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      Rethinking COVID-19 ‘pneumonia’ – is this primarily a vaso-occlusive disease, and can early anticoagulation save the ventilator famine?

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          Preamble As the COVID-19 pandemic rampages around the globe, it remains an enigma as to how a fraction of those infected can turn critically ill with severe hypoxemia – the scale of this problem so massive that hospitals in seriously affected cities see their ventilator capacity overwhelmed. As of 25 April 2020, there are approximately 2.6 million infections with more than 180,000 deaths worldwide. 1 The main driver of mortality and morbidity with COVID-19 has been the acute respiratory syndrome that occurs in 12–32% of patients 2 –4 after the initial upper respiratory tract symptoms. While it is widely suspected that an abnormal host response such as a ‘cytokine storm’ is the driving force in those precariously ill, 5 there are peculiarities in radiological findings and ventilator mechanics that are atypical of the usual viral pneumonia and acute respiratory distress syndrome (ARDS). Increasingly, published data and anecdotal observations indicate that the pathogenesis may lie primarily in the pulmonary vasculature with the newly observed tendency for thrombi formation. Early radiological findings more consistent with diffuse pulmonary microthrombi than airway or interstitial disease The computed tomography (CT) features of the lungs in early-stage COVID-19 (0–4 days from onset of symptoms) are characterised by ground glass opacities (GGOs) distributed in the peripheral and posterior parts of the lungs. 6 The significance of GGO is generally understood to be non-specific and merely implies interstitial edema and/or early alveolar exudate. Disappearance of these lesions after atomised thrombolytic suggests that these opacities are likely due to thrombosis rather than infection or inflammation, 7 and these GGOs may well be a premonitory sign of pulmonary infarction. Anti-phospholipid antibody syndrome with diffuse pulmonary microvascular thrombosis presents with the same picture on high resolution CT scan (HRCT). 8 The progressive stage of COVID-19 on CT (5–8 days from onset of symptoms) is demonstrated by bilateral multi-lobe distribution with diffuse GGO, crazy-paving pattern and wedge-shaped consolidation most aggravated at the lung peripheries. The lack of contiguous spread with central sparing along the proximal airways is not characteristic of a usual viral pneumonia with airway spread or diffuse alveolar damage. The consolidative changes seen on CT are possibly progressive ‘pulmonary infarcts’; however, neither CT pulmonary angiogram nor HRCT are sensitive or specific in diagnosing early microvascular thrombosis in the lung and do not help with primary cause determination. A dual energy CT perfusion scan 9 of the lungs early in the course of illness may give the answer instead, as it allows qualitative assessment of perfusion defects at the microvascular level. Pulmonary microthrombi likely secondary to thrombo-inflammation early in the disease Coagulation abnormalities seen in the early phase of COVID-19 illness do not correspond to a typical septic coagulopathy or disseminated intravascular coagulation. 5,10 In the early course of COVID-19 illness, elevated D-dimer and fibrinogen level indicate the presence of localised fibrin clots, while the absence of thrombocytopenia with normal clotting times argues against a consumptive coagulopathy. Direct endothelial cell infection and endothelitis in COVID-19 can contribute to impaired microcirculatory function in vascular beds 11 and set the milieu for the occurrence of a prothrombotic state early. Autopsies in COVID-19 patients are not widely performed, given the infection control precautions required to be undertaken within forensic departments with the need for negative-pressure autopsy suites or isolation rooms. In small series of autopsies, there were notable CD4 + aggregates around thrombosed small vessels, suggesting thrombotic microangiopathy restricted to the lungs 12 ; fibrinous thrombi demonstrated in pulmonary microvasculature suggest a hypercoagulable state, 13,14 and there was also recently documented generalised thrombotic microvascular injury mediated by intense complement activation. 15 Dissociation between respiratory mechanics and severe hypoxemia suggests an early pulmonary perfusion problem While severe COVID-19 pneumonia can tick off the checklist for the ARDS criteria, 16 intensivists have observed a dissociation between severe hypoxemia and relatively well-preserved lung mechanics. 17 Unlike the usual ARDS phenotype, COVID-19 patients intubated for severe hypoxemia had high respiratory compliance and tidal volumes. In other words, there is still normal alveolar ventilation at the outset, and diffuse alveolar damage is unlikely the inciting event for respiratory failure. The observed lung mechanics mirror that of acute pulmonary embolism 16 ; furthermore, the improvement in oxygenation with prone positioning described in COVID-19 patients is in keeping with regional perfusion defects. 18 Clinical trajectory in severe COVID-19 ‘pneumonia’ reflects pulmonary vaso-occlusive disease COVID-19 patients who are just found to be dyspnoeic or hypoxemic can deteriorate quickly. Due to large flow reserve capacity, more than 40% of the pulmonary vascular bed may be occluded by the time hypoxemia occur, 19 and the risk of cardiorespiratory collapse becomes imminent. Additionally, the paucity of dyspnea despite profound hypoxemia in COVID-19 makes it difficult to identify a high-risk patient clinically. This clinical picture mirrors patients with peripheral subsegmental pulmonary emboli who show minimal or no symptoms that precludes early diagnosis, 20 but risk rapid decline especially with endotracheal intubation. It is plausible that a large number of ‘clinically silent’ pulmonary microvascular thrombosis occurs early in this disease, which goes undetected in routine clotting time studies as well as routine radiology imaging (such as chest radiograph or CT). If left untreated, diffuse pulmonary microthrombi can result in a cascade of thrombo-inflammatory process leading to worsening of the hypercoagulable state, causing rapid clinical deterioration in the patient. This phenomenon is observed in many intensive care patients, and the presence of thromboembolism with significant consumptive coagulopathy should already signify a very advanced stage of this disease process. 21 Major implications of this hypothesis and a silver lining for early intervention Despite the onslaught of patients who desperately need treatment, there is currently no proven therapy for COVID-19. The prediction of trajectory of illness from symptom onset is difficult, and decline to respiratory failure is often abrupt. It is increasingly recognised that severe COVID-19 has a ‘vascular’ component to it, and experts have weighed in on the ventilatory management in the critically ill. Establishing pulmonary microvascular thrombosis as the inciting event for COVID-19 respiratory distress syndrome offers a possibility for early anticoagulation to avert the ventilator famine. Performing dual energy CT perfusion scan of the lungs early in the course of illness before the development of peripheral consolidative changes may be elucidating. High D-dimer levels associated with poor outcomes in COVID-19 may be related to the undetected presence of pulmonary microthrombi and can be utilised to risk stratify patients for anticoagulation. If pulmonary microvascular thrombosis is indeed the primary driver of severe COVID-19, it is conceivable that early diagnosis and timely management could alter the natural course of the disease. This will greatly alleviate the staggering medical, social and economic burden of COVID-19 worldwide.

