Article

Symptoms, Cytokines, and Quality of Life in Patients Diagnosed With Chronic Graft-Versus-Host Disease Following Allogeneic Hematopoietic Stem Cell Transplantation

Debra Lynch Kelly

Debra Lyon

Suzanne A. Ameringer

Ronald K. Elswick

chronic graft-versus-host disease, symptoms, cytokines, inflammation, C-reactive protein, quality of life, cancer, bone marrow transplantation
ONF 2015, 42(3), 265-275. DOI: 10.1188/15.ONF.265-275

Purpose/Objectives: To describe associations among symptoms, cytokines, and quality of life (QOL) of patients with chronic graft-versus-host disease (cGVHD).

Design: Prospective, cross-sectional, cohort.

Setting: The bone marrow transplantation unit at a National Cancer Institute–designated cancer center in Virginia.

Sample: 24 adults diagnosed with cGVHD.

Methods: Data were collected for demographic factors, symptoms, and QOL from medical record and validated questionnaires. Serum was analyzed for cytokine levels.

Main Research Variables: cGVHD, symptoms, cytokines, C-reactive protein, and QOL.

Findings: Participants reported multiple, concurrent symptoms. Cytokine levels were higher in participants with symptoms versus those without symptoms. Cytokine interleukin-6 correlated with lack of energy and dry mouth. Negative correlations were noted between QOL and symptoms.

Conclusions: Findings demonstrated multiple concurrent symptoms present in this sample and significant relationships among symptoms, cytokines, and QOL.

Implications for Nursing: cGVHD is a serious condition affecting QOL in many individuals after bone marrow transplantation for many different cancers. Results from this pilot study indicate that patients experience multiple symptoms, including sexual dysfunction, that adversely affect QOL. Better understanding of the interrelated symptoms of cGVHD and the biomarkers associated with these symptoms may lead to targeted symptom management interventions.

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    Hematopoietic cell transplantation (HCT) is the only curative therapy for many patients with hematologic, metabolic, and immunologic disorders. The number and efficacy of transplantations has increased. The goal of HCT is to cure the underlying disease by replacing destroyed, unhealthy cells with healthy stem cells (Majhail et al., 2012). With an increase in the number of allogeneic HCTs and a decrease in mortality because of earlier transplantation, a resultant shift of focus to survivorship issues has occurred (Flowers et al., 2008). A major survivorship issue for patients receiving allogeneic HCT is the development of graft-versus-host disease (GVHD). About 40%–80% of long-term survivors of HCT experience chronic GVHD (cGVHD), which is a serious and often life-threatening condition. cGVHD may carry a high symptom burden for patients that may negatively affect functional status and quality of life (QOL) (Antin, 2002; Baird & Pavletic, 2006).

    The incidence of cGVHD is rising as an increasing number of transplantations are being performed, particularly in older patients (Hahn et al., 2013; Veltri et al., 2013). Adequate assessment and targeted therapeutic interventions to mitigate distressing symptoms and long-term complications of this chronic condition are needed (Pérez-Simón, Sánchez-Abarca, Díez-Campelo, Caballero, & San Miguel, 2006). In addition, the identification of biomarkers associated with cGVHD is a priority for diagnosing and monitoring progression of cGVHD, as well as evaluating the efficacy of new therapies (Schultz et al., 2006).

    Symptom management is a major concern for patients experiencing cGVHD (Lee, Cook, Soiffer, & Antin, 2002; Pérez-Simón et al., 2006). However, a gap in the literature remains that establishes the relationship between symptoms and QOL in individuals with cGVHD (Lynch Kelly, 2014). Little study has been performed on the relationship between symptoms and biologic markers of cGVHD despite that the interplay between biologic markers and symptoms may affect the frequency and severity of symptoms experienced by patients with cGVHD (Lynch Kelly, 2014). The purpose of this study was to describe levels of symptoms, inflammation (cytokines and C-reactive protein levels), and QOL of patients diagnosed with cGVHD following allogeneic HCT and to examine the relationships among these variables.

    Literature Review

    HCT is a standard treatment for many hematologic disorders, including acute leukemia, chronic leukemia, multiple myeloma, and myelodysplastic syndrome (Pidala, 2011). A 165% increase has occurred in the number of allogeneic HCTs from 1994–2005, and survival rates of more than 100 days after HCT have increased about 86% (Hahn et al., 2013). This increase in the use of HCT is partially related to advances in conditioning regimens with reduced intensity (known as a mini-transplantation), involving lower doses of chemotherapy and radiation and allowing HCT for individuals who may have once been ineligible (Hahn et al., 2013). Although notable survival gains have resulted from HCT, cGVHD remains one of the greatest issues for late-term mortality and morbidity. cGVHD is a serious long-term complication following allogeneic HCT, marked by immune dysregulation and debilitating clinical sequelae (Pérez-Simón et al., 2006). Manifestations of cGVHD usually appear several months after transplantation. Consequences associated with cGVHD include scleroderma, destruction of saliva and tear ducts, and liver and pulmonary dysfunction (Filipovich et al., 2005).

    Acute GVHD usually appears within the first 100 days post-transplantation and involves different immune cell subsets and different cytokine profiles than cGVHD (Ratanatharathorn, Ayash, Lazarus, Fu, & Uberti, 2001). Acute GVHD is speculated to involve alloreactive memory T cells in donor cells. In contrast, symptoms of cGVHD usually occur 100 days or more post-transplantation. To date, the pathobiology of cGVHD is not well known (Pidala, 2011). Although the exact cause of cGVHD is unknown, cGVHD is speculated to involve mechanisms associated with proliferation and exaggeration of inflammation, as occurs with other autoimmune disorders (Baird & Montine, 2008; Bazzichi et al., 2007; Klimiuk, Sierakowski, Domyslawska, & Chwiecko, 2011). Because of the complexity of cGVHD and the need to standardize classification of cGVHD, the National Institutes of Health (NIH) cGVHD consortium developed criteria for distinguishing cGVHD by type of onset, severity of presentation, and number of organs involved (Filipovich et al., 2005). Risk factors for cGVHD include a history of acute GVHD, transplantation conditioning, donor match, and underlying disease process prior to transplantation (Flowers et al., 2011; Remberger et al., 2002). Any of the body systems can be affected by cGVHD. Cutaneous, ocular, and oral cGVDH are the most frequently occurring, but pulmonary and hepatic cGVHD have the highest mortality rates (Pidala et al., 2012).

    Understanding symptoms of cGVHD, including the biologic underpinnings of symptoms, is a fundamental step toward managing symptoms effectively. Knowing the relationships among symptoms and QOL may provide insight about the impact of symptoms on QOL for patients with cGVHD. Therefore, the specific aims of this study were (a) to examine the levels of symptoms (cGVHD-specific, general, and cluster symptoms [pain, depression, and fatigue]); inflammation, including cytokines (interleukin [IL]-1b, IL-6, IL-10, tumor necrosis factor [TNF], and interferon-g) and C-reactive protein (CRP); and QOL in patients diagnosed with cGVHD and (b) to assess the relationships between and among symptoms (top three general symptoms and cluster symptoms), inflammation, and QOL in individuals with cGVHD. Knowledge about symptoms and biologic mechanisms (e.g., increased systemic inflammation expression) involved in symptom manifestation is important for the development and testing of novel interventions to successfully manage symptoms and improve QOL for patients with cGVHD.

