Pathophysiology of COVID-19-associated acute respiratory distress syndrome
Authors: Vasiliki Tsolaki, George E Zakynthinos, Konstantinos Mantzarlis, Vasileios Vazgiourakis, Dimosthenis Makris
Journal: The Lancet Respiratory Medicine (2020)

We read with great interest Giacomo Grasselli and colleagues' study concerning the pathophysiology of COVID-19-associated acute respiratory distress syndrome (ARDS).1Grasselli G Tonetti T Protti A et al.Pathophysiology of COVID-19-associated acute respiratory distress syndrome: a multicentre prospective observational study.Lancet Respir Med. 2020; 8: 1201-1208Summary Full Text Full Text PDF PubMed Scopus (484) Google Scholar The authors conclude that COVID-19 ARDS presents lung mechanics that largely match those of classical ARDS.1Grasselli G Tonetti T Protti A et al.Pathophysiology of COVID-19-associated acute respiratory distress syndrome: a multicentre prospective observational study.Lancet Respir Med. 2020; 8: 1201-1208Summary Full Text Full Text PDF PubMed Scopus (484) Google Scholar However, we feel this conclusion is not supported by their findings. As clearly stated, median static respiratory system compliance was significantly higher in patients with COVID-19 ARDS compared with those with classical ARDS, but the observed 28% difference would have been more pronounced had the groups been better matched (the classical ARDS group had a significantly lower percentage of patients with severe ARDS compared with the COVID-19 ARDS group).1Grasselli G Tonetti T Protti A et al.Pathophysiology of COVID-19-associated acute respiratory distress syndrome: a multicentre prospective observational study.Lancet Respir Med. 2020; 8: 1201-1208Summary Full Text Full Text PDF PubMed Scopus (484) Google Scholar Based on Grasselli and colleagues' findings on static compliance according to ARDS severity, we see that as hypoxaemia worsens, static compliance worsens as well in classical ARDS, in an almost linear way; however, in COVID-19 ARDS, static compliance remains unchanged, despite oxygenation worsening (appendix).1Grasselli G Tonetti T Protti A et al.Pathophysiology of COVID-19-associated acute respiratory distress syndrome: a multicentre prospective observational study.Lancet Respir Med. 2020; 8: 1201-1208Summary Full Text Full Text PDF PubMed Scopus (484) Google Scholar Therefore, additional factors might contribute to the degree of hypoxaemia that are unrelated to alveolar flooding or collapse, which mark the main pathophysiology in classical ARDS. Lung compliance is a marker of the amount of well aerated lung.2Gattinoni L Meissner K Marini JJ The baby lung and the COVID-19 era.Intensive Care Med. 2020; 46: 1438-1440Crossref PubMed Scopus (31) Google Scholar A decrease in oxygenation with preserved lung mechanics implies that the alveoli are fairly intact, meaning diffusion must primarily be affected. It would be very informative if data on lung mechanics (eg, plateau pressure, driving pressure) and particularly positive end-expiratory pressure (PEEP) levels for each COVID-19 ARDS severity category could be provided, as the authors have helpfully done for each D-dimer or static compliance quartile. PEEP seems to have been applied regardless of static compliance,1Grasselli G Tonetti T Protti A et al.Pathophysiology of COVID-19-associated acute respiratory distress syndrome: a multicentre prospective observational study.Lancet Respir Med. 2020; 8: 1201-1208Summary Full Text Full Text PDF PubMed Scopus (484) Google Scholar probably based on values of the ratio of partial pressure of arterial oxygen to fractional concentration of oxygen in inspired air (>14 cm H2O in severe ARDS, according to the ARDSNet protocol). Lower PEEP, when compliance is well preserved, might have decreased dead space, further improving static compliance (appendix). We have found nearly normal static compliance in severe COVID-19 ARDS, while a 25% PEEP reduction improved compliance, decreasing dead space.3Tsolaki V Siempos I Magira E Kokkoris S Zakynthinos GE Zakynthinos S PEEP levels in COVID-19 pneumonia.Crit Care. 2020; 24: 303Crossref PubMed Scopus (35) Google Scholar Unnecessary PEEP increases transpulmonary pressures impeding venous return, ultimately forcing lung zone 3 transition to zone 2 or even 1, inducing dead space. The condition can worsen when the pulmonary capillary bed is injured, as in COVID-19, from extensive microthrombosis, as has been reported by Grasselli and colleagues,1Grasselli G Tonetti T Protti A et al.Pathophysiology of COVID-19-associated acute respiratory distress syndrome: a multicentre prospective observational study.Lancet Respir Med. 2020; 8: 1201-1208Summary Full Text Full Text PDF PubMed Scopus (484) Google Scholar among others.4Ackermann M Verleden SE Kuehnel M et al.Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19.N Engl J Med. 2020; (published online May 21.)https://doi.org/10.1056/NEJMoa2015432Crossref PubMed Scopus (3871) Google Scholar, 5Bilaloglu S Aphinyanaphongs Y Jones S Iturrate E Hochman J Berger JS Thrombosis in hospitalized patients with COVID-19 in a New York City Health System.JAMA. 2020; 324: 799-801Crossref PubMed Scopus (561) Google Scholar Increased PEEP could have contributed to hyperinflation and hypoperfusion affecting mainly the upper-anterior lung zones, as shown in the Article.1Grasselli G Tonetti T Protti A et al.Pathophysiology of COVID-19-associated acute respiratory distress syndrome: a multicentre prospective observational study.Lancet Respir Med. 2020; 8: 1201-1208Summary Full Text Full Text PDF PubMed Scopus (484) Google Scholar In our opinion, this is a study of great scientific importance, clearly showing that COVID-19 ARDS is an alveolar-capillary disease that differs sufficiently from classical ARDS to probably warrant a different ventilatory approach concerning PEEP. Lower PEEP than classically used in severe ARDS, with low tidal volumes, might become the lung-protective ventilation of choice for patients with COVID-19, to ensure that alveolar overdistention is avoided. We declare no competing interests. Download .pdf (.3 MB) Help with pdf files Supplementary appendix Pathophysiology of COVID-19-associated acute respiratory distress syndromeWe congratulate Giacomo Grasselli and colleagues1 on their work in comparing acute respiratory distress syndrome (ARDS) in COVID-19 with classical ARDS. They found that median compliance in COVID-19 ARDS was higher than in classical ARDS, even after stratified analysis. However, they finally concluded that this difference was not significant. There are multiple reasons why important differentiating information might have been lost in the analyses. Full-Text PDF Pathophysiology of COVID-19-associated acute respiratory distress syndrome – Authors' replyLuigi Camporota and colleagues and Vasiliki Tsolaki and colleagues challenge our finding that suggests that patients with COVID-19 have a form of injury that is encompassed by the conceptual model of acute respiratory distress syndrome (ARDS). The argument used by Camporota and colleagues and Tsolaki and colleagues is that the median static compliance we observed in patients with COVID-19-associated ARDS (41 mL/cm H2O) was significantly higher compared with patients with classical ARDS. However, they miss the point that the distribution of compliance in patients with COVID-19 ARDS was wide and only 17 (6%) of 297 patients had compliance greater than the 95th percentile of the classical ARDS cohort. Full-Text PDF Pathophysiology of COVID-19-associated acute respiratory distress syndrome: a multicentre prospective observational studyPatients with COVID-19-associated ARDS have a form of injury that, in many aspects, is similar to that of those with ARDS unrelated to COVID-19. Notably, patients with COVID-19-related ARDS who have a reduction in respiratory system compliance together with increased D-dimer concentrations have high mortality rates. Full-Text PDF Pathophysiology of COVID-19-associated acute respiratory distress syndromeCompared with diseases from other coronaviruses (ie, severe acute respiratory syndrome and Middle East respiratory syndrome), COVID-19 has more adverse effects on the cardiovascular system, leading to a high incidence of cardiovascular events—most notably life-threatening pulmonary vessel injury and cardiac dysfunction, with and without severe myocardial injury.1 Small pulmonary vessel injuries and thrombosis associated with pulmonary blood flow alterations followed by right heart dilation and right ventricular failure have been found among the major causes of death related to COVID‑19. Full-Text PDF Pathophysiology of COVID-19-associated acute respiratory distress syndromeWe congratulate Giacomo Grasselli and colleagues for their important and informative work on the pathophysiology of COVID-19-associated acute respiratory distress syndrome (ARDS).1 In particular, we appreciate the clarity with which the data show that respiratory system compliance was significantly higher in COVID-19-associated ARDS compared with classical aetiology ARDS, despite the former having more severe hypoxaemia. Along this line, we note their result that "static compliance decreased as [the ratio of partial pressure of arterial oxygen to fractional concentration of oxygen in inspired air] decreased in patients with classical ARDS and in a pneumonia subset of patients with ARDS, while it remained unchanged in patients with COVID-19 ARDS". Full-Text PDF