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          Most cited references 20

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          Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

          Summary Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.
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            Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

            Summary Background In December, 2019, a pneumonia associated with the 2019 novel coronavirus (2019-nCoV) emerged in Wuhan, China. We aimed to further clarify the epidemiological and clinical characteristics of 2019-nCoV pneumonia. Methods In this retrospective, single-centre study, we included all confirmed cases of 2019-nCoV in Wuhan Jinyintan Hospital from Jan 1 to Jan 20, 2020. Cases were confirmed by real-time RT-PCR and were analysed for epidemiological, demographic, clinical, and radiological features and laboratory data. Outcomes were followed up until Jan 25, 2020. Findings Of the 99 patients with 2019-nCoV pneumonia, 49 (49%) had a history of exposure to the Huanan seafood market. The average age of the patients was 55·5 years (SD 13·1), including 67 men and 32 women. 2019-nCoV was detected in all patients by real-time RT-PCR. 50 (51%) patients had chronic diseases. Patients had clinical manifestations of fever (82 [83%] patients), cough (81 [82%] patients), shortness of breath (31 [31%] patients), muscle ache (11 [11%] patients), confusion (nine [9%] patients), headache (eight [8%] patients), sore throat (five [5%] patients), rhinorrhoea (four [4%] patients), chest pain (two [2%] patients), diarrhoea (two [2%] patients), and nausea and vomiting (one [1%] patient). According to imaging examination, 74 (75%) patients showed bilateral pneumonia, 14 (14%) patients showed multiple mottling and ground-glass opacity, and one (1%) patient had pneumothorax. 17 (17%) patients developed acute respiratory distress syndrome and, among them, 11 (11%) patients worsened in a short period of time and died of multiple organ failure. Interpretation The 2019-nCoV infection was of clustering onset, is more likely to affect older males with comorbidities, and can result in severe and even fatal respiratory diseases such as acute respiratory distress syndrome. In general, characteristics of patients who died were in line with the MuLBSTA score, an early warning model for predicting mortality in viral pneumonia. Further investigation is needed to explore the applicability of the MuLBSTA score in predicting the risk of mortality in 2019-nCoV infection. Funding National Key R&D Program of China.
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              Acute respiratory distress syndrome: the Berlin Definition.

