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The association of major life events with chronic fatigue
Journal of Psychosomatic Research 125 (2019) 109810
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The association of major life events with chronic fatigue a,⁎
Karen B. Schmaling , Thomas L. Patterson a b
T
b
Washington State University, United States of America University of California San Diego, United States of America
A R T I C LE I N FO
A B S T R A C T
Keywords: Chronic fatigue Life events Outcome Stress
Objective: Major life events have been associated with the onset of unexplained chronic fatigue (CF) and with variability in illness course. The purpose of this study was to characterize the associations of major life events with illness status over time. Method: Sentinel measures of clinical status were collected four times over 18 months in a cohort of 99 persons with CF; participants also were interviewed regarding major life events, which were independently rated by observers. Results: Over time, more major life events attributed to CF predicted a worse clinical course, suggesting that illness-related major life events rather than stressful life events in general are associated with worse clinical status for persons with CF. Conclusion: This study adds to the literature regarding specific types of life events' relationship to illness course, which has implications for the management of CF.
1. Introduction Unexplained chronic fatigue (CF) is defined as new and disabling fatigue lasting six months or longer that is unexplained insofar as it is not attributable to known causes of fatigue such as neoplasms. CF includes chronic fatigue syndrome (CFS) and idiopathic chronic fatigue (ICF). The International CFS Study Group case definition [1] differentiates these two conditions based on the number of symptoms occurring with the fatigue, such as unrefreshing sleep and myalgia. CFS is characterized by presence of four or more symptoms and ICF by less than four symptoms occurring with the fatigue. No physical signs or diagnostic tests are specific to CFS or ICF, and studies comparing the two conditions have found few clinically meaningful distinguishing characteristics [2,3]. This paper focuses on major life events (MLEs) among patients with CF (either CFS or ICF). The literature on the association of MLEs and CF is reviewed below, first focusing on prospective and retrospective studies of the association of MLEs with the onset of CF, followed by studies on cross-sectional associations between MLEs and CF. 1.1. Prospective studies of major life events and CF onset The results of prospective studies of the association of MLEs with CF
onset have been inconsistent. MLEs in the year prior to CF onset were associated with a nearly two-fold increase in the likelihood of having five or more days of fatigue that interfered with functioning [4]. However, two other studies did not identified significant associations. Bruce-Jones, White, Thomas, and Clare [5] found that MLEs and difficulties did not predict incident cases of prolonged fatigue following an acute infection. Similarly, Jason, Katz, Shiraishi, Mears, Im, and Taylor [6] found that MLEs were not associated with the development of CFS following infectious mononucleosis. It should be noted that these studies with negative findings were focused more narrowly on CF following an acute infection [5,6], whereas the study with positive findings did not limit putative predisposing events [4]. 1.2. Retrospective studies of major life events and CF onset Most retrospective studies have found that MLEs precede the onset of CF. Half of the CFS cases identified in one large sample stated they experienced “unusually severe stress at the time of their illness onset and were able to identify a particular stressful event” [7] (p. 572). In three studies, patients with CFS were approximately 14, nine, and two times more likely to report having MLEs in the 12, three, and four months prior to illness onset compared to non-fatigued controls, respectively [8–10]. Another study found seven life events to have
⁎ Corresponding author at: Department of Psychology, Washington State University, 14204 NE Salmon Creek Ave., Vancouver, WA 98686, United States of America. E-mail address: [email protected] (K.B. Schmaling).
https://doi.org/10.1016/j.jpsychores.2019.109810 Received 18 May 2019; Received in revised form 11 August 2019; Accepted 12 August 2019 0022-3999/ © 2019 Elsevier Inc. All rights reserved.
Journal of Psychosomatic Research 125 (2019) 109810
K.B. Schmaling and T.L. Patterson
role of neuroticism in reports of MLEs and CF status.
occurred more frequently (odds ratios ranged from 2.8 to 31.7) prior to the onset of CFS than compared to the controls [11]. In a study examining participants' beliefs about the causes of their CFS, nearly all participants identified a physical illness, most often an infection, as the cause of their CFS, but 56% also identified social stressors (bereavement, financial worries, relationship problems, etc.) as co-occurring causes [12]. However, the number of MLEs in the two years prior to the onset of illness did not differ between patients with CFS, irritable bowel syndrome, or healthy controls [13].
2. Materials and method 2.1. Participants and procedures Patients, study inclusion and exclusion criteria, and their clinical status over time were described previously [25]. Briefly, patients were recruited from a tertiary care CF clinic associated with a medical school-affiliated hospital. Potential participants who were between the ages of 18–65 and met the 1994 International CFS Study Group case criteria for CFS or ICF [1] were screened, and if eligible, were recruited for study participation at their clinic appointment. To be eligible, patients' medical records were reviewed prior to their appointment for recent medical and psychiatric evaluations to confirm CF and exclude other causes of CF; these evaluations were repeated at the index visit and on three subsequent occasions, six months apart (physical examination; laboratory tests; structured psychiatric diagnostic interview; symptom questionnaires). The study was reviewed and approved by the IRB at the first author's institution; all participants provided written informed consent. Participants received honoraria for completing each research appointment.
