Pre-transplant depression decreased overall survival of patients receiving allogeneic hematopoietic stem cell transplantation: a nationwide cohort study.

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Introduction

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) provides curative therapy for patients with malignant and nonmalignant hematologic disorders 1 , 2 . However, allo-HSCT is a highly aggressive and demanding medical supports with a significant risk of mortality 3 . Besides primary hematologic disorder and disease relapse after transplantation, transplant-related mortality is an important obstacle influencing treatment outcome of allo-HSCT 4 . Thus, careful assessment of risk and accurate prediction of mortality are necessary before undertaking allo-HSCT 5 .

Depression is a common comorbidity of oncological and chronic hematologic diseases 6 . Studies showed that more than 20% of patients receiving allo-HSCT experience clinically significant depression before undergoing transplantation 7 . Besides its negative impact on the quality of life, depression is also associated with poor treatment survival outcome in patients receiving allo-HSCT 8 . Thus, most stem cell transplantation centers require patients to receive a comprehensive psychiatric evaluation as a part of the pre-transplant process 9 . Numerous prognostic scoring systems recognizes depression as an important risk factor of post-transplant mortality 10 . The Hematopoietic cell transplantation-specific comorbidity index (HCT-CI), one of the most important prognostic scoring systems in allo-HSCT, acknowledged that depression increases post-transplant mortality with hazard ratio of 1.8 11 .

Studies investigating the impact of pre-transplant depression on overall survival (OS) of patients receiving allo-HSCT have yielded conflicting results 12 , 13 . A study comprising of 123 patients suggested that existing diagnosis of depression before allo-HSCT were not related to post-transplant OS 14 . In contrast, a more recent study showed that, among 190 patients receiving allo-HSCT, depression before transplantation predicted higher 1-year (hazard ratio [HR] = 2.59; p = 0.014) and 3-year mortality (HR = 2.04; 95% p = 0.041) 15 . Thus, studies containing larger cohorts are needed to confirm temporal association between pre-transplant depression and OS of allo-HSCT.

A recent large sized cohort (n = 7,433) study, using data from the Center for International Blood and Marrow Transplant Research (CIBMTR), showed that pre-transplant depression was associated with lower OS (HR = 1.13; 95% confidence interval [CI], 1.04–1.23; p = 0.004) 16 . However, the study neither used a validated measurement nor diagnostic assessment to define pre-transplant depression. Rather, the study merely used retrospective chart review of a single question reported in the CIBMTR database; was there “clinically significant depression requiring treatment?” Inevitably, the diagnosis of depression was prone to reporter bias. To overcome this bias, the study excluded transplant centers having more than 10 transplants without reports of both depressed and nondepressed patients to the registry. By doing so, selection bias became another important limitation. Co-occurrence of anxiety disorder and depression are very common in patients receiving allo-HSCT 17 . By neglecting possible overlapping impact of pre-transplant anxiety, it is still uncertain whether depression truly increased post-transplant mortality independent from the anxiety. Whether anxiety disorder causes additive risk in post-transplantation mortality risk among patients with depression history is another important issue needing investigation. Patients with leukemia are known to have a higher post-transplant mortality than patients with non-malignant hematologic disease 18 , 19 . Thus, subgroup analysis comprising more homogenous group, leukemia patients only, are needed to address detrimental effect of pre-transplant depression in OS of allo-HSCT. Lastly, CIBMTR is an US based registry, so studies containing a large sample size must also be repeated in diverse ethnicities to confirm impact of pre-transplant depression in outcomes of allo-HSCT.

To fill in this important gap, we conducted a nationwide longitudinal cohort study using the National Healthcare Insurance Service (NHIS) database containing data of majority of allo-HSCTs performed in South Korea (hereafter “Korea”). We first replicated previous findings by investigating association of pre-transplant depression in the long-term survival of allo-HSCT in Asian population (Koreans). Beyond replication, we extended previous work by analyzing independent risk of pre-transplant depression, separating possible overlapping effect of anxiety, in OS of allo-HSCT. Whether negative impact of pre-transplant depression in allo-HSCT is augmented by co-morbid anxiety was also evaluated. In addition, sub-group analysis of patients with leukemia was conducted to confirm risk of pre-transplant depression in allo-HSCT among higher risk group. Lastly, landmark analyses were performed at 100 days post-transplant to exclude patients at high risk of early mortality post-transplant and to evaluate the impact of prognostic variables on OS of patients still alive at these time points.