    An adaptation of the Theory of Unpleasant Symptoms (TOUS) (Lenz, Suppe, Gift, Pugh, & Milligan, 1995) provided the theoretical perspective to explore the relationships among symptoms, inflammation, and QOL in patients diagnosed with cGVHD. The TOUS assumes commonalities among symptoms while exhibiting uniqueness (Lenz et al., 1995). The TOUS was modified (see Figure 1) to portray the biobehavioral perspective used to examine the specific aims of this study. Biobehavioral research assumes that biology and behavior are inextricably linked, necessitating examining biologic correlates with behavioral manifestations.

    Methods

    Sample and Setting

    This study used a prospective, cross-sectional, correlational design. Participants were recruited from a bone marrow transplantation (BMT) unit at Virginia Commonwealth University Massey Cancer Center in Richmond, an urban National Cancer Institute (NCI)–designated comprehensive cancer center with continued NCI funding since 1975. Patients were eligible for participation if they were aged 18 years or older, had a diagnosis of cGVHD, and could speak English. Patients were ineligible for participation if they had begun taking antidepressants within the past 30 days, were pregnant, or were incarcerated.

    Procedure

    This study was approved by Virginia Commonwealth University Massey Cancer Center Protocol Review Monitoring Committee and the institutional review board at Virginia Commonwealth University. Patients were referred to the study by the transplantation center’s medical director in consultation with other attending physicians and clinical coordinators. Written consent was obtained from all participants. Individual and disease factors were collected from the medical record and self-report by participants. Severity of cGVHD was obtained using standard criteria based on evaluation of organ systems in accordance with the NIH global rating scale (Filipovich et al., 2005). Symptom and QOL data were collected by patient self-report. A blood draw for measures of inflammatory cytokines and CRP was collected by the clinic nurse via venipuncture or a venous access device at a regularly scheduled clinic visit. Study visits took about one hour to complete, and participants received a $25 Visa card after completing the study.

    Measures

    All individual and disease factors were collected by chart review and patient report. Information collected included demographic information on age, race, ethnicity, and marital status. Other individual factors collected included type of cancer, donor characteristics, and functional status. Disease factors included date of cGVHD onset, NIH global rating, blood platelet and hemoglobin counts, and immunosuppressive therapy.

    The Lee cGVHD Symptom Scale (Lee et al., 2006) consists of seven subscales (skin, eye and mouth, breathing, eating and digestion, muscles and joints, energy, and mental and emotional), each based on the body system that may be affected by cGVHD. Items are rated using a five-point Likert-type scale, with higher scores indicating a greater level of the symptom. A summary score is created by linearly transforming the mean of all items to a 0–100 scale. This measure has demonstrated Cronbach alphas ranging from 0.79–0.9 and has good convergent validity (Lee et al., 2006). The Cronbach alpha for this study was 0.79.

    The Memorial Symptom Assessment Scale (MSAS) was used to assess dimensions (frequency, severity, and distress) of 32 prevalent physical and psychological symptoms (Portenoy et al., 1994). Each item is assessed for the presence or absence of a particular symptom during the past week and uses a four-point Likert-type scale to score each dimension. An average total symptom score is calculated based on the scale, with higher scores indicating higher symptom presentation. This measure has demonstrated Cronbach alphas ranging from 0.76–0.88 (Chang, Hwang, Feuerman, Kasimis, & Thaler, 2000; Portenoy et al., 1994). The Cronbach alpha for this study was 0.89.

    The Brief Pain Inventory (BPI) was used to assess pain severity and interference within the past 24 hours (Cleeland, 2009). Each item is rated on an 11-point Likert-type scale, with higher scores indicating greater levels of pain. A mean score is calculated for each subscale and the total measure. Fifty percent of the questions must be answered to calculate a score. The measure has demonstrated Cronbach alphas ranging from 0.8–0.87 for pain severity items and from 0.89–0.92 for interference items (Cleeland, 2009). The Cronbach alpha for this study was 0.95.

    The depression subscale of the Hospital Anxiety and Depression Scale (HADS) was used to assess depressive symptoms (Zigmond & Snaith, 1983). The depression subscale is comprised of seven items. Each item is rated on a four-point Likert-type scale, with higher scores indicating a greater level of the symptom. The score is the sum of all items for the subscale. The measure has demonstrated Cronbach alphas ranging from 0.82–0.9 (Mykletun, Stordal, & Dahl, 2001). The Cronbach alpha for this study was 0.77.

    The Brief Fatigue Inventory (BFI) was used to assess fatigue severity and interference during the past 24 hours (Mendoza et al., 1999). Each item is rated on an 11-point Likert-type scale, with higher scores indicating greater levels of fatigue. A mean score is calculated for each subscale and the total measure (Mendoza et al., 1999; Seyidova-Khoshknabi, Davis, & Walsh, 2011). The measure has demonstrated Cronbach alphas ranging from 0.95–0.96 (Mendoza et al., 1999, Mendoza, Mayne, Rublee, & Cleeland, 2006). The Cronbach alpha for this study was 0.93.

    Blood was collected in a 3 ml ethylenediaminetetraacetic acid tube and transported on ice to the research laboratory. The blood was centrifuged at 1,030 rpm for 10 minutes at 4°C. Plasma was aliquoted to three microfuge tubes (500 mcl each), and samples were stored in a –80°C freezer until processed for analysis. Serum cytokine levels were analyzed using the Bio-Plex® multiplex assay, which allows for the simultaneous measurement of multiple cytokines in a single biologic sample. Dual-laser technology allows for the detection of multiple analytes across numerous fluorescent spectra, which provides accurate quantification of cytokines. Serum CRP levels were measured using the American Laboratory Products Company high-sensitivity CRP enzyme–linked immunosorbant assay per manufacturer’s protocol.

    The Functional Assessment of Cancer Treatment–BMT (FACT-BMT) was used to measure QOL (McQuellon et al., 1997). The FACT-BMT measures multiple dimensions of QOL. It consists of the 27-item FACT–General (G) and a 12-item BMT subscale. The FACT-G assesses physical well-being (seven items), social and family well-being (six items), emotional well-being (six items), and functional well-being (seven items). The trial outcome index is the sum of the physical and functional well-being and the BMT subscales. Each item is rated on a five-point Likert-type scale, with higher scores indicating more truth to an item during the past week (Lau et al., 2002). To produce the subscale score, the sum of the item scores are multiplied by the number of items in the subscale, then divided by the number of items answered. At least 50% of the items must be answered to score this measure. The total FACT-BMT score is the sum of all subscales. Higher scores indicate greater QOL. The measure has demonstrated Cronbach alphas of 0.84 for physical well-being, 0.69 for social and family well-being, 0.67 for emotional well-being, and 0.78 for functional well-being. The Cronbach alpha was 0.88 for the FACT-G and 0.89 for the FACT-BMT (Kopp et al., 2000; Lau et al., 2002). The Cronbach alpha for the FACT-BMT for this study was 0.91.

