ERS technical standard: Global Lung Function Initiative reference values for exhaled nitric oxide fraction (F ENO50 ).

BACKGROUND: Elevated exhaled nitric oxide fraction at a flow rate of 50 mL·s-1 (F ENO50 ) is an important indicator of T-helper 2-driven airway inflammation and may aid clinicians in the diagnosis and monitoring of asthma. This study aimed to derive Global Lung Function Initiative reference equations and the upper limit of normal for F ENO50 . METHODS: Available individual F ENO50 data were collated and harmonised using consensus-derived variables and definitions. Data collected from individuals who met the harmonised definition of "healthy" were analysed using the generalised additive models of location, scale and shape (GAMLSS) technique. RESULTS: Data were retrospectively collated from 34 782 individuals from 34 sites in 15 countries, of whom 8022 met the definition of healthy (19 sites, 11 countries). Overall, height, age and sex only explained 12% of the between-subject variability of F ENO50 (R2=0.12). F ENO device was neccessary as a predictor of F ENO50 , such that the healthy range of values and the upper limit of normal varied depending on which device was used. The range of F ENO50 values observed in healthy individuals was also very wide, and the heterogeneity was partially explained by the device used. When analysing a subset of data in which F ENO50 was measured using the same device and a stricter definition of health (n=1027), between-site heterogeneity remained. CONCLUSION: Available F ENO50 data collected from different sites using different protocols and devices were too variable to develop a single all-age reference equation. Further standardisation of F ENO devices and measurement are required before population reference values might be derived.

Prognostic value of automated assessment of interstitial lung disease on CT in systemic sclerosis.

OBJECTIVE: Stratifying the risk of death in SSc-related interstitial lung disease (SSc-ILD) is a challenging issue. The extent of lung fibrosis on high-resolution CT (HRCT) is often assessed by a visual semiquantitative method that lacks reliability. We aimed to assess the potential prognostic value of a deep-learning-based algorithm enabling automated quantification of ILD on HRCT in patients with SSc. METHODS: We correlated the extent of ILD with the occurrence of death during follow-up, and evaluated the additional value of ILD extent in predicting death based on a prognostic model including well-known risk factors in SSc. RESULTS: We included 318 patients with SSc, among whom 196 had ILD; the median follow-up was 94 months (interquartile range 73-111). The mortality rate was 1.6% at 2 years and 26.3% at 10 years. For each 1% increase in the baseline ILD extent (up to 30% of the lung), the risk of death at 10 years was increased by 4% (hazard ratio 1.04, 95% CI 1.01, 1.07, P = 0.004). We constructed a risk prediction model that showed good discrimination for 10-year mortality (c index 0.789). Adding the automated quantification of ILD significantly improved the model for 10-year survival prediction (P = 0.007). Its discrimination was only marginally improved, but it improved prediction of 2-year mortality (difference in time-dependent area under the curve 0.043, 95% CI 0.002, 0.084, P = 0.040). CONCLUSION: The deep-learning-based, computer-aided quantification of ILD extent on HRCT provides an effective tool for risk stratification in SSc. It might help identify patients at short-term risk of death.

Collaboration between explainable artificial intelligence and pulmonologists improves the accuracy of pulmonary function test interpretation.

BACKGROUND: Few studies have investigated the collaborative potential between artificial intelligence (AI) and pulmonologists for diagnosing pulmonary disease. We hypothesised that the collaboration between a pulmonologist and AI with explanations (explainable AI (XAI)) is superior in diagnostic interpretation of pulmonary function tests (PFTs) than the pulmonologist without support. METHODS: The study was conducted in two phases, a monocentre study (phase 1) and a multicentre intervention study (phase 2). Each phase utilised two different sets of 24 PFT reports of patients with a clinically validated gold standard diagnosis. Each PFT was interpreted without (control) and with XAI's suggestions (intervention). Pulmonologists provided a differential diagnosis consisting of a preferential diagnosis and optionally up to three additional diagnoses. The primary end-point compared accuracy of preferential and additional diagnoses between control and intervention. Secondary end-points were the number of diagnoses in differential diagnosis, diagnostic confidence and inter-rater agreement. We also analysed how XAI influenced pulmonologists' decisions. RESULTS: In phase 1 (n=16 pulmonologists), mean preferential and differential diagnostic accuracy significantly increased by 10.4% and 9.4%, respectively, between control and intervention (p<0.001). Improvements were somewhat lower but highly significant (p<0.0001) in phase 2 (5.4% and 8.7%, respectively; n=62 pulmonologists). In both phases, the number of diagnoses in the differential diagnosis did not reduce, but diagnostic confidence and inter-rater agreement significantly increased during intervention. Pulmonologists updated their decisions with XAI's feedback and consistently improved their baseline performance if AI provided correct predictions. CONCLUSION: A collaboration between a pulmonologist and XAI is better at interpreting PFTs than individual pulmonologists reading without XAI support or XAI alone.