Results

Participant characteristics

Between January 2002 and December 2018, a total of 7,170 adult patients who received allo-HSCT were included in this study (Table 1 ). 13.3% (N = 956) were diagnosed with and visited hospital due to depression before transplantation whereas 86.7% (N = 6,214) did not. The mean duration of depression and anxiety before transplantations were 609.4 ± 569.3 days (median: 414.5 days) and 710.9 ± 587.5 days (median: 607 days) respectively. The median age at allo-HSCT was higher for depression group than non-depression group. Depression group had more subjects who were females, had leukemia, received peripheral blood as stem cell source, and had previous non-hematologic malignancies. Likewise, diagnosis of anxiety, hypertension, diabetes, dyslipidemia, chronic obstructive pulmonary disease, and cerebro- or cardiovascular disease were also higher in depression group than in non-depression group. Table 1 Basal demographical and clinical characteristics of adult patients who received allo-HSCT. Variables Total cohort (N = 7,170) History of depression before allogeneic-HSCT Yes (N = 956) No (N = 6,214) p -value Median age at transplant, year (range) 45 50 44 < 0.0001 Age ≤ median ( 45 years old) 3,664 (51.1%) 359 (37.6%) 3,305 (53.2%) Age > median ( 45 years old) 3,506 (48.9%) 597 (62.4%) 2,909 (46.8%) Gender < 0.0001 Male, no (%) 3,917 (54.6%) 423 (44.2%) 3,494 (56.2%) Hematologic disease < 0.0001 Leukemia. no (%) 3,676 (51.3%) 587 (61.4%) 3,089 (49.7%) Hodgkin lymphoma, no (%) 23 (0.3%) 6 (0.6%) 17 (0.3%) Non-Hodgkin lymphoma, no (%) 374 (5.2%) 75 (7.8%) 299 (4.8%) Multiple myeloma, no (%) 144 (2.0%) 31 (3.2%) 113 (1.8%) MPN, no (%) 68 ( 0.9%) 11 (1.2%) 57 (0.9%) MDS, no (%) 663 (9.2%) 68 (7.1%) 595 (9.6%) Aplastic anemia, no (%) 464 (6.4%) 41 (4.3%) 423 (6.8%) Unclassified, no (%) 1758 (24.5%) 137 (14.3%) 1621 (26.1%) Stem cell source < 0.0001 Bone marrow, no (%) 747 (10.4%) 77 (8.1%) 670 (10.8%) Peripheral blood, no (%) 4,752 (66.3%) 730 (76.4%) 4,022 (64.7%) Unclassified, no (%) 1671 (23.3%) 149 (15.6%) 1522 (24.5%) Anxiety < 0.0001 No, no (%) 5,752 (80.2%) 482 (50.4%) 5,270 (84.8%) Yes, no (%) 1,418 (19.8%) 474 (49.6%) 944 (15.2%) Previous non-hematologic malignancy < 0.0001 No, no (%) 6,482 (90.4%) 818 (85.6%) 5,664 (91.1%) Yes, no (%) 688 (9.6%) 138 (14.4%) 550 (8.9%) Hypertension < 0.0001 No, no (%) 5,168 (72.1%) 585 (61.2%) 4,583 (73.8%) Yes, no (%) 2002 (27.9%) 371 (38.8%) 1631 (26.2%) Diabetes < 0.0001 No, no (%) 5,284 (73.7%) 600 (62.8%) 4,684 (75.4%) Yes, no (%) 1886 (26.3%) 356 (37.2%) 1,530 (24.6%) Dyslipidemia < 0.0001 No, no (%) 3,736 (52.1%) 364 (38.1%) 3,372 (54.3%) Yes, no (%) 3,434 (47.9%) 592 (61.9%) 2,842 (45.7%) COPD < 0.0001 No, no (%) 6,834 (95.3%) 887 (92.8%) 5,947 (95.7%) Yes, no (%) 336 (4.7%) 69 (7.2%) 267 (4.3%) CVD < 0.0001 No, no (%) 6,905 (96.3%) 895 (93.6%) 6,010 (96.7%) Yes, no (%) 265 (3.7%) 61 (6.4%) 204 (3.3%) COPD Chronic obstructive pulmonary disease; CVD Cerebro- or cardiovascular disease; HSCT Hematopoietic stem cell transplantation; MDS Myelodysplastic syndrome; MPN myeloproliferative neoplasm.