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    Data Analysis

    Descriptive statistics were used to characterize the individual and disease factors of the sample and to profile symptoms, cytokines, and QOL. Frequencies and percentages were used to describe categorical variables. Means and standard deviations or median and ranges were used to describe continuous variables. Student’s t tests were performed to compare cytokine and CRP levels for each item on the MSAS between individuals who reported having the symptom and individuals who did not report having the symptom. Biologic variables were log transformed to meet the statistical assumption of normality. Specificity was evaluated by visually inspecting the dot plot for spectral overlap of biologic data. To test associations among symptoms, cytokines, CRP, and QOL, Pearson product-moment correlation coefficient was used for all pairwise combinations of variables displaying normal distribution. Spearman’s rank correlation coefficient was used to test associations for skewed data. All statistics were calculated using JMP®, version 10.0. Alpha was set at 0.05 for the analysis.

    Results

    Examining Levels of Symptoms

    The first aim of this study was to examine the levels of symptoms (cGVHD-specific, general, and cluster symptoms [pain, depression and fatigue]); inflammation, including cytokines (IL-1b, IL-6, IL-10, TNF, and interferon-g) and CRP; and QOL in patients diagnosed with cGVHD. Individual and disease factors are detailed in Table 1. The majority of participants were female (58%), Caucasian (88%), and married (79%). Half of the participants were not employed. The median age of participants was 54 years, and age ranged from 28–73 years. The median time from transplantation to cGVHD diagnosis was 191 days (range = 123–702). The mean hemoglobin level was 12.5. All participants in this study had a cancer diagnosis for which they received a BMT as a curative measure. The largest percentage (29%) of participants had a diagnosis of acute myelogenous leukemia. Most participants received stem cells from a relative (79%) and were gender matched (59%). Based on criteria from the Eastern Cooperative Oncology Group, functional impairment (score of greater than 0) was noted in 92% of participants.

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    Most participants had multiple cGVHD symptoms (see Table 2). The most frequently reported dermatologic symptom was change in skin color (50%). Dry eyes was the most reported symptom from the eyes and mouth subscale symptom (83%). About half (49%) of participants were either “quite a bit” or “extremely bothered” by dry eyes, and 75% were bothered by having to use eye drops frequently. Shortness of breath was reported by 50% of participants. Two participants reported being “extremely” bothered by the need to use supplemental oxygen. All participants were able to receive nutrition without any IV or feeding tube supplementation. Being bothered by limited joint movement and “aches” was reported by 50% of participants. Loss of energy was reported by 79% of participants, and the need to sleep more was bothersome for 67% of participants. Difficulty sleeping was the most reported symptom (58%) on the mental and emotional subscale.

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    Most participants also reported multiple general symptoms (see Table 3). The most frequently reported symptom was lack of energy (83%), followed by dry mouth (67%). Among those experiencing the symptom, the most often reported symptoms were dry mouth and lack of appetite. The most severe symptoms were pain and sexual dysfunction, and the most distressing symptoms were sexual dysfunction and lack of energy.

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    The majority of participants (54%) reported having pain, and about half (46%) reported interference with activity because of pain. Ninety-six percent of participants reported having some depressive symptoms. Most participants (88%) reported fatigue, and the same high percentage reported interference with daily activity because of fatigue (see Table 4).

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    Serum cytokine levels were obtained for all participants (N = 24). Individual cytokine levels varied among participants; however, the median scores for IL-10 (24), TNF-alpha (27), and interferon-g (126.6) appear to be above established norms for these cytokines (see Table 5). Serum CRP levels were reported for 22 participants. Two participants had values that were out of range. Most participants (n = 21) had CRP levels above the normal range of less than 1,000 ng/ml, with a reported median level for the group of greater than 6,000 ng/ml. Only one participant had a level within the normal range. In addition, participants with moderate or severe cGVHD had higher levels of CRP than those with only mild cGVHD. Cytokine levels varied among participants.

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    The FACT-BMT scores demonstrated impaired QOL for many participants (see Table 6). The functional well-being subscale had the lowest mean of all scales measured by the FACT-BMT, followed by the physical well-being subscale. The trial outcome index subscale score was about 72% of the total physical and functional well-being. The ranges for all scales were varied, with some participants experiencing decreased QOL on all scales.

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    Associations Among Symptoms, Cytokines, and Quality of Life

    The second aim of this study was to examine the relationships between and among symptoms (top three general symptoms and cluster symptoms), inflammation, and QOL in individuals with cGVHD. Six symptoms (i.e., pain, lack of energy, dry mouth, difficulty sleeping, shortness of breath, and sexual dysfunction) were identified by the MSAS that were present in more than 30% of participants, with a total mean score of greater than 2 out of 4. Significant correlations were noted among the MSAS items pain, lack of energy, dry mouth, and sexual dysfunction. The MSAS pain item significantly correlated with the BPI total pain score (r = 0.78, p < 0.01). The MSAS lack of energy item significantly correlated with the MSAS items dry mouth (r = 0.48, p = 0.02) and sexual dysfunction (r = 0.53, p < 0.01). The MSAS item lack of energy also showed significant correlations with cluster symptoms in the HADS depression subscale (r = 0.65, p < 0.01) and the BFI total fatigue score (r = 0.78, p < 0.01). The MSAS sexual dysfunction item significantly correlated with the BFI severity subscale (r = 0.43, p = 0.03). Dimensions of cluster symptoms demonstrated some significant correlations with each other. The BPI did not demonstrate significant correlations with the BFI. The HADS depression subscale demonstrated significant positive correlations with the BPI interference subscale and all scales of the BFI.

    Multiple correlations were found among levels of inflammation and measures of symptoms. Cytokine IL-1b had significant positive correlations with TNF (r = 0.78, p < 0.01), interferon-g (r = 0.97, p < 0.001), IL-6 (r = 0.44, p = 0.031), and IL-10 (r = 0.79, p < 0.001). Cytokine IL-6 showed significant correlations with interferon-g (r = 0.58, p < 0.01), the MSAS item lack of energy (r = 0.42, p = 0.04), the MSAS item dry mouth (r = 0.42, p = 0.04), and near significance with the emotional well-being subscale (r = –0.4, p = 0.05). Cytokine IL-10 showed significant positive correlations with interferon-g (r = 0.78, p < 0.01), TNF (r = 0.82, p < 0.01), and the MSAS item difficulty sleeping (r = 0.43, p = 0.03). TNF was significantly correlated with interferon-g (r = 0.73, p < 0.01). CRP was significantly correlated with the social and family well-being subscale (r = –0.56, p < 0.01) and was nearing significance with the MSAS item sexual dysfunction (r = 0.41, p = 0.05).

    In a comparison of participants with and without reported symptoms, participants reporting lack of energy had significantly elevated (difference of 2.23, standard error [SE] = 0.98, 95% confidence interval [CI] [0.19, 4.27]) serum levels of IL-6 compared to individuals who did not report lack of energy (df = 22, t = 2.07, p = 0.03). Participants reporting problems with urination had significantly higher (difference of 1.81, SE = 0.73, 95% CI [0.3, 3.31]) serum levels of IL-1b compared to individuals who did not report problems with urination (df = 22, t = 2.07, p = 0.02). Participants reporting swelling of arms and legs had significantly lower (difference of 1.18, SE = 0.54, 95% CI [0.06, 2.3]) of serum IL-10 compared to individuals who did not report swelling of arms and legs (df = 22, t = 2.07, p = 0.04).

