COVID-19 Critical Illness Pathophysiology Driven by Diffuse Pulmonary Thrombi and Pulmonary Endothelial Dysfunction Responsive to Thrombolysis

Poor, Hooman; Ventetuolo, Corey E.; Tolbert, Thomas; Chun, Glen; Serrao, Gregory; Zeidman, Amanda Dijanic; Dangayach, Neha; Olin, Jeffrey W.; Kohli‐Seth, Roopa; Powell, Charles A.

doi:10.1101/2020.04.17.20057125

Cited by 25 publications

(20 citation statements)

References 9 publications

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“…Similar histopathological findings were noted in the SARS outbreak in Southeast Asia during 2003, which was attributed to a related virus of the coronavirdae family [4]. To date, COVID-19 infection predominantly affects the respiratory system; however, various organ systems have been impacted such as the central nervous system (CNS), kidneys and heart, likely as a sequala of severe inflammation in the setting of microthrombi disease [7,[11][12].…”

Section: Introductionsupporting

confidence: 52%

“…This end stage severe inflammatory response has been categorized as cytokine storm syndrome (CSS). This multi-organ inflammatory process seems to be triggered by the massive intravascular release of pro-inflammatory cytokines such as interleukin-6 (IL-6) into the bloodstream, contributing to prevalence of diffuse endovascular injury, with significant microthrombi burden reported on autopsy series [7][8][9]. This diffuse microthrombi burden combined with endothelial destabilization results in a severe multifocal inflammatory response, noted by the histological presence of megakaryocytes, platelets, fibrin, neutrophils and other inflammatory cells [9].…”

Section: Introductionmentioning

confidence: 99%

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Incidental PET/CT Findings of Suspected COVID-19 in a Region of High Prevalence

Franceschi¹,

Clifton²,

Ahmed³

et al. 2020

Cureus

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We describe a case of suspected COVID-19 pneumonia in a 61-year-old male with known primary central nervous system diffuse large B-cell lymphoma (DLBCL) who underwent restaging PET/CT during the initial peak of infection of COVID-19 pneumonia within the New York region. At the time of his routine PET-CT to assess for disease progression, typical CT imaging features of COVID-19 pneumonia were identified. Upon further investigation, the patient was asymptomatic, and his infection status remained unknown. He was subsequently lost to follow-up with his COVID-19 status pending.

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Section: Introductionsupporting

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Incidental PET/CT Findings of Suspected COVID-19 in a Region of High Prevalence

Franceschi¹,

Clifton²,

Ahmed³

et al. 2020

Cureus

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“…Dissociation between preserved lung compliance, starkly differing from low compliance typical of ARDS, and severe hypoxemia in critically ill patients with COVID-19 infection prompted questioning of perfusion regulation compromise (15). Later reports also focus on loss of hypoxic vasoconstriction consequent to thrombosis or interstitial edema (17), and autopsy series report platelet-fibrin thrombi disrupting the pulmonary microvasculature (17)(18)(19)(20)(21)(22).…”

Section: E259mentioning

confidence: 99%

Increased Incidence of Barotrauma in Patients with COVID-19 on Invasive Mechanical Ventilation

et al. 2020

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A t New York University Langone Health at the height of the coronavirus disease 2019 (COVID-19) pandemic, 22% of hospitalized patients diagnosed with COVID-19 infection required invasive mechanical ventilation (IMV) (1). We noted many patients with COVID-19 infection who developed pneumothorax, pneumomediastinum, and pneumopericardium, and in some cases, at multiple separate time points. Given this observation, we hypothesized that barotrauma related to IMV was elevated in patients with COVID-19 infection. The purpose of this study was to evaluate the rate of barotrauma in patients who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and who required IMV compared with other patients in the same institution during the same period who also required IMV, and to a temporally remote (pre-COVID-19) historical cohort of patients who required IMV support in the setting of acute respiratory distress syndrome (ARDS). Materials and Methods This retrospective study was performed with institutional review board waiver of authorization and consent (is20-00582) given the current urgent conditions created by the pandemic. Study Population The New York University Langone Health electronic medical record system (Epic Systems, Verona, Wis) was searched for patients age 18 years or older seen in our emergency department between March 1, 2020, and April 6, 2020, with chest imaging within 24 hours of nasopharyngeal or oropharyngeal swab testing for SARS-CoV-2. Test assay techniques are detailed in Appendix E1 (online). Patients with positive real-time reverse transcription polymerase chain reaction assays were deemed COVID-19 positive, and those with negative results were deemed COVID-19 negative. COVID-19 testing was performed in all patients who presented to the emergency

