The present study examined changes in sleep quality following hematopoietic stem cell transplantation (HSCT) and investigated associations with biobehavioral factors. Individuals undergoing HSCT for hematologic malignancies (N=228) completed measures of sleep quality and psychological symptoms pre-transplant and 1, 3, 6 and 12 months post transplant. Circulating inflammatory cytokines (IL-6, TNF-α) were also assessed. Sleep quality was poorest at 1 month post transplant, improving and remaining relatively stable after 3 months post transplant. However, approximately half of participants continued to experience significant sleep disturbance at 6 and 12 months post transplant. Mixed-effects linear regression models indicated that depression and anxiety were associated with poorer sleep quality, while psychological well-being was associated with better sleep. Higher circulating levels of IL-6 were also linked with poorer sleep. Subject-level fixed effects models demonstrated that among individual participants, changes in depression, anxiety and psychological well-being were associated with corresponding changes in sleep after covarying for the effects of time since transplant. Sleep disturbance was most severe when depression and anxiety were greatest and psychological well-being was lowest. Findings indicate that sleep disturbance is a persistent problem during the year following HSCT. Patients experiencing depression or anxiety and those with elevated inflammation may be at particular risk for poor sleep.
Individuals undergoing hematopoietic stem cell transplantation (HSCT) experience significant deficits in quality of life that may persist months or even years after HSCT.1, 2, 3 Although sleep disturbance has not been a focus of most quality-of-life investigations in this patient population, there is accumulating evidence that HSCT recipients experience significant sleep concerns following transplant.4, 5, 6 For example, in one of the only studies to focus primarily on sleep concerns of HSCT patients, Andrykowski et al.7 found that approximately one-half to two-thirds of long-term survivors experienced persistent disturbances in energy and sleep, with up to 20% of patients endorsing moderate to severe symptoms.
During the acute period following HSCT, Rischer et al.8 found that sleep worsened during the initial month following transplant and improved by 100 days post transplant. Difficulty falling asleep and maintaining sleep, along with non-restorative sleep, were the most prominent sleep-related complaints. Although the research was limited by a small sample size, this was one of few studies to use a prospective, longitudinal design to track changes in sleep over time. We sought to build upon these findings by examining changes in sleep disturbance in a larger sample of HSCT patients and extending the follow-up beyond 100 days post transplant.
Another objective was to investigate the biological and behavioral factors associated with sleep problems, which have not been the focus of prior reports. Patients undergoing the demanding and stressful experience of HSCT commonly experience psychological distress, including both depression and anxiety.9, 10, 11, 12 It is already known that depression and anxiety are associated with disrupted sleep,13, 14, 15, 16, 17, 18 but this link has not been studied in HSCT recipients. We therefore examined the extent to which greater psychological distress, including symptoms of anxiety and depression, may be linked with poor sleep.
Emerging literature also indicates that inflammation may adversely affect sleep. Pro-inflammatory cytokines, including IL-6 and TNF-α, activate neural pathways associated with the withdrawal and conservation of energy, evoking behavioral and mood responses including fatigue, depression and sleep disturbance.19 Immunomodulatory therapies and administered cytokines affect sleep architecture and duration.20 The associations between proinflammatory activity and sleep disturbance have been documented among cancer populations; for example, poor sleep quality has been linked to IL-6, IL-1RA and TNF-α levels in breast and prostate cancer patients, although the relationships are not always consistent.21,22 A recent study of allogeneic HSCT recipients found an association between IL-6 and treatment side effects, including poor sleep quality.23 Although intriguing, this paper focused more generally on side effects and used a single question to assess sleep quality. Relationships between inflammation and sleep have not been well-studied among HSCT patients and may be a particular problem because of numerous factors that cause elevated and prolonged inflammation post HSCT, including tissue injury from conditioning therapy, infections and GVHD. Therefore, we also examined the extent to which blood levels of proinflammatory cytokines in systemic circulation were associated with poor sleep quality.
