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Phenotype of Severe COVID-19 Seems to Change Over Time

Key findings

  • This secondary analysis of a prospective observational study involved the measurement of tissue-specific injury markers on hospital days 0, 3, and 7 in 225 patients with COVID-19 who required respiratory support at presentation
  • Elevations in alveolar injury markers diminished over time in both intubated patients and those not intubated but on supplemental oxygen
  • Elevations in endothelial markers were delayed, were limited to intubated patients, and correlated with markers of cardiac and renal injury; moreover, 28-day outcomes were more closely associated with endothelial than alveolar markers
  • Among intubated patients, ventilatory ratios were infrequently high early on despite severe hypoxemia
  • The shift from alveolar- to endothelial-predominant injury might indicate the "natural" course of COVID-19 respiratory failure involves a transition from primarily lung-localized pathology to systemic disease

Since the beginning of the COVID-19 pandemic, experts have debated the relative importance of alveolar and endothelial injury in severe disease. Because COVID-19 causes pneumonia, some think an alveolar injury–phenotype must be predominant. Others consider endothelial injury the driving force, as hypoxemia occurs in the presence of a relatively well-aerated lung and thrombotic complications are common.

Marcia B. Goldberg, MD, clinician-researcher in the Division of Infectious Diseases at Massachusetts General Hospital, Daniel E. Leisman, MD, resident physician in the Department of Medicine, and colleagues have concluded both types of injury occur. In the American Journal of Respiratory and Critical Care Medicine, they say alveolar injury markers increase early in COVID-19, followed by increases in endothelial markers associated with systemic disease and poorer outcomes.


The team performed a secondary analysis of a prospectively enrolled observational cohort of patients hospitalized with COVID-19 at Mass General. The study period was March 24 to April 30, 2020, affording a chance to study the disease course before treatment with dexamethasone became standard.

225 patients were included in the analysis, of whom 67% received supplemental oxygen only and 33% were invasively ventilated at presentation. The researchers measured tissue-specific injury markers on day 0 and, if the patient was still hospitalized, on days 3 and 7. Patients were followed until day 28 or discharge.

Alveolar Markers

The alveolar injury markers measured were RAGE (receptor for advanced glycation end-products), surfactant proteins, and lysosome-associated membrane protein-3:

  • Day 0 markers were generally higher in intubated than non-intubated patients
  • The markers remained higher among intubated patients but decreased over time in both groups, and the differences between groups became less pronounced

Endothelial Markers

Examples of endothelial injury and activation markers studied were angiopoietin-2, tissue plasminogen activator, and von Willebrand factor:

  • At day 0, endothelial injury marker levels were comparable for the two groups
  • Endothelial markers increased after day 0; by day 3, most were significantly higher in intubated patients

Hypoxemia and Ventilatory Ratios

Severe hypoxemia was most prevalent on day 0. Among patients intubated on day 0, hypoxemia generally improved over time.

Ventilatory ratios (an estimate of dead space) were infrequently ≥2 at day 0 but increased over time. That could reflect aggressive low-tidal-volume ventilation and permissive hypercapnia, or it may be that intrapulmonary thrombosis accumulated over time.

Systemic Markers

The dynamics of renin-angiotensin system (RAS) markers (renin, renin receptor, and angiotensin-converting enzyme-2 [ACE2]) and markers of cardiac and kidney injury were similar to the pattern for endothelial markers.

RAS markers were strongly correlated with cardiac and renal injury.


28-day outcomes were more closely associated with endothelial than alveolar markers:

  • Day 3 values were significantly associated with day 28 clinical status on the World Health Organization scale for 92% of endothelial markers vs. 43% of alveolar markers
  • At day 3, effect sizes for endothelial markers were significantly larger than for alveolar markers (median adjusted OR, 3.49 vs. 1.57; P=0.0297)

Worse clinical status on day 28 was also significantly associated with RAS markers.

Interpreting the Findings

Alveolar injury represents an early insult in COVID-induced respiratory failure, this study shows. Decreases in the markers did not signal clinical recovery, though, as many patients required prolonged intubation.

The delayed peak in endothelial markers among intubated patients suggests endothelial injury and activation are prominent features of later severe disease. This shift from alveolar- to endothelial-predominant injury may indicate the "natural" course of COVID-19 respiratory failure involves a transition from primarily lung-localized pathology to systemic disease.

In addition to their bearing on the pathophysiology of severe COVID-19, the study findings may explain the seemingly contradictory findings of ACTIV-4A (published in The New England Journal of Medicine). In that trial, full-dose heparin improved mortality in hospitalized non-intubated patients, but for intubated patients, there was no mortality benefit despite their nearly twofold lower rates of major thrombotic events and similar incidence of major bleeding.

The results of the current study suggest anticoagulation of intubated patients in ACTIV-4A was initiated when alveolar bleeding risk was high and thrombosis was not significantly contributing to hypoxemia. In contrast, non-intubated patients would have been at lower risk of alveolar bleeding and therefore more likely to benefit from anticoagulation.

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