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COVID-19 has overwhelmed health services globally. Oral antiviral therapies are licensed worldwide, but indications and efficacy rates vary. We aimed to evaluate the safety and efficacy of oral favipiravir in patients hospitalised with COVID-19.We conducted a multicentre, open-label, randomised controlled trial of oral favipiravir in adult patients who were newly admitted to hospital with proven or suspected COVID-19 across five sites in the UK (n=2), Brazil (n=2) and Mexico (n=1). Using a permuted block design, eligible and consenting participants were randomly assigned (1:1) to receive oral favipiravir (1800 mg twice daily for 1 day; 800 mg twice daily for 9 days) plus standard care, or standard care alone. All caregivers and patients were aware of allocation and those analysing data were aware of the treatment groups. The prespecified primary outcome was the time from randomisation to recovery, censored at 28 days, which was assessed using an intention-to-treat approach. Post-hoc analyses were used to assess the efficacy of favipiravir in patients aged younger than 60 years, and in patients aged 60 years and older. The trial was registered with clinicaltrials.gov, NCT04373733.Between May 5, 2020 and May 26, 2021, we assessed 503 patients for eligibility, of whom 499 were randomly assigned to favipiravir and standard care (n=251) or standard care alone (n=248). There was no significant difference between those who received favipiravir and standard care, relative to those who received standard care alone in time to recovery in the overall study population (hazard ratio [HR] 1·06 [95% CI 0·89-1·27]; n=499; p=0·52). Post-hoc analyses showed a faster rate of recovery in patients younger than 60 years who received favipiravir and standard care versus those who had standard care alone (HR 1·35 [1·06-1·72]; n=247; p=0·01). 36 serious adverse events were observed in 27 (11%) of 251 patients administered favipiravir and standard care, and 33 events were observed in 27 (11%) of 248 patients receiving standard care alone, with infectious, respiratory, and cardiovascular events being the most numerous. There was no significant between-group difference in serious adverse events per patient (p=0·87).Favipiravir does not improve clinical outcomes in all patients admitted to hospital with COVID-19, however, patients younger than 60 years might have a beneficial clinical response. The indiscriminate use of favipiravir globally should be cautioned, and further high-quality studies of antiviral agents, and their potential treatment combinations, are warranted in COVID-19.LifeArc and CW+.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has brought renewed attention to respiratory aerosol and droplet generation. While many studies have robustly quantified aerosol (20 µm diameter) generated by a cohort of 76 adults and children using a water-sensitive paper droplet deposition approach. Unvoiced and voiced activities spanning different levels of loudness, different lengths of sustained phonation, and a specific manner of articulation in isolation were investigated. We find that oral articulation drives >20 µm droplet generation, with breathing generating virtually no droplets and speaking and singing generating on the order of 250 droplets min−1. Lip trilling, which requires extensive oral articulation, generated the most droplets, whereas shouting “Hey,” which requires minimal oral articulation, generated relatively few droplets. Droplet size distributions were all broadly consistent, and no significant differences between the children and adult cohorts were identified. By comparing the aerosol and droplet emissions for the same participants, the full size distribution of respiratory aerosol (0.5–1000 µm) is reported. Although 20 µm droplets dominate the mass concentration. Accurate quantification of aerosol concentrations in the 10–70 μm size range remains very challenging; more robust aerosol analysis approaches are needed to characterize this size range.

Background: Lung volume reduction coil (LVR-coil) treatment provides a minimally invasive treatment option for severe emphysema patients which has been studied in multiple clinical trials. Objectives: The aim of the study was to assess the effect of LVR-coil treatment on pulmonary function, quality of life, and exercise capacity using individual participant data. Method: PubMed, Web of Science, and EMBASE were searched until May 17, 2021. Prospective single-arm and randomized controlled trials that evaluated the effect of LVR-coil treatment on forced expiratory volume in 1 s (FEV1), residual volume (RV), St. George Respiratory Questionnaire (SGRQ) total score, and/or 6-min walk distance (6MWD) and were registered in an official clinical trial database were eligible for inclusion. Individual patient data were requested, and a linear mixed effects model was used to calculate overall treatment effects. Results: Eight trials were included in the final analysis, representing 680 individual patients. LVR-coil treatment resulted in a significant improvement in FEV1 at 3- (0.09 L [95% confidence interval (95% CI): 0.06–0.12]) and 6-month follow-up (0.07 L [95% CI: 0.03–0.10]), a significant reduction in RV at 3- (−0.45L [95% CI: −0.62 to −0.28]), 6- (−0.33L [95% CI: −0.52 to −0.14]), and 12-month follow-up (−0.36L [95% CI: −0.64 to −0.08]), a significant reduction in SGRQ total score at 3- (−12.3 points [95% CI: −15.8 to −8.8]), 6- (−10.1 points [95% CI: −12.8 to −7.3]), and 12-month follow-up (−9.8 points [95% CI: −15.0 to −4.7]) and a significant increase in 6MWD at 3-month follow-up (38 m [95% CI: 18–58]). Conclusions: LVR-coil treatment in emphysema patients results in sustained improvements in pulmonary function and quality of life and shorter lived improvements in exercise capacity. Since the owner of this LVR-coil has decided to stop the production and newer generations LVR-coils are currently being developed, these results can act as a reference for future studies and clinical guidance.

