Advances in hematopoietic cell transplantation (HCT) have led to a significant increase in survival for patients who undergo the procedure. Recipients of HCT have either an autologous (recipient receives his/her own stem cells) or allogeneic (recipient receives stem cells from a donor that is either related or unrelated) transplant. Despite promising outcomes, long-term sequelae for many allogeneic (allo) HCT recipients include chronic graft-versus-host disease (cGVHD). cGVHD is a serious condition that typically begins at least 100 days after a transplantation and produces a range of symptoms, including fatigue, joint pain, skin rashes, weight loss, and dry eyes or mouth, that reduce quality of life and threatens alloHCT survivorship.1,2 In the past 20 years, the prevalence of cGVHD has increased in accordance with rates of survival for alloHCT; indeed, in a recent review of 3 intervals (1995 to 1999, 2000 to 2003, and 2004 to 2007) with 26 563 patients who had either acute leukemia, chronic myeloid leukemia, or myelodysplastic syndrome, researchers found a significantly increased incidence of cGVHD (odds ratio, 1.19, P < .0001).2 According to a report by the Center for International Bone Marrow Transplant Research Late Effects Working Group, the increase in cGVHD may be a result of the increase in the number of individuals receiving alloHCT, such as older patients and acute GVHD survivors who go on to develop cGVHD; as well, fewer reported deaths within the first 100 days after transplantation have contributed to the increase in cGVHD.3 Treatment for cGVHD is currently limited to supportive therapy and high-dose steroids, which may lead to infection, hyperglycemia, and vascular damage with prolonged use.1 As a result of the limited treatment options and the chronic nature of cGVHD, researchers have renewed their focus on issues related to survivorship in patients who have undergone alloHCT and are examining the range of distressing symptoms that may delay healing in patients who develop cGVHD.
Although the mechanisms of cGVHD are still unclear, most studies have found immune and inflammatory perturbations, most notably increased pro-inflammatory cytokines in individuals who develop cGVHD.4 Over the past decade, research has demonstrated that individuals with cGVHD experience consistently high levels of physical, psychological, and social stress.5 However, there has been little integrated study of the biological, psychological, and social factors that may contribute to the inflammatory milieu. This is important as stress acts as a potent immunomodulator via multiple neuroendocrine pathways, which contribute to chronic inflammation, and has been associated with obesity, autoimmune diseases, and cancer.6,7 Recently, the psychoneuroimmunology model was adapted to describe the mechanisms by which psychological, social, and behavioral factors may impact health and well-being after HCT.8 Specifically, this model posits that psychosocial and behavioral factors activate stress systems (ie, hypothalamic-pituitary-adrenal axis and sympathetic nervous system pathways), causing the release of glucocorticoids and catecholamines and sympathetic innervation of the bone marrow.8 These mechanisms, in turn, result in a heightened inflammatory state that promotes further immunologic perturbations that contribute to the development and progression of cGVHD.8
Given the relatively new focus on survivorship issues in individuals receiving HCT and, in particular, the subset of individuals with cGVHD, there has been little research to examine the effect of health-promoting lifestyle behaviors on levels of perceived stress and inflammation. Although it is well established that maintaining a healthy lifestyle may reduce levels of perceived stress and enhance quality of life, relatively little is known about the lifestyle behaviors of individuals after receiving HCT, especially those diagnosed with cGVHD after alloHCT.9 In this secondary analysis of a cohort of individuals diagnosed with cGVHD, we examined potentially modifiable lifestyle behaviors hypothesized to correlate with inflammation and stress. The specific aims of this study are to examine (1) the levels of health-promoting lifestyle behaviors, perceived stress, and inflammation (cytokines and C-reactive protein [CRP]) of individuals diagnosed with cGVHD and (2) the associations among health-promoting lifestyle behaviors, perceived stress, and inflammation (cytokines and CRP) in individuals diagnosed with cGVHD. Examining these relationships may inform the development of interventions that can be self-implemented to improve the health outcomes of individuals with cGVHD.
This study used existing data from a previous study.10 A detailed description of patient characteristics and data collection methods has been reported in the original study of this sample.10 Briefly, participants were recruited from an urban, level 1 trauma center bone marrow transplant unit. This was a convenience sample that was recruited from all known alloHCT recipients receiving HCT at least 3 months before enrollment. After identification and discussion with the transplant team, potential participants were contacted and, if interested, a meeting was scheduled to discuss possible enrollment in the study. After informed consent was obtained, participants completed questionnaires and had a blood sample taken (less than 1 tablespoon) from an appropriate vein or venous access device.
