Abstract
Objective
The objective of this study was to determine potential inflammatory predictors of fatigue in obstructive sleep apnea (OSA).
Materials and methods
Fifty-six women and men untreated OSA patients had their sleep monitored with polysomnography. Fatigue was assessed by the Multidimensional Fatigue Symptom Inventory-Short Form. Depressed mood was assessed by the Center for Epidemiologic Studies-Depression Scale. Blood was drawn to assess circulating levels of Interleukin-6 (IL-6) and soluble tumor necrosis factor receptor I (sTNF-RI). Age, gender, body mass index (BMI), blood pressure, OSA severity, depressed mood, and inflammatory biomarkers were entered into a hierarchical multiple linear regression analysis predicting self-reported fatigue.
Results
Approximately 42% of the patients reported significant amounts of fatigue. Higher BMI (p=0.014), greater depressed mood (p=0.004), and higher sTNF-RI levels (p=0.033) were independent predictors of fatigue in the final model (full model R2=.571; p=.003). Age, gender, blood pressure and apnea severity were unrelated to fatigue.
Conclusion
The findings suggest that in addition to depressed mood, fatigue in OSA may be associated with increased body weight and elevated levels of the proinflammatory cytokine receptor sTNF-RI. The findings support a linkage between the widely reported fatigue in OSA and a sleep-related component of inflammation.
Keywords: Obstructive sleep apnea, Fatigue, Cytokines, Body mass index, Depression
Introduction
Fatigue is a common complaint in obstructive sleep apnea (OSA) and frequently associated with depressive symptoms [1, 2]. Fatigue is also a common and troubling symptom in cancer survivors, and is associated with the degree of systemic inflammation as assessed by elevated proinflammatory cytokine levels, including soluble tumor necrosis factor (TNF) receptors [3, 4]. A prior study with a limited sample size compared groups of sleep apneics and hyper-somniacs to normal controls and found that circulating TNF-α and IL-6 were elevated in the sleep apneics compared to the controls [5]. The purpose of the current study was to examine circulating inflammatory marker levels as potential predictors of fatigue after controlling for demographic variables, depressive mood, and apnea severity within a group of OSA patients complaining of a broad range of fatigue symptoms.
Materials and methods
Participants
Fifteen women and 41 men with untreated OSA (mean age 49.2 years) were recruited by advertising and word-of-mouth referral. Participants were excluded if they reported a history of major medical illnesses (other than OSA and hypertension), current psychiatric diagnoses, or if they were receiving psychotropic medication. Patients who were receiving anti-hypertensive medications had their medications tapered for 3 weeks before participation. Blood pressure readings were obtained using a manual cuff while the patients were seated, and averaged across three measurements. The protocol was approved by the University of California San Diego (UCSD) Human Subjects Committee. After a description of the study, a written informed consent was obtained.
Sleep monitoring
Participants had their sleep monitored at the UCSD General Clinical Research Center with a standard regimen of polysomnography. Apneas were defined as decrements in airflow of ≥90% from baseline for ≥10 s. Hypopneas were defined as decrements in airflow of ≥50% but <90% from baseline for ≥10 s. The numbers of apneas and hypopneas per hour were calculated to obtain the apnea hypopnea index (AHI). Participants with an AHI ≥ 15 were considered to have OSA and included in the study. Oxyhemoglobin saturation was monitored with a pulse oximeter (Biox 3740, Datex-Ohmeda, Louisville, CO) and analyzed using Profox software (Associates, Escondido, CA). AHI and mean oxygen saturation (SaO2) were taken as indicators of OSA severity.
Fatigue and depressed mood assessments
Participants completed the Multidimensional Fatigue Symptom Inventory-short form (MFSI-sf) and the Center for Epidemiologic Studies-Depression (CES-D) Scale. The MFSI-sf is a 30-item self-report measure designed to assess the principal manifestations of fatigue, yielding a total fatigue score [6]. Items are rated on a 5-point scale indicating how true each statement was for the respondent during the previous week (0 = not all; 4 = extremely). MFSI-sf scores above 0.85 are considered to be significant fatigue [7]. The CES-D is a frequently used 20-item self-report scale that has been shown to be reliable and valid for assessing depressive symptoms [8]. CES-D scores above 16 are considered depressed mood. The CES-D primarily taps cognitive/affective aspects of depression and has been shown to be useful in chronically ill groups, including obstructive sleep apnea patients.
Blood sampling and assays
Blood samples were collected in EDTA at approximately 6:30 a.m. following the morning after sleep monitoring but before the subject was ambulatory. Samples were collected from an indwelling catheter that had been placed the night before, spun in a refrigerated centrifuge, and the plasma immediately frozen at -80°C until assay. IL-6 and soluble sTNF-RI (p55) were determined by commercial ELISA (R&D Systems, Minneapolis, MN) using samples that had not been previously freeze-thawed. Intra-assay and inter-assay coefficients of variation were <10%. Sensitivity values were <0.72 pg/ml and <0.61 pg/ml for IL-6, and sTNF-RI, respectively.
Statistical analysis
Hierarchical linear regression analysis was performed using MFSI-sf total score as the dependent variable, with step 1 forced entry of age, gender, and BMI; step 2 forced entry of blood pressure; step 3 forced entry of OSA severity variables AHI and average SaO2; step 4 forced entry of CES-D; and step 5 forced entry of IL-6 and sTNF-RI levels. Data were analyzed using SPSS 15.0 software (Chicago, IL, 2006). Statistical significance was set at p<0.05.