Survival outcome: total cohort (N = 7,170)

After a median follow-up of 29.1 months (range 0 to 207), the estimated overall survival (OS) rates at 5 years were 63.1% (supplementary Fig. 1 ). Supplementary Table 1 summarizes the unadjusted analyses comparing allo-HCT outcomes between depression and non-depression group. Patients with pre-transplant depression (depression only group) and anxiety (anxiety only group) had lower 5 year-OS than those who neither had depression nor anxiety (none group), and 5 year-OS was the lowest in patients having both depression and anxiety (both depression and anxiety group) (Fig. 1 A). Figure 1 Overall survival outcome difference according to depression and or anxiety history; ( A ) in total cohort ( B ) in landmark cohort at the designated 100 days post-transplant.

The factors found to be significant in the univariable analysis were all included in the final multivariable analysis (Table 2 ). The post-transplantation OS decreased sequentially from none group (adjusted hazard ratio [aHR] = 1) to depression only group (aHR = 1.167, CI: 1.007–1.352, p = 0.04), and to both depression and anxiety group (aHR = 1.202, CI: 1.038–1.393, p = 0.014). However, anxiety only group did not have significant influence in OS. Table 2 Multivariable analysis of factors affecting overall survival of allo-HSCT in all patients (N = 7,170). Variable Hazard ratio (95% CI) p -value Age Age ≤ median (45 years old) 1 Age > median (45 years old) 1.249 (1.143–1.367) < 0.0001 Sex Female 1 Male 1.151 (1.060–1.250) < 0.0001 Pre-transplantation depression No without anxiety (none) 1 Yes without anxiety (depression only) 1.167 (1.007–1.352) 0.040 No with anxiety (anxiety only) 1.038 (0.927–1.162) 0.519 Yes with anxiety (depression and anxiety) 1.202 (1.038–1.393) 0.014 Hematologic disease Aplastic anemia 1 MDS/MPN 2.083 (1.611–2.693) < 0.0001 Leukemia/all lymphomas/Multiple myeloma 3.063 (2.435–3.853) < 0.0001 Stem cell source Bone marrow 1 Peripheral blood 1.457 (1.268–1.675) < 0.0001 Previous other malignancy No 1 Yes 1.188 (1.052–1.343) 0.006 Hypertension No 1 Yes 1.260 (1.152–1.377) < 0.0001 Diabetes No 1 Yes 1.080 (0.985–1.183) 0.099 Dyslipidemia No 1 Yes 1.030 (0.985–1.123) 0.509 COPD No 1 Yes 1.065 (0.893–1.270) 0.486 CVD No 1 Yes 1.438 (1.206–1.715) < 0.0001 COPD Chronic obstructive pulmonary disease; CVD Cerebro- or cardiovascular disease; HSCT Hematopoietic stem cell transplantation; MDS Myelodysplastic syndrome; MPN myeloproliferative neoplasm.

Survival outcome: landmark cohort (N = 6,391)

Among 7,170 adult patients who received allo-HSCT, 6,391 patients were alive at the designated 100 days landmark and were included in the landmark analysis (supplementary Fig. 2 for OS). In line with total cohort, depression only group and anxiety only group had lower 5 year-OS, with the both depression and anxiety group having the lowest 5 year-OS (Fig. 1 B). The factors found to be significant in the univariable analysis (supplementary Table 2 ) were all included in the final multivariable analysis (Table 3 ). However, the multivariable analysis of the landmark cohort showed that the OS after transplantation was significantly lower only in both depression and anxiety group (aHR = 1.253, CI: 1.061–1.479, p < 0.001), and neither depression only nor anxiety only group showed statistical significance. Table 3 Multivariable analysis of factors affecting overall survival of allo-HSCT in landmark cohort (N = 6,391). Variable Hazard ratio (95% CI) p -value Age Age ≤ median (45 years old) 1 Age > median (45 years old) 1.265 (1.144–1.400) < 0.0001 Sex Female 1 Male 1.196 (1.089–1.312) < 0.0001 Pre-transplantation depression None 1 Depression only 1.155 (0.975–1.369) 0.0947 Anxiety only 1.083 (0.955–1.229) 0.2149 Depression and anxiety 1.253 (1.061–1.479) < 0.001 Hematologic disease Aplastic anemia 1 MDS/MPN 3.006 (2.156–4.191) < 0.0001 Leukemia/all lymphomas/Multiple myeloma 4.785 (3.530–6.487) < 0.0001 Stem cell source Bone marrow 1 Peripheral blood 1.416 (1.215–1.651) < 0.0001 Previous other malignancy No 1 Yes 1.109 (0.960–1.281) 0.1597 Hypertension No 1 Yes 1.208 (1.091–1.338) < 0.0001 Diabetes No 1 Yes 1.104 (0.995–1.225) 0.0609 Dyslipidemia No 1 Yes 1.040 (0.943–1.148) 0.4536 COPD No 1 Yes 1.009 (0.822–1.240) 0.9288 CVD No 1 Yes 1.448 (1.180–1.778) < 0.0001 COPD Chronic obstructive pulmonary disease; CVD Cerebro- or cardiovascular disease; HSCT Hematopoietic stem cell transplantation; MDS Myelodysplastic syndrome; MPN myeloproliferative neoplasm.