The study visit, including the consent process, questionnaires, and specimen collection, took approximately 1 hour to complete. Study visits were conducted during a routine clinic visit. This study was approved by the institutional review board and written consent was obtained from all participants. A total of 24 adults were enrolled in this study.
Participants were considered eligible for the study if they were older than 18 years and diagnosed with cGVHD according to criteria proposed by the National Institutes of Health cGVHD Consortium Working Group. Diagnosis was verified by skin biopsy and clinical presentation for skin cGVHD or by clinical presentation, pulmonary function tests, and chest x-rays for lung cGVHD before study enrollment.11 In addition to the exclusion criteria presented in the parent study, participants were excluded from this analysis if they had a concurrent secondary cancer, a history of inflammatory diseases such as rheumatoid arthritis, or a diagnosis of current psychosis. All of the data used in this analysis were collected and processed for analyses at the time of the parent study. Samples were collected at a routinely scheduled clinic visit to reduce participant burden. Consent was given to obtain and analyze inflammatory markers as well as the health-promoting behavior questionnaire responses. This analysis included the complete panel of cytokines analyzed to ascertain unexamined associations with health-promoting behaviors and perceived stress. The conceptual model shown in the Figure was used to guide the proposed research study is based on the psychoneuroimmunological paradigm.8
Individual and Disease Factors
Data on individual factors and disease factors were collected by either chart review or patient report. Information collected included demographic information on age, race, ethnicity, and marital status. Other individual factors collected included type of cancer for which the individual received the alloHCT, donor characteristics, and functional status. Disease factors were related to cGVHD onset, the National Institutes of Health global rating, blood platelet count, and immunosuppressive therapy.
Health-Promoting Lifestyle Behaviors
The Health-Promoting Lifestyle Profile II (HPLP-II) was used to assess health-promoting lifestyle behaviors.12 The HPLP-II measures health-promoting behaviors, which are “conceptualized as a multidimensional pattern of self-initiated actions and perceptions that serve to maintain or enhance the level of wellness, self-actualization, and fulfillment of the individual.”12 The 52-item summated behavior rating scale uses a 4-point response scale to measure the frequency of self-reported health-promoting behaviors in the domains of health responsibility, physical activity, nutrition, spiritual growth, interpersonal relations, and stress management. A score is obtained by calculating a mean of all responses. Similarly, a score can be obtained for each of the domains. Higher scores indicate more frequent engagement in behaviors that promote a healthy lifestyle. Cronbach's α was .94 for the HPLP-II.10
Health responsibility involves engagement in healthy lifestyle behaviors and participation in care that supports personal health.13 There are a total of 9 items on the health responsibility subscale. Each item is rated 1 (never) to 4 (routinely engages in health responsibility behavior). A score is obtained by calculating the mean of the 9 items. Higher scores indicate engagement in activities supportive of healthcare decision making.13
Physical activity is the extent to which one engages in light, moderate, or vigorous activity and includes planned or coincidental activity.13 There are a total of 8 items on the physical activity subscale. Each item is rated 1 (never) to 4 (routinely engages in physical activity behavior). A score is obtained by calculating the mean of the 8 items. Higher scores indicate more frequent engagement in behaviors that promote physical activity.
Nutrition is defined as the knowledgeable selection and consumption of a balanced diet.13 There are a total of 9 items on the health responsibility subscale. Each item is rated 1 (never) to 4 (routinely engages in dietary behavior). A score is calculated by calculating the mean of the 9 items. Higher scores indicate engagement in healthy dietary behaviors.
Spiritual growth is the development of inner resources that allows one to “become something more by going beyond what one is currently.”13 In addition, it involves feeling harmony with the universe, a search for purpose and meaning, and setting lifetime goals.13 There are 9 items on the spiritual growth behavior subscale. Each item is rated 1 (never) to 4 (routinely engages in health responsibility behavior). A score is obtained by calculating the mean of the 9 items. Higher scores indicate engagement in spiritual growth behaviors.13
Interpersonal relations is the extent to which one uses communication to reach a level of intimacy within relationships, which involves using communication to reach a sense of intimacy within meaningful relationships.13 There are a total of 9 items on the health responsibility subscale. Each item is rated 1 (never) to 4 (routinely engages in interpersonal relationship behavior). A score is obtained by calculating the mean of the 9 items. Higher scores indicate engagement in behaviors that promote healthy interpersonal relationships.