    Significant correlations were found among QOL and pain, as well as depression and fatigue. The MSAS pain item significantly correlated with the physical well-being subscale (r = –0.57, p < 0.01). The MSAS item lack of energy showed significant correlations with the physical well-being subscale (r = –0.7, p < 0.01), the functional well-being subscale (r = –0.53, p < 0.01), the BMT subscale (r = –0.71, p < 0.01), the FACT-G subscale (r = –0.64, p < 0.01), and the FACT-BMT (r = –0.68, p < 0.01). The MSAS dry mouth item correlated to the BMT subscale (r = –0.55, p < 0.01), the trial outcome index subscale (r = –0.41, p = 0.04), and the FACT-BMT (r = –0.42, p = 0.04). The MSAS sexual dysfunction item correlated with the social and family well-being subscale (r = –0.44, p = 0.03) and the BMT subscale (r = –0.44, p = 0.03). Cluster symptoms of pain, depression, and fatigue showed significant correlations with the FACT-BMT and the subscales of FACT-G, trial outcome index, and BMT.

    Discussion

    This study examined the levels of symptoms, inflammation, and QOL, as well as associations among these variables in a sample of patients diagnosed with cGVHD following allogeneic HCT. A high number of psychological and physical manifestations of symptoms that were associated with cGVHD were demonstrated in this sample.

    In this study, the most pronounced symptoms were dry mouth, difficulty sleeping, shortness of breath, and sexual dysfunction. Dry mouth was reported among participants with and without oral cGVHD. Certain medications and treatments can cause dry mouth. Dry mouth can cause serious health issues, such as an increased number of dental carries, and creates an environment for invasion of opportunistic microorganisms (Visvanathan & Nix, 2010). A positive association was found between dry mouth and inflammatory marker IL-6, which has been associated with Sjögren’s syndrome, a complication of inflammatory cell infiltration of the lacrimal and salivary ducts, manifesting as dryness of the eyes and mouth (Ratanatharathorn et al., 2001). Secondary Sjögren’s syndrome may be a clinical sequela of cGVHD (Kawanami et al., 2012). This association supports findings by Fall-Dickson et al. (2010), identifying IL-6 as a candidate biomarker for oral cGVHD. The significant correlation between dry mouth and lack of energy, as well as a negative trend between dry mouth and QOL, warrant further exploration of these findings. Shortness of breath was reported among all participants with pulmonary cGVHD regardless of cGVHD severity.

    Pulmonary cGVHD carries a higher rate of mortality than cGVHD of other body systems (Gazourian et al., 2014). Careful attention to the respiratory status of patients, including assessment of shortness of breath, is essential for early detection of pulmonary complications. After allogeneic HCT, more frequent monitoring may be indicated for individuals with dyspnea. Strategies to alert providers to a decline in pulmonary function earlier than conventional practice could lead to earlier interventions that may result in sustaining acceptable pulmonary function (Stadler et al., 2009).

    Another notable symptom of cGVHD was sexual dysfunction in men and women. Sexual dysfunction among individuals with cGVHD has focused primarily on women with vaginal cGVHD. Advancements have been made in treatments and strategies to mitigate this symptom; however, it remains problematic. In a study of 23 women diagnosed with genital cGVHD, 21 women were unable to remain sexually active because of complications such as pain, scarring, and strictures (Stratton et al., 2007). In the current study, of the 11 participants reporting sexual dysfunction, two of seven female participants were diagnosed with vaginal cGVHD. Therefore, this appears to be an issue to assess for all individuals with cGVHD (Wong et al., 2013). To date, little study has been done on sexual dysfunction in men with cGVHD.

    Pain, depression, and fatigue are established in the literature as being among the most common symptoms of patients with cancer. Significant positive correlations were demonstrated among this cluster of symptoms in this sample. This finding suggests that further study of this cluster in larger samples is indicated.

    Cytokines play a major role in influencing and regulating inflammatory responses. Dysregulation of cytokines has been associated with autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus (Kishimoto, 2010; Munroe et al., 2014). Significant correlations were found among cytokines IL-1b, IL-6, IL-10, and interferon-g. This finding is consistent with the cytokine pathways (Kishimoto, 2010). A significant increase in serum IL-6 levels between patients with and without lack of energy was found; however, no difference was noted in IL-6 levels of patients with mild, moderate, or severe cGVHD. A study conducted by Rohleder, Aringer, and Boentert (2012) found increased IL-6 levels in individuals with impaired sleep and fatigue. The positive correlations among symptoms and cytokines IL-6, IL-10, and CRP merit examination in a larger sample.

    The National Institute of Nursing Research (2011) recognizes the negative impact that symptoms have on QOL and supports research to improve understanding symptoms and the biologic mechanisms underlying symptoms, the goal of which is to improve QOL through better symptom management. In studies of patients who received HCT, patients without cGVHD one to two years following HCT did not report having impaired QOL, whereas patients with cGVHD reported QOL scores below that of population norms and other patients with cancer (Baker & Fraser, 2008; Fall-Dickson et al., 2010; Webster, Cella, & Yost, 2003). Some participants in the current study had QOL scores that were below general U.S. population and cancer population normative values. Although this study reports mean QOL scores similar to U.S. population normative values, significant negative correlations were noted among symptoms and QOL. Severity of cGVHD and symptoms have demonstrated a negative correlation to QOL (Pidala et al., 2011, 2012). Findings of the significant negative correlations among symptoms and QOL suggest that symptoms may be a predictor of QOL outcomes, but this needs to be examined further.

    Limitations

    The current study was limited by small sample size and lack of a comparison group. This study was conducted at a single site, limiting the number of participants eligible for this study. In addition, the study was conducted at a long-term follow-up clinic. As such, patients are monitored closely and consistently for complications and may receive intervention earlier and more frequently than individuals in other institutions that perform BMT without a long-term follow-up clinic. This may partially explain the low pain scores and higher mean QOL scores noted in this study. No eligibility criteria were set for the length of time since diagnosis, but this was captured as an individual and disease factor. In addition, the length of time that participants had been living with cGVHD was highly varied. Some participants may have adapted to their symptoms over time. The cross-sectional design does not permit the examination of changes over time.

    Implications for Nursing Practice

    cGVHD is a serious condition that affects QOL in many individuals after BMT for hematologic and other types of cancer. Results from this pilot study indicate that patients experience multiple symptoms, including sexual dysfunction, that adversely affect QOL. By thoroughly assessing symptoms, nurses are poised to advocate for adequate management of symptoms for patients with cGVHD that may otherwise go unreported or unnoticed. Measures may include coordination for proper referral and treatment for individuals who are experiencing sexual dysfunction.

    Fatigue was noted more than any other symptom in this study and was significantly negatively associated with QOL. Participants with fatigue had significantly elevated levels of IL-6. Education about fatigue and management strategies to combat fatigue may be crucial for these patients because mitigating fatigue may increase QOL and decrease inflammation for these patients.

