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

Prevalence of cancer increases steadily over time [1] and is a leading cause of death worldwide, especially in developed countries [2]. This increasing prevalence may be explained by improved sensitivity of diagnostic tests, enhanced efficacy and reduced toxicities of chemotherapy regimens [3], recently released targeted therapies and new drugs contributing to increase overall survival [4], as well as recent advances in stem cell transplantations [5].

Acute respiratory failure (ARF) is the most frequent complication in hematological malignancy (HM) patients, with an incidence reaching 50% [6, 7], leading to high rate of ICU admission [8–11]. Although prognosis of critically ill HM patients improved over the last years [12–17], ARF remains associated with high mortality [8]. Strikingly, mortality rate in that setting is related to ARF etiology [18–20], suggesting that the diagnostic strategy could impact on outcomes.

ARF etiologies are numerous [6, 20–25] mainly related to bacterial or opportunistic infections, underlying disease-specific infiltration [26], or drug-related pulmonary toxicity [27]. Age and associated comorbidities also account for less specific ARF causes such as COPD exacerbation or cardiac pulmonary edema (CPE) [28]. Therefore, diagnosis of ARF could be difficult to identify. Then, a careful, accurate and efficient diagnostic strategy should be implemented to increase diagnostic rate [29, 30]. For instance, a clinical approach easily feasible at the bedside can both assess the most likely diagnosis and guide the best diagnostic approach using noninvasive diagnostic tests or fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) (the DIRECT approach [6, 31]). In that strategy, invasive diagnostic tests, including BAL, would be performed only for specific situations [32–34].

ARF etiology remains undetermined despite a comprehensive diagnostic workup in up to 25% of the cases [33, 35]. Moreover, several studies have reported that immunocompromised patients with undetermined ARF etiology have an increased mortality [18, 32, 36]. However, this finding has never been properly assessed in a large study. Higher mortality for patients with undetermined diagnosis could lead to reinforce our willingness to improve overall diagnostic strategy or to develop new diagnostic tools before discussing lung biopsy.

We sought to appraise the relation between an undetermined ARF etiology and mortality in a large cohort of critically ill hematology patients. The second objective of this study was to assess the yield of invasive procedures, such as BAL, in recent years.

This research is a post hoc analysis of a prospective cohort including 1011 hematological patients admitted to ICU (a study led by the Groupe de Recherche en Réanimation Respiratoire en Onco-Hématologie (GRRR-OH)). As previously published [8], fifteen French and two Belgian ICUs, all familiar with the management of critically ill HM patients, included patients in this cohort within a 16-month period (January 2010–May 2011). The study was approved by the appropriate ethics committees in France (CEERB Bichat, 0235) and Belgium (a different IRB for Brussels and Ghent) and declared on clinical trial (ClinicalTrials.Gov: NCT01172132). All patients or relatives were informed and consented to participate in the study.

Briefly, in the prospective cohort, all patients admitted to ICU with HM were included in the study regardless of the reason of admission. HM was considered if initial diagnosis was performed or relapse occurs within 5 years before ICU admission. Patients’ characteristics at admission and during ICU stay were prospectively collected in a dedicated electronic form. For this post hoc study, only patients with acute respiratory failure (ARF) at ICU admission were analyzed. ARF was defined by an oxygen saturation <90% or PaO2 <60 mmHg on room air, tachypnea (respiratory rate >30/min) or labored breathing, starting within the last 72 h before ICU admission. ARF patients were included regardless of their need for high flow oxygen, noninvasive or invasive mechanical ventilation (IMV).

Patients underwent a global comprehensive assessment to identify ARF etiologies. Invasive or noninvasive diagnostic strategy was performed according to clinical evaluation and CT findings, as previously described [33]. Noninvasive diagnostic tests were blood culture, PCRs for HSV and CMV, serum aspergillus galactomannan, sputa examination, urine antigen tests for Streptococcus pneumoniae and Legionella pneumophila, nasopharyngeal aspirate or swab including atypical bacteria tests, blood cultures and echocardiography (see Additional file 1). Diagnostic tests were analyzed if they were performed between 2 days before and 4 days after ICU admission. Considering that all participating centers were used to manage such immunocompromised critically ill HM patients and participated in previous studies concerning the diagnostic management of these patients [32, 33], diagnostic strategy performed was the one of the previous studies [33].

Four diagnostic categories were a priori defined by the investigators, based on the need of specific patient’s management (i.e., antibiotics, chemotherapy and steroids, or antifungal, antipneumocystis or antiviral agents) and on previous studies from this group [33]. For each patient, three investigators (EA, VL and FV) analyzed the charts blinded from the diagnosis established by clinicians in charge. Cases of disagreement were then discussed among the three investigators until a consensus could be reached. For 17 patients, no consensus could be reached, the complete charts were analyzed and the diagnosis retained by 2 of the 3 investigators was kept. For 5 patients, the three investigators concluded on a different diagnosis, and no consensus could be reached. These patients were left with an undetermined diagnosis.

Among the four diagnostic categories, the first group included patients with pneumonia as defined by a clinically or microbiologically documented low respiratory tract infection. Clinically documented infection referred to patients with all clinical and radiological criteria for bacterial pneumonia without any microbiological positive results [33]. Microbiologically documented infections were pneumonia with a positive bacterial or viral result from blood cultures (including HSV pneumonia), sputa, nasopharyngeal aspirates, tracheal aspirates or BAL. The second group included patients with non-infectious diagnoses, mostly corresponding to cases of ARF from pulmonary infiltration by the malignancy [26], CPE and drug-related pulmonary toxicity [27]. The third group included patients with ARF from opportunistic infections corresponding to invasive pulmonary aspergillosis according to EORTC criteria [37], proven pneumocystis pneumonia (positive direct examination or immunofluorescence on induced sputa or BAL) and other invasive fungal infections, CMV infections and parasitic infections [33]. Last, patient had undetermined diagnosis when no diagnosis could be made despite noninvasive diagnostic tests, bronchoscopy and BAL when performed and a global patient’s assessment by the ICU team and the hematologist consultant (see Additional file 1).

Results were expressed as median and 25th and 75th quartiles [Q1–Q3] for continuous data and numbers and percentages for categorical data. Marginal association between single variables and outcome was assessed by Wilcoxon rank-sum tests for quantitative variables and Fisher’s exact test or Chi-square test with Yates’ continuity correction for categorical variables when Fisher’s exact test was computationally impossible.

Factors associated with mortality were assessed using multivariate logistic model. Variables associated with the outcome in the first study [8] (poor performance status, Charlson comorbidity index, recipient of allogeneic hematopoietic stem cell transplantation (AHSCT), complete or partial remission, time for hospital to ICU admission <24 h, SOFA score, admission for cardiac arrest, admission for acute respiratory failure, organ infiltration by the malignancy and invasive pulmonary aspergillosis) were included in the model. Invasive mechanical ventilation and undetermined diagnosis were included in the model for this study. A selection procedure was performed using a backward algorithm with a stopping criteria defined by p values below 0.05 for all variables included in the model. Odds ratios of variables present in the final model are given with their 95% confidence intervals. Goodness-of-fit test of the final model was checked using the le Cessie–van Houwelingen test statistic [38].

Survival curves were obtained using the Kaplan–Meier estimator. Differences between survivals were tested using log-rank test. All tests were two sided at the 0.05 significance level. Analyses were performed using R statistical package (http://www.R-project.org).