Respiratory recovery trajectories after severe-to-critical COVID-19: a 1-year prospective multicentre study.

BACKGROUND: Survivors of severe-to-critical coronavirus disease 2019 (COVID-19) may have functional impairment, radiological sequelae and persistent symptoms requiring prolonged follow-up. This pragmatic study aimed to describe their clinical follow-up and determine their respiratory recovery trajectories, and the factors that could influence them and their health-related quality of life. METHODS: Adults hospitalised for severe-to-critical COVID-19 were evaluated at 3 months and up to 12 months post-hospital discharge in this prospective, multicentre, cohort study. RESULTS: Among 485 enrolled participants, 293 (60%) were reassessed at 6 months and 163 (35%) at 12 months; 89 (51%) and 47 (27%) of the 173 participants initially managed with standard oxygen were reassessed at 6 and 12 months, respectively. At 3 months, 34%, 70% and 56% of the participants had a restrictive lung defect, impaired diffusing capacity of the lung for carbon monoxide (D LCO) and significant radiological sequelae, respectively. During extended follow-up, both D LCO and forced vital capacity percentage predicted increased by means of +4 points at 6 months and +6 points at 12 months. Sex, body mass index, chronic respiratory disease, immunosuppression, pneumonia extent or corticosteroid use during acute COVID-19 and prolonged invasive mechanical ventilation (IMV) were associated with D LCO at 3 months, but not its trajectory thereafter. Among 475 (98%) patients with at least one chest computed tomography scan during follow-up, 196 (41%) had significant sequelae on their last images. CONCLUSIONS: Although pulmonary function and radiological abnormalities improved up to 1 year post-acute COVID-19, high percentages of severe-to-critical disease survivors, including a notable proportion of those managed with standard oxygen, had significant lung sequelae and residual symptoms justifying prolonged follow-up.

Improving lung health in low-income and middle-income countries: from challenges to solutions.

Low-income and middle-income countries (LMICs) bear a disproportionately high burden of the global morbidity and mortality caused by chronic respiratory diseases (CRDs), including asthma, chronic obstructive pulmonary disease, bronchiectasis, and post-tuberculosis lung disease. CRDs are strongly associated with poverty, infectious diseases, and other non-communicable diseases (NCDs), and contribute to complex multi-morbidity, with major consequences for the lives and livelihoods of those affected. The relevance of CRDs to health and socioeconomic wellbeing is expected to increase in the decades ahead, as life expectancies rise and the competing risks of early childhood mortality and infectious diseases plateau. As such, the World Health Organization has identified the prevention and control of NCDs as an urgent development issue and essential to the achievement of the Sustainable Development Goals by 2030. In this Review, we focus on CRDs in LMICs. We discuss the early life origins of CRDs; challenges in their prevention, diagnosis, and management in LMICs; and pathways to solutions to achieve true universal health coverage.

European Respiratory Society statement on long COVID follow-up.

Patients diagnosed with coronavirus disease 2019 (COVID-19) associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection frequently experience symptom burden post-acute infection or post-hospitalisation. We aimed to identify optimal strategies for follow-up care that may positively impact the patient's quality of life (QoL). A European Respiratory Society (ERS) Task Force convened and prioritised eight clinical questions. A targeted search of the literature defined the timeline of "long COVID" as 1-6 months post-infection and identified clinical evidence in the follow-up of patients. Studies meeting the inclusion criteria report an association of characteristics of acute infection with persistent symptoms, thromboembolic events in the follow-up period, and evaluations of pulmonary physiology and imaging. Importantly, this statement reviews QoL consequences, symptom burden, disability and home care follow-up. Overall, the evidence for follow-up care for patients with long COVID is limited.

Elastic Registration-driven Deep Learning for Longitudinal Assessment of Systemic Sclerosis Interstitial Lung Disease at CT.