Background: Asthma is a heterogeneous disease with differences in onset, severity, and inflammation. Bronchial epithelial cells (BECs) contribute to asthma pathophysiology.Objective: We determined whether transcriptomes of BECs reflect heterogeneity in inflammation and severity in asthma, and whether this was affected in BECs from patients with severe asthma after their regeneration by bronchial thermoplasty.Methods: RNA sequencing was performed on BECs obtained by bronchoscopy from healthy controls (n = 16), patients with mild asthma (n = 17), patients with moderate asthma (n = 5), and patients with severe asthma (n = 17), as well as on BECs from treated and untreated airways of the latter (also 6 months after bronchial thermoplasty) (n = 23). Lipidome and metabolome analyses were performed on cultured BECs from healthy controls (n = 7); patients with severe asthma (n = 9); and, for comparison, patients with chronic obstructive pulmonary disease (n = 7).Results: Transcriptome analysis of BECs from patients showed a reduced expression of oxidative phosphorylation (OXPHOS) genes, most profoundly in patients with severe asthma but less profoundly and more heterogeneously in patients with mild asthma. Genes related to fatty acid metabolism were significantly upregulated in asthma. Lipidomics revealed enhanced levels of lipid species (phosphatidylcholines, lysophosphatidylcholines. and bis(monoacylglycerol)phosphate), whereas levels of OXPHOS metabolites were reduced in BECs from patients with severe asthma. BECs from patients with mild asthma characterized by hyperresponsive production of mediators implicated in neutrophilic inflammation had decreased expression of OXPHOS genes compared with that in BECs from patients with mild asthma with normoresponsive production. BECs obtained after thermoplasty had significantly increased expression of OXPHOS genes and decreased expression of fatty acid metabolism genes compared with BECs obtained from untreated airways.Conclusion: BECs in patients with asthma are metabolically different from those in healthy individuals. These differences are linked with inflammation and asthma severity, and they can be reversed by bronchial thermoplasty.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a worldwide pandemic. People with airways disease are at higher risk of respiratory infection, and viruses can trigger respiratory exacerbations. Patients with airways disease may therefore be more susceptible to SARS-CoV-2 infection, development of covid-19, or be at higher risk of adverse outcomes. Here we review susceptibility, based on current epidemiological studies, and explore biological mechanisms. Evidence from multiple large observational studies has shown chronic obstructive pulmonary disease (COPD) is a significant risk factor for covid-19 related mortality. Whether people with asthma are more susceptible to infection or severe outcomes has been much debated but appears to be related to their asthma phenotype and severity. To what extent these differences are biological or influenced by public health non-pharmacological interventions is difficult to quantify. Biological mechanisms that may influence susceptibility and adverse outcomes in airways disease include the increased expression of protein receptors enabling viral cell entry, dysfunctional epithelial airway immunity, type-2 inflammation and the use of inhaled corticosteroids. A better understanding of the susceptibility and mechanisms is essential for developing preventative and therapeutic strategies. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction.Voice assessment and treatment involve the manipulation of all the subsystems of voice production, and may lead to production of respirable aerosol particles that pose a greater risk of potential viral transmission via inhalation of respirable pathogens (e.g. SARS-CoV-2) than quiet breathing or conversational speech. Objective: To characterise the production of respirable aerosol particles during a selection of voice assessment therapy tasks.MethodsWe recruited 23 healthy adult participants (12 males, 11 females), 11 of whom were speech-language pathologists specialising in voice disorders. We used an aerodynamic and optical particle sizer to measure the number concentration and particle size distributions of respirable aerosols generated during a variety of voice assessment and therapy tasks. The measurements were carried out in a laminar flow operating theatre, with a near-zero background aerosol concentration, allowing us to quantify the number concentration and size distributions of respirable aerosol particles produced from assessment/therapy tasks studied. ResultsAerosol number concentrations generated while performing assessment/therapy tasks were log-normally distributed among individuals with no significant differences between professionals (speech-language pathologists) and non-professionals or between males and females. Activities produced up to 32 times the aerosol number concentration of breathing and 24 times that of speech at 70-80 dBA. In terms of aerosol mass, activities produced up to 163 times the mass concentration of breathing and up to 36 times the mass concentration of speech. Voicing was a significant factor in aerosol production; aerosol number/mass concentrations generated during voiced activities were 1.1-5 times higher than their unvoiced counterpart activities. Additionally, voiced activities produced bigger respirable aerosol particles than their unvoiced variants except the trills. Humming generated higher aerosol concentrations than sustained /a/, fricatives, speaking (70-80 dBA), and breathing. Oscillatory semi-occluded vocal tract exercises (SOVTEs) generated higher aerosol number/mass concentrations than activities without oscillation. Water resistance therapy (WRT) generated the most aerosol of all activities, ~10 times higher than speaking at 70-80 dBA and >30 times higher than breathing.ConclusionsAll activities generated more aerosol than breathing, although a sizeable minority were no different to speaking. Larger number concentrations and larger particle sizes appear to be generated by activities with higher suspected airflows, with the greatest involving intraoral pressure oscillation and/or an oscillating oral articulation (WRT or trilling).

