specialised clinic in Florence, Italy, from 2008 to 2018., Methods: Demographic, environmental, lifestyle and clinical information was collected at enrolment by means of a custom-designed electronic questionnaire that only allowed for uniform responses. A subjective measure of cough-related discomfort (cough score) was also obtained using a modified Borg Scale. A multivariable logistic regression model was defined to identify the patients' characteristics associated with the cough score., Results: The characteristics of the examined population (n = 1204 outpatients) were strikingly similar to those described elsewhere. Female patients outnumbered the males [n = 847 females, (70.0%)]; both females and males displayed the same average cough score. The median age of outpatients was 61 (quartile 1 = 48; quartile 3 = 70) years; age and cough duration were unrelated to the cough score. Nasal obstruction, coughing during consultation, coughing during meals, throat clearing and the presence of respiratory abnormalities were correlated with the degree of discomfort caused by coughing., Discussion: The features of chronic cough patients are similar worldwide. The process of cough reflex hypersensitisation may soothe sex-related perceptual differences, leading to similar levels of discomfort., Conclusions: There seem to be clinical indicators that help in assessing the level of cough-related discomfort.

Factors related to the discrepancy between patient-perceived and actual disease control remain unclear. Identifying patients at risk of overestimation of asthma control remains elusive. This study aimed to (i) investigate the relationship between patient-reported and actual level of asthma control (ii), compare the characteristics between patients who believe their asthma is well controlled that accurately report 'well-controlled' asthma with those that do not, and (iii) identify factors associated with inaccurately reported 'well-controlled' asthma. A historical, multinational, cross-sectional study using data from the iHARP (initiative Helping Asthma in Real-life Patients) review service for adults with asthma prescribed fixed-dose combination therapy. Data from 4274 patients were analysed. A major discrepancy between patient-reported and Global Initiative for Asthma defined asthma control was detected; 71.1% of patients who reported 'well-controlled' asthma were inaccurate in their perception despite receiving regular maintenance therapy. Significant differences were noted in age, gender, body mass index, education level, medication use, side effects, attitudes to preventer inhaler use, inhaler technique review and respiratory specialist review between patients who accurately reported 'well-controlled' asthma and those who did not. Independent risk factors associated with inaccurately reported 'well-controlled' asthma were: having taken a maximum of 5-12 puffs or more of reliever inhaler on at least one day within the previous 4 weeks; being female; having seen a respiratory specialist more than a year ago (rather than in the previous year); and having required oral corticosteroids for worsening asthma in the previous year. The study highlighted the significant hidden burden associated with under-recognition of poor asthma control, on the part of the patient and the need for targeted interventions designed to address the continuing discrepancy between perceived and actual disease control.

The human respiratory tract, usually considered sterile, is currently being investigated for human-associated microbial communities. According to Dickson's conceptual model, the lung microbiota (LMt) is a dynamic ecosystem, whose composition, in healthy lungs, is likely to reflect microbial migration, reproduction, and elimination. However, which microbial genera constitutes a "healthy microbiome" per se remains hotly debated. It is now widely accepted that a bi-directional gut-lung axis connects the intestinal with the pulmonary microbiota and that the diet could have a role in modulating both microbiotas as in health as in pathological status. The LMt is altered in numerous respiratory disorders such as obstructive airway diseases, interstitial lung diseases, infections, and lung cancer. Some authors hypothesize that the use of specific bacterial strains, termed "probiotics," with positive effects on the host immunity and/or against pathogens, could have beneficial effects in the treatment of intestinal disorders and pulmonary diseases. In this manuscript, we have reviewed the literature available on the LMt to delineate and discuss the potential relationship between composition alterations of LMt and lung diseases. Finally, we have reported some meaningful clinical studies that used integrated probiotics' treatments to contrast some lung-correlated disorders.

