Long-term health-related quality of life of critically ill patients with haematological malignancies: a prospective observational multicenter study

The study was approved by the appropriate ethics committees in France and Belgium. All patients or relatives were informed and consented to participate in the study. The TRIALOH study was carried out in 17 university or university-affiliated centres in France and Belgium that belonged to a research network instituted in 2005 [1]. From 1 January 2010, to 1 May 2011, consecutive patients with HMs who were admitted to the participating ICUs for any reason were included.

Exclusion criteria were: complete cure of the malignancy for more than 5 years, ICU admission only to maximize safety of a procedure and age younger than 18 years. In each centre, we reported the ICU refusal rate (number of patients considered for ICU admission but eventually not admitted/number of patients admitted to the ICU throughout the study period).

In each centre, a standardized electronic case-report form was used to collect the study data. All QOL-related data were collected prospectively. Ninety days and 1 year after ICU discharge, HRQOL was assessed by asking alive patients to complete the SF-36 questionnaire (SF-36) during a telephone interview by a trained social worker.

The SF-36 includes one multi-item scale that assesses eight health concepts: (1) limitations in physical activities because of health problems; (2) limitations in social activities because of physical or emotional problems; (3) limitations in usual role activities because of physical health problems; (4) bodily pain; (5) general mental health (psychological distress and well-being); (6) limitations in usual role activities because of emotional problems; (7) vitality (energy and fatigue); and (8) general health perceptions [12]. Higher scores represent better functioning, with a range from 0 to 100. Physical and mental summary components (PCS and MCS, respectively) constitute aggregates of the eight individual dimensions and provide norm-based summary scores from physically and mentally oriented subscales. IES and HAD scale (HADS) are self-report instruments that assess the essential characteristics associated with stress and anxiety disorders among patients in a non-psychiatric hospital. The HADS is a 14-item self-report measure of psychological distress. The HADS has two subscales (anxiety and depression), each ranging from 0 to 21. Each item is rated on a scale from 0 (“not at all”) to 3 (“very much”), and higher scores indicate greater anxiety and depression. Scores from the two subscales are combined into a full-scale score that is indicative of a clinical disorder if greater than or equal to 12 points [13]. The IES is a widely used self-report measure of traumatic stress based on two subscales, evaluating intrusion and avoidance. Score of 33 points or more is described as a cut-off for a probable diagnosis of post-traumatic syndrome disorder (PTSD) [14].

Malignancies were considered as newly diagnosed if they had been diagnosed within the past 4 weeks before ICU admission. The sepsis-related organ failure assessment (SOFA) score was computed at admission then daily throughout the patient’s stay in the ICU; this score provides an estimate of the risk of ICU death based on organ dysfunction [15]. Performance status was evaluated using the Eastern Cooperative Oncology Group scale (ECOG). Fully active, able to carry on all pre-disease performance without restriction; restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g. light house work, office work; ambulatory and capable of all self-care but unable to carry out any work activities; up and about more than 50% of waking hours; capable of only limited self-care; confined to bed or chair more than 50% of waking hours; completely disabled; cannot carry on any self-care; totally confined to bed or chair; dead. The ECOG performance status and Charlson comorbidity index were determined at ICU admission [16, 17].

Reasons for ICU admission were recorded based on the main symptoms at ICU admission. Aetiologic diagnoses of sepsis and acute respiratory failure were made by consensus by the intensivists, hematologists and consultants. In particular, aetiologies of pulmonary involvement were diagnosed based on predefined criteria [1, 18].

Continuous variables are described as medians and interquartile ranges (IQRs) and were compared between groups using the Wilcoxon’s rank-sum test. Discrete variables are described with counts and percentages and were compared using Fisher’s exact test. We report norm-based measurements of the SF-36 subscores (mean 50, SD 10), after age and sex standardization using reference values for the French population [19]. SF-36 aggregate components (i.e. PCS and MCS) were computed as recommended [8, 20] and expressed on a normalized scale centred on 50 representing the population norm (i.e. values > or < 50 reflecting values higher or lower than age–sex standardized French values). Missing data in the individual SF-36 questions were imputed using the personal mean score approach [21]. The SF-36 aggregate scores (PCS and MCS) were compared using Wilcoxon’s rank-sum test among groups defined by categorical factors in univariate analysis. Correlations between SF-36 aggregate scores and quantitative variables were estimated and tested using Spearman correlation coefficient (with its 95% confidence interval [95% CI], estimated by bootstrap with 1000 replications). Adjusted multivariate models of factors associated with PCS and MCS were selected, using linear regression models: characteristics available at ICU admission associated with p values less than 0.2 by univariate analysis were candidates, and final models were selected using backward stepwise procedures (based on a p value < 0.20).

SF-36 scores at 3 months versus 1 year after discharge from the ICU were compared using Wilcoxon’s signed-rank test. Factors associated with the variation of SF-36 were examined using Wilcoxon and Kruskal–Wallis tests (discrete variables), or using Spearman correlation coefficient testing (continuous variables). Last, the age–sex standardized norm-based SF-36 items and aggregate scores in the HM cohort were compared to those of a sepsis cohort of 37 patients, including adult (≥ 18 years old) patients surviving to an ICU hospitalization for a septic shock without HM. These patients were recruited from two prospective studies on sepsis [22, 23]. Secondarily, the comparison was performed after matching patients on age and sex. Factors associated with the IES and HADS scores were investigated with a similar approach, in univariate analysis.