Background The coronavirus disease-19 (COVID-19) pandemic led to the prohibition of group-based exercise and the cancellation of sporting events. Evaluation of respiratory aerosol emissions is necessary to quantify exercise-related transmission risk and inform mitigation strategies. Methods Aerosol mass emission rates are calculated from concurrent aerosol and ventilation data, enabling absolute comparison. An aerodynamic particle sizer (0.54–20 μm diameter) samples exhalate from within a cardiopulmonary exercise testing mask, at rest, while speaking and during cycle ergometer-based exercise. Exercise challenge testing is performed to replicate typical gym-based exercise and very vigorous exercise, as determined by a preceding maximally exhaustive exercise test. Results We present data from 25 healthy participants (13 males, 12 females; 36.4 years). The size of aerosol particles generated at rest and during exercise is similar (unimodal ~0.57–0.71 µm), whereas vocalization also generated aerosol particles of larger size (i.e. was bimodal ~0.69 and ~1.74 µm). The aerosol mass emission rate during speaking (0.092 ng s−1; minute ventilation (VE) 15.1 L min−1) and vigorous exercise (0.207 ng s−1, p = 0.726; VE 62.6 L min−1) is similar, but lower than during very vigorous exercise (0.682 ng s−1, p −1). Conclusions Vocalisation drives greater aerosol mass emission rates, compared to breathing at rest. Aerosol mass emission rates in exercise rise with intensity. Aerosol mass emission rates during vigorous exercise are no different from speaking at a conversational level. Mitigation strategies for airborne pathogens for non-exercise-based social interactions incorporating vocalisation, may be suitable for the majority of exercise settings. However, the use of facemasks when exercising may be less effective, given the smaller size of particles produced.

Rationale: Bronchial thermoplasty (BT) is a bronchoscopic treatment for severe asthma targeting airway smooth muscle (ASM). Observational studies have shown ASM mass reduction after BT, but appropriate control groups are lacking. Furthermore, as treatment response is variable, identifying optimal candidates for BT treatment is important. Objectives: First, to assess the effect of BT on ASM mass, and second, to identify patient characteristics that correlate with BT response. Methods: Patients with severe asthma (n = 40) were randomized to immediate (n = 20) or delayed (n = 20) BT treatment. Before randomization, clinical, functional, blood, and airway biopsy data were collected. In the delayed control group, reassessment, including biopsies, was performed after 6 months of standard clinical care, followed by BT. In both groups, post-BT data including biopsies were obtained after 6 months. ASM mass (% positive desmin or a-smooth muscle actin area in the total biopsy) was calculated with automated digital analysis software. Associations between baseline characteristics and Asthma Control Questionnaire and Asthma Quality of Life Questionnaire (AQLQ) improvement were explored. Measurements and Main Results: Median ASM mass decreased by .50% in the immediate BT group (n = 17) versus no change in the delayed control group (n = 19) (P = 0.0004). In the immediate group, Asthma Control Questionnaire scores improved with 20.79 (interquartile range [IQR], 21.61 to 0.02) compared with 0.09 (IQR, 20.25 to 1.17) in the delayed group (P = 0.006). AQLQ scores improved with 0.83 (IQR, 20.15 to 1.69) versus 20.02 (IQR, 20.77 to 0.75) (P = 0.04). Treatment response in the total group (n = 35) was positively associated with serum IgE and eosinophils but not with baseline ASM mass. Conclusions: ASM mass significantly decreases after BT when compared with a randomized non–BT-treated control group. Treatment response was associated with serum IgE and eosinophil levels but not with ASM mass.

Background: So far, 3 randomized controlled trials have shown that the endobronchial treatment using coils is safe and effective. However, the more exact underlying mechanism of the treatment and best predictors of response are unknown. Objectives: The aim of the study was to gain more knowledge about the underlying physiological mechanism of the lung volume reduction coil treatment and to identify potential predictors of response to this treatment. Methods: This was a prospective nonrandomized single-center study which included patients who were bilaterally treated with coils. Patients underwent an extensive number of physical tests at baseline and 3 months after treatment. Results: Twenty-four patients (29% male, mean age 62 years, forced expiratory volume in 1 s [FEV1] 26% pred, residual volume (RV) 231% pred) were included. Three months after treatment, significant improvements were found in spirometry, static hyperinflation, air trapping, airway resistance, treated lobe RV and treated lobes air trapping measured on CT scan, exercise capacity, and quality of life. The change in RV and airway resistance was significantly associated with a change in FEV1, forced vital capacity, air trapping, maximal expiratory pressure, dynamic compliance, and dynamic hyperinflation. Predictors of treatment response at baseline were a higher RV, larger air trapping, higher emphysema score in the treated lobes, and a lower physical activity level. Conclusions: Our results confirm that emphysema patients benefit from endobronchial coil treatment. The primary mechanism of action is decreasing static hyperinflation with improvement of airway resistance which consequently changes dynamic lung mechanics. However, the right patient population needs to be selected for the treatment to be beneficial which should include patients with severe lung hyperinflation, severe air trapping, and significant emphysema in target lobes.

Objectives The West London lung screening pilot aimed to identify early-stage lung cancer by targeting low-dose CT (LDCT) to high risk participants. Successful implementation of screening requires maximising participant uptake and identifying those at highest risk. As well as reporting pre-specified baseline screening metrics, additional objectives were to 1) compare participant uptake between a mobile and hospital-based CT scanner and 2) evaluate the impact on cancer detection using two lung cancer risk models. Methods From primary care records, ever-smokers aged 60–75 were invited to a lung health check at a hospital or mobile site. Participants with PLCOM2012 6-yr risk ≥1.51 % and/or LLPv2 5-yr risk ≥2.0 % were offered a LDCT. Lung cancer detection rate, stage, and recall rates are reported. Participant uptake was compared at both sites (chi-squared test). LDCT eligibility and cancer detection rate were compared between those recruited under each risk model. Results Of 8366 potential participants invited, 1047/5135 (20.4 %) invitees responded to an invitation to the hospital site, and 702/3231 (21.7 %) to the mobile site (p = 0.14). The median distance travelled to the hospital site was less than to the mobile site (3.3 km vs 6.4 km, p Conclusion Targeted screening is effective in detecting early-stage lung cancer. Similar levels of participant uptake at a mobile and fixed site scanner were demonstrated, indicating that uptake was driven by factors in addition to scanner location. The LLPv2 model was more permissive; recruitment with PLCOM2012 alone would have missed several cancers.