1.3. Cross-sectional covariation of major life events with CF symptoms In addition to the question of an association between stressful events and CF onset, it is also of interest how stressful events covary with CF symptoms among those already recognized as having CF. These studies' finding have been equivocal. Positive associations were found in three studies: Three months following the end of a clinical trial, patients who had worsened since the end of the trial were likely to attribute these changes to life events, such as job loss and motor vehicle accidents, as well as to higher levels of general stress [14]. Patients with CFS living in the area proximal to Hurricane Andrew were more likely to have clinician-observed relapses than patients living farther away from the hurricane [15]. In a large surveillance study, those with CFS had more MLEs in the past year, especially MLES perceived as having a negative impact, compared to non-fatigued participants, after controlling for sociodemographic variables [16]. However, another study found that negative MLEs were unrelated to fatigue severity, but positive life events were related to less fatigue severity [17]. In summary, most previous studies found MLEs to be associated with CF onset or worsened CF symptoms. It is well recognized that stress can have negative effects on health through a number of possible mechanisms. Sensitization is one such model for the deleterious effects of stress. This model involves hyperresponsiveness of the central nervous system to a variety of stimuli; in CF, stress heightens this hyperresponsivness further [18]. In a sensitization model of CF, reactions to stressful events may be examples of the “…cognitive and emotional factors contributing to and possibly sustaining the mechanism of central sensitization in CFS” (p. 208) [18]. Furthermore, the extant literature includes at least three potential limitations. First, studies regarding MLEs in CF are largely based on patient reports provided via questionnaire or interview. Rarely have life events been evaluated by standardized interviewer ratings following structured interviews [5]. Standardized interviewer ratings separate the assessment of exposure to stress from subjects' reactions to stress [19], which increases consistency in the evaluation of MLEs across subjects, and has had differential power to predict outcomes in previous studies [20]. Second, to our knowledge, only one previous study considered if MLEs could be attributed to CF, and that study excluded MLEs deemed related to CF [5]. Some of the variability in previous studies' results may have been due to combining MLEs related to and independent of CF. Consistent with a sensitization model, MLEs related to CF may be most salient for CF clinical status. Third, some previous studies did not investigate psychological characteristics related to subjects' reactions to MLEs. Neuroticism – also termed negative affectivity or emotional instability – is the tendency to experience negative emotions such as anxiety, tension, and sadness, and has been elevated among those with CF [4,21,22]. Neuroticism has been associated with the perception of stress [23,24], and thus, could also be associated with patients' reporting tendencies. The primary goal of this study was to examine the relationship of patient- and observer-rated life events to clinical status over time. It was predicted that undesirable MLEs would be associated with worse clinical status over time, consistent with most previous studies' results. This study also sought to address three potential limitations in the literature by using both patient and standardized observer measures of life events; examining both MLEs related and unrelated to CF; and examining the
2.2. Measures 2.2.1. Descriptive variables Age, gender, years of CF, years of education, ethnicity (recoded as either Caucasian or non-Caucasian), relationship status (recoded as either married or living with an intimate partner versus single, widowed, or divorced), and employment status (recoded as either working partor full-time versus not working) were gathered to describe the sample. 2.2.2. Clinical status 2.2.2.1. CF symptoms. The total patient-rated frequency of experiencing the nine symptoms in the International CFS Study Group case definition (fatigue, memory or concentration problems, sore throat, painful lymph nodes, muscle pain, joint pain, headaches, unrefreshing sleep, and feeling poorly after exertion) on a five-point scale (0 = not at all to 4 = constantly), yielded a possible score range of 0–36. In this sample, the internal consistency of this scale (Cronbach's alpha) averaged 0.75 (range: 0.64–0.82) across its four administrations, and decreased significantly over time [25]. 2.2.2.2. Functional status. The vitality score from the Short Form-36 [26] was used to evaluate functional status relevant to fatigue. Higher scores indicate better functioning, each score ranges from 0 to 100, and the normal range of scores is considered to be 80 and above. This score was chosen on the basis of its demonstrated tendency to be sensitive to change over time in samples with CF [27], including the cohort in the present study [25]. The internal consistency of this scale averaged 0.96 (range: 0.92 to 0.97) across its four administrations. 2.2.3. Major life events 2.2.3.1. Patient-rated major life events. The modified Psychiatric Epidemiology Research Interview (PERI) [28] is a structured interview that queries the patient about the occurrence of 133 events in the six months before the research appointment. For each event, the interviewer obtained a description of the event including its context and consequences. Next, the patient rated the event's desirability on a 7-point scale, and its perceived association with CF on a 5-point scale. The number of MLEs for each six month period was based on patient desirability ratings of 1 (“extremely negative”) or 2 (“moderately negative”). The number of MLEs perceived as related to CF were based on participant ratings of two or greater (2=“a little bit,” 3 = “moderately,” 4=“quite a bit,” 5 = “extremely”), and those not 2
Journal of Psychosomatic Research 125 (2019) 109810
K.B. Schmaling and T.L. Patterson
patients at each research appointment, which ranged from 1 to 11 events per patient. At the index visit, patients reported a variety of events, endorsing 90 of the 133 possible categories one or more times. The most frequently-reported events were those related to health (“suffered from a physical illness or disability lasting a month or more, not requiring hospitalization,” 12.1%; “ongoing medical or psychiatric treatment,” 11.9%; “chronic poor health,” 6.0%; “sustained a minor injury,” 3.2%), finances (“chronic financial stress,” 4.8%; “financial situation worsened,” 3.7%; “insurance company problems,” 3.4%), self (“revision of personal habits, including sleeping eating, exercising,” 3.9%), and others (“close family member became or was pregnant,” 2.7%; ‘attended funerals,” 2.4%). These ten most-frequently endorsed categories changed little over time with few exceptions. At the six month appointment, “sexual difficulties” was endorsed by 2.4%; at the one-year appointment, “close family member was hospitalized for a lifethreatening physical illness, disability, or major surgery” was endorsed by 2.4%, and “conditions at work got worse” by 1.9%; and at the 18 month appointment, “new person became resident in the household” by 2.7% and death of “someone else who was important to you” other than family or friends by 2.2%.
perceived as related to CF had ratings of one. For example, participants might rate being fired from a job secondary to absenteeism due to illness as an event related to CF, but not the death of a loved one. 2.2.3.2. Observer-rated major life events. The PERI interview was transcribed and trained observers rated each event according to Brown and Harris's contextual rating system [29]. Discrete events (e.g., a death in the family) were rated in terms of short-term and long-term threat on a 4-point scale, and their association with CF on a 3-point scale. Ongoing events (e.g., having a disabled partner) were rated in terms of difficulty on a 6-point scale, along with association with CF. The number of MLEs for each six month period was based on discrete events with severe impact ratings, i.e., short-term threat ratings of 1 (severe), long-term threat ratings of 1 or 2 (moderate or severe), or ongoing difficulties rated 1, 2, or 3 (moderate or severe, sufficient to be judged as role disruptive, such as being unable to work). Designation as an event related to CF was based on ratings of 1 (“possibly or probably CF related”) or 2 (“definitely CF related”). Trained interviewers made the initial ratings, then the transcripts and ratings were reviewed by the trainer, and any discrepancies were discussed to consensus. 2.2.4. Neuroticism The neuroticism scale from the NEO Five-Factor Inventory [30] was administered at the index visit to control for the potential effects of a negative response set in the self –report measures. The internal consistency of this 12-item scale was 0.85 in this sample; the gender-based normed scores were retained for analysis.