In sum, the present study had two primary aims. First, we investigated the prevalence and severity of poor sleep quality during the 12 months following transplant. We conducted a comprehensive assessment of dimensions of sleep quality to determine which sleep domains are most problematic and tracked changes in sleep quality over time. The second aim was to investigate psychological and biological factors related to sleep difficulty. Given the known contributions of depression and anxiety to sleep problems in other populations and their high prevalence among HSCT recipients, we hypothesized that patients with greater depression and anxiety symptoms would experience poorer sleep quality whereas a sense of psychological well-being would be a protective factor. Moreover, because of the well-documented relationships between inflammation and sleep impairment, and elevated levels of inflammatory cytokines in the setting of HSCT, we hypothesized that patients with higher levels of inflammatory cytokines would experience poorer sleep quality. In addition to examining participant differences in these biobehavioral factors, we took advantage of our longitudinal design to determine whether changes in psychological symptoms and inflammation within individual participants over the study period were associated with corresponding changes in sleep quality.
Materials and Methods
The study sample included 228 adults who underwent HSCT at the University of Wisconsin Carbone Cancer Center for treatment of a hematologic disease. Participants were part of a larger, IRB-approved study examining psychological predictors of post-transplant recovery. The study enrolled 59.3% of eligible patients at our institution. A common reason for non-enrollment was the patient starting the transplant regimen before study personnel were aware of eligibility. Of those approached for the study, approximately 80% enrolled. The most commonly stated reasons for declining participation were not having enough time, feeling overwhelmed or feeling too unwell.
Data from participants who completed the pre-transplant assessment and at least one post-transplant assessment were included in the analyses (N=228). Because of study attrition, missing data or mortality, data were available from fewer patients at the 1-(96%), 3-(89%), 6-(82%) and 12-(78%) month follow-up assessments. Known reasons for attrition were death (n=25) and declining to continue participation (n=2). Those enrolled were a mean of 51 years of age (range: 19–74) at the time of transplant. The sample included both autologous (n=128) and allogeneic (n=100) transplant recipients. Additional demographic and medical characteristics are detailed in Tables 1 and 2.
Individuals who agreed to participate provided informed consent and completed study assessments prior to transplant and approximately 1, 3, 6 and 12 months post transplant. Blood samples were also obtained for a subset of participants at all assessment points except the 12-month follow-up.
Participants completed the 21-item Pittsburgh Sleep Quality Inventory (PSQI) at each time point. The PSQI assesses seven domains of sleep quality: subjective sleep quality, latency, duration, sleep efficiency (calculated by participant report of time spent asleep in relation to report of time spent in bed), nighttime disturbance, sleep medication use and daytime dysfunction.24 The PSQI global score is the sum of the seven domains and ranges from 0 to 21, with higher scores indicating poorer sleep quality. PSQI global scores greater than 5 indicate poor sleep quality.24 However, others have proposed a cut score of 8 for significantly ill populations.25 The PSQI has also been found to be a reliable measure in cancer populations, with a reliability coefficient of á =0.73 in the present study.25
Participants completed the 64-item Inventory of Depression and Anxiety Symptoms (IDAS) at each time point. This scale measures symptoms of depression and anxiety as well as general psychological well-being.26 We focused on dysphoria, a measure of cognitive and affective depression symptoms; (for example, ‘I felt depressed;’ ‘I blamed myself for things’), panic/somatic anxiety (for example, ‘I was trembling or shaking;’ ‘My heart was racing or pounding’) and psychological well-being scales (for example, ‘I felt optimistic;’ ‘I felt that I had a lot to look forward to’). The IDAS has several advantages over other depression and anxiety measures, including superior ability to discriminate between depression and anxiety symptoms, content that more closely reflects DSM criteria, the ability to examine symptom dimensions, and a quick and efficient format. Moreover, the IDAS is particularly well-suited for populations where medical symptoms may overlap with depression and anxiety symptoms.27,28 IDAS scores also show strong correlations with structured interview diagnoses of depression and anxiety.26 In the present sample, the IDAS scales demonstrated excellent reliability (á coefficients ranged from 0.85 to 0.90).
Peripheral blood was obtained from a subsample of participants to assess circulating levels of IL-6 and TNF-α. Cytokine assessments were added to the study protocol later, and therefore were available for the most recently enrolled participants (n=91). IL-6 and TNF-α are potent inflammatory cytokines that have been linked to quality-of-life measures, including sleep, among healthy populations as well as cancer patients.29, 30, 31
Blood samples were centrifuged and separated plasma frozen at −80 °C. ELISA was used to assess cytokine levels using standard high sensitivity kits (R&D Diagnostics, Minneapolis, MN, USA). For all cytokine analyses, samples were classified as falling into low/normal range versus elevated on the basis of established field-relevant values and reference ranges from the manufacturer.32 Cutoffs for elevated scores were as follows: above 3 pg/mL for IL-6 and 1.41 pg/mL for TNF-α. At the four assessment points, 12–32% of patients exceeded the cutoff for elevated IL-6, and 25–50% exceeded the cutoff for TNF-α.