Subgroup analysis of patients with leukemia

In the multivariable analysis of total and landmark cohort, hematologic disease had the highest aHR (2.083–3.063 for total cohort and 3.006–4.785 for landmark cohort) (Tables 2 , 3 ). In order to completely eliminate disease as a co-factor, we conducted sub-group analysis in patients with a more homogenous group, leukemia only. A total of 3,809 patients received allo-HSCT due to leukemia, and their baseline demographic and clinical data are summarized in Table 4 , and OSs are shown in supplementary Fig. 3 . Same trend was noted for univariable analyses (supplementary Table 3 ) and multivariable model (Table 5 ). Unadjusted analyses showed that depression only group, anxiety only group, and both depression and anxiety group all had lower 5 year-OS than none group (Fig. 2 ). Once again, the association was not detected for anxiety only group after adjusting for significant variables. In line with the total cohort, OS decreased sequentially from none group (aHR = 1) to depression only group (aHR = 1.220, CI: 1.031–1.444, p = 0.021), and to both depression and anxiety disorder group (aHR = 1.238, CI: 1.046–1.465, p = 0.0132). Table 4 Baseline demographical and clinical characteristics of adult patients who received allo-HSCT due to leukemia. Variables Cohort (N = 3,809) History of depression p -value Yes (N = 613) No (N = 3,196) Median age at transplant, year (range) 47 (18–74) 49(18–72) 46(18–74) < 0.0001 Under 47, no (%) 1809 (52.2%) 344 (56.1%) 1,465 (45.8%) Over 47, no (%) 2000 (47.8%) 269 (43.9%) 1731 (54.2%) Gender Male, no (%) 2055 (54.0%) 255 (41.6%) 1,800 (56.3%) < 0.0001 Anxiety No 2,909 (76.4%) 305 (49.8%) 2,604 (81.5%) Yes 900 (23.6%) 308 (50.2%) 592 (18.5%) Stem cell source 0.114 Bone marrow, no (%) 469 (12.3%) 62 (10.1%) 407 (12.7%) Peripheral blood, no (%) 3,246 (85.2%) 534 (87.1%) 2,712 (84.9%) Unclassified, no (%) 94 (2.5%) 17 (2.8%) 77 (2.4%) Previous non-hematologic malignancy 0.010 No, no (%) 3,422 (89.8%) 528 (86.1%) 2,894 (90.6%) Yes, no (%) 387 (10.2%) 85 (13.9%) 302 (9.4%) Hypertension 0.005 No, no (%) 1,224 (32.1%) 378 (61.7%) 2,207 (69.1%) Yes, no (%) 1,224 (32.1%) 235 (38.3%) 989 (30.9%) Diabetes 0.002 No, no (%) 2,684 (70.5%) 400 (65.3%) 1,446 (45.2%) Yes, no (%) 1,125 (29.5%) 213 (34.7%) 912 (28.5%) Dyslipidemia < 0.0001 No, no (%) 1674 (43.9%) 228 (37.2%) 1,446 (45.2%) Yes, no (%) 2,135 (56.1%) 385 (62.8%) 1,750 (54.8%) COPD 0.022 No, no (%) 3,618 (95.0%) 570 (93.0%) 3,048 (95.4%) Yes, no (%) 191 (5.0%) 43 (7.0%) 148 (4.6%) CVD 0.079 No, no (%) 3,643 (95.6%) 579 (94.5%) 3,064 (95.9%) Yes, no (%) 166 (4.4%) 34 (5.5%) 132 (4.1%) COPD Chronic obstructive pulmonary disease; CVD Cerebro- or cardiovascular disease; HSCT Hematopoietic stem cell transplantation; MDS Myelodysplastic syndrome; MPN myeloproliferative neoplasm. Table 5 Multivariable analysis of factors affecting overall survival of patients receiving allogeneic hematopoietic stem cell transplantation due to leukemia (all leukemia, N = 3,809). Variable Hazard ratio (95% CI) p -value Age Age ≤ median (47 years old) 1 Age > median (47 years old) 1.185 (1.068–1.314) < 0.0001 Sex Female 1 Male 1.144 (1.040–1.259) 0.006 Pre-transplantation depression Neither depression nor anxiety (none) 1 Depression without anxiety (depression only) 1.220 (1.031–1.444) 0.021 Anxiety without depression (anxiety only) 1.107 (1.031–1.259) 0.1244 Both depression and anxiety (depression and anxiety) 1.238 (1.046–1.465) 0.0132 Stem cell source Bone marrow 1 Peripheral blood 1.498 (1.285–1.746) < 0.0001 Previous other malignancy No 1 Yes 1.161 (0.997–1.352) 0.0545 Hypertension No 1 Yes 1.162 (1.046–1.291) 0.005 Diabetes No 1 Yes 0.995 (0.893–1.109) 0.9288 Dyslipidemia No 1 Yes 1.055 (0.954–1.167) 0.2961 Chronic obstructive pulmonary disease No 1 Yes 1.033 (0.832–1.281) 0.7704 Cerebro- or cardiovascular disease No 1 Yes 1.510 (1.224–1.861) < 0.0001 Figure 2 Overall survival outcome difference according to depression and or anxiety history in patients with leukemia.

