key: cord-0991498-ea94wn3f
authors: Fowler, Alexander J.; Wan, Yize I.; Carenzo, Luca; Haines, Ryan W.
title: COVID-19 Phenotypes and Potential Harm of Conventional Treatments: How to Prove the Hypothesis
date: 2020-08-15
journal: Am J Respir Crit Care Med
DOI: 10.1164/rccm.202004-1293le
sha: 64b991ec28640ba483d733511ef57dd4c740c5f8
doc_id: 991498
cord_uid: ea94wn3f

nan

(1). In this letter, the authors describe 16 patients with coronavirus disease (COVID-19) who have a mean respiratory system compliance of 50.2 6 14.3 ml/cm H 2 O and marked shunt physiology. The authors suggest that these patients are representative of the primary pattern of physiologic derangements among their patients and those of colleagues with whom they've conferred. They discourage the use of prone positioning when compliance is "relatively high," similar to their recommendations in a recent article in which they additionally support ventilation with VT up to 9 ml/kg in select patients with COVID-19 and relatively preserved compliance (2) . We appreciate the authors' clinical observations and their expertise; however, we have several concerns with these two recommendations, which diverge from the best established evidence for acute respiratory distress syndrome (ARDS).

First, the authors' reported cohort is small and heterogeneous, in keeping with the well-established heterogeneity of ARDS. Many of their patients have similar compliance to those enrolled in clinical trials for ARDS therapies (3) . For reference, patients enrolled in the PROSEVA (Prone Positioning in Severe ARDS) trial had a mean respiratory system compliance of 35 ml/cm H 2 O (SD, 15) at the time of enrollment (3). Interestingly, a recent report of patients with COVID-19 from Seattle, Washington, described median respiratory system compliance of 29 ml/cm H 2 O (interquartile range, 25-36) (4) . That is to say, 75% of the patients in the Seattle cohort had lung compliance of 36 ml/cm H 2 O or less. The discrepancy between the compliance measurements in the cohorts from Gattinoni and colleagues and Seattle highlights the difficulty in interpreting observations of small cohorts in a disease with well-established marked heterogeneity such as ARDS (5) . Second, respiratory system compliance was not used to determine eligibility for prone positioning in past trials. The PROSEVA trial enrolled severely hypoxemic patients, meeting the Berlin criteria for ARDS, who failed to stabilize early in the course of management (3) . Though the authors may not support prone ventilation in patients with "relatively high compliance," exclusion of patients by these criteria would be inconsistent with existing evidence. Also, the effects of prone position on gas exchange are not limited to the shunt in fully atelectatic regions but instead include changes in edematous regions. Discouraging prone position based on a perception of limited recruitability risks foregoing a therapy with mortality benefit (3) .

Finally, progression to a classic ARDS with dense posterior consolidation and elevated critical opening pressures (recruitability) is well described after mechanical ventilation, even in patients with initially preserved mechanics and without established lung injury (6) . Patients with COVID-19-associated respiratory failure have multifocal pneumonia even in milder stages, and these regions are expected to have different elastic properties than unaffected tissue, causing regional stress and strain concentrations with potential to progress to severe ARDS (2, 4) . Lung-protective strategies, including low VT and prone positioning, exist to prevent this progression of lung injury.

We fully agree with the authors' final sentiment that patience and gentle ventilation are the best therapies for COVID-19 with associated ARDS. Furthermore, the rapid search for new insights into COVID-19 is appropriate and commendable. However, adopting the paradigm that COVID-19 is inconsistent with ARDS, with resulting specific treatment recommendations, risks discouraging compliance with our best evidence-based standards of care. Evidence from randomized controlled trials suggests that prone positioning and low VT ventilation are the precise strategies for gentle ventilation that patients with ARDS, "typical" or not, should receive. n Author disclosures are available with the text of this letter at www.atsjournals.org. 

To the Editor:

On the basis of recent correspondence (1) and an expert editorial (2), two phenotypes of severe coronavirus disease (COVID-19) pneumonia have been proposed: "Type L, characterized by Low elastance (i.e., high compliance), Low ventilation to perfusion ratio, Low lung weight and Low recruitability and Type H, characterized by High elastance, High right-to-left shunt, High lung weight and High recruitability" (2). Features of the L phenotype are not typical of acute respiratory distress syndrome (ARDS) as defined by the Berlin criteria. Importantly, the authors suggest that recommended treatment strategies for severe COVID-19 pneumonia based on ARDS management (3) may lead to disease progression and excess harm (1, 2) . The authors provide anecdotal evidence for their observations based on their combined experience of treating several hundred severe COVID-19 cases. As outlined by Singer and colleagues (4), we need a rational approach. Considering the potential importance for modifying the management of these patients and the growing volume of data available from China and Italy, quantitative data are needed to test this hypothesis. Balancing the trade-off between "learning" and "doing" in this pandemic is crucial (5) . Large randomized controlled trials are not yet available, and observational data remain at high risk of bias. A number of predictive models have been described with severe methodological flaws (6). The appropriate use of emerging observational data requires collaborative input to improve understanding of treatment effects and complement the results of ongoing randomized controlled studies.

