Intensive Care Med https://doi.org/10.1007/s00134-020-06233-w EDITORIAL COVID‑19‑related and non‑COVID‑related acute respiratory distress syndrome: two sides of the same coin? Audrey de Jong1,2, Oriol Roca3,4,5 and Claude Guérin6,7,8* © 2020 Springer-Verlag GmbH Germany, part of Springer Nature In the setting of the coronavirus disease 2019 (COVID- patients with COVID-19 present early with the type L 19) pandemic that has hit ICUs worldwide Ferrando et al. phenotype, and that some of them evolve to the type H [1] recently published a prospective multicentre study phenotype due to COVID-19 progression and a mecha- conducted in 36 Spanish ICUs. The study focused on nism reported to lead to patient self-inflicted lung injury consecutive patients with COVID-19-related acute res- [4]. Calfee et al. [5] have previously sought to pheno- piratory distress syndrome (COVID ARDS) who required type non-COVID ARDS. Using the latent class analysis invasive mechanical ventilation. Among the wealth of method, they identified a hyper-inflammatory pheno- important and carefully recorded information provided type and a low-inflammatory phenotype characterised by this study, the present editorial focuses on anticipated by different responses to PEEP. The results of several differences between COVID ARDS and non-COVID- studies of COVID ARDS have suggested that the respira- 19-related ARDS (non-COVID ARDS), on tidal volume tory mechanics and lung recruitability in these patients setting, adjunct therapies and on methodological aspects. may be similar to those observed in non-COVID ARDS The first, and main, controversy concerns the idea that patients. In their large multicentre study, Ferrando et al. “COVID-19 does not lead to a typical ARDS”, a hypoth- [1] attempted to corroborate this hypothesis by compar- esis supported by the observation of 16 patients who ing their results with the averaged results of previous were severely hypoxaemic but had relatively preserved studies. No differences were observed in Crs, plateau respiratory system compliance (Crs) together with good pressure, or driving pressure. lung aeration on CT scan [2]. On the basis of these find- Roughly 75% of their patients received a tidal volume ings the authors proposed avoiding high levels of posi- (VT) greater than 6 ml/kg predicted body weight (PBW), tive end-expiratory pressure (PEEP) and suggested that with 25% of them receiving a VT greater than 9.5 ml/kg proning may be associated with limited benefits that, in PBW. Furthermore, confirming the findings of the LUNG the context of the pandemic, must be balanced with the SAFE study in non-COVID ARDS [6], VT was similar high cost of human resources. In another editorial [3], across ARDS severity categories. An important part of the same authors described the existence of two differ- the paper concerned the comparison between patients ent phenotypes based on: elastance levels (1/Crs), pul- with a normal (≥ 50 ml/cmH2O) versus low (< 50 ml/ monary ventilation-to-perfusion ratio, lung weight, and cmH2O) Crs [3]. Remarkably, VT was not found to dif- lung recruitability. These two phenotypes, named types fer between the two groups, and the same applied to the L and H, are characterised by low and high levels of all other ventilator settings including PEEP. The first ques- these variables, respectively. It has been proposed that tion that arises is why measure Crs? The finding that Crs reflects the amount of aerated lung [7] previously led to the baby lung concept. According to this concept, the *Correspondence: claude.guerin@chu‑lyon.fr 6 greater the amount of aerated (open) lung the higher Medecine Intensive‑Réanimation, Groupement Hospitalier Lyon Centre, Hôpital Edouard-Herriot, 5 Place d’Arsonval, 69003 Lyon, France the VT should be, at a given PEEP. A secondary analysis Full author information is available at the end of the article of the ARMA trial [8] found that raising VT decreased mortality in patients with higher pre-randomisation It should be mentioned that the procedure was used in Crs, but increased mortality in those with lower pre- more than 60% of mild COVID ARDS patients, even randomisation Crs [9]. However, a subsequent increase though use of the prone postion in mild ARDS is not in VT was found to increase (by 15% per 1 ml/kg PBW evidence-based. VT increase) the risk of death in a prospective cohort of Regarding the statistical analysis and methodology non-COVID ARDS patients [10]. Crs was not taken into employed, the study of Ferrando et al. [1] has several account in that cohort study. Therefore, it is not clear strengths and limitations. The large sample size and the how those clinicians set VT and whether they would multicentre design allow the results to be extrapolated to adopt a Crs strategy for that, as they seem keener to fol- other ICUs in Spain and worldwide. The observational low a strategy based on driving pressure to adjust VT and “real-life” design prevents selection and information PEEP. Second, lung compliance may be more useful than biases [13]. However, the flow chart does not give the Crs to characterise patients according to obesity differ- total number of patients admitted to the ICUs during the ence between the two Crs groups. Crs and lung