Stress management relates to how a person identifies and uses resources to reduce or control tension.13 There are a total of 8 items on the stress management activity subscale. Each item is rated 1 (never) to 4 (routinely engages in physical activity behavior). A score is obtained by calculating the mean of the 8 items. Higher scores indicate engagement in behaviors that help reduce or control tension.13
The Perceived Stress Scale (PSS) is used to assess the degree to which individuals perceive life as stressful.14 This is a 10-item scale ranging from 0 (never) to 4 (very often) that measures how often individuals have perceived life as unpredictable, uncontrollable, and overloaded within the last month. Higher scores indicate higher levels of perceived stress. Cronbach's α was .78 for the PSS.15
In this study, blood was collected in a 3-mL ethylenediamineteraacidic tube and transported (on ice) to the research laboratory. The blood was centrifuged at 1030 rpm for 10 minutes at 4°C. Plasma was aliquoted to 3 microfuge tubes (500 μL each). Samples were stored in a −80°C freezer until they were processed for analysis.
The BioPlex (Bio-Rad) multiplex assay was used to analyze levels of serum interleukin (IL) cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, and IL-17), granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor, interferon-γ, monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1 (MIP-1), and tumor necrosis factor α. Bioplex allows the simultaneous measurement of multiple cytokines in a single biological sample.
Serum CRP levels were measured using ALPCO's (American Laboratory Products Company) high-sensitivity CRP enzyme-linked immunosorbent assay per manufacturer's protocol.
All data for this secondary analysis were examined to determine intrameasure missing items, implausible values, and distributional forms. Descriptive statistics (counts and percentages) were reported for categorical data. Means and standard deviations or medians and ranges were calculated for continuous variables depending on data distribution. Biologic data (cytokines and CRP) data were log transformed to meet the assumption of normality for the sample. To investigate associations among study variables, correlational testing was performed using Spearman correlation analysis after assessing for normality and linear relationships. All analyses were performed using SAS software version 9.3 (Cary, North Carolina). Given the exploratory nature of this study to examine yet unknown associations, the level of significance was set at .05.
Study Sample Characteristics
The demographic and disease characteristics of this sample are described in detail elsewhere.8 Briefly, the mean (SD) age of study participants was 53 (10) years, and most of the participants were white (87.5%) and female (58.3%). Most (85.8%) of participants had education beyond high school and reported being married or in a relationship with a significant other (79.2%). Most participants (29.2%) received a transplant to treat acute myeloid leukemia, followed by myelodysplastic syndrome (16.7%) and either chronic myeloid leukemia or multiple myeloma (12.5%). All participants (100%) were human leukocyte antigen matched. Most participants (79.2%) received stem cells from a relative. Also, most participants (63.6%) received stem cells from a donor of the same sex. Moderate to severe cGVHD was present in a large percentage (83.3%) of the sample, over half (62.5%) had 3 to 5 affected organs, and all participants had at least some functional impairment (score > 0) as measured by the Eastern Cooperative Oncology Group performance scale. More 80% of this sample had moderate to severe cGVHD and 92% of the sample was being treated with steroids.
Aim 1: Levels of Health-Promoting Lifestyle Behaviors, Stress, and Inflammation
The first aim of this study is to examine the levels of health-promoting lifestyle behaviors, stress, and inflammation of individuals diagnosed with cGVHD. Table 1 summarizes the frequency of participant engagement in health-promoting behaviors. Health-promoting lifestyle behavior scores were lowest on the activity subscale, followed by scores on the nutrition, stress management, and health responsibility subscales of the HPLP-II. Participants reported engaging in health-promoting lifestyle behaviors “sometimes” to “often” and spiritual growth and relationship behaviors “often” to “routinely.” Overall, participants reported engaging in health-promoting lifestyle behaviors near the “often” range; however, participants did not report “routinely” engage in any of the health-promoting lifestyle subscales assessed.
Table 1 also displays the scores for individual items on the PSS. Two items (item 4 and item 5) had a mean score greater than 3 on a scale of 0 to 4, with higher scores indicating greater negative feelings and perceived stress. Item 4 captured an individual’s confidence in handling personal problems and item 5 captured how often an individual felt that things were going well. In this study, respondents expressed the most positive feelings about the ability to control important things (mean [SD], 1.5 [0.9]) and overcome difficulties (mean [SD], 1.0 [1.0]). Levels of inflammatory markers are reported in Table 1. Individual cytokine levels were varied across the sample. The normal range of CRP is less than 1000 ng/mL in the general population. Participants in this sample had a mean CRP level that was more than 8 times higher than the established normal level.
