Acute respiratory distress syndrome (ARDS), defined by diffuse radiological lesions, PaO₂/FiO₂ less than 300 mmHg within seven days of pulmonary or extra-pulmonary injury [1] , is a common and serious complication of coronavirus disease (COVID-19). In fact, of the 5% of patients with COVID-19 who require intensive care, approximately 88% present with severe hypoxaemia fulfilling the criteria for ARDS, requiring mechanical ventilation in the study of Grasselli et al. [2] ; 81% in the study done by Yang et al. [3] and all the patients were admitted for hypoxemic respiratory failure; 75% needed mechanical ventilation in the study of Bhatraju et al. [4] . Finally, follow-up of large series has shown that the characteristics of ARDS associated with COVID-19 are identical to those of ARDS associated with other causes [5] .

Therefore, based on the current state of knowledge, there is no good reason to propose specific ventilatory management in ARDS in the context of COVID-19. The COVID-19 subcommittee of the surviving sepsis campaign (SSC) [6] recommends that the same principles of protective mechanical ventilation combined with the prescription of prone sessions should be applied to these patients as to patients with “classic” ARDS.

As a reminder, the so-called “protective” ventilation technique consists of combining low tidal volumes of around 6 to 8 ml/kg of weight predicted by height (WPH) with a limitation of airway pressures (maximum alveolar pressure at 30 cmH₂O).

If the patient’s oxygenation remains inadequate, ventilation should be optimised by adjusting end-expiratory pressure (EEP), curarisation and possibly positioning the patient in the prone position (PP) [7] .

In 2013, a multi-centre randomised trial (PROSEVA trial) [8] demonstrated a reduction in mortality from 32.8% to 16% (p < 0.001) in patients with ARDS who received 16 hours of protective mechanical ventilation per day in the prone position compared to patients who remained in the supine position.

With particular reference to patients with COVID-19, studies have shown that patients receiving a mechanical ventilation protocol identical to that used in PROSEVA, combining protective ventilation and prone positioning, improved their oxygenation with a success rate of over 80% [5] [9] . Prone positioning has even been suggested for non-intubated patients, with a possible benefit on intubation rates and in-hospital mortality [10] .

It has therefore been established that the use of PEEP and the use of PP in patients with COVID-19 improves their oxygenation. However, the physiological aspects of this efficacy are not fully elucidated. The data currently available have shown that the response of COVID-19 patients is highly variable from one patient to another, without it being known which type of patients are good responders [11] . We therefore thought it would be useful to characterise COVID-19 patients who respond to the ventilatory strategy recommended for “classic” ARDS. For this reason, we conducted the present study on patients under our care in the intensive care unit of the Gaston Ramon Hospital in Sens, France, during the public health crisis of the COVID-19 pandemic.

In our study, all patients received standard ventilation and the use of positive end-expiratory pressure (PEEP) alone improved oxygenation in 12.5% of patients. The combination of high PEEP and prone position (PP) was necessary to improve oxygenation in 60% of patients. Patients who responded well to this strategy tended to be obese, although this was not statistically significant.

The characteristics of the patients in our study were similar to previously published studies in terms of age, sex ratio, comorbidities and symptoms on admission. The mean age in our study was 69.05 (65 - 73) ± 10.81 years. In a study conducted in Amiens, France, Brault et al. [13] found a mean age of 67 years. In an Italian series, Scaramuzzo et al. [14] found an average age of 66.

It is now known that people of any age can contract this infection. However, patients aged ≥ 60 years and those with underlying medical comorbidities have an increased risk of developing a severe form of COVID-19. The immune system deteriorates with age, making patients more vulnerable to attacks, particularly viral attacks. In addition, the onset of comorbidities is correlated with increasing age, which increases the risk of developing severe forms of COVID-19.

In addition, as in our study, several authors have reported a predominance of males among patients admitted to the intensive care unit (ICU). In our study, 70% were men. In a study of 149 ICU in France, Belgium and Switzerland, the proportion of men was 74% [15] .

Several studies in different countries have shown that the angiotensin converting enzyme 2 (ACE2) plays a crucial role in the greater susceptibility of men, due to higher blood concentrations of ACE2.

Certain organs are thought to act as “reservoirs” for the virus: the lungs, the digestive system, the kidneys and the testicles. In addition, some authors suggested that women develop a stronger immune response, mainly due to the presence of two X chromosomes. As their innate and adaptive immune responses are higher than those of men, this would favour more rapid elimination of the virus [16] .

We found a predominance of obesity and hypertension among the comorbidities of patients in our cohort. This finding agrees with the literature. In fact, the presence of comorbidities such as diabetes, hypertension, heart disease, chronic lung disease and cancer have been described as risk factors for severe forms of COVID-19 that may lead to intensive care hospitalisation [17] .