3.2. Number of major life events At the index appointment, 96.9% and 45.8% of patients and 58.3% and 9.4% of observers rated MLEs related and unrelated to CF, respectively. Table 1 also shows the number of MLEs at each research appointment based on patient- and observer-ratings, and by relationship to CF. Based on PERI ratings [28], patients reported approximately two MLEs related to CF and less than one MLE unrelated to CF at each research appointment; based on Brown and Harris' contextual rating system [29], observers rated less than one MLE as related to CF and few MLEs unrelated to CF as each research appointment. The numbers of MLEs decreased over time. Patient- and observer-rated measures of MLEs were modestly associated: r = 0.22 for CF-related, and r = 0.19 for CF-unrelated MLEs.
2.3. Data analysis Descriptive statistics were used to characterize the sample and the number of life events at each research appointment, as rated by patients and by observers. Hierarchical linear models were used to examine the association of MLEs with clinical outcome variables over time, with repeated measures for each research appointment. In addition to the repeated measure of research appointment, the predictors included a main effect for neuroticism, and the interaction of time (research appointment) with each of four MLE variables: patient perceived MLEs attributed to CF in the past six months and MLEs not attributed to CF in the past six months, and observer-reported MLEs attributed to CF in the past six months and MLEs not attributed to CF in the past six months. The analysis was repeated twice for each clinical outcome variable (SF36 vitality and CF symptom severity). As described above, the PERI queries the occurrence of events in the six months before the research appointment. As such, an association of MLEs and clinical outcomes collected at the same research appointment is expected to reflect the relationship of the previous six months' events with contemporary clinical status.
3.3. Association of major life events with clinical status over time At the index appointment, patients' average vitality scores were well below the normal range (M = 16.79, SD = 14.70), and CF symptom scores averaged 22.05 (SD = 4.45) out of 36 possible points. Normed neuroticism scores averaged 50.70 (M = 10.24). At the index appointment, neuroticism was correlated with MLE variables as follows: patient-reported MLEs related to CF, r = 0.26; patient-reported MLEs not related to CF, r = 0.08; observer-rated MLEs related to CF, r = 0.13; observer-rated MLEs not related to CF, r = 0.08. The HLM analyses of CF symptoms was based on 352 observations. CF symptoms decreased significantly over time, as was reported previously [25], and neuroticism was not significantly related to CF symptoms. The interactions of MLE variables with time were of primary interest. The interactions of time with the numbers of MLEs related to CF by patients and by observers were significantly associated with fatigue symptoms; the interactions of MLEs not related to CF were not significant. Table 2 shows a summary of the results of the HLM analyses, which indicate that over time, increasing MLEs related to CF – as rated by both patient and observer – were associated with increasing CF symptoms. In order to examine this effect further, Fig. 1 graphically depicts the average estimated CF symptom scores at each research appointment across patients, with separate lines for each number of life events from zero through six as reported by patients (the numbers of patients reporting more than six MLEs were small: n = 4 at the index appointment; n = 2 at the 6 month appointment; n = 0 at the 12 month appointment, and n = 1 at the 18 month appointment). This graph suggests that in particular five or six MLEs related to CF were associated with greater CF symptoms over time whereas fewer such MLEs were
3. Results The sample consisted of 99 patients that averaged 43.86 years of age (SD = 9.52), 14.66 years of education (SD = 2.42), and who reported having CF an average of 6.24 years (SD = 4.02) at the time of their index visit. Ninety-three percent of patients met case criteria for CFS and the remaining 7% met case criteria for ICF. Consistent with the characteristics of clinical samples of CF patients [2,3,27], 82% of the patients were female and 92% were Caucasian. Sixty-one percent were partnered (married or living with an intimate partner), 40% were employed (21% were employed full-time or 35 or more hours per week, and 19% part-time), and of the remaining 60% who were unemployed, 33% were receiving disability compensation, and 27% were not. 3.1. Number and type of life events Table 1 shows the average number of life events reported by 3
Journal of Psychosomatic Research 125 (2019) 109810
K.B. Schmaling and T.L. Patterson
Table 1 Average numbers of life events by research appointment.
N Total patient-reported life events Major life events related to CF Patient rated Observer rated Major life events not related to CF Patient rated Observer rated
Index appointment
6 months
12 months
18 months
96 6.11 (2.66)
83 5.48 (2.58)
88 4.82 (2.64)
88 4.57 (2.45)
2.45 (1.72) 0.66 (0.61)
2.44 (1.52) 0.62 (0.62)
1.98 (1.21) 0.51 (0.61)
1.76 (1.28) 0.44 (0.52)
0.80 (1.05) 0.13 (0.47)
0.73 (1.02) 0.20 (0.53)
0.63 (1.03) 0.21 (0.53)
0.74 (1.02) 0.22 (0.47)
Table 2 Major life event predictors of clinical status over time. Clinical status
Predictor
t
df
p=
CF symptoms
Research appointment (time) Neuroticism Patient: MLEs related to CF Patient: MLEs not related to CF Observer: MLEs related to CF Observer: MLEs not related to CF Research appointment (time) Neuroticism Patient: MLEs related to CF Patient: MLEs not related to CF Observer: MLEs related to CF Observer: MLEs not related to CF
−3.51 1.86 2.38 −0.96 2.84 0.35 4.44 3.35 −1.24 0.43 −2.86 −1.53
326.73 97.63 294.72 256.72 320.42 236.80 341.70 112.98 334.29 293.39 339.62 260.37
0.00 0.07 0.02 0.34 0.01 0.73 0.00 0.07 0.22 0.67 0.00 0.13
SF-36 vitality
Note: MLE = major life event. Fig. 2. Average SF-36 vitality scores by time and number of observer-rated major life events related to CF. Note: the top, solid line are patients with zero observer-rated CF-related MLEs at each research appointment; the middle line (shorter dashes) are those with one MLE; and the bottom line (longer dashes) are those with two MLEs.
MLEs related to CF with time on vitality such that, over time, fewer MLEs related to CF were associated with increasing vitality. Fig. 2 graphically depicts this effect with the average estimated SF-36 vitality scores at each research appointment across patients, with separate lines for zero, one, and two observer-rated MLEs related to CF. This graph suggests that two MLEs were associated with little change in vitality over time, whereas no MLEs, and to a lesser extent, one MLE, were associated with greater vitality over time. The other interactions of patient rated MLEs related to CF and both observer and patient perceived MLEs not related to CF with time were not significant. Fig. 1. Average cf symptom scores by time and number of patient-rated major life events related to CF. Note: from the bottom to the top of the figure, the bottom four solid lines show average CF symptoms scores for patients who reported zero, one, two, and three major life events related to CF in the six months prior to each research appointment, respectively. The top two dashed lines are those who reported five and six MLEs at each research appointment, respectively. The solid lines suggest decreasing or steady CF symptoms across time for those with zero through four major life events; the dashed lines suggest that five or six major life events are associated with increasing CF symptoms.