Background Longitudinal follow-up of interstitial lung diseases (ILDs) at CT mainly relies on the evaluation of the extent of ILD, without accounting for lung shrinkage. Purpose To develop a deep learning-based method to depict worsening of ILD based on lung shrinkage detection from elastic registration of chest CT scans in patients with systemic sclerosis (SSc). Materials and Methods Patients with SSc evaluated between January 2009 and October 2017 who had undergone at least two unenhanced supine CT scans of the chest and pulmonary function tests (PFTs) performed within 3 months were retrospectively included. Morphologic changes on CT scans were visually assessed by two observers and categorized as showing improvement, stability, or worsening of ILD. Elastic registration between baseline and follow-up CT images was performed to obtain deformation maps of the whole lung. Jacobian determinants calculated from the deformation maps were given as input to a deep learning-based classifier to depict morphologic and functional worsening. For this purpose, the set was randomly split into training, validation, and test sets. Correlations between mean Jacobian values and changes in PFT measurements were evaluated with the Spearman correlation. Results A total of 212 patients (median age, 53 years; interquartile range, 45-62 years; 177 women) were included as follows: 138 for the training set (65%), 34 for the validation set (16%), and 40 for the test set (21%). Jacobian maps demonstrated lung parenchyma shrinkage of the posterior lung bases in patients found to have worsened ILD at visual assessment. The classifier detected morphologic and functional worsening with an accuracy of 80% (32 of 40 patients; 95% confidence interval [CI]: 64%, 91%) and 83% (33 of 40 patients; 95% CI: 67%, 93%), respectively. Jacobian values correlated with changes in forced vital capacity (R = -0.38; 95% CI: -0.25, -0.49; P < .001) and diffusing capacity for carbon monoxide (R = -0.42; 95% CI: -0.27, -0.54; P < .001). Conclusion Elastic registration of CT scans combined with a deep learning classifier aided in the diagnosis of morphologic and functional worsening of interstitial lung disease in patients with systemic sclerosis. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Verschakelen in this issue.

Low-cost, easy-to-build noninvasive pressure support ventilator for under-resourced regions: open source hardware description, performance and feasibility testing.

AIM: Current pricing of commercial mechanical ventilators in low-/middle-income countries (LMICs) markedly restricts their availability, and consequently a considerable number of patients with acute/chronic respiratory failure cannot be adequately treated. Our aim was to design and test an affordable and easy-to-build noninvasive bilevel pressure ventilator to allow a reduction in the serious shortage of ventilators in LMICs. METHODS: The ventilator was built using off-the-shelf materials available via e-commerce and was based on a high-pressure blower, two pressure transducers and an Arduino Nano controller with a digital display (total retail cost <75 USD), with construction details provided open source for free replication. The ventilator was evaluated, and compared with a commercially available device (Lumis 150 ventilator; Resmed, San Diego, CA, USA): 1) in the bench setting using an actively breathing patient simulator mimicking a range of obstructive/restrictive diseases; and b) in 12 healthy volunteers wearing high airway resistance and thoracic/abdominal bands to mimic obstructive/restrictive patients. RESULTS: The designed ventilator provided inspiratory/expiratory pressures up to 20/10 cmH2O, respectively, with no faulty triggering or cycling; both in the bench test and in volunteers. The breathing difficulty score rated (1-10 scale) by the loaded breathing subjects was significantly (p<0.005) decreased from 5.45±1.68 without support to 2.83±1.66 when using the prototype ventilator, which showed no difference with the commercial device (2.80±1.48; p=1.000). CONCLUSION: The low-cost, easy-to-build noninvasive ventilator performs similarly to a high-quality commercial device, with its open-source hardware description, which will allow for free replication and use in LMICs, facilitating application of this life-saving therapy to patients who otherwise could not be treated.

Pulmonary vascular endothelium: the orchestra conductor in respiratory diseases: Highlights from basic research to therapy.

The European Respiratory Society (ERS) Research Seminar entitled "Pulmonary vascular endothelium: orchestra conductor in respiratory diseases - highlights from basic research to therapy" brought together international experts in dysfunctional pulmonary endothelium, from basic science to translational medicine, to discuss several important aspects in acute and chronic lung diseases. This review will briefly sum up the different topics of discussion from this meeting which was held in Paris, France on October 27-28, 2016. It is important to consider that this paper does not address all aspects of endothelial dysfunction but focuses on specific themes such as: 1) the complex role of the pulmonary endothelium in orchestrating the host response in both health and disease (acute lung injury, chronic obstructive pulmonary disease, high-altitude pulmonary oedema and pulmonary hypertension); and 2) the potential value of dysfunctional pulmonary endothelium as a target for innovative therapies.