A high number of comorbidities were associated with the severity and mortality in patients with COVID-19 ARDS [18] - [20] . The need for hospitalisation was six times higher in patients with pre-existing health problems (45.4% versus 7.6%) [19] . Similarly, mortality was 12 times higher in this category of the population (19.5% versus 1.6%) [19] .

The ventilatory mechanics of the patients in our series were similar to those reported in series of critically ill patients requiring resuscitation [5] . The mean compliance of our patients was 28.43 ml/cmH₂O (26.10 - 31.41) ± 6.76.

In the series by Zierh et al. [5] of 66 intubated critical care patients, compliance was 35ml/cmH₂O IQR (30 - 43).

The majority of patients in this series presented with bilateral hypoxaemic radiological lesions without cardiogenic cause, meeting the definition of ARDS.

The only criterion not included in the definition of ARDS for the patients in our series was the time from symptom onset to ICU admission, which was 8.3 days, longer than the 7 days set by the Berlin definition [1] . Several authors have reported a delay of between 8 and 12 days [3] , which is beginning to raise the interest in revising or updating the Berlin definition.

After orotracheal intubation, our patients received “protective” ventilation as described by learned societies [7] . According to the current state of knowledge, there is no indication that a specific ventilator adjustment strategy different from that recommended for conventional ARDS should be used for COVID-related ARDS [6] .

We systematically started ventilation with low PEEP, less than or equal to 8 cmH₂O, but ≥5 cmH₂O as recommended [7] . This was then increased above 8 cmH₂O only if there was no response to low PEEP. A total of 10 patients (25%) improved their oxygenation with “titrated” PEEP.

In a series of 25 patients with COVID-19 ARDS, Beloncle F found that 64% of patients had a high relapse rate with a good response to PEEP. At the same time, he noted the heterogeneity of the response and advocated titration of PEEP to limit its adverse effects [21] .

After initiation of prone position, we observed a response rate of 80%. This rate is similar to those reported in the literature for patients with COVID-19 ARDS [9] [12] and those with non-COVID ARDS [8] [22] . In fact, as in our series, Gleissman et al. in Sweden [9] and Brault et al. [13] in France both found an 82% response rate to prone position in patients with severe COVID-19 ARDS. In ARDS of other causes, similar rates have been reported [8] [22] . The response to prone position seems to be common to all ARDS without aetiological distinction.

In our series, obese patients required prone positioning and high PEEP. Advanced age seemed to be a factor in good response to high PEEP. In Gleissman et al.’s series in Sweden [9] , age, sex, BMI or SAPS 3 did not predict the success of increasing the P/F ratio in his 44 patients. In obese patients, the negative effects of chest wall weight and abdominal fat mass on lung compliance lead to a reduction in functional residual capacity (FRC) and arterial oxygenation. These phenomena are exacerbated in the supine position and worsen after sedation and mechanical ventilation, leading to atelectasis. These are recruited in prone position, hence the good response to oxygenation. Older age, which appears to be a factor in non-response to prone position in our series, may be a confounding factor because obesity, although increasing with age, is less prevalent after the 7th decade of life [23] . Older patients would therefore be less obese and therefore less likely to respond to prone position placement due to a lack of areas to re-aerate. Although, we seem to find certain characteristics of responders unlike other authors, we cannot formally confirm this.

The mortality rate was 40%. In the literature, the mortality rate varies between 26% and 61.5% in patients with severe forms of COVID [2] - [4] . Our mortality rate is very close to those found by Scaramuzzo et al. in Italy [14] and Brault et al. in Amiens [13] , which were 42% and 43% respectively. This closeness can be justified by the overall similarity of the population. The clinical characteristics of our patients were similar in terms of age, sex, comorbidities, ethnic origin and ventilatory mechanics.

Our limitations include the small sample size and the lack of a supine control group. However, our study serves to guide the design of randomised trials to determine the clinico-biological characteristics that predict response to prone position with a view to prioritising management decisions.

At the end of this study, patients with COVID-19 ARDS had ventilatory mechanics similar to those described in patients with non-COVID-19 ARDS. The use of PEEP and the use of prone position increased the P/F ratio in the vast majority of patients, particularly those who were obese. No characteristic was associated with non-response.

Our study shows the value of systematically including all patients with an indication for prone position, regardless of their characteristics.

Analytical studies with much larger sample sizes should be carried out to identify the real factors associated with good or poor response to prone positions.

Chris Nsitwavibidila: Study design, data collection and drafting of the manuscript. Wilfrid Mbombo: Drafting of the manuscript. John Nsiala: Study design, bibliographic research and corrections of the manuscript. Daniel Tonduangu: Bibliographic research and correction of the manuscript. Dominique Gizolme: Database creation and data collection. Junior Poba: Statistical analysis. Youssef Lutangu: Generation of tables and figures. All other authors: Correction of the manuscript.

We thank the nursing staff of the intensive care unit of the Sens Hospital and the medical secretaries, Cindy Goncalves and Isabelle Lafargue, for access to our data. We would also thank Thaddée Tshiyamba for improving the figure.