4. Discussion This study adds to the literature on the associations of MLEs and CF illness over time, uniquely examining two measures of MLEs by patients and observers, separating MLEs related to CF from those unrelated to CF, and controlling for negative response set. The patients in this sample reported between four and six total life events per six month period, most frequently health- and finance-related events. Of those total events, patients rated between two and three events as significantly undesirable, 70%–77% of which were related to CF. By comparison, observers rated about one event per six month period as having severe impacts, with CF-related events accounting for between 67%–84% of these events. A previous study of patients with alcohol use disorders also assessed MLEs based on both patient reports and observer ratings [31]. The proportions of participants with MLEs in that study can be compared to those of the current study, although there were differences in study methodology. In the current study, six month MLEs unrelated to CF based on patient and observer ratings were more and less common, respectively, compared to three month MLEs
associated with steady or lesser CF symptoms over time. (The graph of this effect based on observer-reported events, which ranged from zero to two, was similar, with the CF symptom values declining across time for those with zero events, increasing for those with two events, and changing little for those with one event.) The HLM analysis of SF-36 vitality was based on 349 observations. Vitality increased significantly over time, as was reported previously [25], and neuroticism was not significantly related to vitality. There was a significant effect of the interaction of observer-rated numbers of 4
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K.B. Schmaling and T.L. Patterson
5. Conclusions
unrelated to alcohol abuse (patient: 46% vs. 27%; observer: 9% vs. 18%) [31]. The numbers of observer-rated MLEs in the present and past [31] studies involving patient samples are greater than an approximate 3% MLE rate in a three-week period in a population-based sample [29]. This study found that greater numbers of major life events related to CF are associated with worse CF clinical status over time. Specifically, more MLEs were associated with increasing CF symptoms and vitality scores lower than the normal range. These results were stronger for standardized observer ratings of life events than for patient-related life events: the effects were found for observer rated life events for both outcome variables but for only one outcome variable for patient rated events. This pattern of results, in consort with the findings that clinical outcome measures were not significantly related to negative response set, suggests that the results are unlikely attributable to reporting biases. Specifically, patients who reported five and six MLEs related to CF, or had two observed-rated MLEs related to CF, appeared to have more CF symptoms over time than those with fewer MLEs (see Fig. 1). Furthermore, this cohort of patients began the study with similar scores on the clinical status variables. These patients' clinical states became increasingly differentiated over time according to the number of MLEs. If the results simply reflected reporting or method biases, this pattern would likely not have emerged. When living with a chronic illness, particularly one with unclear prognosis and treatment options such as CF, attentiveness regarding events with the potential for negative illness consequences is understandable, and consistent with a sensitization model [18]. Although untested in the present study, at a physiological level, others have observed blunted cortisol responses to stress in CF [18,32], which might contribute to sensitivity [18]. At a psychological level, attentiveness appears to be specific to CF-related events – akin to the selective cognitive processing priority sensitization model proposed by Brosschot [33]. Specifically, worse clinical status was related to negative MLEs related to CF more than to generalized negativity (i.e., neuroticism). Stress management may have a useful role in the treatment of CF, as others have recommended [34]. While we are aware of only two clinical trials of stress management for CF thus far, stress management resulted in significantly decreased CF symptom severity in both trials [35,36]. The results of this study suggest several directions for future research, including addressing several limitations. First, there are several methodological limitations. Patient- and observer-rated MLEs could not be compared directly because they involved different methodology. For example, there were cases in which chronic financial stress was rated as extremely negative by patients, but observers rated this difficulty as having moderate impacts, although there was agreement that it was related to CF. The list of life events [28] is relatively more focused on negative than positive life events. Because positive life events were associated with less fatigue severity in a previous study [17], future research should provide a more thorough evaluation of positive events and their association with illness course. A challenge for CF research is its reliance on patient report. The present study included a measure of negative affectivity and used standardized observer ratings of events in order to mitigate the effects of potential reporting biases. The use of objective measures and/or independent reports that complement patient reports will increase confidence in the results. Second, the sample was recruited from a tertiary care center and the results of the study cannot be generalized to all patients with unexplained CF. Third, the study allowed us to model the association of life events and CF over time, but cannot determine if life events play a causal role in CF. The cohort in this study was ill prior to study initiation; future research would need to assess life events and stress sensitivity (e.g., neuroticism) prior to illness onset in order to examine their precipitating functions. In addition to addressing these limitations, future studies could examine the biological underpinnings and associative learning in relating stressful events and CF noted in the present study.