Inhalable medications for patients with asthma and chronic obstructive pulmonary disease (COPD) can be confusing even for health care professionals because of the multitude of available devices each with different operating principles. Dry powder inhalers (DPI) are a valuable option for almost all of the patients with asthma or COPD. Based on recorded patient inspiratory profiles, the peak inspiratory flow requirement of 30 L min -1 of high-resistance devices does not usually pose any practical limitations for the patients. Suboptimal adherence and errors in device handling are common and require continuous checking and patient education in order to avoid these pitfalls of all inhalation therapy. The aim of this opinion paper is to describe the working principles of DPIs and to summarise their key properties in order to help prescribing the correct inhaler for each patient.Funding: Orion Pharma.

Inhalation therapy is likely to continue to dominate asthma and chronic obstructive pulmonary disease (COPD) treatment. The pressurised metered-dose inhaler (pMDI) accounts for most of the global inhaler market, but this kind of device is difficult to use properly. Dry powder inhalers (DPIs) have several advantages over pMDIs: they are breath-activated, easy and convenient to use, and environmentally friendly. The Easyhaler ® (Orion; Finland) is a multidose reservoir-type DPI developed to efficiently deliver a wide range of medications, including fixed-dose combinations of bronchodilators and corticosteroids. Easyhaler shares a similar shape with the pMDI, and its performance is unaffected by moisture, dropping, vibration, and freezing/thawing. For these reasons, Easyhaler may be considered one of the most convenient inhalers for daily use in patients with asthma or COPD., Competing Interests: Disclosure and potential conflicts of interest: In the last 3 years, Federico Lavorini has received grants for research, as well as fees for lectures and advisory boards, from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Menarini International, Novartis, Orion Pharma, Teva, and Trudell. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors is available for download at http://www.drugsincontext.com/wp-content/uploads/2019/05/dic.212596-COI.pdf

Background: The mechanisms underlying airflow obstruction in COPD cannot be distinguished by standard spirometry. We ascertain whether mathematical modeling of airway biomechanical properties, as assessed from spirometry, could provide estimates of emphysema presence and severity, as quantified by computed tomography (CT) metrics and CT-based radiomics., Methods: We quantified presence and severity of emphysema by standard CT metrics (VIDA) and co-registration analysis (ImbioLDA) of inspiratory-expiratory CT in 194 COPD patients who underwent pulmonary function testing. According to percentages of low attenuation area below - 950 Hounsfield Units (%LAA -950insp ) patients were classified as having no emphysema (NE) with %LAA -950insp  < 6, moderate emphysema (ME) with %LAA -950insp  ≥ 6 and < 14, and severe emphysema (SE) with %LAA -950insp  ≥ 14. We also obtained stratified clusters of emphysema CT features by an automated unsupervised radiomics approach (CALIPER). An emphysema severity index (ESI), derived from mathematical modeling of the maximum expiratory flow-volume curve descending limb, was compared with pulmonary function data and the three CT classifications of emphysema presence and severity as derived from CT metrics and radiomics., Results: ESI mean values and pulmonary function data differed significantly in the subgroups with different emphysema degree classified by VIDA, ImbioLDA and CALIPER (p < 0.001 by ANOVA). ESI differentiated NE from ME/SE CT-classified patients (sensitivity 0.80, specificity 0.85, AUC 0.86) and SE from ME CT-classified patients (sensitivity 0.82, specificity 0.87, AUC 0.88)., Conclusions: Presence and severity of emphysema in patients with COPD, as quantified by CT metrics and radiomics can be estimated by mathematical modeling of airway function as derived from standard spirometry.

Inhalation therapy is one of the oldest approaches to the therapy of diseases of the respiratory tract. It is well recognised today that the most effective and safe means of treating the lungs is to deliver drugs directly to the airways. Surprisingly, the delivery of therapeutic aerosols has a rich history dating back more than 2,000 years to Ayurvedic medicine in India, but in many respects, the introduction of the first pressurised metered-dose inhaler (pMDI) in 1956 marked the beginning of the modern pharmaceutical aerosol industry. The pMDI was the first truly portable and convenient inhaler that effectively delivered drug to the lung and quickly gained widespread acceptance. Since 1956, the pharmaceutical aerosol industry has experienced dramatic growth. The signing of the Montreal Protocol in 1987 to reduce the use of CFCs as propellants for aerosols led to a surge in innovation that resulted in the diversification of inhaler technologies with significantly enhanced delivery efficiency, including modern pMDIs, dry powder inhalers and nebuliser systems. There is also great interest in tailoring particle size to deliver drugs to treat specific areas of the respiratory tract. One challenge that has been present since antiquity still exists, however, and that is ensuring that the patient has access to the medication and understands how to use it effectively. In this article, we will provide a summary of therapeutic aerosol delivery systems from ancient times to the present along with a look to the future.

