Reply: Understanding COVID-19 Acute Respiratory Distress Syndrome: New Pathogen, Same Heterogeneous Syndrome.

From the Authors:

In their thoughtful commentary on our study (1), Singh and colleagues remind us of the core scientific motivation for our original investigation: “Does this new disease COVID-19 [coronavirus disease] have similar physiology to ARDS [acute respiratory distress syndrome] as we have known it or are there important differences mandating alternative management?” To answer this question, we first considered the hallmark physiologic features that run (-drome) together (syn-) in ARDS, even if not formally included in the Berlin definition: low compliance and high dead-space ventilation. Early on, a heated debate erupted in the literature around the recognition of an atypical, “high compliance” phenotype of COVID-19 that would not benefit from standard lung-protective ventilatory strategies. Despite provocative early case reports, accumulating data (including ours) (1) formed a familiar, heterogeneous picture: patients with COVID-19 ARDS had, on average, similar compliance as patients with non–COVID-19 ARDS, yet with a wide distribution, encompassing patients on both ends of the spectrum of stiffness versus compliance.

Beyond respiratory mechanics, the emerging evidence on pulmonary microthrombosis with COVID-19 supported the hypothesis that diffuse ventilation-perfusion mismatches should lead to increased dead-space ventilation. Singh and colleagues astutely noted that, contrary to this hypothesis, we observed lower minute ventilation in subjects with COVID-19 compared with subjects with bacterial and culture-negative ARDS, which should indicate a lower fraction of dead space. This surprising finding appeared to contradict other reports with the expected result of higher dead-space ventilation in subjects with COVID-19 ARDS (2). For symmetry, we calculated the ventilatory ratio (VR) as an estimate of dead-space ventilation: (tidal volume × respiratory rate × arterial carbon dioxide pressure) / (predicted body weight × 100 × 37.5). We excluded patients on extracorporeal membrane oxygenation (n = 7) because of confounding effects of extremely low tidal volumes and extracorporeal arterial carbon dioxide pressure clearance. We found no significant difference in VR among different ARDS groups: COVID-19 median, 1.67 (interquartile range: 1.49–2.24); viral median, 1.84 (1.59–2.33); bacterial median, 2.09 (1.60–2.49); and culture-negative median, 2.09 (1.85–2.45). Our VR comparisons do not support the hypothesis of a relatively increased dead-space ventilation in subjects with COVID-19 ARDS, similar to other recent reports (3, 4). In fact, compared with VR estimates from a large cohort of subjects with non–COVID-19 ARDS, nearly all values from our subjects with COVID-19 (1.67 [1.49–2.24]) would have fallen within the second and third quartile (1.44–2.13) of a non–COVID-19 ARDS distribution for VR (5).

Singh and colleagues raised the issue of our small sample size and a concern for the use of differential selection criteria by group. For the latter issue, we clarify that we used identical selection criteria for both COVID-19 and non–COVID-19 groups. Our study contributed a careful classification of non–COVID-19 ARDS by specific pathogen-group etiology, providing previously unrecognized pathophysiologic insights, such as the differential levels of interleukin-6 by ARDS subgroup. We recognize that our cohort’s small sample size limits the statistical power to detect significant differences in VR, if truly present. However, by contextualizing our results with the available comparative reports (3, 4) and historical estimates of non–COVID-19 ARDS VRs (5), COVID-19 is more similar than dissimilar to non–COVID-19 ARDS in terms of dead-space ventilation.

Therefore, it appears that accumulating clinical data do not support intriguing theories on a distinctive COVID-19 ARDS physiology. Whereas the role of the vasculature and microthrombosis in patients with COVID-19 is being investigated, it is plausible that such mechanisms, which remain to be identified, influence the clinical course of subsets of patients. During the COVID-19 pandemic, we have gained enhanced appreciation of how heterogeneous a clinical syndrome can be, even when millions of patients are sickened by the same pathogen. We concur with Singh and colleagues that further progress in the field will require an improved understanding of ARDS heterogeneity as well as careful identification of biological endotypes and physiologic phenotypes, including when caused by COVID-19, to foster personalized medicine approaches for better patient outcomes.