This study examined the associations of MLEs and CF illness over time and examined MLEs related to CF and non-CF as rated by patients and by observers. As judged by both patients and observers, MLEs related to CF were associated with worse CF clinical status over time, which was not related to patients' negative response set. This study adds to the literature regarding specific types of life events' relationship to illness course. A clinical implication of the results is that stress management may be relevant and helpful in the treatment of CF. Funding This work was supported by the National Institutes of Health, U19AI38429. Declaration of Competing Interest None. Acknowledgements The authors wish to extend their sincere thanks to the patients who participated in this study, and to those who helped with data collection. References [1] K. Fukuda, S.E. Straus, I. Hickie, M.C. Sharpe, J.G. Dobbins, A. Komaroff, the International Chronic Fatigue Syndrome Study Group, The chronic fatigue syndrome: a comprehensive approach to its definition and study, Ann. Intern. Med. 121 (1994) 953–959, https://doi.org/10.7326/0003-4819-121-12-199412150-00009. [2] D. Buchwald, T. Pearlman, P. Kith, W. Katon, K. Schmaling, Screening for psychiatric disorders in chronic fatigue and chronic fatigue syndrome, J. Psychosom. Res. 42 (1997) 87–94, https://doi.org/10.1016/S0022-3999(96)00234-6. [3] D. Buchwald, T. Pearlman, J. Umali, K. Schmaling, W. Katon, Functional status in patients with chronic fatigue syndrome, other fatiguing illnesses, and healthy individuals, Am. J. Med. 171 (1996) 364–370, https://doi.org/10.1016/S00029343(96)00234-3. [4] P.F. Sullivan, P. Kovalenko, T.P. York, C.A. Prescott, K.S. Kendler, Fatigue in a community sample of twins, Psychol. Med. 33 (2003) 263–281, https://doi.org/10. 1017/S0033291702007031. [5] W.D.A. Bruce-Jones, P.D. White, J.M. Thomas, A.W. Clare, The effect of social adversity on the fatigue syndrome, psychiatric disorders and physical recovery, following glandular fever, Psychol. Med. 24 (1994) 651–659, https://doi.org/10. 1017/S003329170002780X. [6] L.A. Jason, B.Z. Katz, Y. Shiraishi, C.J. Mears, Y. Im, R.R. Taylor, Predictors of postinfectious chronic fatigue syndrome in adolescents, Health Psychol. Behav. Med. 2 (1) (2014) 41–51, https://doi.org/10.1080/21642850.2013.869176. [7] L.A. Jason, R.R. Taylor, C.L. Kennedy, S. Song, D. Johnson, S. Torres, Chronic fatigue syndrome: occupation, medical utilization, and subtypes in a communitybased sample, J. Nerv. Ment. Dis. 188 (9) (2000) 568–576. [8] I.E. Salit, Precipitating factors for the chronic fatigue syndrome, J. Psychiatr. Res. 31 (1997) 59–65, https://doi.org/10.1016/S0022-3956(96)00050-7. [9] S. Hatcher, A. House, Life events, difficulties and dilemmas in the onset of chronic fatigue syndrome: a case-control study, Psychol. Med. 33 (2003) 1185–1192, https://doi.org/10.1017/S0033291703008274. [10] T. Theorell, V. Blomkvist, G. Lindh, B. Evengard, Critical life events, infections, and symptoms during the year preceding chronic fatigue syndrome (CFS): an examination of CFS patients and subjects with a nonspecific life crisis, Psychosomatic Medicine 61 (1999) 304–310 doi. [11] I. Gimno Pi, M.L. Guitard Sein-Echaluce, L. Rosselló Aubach, J. Torres Puig-Gros, J. Fernández Solà, Stressful events in the onset of chronic fatigue syndrome, Revista Española de Salud Pública (Spanish J. Public Health) 18 (2016) e1–e7. [12] A. Clements, M. Sharpe, S. Simkin, J. Borrill, K. Hawton, Chronic fatigue syndrome: a qualitative investigation of patients’ beliefs about the illness, J. Psychosom. Res. 42 (6) (1997) 615–624, https://doi.org/10.1016/S0022-3999(97)00087-1. [13] S. Lewis, C.L. Cooper, D. Bennett, Psychosocial factors and chronic fatigue syndrome, Psychol. Med. 24 (1994) 661–671, https://doi.org/10.1017/ S0033291700027811. [14] F. Friedberg, J. Coronel, V. Seva, J.L. Adamowicz, A. Napoli, Participant attributions for global change ratings in unexplained chronic fatigue and chronic fatigue syndrome, J. Health Psychol. 21 (2016) 690–698, https://doi.org/10.1177/ 1359105314535458. [15] S.K. Lutgendorf, M.H. Antoni, G. Ironson, M.A. Fletcher, F. Penedo, A. Baum, N. Schneiderman, N. Klimas, Physical symptoms of chronic fatigue syndrome are exacerbated by the stress of Hurricane Andrew, Psychosom. Med. 57 (1995) 310–323, https://doi.org/10.1097/00006842-199507000-00002.
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[27] A.L. Komaroff, L.R. Fagiolo, T.H. Doolittle, B. Gandek, M.A. Gleit, R.T. Guerriero, J. Kornish, N.C. Ware, J.E. Ware, D.W. Bates, Health status in patients with chronic fatigue syndrome and in general population and disease comparison groups, Am. J. Med. 101 (1996) 281–290, https://doi.org/10.1016/S0002-9343(96)00174-X. [28] R.M.A. Hirschfield, G.L. Lerman, A.P. Schless, J. Endicott, S. Lichtenstaeder, P.J. Clayton, Modified Life Events Sections of the Psychiatric Epidemiology Research Interview (PERI-M), National Institute of Mental Health, Bethesda, MD, 1977. [29] G.W. Brown, Life events and measurement, in: G.W. Brown, T.O. Harris (Eds.), Life Events and Illness, Guilford, New York, 1989, pp. 3–45. [30] P.T. Costa, R.R. McCrae, Revised NEO Personality Inventory (NEO-PI-R) and NEO Five-Factor Inventory (NEO-FFI) Professional Manual, Psychological Assessment Resources, Odessa, FL, 1992. [31] S.A. Brown, P.W. Vik, J.R. McQuaid, T.L. Patterson, M.R. Irwin, I. Grant, Severity of psychosocial stress and outcome of alcoholism treatment, J. Abnorm. Psychol. 99 (1990) 344–348, https://doi.org/10.1037/0021-843X.99.4.344. [32] K.B. Schmaling, J.M. Romano, M.P. Jensen, C.W. Wilkinson, S. McPherson, Salivary cortisol responses to household tasks among couples with unexplained chronic fatigue, J. Fam. Psychol. 29 (2) (2015) 296–301, https://doi.org/10.1037/ fam0000074. [33] J.F. Brosschot, Cognitive-emotional sensitization and somatic health complaints, Scand. J. Psychol. 43 (2002) 113–121, https://doi.org/10.1111/1467-9450.00276. [34] J. Nijs, M. Meeus, J. Van Oosterwijck, N. Roussel, M. De Kooning, K. Ickmans, M. Matic, Treatment of central sensitization in patients with ‘unexplained’ chronic pain: what options do we have? Expert. Opin. Pharmacother. 12 (2011) 1087–1098, https://doi.org/10.1517/14656566.2011.547475. [35] D.L. Hall, E.G. Lattie, S.F. Milrad, S. Czaja, M.A. Fletcher, N. Klimas, D. Perdomo, M.H. Antoni, Telephone-administered versus live group cognitive-behavioral stress management for adults with CFS, J. Psychosom. Res. 93 (2017) 41–47, https://doi. org/10.1016/j.jpsychores.2016.12.004. [36] C. Lopez, M. Antoni, F. Penedo, D. Weiss, S. Cruess, M.C. Segotas, L. Helder, S. Siegel, N. Klimas, M.A. Fletcher, A pilot study of cognitive behavioral stress management effects on stress, quality of life, and symptoms in persons with chronic fatigue syndrome, J. Psychosom. Res. 70 (2011) 328–334, https://doi.org/10. 1016/j.jpsychores.2010.11.010.