              The acute respiratory distress syndrome (ARDS) was defined in 1994 by the American-European Consensus Conference (AECC); since then, issues regarding the reliability and validity of this definition have emerged. Using a consensus process, a panel of experts convened in 2011 (an initiative of the European Society of Intensive Care Medicine endorsed by the American Thoracic Society and the Society of Critical Care Medicine) developed the Berlin Definition, focusing on feasibility, reliability, validity, and objective evaluation of its performance. A draft definition proposed 3 mutually exclusive categories of ARDS based on degree of hypoxemia: mild (200 mm Hg < PaO2/FIO2 ≤ 300 mm Hg), moderate (100 mm Hg < PaO2/FIO2 ≤ 200 mm Hg), and severe (PaO2/FIO2 ≤ 100 mm Hg) and 4 ancillary variables for severe ARDS: radiographic severity, respiratory system compliance (≤40 mL/cm H2O), positive end-expiratory pressure (≥10 cm H2O), and corrected expired volume per minute (≥10 L/min). The draft Berlin Definition was empirically evaluated using patient-level meta-analysis of 4188 patients with ARDS from 4 multicenter clinical data sets and 269 patients with ARDS from 3 single-center data sets containing physiologic information. The 4 ancillary variables did not contribute to the predictive validity of severe ARDS for mortality and were removed from the definition. Using the Berlin Definition, stages of mild, moderate, and severe ARDS were associated with increased mortality (27%; 95% CI, 24%-30%; 32%; 95% CI, 29%-34%; and 45%; 95% CI, 42%-48%, respectively; P < .001) and increased median duration of mechanical ventilation in survivors (5 days; interquartile [IQR], 2-11; 7 days; IQR, 4-14; and 9 days; IQR, 5-17, respectively; P < .001). Compared with the AECC definition, the final Berlin Definition had better predictive validity for mortality, with an area under the receiver operating curve of 0.577 (95% CI, 0.561-0.593) vs 0.536 (95% CI, 0.520-0.553; P < .001). This updated and revised Berlin Definition for ARDS addresses a number of the limitations of the AECC definition. The approach of combining consensus discussions with empirical evaluation may serve as a model to create more accurate, evidence-based, critical illness syndrome definitions and to better inform clinical care, research, and health services planning.

                Author and article information

                Pulm Circ
                Pulm Circ
                Pulmonary Circulation
                SAGE Publications (Sage UK: London, England )
                2 June 2020
                Jul-Sep 2020
                : 10
                : 3
                [1 ]Department of Cardiology, National University Heart Centre Singapore, Singapore
                [2 ]Division of Neurology, National University Hospital, Singapore
                [3 ]Department of Haematology-Oncology, National University Cancer Institute, Singapore
                [4 ]Department of Medicine, National University Hospital, Singapore
                [5 ]Department of Diagnostic Imaging, National University Hospital, Singapore
                Author notes

                *Co-first authors.

                Ting Ting Low, Department of Cardiology National University Heart Centre Singapore, NUHS Tower Block, Level 9, 1E Kent Ridge Road, Singapore 119228. Email: ting_ting_low@
                © The Author(s) 2020

                Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (

                Letter to the Editor
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                July-September 2020

                Respiratory medicine


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