ERS/ECDC Statement: European Union standards for tuberculosis care, 2017 update.

The International Standards for Tuberculosis Care define the essential level of care for managing patients who have or are presumed to have tuberculosis, or are at increased risk of developing the disease. The resources and capacity in the European Union (EU) and the European Economic Area permit higher standards of care to secure quality and timely TB diagnosis, prevention and treatment. On this basis, the European Union Standards for Tuberculosis Care (ESTC) were published in 2012 as standards specifically tailored to the EU setting. Since the publication of the ESTC, new scientific evidence has become available and, therefore, the standards were reviewed and updated.A panel of international experts, led by a writing group from the European Respiratory Society (ERS) and the European Centre for Disease Prevention and Control (ECDC), updated the ESTC on the basis of new published evidence. The underlying principles of these patient-centred standards remain unchanged. The second edition of the ESTC includes 21 standards in the areas of diagnosis, treatment, HIV and comorbidities, and public health and prevention.The ESTC target clinicians and public health workers, provide an easy-to-use resource and act as a guide through all the required activities to ensure optimal diagnosis, treatment and prevention of TB.

Macrophage Migration Inhibitory Factor (MIF) Inhibition in a Murine Model of Bleomycin-Induced Pulmonary Fibrosis.

BACKGROUND: Pulmonary hypertension (PH) is a common complication of idiopathic pulmonary fibrosis (IPF) that significantly contributes to morbidity and mortality. Macrophage migration inhibitory factor (MIF) is a critical factor in vascular remodeling of the pulmonary circulation. OBJECTIVES: We tested the effects of two small molecules targeting MIF on bleomycin (BLM)-induced collagen deposition, PH, and vascular remodeling in mouse lungs. METHODS: We examined the distribution pattern of MIF, CD74, and CXCR4 in the lungs of patients with IPF-PH and the lungs of BLM-injected mice. Then, treatments were realized with (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) and N-(3-hydroxy-4-fluorobenzyl)-5 trifluoromethylbenzoxazol-2-thione 31 (20 mg/kg/day per os for 3 weeks) started 24 h after an intratracheal BLM administration. RESULTS: More intense immunoreactivity was noted for MIF, CD74, and CXCR4 in lungs from IPF-PH patients and BLM-injected mice. Furthermore, we found that treatments of BLM-injected mice with ISO-1 or compound 31 attenuated lung collagen deposition and right ventricular systolic pressure increase. Additionally, reduced pulmonary inflammatory infiltration and pulmonary arterial muscularization were observed in the lungs of BLM-injected mice treated with ISO-1 or compound 31. CONCLUSIONS: Treatments with ISO-1 or compound 31 attenuates BLM-induced inflammation and fibrosis in lung, and prevents PH development in mice, suggesting that MIF is an important factor for IPF-PH development.

Combined measurement of carbon monoxide and nitric oxide lung transfer does not improve the identification of pulmonary hypertension in systemic sclerosis.

Screening is important to determine whether patients with systemic sclerosis (SSc) have pulmonary hypertension because earlier pulmonary hypertension treatment can improve survival in these patients. Although decreased transfer factor of the lung for carbon monoxide (TLCO) is currently considered the best pulmonary function test for screening for pulmonary hypertension in SSc, small series have suggested that partitioning TLCO into membrane conductance (diffusing capacity) for carbon monoxide (DMCO) and alveolar capillary blood volume (VC) through combined measurement of TLCO and transfer factor of the lung for nitric oxide (TLNO) is more effective to identify pulmonary hypertension in SSc patients compared with TLCO alone. Here, the objective was to determine whether combined TLCO-TLNO partitioned with recently refined equations could more accurately detect pulmonary hypertension than TLCO alone in SSc.For that purpose, 572 unselected consecutive SSc patients were retrospectively recruited in seven French centres.Pulmonary hypertension was diagnosed with right heart catheterisation in 58 patients. TLCO, TLNO and VC were all lower in SSc patients with pulmonary hypertension than in SSc patients without pulmonary hypertension. The area under the receiver operating characteristic curve for the presence of pulmonary hypertension was equivalent for TLCO (0.82, 95% CI 0.79-0.85) and TLNO (0.80, 95% CI 0.76-0.83), but lower for VC (0.75, 95% CI 0.71-0.78) and DMCO (0.66, 95% CI 0.62-0.70).Compared with TLCO alone, combined TLCO-TLNO does not add capability to detect pulmonary hypertension in unselected SSc patients.