All tests were two-sided, and p values less than .05 were considered significant. Analyses were performed using R software version 3.2.2 [24].

In total, 1011 patients were included in the TRIALOH study. In-hospital mortality rates at 3 months and 1 year were 39.1, 50.7 and 57.2%, respectively. At 3 months, 278, 271 and 269 patients completed the SF-36, HADS and IES forms, respectively (Fig. 1).

Table 1 shows patient characteristics of the ICU survivors. Among them, patients who did not complete the SF-36 form at 3 months were older and more likely to require renal replacement therapy than those who completed the form (p = 0.02 and p = 0.025, respectively). Conversely, bone marrow transplant recipients were more likely to complete the form at 3 months (p = 0.024) and 1 year (p = 0.062) (Table 1 and Additional file 1: Table S1). At 1 year, we did not find any other difference between responders and non-responders (Additional file 1: Table S1).

The results of SF-36 scores at 3 months and 1 year are shown in Fig. 2. At 3 months, the median [IQR] age–sex standardized norm-based physical component summary score (PCS) was 37 [28–46], which corresponds to − 1.3 SD compared to the French general population, and the median [IQR] mental component summary score (MCS) was 51 [45–58]. Median age–sex standardized MCS values were similar (0.1 SD) to those of the general population in HMs patients (Table 2).

All subscores were not affected proportionally: while the median role function—physical (RP), median vitality (VT) and median general health (GH) scores were 32 [26–41], 41 [31–48] and 38 [30–48], respectively, median role function—emotional (RE) score, median mental health (MH), median social functioning (SF) and bodily pain (BP) scores were 54 [38–55], 53 [45–60], 51 [31–58] and 50 [38–62], respectively.

Evolution of these scores over time is shown in Fig. 2 and Table 2. MH, RE and GH scores decreased significantly between 3 months and 1 year after ICU discharge (p = 0.003, p = 0.005 and p = 0.038, respectively). MCS decreased significantly between 3 months and 1 year (p = 0.006). Conversely, RP increased significantly between 3 months and 1 year (p = 0.0004). Performance status has been shown to be strongly correlated with physical role functioning and functional capacity [25, 26]. When considering the performance status as a marker of functional capacity at baseline, we found a decrease in functional capacity from ICU admission to 3 months, with partial recovery in survivors at 1 year (Additional file 1: Figure S1).

Detailed answers to the question “Compared to 1 year ago, how would you rate your health in general now?” (item 2 of the SF-36) are shown in Fig. 3. Among survivors, 42% of patients felt better than 1 year before and 38.6% felt worse than 1 year before.

We then compared QOL 3 months after discharge in critically ill patients with HMs with QOL in critically ill patients with septic shock without HMs. After matching for age and sex, we found that median PCS values were higher in septic shock patients than in HMs patients (52 [37–59] vs. 37 [29–46], p = 0.007, respectively). There was no significant difference between HMs and septic shock survivors regarding the MCS aggregate of the SF-36 questionnaire (54 [45–58] vs. 50 [45–58], p = 0.99, respectively) (Table 3). PF, RP, VT and SF subscores were significantly higher in septic shock patients than in HMs patients (p = 0.016, p = 0.007, p = 0.035 and p = 0.007, Table 3).

Overall, 3 months after ICU discharge, the need for invasive mechanical ventilation (MV), baseline status of the underlying malignancy (partial or complete remission of the disease vs. evolutive), the need for renal replacement therapy, the need for vasopressors, sedation, SOFA score and haematopoietic stem cell transplant were associated with the MCS at a 20% level in univariate analysis (Additional file 1: Table S2); they were included as candidate factors in a multivariate adjusted model. After selection, SOFA score and baseline status of the underlying malignancy remained independently associated with MCS impairment (− 0.54 points [95% CI − 0.99; − 0.1], p = 0.018 and − 4.83 points [95% CI − 8.44; − 1.22], p = 0.009, respectively) (Fig. 4).

The only variable associated with PCS impairment at 3 months at a 20% level in univariate analysis was the Charlson index (Additional file 1: Table S3).

Of note, patients in partial or complete remission had a longer median time from the diagnosis of the underlying malignancy and ICU admission than patients classified as having an evolutive disease. Indeed, most patients in the latter case (57.3% of the patients classified as having an evolutive disease) had a newly diagnosed malignancy when admitted to the ICU (Additional file 1: Figure S2)

We did not find any association between these variables and MCS or PCS at 1 year after ICU discharge. (Univariate analyses are shown in Additional file 1: Tables S4 and S5.)

Three months after ICU discharge, 269 patients completed the IES form. The median IES score was 8 [3, 16]. The median intrusion subscore was 3 [0; 9], and the median avoidance subscore was 3 [0; 8]. Overall, 22 (8%) patients had an IES score greater than 35 points, which is considered the threshold for PTSD.

Men had a higher IES score than women (10 [4–21] vs. 6 [1–13], respectively, p = 0.0008). The IES score was positively correlated with length of stay in the ICU (correlation coefficient 0.14 [95% CI 0.02; 0.026], p = 0.025) (Additional file 1: Figure S3). By univariate analysis, ICU length of stay was associated with IES score at 3 months (Additional file 1: Table S6).

Three months after ICU discharge, patients had a median combined HAD score of 8 [5–13]. Considering both the subscales separately, 42 patients (15.5%) had an anxiety score > 8 and 41 patients (15%) had a depression score > 8, which are considered clinical disorders.