[16] U.M. Nater, E. Maloney, C. Heim, W.C. Reeves, Cumulative life stress in chronic fatigue syndrome, Psychiatry Res. 189 (2011) 318–320, https://doi.org/10.1016/j. psychres.2011.07.015. [17] C. Ray, S. Jefferies, W.R.C. Weir, Life-events and the course of chronic fatigue syndrome, Br. J. Med. Psychol. 68 (1995) 323–331, https://doi.org/10.1111/j. 2044-8341.1995.tb01839.x. [18] J. Nijs, M. Meeus, J. Van Oosterwijck, K. Ickmans, G. Moorkens, G. Hans, L.S. De Clerck, In the mind or in the brain? Scientific evidence for central sensitization in chronic fatigue syndrome, Eur. J. Clin. Investig. 42 (2012) 203–212, https://doi. org/10.1111/j.1365-2362.2011.02575.x. [19] K.L. Harkness, S.M. Monroe, The assessment and measurement of adult life stress: basic premises, basic principles, and design requirements, J. Abnorm. Psychol. 125 (2016) 727–745, https://doi.org/10.1037/abn0000178. [20] J.R. McQuaid, S.M. Monroe, J.E. Roberts, D.J. Kupfer, E. Frank, A comparison of two life stress assessment approaches: prospective prediction of treatment outcome in recurrent depression, J. Abnorm. Psychol. 109 (2000) 787–791, https://doi.org/ 10.1037/0021-843X.109.4.787. [21] M.A. Besharat, A. Behpajooh, H. Poursharifi, F. Zarani, Personality and chronic fatigue syndrome: the role of the five-factor model, Asian J. Psychiatr. 4 (2011) 55–59, https://doi.org/10.1016/j.ajp.2010.12.001. [22] B. Poeschla, E. Strachan, E. Dansie, D.S. Buchwalk, N. Afari, Chronic fatigue and personality: a twin study of causal pathways and shared liabilities, Ann. Behav. Med. 45 (2013) 289–298, https://doi.org/10.1007/s12160-012-9463-5. [23] B.F. Jeronimus, H. Riese, R. Sanderman, J. Ormel, Mutual reinforcement between neuroticism and life experiences: a five-wave, 16-year study to test reciprocal causation, J. Pers. Soc. Psychol. 107 (4) (2014) 751–764, https://doi.org/10.1037/ a0037009. [24] K.S. Kendler, J. Kuhn, C.A. Prescott, The interrelationship of neuroticism, sex, and stressful life events in the prediction of episodes of major depression, Am. J. Psychiatr. 161 (2004) 631–636, https://doi.org/10.1176/appi.ajp.161.4.631. [25] K.B. Schmaling, J.I. Fiedelak, D.S. Buchwald, W.J. Katon, J.O. Bader, Prospective study of the prognosis of unexplained chronic fatigue in a clinic-based cohort, Psychosom. Med. 65 (2003) 1047–1054, https://doi.org/10.1097/01.PSY. 0000088587.29901.69. [26] J.E. Ware, SF-36 Health Survey: Manual and Interpretation Guide, The Health Institute, New England Medical Center, Boston, MA, 1993.
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The association of major life events with chronic fatigue a,⁎
Karen B. Schmaling , Thomas L. Patterson a b
T
b
Washington State University, United States of America University of California San Diego, United States of America
A R T I C LE I N FO
A B S T R A C T
Keywords: Chronic fatigue Life events Outcome Stress
Objective: Major life events have been associated with the onset of unexplained chronic fatigue (CF) and with variability in illness course. The purpose of this study was to characterize the associations of major life events with illness status over time. Method: Sentinel measures of clinical status were collected four times over 18 months in a cohort of 99 persons with CF; participants also were interviewed regarding major life events, which were independently rated by observers. Results: Over time, more major life events attributed to CF predicted a worse clinical course, suggesting that illness-related major life events rather than stressful life events in general are associated with worse clinical status for persons with CF. Conclusion: This study adds to the literature regarding specific types of life events' relationship to illness course, which has implications for the management of CF.
1. Introduction Unexplained chronic fatigue (CF) is defined as new and disabling fatigue lasting six months or longer that is unexplained insofar as it is not attributable to known causes of fatigue such as neoplasms. CF includes chronic fatigue syndrome (CFS) and idiopathic chronic fatigue (ICF). The International CFS Study Group case definition [1] differentiates these two conditions based on the number of symptoms occurring with the fatigue, such as unrefreshing sleep and myalgia. CFS is characterized by presence of four or more symptoms and ICF by less than four symptoms occurring with the fatigue. No physical signs or diagnostic tests are specific to CFS or ICF, and studies comparing the two conditions have found few clinically meaningful distinguishing characteristics [2,3]. This paper focuses on major life events (MLEs) among patients with CF (either CFS or ICF). The literature on the association of MLEs and CF is reviewed below, first focusing on prospective and retrospective studies of the association of MLEs with the onset of CF, followed by studies on cross-sectional associations between MLEs and CF. 1.1. Prospective studies of major life events and CF onset The results of prospective studies of the association of MLEs with CF
onset have been inconsistent. MLEs in the year prior to CF onset were associated with a nearly two-fold increase in the likelihood of having five or more days of fatigue that interfered with functioning [4]. However, two other studies did not identified significant associations. Bruce-Jones, White, Thomas, and Clare [5] found that MLEs and difficulties did not predict incident cases of prolonged fatigue following an acute infection. Similarly, Jason, Katz, Shiraishi, Mears, Im, and Taylor [6] found that MLEs were not associated with the development of CFS following infectious mononucleosis. It should be noted that these studies with negative findings were focused more narrowly on CF following an acute infection [5,6], whereas the study with positive findings did not limit putative predisposing events [4]. 1.2. Retrospective studies of major life events and CF onset Most retrospective studies have found that MLEs precede the onset of CF. Half of the CFS cases identified in one large sample stated they experienced “unusually severe stress at the time of their illness onset and were able to identify a particular stressful event” [7] (p. 572). In three studies, patients with CFS were approximately 14, nine, and two times more likely to report having MLEs in the 12, three, and four months prior to illness onset compared to non-fatigued controls, respectively [8–10]. Another study found seven life events to have
⁎ Corresponding author at: Department of Psychology, Washington State University, 14204 NE Salmon Creek Ave., Vancouver, WA 98686, United States of America. E-mail address: [email protected] (K.B. Schmaling).
https://doi.org/10.1016/j.jpsychores.2019.109810 Received 18 May 2019; Received in revised form 11 August 2019; Accepted 12 August 2019 0022-3999/ © 2019 Elsevier Inc. All rights reserved.