Aim 2: Associations Among Health-Promoting Lifestyle Behaviors, Perceived Stress, and Inflammation
The second aim of this study was to examine the associations among health-promoting lifestyle behaviors, perceived stress, and levels of inflammation of individuals diagnosed with cGVHD. Associations among health-promoting lifestyle behaviors and perceived stress are described in Table 2. There was a significant negative association between spiritual growth and total perceived stress (r = −0.68, P = .0002) and a near significant association between relationship and perceived stress item 6 (r = 0.38; P = .06). There were no significant associations between other domains of health-promoting lifestyle behaviors or the combined domains of health-promoting lifestyle behaviors and total perceived stress.
There were significant associations among several domains of health-promoting lifestyle behaviors and several inflammatory markers (see Table 3) as well as between activity and cytokines (IL-2, IL-4, IL-5, IL-7, IL-10, IL-12, IL-13, IL-17, and granulocyte colony-stimulating factor). Results also revealed a significant negative association between nutrition (r = −0.49, P = .02) and CRP. Stress management was significantly related to cytokines IL-2 and MCP-1. The combined domains of health-promoting lifestyle behaviors were significantly related to MCP-1 (r = −0.50, P = .013).
There were no significant associations between total perceived stress and markers of inflammation in this sample. However, significant associations were noted among many items of the PSS and cytokine levels (see Table 4). In particular, item 3 of the PSS was significantly associated with cytokines IL-6; items 1, 5, and 9 of the PSS were significantly associated with cytokine IL-12; and items 2 and 6 of the PSS were significantly associated with cytokine MIP-1b.
This analysis examined health-promoting lifestyle behaviors, perceived stress, and markers of inflammation of a group of individuals diagnosed with cGVHD after alloHCT. Participants did not routinely engage in health-promoting lifestyle behaviors and reported higher levels of overall stress than normal controls. There were several significant associations noted among health-promoting lifestyle behaviors, perceived stress and inflammation in this sample of alloHCT survivors.
Overall, results indicated that individuals with cGVHD are not “routinely” engaging in health-promoting lifestyle behaviors. Indeed, lifestyle behaviors that enhance optimal nutrition, activity, and stress management were in the low range for the majority of the sample. This finding has been noted in other studies of HCT and other cancer conditions.15–17 Not surprisingly, levels of perceived stress (mean [SD], 13.5 [6.3]) in this sample were higher than the levels of perceived stress from the control group (mean [SD], 11.9 [6.9]) used by the developer of the tool from his study.14 Although the PSS scores in this study were numerically higher than those of the general population, we did not conduct a t test or other statistical analyses to determine significance.
One notable association in this study existed among health-promoting lifestyle behaviors, perceived stress, and markers of inflammation: spiritual growth was significantly inversely associated with perceived stress. Similar associations have been described in the literature among healthy adults, older adults with chronic illness, and cancer.18–20 However, there were no other significant associations among health-promoting lifestyle behaviors and perceived stress, a finding that is not consistent with the literature. One study found that sleep, social support, and self-care accounted for 39% of the variability of stress (P < .0001), whereas only 10% of the variability was due to demographic variables.21 Another study found that exercise was significantly related to perceived stress (P = .01) in a sample of working adults.22 This study demonstrated a significant reduction in stress among those individuals engaging in moderate to strenuous exercise. This is a consistent finding in the literature, with multiple studies demonstrating a decreased level of perceived stress related to exercise.23,24 For example, a recent study reports that perceived stress was associated with lower physical activity and intake of fruits, vegetables, fiber, and proteins as well as a higher consumption of starches.25 Furthermore, stress management strategies such as mindfulness interventions have been shown to reduce stress.26 The inconsistency between our findings and other, similar studies may be a result of the small sample size of this cohort, which perhaps did not allow us to adequately power our study to observe significance with this effect size. Also, some individuals had been diagnosed with cGVHD for several months, which may indicate a “normalization” of one's situation and lower perceived stress; however, no baseline or longitudinal data were collected to measure this assumption.