Inhaled therapies are the cornerstone of treatment in asthma and chronic obstructive pulmonary disease, and there are a multitude of devices available. There is, however, a distinct lack of evidence-based guidance for healthcare providers on how to choose an appropriate inhaler. This review aims to summarise recent updates on topics related to inhaler choice, and to offer practical considerations for healthcare providers regarding currently marketed devices. The importance of choosing the right inhaler for the right patient is discussed, and the relative merits of dry powder inhalers, pressurised metered dose inhalers, breath-actuated pressurised metered dose inhalers, spacers and soft mist inhalers are considered. Compiling the latest studies in the devices therapy area, this review focuses on the most common types of handling errors, as well as the comparative rates of incorrect inhalation technique between devices. The impact of device-specific handling errors on inhaler performance is also discussed, and the characteristics that can impair optimal drug delivery, such as inhalation flow rate, inhalation volume and particle size, are compared between devices. The impact of patient perceptions, behaviours and problems with inhalation technique is analysed, and the need for appropriate patient education is also highlighted. The continued development of technology in inhaler design and the need to standardise study assessment, endpoints and patient populations are identified as future research needs. The reviews of this paper are available via the supplemental material section .

Idiopathic pulmonary fibrosis is a peripheral subpleural interstitial lung disorder limited to the lung not involving the airways. It has a poor prognosis (survival less than 5 years) and commonly an interstitial pneumonia radiological pattern. Patients complain of a chronic dry cough in 80% of cases. A cough is often the first symptom of this rare disease, preceding dyspnea by years, and is associated with a poor prognosis, high dyspnea scores and low FVC percentages. The pathogenetic mechanisms leading to coughing in IPF are unclear. This review focuses on recent evidence of cough pathophysiology in this disease. Gastroesophageal reflux may promote coughing in IPF patients; bile salts and pepsin may be abundant in BAL of these patients, inducing overproduction of TGF-β by airway epithelial cells and mesenchymal transition with fibroblast recruitment/activation and extracellular matrix deposition. Patients have an enhanced cough reflex to capsaicin and substance P with respect to control subjects. Moreover, patients with the MUC5B polymorphism show more severe coughing as MUC5B encodes for the dominant mucin in the honeycomb cysts of IPF patients. Comorbidities, including asthma, gastroesophageal reflux, hypersensitivity pneumonitis, bronchiectasis, chronic obstructive pulmonary disease and emphysema, can induce coughing in IPF patients. There is no clear explanation of the causes of coughing in IPF. Further research into the pathophysiology of IPF and the pathogenetic mechanisms of coughing is necessary to improve survival and quality of life.