StataSE statistical package was used to analyze data. All statistical tests were two-sided, and results considered significant at P<0.05. Sleep was treated as a continuous variable in all analyses. Repeated measures ANOVA was used to examine changes in sleep quality across the five study time points. Significant temporal changes were explored with post hoc pairwise comparisons between time points.
Relationships between time-varying biobehavioral factors (psychological symptoms and circulating cytokine levels) and time-varying global sleep quality were assessed with mixed-effects and fixed-effects regression models. Separate models were run for each psychological measure or cytokine. Several potential covariates were considered for inclusion in the models, including age, sex, graft type (allogeneic versus autologous transplant), conditioning regimen (myeloablative versus nonmyeloablative), TBI, initial diagnosis, disease status (remission versus recurrence/progression), steroid use and occurrence of infections. Women, younger patients and those who had experienced disease recurrence or progression reported significantly poorer sleep quality at some post transplant time points (P values<0.05), and steroid use was marginally linked to sleep quality at some time points (P values<0.10). Therefore, sex, age, disease status and steroid use were included as covariates in subsequent analyses. Other demographic and clinical variables were not associated with sleep quality. However, graft type and conditioning regimen were included as a conservative step given the different side effect profiles and recovery time anticipated with different treatment regimens.
Mixed-effects linear regression models examined relationships between participant differences in biobehavioral variables and sleep quality. All models included time since transplant entered as a factor variable and adjusted for between-subjects covariates, including sex, age, graft type and conditioning regimen, as well as time-varying covariates, including steroid use and disease status. Time-varying psychological predictors were standardized based on 12-month post-transplant means and standard deviations. before being entered in the models to improve interpretability of the model coefficients. Subject-level fixed effects models were then employed to determine the extent to which changes in psychological symptoms and circulating cytokines within individual participants were associated with corresponding changes in global sleep quality, effectively allowing each participant to act as his/her own control. These models also included time since transplant as a factor variable and time varying-covariates, including steroid use and disease status. Although not a primary study aim, mixed-effects linear regression models were also used to examine relationships between the psychological variables and cytokine levels.
Poor sleep quality prevalence, severity and change over time
Table 3 provides descriptive information about the percent of participants who endorsed various response categories for each of the PSQI domains and who fell above global PSQI cut scores. The majority of participants exceeded the standard cut score of 5 at most time points.
Figure 1 illustrates mean global sleep quality scores across the time points, with higher scores indicating poorer sleep quality. Significant changes in global sleep quality were evident over time, F(4, 778)=20.87, P<0.001. Post hoc comparisons clarified that sleep quality declined significantly from pre-transplant (M=6.98, s.d.=4.11) to 1 month post transplant (M=8.11, s.d.=4.17) followed by improvement at 3 months post transplant (M=6.49, s.d.=3.73) after which sleep remained relatively stable through 6 months (M=6.18, s.d.=3.76) and 12 months post transplant (M=6.07, s.d.=3.65). Mean sleep quality scores were poorer than population norms at all time points.24
Figure 2 illustrates the trajectory of each sleep quality dimension over time; these seven dimensions comprise the global sleep quality score. The highest mean scores (indicating poorer sleep) were seen for difficulty staying asleep (nighttime disturbance), followed by difficulty falling asleep (latency) and daytime dysfunction because of sleep disturbance. Sleep duration had the lowest scores (indicating that most patients were sleeping a sufficient number of hours). Significant changes over time were seen in five of the seven sleep domains, including subjective sleep, F(4, 778)=10.62, P<0.001; sleep duration, F(4, 773)=9.12, P<0.001; sleep efficiency, F(4, 749)=8.96, P<0.001; sleep medication use, F(4, 776)=15.65, P<0.001; and daytime dysfunction, F(4, 781)=8.85, P<0.001. Post hoc comparisons indicated that sleep efficiency, sleep medication use and daytime dysfunction followed the same temporal trajectory as global sleep quality. Subjective sleep and sleep duration followed a slightly different pattern, with consistently high scores (indicating impairment) at pre-transplant and 1 month post transplant, followed by improvement at 3 months post transplant. Sleep latency and nighttime disturbance did not significantly change over time, all P values>0.10.
