Rationale: Clinical and epidemiologic data in coronavirus disease (COVID-19) have accrued rapidly since the outbreak, but few address the underlying pathophysiology. Objectives: To ascertain the physiologic, hematologic, and imaging basis of lung injury in severe COVID-19 pneumonia. Methods: Clinical, physiologic, and laboratory data were collated. Radiologic (computed tomography (CT) pulmonary angiography [n = 39] and dual-energy CT [DECT, n = 20]) studies were evaluated: observers quantified CT patterns (including the extent of abnormal lung and the presence and extent of dilated peripheral vessels) and perfusion defects on DECT. Coagulation status was assessed using thromboelastography. Measurements and Results: In 39 consecutive patients (male: female, 32:7; mean age, 53 6 10 yr [range, 29-79 yr]; Black and minority ethnic, n = 25 [64%]), there was a significant vascular perfusion abnormality and increased physiologic dead space (dynamic compliance, 33.7 6 14.7 ml/cm H 2 O; Murray lung injury score, 3.14 6 0.53; mean ventilatory ratios, 2.6 6 0.8) with evidence of hypercoagulability and fibrinolytic "shutdown". The mean CT extent (6SD) of normally aerated lung, ground-glass opacification, and dense parenchymal opacification were 23.5 6 16.7%, 36.3 6 24.7%, and 42.7 6 27.1%, respectively. Dilated peripheral vessels were present in 21/33 (63.6%) patients with at least two assessable lobes (including 10/21 [47.6%] with no evidence of acute pulmonary emboli). Perfusion defects on DECT (assessable in 18/20 [90%]) were present in all patients (wedge-shaped, n = 3; mottled, n = 9; mixed pattern, n = 6). Conclusions: Physiologic, hematologic, and imaging data show not only the presence of a hypercoagulable phenotype in severe COVID-19 pneumonia but also markedly impaired pulmonary perfusion likely caused by pulmonary angiopathy and thrombosis.

RationalePrimary graft dysfunction in lung transplant recipients derives from the initial, largely leukocyte-dependent, ischaemia-reperfusion injury. Intravascular lung-marginated monocytes have been shown to play key roles in experimental acute lung injury, but their contribution to lung ischaemia-reperfusion injury post transplantation is unknown.ObjectiveTo define the role of donor intravascular monocytes in lung transplant-related acute lung injury and primary graft dysfunction.MethodsIsolated perfused C57BL/6 murine lungs were subjected to warm ischaemia (2 hours) and reperfusion (2 hours) under normoxic conditions. Monocyte retention, activation phenotype and the effects of their depletion by intravenous clodronate-liposome treatment on lung inflammation and injury were determined. In human donor lung transplant samples, the presence and activation phenotype of monocytic cells (low side scatter, 27E10+, CD14+, HLA-DR+, CCR2+) were evaluated by flow cytometry and compared with post-implantation lung function.ResultsIn mouse lungs following ischaemia-reperfusion, substantial numbers of lung-marginated monocytes remained within the pulmonary microvasculature, with reduced L-selectin and increased CD86 expression indicating their activation. Monocyte depletion resulted in reductions in lung wet:dry ratios, bronchoalveolar lavage fluid protein, and perfusate levels of RAGE, MIP-2 and KC, while monocyte repletion resulted in a partial restoration of the injury. In human lungs, correlations were observed between pre-implantation donor monocyte numbers/their CD86 and TREM-1 expression and post-implantation lung dysfunction at 48 and 72 hours.ConclusionsThese results indicate that lung-marginated intravascular monocytes are retained as a ‘passenger’ leukocyte population during lung transplantation, and play a key role in the development of transplant-associated ischaemia-reperfusion injury.

IntroductionTo explore the hypothesis that early ventilation strategies influence clinical outcomes in lung transplantation, we have examined our routine ventilation practices in terms of tidal volumes (Vt) and inflation pressures.Methods 124 bilateral lung transplants between 2010 and 2013 were retrospectively assigned to low (<6ml/kg), medium (6-8ml/kg) and high (>8ml/kg) Vt groups based on ventilation characteristics during the first 6 hours after surgery. Those same 124 patients were also stratified to low-pressure (<25cm H2O) and high-pressure (≥25cm H2O) groups. ResultsEighty per cent of patients were ventilated using pressure control mode. Low, medium and high tidal volumes were applied to 10%, 43%, and 47% of patients respectively. After correcting for patients requiring extracorporeal support, there was no difference in short to mid-term outcomes among the different Vt groups. Low inflation pressures were applied to 61% of patients, who had a shorter length of ICU stay (5 vs. 12 days; p=0.012), higher FEV1 at 3 months (77.8% vs. 60.3%; p<0.001), and increased 6-month survival rate (95% vs. 77%; p=0.008). ConclusionLow Vt ventilation has not been fully adopted in our practice. Ventilation with higher inflation pressures, but not tidal volumes, were significantly associated with poorer outcomes after lung transplantation.Response to Reviewers: Dear Prof. Lumb, Article ID: JCRC-D-15-00340 -Mechanical ventilation following lung transplantationWe are most grateful to the reviewers for taking the time and care to appraise this manuscript, and for your constructive critique. We have addressed all of the points that were raised and have amended the manuscript accordingly. We feel that your suggestions has significantly improved the original manuscript.Responses to Reviewer #1 Reviewer #1: "The manuscript does not add anything new to the literature. It has been known for a very long time that excessive tidal volume and/or inflation pressures adversely affect patient outcome."Author response: We are grateful that you have taken the time to review our manuscript, although we are disappointed by your conclusions. We have made detailed arguments in both the introduction and discussion that highlight the need for this work within lung transplantation, combined with our unique approach to this clinical problem. Your statement is in direct opposition with the views of the other reviewers, who have helpfully pointed out the potential importance of our study within this field. Your critique also fails to acknowledge the major ongoing debate regarding the special importance of driving pressures, and the relative roles of tidal volumes and pressures in acute lung injury. As a rebuttal, we would respectfully suggest that our manuscript does add to the existing body of knowledge on this topic. As stated in the manuscript, we believe that our manuscript fills an important gap within the literature on VALI by providing new observations on lung ventilation practices in lung transplant recipients, a population that was...