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“…This double hit affecting the ventilation and perfusion simultaneously underlies the intractable hypoxemia that contributed to the high mortality. None of the animal models replicated the respiratory failure, thromboembolic manifestations, and their The mechanisms of the lung injury and coagulopathy are not well understood, although several known pathways were postulated including cytokine storm leading to upregulation of tissue factor [5,9,24], activation/injury of the endothelium infected by the virus [30,67,71], complement activation [72], alveolar hypoxia promoting thrombosis [73], and autoantibodies against phospholipid and lupus anticoagulant [74,75] modulating the hemostasis and coagulation cascade directly. Hence, the development of animal models that replicate the dysregulation of the inflammation and coagulation could be important, as these would allow the deciphering of the intimate mechanisms at play.…”

Section: Discussionmentioning

confidence: 99%

“…Clinical and post-mortem studies of fatal cases of COVID-19 demonstrated major alteration of coagulation and fibrinolysis [17,18]. This was associated with widespread thrombosis of small and large vessels, particularly of the pulmonary circulation contributing to death in a third of patients [8,[28][29][30][31][32][33]. These observations suggest that dysregulated coagulation may be an important mechanism of COVID-19 morbidity and mortality [34].…”

mentioning

confidence: 98%

Evidence of a wide gap between COVID-19 in humans and animal models: a systematic review

et al. 2020

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Background Animal models of COVID-19 have been rapidly reported after the start of the pandemic. We aimed to assess whether the newly created models reproduce the full spectrum of human COVID-19. Methods We searched the MEDLINE, as well as BioRxiv and MedRxiv preprint servers for original research published in English from January 1 to May 20, 2020. We used the search terms (COVID-19) OR (SARS-CoV-2) AND (animal models), (hamsters), (nonhuman primates), (macaques), (rodent), (mice), (rats), (ferrets), (rabbits), (cats), and (dogs). Inclusion criteria were the establishment of animal models of COVID-19 as an endpoint. Other inclusion criteria were assessment of prophylaxis, therapies, or vaccines, using animal models of COVID-19. Result Thirteen peer-reviewed studies and 14 preprints met the inclusion criteria. The animals used were nonhuman primates (n = 13), mice (n = 7), ferrets (n = 4), hamsters (n = 4), and cats (n = 1). All animals supported high viral replication in the upper and lower respiratory tract associated with mild clinical manifestations, lung pathology, and full recovery. Older animals displayed relatively more severe illness than the younger ones. No animal models developed hypoxemic respiratory failure, multiple organ dysfunction, culminating in death. All species elicited a specific IgG antibodies response to the spike proteins, which were protective against a second exposure. Transient systemic inflammation was observed occasionally in nonhuman primates, hamsters, and mice. Notably, none of the animals unveiled a cytokine storm or coagulopathy. Conclusions Most of the animal models of COVID-19 recapitulated mild pattern of human COVID-19 with full recovery phenotype. No severe illness associated with mortality was observed, suggesting a wide gap between COVID-19 in humans and animal models.

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COVID-19 Critical Illness Pathophysiology Driven by Diffuse Pulmonary Thrombi and Pulmonary Endothelial Dysfunction Responsive to Thrombolysis

Cited by 25 publications

References 9 publications

Incidental PET/CT Findings of Suspected COVID-19 in a Region of High Prevalence

Incidental PET/CT Findings of Suspected COVID-19 in a Region of High Prevalence

Increased Incidence of Barotrauma in Patients with COVID-19 on Invasive Mechanical Ventilation

Evidence of a wide gap between COVID-19 in humans and animal models: a systematic review

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