Discussion

Our results showed that pre-transplant depression, independent from anxiety, decreased OS of adult patients receiving allo-HSCT. We also showed that co-occurrence of depression with anxiety disorder further decreased post-transplant OS, but pre-transplantation anxiety disorder did not independently increase mortality after allo-HSCT. In terms of sub-group analysis, same trend was found in patients who received allo-HSCT due to leukemia. The post-transplantation OS decreased sequentially from neither depression nor anxiety group (none; aHR = 1) to having depression only (aHR = 1.202), and then to having both depression and anxiety (aHR = 1.231). However, in the landmark analysis at 100 days post-transplantation, OS after transplantation was significantly lower only in patients having both depression and anxiety (aHR = 1.253).

Numerous studies suggested association of pre-transplantation depression with lower OS in allo-HSCT 15 , 20 – 22 . However, only one large sized longitudinal cohort study conducted in the US using CIBMTR data showed that depression history decreases the OS with aHR of 1.13 16 . To the best of our knowledge, this is the largest nationwide cohort study conducted in Asia, or outside US, showing the risk of pre-transplantation depression in OS of allo-HSCT. We replicated previous research and showed that pre-transplant depression decreases OS with aHR of 1.167, which was very similar to the HR reported by El-Jawahri et al. By carefully sub-classifying patients according to their anxiety disorder history, we were able to eliminate overlapping impact of pre-transplant anxiety from that of depression. Thus, our findings more specifically confirmed that pre-transplant depression independently decreases OS of allo-HSCT regardless of anxiety disorder. We also extended previous work by showing that OS decrement was more pronounced in patients who had both depression and anxiety before allo-HSCT (aHR = 1.202).

Interestingly, we did not detect significant association between anxiety disorder and OS of allo-HSCT. Anxiety is a frequent response to threat, so it is commonly found in patients having severe medical conditions 23 . Consequently, it is difficult to accurately distinguish normal anxiety or adjustment reaction from that of true morbid anxiety 24 . Thus, patients having anxiety reaction could have been over-diagnosed as having anxiety disorder in our cohort, which might have led to decreased significance in OS. In line with this hypothesis, patients in our cohort had twice more history of anxiety than depression. Previous study also showed that patients having pre-transplantation depression more concordantly experienced clinically significant depression even after transplantation, whereas patients having pre-transplant anxiety tended to experience anxiety symptoms less continuously 17 , 25 , 26 . Thus, depression might had longer impact than anxiety in OS of patients receiving allo-HSCT. In addition, landmark analyses performed at 100 days post-transplant, which excluded patients at high risk of early mortality post-transplant, showed that OS was significantly lower only in patients who had both depression and anxiety disorder. Thus, prospective studies which include more complete predictors of mortality in allo-HSCT are needed to confirm complicated relationship among depression, anxiety, and survival outcome after allo-HSCT.

Our results have additional strengths. First, by conducing a nationwide cohort study, we included all adult patients who received allo-HSCT from 2002 to 2018. We were able to prevent selection bias and minimize recruitment setting effect, so our results have higher generalizability. Second, a more stringent definition was used to determine pre-transplant depression. Rather than using a single questionnaire or retrospective chart review, all patients with pre-transplant depression visited hospital due to exact diagnosis of depression [ICD-10 code for major depressive disorder (F32 × or F33 ×)]. Thus, we further prevented selection and reporting bias. Lastly, by conducting a subgroup analysis comprising of patients with leukemia only, we eliminated underlying hematologic disease as a possible co-factor and confirmed the negative impact of depression, and additive effect of anxiety, in post-transplant mortality.