compli- study period. Similarly, the nature of missing data (com- ance can be expressed as percentage of predicted values pletely missing or partly missing, at random or not at [11]. The rate of use of adjunct therapies was also similar random) [14] was not assessed. Some important respira- between the two Crs groups. Use of inhaled nitric oxide tory variables such as mechanical power [15, 16] were was not mentioned, whereas a role of lung microcircula- not reported. A further limitation is the lack of a con- tion in COVID ARDS was suggested. A large majority of trol group with non-COVID ARDS in the same cohort patients received recruitment manoeuvers irrespective of patients during the same period. The comparison was of ARDS severity and without assessment of the under- not done with non COVID-19 cohorts gathered in the lying recruitability. Prone position was largely used in same time as the present COVID-19 cohort. Moreover, in both groups, e.g. at a more than twice the rate found in lacking an a priori specified hypothesis and pre-defined a previous study [12]. This result strongly suggests that sample size, the study fails to comply with the STROBE clinicians have now adopted the prone position strategy. statement for reporting observational studies [17]. It Fig. 1 Some important aspects to bear in mind when designing and reporting an observational study is therefore possible that readers may misinterpret the management, and outcome of ARDS caused by COVID-19 are similar to other causes of ARDS. Intensive Care Med. https​://doi.org/10.1007/s0013​ lack of statistically significant differences between mild, 4-020-06192​-2 moderate and severe ARDS patients, low and normal Crs 2. Gattinoni L, Coppola S, Cressoni M, Busana M, Rossi S, Chiumello D (2020) patients, or COVID and non-COVID ARDS patients, COVID-19 does not lead to a “typical” acute respiratory distress syndrome. Am J Respir Crit Care Med 201:1299–1300 particularly as evaluation of such differences was not the 3. Gattinoni L, Chiumello D, Caironi P, Busana M, Romitti F, Brazzi L, Camp- main objective of the study. Furthermore, because of the orota L (2020) COVID-19 pneumonia: different respiratory treatments for low grade of imbalance between groups in the relevant different phenotypes? Intensive Care Med 46:1099–1102 4. Brochard L, Slutsky A, Pesenti A (2017) Mechanical ventilation to minimize baseline variables, the statistical analysis was not adjusted progression of lung injury in acute respiratory failure. Am J Respir Crit for confounding factors. An adjustment performed Care Med 195:438–442 according to predefined variables, available in the litera- 5. Calfee CS, Delucchi K, Parsons PE, Thompson BT, Ware LB, Matthay MA (2014) Subphenotypes in acute respiratory distress syndrome: latent class ture, would have strengthened the results presented. Fig- analysis of data from two randomised controlled trials. Lancet Respir Med ure 1 highlights some important aspects to bear in mind 2:611–620 when designing and reporting an observational study. 6. Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, Gattinoni L, van Haren F, Larsson A, McAuley DF, Ranieri M, Rubenfeld G, Thompson Given all these limitations and considering the inher- BT, Wrigge H, Slutsky AS, Pesenti A, Investigators LS, Group ET (2016) ent heterogeneity of ARDS, it could be that, at the time Epidemiology, patterns of care, and mortality for patients with acute res- of intubation, COVID ARDS is not different from ARDS piratory distress syndrome in intensive care units in 50 countries. JAMA 315:788–800 of other causes. The results presented by Ferrando et al. 7. Gattinoni L, Pesenti A, Avalli L, Rossi F, Bombino M (1987) Pressure- must be considered descriptive and exploratory, and no volume curve of total respiratory system in acute respiratory failure. firm conclusion can be drawn from them without addi- Computed tomographic scan study. Am Rev Respir Dis 136:730–736 8. Brower RG, Matthay MA, Morris A, Schoenfeld D, Thompson BT, Wheeler A tional data. However, it can be stated that after careful (2000) Ventilation with lower tidal volumes as compared with traditional bedside physiological assessment, COVID ARDS patients tidal volumes for acute lung injury and the acute respiratory distress may be managed according to the evidence-based syndrome. N Engl J Med 342:1301–1308 9. Deans KJ, Minneci PC, Cui X, Banks SM, Natanson C, Eichacker PQ (2005) recommendations. Mechanical ventilation in ARDS: one size does not fit all. Crit Care Med 33:1141–1143 10. 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Guérin C, Terzi N, Galerneau LM, Mezidi M, Yonis H, Baboi L, Kreitmann L, Intensiva, Hospital Universitari Vall d’Hebron, Institut de Recerca Vall d’Hebron, Turbil E, Cour M, Argaud L, Louis B (2020) Lung and chest wall mechan- Barcelona, Spain. 4 Departament de Medicina, Universitat Autònoma de Barce- ics in patients with acute respiratory distress syndrome, expiratory flow lona, Bellaterra, Spain. 5 Ciber Enfermedades Respiratorias (Ciberes), Instituto limitation, and airway closure. J Appl Physiol (1985) 128:1594–1603 de Salud Carlos III, Madrid, Spain. 6 Medecine Intensive‑Réanimation, Groupe- 12. 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