    Other implications for nursing include anticipatory guidance for individuals and caregivers about the potential to experience several symptoms and the necessity to report symptoms to healthcare providers when they are first occurring and not delay treatment. One symptom may potentiate others, and a multiplicative effect could occur on symptoms and inflammation. Better understanding of the interrelated symptoms present in individuals with cGVHD and biologic mechanisms associated with these symptoms may lead to targeted symptom management interventions.

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    Conclusion

    The findings of this study provide a profile of the symptoms, inflammation, and QOL of patients diagnosed with cGVHD and associations among those variables. Evidence of associations were noted among symptoms and inflammation, and significant negative associations were noted among symptoms and QOL. Further examination of these associations should be tested using a larger sample with a longitudinal design to better understand the effect of time on these relationships and the impact of the symptom trajectory on QOL. A larger sample with comparison group would be useful to compare levels of symptoms and biologic markers between groups, with the possibility of stratification by those with high levels of symptoms. The presence of symptoms that individuals with cGVHD experience emphasizes the significance for clinical evaluation of symptoms in this population and draws attention to existent relationships among symptoms, inflammation, and QOL. Further exploration of these relationships is pivotal in understanding the interplay among symptoms and inflammation and their impact on QOL, and is essential to developing targeted interventions aimed at mitigating symptoms of cGVHD.

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    Baird, G.S., & Montine, T.J. (2008). Multiplex immunoassay analysis of cytokines in idiopathic inflammatory myopathy. Archives of Pathology and Laboratory Medicine, 132, 232–238.

    Baird, K., & Pavletic, S.Z. (2006). Chronic graft versus host disease. Current Opinion in Hematology, 13, 426–435. doi:10.1097/01.moh.0000245689.47333

    Baker, K.S., & Fraser, C.J. (2008). Quality of life and recovery after graft-versus-host disease. Best Practice and Research in Clinical Haematology, 21, 333–341. doi:10.1016/j.beha.2008.03.002

    Bazzichi, L., Rossi, A., Massimetti, G., Giannaccini, G., Giuliano, T., De Feo, F., . . . Bombardieri, S. (2007). Cytokine patterns in fibromyalgia and their correlation with clinical manifestations. Clinical and Experimental Rheumatology, 25, 225–230.

    Chang, V.T., Hwang, S.S., Feuerman, M., Kasimis, B.S., & Thaler, H.T. (2000). The Memorial Symptom Assessment Scale Short Form (MSAS-SF): Validity and reliability. Cancer, 89, 1162–1171. doi:10.1002/1097-0142(20000901)

    Cleeland, C.S. (2009). The Brief Pain Inventory: User guide. Retrieved from http://www.mdanderson.org/education-and-research/departments-programs-a…

    Fall-Dickson, J.M., Mitchell, S.A., Marden, S., Ramsay, E.S., Guadagnini, J.P., Wu, T., . . . Pavletic, S.Z. (2010). Oral symptom intensity, health-related quality of life, and correlative salivary cytokines in adult survivors of hematopoietic stem cell transplantation with oral chronic graft-versus-host disease. Biology of Blood and Marrow Transplantation, 16, 948–956. doi:10.1016/j.bbmt.2010.01.017

    Filipovich, A.H., Weisdorf, D., Pavletic, S., Socie, G., Wingard, J.R., Lee, S.J., . . . Flowers, M.E. (2005). National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biology of Blood and Marrow Transplantation, 11, 945–956. doi:10.1016/j.bmt.2005.09.004

    Flowers, M.E., Apperley, J.F., van Besien, K., Elmaagacli, A., Grigg, A., Reddy, V., . . . Greinix, H.T. (2008). A multicenter prospective phase 2 randomized study of extracorporeal photopheresis for treatment of chronic graft-versus-host disease. Blood, 112, 2667–2674. doi:10.1182/blood-2008-03-141481

    Flowers, M.E., Inamoto, Y., Carpenter, P.A., Lee, S.J., Petersdorf, E.W., Pereira, S.E., . . . Martin, P.J. (2011). Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria. Blood, 117, 3214–3219. doi:10.1182/blood-2010-08-302109

    Gazourian, L., Rogers, A.J., Ibanga, R., Weinhouse, G.L., Pinto-Plata, V., Ritz, J., . . . Ho, V.T. (2014). Factors associated with bronchiolitis obliterans syndrome and chronic graft-versus-host disease after allogeneic hematopoietic cell transplantation. American Journal of Hematology, 89, 404–409. doi:10.1002/ajh.23656

    Hahn, T., McCarthy, P.L., Jr., Hassebroek, A., Bredsen, C., Gajewski, J.L., Hale, G.A., . . . Majhail, N.S. (2013). Significant improvement in survival after allogeneic hematopoietic cell transplantation during a period of significantly increased use, older recipient age, and use of unrelated donors. Journal of Clinical Oncology, 31, 2437–2449. doi:10.1200/JCO.2012.46.6193

    Kawanami, T., Sawaki, T., Sakai, T., Miki, M., Iwao, H., Nakajima, A., . . . Umehara, H. (2012). Skewed production of IL-6 and TGFa by cultured salivary gland epithelial cells from patients with Sjögren’s symdrome. PLoS ONE, 7, e45689. doi:10.1371/journal.pone.0045689.g002

    Kishimoto, T. (2010). IL-6: From its discovery to clinical applications. International Immunology, 22, 347–352. doi:10.1093/intimm/dxq030

    Klimiuk, P.A., Sierakowski, S., Domyslawska, I., & Chwiecko, J. (2011). Serum chemokines in patients with rheumatoid arthritis treated with etanercept. Rheumatology International, 31, 457–461. doi:10.1007/s00296-009-1299-3

    Kopp, M., Schweigkofler, H., Holzner, H., Nachbaur, D., Neiderwieser, D., Fleischhacker, W.W., . . . Sperner-Unterweger, B. (2000). EORTC QLQ-C30 and FACT-BMT for the measurement of quality of life in bone marrow transplant recipients: A comparison. European Journal of Haematology, 65, 97–103. doi:10.1034/j.1600-0609.2000.90143.x

    Lau, A.K., Chang, C.H., Tai, J.W., Eremenco, S. Liang, R., Lie, A.K., . . . Lau, C.M. (2002). Translation and validation of the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) Version 4 quality of life instrument into traditional Chinese. Bone Marrow Transplantation, 29, 41–49. doi:10.1038/sj/bmt/1703313

    Lee, S., Cook, E.F., Soiffer, R., & Antin, J.H. (2002). Development and validation of a scale to measure symptoms of chronic graft-versus-host disease. Biology of Blood and Marrow Transplantation, 8, 444–452.

    Lee, S.J., Kim, H.T., Ho, V.T., Cutler, C., Alyea, E.P., Soiffer, R.J., & Antin, J.H. (2006). Quality of life associated with acute and chronic graft-versus-host disease. Bone Marrow Transplantation, 38, 305–310. doi:10.1038/sj.bmt.1705434

    Lenz, E.R., Suppe, F., Gift, A.G., Pugh, L.C., & Milligan, R.A. (1995). Collaborative development of middle-range nursing theories: Toward a theory of unpleasant symptoms. Advances in Nursing Science, 17, 1–13.