The wealth of data generated by critically ill patients and the complexity of covariate interactions make it challenging to use traditional statistical modeling to establish causal relationships. We aim to determine the causal pathway between the use of an ARDS management strategy for L-phenotype patients and subsequent harm using a directed acyclic graph (DAG) (Figure 1 ). The DAG achieves two things. First, we can construct a complex system of interacting baseline, clinical, and disease features, allowing explicit statement of prior knowledge before any data analysis. Second, we can use the DAG to determine a minimal adjustment set of variables to reliably estimate the direct effect of our exposure (ARDS ventilation strategy in COVID-19 L-phenotype patients) and outcome (ICU mortality).

The DAG was developed on the basis of the information in the expert editorial outlining the two phenotypes. In doing so, we have transformed the initial hypothetical construct into a testable mechanistic structure. Arrows represent proposed causal pathways, such as the link between a high positive end-expiratory pressure strategy of standard ARDS management and worsening edema and cardiovascular instability. Combined, these paths can be used to elucidate the appropriate adjustment set of variables. In this case, one adjustment set included cardiovascular instability, hypoxia, and acute kidney injury, all of which are readily measurable among intensive-care patients receiving treatment for COVID-19.

This approach has a number of limitations, including the fact that the evidence underpinning the structure is currently anecdotal. Without high-quality, unbiased evidence, it will be challenging to determine the true direct effect because of unmeasured confounders. Highlighting different phenotypes and different responses to treatment is a welcome approach that echoes the thoughts of some intensivists treating patients with COVID-19 and, if supported through the appropriate use of data, has the potential to reduce harm to future patients. The DAG allows easy inclusion of increasing knowledge as new findings emerge and provides an objective analytical framework to facilitate ongoing discussion. We welcome comments and encourage readers to examine the structure themselves by running the code (code freely available on request). We would also be interested to know the calculated effects if anyone wishes to test the hypothesis with appropriately collected data. n Author disclosures are available with the text of this letter at www.atsjournals.org. 

To the Editor:

Luciano Gattinoni is widely acknowledged and respected for his work on acute respiratory distress syndrome, and this time he has suggested a very interesting concept describing the pathophysiology of the atypical presentation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced respiratory failure (1). Based on detailed observation of several cases, the hypothesis of dividing the time-related disease spectrum within two primary "phenotypes," type L and type H, looks logical and might be helpful in the management of patients with coronavirus disease (COVID-19) . The suggested cause of hypoxemia in type L is the loss of regulation of perfusion and loss of hypoxic vasoconstriction. Hypoxemia, leading to increased minute ventilation, primarily by increasing the VT (up to 15-20 ml/kg), is associated with a more negative intrathoracic inspiratory pressure, and the magnitude of this pressure swing is projected as a factor that may determine the transition from the type L to the type H phenotype. However, the authors did not give an explanation for loss of regulation of perfusion and loss of hypoxic pulmonary vasoconstriction.

We believe that diffuse pulmonary microvascular thrombosis is the cause of hypoxemia in early pneumonia by SARS-CoV-2. The histologic and immunohistochemistry studies suggest that in severe COVID-19 infection, a catastrophic, complement-mediated thrombotic microvascular injury occurs, with sustained activation of the actin pathway and lectin pathway cascades (2), leading to the recommendation of the use of early anticoagulation with low-molecular-weight heparin (3) .

We agree with the authors that to reverse hypoxemia, oxygenation by high-flow nasal cannula may be tried in patients with type L. However, we have reservations on the "early intubation and the use of PEEP [positive end-expiratory pressure] to prevent the transition to type H," as the authors themselves have suggested that "the lung conditions are too good." Effective oxygenation using high-flow nasal cannula/extracorporeal membrane oxygenation in type L should prevent pleural pressure swings and self-inflicted lung injury, leading to transition to type H. 

COVID-19 does not lead to a "typical

COVID-19 pneumonia: different respiratory treatments for different phenotypes?

PROSEVA Study Group. Prone positioning in severe acute respiratory distress syndrome

Covid-19 in critically ill patients in the Seattle region -case series

Comparison of the Berlin definition for acute respiratory distress syndrome with autopsy

Ventilator-associated lung injury in patients without acute lung injury at the onset of mechanical ventilation

COVID-19 does not lead to a "typical

COVID-19 pneumonia: different respiratory treatments for different phenotypes?

Surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19)

A call for rational intensive care in the era of COVID-19

Optimizing the trade-off between learning and doing in a pandemic

Prediction models for diagnosis and prognosis of COVID-19 infection: systematic review and critical appraisal