Psychological symptoms and sleep quality
Mixed-effects linear regression models revealed that participants who reported greater depression and anxiety experienced poorer sleep quality, after covarying for the effects of time since transplant, sex, age, graft type, conditioning regimen, steroid use and disease status. In contrast, participants who reported greater psychological well-being experienced better sleep quality during the 12 months following transplant. Coefficients, test statistics and P values are provided in Table 4.
Among individual participants, subject-level fixed effects models indicated that changes in depression and anxiety were associated with corresponding changes in sleep quality, with the most severe disturbances in sleep occurring when depression and anxiety were most elevated. Similarly, changes in psychological well-being were associated with corresponding changes in sleep quality, with the most severe disturbances in sleep occurring when psychological well-being was lowest. These relationships were seen after accounting for the effects of time since transplant, steroid use and disease status. Coefficients, test statistics and P values are provided in Table 4.
Circulating cytokine levels and sleep quality
Mixed-effects linear regression models revealed that participants with elevated levels of IL-6 reported poorer sleep quality across all assessment points through 6 months post transplant as compared with those with low IL-6. Subject-level fixed effects models showed that changes in levels of IL-6 within individual participants were not significantly associated with corresponding changes in sleep quality. TNF-α was not associated with sleep quality. Coefficients, test statistics and P values are provided in Table 4.
We also examined whether psychological indices (depression, anxiety, well-being) were associated with IL-6 or TNF-α. No significant relationships were seen between the psychological variables and cytokines, all P values>0.10.
Our results indicate that patients undergoing HSCT experience significant disturbances in sleep during the 12 months following transplant. Among HSCT recipients in this study, 69% report poor sleep quality during early post-transplant recovery, with 48% continuing to report moderate to severe disturbances at 12 months post transplant. Consistent with prior research, the most problematic domains were difficulty falling asleep and awakening during the night.5,8
Sleep quality was evaluated at specific milestones in the post-HSCT recovery process. A consistent pattern of changes in sleep quality was evident from pre- to post-transplant periods and during the year following transplant. Sleep quality was poorest at 1 month post transplant, at which point most patients are typically still experiencing treatment-related side effects and complications of infections.33 Sleep quality returned to pre-transplant levels by 3 months post transplant, a clinical milestone at which disease outcomes are evaluated.33,34 Sleep quality stabilized by 6 months post transplant and remained stable through 12 months post transplant, which represent important transitional points in the recovery process when patients may be returning to work and resuming more normal routines, assuming a good HSCT outcome.35,36 This overall pattern of change was seen across five of the seven domains of sleep quality as well as for global sleep, and likely reflects the effects of conditioning therapy, immunosuppression, medications, long hospital stays, stress and adverse physical side effects of the intensive therapeutic regimen.
The temporal changes in global sleep observed are consistent with Rischer et al.8 and indicate that sleep disturbances return to pre-transplant levels by 3 months post transplant. However, we extend these prior findings to show that approximately half of participants continued to show persistently poorer sleep quality at 6 and 12 months post transplant. Our results indicate that patients had impaired sleep both immediately prior to and following transplant and suggest that without intervention, many HSCT survivors are at risk for persistent sleep problems. Sleep disturbances such as insomnia increase risk for psychiatric disorders,37,38 comorbidities such as cardiovascular disease and diabetes,39 and mortality;40 thus, findings have important clinical implications in placing HSCT recipients at risk for more challenged short- and long-term recovery and overall health.
This study is the first to examine potential psychological and biological underpinnings of sleep disturbance following HSCT. Consistent with initial hypotheses, our data suggest that patients who report greater depression and anxiety symptoms may be more at risk for sleep difficulties during the 12 months following transplant. In contrast, a sense of psychological well-being appears to be protective, with patients who report greater psychological well-being experiencing less sleep difficulty. The same pattern of relationships was seen in examining changes in depression, anxiety and well-being within individual participants using a within-subjects analysis that capitalized on the longitudinal study design and multiple assessment points. Here we saw that for individual participants, sleep disturbance was worst when anxiety and depression were most elevated, after adjusting for the effects of time since transplant. Findings also highlight the importance of a potentially protective psychological factor, having a sense of well-being. There is growing interest in measures of well-being among cancer survivors,9 and our results suggest that further attention to these protective factors may be an important avenue for assisting transplant recipients during the recovery process.