Background: Incorrect inhaler technique is a common cause of poor asthma control. This two-phase pragmatic study evaluated inhaler technique mastery and maintenance of mastery with DuoResp® (budesonide-formoterol [BF]) Spiromax® compared with Symbicort® (BF) Turbuhaler® in patients with asthma who were receiving inhaled corticosteroids/long-acting β2-agonists., Methods: In the initial cross-sectional phase, patients were randomized to a 6-step training protocol with empty Spiromax and Turbuhaler devices. Patients initially demonstrating ≥1 error with their current device, and then achieving mastery with both Spiromax and Turbuhaler (absence of healthcare professional [HCP]-observed errors), were eligible for the longitudinal phase. In the longitudinal phase, patients were randomized to BF Spiromax or BF Turbuhaler. Co-primary endpoints were the proportions of patients achieving device mastery after three training steps and maintaining device mastery (defined as the absence of HCP-observed errors after 12 weeks of use). Secondary endpoints included device preference, handling error frequency, asthma control, and safety. Exploratory endpoints included assessment of device mastery by an independent external expert reviewing video recordings of a subset of patients., Results: Four hundred ninety-three patients participated in the cross-sectional phase, and 395 patients in the longitudinal phase. In the cross-sectional phase, more patients achieved device mastery after three training steps with Spiromax (94%) versus Turbuhaler (87%) (odds ratio [OR] 3.77 [95% confidence interval (CI) 2.05-6.95], p < 0.001). Longitudinal phase data indicated that the odds of maintaining inhaler mastery at 12 weeks were not statistically significantly different (OR 1.26 [95% CI 0.80-1.98], p = 0.316). Asthma control improved in both groups with no significant difference between groups (OR 0.11 [95% CI -0.09-0.30]). An exploratory analysis indicated that the odds of maintaining independent expert-verified device mastery were significantly higher for patients using Spiromax versus Turbuhaler (OR 2.11 [95% CI 1.25-3.54])., Conclusions: In the cross-sectional phase, a significantly greater proportion of patients using Spiromax versus Turbuhaler achieved device mastery; in the longitudinal phase, the proportion of patients maintaining device mastery with Spiromax versus Turbuhaler was similar. An exploratory independent expert-verified analysis found Spiromax was associated with higher levels of device mastery after 12 weeks. Asthma control was improved by treatment with both BF Spiromax and BF Turbuhaler., Trial Registration: EudraCT 2013-004630-14 (registration date 23 January 2014); NCT02570425 .

Nonadherence to treatment, and its associated health and economic burden, is particularly problematic in asthma and chronic obstructive pulmonary disease management because of heterogeneous patient populations and the need for an inhaled route of drug administration. Symptom variability, comorbidities, and device switching further add to suboptimal adherence rates. As opposed to controlled clinical trials, real-life studies show consistently low inhaler adherence in daily practice, yet exact adherence rates have long been affected by disagreement on standardized definitions. The recently developed Ascertaining Barriers to Compliance taxonomy helps to address adherence research disparities by identifying 3 phases of adherence (initiation, implementation [including correct inhaler technique], and discontinuation). This review considers the reasons for and impact of suboptimal adherence, together with summaries of key studies that demonstrate how improving adherence can reduce exacerbations, inhaled corticosteroid use (in cases of better inhaler technique), hospitalizations, and treatment costs. Strategies to help ensure optimal adherence are discussed, including the choice of a patient-tailored inhaler, patient empowerment, education and training, and the potential of electronic monitoring and digital technology. It is concluded that a combined effort from payers, health care professionals, and manufacturers could make a real difference to asthma and chronic obstructive pulmonary disease control, as well as to health care budgets., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Proceedings of the European Seminars in Respiratory Medicine course, Inhalation therapy in the next decade: Determinants of adherence to treatment in asthma and COPD, held in Taormina, Italy, on 3-4 March, 2017.

Background: Inhaled drug delivery is the cornerstone treatment for asthma and chronic obstructive pulmonary disease (COPD). However, use of inhaler devices can be challenging, potentially leading to critical errors in handling that can significantly reduce drug delivery to the lungs and effectiveness of treatment., Methods: A systematic review was conducted to define 'critical' errors and their impact on health outcomes and resource use between 2004 and 2016, using key search terms for inhaler errors in asthma and COPD (Search-1) and associated health-economic and patient burden (Search-2)., Results: Search-1 identified 62 manuscripts, 47 abstracts, and 5 conference proceedings (n = 114 total). Search-2 identified 9 studies. We observed 299 descriptions of critical error. Age, education status, previous inhaler instruction, comorbidities and socioeconomic status were associated with worse handling error frequency. A significant association was found between inhaler errors and poor disease outcomes (exacerbations), and greater health-economic burden., Conclusions: We have shown wide variations in how critical errors are defined, and the evidence shows an important association between inhaler errors and worsened health outcomes. Given the negative impact diminished disease outcomes impose on resource use, our findings highlight the importance of achieving optimal inhaler technique, and a need for a consensus on defining critical and non-critical errors.