In this study, 4 domains of health-promoting lifestyle behaviors (activity, nutrition, stress management, and relationships) were associated with cytokine levels and CRP. Most notably, activity was positively associated with many proinflammatory and anti-inflammatory cytokines (see Table 4), perhaps because activity stimulates the immune system and the production of proinflammatory and anti-inflammatory cytokines to maintain homeostasis. This process serves to increase efficiency of the immune system to prevent chronic inflammation.27–29 Our results support the findings of other researchers, who have found negative correlations among exercise, white blood cell count, and levels of CRP, a measure of inflammation.30 It is possible that exercise influences the efficiency of the immune system, which may lead to a reduction of cGVHD symptoms and an increase in quality of life for individuals with cGVHD.31
Like activity, nutrition was also shown in this study to reduce inflammation, as indicated by lower levels of CRP in participants who reported a well-balanced diet. Boer et al. report high glycemic foods are associated with elevated levels of CRP and IL-6, IL7, and IL-18.8 This finding is consistent with studies that include participants with other chronic diseases such as diabetes; indeed, these studies have consistently found nutrition to be associated with markers.9,31,32
Our findings indicate that activity and nutrition may act independently to reduce levels of inflammation; thus, it is not surprising that participants who are active and eat a healthy diet demonstrate the lowest levels of inflammation. Indeed, during analysis of a cohort from The National Health and Nutrition Examination Survey (2005-2006), Loprinzi and Walker31 found that the combination of diet and exercise was significantly correlated with levels of inflammation. Incidents of cognitive and functional decline in older adults and cardiovascular events in diabetics were found to be 25% to 50% lower in individuals who were physically active.33
In this study, results demonstrated no significant associations between the total PSS score and markers of inflammation. This finding is inconsistent with a report on the state of the science regarding stress, inflammation, and cancer and could be explained by the small sample size and time since diagnosis, which varied from 3 months to 10 years.34 However, several items on the PSS, which was constructed as a measure of 3 distinct constructs (predictability, control, and ability to cope [how overloaded an individual feels]), were significantly related to markers of inflammation. For example, inflammatory marker IL-12, a pro-inflammatory cytokine, was associated with predictability and control items, indicating that individuals who feel a lack of control or unable to predict events experience higher levels of stress.35 Similarly, inflammatory marker MIP-1b, which induces the synthesis and release of IL-6, was associated with controllability and overload or burden, and IL-6, an indicator of perceived and chronic stress, was associated with 2 overload or burden items.36–39 These results are intriguing and perhaps constructs such as coping and self-efficacy need to be further explored in this unique chronic condition. Levels of selected markers of inflammation are reported elsewhere and demonstrate significance with cGVHD severity and symptoms of cGVHD.10 Indeed, it is possible that improving lifestyle behaviors may lead to decreased symptoms and increased quality of life for individuals with cGVHD.
Implications for Nursing
Nurses play a vital role as coordinators and providers of care for patients who have undergone alloHCT and have developed cGVHD. In addition to these accepted roles, nurses can help individuals engage in self-care strategies and educate individuals and caregivers about the contributions of health-promoting lifestyle behaviors to wellness. This care, in conjunction with follow-up care plans and coordination of medical care, may help patients with cGVHD improve their survivorship and overall quality of life.
As individuals are living longer with cancer owing to advances in HCT and other treatment options, researchers need to focus on survivorship issues that significantly affect individuals diagnosed with cancer, their families, and their caregivers. There were several associations noted among health-promoting lifestyle behaviors, perceived stress, and markers of inflammation in this group of individuals with cGVHD. Findings indicate the usefulness of examining these potentially modifiable variables as part of future interventions to mitigate the distress of cGVHD.
The sample in this study is heterogeneous and the inclusion and exclusion criteria are not restrictive. This was debated among the investigators. There is a knowledge gap about cGVHD and the variables of this study. The criteria were open to be as inclusive as possible for study enrollment. The investigators recognize that this study is not powered to detect small to moderate effect sizes; however, this was an exploratory study to provide initial information regarding important factors that may be modified for improved outcomes for individuals with cGVHD. Another limitation was the timing of the blood draws. As cytokine levels fluctuate and may show elevations at different times throughout the day (as in circadian rhythms), there is a potential for associations to also change depending on timing of the blood draw; however, the associations found in this study suggest looking into these associations further and could provide useful information for informing future studies aimed at linking health behaviors with stress and inflammation. We understand the risk for type 1 errors due to multiple statistical tests; however, there were several significant findings that provide information that is thought provoking and warrant further investigation. Investigation of cGVHD has many challenges, including the mainstay treatment with high-dose steroids; however, cGVHD is an immune complication and nearly all of the participants were receiving steroids thereby mitigating a steroid effect for analysis.
Given these promising findings, further research is needed to better understand these associations. Longitudinal studies may provide useful information regarding the temporal nature of these associations and about the appropriate timing of interventions. In addition, a greater understanding of potentially modifiable, health-promoting behaviors may lead to the development of self-management strategies that can mitigate the effects of cGVHD and improve the quality of life of individuals diagnosed with cGVHD. Interventions may include strategies to improve nutrition, activity, and stress management, which can lead to decreased inflammation and reduce comorbidity conditions such as metabolic syndrome and potentially decrease disease recurrence.
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