Standardisation and application of the single-breath determination of nitric oxide uptake in the lung.

Diffusing capacity of the lung for nitric oxide (DLNO), otherwise known as the transfer factor, was first measured in 1983. This document standardises the technique and application of single-breath DLNO This panel agrees that 1) pulmonary function systems should allow for mixing and measurement of both nitric oxide (NO) and carbon monoxide (CO) gases directly from an inspiratory reservoir just before use, with expired concentrations measured from an alveolar "collection" or continuously sampled via rapid gas analysers; 2) breath-hold time should be 10 s with chemiluminescence NO analysers, or 4-6 s to accommodate the smaller detection range of the NO electrochemical cell; 3) inspired NO and oxygen concentrations should be 40-60 ppm and close to 21%, respectively; 4) the alveolar oxygen tension (PAO2 ) should be measured by sampling the expired gas; 5) a finite specific conductance in the blood for NO (θNO) should be assumed as 4.5 mL·min-1·mmHg-1·mL-1 of blood; 6) the equation for 1/θCO should be (0.0062·PAO2 +1.16)·(ideal haemoglobin/measured haemoglobin) based on breath-holding PAO2 and adjusted to an average haemoglobin concentration (male 14.6 g·dL-1, female 13.4 g·dL-1); 7) a membrane diffusing capacity ratio (DMNO/DMCO) should be 1.97, based on tissue diffusivity.

A European Respiratory Society technical standard: exhaled biomarkers in lung disease.

Breath tests cover the fraction of nitric oxide in expired gas (FeNO), volatile organic compounds (VOCs), variables in exhaled breath condensate (EBC) and other measurements. For EBC and for FeNO, official recommendations for standardised procedures are more than 10 years old and there is none for exhaled VOCs and particles. The aim of this document is to provide technical standards and recommendations for sample collection and analytic approaches and to highlight future research priorities in the field. For EBC and FeNO, new developments and advances in technology have been evaluated in the current document. This report is not intended to provide clinical guidance on disease diagnosis and management.Clinicians and researchers with expertise in exhaled biomarkers were invited to participate. Published studies regarding methodology of breath tests were selected, discussed and evaluated in a consensus-based manner by the Task Force members.Recommendations for standardisation of sampling, analysing and reporting of data and suggestions for research to cover gaps in the evidence have been created and summarised.Application of breath biomarker measurement in a standardised manner will provide comparable results, thereby facilitating the potential use of these biomarkers in clinical practice.

RhoA/Rho-kinase activation promotes lung fibrosis in an animal model of systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is a connective-tissue disease characterized by vascular injury, immune-system disorders, and excessive fibrosis of the skin and multiple internal organs. Recent reports found that RhoA/Rho-kinase (ROCK) pathway is implicated in various fibrogenic diseases. Intradermal injection of hypochlorous acid (HOCl)-generating solution induced inflammation, autoimmune activation, and fibrosis, mimicking the cutaneous diffuse form of SSc in humans. Our study aimed firstly to describe pulmonary inflammation and fibrosis induced by HOCl in mice, and secondly to determine whether fasudil, a selective inhibitor of ROCK, could prevent lung and skin fibroses in HOCl-injected mice. METHODS: Female C57BL/6 mice received daily intradermal injection of hypochlorous acid (HOCl) for 6 weeks to induce SSc, with and without daily treatment with fasudil (30 mg·kg(-1)·day(-1)) by oral gavage. RESULTS: HOCl intoxication induced significant lung inflammation (macrophages and neutrophils infiltration), and fibrosis. These modifications were prevented by fasudil treatment. Simultaneously, HOCl enhanced ROCK activity in lung and skin tissues. Inhibition of ROCK reduced skin fibrosis, expression of α-smooth-muscle actin and 3-nitrotyrosine, as well as the activity of ROCK in the fibrotic skin of HOCl-treated mice, through inhibition of phosphorylation of Smad2/3 and ERK1/2. Fasudil significantly decreased the serum levels of anti-DNA-topoisomerase-1 antibodies in mice with HOCl-induced SSc. CONCLUSIONS: Our findings confirm HOCl-induced pulmonary inflammation and fibrosis in mice, and provide further evidence for a key role of RhoA/ROCK pathway in several pathological processes of experimental SSc. Fasudil could be a promising therapeutic approach for the treatment of SSc.