Objective: Healthcare professionals (HCPs) are required to assess and train patients in the correct use of inhalers but are often unable to demonstrate correct technique themselves. We sought to assess the level of training required for HCPs to master and maintain device mastery when using two different dry powder inhalers (DPIs)., Methods: We conducted a randomized, un-blinded, crossover study in undergraduate HCPs who undertook a six-step training procedure (intuitive use, patient information leaflet, instructional video, individual tuition from expert, then two repeats of individual tuition) for the use of Turbuhaler® (an established device) and Spiromax® (a newer device, reportedly easier to use). Device mastery (absence of errors) was evaluated by expert assessors at each training step. Maintenance of mastery was assessed 4 ± 1 week (visit 2) and 8 ± 2 weeks (visit 3) after initial training (visit 1)., Results: Of 516 eligible participants, 113 (22%) demonstrated device mastery prior to training on Spiromax® compared with 20 (4%) on Turbuhaler® (p < 0.001). The median number of training steps required to achieve mastery was 2 (interquartile range [IQR] 2-4) for Spiromax® and 3 (IQR 2-4) for Turbuhaler® (p < 0.001). A higher number of participants maintained mastery with Spiromax® compared with Turbuhaler®, at visits 2 and 3 (64% vs 41% and 79% vs 65%, respectively; p < 0.001)., Conclusions: There are significant differences in the nature and extent of training required to achieve and maintain mastery for Spiromax® and Turbuhaler® devices. The implications on clinical practice, device education delivery, and patient outcomes require further evaluation.

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease with a poor prognosis and an undefined etiopathogenesis. Oxidative stress contributes to alveolar injury and fibrosis development and, because transition metals are essential to the functioning of most proteins involved in redox reactions, a better knowledge of metal concentrations and metabolism in the respiratory system of IPF patients may provide a valuable complementary approach to prevent and manage a disease which is often misdiagnosed or diagnosed in later stages. The present review summarizes and discusses literature data on the elemental composition of bronchoalveolar lavage (BAL), induced sputum and exhaled breath condensate (EBC) from patients affected by IPF and healthy subjects. Available data are scanty and the lack of consistent methods for the collection and analysis of lung and airways lining fluids makes it difficult to compare the results of different studies. However, the elemental composition of BAL samples from IPF patients seems to have a specific profile that can be distinguished from that of patients with other interstitial lung diseases (ILD) or control subjects. Suggestions are given towards standard sampling and analytical procedures of BAL samples, in the aim to assess typical element concentration patterns and their potential role as biomarkers of IPF., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

Background: Poor inhaler technique has been linked to poor asthma outcomes. Training can reduce the number of inhaler errors, but it is unknown which errors have the greatest impact on asthma outcomes., Objective: The CRITical Inhaler mistaKes and Asthma controL study investigated the association between specific inhaler errors and asthma outcomes., Methods: This analysis used data from the iHARP asthma review service-a multicenter cross-sectional study of adults with asthma. The review took place between 2011 and 2014 and captured data from more than 5000 patients on demographic characteristics, asthma symptoms, and inhaler errors observed by purposefully trained health care professionals. People with asthma receiving a fixed-dose combination treatment with inhaled corticosteroids and long-acting beta agonist were categorized by the controller inhaler device they used-dry-powder inhalers or metered-dose inhalers: inhaler errors were analyzed within device cohorts. Error frequency, asthma symptom control, and exacerbation rate were analyzed to identify critical errors., Results: This report contains data from 3660 patients. Insufficient inspiratory effort was common (made by 32%-38% of dry-powder inhaler users) and was associated with uncontrolled asthma (adjusted odds ratios [95% CI], 1.30 [1.08-1.57] and 1.56 [1.17-2.07] in those using Turbohaler and Diskus devices, respectively) and increased exacerbation rate. In metered-dose inhaler users, actuation before inhalation (24.9% of patients) was associated with uncontrolled asthma (1.55 [1.11-2.16]). Several more generic and device-specific errors were also identified as critical., Conclusions: Specific inhaler errors have been identified as critical errors, evidenced by frequency and association with asthma outcomes. Asthma management should target inhaler training to reduce key critical errors., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)