    Lynch Kelly, D. (2014, February). Symptoms, cytokines and quality of life in patients with chronic graft-versus-host disease: A cross-sectional study. Poster presented at the Southern Nursing Research Society Conference on Enhancing Value-Based Care: Enhancing New Knowledge, San Antonio, TX.

    Majhail, N.S., Rizzo, J.D., Lee, S.J., Aljurf, M., Atsuta, Y., Bonfim, C., . . . Tichelli, A. (2012). Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation. Bone Marrow Transplantation, 47, 337–341. doi:10.1038/bmbt.2012.5

    McQuellon, R.P., Russell, G.B., Cella, D.F., Craven, B.L., Brady, M., Bonomi, A., & Hurd, D.D. (1997). Quality of life measurement in bone marrow transplantation: Development of the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) scale. Bone Marrow Transplantation, 19, 357–365.

    Mendoza, T., Mayne, T., Rublee, D., & Cleeland, C. (2006). Reliability and validity of a modified Brief Pain Inventory short form in patients with osteoarthritis. European Journal of Pain, 10, 353–361. doi:10.1016/j.ejpain.2005.06.002

    Mendoza, T.R., Wang, X.S., Cleeland, C.S. Morrissey, M., Johnson, B.A., Wendt, J.K., & Huber, S.L. (1999). The rapid assessment of fatigue severity in cancer patients: Use of the Brief Fatigue Inventory. Cancer, 85, 1186–1196.

    Munroe, M.E., Vista, E.S., Guthridge, J.M., Thompson, L.F., Merrill, J.T., & James, J.A., (2014). Proinflammatory adaptive cytokines and shed tumor necrosis receptors are elevated preceding systemic lupus erythematosus disease flare. Arthritis and Rheumatology, 66, 1888–1899. doi:10.1002/art.38573.

    Mykletun, A., Stordal, E., & Dahl, A.A. (2001). Hospital Anxiety and Depression (HAD) scale: Factor structure, items analysis and internal consistency in a large population. British Journal of Psychiatry, 179, 540–544. doi:10.1192/bpj.179.6.540

    National Institute of Nursing Research. (2011). Bringing science to life: NINR strategic plan. Retrieved from http://www.ninr.nih.gov/sites/www.ninr.nih.gov/files/ninr-strategic-pla…

    Pérez-Simón, J.A., Sánchez-Abarca, I., Díez-Campelo, M., Caballero, D., & San Miguel, J. (2006). Chronic graft-versus-host disease: Pathogenesis and clinical management. Drugs, 66, 1041–1057.

    Pidala, J. (2011). Graft-vs-host disease following allageneic hematopoietic cell transplantation. Cancer Control, 18, 268–278.

    Pidala, J., Kurland, B.F., Chai, X., Vogelsang, G., Weisdorf, D.J., Pavletic, S., . . . Lee, S.J. (2011). Sensitivity of changes in chronic graft-versus-host disease activity to changes in patient-reported quality of life: Results from the Chronic Graft-Versus-Host Disease Consortium. Haematologica, 96, 1528–1535.

    Pidala, J., Vogelsang, G., Martin, P., Chai, X., Storer, B., Pavletic, S., . . . Lee, S.J. (2012). Overlap subtype of chronic graft-versus-host disease is associated with an adverse prognosis, functional impairment, and inferior patient-reported outcomes: A Chronic Graft-Versus-Host Disease Consortium study. Haematologica, 97, 451–458. doi:10.3324/haematol.2011.055186

    Portenoy, R.K., Thaler, H.T., Kornblith, A.B., Lepore, J.M., Friedlander-Klar, H., Kiyasu, E., . . . Scher, H. (1994). The Memorial Symptom Assessment Scale: An instrument for the evaluation of symptoms prevalence, characteristics and distress. European Journal of Cancer, 30A, 1326–1336.

    Ratanatharathorn, V., Ayash, L., Lazarus, H.M., Fu, J., & Uberti, J.P. (2001). Chronic graft-versus-host disease: Clinical manifestation and therapy. Bone Marrow Transplantation, 28, 121–129.

    Remberger, M., Kumlien, G., Aschan, J., Barkbolt, L., Hentschke, P., Ljungman, P., . . . Ringdén, O. (2002). Risk factors for moderate-to-severe chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Biology of Blood and Marrow Transplantation, 8, 674–682.

    Rohleder, N., Aringer, M., & Boentert, M. (2012). Role of interleukin-6 in stress, sleep, and fatigue. Annals of the New York Academy of Sciences, 1261, 88–96. doi:10.1111/j.1749-6632.2012.06634

    Schultz, K.R., Miklos, D.B., Fowler, D., Cooke, K., Shizuru, J., Zorn, E., . . . Pavletic, S.Z. (2006). Toward biomarkers for chronic graft-versus-host disease: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: III. Biomarker working group report. Biology of Blood and Marrow Transplantation, 12, 126–137.

    Seyidova-Khoshknabi, D., Davis, M.P., & Walsh, D. (2011). Review article: A systematic review of cancer-related fatigue measurement questionnaires. American Journal of Hospice and Palliative Medicine, 28, 119–129. doi:10.1177/1049909110381590

    Stadler, M., Ahlborn, R., Kamal, H., Diedrich, H., Buchholz, S., Eder, M., & Ganser, A. (2009). Limited efficacy of imatinib in severe pulmonary chronic graft-versus-host disease. Blood, 114, 3718–3719.

    Stratton, P., Turner, M.L., Childs, R., Barrett, J., Bishop, M., Wayne, A.S., & Pavletic, S. (2007). Vulvovaginal chronic graft-versus-host disease with allogeneic hematopoietic stem cell transplantation. Obstetrics and Gynecology, 110, 1041–1049. doi:10.1097/01.aog.0000285998.75450.86

    Veltri, L., Regier, M., Cumpston, A., Leadmon, S., Tse, W., Craig, M., & Hamadani, M. (2013). Incidence and pattern of graft-versus-host disease in patients undergoing allogeneic transplantation after nonmyeloablative conditioning with total lymphoid irradiation and antithymocyte globulin. Bone Marrow Research, 2013, 1414959. doi:10.1155/2013/414959

    Visvanathan, V., & Nix, P. (2010). Managing the patient presenting with xerostomia: A review. International Journal of Clinical Practice, 64, 404–407. doi:10.1111/j.1742-1241.2009.02132

    Webster, K., Cella, D., & Yost, K., (2003). The Functional Assessment of Chronic Illness Therapy (FACIT) measurement system: Properties, applications, and interpretation. Health and Quality of Life Outcomes, 1, 79. doi:10.1186/1477-7275-1-79

    Wong, F.L., Francisco, L., Togawa, K., Kim, H., Bosworth, A., Atencio, L., . . . Bhatia, S. (2013). Longitudinal trajectory of sexual functioning after hematopoietic cell transplantation: Impact of chronic graft-versus-host disease and total body irradiation. Blood, 122, 3973–3981. doi:10.1182/blood-2013-05-499806

    Zigmond, A.S., & Snaith, R.P. (1983). The Hospital Anxiety and Depression Scale. Acta Psychiatrica Scandinavica, 67, 367–370.