Results
Sample characteristics with means, standard deviations, and ranges are presented in Table 1. The mean MFSI-sf total score was 10.1, with a range of -15.0 to 66.1. Twenty-four (42.8%) of our OSA participants reported significant fatigue (i.e., scored above 0.85. The mean CES-D score was 13.4, with a range of 0 to 35. Eighteen (32.1%) of our OSA participants reported depression (i.e., scores above the 17).
Table 1.
Sample characteristics
| Variables | Mean (± SD) | Range |
|---|---|---|
| Age (years) | 49.2 (11.1) | 29-65 |
| Systolic blood pressure (mmHg) | 132.8 (15) | 102-163 |
| Diastolic blood pressure (mmHg) | 79.8 (11) | 56-106 |
| Body mass index (kg/m2) | 31.5 (7.3) | 23.1-51.3 |
| Apnea hypopnea index | 61.8 (29.6) | 16.2-135.9 |
| Mean oxygen saturation (SpO2) (%) | 94.3 (4.6) | 79.6-97.4 |
| Multidimensional Fatigue Symptom inventory - short form | 10.1 (17.4) | -15.0-66.1 |
| Center for Epidemiologic Studies Depression Scale | 13.4 (8.9) | 0-35 |
| IL-6 (pg/ml) | 3.26 (2.3) | 0.21-9.4 |
| sTNF-RI (pg/ml) | 871 (205.6) | 503.5-1356.5 |
Table 2 presents the results of the multiple linear regression analysis. Throughout the five steps of the analysis, BMI was a consistent significant predictor of fatigue (p’s<0.03). Neither age, gender, blood pressure, nor the apnea severity variables were significant predictors of fatigue. The addition of CES-D to the model in step 4 accounted for the single largest amount of variance, accounting for an R2 increase of.200 (p<0.01). In step 5 of the regression, sTNF-RI levels (p<0.05) but not IL-6 levels (p=0.39) were a significant predictor of fatigue (change in R2=0.071), accounting for an additional 7% of the variance in fatigue levels. The final model, consisting of significant predictors of BMI, CES-D, and sTNF-RI, and controlling for age, gender, blood pressure, apnea severity, and IL-6 levels, accounted for 57.1% of the variance in fatigue (F=4.37 p=0.003).
Table 2.
Multiple regression predictors of fatiguea in OSA
| Additional variables in each regression block | Significant individual predictor variables with standardized β coefficient and p value | Model R2; ΔR2; p value |
|---|---|---|
| 1. Age, gender | BMI (0.473, 0.005) | 0.217; -; 0.008 |
| 2. Age, gender, BP | BMI (0.476, 0.008) | 0.234; 0.017; 0.024 |
| 3. Age, gender, BP, AHI, SpO2 | BMI (0.535, 0.025) | 0.275; 0.041; .0070 |
| 4. Age, gender, BP, AHI, SpO2 | BMI (0.501, 0.016); CES-D (0.517, 0.005) | 0.475; 0.200; 0.005 |
| 5. Age, gender, BP, AHI, SpO2, IL-6 | BMI (0.488, 0.014); CES-D (0.508, 0.004); sTNF-RI (0.365, 0.033) | 0.571; 0.071; 0.003 |
BP blood pressure, BMI body mass index, AHI apnea hypopnea index, SpO2 mean oxygen saturation, CES-D Center for Epidemiologic Studies Depression Scale
Multidimensional Fatigue Symptom Inventory-short form
Discussion
Within a group of OSA patients reporting a broad range of fatigue, including approximately 42% self-reporting a significant amount of fatigue, we demonstrated that in addition to depressed mood and body mass, and the inflammatory biomarker sTNF-RI (but not IL-6) is associated with fatigue. The findings implicate that inflammatory processes may be associated with fatigue even after controlling for demographic and psychological factors that have been previously shown to influence fatigue levels in OSA. The association of fatigue with increased body mass and depressed mood is consistent with a recent review by Vgontzas et al. [9], which showed that in sleep disorders the primary determinants of sleepiness and fatigue are depression and obesity. Also consistent with prior observations is the finding that the severity of fatigue in OSA is not associated with the severity of sleep apnea [2, 9]. A limitation of this short communication is the absence of a non-OSA control group. Being limited to OSA patients, the findings need to be examined in other populations to determine potential generalizability, or lack thereof.
Numerous studies demonstrate involvement of the TNF-α system in sleep-wake regulation. sTNF-RI is elevated following sleep deprivation [10]. Being released from activated immunologically competent cells, sTNF-RI indicates activated inflammatory processes [11]. The current findings suggest that sleep-related components of the inflammation observed in OSA [5] are associated with widely reported fatigue in OSA.
Acknowledgments
This work was supported in part National Institutes of Health grants HL073355, HL44915 and CA23100 and the National Cancer Center Korea, Seoul, South Korea
Contributor Information
Paul J. Mills, Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA & Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
Jong-Heun Kim, Psycho-Oncology Clinic, National Cancer Center, Seoul, Republic of South Korea & Psycho-Oncology Clinic, National Cancer Center, Goyang, Republic of Korea.
Wayne Bardwell, Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA & Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
Suzi Hong, Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.
Joel E. Dimsdale, Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA & Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
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