Some patients hospitalized with acute COVID-19 suffer respiratory symptoms that persist for many months. We delineated the immune-proteomic landscape in the airway and peripheral blood of healthy controls and post-COVID-19 patients 3 to 6 months after hospital discharge. Post-COVID-19 patients showed abnormal airway (but not plasma) proteomes, with elevated concentration of proteins associated with apoptosis, tissue repair and epithelial injury versus healthy individuals. Increased numbers of cytotoxic lymphocytes were observed in individuals with greater airway dysfunction, while increased B cell numbers and altered monocyte subsets were associated with more widespread lung abnormalities. 1 year follow-up of some post-COVID-19 patients indicated that these abnormalities resolved over time. In summary, COVID-19 causes a prolonged change to the airway immune landscape in those with persistent lung disease, with evidence of cell death and tissue repair linked to ongoing activation of cytotoxic T cells., Graphical Abstract, Many individuals recovering from acute SARS-CoV-2 infection suffer prolonged respiratory dysfunction for months to years after viral clearance. Vijayakumar, Boustani, Ogger, Papadaki et al. show that individuals with persistent symptoms 3-6 months after infection have an altered airway immune cell landscape and evidence of ongoing lung damage. Importantly, different immune cell types correlate with the severity of distinct aspects of ongoing respiratory disease.

Introduction Our goal was to evaluate if traffic-light driven personalized care for COVID-19 was associated with improved survival in acute hospital settings. Methods Discharge outcomes were evaluated before and after prospective implementation of a real-time dashboard with feedback to ward-based clinicians. Thromboembolism categories were “medium-risk” (D-dimer >1000 ng/mL or CRP >200 mg/L); “high-risk” (D-dimer >3000 ng/mL or CRP >250 mg/L) or “suspected” (D-dimer >5000 ng/mL). Cytokine storm risk was categorized by ferritin. Results 939/1039 COVID-19 positive patients (median age 67 years, 563/939 (60%) male) completed hospital encounters to death or discharge by 21st May 2020. Thromboembolism flag criteria were reached by 568/939 (60.5%), including 238/275 (86.6%) of the patients who died, and 330/664 (49.7%) of the patients who survived to discharge, p < 0.0001. Cytokine storm flag criteria were reached by 212 (22.6%) of admissions, including 80/275 (29.1%) of the patients who died, and 132/664 (19.9%) of the patients who survived, p < 0.0001. The maximum thromboembolism flag discriminated completed encounter mortality (no flag: 37/371 [9.97%] died; medium-risk: 68/239 [28.5%]; high-risk: 105/205 [51.2%]; and suspected thromboembolism: 65/124 [52.4%], p < 0.0001). Flag criteria were reached by 535 consecutive COVID-19 positive patients whose hospital encounter completed before traffic-light introduction: 173/535 (32.3% [95% confidence intervals 28.0, 36.0]) died. For the 200 consecutive admissions after implementation of real-time traffic light flags, 46/200 (23.0% [95% confidence intervals 17.1, 28.9]) died, p = 0.013. Adjusted for age and sex, the probability of death was 0.33 (95% confidence intervals 0.30, 0.37) before traffic light implementation, 0.22 (0.17, 0.27) after implementation, p < 0.001. In subgroup analyses, older patients, males, and patients with hypertension (p ≤ 0.01), and/or diabetes (p = 0.05) derived the greatest benefit from admission under the traffic light system. Conclusion Personalized early interventions were associated with a 33% reduction in early mortality. We suggest benefit predominantly resulted from early triggers to review/enhance anticoagulation management, without exposing lower-risk patients to potential risks of full anticoagulation therapy.

For over 150 years, bronchoscopy, especially flexible bronchoscopy, has been a mainstay for airway inspection, the diagnosis of airway lesions, therapeutic aspiration of airway secretions, and transbronchial biopsy to diagnose parenchymal lung disorders. Its utility for the diagnosis of peripheral pulmonary nodules and therapeutic treatments besides aspiration of airway secretions, however, has been limited. Challenges to the wider use of flexible bronchoscopy have included difficulty in navigating to the lung periphery, the avoidance of vasculature structures when performing diagnostic biopsies, and the ability to biopsy a lesion under direct visualization. The last 10-15 years have seen major advances in thoracic imaging, navigational platforms to direct the bronchoscopist to lung lesions, and the ability to visualize lesions during biopsy. Moreover, multiple new techniques have either become recently available or are currently being investigated to treat a broad range of airway and lung parenchymal diseases, such as asthma, emphysema, and chronic bronchitis, or to alleviate recurrent exacerbations. New bronchoscopic therapies are also being investigated to not only diagnose, but possibly treat, malignant peripheral lung nodules. As a result, flexible bronchoscopy is now able to provide a new and expanding armamentarium of diagnostic and therapeutic tools to treat patients with a variety of lung diseases. This State-of-the-Art review succinctly reviews these techniques and provides clinicians an organized approach to their role in the diagnosis and treatment of a range of lung diseases.