The pathophysiological basis of pre-transplantation depression having a negative impact in OS of patients receiving allo-HSCT is still obscure. Nevertheless, our findings could be predicted by association of depression with immune system dysregulations 27 . Studies showed that depression is often accompanied by inflammatory diseases including irritable bowel syndrome, type 2 diabetes, arthritis and autoimmune disorders, which can activate the peripheral and central inflammatory response 28 . Furthermore, other studies illustrated that depression and acute graft-versus-host-disease (GVHD) share common pro-inflammatory reactions: increment of inflammatory cytokines (i.e. tumor necrosis factor-alpha) and shifting toward T helper 1 response system 29 , 30 . Likewise, past study showed that pre-HCT depression increased the incidence of acute GVHD 16 . Poor treatment adherence due to depression is another important cause of higher mortality 31 . However, additional prospective studies focusing on biological mechanism are needed to define common pathway linking depression, and anxiety, with that of post-transplantation mortality in patients receiving allo-HSCT.

Several limitations should also be noted. First, occurrence of depression was based on clinical diagnosis with hospital visit records rather than using objective depressive scale measurements. As a result, we were unable to assess mortality difference depending on the depression severity. Since the depression severity is not known, some patients in the non-depression group may have had depression but have been undiagnosed. Second, we were also unable to investigate antidepressant effect, or treatment effect, in the risk of mortality. Likewise, depression episodes after transplantation were not considered. Thus, the effect of depression recurrence or chronicity in the post-transplant mortality were not studied. Third, whether time to diagnosis from depression and anxiety or duration of their illnesses influenced OS were not analyzed. Fourth, unbalanced baseline characteristics between depression group and non-depression group could harbor possible bias. Fifth, the cause of death, and relapse related and non-relapse related mortality according to depression were not investigated. In addition, other important clinical factors such as GVHD and infection episodes after transplantation, pre-transplantation conditioning, performance score, remission status at time of transplant, type of donor, smoking history, and alcohol status were not considered. Lastly, although Korea has a mandatory public health insurance system providing a comprehensive medical coverage to all residents of Korea, socioeconomic status could still have influenced the OS.

In conclusion, pre-transplant depression, independent from anxiety, decreased OS of adult patients receiving allo-HSCT. The mortality risk was higher in patients who had both depression and anxiety than patients having neither. Same trend was noted in patients who received allo-HSCT due to leukemia. Thus, our results suggest that patients having depression, especially both depression and anxiety, before allo-HSCT have a higher risk of post-transplantation mortality needing more intensive care.

Methods

Data source and study population

The Korean National Health Insurance Service (KNHIS) is a mandatory public health insurance system of Korea and offers comprehensive medical coverage to all residents of Korea. Data were acquired from the KNHIS database, which contains all medical claims for the population covered under the KNHIS. The database has been widely used in various epidemiological studies and is described in detail elsewhere 32 – 34 .

Adult patients (≥ 18 years) who underwent allo-HSCT between 2002 and 2018 were identified using KNHIS database procedure codes X5061 for bone marrow and X5063 for peripheral blood allo-HSCT. For those who received second allo-HSCT, we used first allo-HSCT data as their baseline values. As a result, nearly all allo-HSCTs performed in Korea during the study period were included in the analysis. Comorbidities including hypertension, diabetes mellitus, chronic obstructive pulmonary disease, cerebro- or cardiovascular disease, and anxiety disorder were also extracted using International Classification of Diseases, Tenth Revision (ICD-10) codes. This study was approved by the institutional review board of Seoul St. Mary’s Hospital, Seoul, Korea (KC19ZNSI0396). Consent from individual subjects were not needed because the study used publicly open, anonymous data.

Outcome variable and statistical analysis

The primary endpoint of this study was OS difference after allo-HSCT according to pre-transplant depression history. In order to utilize more conservative definition of depression, patients having ICD-10 code for major depressive disorder (F32 × or F33 ×) and visited hospital due to the same code within five years prior to the allo-HSCT was defined as having pre-transplant depression. Difference between the two groups (depression group and non-depression group) in baseline demographic and clinical characteristics were compared using student’s-T test for continuous variables and Chi-squared test for categorical variables.

To investigate independent risk of pre-transplant depression, and prevent overlapping impact of anxiety, we also identified patients who were diagnosed with and visited hospital due to anxiety disorder (F30 ×) before allo-HSCT. Thus, patients were subdivided in to four groups; no history of depression and anxiety disorder (none), depression history without anxiety (depression only), anxiety disorder without depression (anxiety only), and having both depression and anxiety disorder (both depression and anxiety).