Participants who had elevated levels of IL-6 in systemic circulation reported greater sleep disturbance during the 6 months following transplant as compared with those with normal IL-6 levels. However, changes over time in IL-6 within individual participants from elevated to normal or vice-versa were not associated with changes in sleep, after accounting for the effects of time since transplant. This may have been because of the relative stability in IL-6 levels for most participants. Circulating levels of TNF-α were not associated with sleep disturbance. This study is the first that we are aware of to examine relationships between inflammatory markers and a comprehensive measure of sleep disturbance among HSCT recipients. Findings build upon a prior report by Wang et al.23 which found an association between HSCT symptoms and IL-6 during the initial month following transplant, showing that relationships between inflammation and sleep disturbance in particular can persist beyond the acute recovery period through 6 months post transplant. Inflammation related to tissue injury from conditioning regimens, the development of GVHD or infections may exacerbate sleep disturbance following HSCT. The lack of a relationship between sleep and TNF-α levels is consistent with prior literature, which has generally found IL-6 to be a more sensitive biomarker when examining relationships with behavioral factors such as sleep.23,41 TNF-α levels may not have been predictive because elevations may have been more transient and therefore less likely to have an impact. It is known that TNF-α is a very fast-responding cytokine, which tends to return to lower basal levels quickly, except in extreme inflammatory conditions such as sepsis.41,42
The current study is one of the first to use a prospective, longitudinal design to evaluate changes in sleep quality over time and sleep disturbance both pre- and post transplant. This approach enabled us not only to examine both the effects of individual differences in psychological indices and inflammatory markers but also the extent to which changes in sleep tracked changes in these measures over time within participants. Given that the patients were undergoing intensive treatments for potentially life-threatening cancers, there were some restrictions and limitations, including reliance on self-report assessments of sleep quality, rather than clinical diagnoses of insomnia. Future studies should also consider other measures of sleep–wake disturbance, such as wrist actigraphy or polysomnography. In addition, our capacity to generalize the conclusions to other populations is limited. Given the patients seen by our cancer center, there was not a wide range of racial/ethnic diversity. Finally, this is an observational study relying on correlations, and therefore we cannot determine with certainty the direction of the effects or causal mechanisms. Although our analyses used biobehavioral factors as the predictors in the models, sleep disturbance may in turn exacerbate depression and anxiety and may even alter circulating IL-6.19 Interventional study designs could help to tease apart the likely complex, bidirectional relationships.
Although survival rates have increased over the course of the previous decade, HSCT patients remain at risk for a host of medical and quality-of-life complications. Diminished sleep quality is a significant and persistent problem that can exacerbate other quality-of-life concerns and may even contribute to morbidity and mortality. The risk for sleep problems is highest in the early recovery period, and individuals with high levels of psychological distress and inflammation may be at greatest risk, highlighting important time points and targets for both screening and behavioral or pharmacological interventions targeting sleep concerns. The National Comprehensive Cancer Network Distress Thermometer is frequently employed in cancer centers and includes items pertaining to sleep, depression and anxiety, making this a useful initial screening tool.43 Other distress or depression screeners could also be utilized. With regard to interventions, although sleep medications are commonly employed, non-medication strategies may be more ideal given their efficacy, lack of side effects and growing evidence base in cancer populations. Cognitive-behavioral therapy for insomnia44 and bright light therapy for circadian rhythm disturbances45 are empirically supported treatments that are particularly promising for the HSCT setting. In addition to approaches focusing directly on sleep, interventions that alleviate anxiety and depression and promote psychological well-being may be important to consider as well.
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This work was supported by Grants R21 CA133343 and K07 CA136966 from the National Cancer Institute to ESC, KL2 RR0205012 from the National Center for Research Resources, P30 CA014520 from the UWCCC, and an award from the Forward Lymphoma Foundation.
The authors declare no conflicts of intrest.
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Nelson, A., Coe, C., Juckett, M. et al. Sleep quality following hematopoietic stem cell transplantation: longitudinal trajectories and biobehavioral correlates. Bone Marrow Transplant 49, 1405–1411 (2014). https://doi.org/10.1038/bmt.2014.179
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