The largest randomised controlled trial evaluating results of lung volume reduction surgery (LVRS) was conducted by the National Emphysema Treatment Trial (NETT) that published a series of reports for outcomes up to 24 months. However, patient outcomes were difficult to interpret due to limitations in and the presentation of conventional statistical analyses applied to longitudinal data. We reevaluated the NETT results using longitudinal data methodology to report longer-term outcomes to facilitate interpretation by clinicians and patients who are considering LVRS for emphysema management.Trial data were released by the United States National Institutes of Health and the National Heart, Lung, and Blood Institute and analyzed using a mixed-effects model. Data on the difference in lung function variables between patients receiving LVRS vs medical care out to 5 years were estimated and are presented.The 5-year differences in patients randomised to LVRS were a small but sustained improvement in lung function indicators of forced expiratory volume in 1 second, forced vital capacity, and residual volume of +1.4% (P.001), +3.44% (P.001) and -19.49% (P.001) of the predicted values, respectively. With regards to physiological function, the 5-year difference in patients randomised to LVRS was an overall 0.89 W improvement in maximum workload (P = .069), -4.12 improvement in shortness of breath score (P.001), and 0.088 improvement in quality of well-being score (P = .102).Our results suggest that LVRS continues to have an important role in the treatment of patients with severe emphysema, with long-term benefits to lung function variables and a sustained improvement to the relief of dyspnea.

Purpose of review The field of interventional pulmonology has ushered in a wave of innovations for individuals with obstructive airways disease in whom established medical therapies have failed. Leading the charge are bronchial thermoplasty for severe refractory asthma and uni-directional valves for severe emphysema with hyperinflation: both have received regulatory approvals in the United Kingdom and United States. With the commissioning of these novel treatments comes new challenges relating to implementation, positioning within therapeutic algorithms, honing of patient selection, and establishing long-term safety and benefits beyond 5 years. Recent findings This review summarises the evidence for their safety and efficacy, predictors of therapeutic response, mechanism(s) of action and emerging data supporting the durability of outcomes out to at least ten years. Summary It is anticipated the experience of treating increasing numbers of patients, the adoption of international registries, and ongoing research evaluations will serve to optimise these therapies for future generations of patients.

Aerosol particles of respirable size are exhaled when individuals breathe, speak and sing and can transmit respiratory pathogens between infected and susceptible individuals. The COVID-19 pandemic has brought into focus the need to improve the quantification of the particle number and mass exhalation rates as one route to provide estimates of viral shedding and the potential risk of transmission of viruses. Most previous studies have reported the number and mass concentrations of aerosol particles in an exhaled plume. We provide a robust assessment of the absolute particle number and mass exhalation rates from measurements of minute ventilation using a non-invasive Vyntus Hans Rudolf mask kit with straps housing a rotating vane spirometer along with measurements of the exhaled particle number concentrations and size distributions. Specifically, we report comparisons of the number and mass exhalation rates for children (12–14 years old) and adults (19–72 years old) when breathing, speaking and singing, which indicate that child and adult cohorts generate similar amounts of aerosol when performing the same activity. Mass exhalation rates are typically 0.002–0.02 ng s−1from breathing, 0.07–0.2 ng s−1from speaking (at 70–80 dBA) and 0.1–0.7 ng s−1from singing (at 70–80 dBA). The aerosol exhalation rate increases with increasing sound volume for both children and adults when both speaking and singing.

SummarySome patients hospitalized with acute COVID19 suffer respiratory symptoms that persist for many months. To characterize the local and systemic immune responses associated with this form of ‘Long COVID’, we delineated the immune and proteomic landscape in the airway and peripheral blood of normal volunteers and patients from 3 to 6 months after hospital discharge. The bronchoalveolar lavage (but not peripheral blood) proteome was abnormal in patients with post-COVID19 lung disease with significantly elevated concentration of proteins associated with apoptosis, tissue repair and epithelial injury. This correlated with an increase in cytotoxic lymphocytes (especially tissue resident CD8+T cells), lactate dehydrogenase and albumin (biomarkers of cell death and barrier integrity). Follow-up of a subset of these patients greater than 1-year post-COVID19 indicated these abnormalities resolved over time. Collectively, these data indicate that COVID-19 results in a prolonged change to the airway immune landscape in those with persistent lung disease, with evidence of cell death and tissue repair linked to ongoing activation of cytotoxic T cells.HighlightsThe post-COVID19 airway is characterized by increased cytotoxic lymphocytes.Distinct airway proteomes are associated with the airway immune cell landscape.The peripheral blood does not predict immune-proteome alterations in the airway post-COVID19.Persistent abnormalities in the airway immune-proteome post-COVID19 airways correlate with ongoing epithelial damage.

As many as 25% of all patients undergoing invasive pulmonary procedures are receiving at least one antiplatelet or anticoagulant agent. For those undergoing elective procedures, the decision-making process is uncomplicated and the procedure may be postponed until the antiplatelet or anticoagulant agent may be safely held. However, many invasive pulmonary procedures are semi-elective or emergent in nature in which case a risk-benefit calculation and discussion occur between the provider and patient or surrogate decision-maker. Therefore, it is critical for providers to have an awareness of the risk of bleeding complications with different pulmonary procedures on various antiplatelet and anticoagulant agents. This systematic review summarizes the bleeding complications associated with different pulmonary procedures in patients on various antiplatelet or anticoagulant agents in the literature and reveals a paucity of high-quality evidence across a wide spectrum of pulmonary procedures and antiplatelet or anticoagulant agents. The results of this review can help inform providers of the bleeding risk in these patients to aid in the shared decision-making process and risk vs benefit discussion.