    About the Author(s)

    Debra Lynch Kelly, PhD, RN, OCN®, is an assistant professor and Debra E. Lyon, RN, PhD, FAAN, is an executive associate dean and the Thomas M. and Irene B. Kirbo endowed chair, both in the Department of Adult and Elderly Nursing at the University of Florida in Gainesville; and Suzanne A. Ameringer, PhD, RN, is an associate professor and Ronald K. Elswick Jr., PhD, NREMT-B, is a professor, both in the Department of Family and Community Health Nursing, and John M. McCarty, MD, is the medical director and full medical professor of the Bone Marrow Transplant Program, all at Virginia Commonwealth University in Richmond. No financial relationships to disclose. Description of products does not indicate or imply endorsement by the Oncology Nursing Forum or the Oncology Nursing Society. Lynch Kelly can be reached at dlynchkelly@ufl.edu, with copy to editor at ONFEditor@ons.org. (Submitted August 2014. Accepted for publication November 15, 2014.)

     

    References

    Antin, J.H. (2002). Clinical practice. Long-term care after hematopoietic-cell transplantation in adults. New England Journal of Medicine, 347, 36–42. doi:10.1056/NEJMcp010518
    Baird, G.S., & Montine, T.J. (2008). Multiplex immunoassay analysis of cytokines in idiopathic inflammatory myopathy. Archives of Pathology and Laboratory Medicine, 132, 232–238.
    Baird, K., & Pavletic, S.Z. (2006). Chronic graft versus host disease. Current Opinion in Hematology, 13, 426–435. doi:10.1097/01.moh.0000245689.47333
    Baker, K.S., & Fraser, C.J. (2008). Quality of life and recovery after graft-versus-host disease. Best Practice and Research in Clinical Haematology, 21, 333–341. doi:10.1016/j.beha.2008.03.002
    Bazzichi, L., Rossi, A., Massimetti, G., Giannaccini, G., Giuliano, T., De Feo, F., . . . Bombardieri, S. (2007). Cytokine patterns in fibromyalgia and their correlation with clinical manifestations. Clinical and Experimental Rheumatology, 25, 225–230.
    Chang, V.T., Hwang, S.S., Feuerman, M., Kasimis, B.S., & Thaler, H.T. (2000). The Memorial Symptom Assessment Scale Short Form (MSAS-SF): Validity and reliability. Cancer, 89, 1162–1171. doi:10.1002/1097-0142(20000901)
    Cleeland, C.S. (2009). The Brief Pain Inventory: User guide. Retrieved from http://www.mdanderson.org/education-and-research/departments-programs-a…
    Fall-Dickson, J.M., Mitchell, S.A., Marden, S., Ramsay, E.S., Guadagnini, J.P., Wu, T., . . . Pavletic, S.Z. (2010). Oral symptom intensity, health-related quality of life, and correlative salivary cytokines in adult survivors of hematopoietic stem cell transplantation with oral chronic graft-versus-host disease. Biology of Blood and Marrow Transplantation, 16, 948–956. doi:10.1016/j.bbmt.2010.01.017
    Filipovich, A.H., Weisdorf, D., Pavletic, S., Socie, G., Wingard, J.R., Lee, S.J., . . . Flowers, M.E. (2005). National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biology of Blood and Marrow Transplantation, 11, 945–956. doi:10.1016/j.bmt.2005.09.004
    Flowers, M.E., Apperley, J.F., van Besien, K., Elmaagacli, A., Grigg, A., Reddy, V., . . . Greinix, H.T. (2008). A multicenter prospective phase 2 randomized study of extracorporeal photopheresis for treatment of chronic graft-versus-host disease. Blood, 112, 2667–2674. doi:10.1182/blood-2008-03-141481
    Flowers, M.E., Inamoto, Y., Carpenter, P.A., Lee, S.J., Petersdorf, E.W., Pereira, S.E., . . . Martin, P.J. (2011). Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria. Blood, 117, 3214–3219. doi:10.1182/blood-2010-08-302109
    Gazourian, L., Rogers, A.J., Ibanga, R., Weinhouse, G.L., Pinto-Plata, V., Ritz, J., . . . Ho, V.T. (2014). Factors associated with bronchiolitis obliterans syndrome and chronic graft-versus-host disease after allogeneic hematopoietic cell transplantation. American Journal of Hematology, 89, 404–409. doi:10.1002/ajh.23656
    Hahn, T., McCarthy, P.L., Jr., Hassebroek, A., Bredsen, C., Gajewski, J.L., Hale, G.A., . . . Majhail, N.S. (2013). Significant improvement in survival after allogeneic hematopoietic cell transplantation during a period of significantly increased use, older recipient age, and use of unrelated donors. Journal of Clinical Oncology, 31, 2437–2449. doi:10.1200/JCO.2012.46.6193
    Kawanami, T., Sawaki, T., Sakai, T., Miki, M., Iwao, H., Nakajima, A., . . . Umehara, H. (2012). Skewed production of IL-6 and TGFa by cultured salivary gland epithelial cells from patients with Sjögren’s symdrome. PLoS ONE, 7, e45689. doi:10.1371/journal.pone.0045689.g002
    Kishimoto, T. (2010). IL-6: From its discovery to clinical applications. International Immunology, 22, 347–352. doi:10.1093/intimm/dxq030
    Klimiuk, P.A., Sierakowski, S., Domyslawska, I., & Chwiecko, J. (2011). Serum chemokines in patients with rheumatoid arthritis treated with etanercept. Rheumatology International, 31, 457–461. doi:10.1007/s00296-009-1299-3
    Kopp, M., Schweigkofler, H., Holzner, H., Nachbaur, D., Neiderwieser, D., Fleischhacker, W.W., . . . Sperner-Unterweger, B. (2000). EORTC QLQ-C30 and FACT-BMT for the measurement of quality of life in bone marrow transplant recipients: A comparison. European Journal of Haematology, 65, 97–103. doi:10.1034/j.1600-0609.2000.90143.x
    Lau, A.K., Chang, C.H., Tai, J.W., Eremenco, S. Liang, R., Lie, A.K., . . . Lau, C.M. (2002). Translation and validation of the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) Version 4 quality of life instrument into traditional Chinese. Bone Marrow Transplantation, 29, 41–49. doi:10.1038/sj/bmt/1703313
    Lee, S., Cook, E.F., Soiffer, R., & Antin, J.H. (2002). Development and validation of a scale to measure symptoms of chronic graft-versus-host disease. Biology of Blood and Marrow Transplantation, 8, 444–452.
    Lee, S.J., Kim, H.T., Ho, V.T., Cutler, C., Alyea, E.P., Soiffer, R.J., & Antin, J.H. (2006). Quality of life associated with acute and chronic graft-versus-host disease. Bone Marrow Transplantation, 38, 305–310. doi:10.1038/sj.bmt.1705434
    Lenz, E.R., Suppe, F., Gift, A.G., Pugh, L.C., & Milligan, R.A. (1995). Collaborative development of middle-range nursing theories: Toward a theory of unpleasant symptoms. Advances in Nursing Science, 17, 1–13.