Journal of Psychosomatic Research 125 (2019) 109810
K.B. Schmaling and T.L. Patterson
role of neuroticism in reports of MLEs and CF status.
occurred more frequently (odds ratios ranged from 2.8 to 31.7) prior to the onset of CFS than compared to the controls [11]. In a study examining participants' beliefs about the causes of their CFS, nearly all participants identified a physical illness, most often an infection, as the cause of their CFS, but 56% also identified social stressors (bereavement, financial worries, relationship problems, etc.) as co-occurring causes [12]. However, the number of MLEs in the two years prior to the onset of illness did not differ between patients with CFS, irritable bowel syndrome, or healthy controls [13].
2. Materials and method 2.1. Participants and procedures Patients, study inclusion and exclusion criteria, and their clinical status over time were described previously [25]. Briefly, patients were recruited from a tertiary care CF clinic associated with a medical school-affiliated hospital. Potential participants who were between the ages of 18–65 and met the 1994 International CFS Study Group case criteria for CFS or ICF [1] were screened, and if eligible, were recruited for study participation at their clinic appointment. To be eligible, patients' medical records were reviewed prior to their appointment for recent medical and psychiatric evaluations to confirm CF and exclude other causes of CF; these evaluations were repeated at the index visit and on three subsequent occasions, six months apart (physical examination; laboratory tests; structured psychiatric diagnostic interview; symptom questionnaires). The study was reviewed and approved by the IRB at the first author's institution; all participants provided written informed consent. Participants received honoraria for completing each research appointment.
1.3. Cross-sectional covariation of major life events with CF symptoms In addition to the question of an association between stressful events and CF onset, it is also of interest how stressful events covary with CF symptoms among those already recognized as having CF. These studies' finding have been equivocal. Positive associations were found in three studies: Three months following the end of a clinical trial, patients who had worsened since the end of the trial were likely to attribute these changes to life events, such as job loss and motor vehicle accidents, as well as to higher levels of general stress [14]. Patients with CFS living in the area proximal to Hurricane Andrew were more likely to have clinician-observed relapses than patients living farther away from the hurricane [15]. In a large surveillance study, those with CFS had more MLEs in the past year, especially MLES perceived as having a negative impact, compared to non-fatigued participants, after controlling for sociodemographic variables [16]. However, another study found that negative MLEs were unrelated to fatigue severity, but positive life events were related to less fatigue severity [17]. In summary, most previous studies found MLEs to be associated with CF onset or worsened CF symptoms. It is well recognized that stress can have negative effects on health through a number of possible mechanisms. Sensitization is one such model for the deleterious effects of stress. This model involves hyperresponsiveness of the central nervous system to a variety of stimuli; in CF, stress heightens this hyperresponsivness further [18]. In a sensitization model of CF, reactions to stressful events may be examples of the “…cognitive and emotional factors contributing to and possibly sustaining the mechanism of central sensitization in CFS” (p. 208) [18]. Furthermore, the extant literature includes at least three potential limitations. First, studies regarding MLEs in CF are largely based on patient reports provided via questionnaire or interview. Rarely have life events been evaluated by standardized interviewer ratings following structured interviews [5]. Standardized interviewer ratings separate the assessment of exposure to stress from subjects' reactions to stress [19], which increases consistency in the evaluation of MLEs across subjects, and has had differential power to predict outcomes in previous studies [20]. Second, to our knowledge, only one previous study considered if MLEs could be attributed to CF, and that study excluded MLEs deemed related to CF [5]. Some of the variability in previous studies' results may have been due to combining MLEs related to and independent of CF. Consistent with a sensitization model, MLEs related to CF may be most salient for CF clinical status. Third, some previous studies did not investigate psychological characteristics related to subjects' reactions to MLEs. Neuroticism – also termed negative affectivity or emotional instability – is the tendency to experience negative emotions such as anxiety, tension, and sadness, and has been elevated among those with CF [4,21,22]. Neuroticism has been associated with the perception of stress [23,24], and thus, could also be associated with patients' reporting tendencies. The primary goal of this study was to examine the relationship of patient- and observer-rated life events to clinical status over time. It was predicted that undesirable MLEs would be associated with worse clinical status over time, consistent with most previous studies' results. This study also sought to address three potential limitations in the literature by using both patient and standardized observer measures of life events; examining both MLEs related and unrelated to CF; and examining the
2.2. Measures 2.2.1. Descriptive variables Age, gender, years of CF, years of education, ethnicity (recoded as either Caucasian or non-Caucasian), relationship status (recoded as either married or living with an intimate partner versus single, widowed, or divorced), and employment status (recoded as either working partor full-time versus not working) were gathered to describe the sample. 2.2.2. Clinical status 2.2.2.1. CF symptoms. The total patient-rated frequency of experiencing the nine symptoms in the International CFS Study Group case definition (fatigue, memory or concentration problems, sore throat, painful lymph nodes, muscle pain, joint pain, headaches, unrefreshing sleep, and feeling poorly after exertion) on a five-point scale (0 = not at all to 4 = constantly), yielded a possible score range of 0–36. In this sample, the internal consistency of this scale (Cronbach's alpha) averaged 0.75 (range: 0.64–0.82) across its four administrations, and decreased significantly over time [25]. 2.2.2.2. Functional status. The vitality score from the Short Form-36 [26] was used to evaluate functional status relevant to fatigue. Higher scores indicate better functioning, each score ranges from 0 to 100, and the normal range of scores is considered to be 80 and above. This score was chosen on the basis of its demonstrated tendency to be sensitive to change over time in samples with CF [27], including the cohort in the present study [25]. The internal consistency of this scale averaged 0.96 (range: 0.92 to 0.97) across its four administrations. 2.2.3. Major life events 2.2.3.1. Patient-rated major life events. The modified Psychiatric Epidemiology Research Interview (PERI) [28] is a structured interview that queries the patient about the occurrence of 133 events in the six months before the research appointment. For each event, the interviewer obtained a description of the event including its context and consequences. Next, the patient rated the event's desirability on a 7-point scale, and its perceived association with CF on a 5-point scale. The number of MLEs for each six month period was based on patient desirability ratings of 1 (“extremely negative”) or 2 (“moderately negative”). The number of MLEs perceived as related to CF were based on participant ratings of two or greater (2=“a little bit,” 3 = “moderately,” 4=“quite a bit,” 5 = “extremely”), and those not 2
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patients at each research appointment, which ranged from 1 to 11 events per patient. At the index visit, patients reported a variety of events, endorsing 90 of the 133 possible categories one or more times. The most frequently-reported events were those related to health (“suffered from a physical illness or disability lasting a month or more, not requiring hospitalization,” 12.1%; “ongoing medical or psychiatric treatment,” 11.9%; “chronic poor health,” 6.0%; “sustained a minor injury,” 3.2%), finances (“chronic financial stress,” 4.8%; “financial situation worsened,” 3.7%; “insurance company problems,” 3.4%), self (“revision of personal habits, including sleeping eating, exercising,” 3.9%), and others (“close family member became or was pregnant,” 2.7%; ‘attended funerals,” 2.4%). These ten most-frequently endorsed categories changed little over time with few exceptions. At the six month appointment, “sexual difficulties” was endorsed by 2.4%; at the one-year appointment, “close family member was hospitalized for a lifethreatening physical illness, disability, or major surgery” was endorsed by 2.4%, and “conditions at work got worse” by 1.9%; and at the 18 month appointment, “new person became resident in the household” by 2.7% and death of “someone else who was important to you” other than family or friends by 2.2%.