Retrospective cohorts were followed from the day they received allo-HSCT to the occurrence of death or the last follow-up day (December 31, 2018), whichever came first. The OS rate represents the proportion of patients who were alive at the specified time after the date of transplantation and was associated with death due to any cause. Cox proportional-hazard regression evaluated risk of post-transplant mortality related to depression. All risk factors with p < 0.10 in univariable analysis were included in the single multivariable model. Thereafter, the factors found to be significant in this single multivariable model with depression variable were all included in the final multivariable model. For all statistical analysis, we used R statistical software (ver. 3.1.1, R Foundation for Statistical Computing, Vienna, Austria, 2012).

Ethical approval

All procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008.

Supplementary information

Supplementary Information.

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

These authors contributed equally: Sheng-Min Wang, Sung-Soo Park, Seunghoon Han and Hyun Kook Lim.

Supplementary information

is available for this paper at 10.1038/s41598-020-71208-2.

Author contributions

S.-M.W., S.-S.P., S.H., and H.K.L. drafted the manuscript and contributed to project design, data collection, management, analysis and interpretation; S.-H.P. contributed to project design, data collection, statistical analysis, and management; N.-Y.K., D.W.K., H.-R.N., J.W.L. contributed to project design, data management and manuscript revision. All authors have read and approved the revised manuscript.

Funding

This work was supported by the National Research Foundation of Korea (NRF) Grant funded by the Korea government (MSIT) (NRF-2019R1C1C1011664).

Competing interests

The authors declare no competing interests.

References

1. Mahmoud HK Allogeneic hematopoietic stem cell transplantation for non-malignant hematological disorders J. Adv. Res. 2015 6 449 458 10.1016/j.jare.2014.11.001 26257943 PMC4522586

2. Wildes TM Stirewalt DL Medeiros B Hurria A Hematopoietic stem cell transplantation for hematologic malignancies in older adults: geriatric principles in the transplant clinic J. Natl. Compr. Cancer Netw. 2014 12 128 136 10.6004/jnccn.2014.0010 PMC4010196 24453296

3. Copelan EA Chojecki A Lazarus HM Avalos BR Allogeneic hematopoietic cell transplantation; the current renaissance Blood Rev. 2019 34 34 44 10.1016/j.blre.2018.11.001 30467067

4. Bacigalupo A Reducing transplant-related mortality after allogeneic hematopoietic stem cell transplantation Haematologica 2004 89 1238 1247 15477210

5. Shouval R External validation and comparison of multiple prognostic scores in allogeneic hematopoietic stem cell transplantation Blood Adv. 2019 3 1881 1890 10.1182/bloodadvances.2019032268 31221661 PMC6595255

6. Abuelgasim KA Depression and anxiety in patients with hematological malignancies, prevalence, and associated factors Saudi Med. J. 2016 37 877 881 10.15537/smj.2016.8.14597 27464865 PMC5018705

7. Amonoo HL Psychological considerations in hematopoietic stem cell transplantation Psychosomatics 2019 60 331 342 10.1016/j.psym.2019.02.004 31072626 PMC6626677

8. Andrykowski MA Brady MJ Henslee-Downey PJ Psychosocial factors predictive of survival after allogeneic bone marrow transplantation for leukemia Psychosom. Med. 1994 56 432 439 10.1097/00006842-199409000-00008 7809343

9. Yalvac HD Kotan Z Tekgunduz E Caykoylu A Altuntas F Could psychiatric assessment before hematopoietic stem cell transplantation predict the need for psychiatric consultation during transplantation period? Transfus. Apher. Sci. 2016 54 85 90 10.1016/j.transci.2016.01.019 26825282

10. Potdar R Prognostic scoring systems in allogeneic hematopoietic stem cell transplantation: where do we stand? Biol. Blood Marrow Transpl. 2017 23 1839 1846 10.1016/j.bbmt.2017.07.028 28797781

11. Sorror ML Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT Blood 2005 106 2912 2919 10.1182/blood-2005-05-2004 15994282 PMC1895304

12. Hoodin F Uberti JP Lynch TJ Steele P Ratanatharathorn V Do negative or positive emotions differentially impact mortality after adult stem cell transplant? Bone Marrow Transpl. 2006 38 255 264 10.1038/sj.bmt.1705419 16785869

13. Akaho R Psychological factors and survival after bone marrow transplantation in patients with leukemia Psychiatry Clin. Neurosci. 2003 57 91 96 10.1046/j.1440-1819.2003.01084.x 12519460