    Lynch Kelly, D. (2014, February). Symptoms, cytokines and quality of life in patients with chronic graft-versus-host disease: A cross-sectional study. Poster presented at the Southern Nursing Research Society Conference on Enhancing Value-Based Care: Enhancing New Knowledge, San Antonio, TX.
    Majhail, N.S., Rizzo, J.D., Lee, S.J., Aljurf, M., Atsuta, Y., Bonfim, C., . . . Tichelli, A. (2012). Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation. Bone Marrow Transplantation, 47, 337–341. doi:10.1038/bmbt.2012.5
    McQuellon, R.P., Russell, G.B., Cella, D.F., Craven, B.L., Brady, M., Bonomi, A., & Hurd, D.D. (1997). Quality of life measurement in bone marrow transplantation: Development of the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) scale. Bone Marrow Transplantation, 19, 357–365.
    Mendoza, T., Mayne, T., Rublee, D., & Cleeland, C. (2006). Reliability and validity of a modified Brief Pain Inventory short form in patients with osteoarthritis. European Journal of Pain, 10, 353–361. doi:10.1016/j.ejpain.2005.06.002
    Mendoza, T.R., Wang, X.S., Cleeland, C.S. Morrissey, M., Johnson, B.A., Wendt, J.K., & Huber, S.L. (1999). The rapid assessment of fatigue severity in cancer patients: Use of the Brief Fatigue Inventory. Cancer, 85, 1186–1196.
    Munroe, M.E., Vista, E.S., Guthridge, J.M., Thompson, L.F., Merrill, J.T., & James, J.A., (2014). Proinflammatory adaptive cytokines and shed tumor necrosis receptors are elevated preceding systemic lupus erythematosus disease flare. Arthritis and Rheumatology, 66, 1888–1899. doi:10.1002/art.38573.
    Mykletun, A., Stordal, E., & Dahl, A.A. (2001). Hospital Anxiety and Depression (HAD) scale: Factor structure, items analysis and internal consistency in a large population. British Journal of Psychiatry, 179, 540–544. doi:10.1192/bpj.179.6.540
    National Institute of Nursing Research. (2011). Bringing science to life: NINR strategic plan. Retrieved from http://www.ninr.nih.gov/sites/www.ninr.nih.gov/files/ninr-strategic-pla…
    Pérez-Simón, J.A., Sánchez-Abarca, I., Díez-Campelo, M., Caballero, D., & San Miguel, J. (2006). Chronic graft-versus-host disease: Pathogenesis and clinical management. Drugs, 66, 1041–1057.
    Pidala, J. (2011). Graft-vs-host disease following allageneic hematopoietic cell transplantation. Cancer Control, 18, 268–278.
    Pidala, J., Kurland, B.F., Chai, X., Vogelsang, G., Weisdorf, D.J., Pavletic, S., . . . Lee, S.J. (2011). Sensitivity of changes in chronic graft-versus-host disease activity to changes in patient-reported quality of life: Results from the Chronic Graft-Versus-Host Disease Consortium. Haematologica, 96, 1528–1535.
    Pidala, J., Vogelsang, G., Martin, P., Chai, X., Storer, B., Pavletic, S., . . . Lee, S.J. (2012). Overlap subtype of chronic graft-versus-host disease is associated with an adverse prognosis, functional impairment, and inferior patient-reported outcomes: A Chronic Graft-Versus-Host Disease Consortium study. Haematologica, 97, 451–458. doi:10.3324/haematol.2011.055186
    Portenoy, R.K., Thaler, H.T., Kornblith, A.B., Lepore, J.M., Friedlander-Klar, H., Kiyasu, E., . . . Scher, H. (1994). The Memorial Symptom Assessment Scale: An instrument for the evaluation of symptoms prevalence, characteristics and distress. European Journal of Cancer, 30A, 1326–1336.
    Ratanatharathorn, V., Ayash, L., Lazarus, H.M., Fu, J., & Uberti, J.P. (2001). Chronic graft-versus-host disease: Clinical manifestation and therapy. Bone Marrow Transplantation, 28, 121–129.
    Remberger, M., Kumlien, G., Aschan, J., Barkbolt, L., Hentschke, P., Ljungman, P., . . . Ringdén, O. (2002). Risk factors for moderate-to-severe chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Biology of Blood and Marrow Transplantation, 8, 674–682.
    Rohleder, N., Aringer, M., & Boentert, M. (2012). Role of interleukin-6 in stress, sleep, and fatigue. Annals of the New York Academy of Sciences, 1261, 88–96. doi:10.1111/j.1749-6632.2012.06634
    Schultz, K.R., Miklos, D.B., Fowler, D., Cooke, K., Shizuru, J., Zorn, E., . . . Pavletic, S.Z. (2006). Toward biomarkers for chronic graft-versus-host disease: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: III. Biomarker working group report. Biology of Blood and Marrow Transplantation, 12, 126–137.
    Seyidova-Khoshknabi, D., Davis, M.P., & Walsh, D. (2011). Review article: A systematic review of cancer-related fatigue measurement questionnaires. American Journal of Hospice and Palliative Medicine, 28, 119–129. doi:10.1177/1049909110381590
    Stadler, M., Ahlborn, R., Kamal, H., Diedrich, H., Buchholz, S., Eder, M., & Ganser, A. (2009). Limited efficacy of imatinib in severe pulmonary chronic graft-versus-host disease. Blood, 114, 3718–3719.
    Stratton, P., Turner, M.L., Childs, R., Barrett, J., Bishop, M., Wayne, A.S., & Pavletic, S. (2007). Vulvovaginal chronic graft-versus-host disease with allogeneic hematopoietic stem cell transplantation. Obstetrics and Gynecology, 110, 1041–1049. doi:10.1097/01.aog.0000285998.75450.86
    Veltri, L., Regier, M., Cumpston, A., Leadmon, S., Tse, W., Craig, M., & Hamadani, M. (2013). Incidence and pattern of graft-versus-host disease in patients undergoing allogeneic transplantation after nonmyeloablative conditioning with total lymphoid irradiation and antithymocyte globulin. Bone Marrow Research, 2013, 1414959. doi:10.1155/2013/414959
    Visvanathan, V., & Nix, P. (2010). Managing the patient presenting with xerostomia: A review. International Journal of Clinical Practice, 64, 404–407. doi:10.1111/j.1742-1241.2009.02132
    Webster, K., Cella, D., & Yost, K., (2003). The Functional Assessment of Chronic Illness Therapy (FACIT) measurement system: Properties, applications, and interpretation. Health and Quality of Life Outcomes, 1, 79. doi:10.1186/1477-7275-1-79
    Wong, F.L., Francisco, L., Togawa, K., Kim, H., Bosworth, A., Atencio, L., . . . Bhatia, S. (2013). Longitudinal trajectory of sexual functioning after hematopoietic cell transplantation: Impact of chronic graft-versus-host disease and total body irradiation. Blood, 122, 3973–3981. doi:10.1182/blood-2013-05-499806
    Zigmond, A.S., & Snaith, R.P. (1983). The Hospital Anxiety and Depression Scale. Acta Psychiatrica Scandinavica, 67, 367–370.