Increased mortality in hematological malignancy patients with acute respiratory failure from undetermined etiology: a Groupe de Recherche en Réanimation Respiratoire en Onco-Hématologique (Grrr-OH) study

In this multicenter study conducted on a prospective cohort of 604 patients with ARF and HM, an undetermined etiological diagnosis was strongly associated with higher hospital mortality. Although previously suggested, this is the largest study that specifically addressed this major clinical question. Moreover, in this study, BAL remained an important diagnostic tool for pneumocystis pneumonia but did not improve diagnostic rate or outcome of ARF.

One of the striking results of the present work is the lower rate of undetermined diagnosis than previously reported (12.9 vs 20–30%) [7, 9, 18, 33, 35]. This result might be related to the recent advances in the management of patients with HM as well as non-immunocompromised patients and the improvement of noninvasive tests [40–45] leading to higher number of diagnoses. By multivariate analysis adjusted on confounders, having an undetermined ARF etiology was independently associated with mortality.

The impact of undetermined ARF etiology on outcome has been assessed only in a single-center study on cancer patients [18]. In that study, patients in whom no ARF etiology could be identified had a 66% mortality rates, and those with known ARF etiology had a 43% mortality rate (p = 0.008), in the same ranges than both groups in the present study [18]. Furthermore, a more recent study from our group on patients with solid tumors and HM reported the same finding [32].

Besides undetermined ARF etiology, this study identifies three factors significantly associated with hospital mortality, namely IMV in the first 24 h, invasive pulmonary aspergillosis and a SOFA score 7. IMV is a well-known risk factor for death among hematology patients with ARF [18, 32, 46, 47]. Invasive fungal infections such as pulmonary aspergillosis have also been associated with high-case fatality rates in this population [18, 48].

Noteworthy, diagnostic impact of bronchoscopy and BAL was limited in this study, in agreement with earlier findings [32], even if it was performed in a subgroup of patients. As noninvasive diagnostic tests have been widely used, BAL was the only yielding test in few patients. In a randomized controlled trial published in 2010, we also reported that BAL was diagnostic in only 18% of the patients and that a strategy without bronchoscopy and BAL was not inferior to routine use of BAL [33]. Such low diagnostic yield from BAL may pertain to the number of patients receiving prophylaxis or empirical therapy, to the number of AHSCT recipients in whom all diagnostic tests are less efficient and to the experience of this study group used to manage hematology patients using noninvasive diagnostic tests. However, it should be noted that BAL had high diagnostic yield in pneumocystis pneumonia and remains the only reliable diagnostic tool in patients with alveolar hemorrhage, hypersensitivity pneumonitis, drug-related pulmonary toxicity or acute interstitial pneumonia. Diagnostic contribution of alveolar cellular patterns and cytology still needs additional investigations [49].

This study has several limitations. First, as in a cohort study with no protocolized intervention, not all diagnostic tests could be performed in each patient. Identifying ARF etiology may be related to the number of tests performed. Moreover, patients who died in the first days of ICU admission would not have number of investigation tests. Yet, in this study, patients with undetermined diagnosis died earlier than the others (Fig. 3). Then, undetermined diagnosis might be actually some of undiagnosed infections. Moreover, although all the participating ICUs were high-volume centers used to manage critically ill hematological patients, we could not be sure that diagnosis strategy was the same in all centers. However, rate of undetermined diagnosis was lower than the rate in previous study [33], and we did not find any center effect. Second, BAL was performed according to physician’s decision, and most of patients were intubated before BAL. However, diagnostic yield of bronchoscopy and BAL is in the same ranges than previous reports. Third, these results were obtained in high-volume centers and may not be generalizable to all centers. However, most of hematology patients are managed in highly specialized comprehensive cancer centers with unique collaboration between hematologists, intensivists and other specialists. Fourth, this cohort included a wide variability of patients, in terms of HM, neutropenia, stage of disease, cause of ARF and stem cell transplantation. Last, none of the patients without documented ARF etiology underwent pulmonary biopsy. However, active malignancies and thrombocytopenia, severe hypoxemic pulmonary involvement, associated organ dysfunction and hemostatic disorders precluded this invasive investigation. Nevertheless, mortality related to undetermined diagnosis in this study suggests to reappraise the risk–benefit ratio for these high-risk patients.