Background Severe emphysema is a debilitating condition with few treatment options. Lung volume reduction procedures in the treatment of severe emphysema have shown excellent results in selected patients but their exact role remains unclear with studies reporting a wide variation in outcomes. We therefore aimed to evaluate the effects of volume reduction. Methods We did a systematic review and meta-analysis. We searched MEDLINE on Sept 29, 2016, for trials of lung volume reduction in patients with emphysema, and we did an updated search on Embase and PubMed on June 18, 2018. We only included randomised controlled studies published in English evaluating the intervention with either sham or standard of care. Inclusion was limited to trials of techniques in which there was sustainable volume reduction. Primary outcomes were residual volume, FEV 1, St George's Respiratory Questionnaire (SGRQ), and 6-min walk distance (6MWT). Secondary outcomes were severe adverse events (including mortality), short-term mortality, and overall mortality. We extracted summary level data from the trial publications and where necessary we obtained unpublished data. A random-effects model with the I (2) statistic was used to determine heterogeneity and trial weight in each analysis. The study is registered with the PROSPERO database, number CRD42016045705. Findings We identified 4747 references in the search, and included 20 randomised controlled trials of lung volume reduction involving 2794 participants with emphysema. Following lung volume reduction from any of the interventions in pooled analyses (ie, surgery, endobronchial valve, endobronchial coil, or sclerosing agents), the mean differences compared with the control were reduction in residual volume of 0.58 L (95% CI -0.80 to -0.37), increase in FEV1 of 15.87% (95% CI 12.27 to 19.47), improvement in 6MWT of 43.28 m (31.36 to 55.21), and reduction in the SGRQ of 9.39 points (-10.92 to -7.86). The odds ratio for a severe adverse event, which included mortality, was 6.21 (95% CI 4.02 to 9.58) following intervention. Regression analysis showed improvements relative to the degree of volume reduction: FEV 1 (r(2) = 0.86; p Interpretation Despite limitations of high risk of bias and heterogeneity for some analyses, our results provide support that lung volume reduction in patients with severe emphysema on maximal medical treatment has clinically meaningful benefits. These benefits should be considered alongside potential adverse events. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

Rationale: This is the first multicenter randomized controlled trial to evaluate the effectiveness and safety of Zephyr Endobronchial Valve (EBV) in patients with little to no collateral ventilation out to 12 months.Objectives: To evaluate the effectiveness and safety of Zephyr EBV in heterogeneous emphysema with little to no collateral ventilation in the treated lobe.Methods: Subjects were enrolled with a 2:1 randomization (EBV/standard of care [SoC]) at 24 sites. Primary outcome at 12 months was the Delta EBV-SoC of subjects with a post-bronchodilator FEV1 improvement from baseline of greater than or equal to 15%. Secondary endpoints included absolute changes in post-bronchodilator FEV1, 6-minute-walk distance, and St. George's Respiratory Questionnaire scores.Measurements and Main Results: A total of 190 subjects (128 EBV and 62 SoC) were randomized. At 12 months, 47.7% EBV and 16.8% SoC subjects had a Delta FEV1 greater than or equal to 15% (P Conclusions: Zephyr EBV provides clinically meaningful benefits in lung function, exercise tolerance, dyspnea, and quality of life out to at least 12 months, with an acceptable safety profile in patients with little or no collateral ventilation in the target lobe.

Introduction COVID-19 mortality rates are high, particularly in patients requiring invasive ventilatory support, developing a cytokine storm, or experiencing thromboembolic disease Our goal was to determine if traffic-light driven, personalised care was associated with improved survival in acute hospital settings Methods Outcomes were evaluated during two implementation phases of a real-time clinical decision support tool that had been developed as part of a Trust's COVID-19 response, using a reporting and bioinformatics team to support Clinical and Operational teams Following optimisation, the tool defined patients' clinical status in terms of risk of preventable complications based on blood test results (Ddimer, C reactive protein and ferritin) Feedback to wardbased clinicians enabled rapid modification of care pathways, in the first phase following a daily review, and in the second phase, in real-time (dashboard updated every 10 minutes) Results 1039 COVID-19 positive patients were admitted by 21/05/2020 Focusing on the first 939 completed encounters to death or home discharge (median age 69ys;60% [563/939] male), 568/939 (60 4%) received thromboembolism risk flags, and 212/939 (22 5%) cytokine storm flags The maximum thromboembolism flag discriminated completed encounter mortality between no flag (9 97% [37/371]);medium-risk (28 5% [68/239]);high-risk (51 2% [105/205]);and suspected thromboembolism (52 4% [65/124]), Kruskal Wallis p

Background Lung volume reduction (LVR) can transform the lives of patients with severe emphysema. Patient selection is predicated by the quantification of emphysema distribution using computed tomography (CT) and lobar perfusion using single photon emission CT perfusion scintigraphy (SPECTPS). We hypothesize contrast-enhanced dual energy CT (DECT) angiography will accurately estimate lobar iodine distribution and may provide a surrogate marker for lobar perfusion. Purpose To quantify the correlation between lobar contrast agent distribution on DECT and SPECTPS. Materials and Methods Institutional review board approval was obtained for this retrospective study. Between May 2018 and February 2020, 152 patients (89 male, 63 female, 64.5 ± 8.6 years, forced expiratory volume in 1 s (FEV1) 31.5 ± 12.3% (predicted)) were eligible for inclusion. DECT data was reconstructed using prototype artificial intelligence software (eXamine, Siemens Healthineers, Forchheim, Germany) and recorded in a blinded fashion. Contrast agent lobar distribution on DECT and SPECTPS images were calculated by dividing contrast agent distribution in individual lobes by the total amount in both lungs. Effective radiation dose, adverse reactions, need for manual corrections and processing time were calculated. Bland-Altman analysis (limits of agreement, LoA) and Pearson correlation were used for intermodality comparison using Prism8. Results There is strong agreement between lobar perfusion values acquired using DECT compared to SPECTPS (r= 0.86, p Conclusion DECT pulmonary angiography accurately quantifies lobar perfusion, and streamlines the LVR patient selection paradigm. Software efficiency improvements are necessary for the implementation of DECT angiography into mainstream clinical practice.