The COVID-19 pandemic brought many serious challenges to the clinical workplace, and was a catalyst to novel approaches to the way in which we practice medicine. These challenges include extreme numbers of critically ill patients overwhelming many intensive care units, how to maintain the flow of communication between clinicians, patients and their families, and how to prevent the spread of infection working on quarantined units in personal protective equipment. The Royal Brompton and Harefield Hospitals deployed a series of digital solutions to try to address some of those challenges and a series of case studies describes their clinical application in three clinical domains: communicating with families, clinical communication between clinicians and the delivery of clinical education.

Primary graft dysfunction (PGD) is a major determinant of morbidity and mortality following lung transplantation. Delineating basic mechanisms and molecular signatures of PGD remain a fundamental challenge. This pilot study examines if the pulmonary volatile organic compound (VOC) spectrum relate to PGD and postoperative outcomes. The VOC profiles of 58 bronchoalveolar lavage fluid (BALF) and blind bronchial aspirate samples from 35 transplant patients were extracted using solid-phase-microextraction and analyzed with comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry. The support vector machine algorithm was used to identify VOCs that could differentiate patients with severe from lower grade PGD. Using 20 statistically significant VOCs from the sample headspace collected immediately after transplantation (< 6 h), severe PGD was differentiable from low PGD with an AUROC of 0.90 and an accuracy of 0.83 on test set samples. The model was somewhat effective for later time points with an AUROC of 0.80. Three major chemical classes in the model were dominated by alkylated hydrocarbons, linear hydrocarbons, and aldehydes in severe PGD samples. These VOCs may have important clinical and mechanistic implications, therefore large-scale study and potential translation to breath analysis is recommended.

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IntroductionTo explore the hypothesis that early ventilation strategies influence clinical outcomes in lung transplantation, we have examined our routine ventilation practices in terms of tidal volumes (Vt) and inflation pressures.Methods 124 bilateral lung transplants between 2010 and 2013 were retrospectively assigned to low (<6ml/kg), medium (6-8ml/kg) and high (>8ml/kg) Vt groups based on ventilation characteristics during the first 6 hours after surgery. Those same 124 patients were also stratified to low-pressure (<25cm H2O) and high-pressure (≥25cm H2O) groups. ResultsEighty per cent of patients were ventilated using pressure control mode. Low, medium and high tidal volumes were applied to 10%, 43%, and 47% of patients respectively. After correcting for patients requiring extracorporeal support, there was no difference in short to mid-term outcomes among the different Vt groups. Low inflation pressures were applied to 61% of patients, who had a shorter length of ICU stay (5 vs. 12 days; p=0.012), higher FEV1 at 3 months (77.8% vs. 60.3%; p<0.001), and increased 6-month survival rate (95% vs. 77%; p=0.008). ConclusionLow Vt ventilation has not been fully adopted in our practice. Ventilation with higher inflation pressures, but not tidal volumes, were significantly associated with poorer outcomes after lung transplantation.Response to Reviewers: Dear Prof. Lumb, Article ID: JCRC-D-15-00340 -Mechanical ventilation following lung transplantationWe are most grateful to the reviewers for taking the time and care to appraise this manuscript, and for your constructive critique. We have addressed all of the points that were raised and have amended the manuscript accordingly. We feel that your suggestions has significantly improved the original manuscript.Responses to Reviewer #1 Reviewer #1: "The manuscript does not add anything new to the literature. It has been known for a very long time that excessive tidal volume and/or inflation pressures adversely affect patient outcome."Author response: We are grateful that you have taken the time to review our manuscript, although we are disappointed by your conclusions. We have made detailed arguments in both the introduction and discussion that highlight the need for this work within lung transplantation, combined with our unique approach to this clinical problem. Your statement is in direct opposition with the views of the other reviewers, who have helpfully pointed out the potential importance of our study within this field. Your critique also fails to acknowledge the major ongoing debate regarding the special importance of driving pressures, and the relative roles of tidal volumes and pressures in acute lung injury. As a rebuttal, we would respectfully suggest that our manuscript does add to the existing body of knowledge on this topic. As stated in the manuscript, we believe that our manuscript fills an important gap within the literature on VALI by providing new observations on lung ventilation practices in lung transplant recipients, a population that was...