The main results of the current study are as follows: (1) in a large, prospective, international, multicenter cohort, eight percent of patients with ARDS had no risk factor identified at the end of their ICU stay; (2) about 80% of these had no etiological diagnosis made, and, despite slightly more chest CT scans and lung biopsy performed than in other patients, specific investigations aimed at diagnosing unusual causes of ARDS  were rarely performed. Assessment of left heart filling pressure was not more common than in other patients; and (3) although these patients presented a different clinical phenotype than others, with more comorbidities and less severe pulmonary and non-pulmonary organ failures, their outcomes were not significantly different from those of patients having one or more risk factor identified.
Eight percent of patients meeting ARDS criteria within 48 h of acute hypoxemic respiratory failure onset had no common risk factor for ARDS identified upon ARDS diagnosis or later during the stay. This figure is consistent with a previous retrospective study, which reported a prevalence of 7.5% , and confirms that this subgroup represents a significant proportion of patients with ARDS. Strikingly, an objective assessment of left heart filling pressures to rule out a pulmonary edema of the hydrostatic type was performed in less than 70% of cases, and no more frequently than in other patients, although this criterion is required by the Berlin definition of ARDS when no risk factor has been identified [1, 11]. Thus, one cannot exclude that some of these patients had in fact a pulmonary edema of the hydrostatic type, even if managing physicians declared that the acute respiratory failure was not entirely related to cardiac failure. Of note, the comparison of patients who underwent an objective assessment of LHFP to those who did not (Additional file 1: e-Table 3) revealed that the latter had less cardiac and renal comorbidities, suggesting they were at lower risk of developing a mere cardiogenic pulmonary edema, possibly explaining why physicians did not deem necessary to further explore cardiac function, even if required by the Berlin definition in this setting. Eighty percent of patients within this subgroup had eventually no risk factor nor etiology retrieved, demonstrating that in spite of an extensive literature on the unusual etiologies of ARDS (e.g., auto-immune and drug-induced diseases, organizing pneumonia, diffuse alveolar hemorrhage, lung tumor infiltration, acute pulmonary edema, pulmonary embolism) [7, 12,13,14] mainly coming from autopsy [4, 15] or lung biopsy studies [16,17,18], under “real-life” conditions, no etiological diagnosis is made in most of the cases. Indeed, in the current series, although chest CT scans were more frequently performed in patients with no risk factor than in others, key investigations aimed at identifying the cause of ARDS, including BAL cytological examination, immunological tests  and open lung biopsy  were performed in a minority of cases (9, 5, and 3%, respectively), despite the fact that investigators were prospectively requested to fill in a dedicated form addressing these aspects. This failure to identify the cause of ARDS in 80% of patients from the no risk factor group suggests that the individualization of patients’ management might have not been optimal. Indeed, specific interventions have been suggested to be beneficial in targeted cases. For instance, patients with auto-immune or drug-induced disorders, organizing pneumonia, or diffuse alveolar hemorrhage could benefit from anti-inflammatory treatments (e.g., corticosteroids) [7, 12, 13]. Interestingly, patients from the no risk factor group did not receive more frequent corticosteroids than others, both within 72 h of ARDS onset and during ICU stay, and the overall rate of corticosteroids administration was low (about 18%). In all, our findings suggest that the low diagnostic yield in the subgroup of ARDS patients with no risk factor precluded the administration of individualized treatments. Other differences observed in treatments administered (i.e., neuromuscular blocking agents and inhaled vasodilators) and mechanical ventilation settings between both groups of patients likely resulted from differences in patients’ severity.
The current study provides a picture of the clinical presentation of ARDS patients with no risk factor identified and shows that these patients have a different clinical phenotype than others. Indeed, we not only observed differences regarding patients age and comorbidities, but also regarding the severity of ARDS and of associated organ failures, patients with no risk factor being less severe than others. Of note, such phenotype differences between patients without and with ARDS risk factors match those observed between patients with non-DAD vs. DAD ARDS, as recently shown in lung biopsy series [3, 16,17,18]. This observation corroborates the hypothesis that ARDS with no risk factor might be associated with a greater proportion of non-DAD lung histologies (sometimes termed “ARDS mimickers” [7, 13, 20]) than ARDS with one or more identified risk factors. However, we could not confirm this hypothesis due to the limited number of histological examinations performed in our study. In fact, the rate of open lung biopsy performed was strikingly low (n = 11/2813 in total, 0.4% of the whole cohort), illustrating that this procedure is exceptionally performed in ARDS patients. Yet, previous studies suggested that open lung biopsy, when performed in carefully selected patients, might not only allow for distinguishing patients with DAD and non-DAD ARDS, as discussed above, but have also been reported to allow for diagnoses to be made in 84% of cases and to alter management in 73% . Thus, we believe that in patients with persisting ARDS, when a comprehensive diagnostic work-up has been performed, including—but not limited to—bronchoscopy with BAL fluid examination with extended microbiological and cytological analyses, CT scan examination, and immunological tests, and when no definite diagnosis has been retained, there might be room for open lung biopsy . Of note, studies aiming at assessing the performances of a diagnostic work-up/algorithm in ARDS patients have, to the best of our knowledge, never been performed and would certainly be welcome.
In the current study, patients with no ARDS risk factor identified had a lower ICU mortality but no statistically different hospital mortality, as compared with others. A propensity score-matched analysis further confirmed the lack of significant differences both in ICU and hospital mortality between patients with and without ARDS risk factors, suggesting that the ICU mortality difference observed in the whole cohort was likely related to associated factors rather than to the lack of ARDS risk factor identification per se. Such results contrast with a previous study , in which we had reported a significant relationship between the lack of ARDS risk factor and mortality. Several factors might account for these conflicting results including differences in case mix and in patients’ management, particularly regarding the diagnostic work-up performed and the administration of corticosteroids in patients having no risk factor identified. We can only speculate on whether a more extensive work-up could have provided more diagnosis responding to specific therapies [10, 22, 23]. Indeed, the lack of specific procedures in most patients of the no risk factor group (e.g., BAL, lung biopsy) suggests that other diagnoses may have been missed. A special effort should be made in the future to target this group through guidelines and recommendations.
Our study has the following limitations: First, the current study is an ancillary study of a large prospective, international, multicenter study , and was thus not specifically designed for studying the subgroup of ARDS patients with no risk factor. However, the current study had been designed and approved before the enrollment period began and a dedicated section of the online case report form had been elaborated a priori for the prospective collection of data pertaining to ARDS with no risk factor; Second, although this study was performed in 459 ICUs worldwide, selection bias related to participating centers might have occurred, thereby limiting the generalizability of the findings; Third, we lacked access to the source data, implying that patients with ARDS might have been missed and that risk factors for ARDS might have been omitted, and thus some patients misclassified.