Contains fulltext : 232904.pdf (Publisher’s version ) (Open Access) PURPOSE: For a successful bronchoscopic lung volume reduction coil treatment it is important to place the coils in the most emphysematous lobes. Therefore assessment of the lobe with greatest destruction is essential. Our aims were to investigate the level of agreement among expert reviewers of HRCT-scans in emphysema patients and the comparison with QCT (quantitative computed tomography) software. METHOD: Five experienced CT-assessors, conducted a visual assessment of the baseline HRCT-scans of emphysema patients who participated in the RENEW bronchoscopic lung volume reduction coil study. On the same HRCT-scans, a QCT analysis was performed. RESULTS: In total 134 HRCT-scans were rated by all 5 experts. All 5 CT-assessors agreed on which was the most destructed lobe in 61 % of the left lungs (k:0.459) and 60 % of the right lungs (k:0.370). The consensus of the 5 assessors matched the QCT in the left lung for 77 % of the patients (k:0.425) and in the right lung for 82 % (k:0.524). CONCLUSIONS: Our results show that the interobserver agreement between five expert CT-assessors was only fair to moderate when evaluating the most destructed lobe. CT-assessor consensus improved matching with QCT determination of lobar destruction compared to individual assessor determinations. Because some CT-features are associated with treatment outcomes and important for optimal patient selection of bronchoscopic lung volume reduction treatment, we recommend including more than one CT-reviewer and supported by QCT measurements.

Despite advances in the pathophysiology of chronic obstructive pulmonary disease (COPD), there is a distinct lack of biochemical markers to aid clinical management. Microvesicles (MVs) have been implicated in the pathophysiology of inflammatory diseases including COPD, but their association to COPD disease severity remains unknown. We analyzed different MV populations in plasma and bronchoalveolar lavage fluid (BALF) taken from 62 patients with mild to very severe COPD (51% male; mean age: 65.9 yr). These patients underwent comprehensive clinical evaluation (symptom scores, lung function, and exercise testing), and the capacity of MVs to be clinical markers of disease severity was assessed. We successfully identified various MV subtype populations within BALF [leukocyte, polymorphonuclear leukocyte (PMN; i.e., neutrophil), monocyte, epithelial, and platelet MVs] and plasma (leukocyte, PMN, monocyte, and endothelial MVs) and compared each MV population to disease severity. BALF neutrophil MVs were the only population to significantly correlate with the clinical evaluation scores including forced expiratory volume in 1 s, modified Medical Research Council dyspnea score, 6-min walk test, hyperinflation, and gas transfer. BALF neutrophil MVs, but not neutrophil cell numbers, also strongly correlated with BODE index. We have undertaken, for the first time, a comprehensive evaluation of MV profiles within BALF/plasma of COPD patients. We demonstrate that BALF levels of neutrophil-derived MVs are unique in correlating with a number of key functional and clinically relevant disease severity indexes. Our results show the potential of BALF neutrophil MVs for a COPD biomarker that tightly links a key pathophysiological mechanism of COPD (intra-alveolar neutrophil activation) with clinical severity/outcome.

The global COVID-19 pandemic has accelerated the development of numerous digital technologies in medicine from telemedicine to remote monitoring. Concurrently, the pandemic has resulted in huge pressures on healthcare systems. Medical imaging (MI) from chest radiographs to computed tomography and ultrasound of the thorax have played an important role in the diagnosis and management of the coronavirus infection.We conducted the, to date, largest systematic review of the literature addressing the utility of Artificial Intelligence (AI) in MI for COVID-19 management. Through keyword matching on PubMed and preprint servers, including arXiv, bioRxiv and medRxiv, 463 papers were selected for a meta-analysis, with manual reviews to assess the clinical relevance of AI solutions. Further, we evaluated the maturity of the papers based on five criteria assessing the state of the field: peer-review, patient dataset size and origin, algorithmic complexity, experimental rigor and clinical deployment.In 2020, we identified 4977 papers on MI in COVID-19, of which 872 mentioned the term AI. 2039 papers of the 4977 were specific to imaging modalities with a majority of 83.8% focusing on CT, while 10% involved CXR and 6.2% used LUS. Meanwhile, the AI literature predominantly analyzed CXR data (49.7%), with 38.7% using CT and 1.5% LUS. Only a small portion of the papers were judged as mature (2.7 %). 71.9% of AI papers centered on disease detection.This review evidences a disparity between clinicians and the AI community, both in the focus on imaging modalities and performed tasks. Therefore, in order to develop clinically relevant AI solutions, rigorously validated on large-scale patient data, we foresee a need for improved collaboration between the two communities ensuring optimal outcomes and allocation of resources. AI may aid clinicians and radiologists by providing better tools for localization and quantification of disease features and changes thereof, and, with integration of clinical data, may provide better diagnostic performance and prognostic value.