14. Broers S Are pretransplant psychological variables related to survival after bone marrow transplantation? A prospective study of 123 consecutive patients J. Psychosom. Res. 1998 45 341 351 10.1016/s0022-3999(98)00003-8 9794280

15. Prieto JM Role of depression as a predictor of mortality among cancer patients after stem-cell transplantation J. Clin. Oncol. 2005 23 6063 6071 10.1200/JCO.2005.05.751 16087949

16. El-Jawahri A Impact of pre-transplant depression on outcomes of allogeneic and autologous hematopoietic stem cell transplantation Cancer 2017 123 1828 1838 10.1002/cncr.30546 28102896 PMC5419891

17. Seo HJ Anxiety and depression of the patients with hematological malignancies during hospitalization for hematopoietic stem cell transplantation Psychiatry Investig. 2019 16 751 758 10.30773/pi.2019.07.12 31558690 PMC6801322

18. Parimon T Au DH Martin PJ Chien JW A risk score for mortality after allogeneic hematopoietic cell transplantation Ann. Intern. Med. 2006 144 407 414 10.7326/0003-4819-144-6-200603210-00007 16549853

19. Thanarajasingam G Outcome and prognostic factors for patients who relapse after allogeneic hematopoietic stem cell transplantation Biol. Blood Marrow Transpl. 2013 19 1713 1718 10.1016/j.bbmt.2013.09.011 PMC3848699 24076323

20. Loberiza FR Jr Association of depressive syndrome and early deaths among patients after stem-cell transplantation for malignant diseases J. Clin. Oncol. 2002 20 2118 2126 10.1200/JCO.2002.08.757 11956273

21. Pillay B Lee SJ Katona L Burney S Avery S Psychosocial factors associated with quality of life in allogeneic stem cell transplant patients prior to transplant Psychooncology 2014 23 642 649 10.1002/pon.3462 24375571

22. Socie G Long-term survival and late deaths after allogeneic bone marrow transplantation. Late effects working committee of the international bone marrow transplant registry N. Engl. J. Med. 1999 341 14 21 10.1056/NEJM199907013410103 10387937

23. Stark DP House A Anxiety in cancer patients Br. J. Cancer 2000 83 1261 1267 10.1054/bjoc.2000.1405 11044347 PMC2408796

24. Appart A Lange AK Sievert I Bihain F Tordeurs D Adjustment disorder and DSM-5: a review Encephale 2017 43 41 46 10.1016/j.encep.2015.06.007 27216596

25. Fife BL Longitudinal study of adaptation to the stress of bone marrow transplantation J. Clin. Oncol. 2000 18 1539 1549 10.1200/JCO.2000.18.7.1539 10735903

26. Pillay B A prospective study of the relationship between sense of coherence, depression, anxiety, and quality of life of haematopoietic stem cell transplant patients over time Psychooncology 2015 24 220 227 10.1002/pon.3633 25052297

27. Leonard BE Inflammation and depression: a causal or coincidental link to the pathophysiology? Acta Neuropsychiatr. 2018 30 1 16 10.1017/neu.2016.69 28112061

28. Leonard BE The concept of depression as a dysfunction of the immune system Curr. Immunol. Rev. 2010 6 205 212 10.2174/157339510791823835 21170282 PMC3002174

29. Huang TL Lee CT T-helper 1/T-helper 2 cytokine imbalance and clinical phenotypes of acute-phase major depression Psychiatry Clin. Neurosci. 2007 61 415 420 10.1111/j.1440-1819.2007.01686.x 17610667

30. El-Jawahri A Chen YB Pleiotropic approach to graft-versus-host disease J. Clin. Oncol. 2013 31 4462 4464 10.1200/JCO.2013.52.8182 24166516

31. Bortolato B Depression in cancer: the many biobehavioral pathways driving tumor progression Cancer Treat Rev. 2017 52 58 70 10.1016/j.ctrv.2016.11.004 27894012

32. Song SO Background and data configuration process of a nationwide population-based study using the korean national health insurance system Diabetes Metab. J. 2014 38 395 403 10.4093/dmj.2014.38.5.395 25349827 PMC4209354

33. Im GJ Prevalence of severe-profound hearing loss in South Korea: a nationwide population-based study to analyse a 10-year trend (2006–2015) Sci. Rep. 2018 8 9940 10.1038/s41598-018-28279-z 29967396 PMC6028585

34. Moon I Trends of the prevalence and incidence of hypertrophic cardiomyopathy in Korea: a nationwide population-based cohort study PLoS ONE 2020 15 e0227012 10.1371/journal.pone.0227012 31929538 PMC6957184