Introduction: Bronchoscopic visualisation of the lungs, has proved an invaluable aid for many specialities. There has been an exponential increase in interventional therapies. Their safe delivery is crucially dependent on the expertise of skilled endoscopy team. However, structured training for bronchoscopy nurses is limited. An in-house patient experience survey highlighted a frequent lack of understanding of bronchoscopy for example, anti-coagulant care and post procedure complications such as infection. Aim: To improve patient communication and nursing training in bronchoscopy. Method: A bronchoscopy care bundle (BCB) was developed to address communication. It incorporates a pre-assessment itinerary 1 week prior to the procedure and provision of a point-of-contact mobile number which connects to an ‘on-call’ specialist bronchoscopy nurse for post-procedure side-effects/complications. We also designed an education programme comprising didactic lectures, group tutorials and hands-on simulation using the Bronchoscopy BioSim [JLG] training tool. Results: Conclusion: These simple and regular interventions resulted in sustained benefits over the 6 months duration. Limitations of this project are the relatively small numbers of patients and staff members evaluated and the short-term duration of the project. Future work includes undertaking a multicentre study.

Introduction: Chronic bronchitis (CB) is a phenotype of chronic obstructive pulmonary disease characterised by bronchial epithelial hyperplasia. Metered cryospray (MSC) (RejuvenAir® system) is a novel, bronchoscopic treatment that utilises titrated sprays of liquid nitrogen to enact controlled epithelial ablation, triggering the regeneration of bronchial tissue from pulmonary progenitors. Objective: To investigate the effect of MCS on human bronchial epithelium gene expression in patients with CB. Methods: Endobronchial brushings were collected from subjects at baseline and at 3-months post-MCS (n=7). The relative expression of 4 genes associated with remodelling: MUC5AC, TP63, S100A4 and TGFB1, was assessed by RT-qPCR. SGRQ and 6MWT were performed at baseline and at 3, 6, 9 and 12 months post-MCS. Results: The relative expression of MUC5AC (p=0.02), TP63 (p=0.02), S100A4 (p=0.03) and TGFB1 (p=0.02) were increased at 3-months post-MCS, relative to baseline. Significant improvement in 6MWT was demonstrated over the regime period (p=0.0043). Significant reduction in SGRQ total score was demonstrated over the regime period (p=0.0143). Significant reduction in SGRQ symptom score was recorded at 12 months relative to baseline (-19.9 points; p=0.031). Conclusions: The expression of genes associated with epithelial remodelling were increased at 3-months post-MCS, indicating epithelial repopulation continues far longer than traditionally considered. In conjunction with the significant improvement found in clinical parameters, the changes in gene expression potentially allude to the post-MCS repopulated epithelium expressing a reduced phenotypic aberrancy.

Chronic bronchitis is a chronic, progressive disease that is difficult to treat. Despite much effort, patients remain highly symptomatic. Currently, a number of innovative bronchoscopic treatments for this disease are under investigation. Liquid nitrogen metered cryospray, bronchial rheoplasty and balloon desobstruction all aim to destroy the hyperplastic goblet cells and excess submucous glands using different strategies. These therapies are in an early phase of clinical research and larger randomised controlled trials are needed to confirm the pilot data available and to evaluate the treatment durability. The fourth technique, targeted lung denervation (TLD), aims to decrease the release of acetylcholine, which regulates smooth muscle tone and mucus production by ablating the parasympathetic nerves running alongside the main bronchi. Evaluation of this treatment is at a more advanced stage and promising effects on exacerbation frequency have been shown. However, confirmation of the benefit in improvement in chronic bronchitis symptoms is still needed.

Severe emphysema with hyperinflation presents a therapeutic challenge. Inhaled medication has limited efficacy in individuals with mechanical constraints to the respiratory pump and impaired gas exchange. Lung volume reduction surgery (LVRS) reestablishes some semblance of normal physiology, resecting grossly expanded severely diseased tissue to restore the function of compromised relatively healthy lung, and has been shown to significantly improve exercise capacity, quality of life, and survival, especially in individuals with upper-lobe predominant emphysema and low-baseline exercise capacity, albeit with higher early morbidity and mortality. Bronchoscopic lung volume reduction achieved by deflating nonfunctioning parts of the lung is promoted as a less invasive and safer approach. Endobronchial valve implantation has demonstrated comparable outcomes to LVRS in selected individuals and has recently received approvals by the National Institute of Clinical Excellence in the United Kingdom and the Food and Drug Administration in the United States of America. Endobronchial coils are proving a viable treatment option in severe hyperinflation in the presence of collateral ventilation in selected cases of homogeneous disease. Modalities including vapor and sealant are delivered using a segmental strategy preserving healthier tissue within the same target lobe-efficacy and safety-data are, however, limited. This article will review the data supporting these novel technologies.

Robotic bronchoscopic intervention requires detailed 3D airway maps for both localisation and enhanced visualisation, especially at peripheral airways. Patient-specific airway maps can be generated from preoperative chest CT scans. Due to pathological abnormalities and anatomical variations, automatically delineating the airway tree with distal branches is a challenging task. In the paper, we propose a cascaded 2D+3D model that has been tailored for airway segmentation from pathological CT scans. A novel 2D neural network is developed to generate the initial predictions where the peripheral airways are refined by a 3D adversarial training model. A sampling strategy based on a sequence of morphological operations is employed for the concatenation of the 2D and 3D models. The method has been validated on 20 pathological CT scans with results demonstrating improved segmentation accuracy and consistency, especially in peripheral airways.