perceived as related to CF had ratings of one. For example, participants might rate being fired from a job secondary to absenteeism due to illness as an event related to CF, but not the death of a loved one. 2.2.3.2. Observer-rated major life events. The PERI interview was transcribed and trained observers rated each event according to Brown and Harris's contextual rating system [29]. Discrete events (e.g., a death in the family) were rated in terms of short-term and long-term threat on a 4-point scale, and their association with CF on a 3-point scale. Ongoing events (e.g., having a disabled partner) were rated in terms of difficulty on a 6-point scale, along with association with CF. The number of MLEs for each six month period was based on discrete events with severe impact ratings, i.e., short-term threat ratings of 1 (severe), long-term threat ratings of 1 or 2 (moderate or severe), or ongoing difficulties rated 1, 2, or 3 (moderate or severe, sufficient to be judged as role disruptive, such as being unable to work). Designation as an event related to CF was based on ratings of 1 (“possibly or probably CF related”) or 2 (“definitely CF related”). Trained interviewers made the initial ratings, then the transcripts and ratings were reviewed by the trainer, and any discrepancies were discussed to consensus. 2.2.4. Neuroticism The neuroticism scale from the NEO Five-Factor Inventory [30] was administered at the index visit to control for the potential effects of a negative response set in the self –report measures. The internal consistency of this 12-item scale was 0.85 in this sample; the gender-based normed scores were retained for analysis.
3.2. Number of major life events At the index appointment, 96.9% and 45.8% of patients and 58.3% and 9.4% of observers rated MLEs related and unrelated to CF, respectively. Table 1 also shows the number of MLEs at each research appointment based on patient- and observer-ratings, and by relationship to CF. Based on PERI ratings [28], patients reported approximately two MLEs related to CF and less than one MLE unrelated to CF at each research appointment; based on Brown and Harris' contextual rating system [29], observers rated less than one MLE as related to CF and few MLEs unrelated to CF as each research appointment. The numbers of MLEs decreased over time. Patient- and observer-rated measures of MLEs were modestly associated: r = 0.22 for CF-related, and r = 0.19 for CF-unrelated MLEs.
2.3. Data analysis Descriptive statistics were used to characterize the sample and the number of life events at each research appointment, as rated by patients and by observers. Hierarchical linear models were used to examine the association of MLEs with clinical outcome variables over time, with repeated measures for each research appointment. In addition to the repeated measure of research appointment, the predictors included a main effect for neuroticism, and the interaction of time (research appointment) with each of four MLE variables: patient perceived MLEs attributed to CF in the past six months and MLEs not attributed to CF in the past six months, and observer-reported MLEs attributed to CF in the past six months and MLEs not attributed to CF in the past six months. The analysis was repeated twice for each clinical outcome variable (SF36 vitality and CF symptom severity). As described above, the PERI queries the occurrence of events in the six months before the research appointment. As such, an association of MLEs and clinical outcomes collected at the same research appointment is expected to reflect the relationship of the previous six months' events with contemporary clinical status.
3.3. Association of major life events with clinical status over time At the index appointment, patients' average vitality scores were well below the normal range (M = 16.79, SD = 14.70), and CF symptom scores averaged 22.05 (SD = 4.45) out of 36 possible points. Normed neuroticism scores averaged 50.70 (M = 10.24). At the index appointment, neuroticism was correlated with MLE variables as follows: patient-reported MLEs related to CF, r = 0.26; patient-reported MLEs not related to CF, r = 0.08; observer-rated MLEs related to CF, r = 0.13; observer-rated MLEs not related to CF, r = 0.08. The HLM analyses of CF symptoms was based on 352 observations. CF symptoms decreased significantly over time, as was reported previously [25], and neuroticism was not significantly related to CF symptoms. The interactions of MLE variables with time were of primary interest. The interactions of time with the numbers of MLEs related to CF by patients and by observers were significantly associated with fatigue symptoms; the interactions of MLEs not related to CF were not significant. Table 2 shows a summary of the results of the HLM analyses, which indicate that over time, increasing MLEs related to CF – as rated by both patient and observer – were associated with increasing CF symptoms. In order to examine this effect further, Fig. 1 graphically depicts the average estimated CF symptom scores at each research appointment across patients, with separate lines for each number of life events from zero through six as reported by patients (the numbers of patients reporting more than six MLEs were small: n = 4 at the index appointment; n = 2 at the 6 month appointment; n = 0 at the 12 month appointment, and n = 1 at the 18 month appointment). This graph suggests that in particular five or six MLEs related to CF were associated with greater CF symptoms over time whereas fewer such MLEs were
3. Results The sample consisted of 99 patients that averaged 43.86 years of age (SD = 9.52), 14.66 years of education (SD = 2.42), and who reported having CF an average of 6.24 years (SD = 4.02) at the time of their index visit. Ninety-three percent of patients met case criteria for CFS and the remaining 7% met case criteria for ICF. Consistent with the characteristics of clinical samples of CF patients [2,3,27], 82% of the patients were female and 92% were Caucasian. Sixty-one percent were partnered (married or living with an intimate partner), 40% were employed (21% were employed full-time or 35 or more hours per week, and 19% part-time), and of the remaining 60% who were unemployed, 33% were receiving disability compensation, and 27% were not. 3.1. Number and type of life events Table 1 shows the average number of life events reported by 3
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Table 1 Average numbers of life events by research appointment.
N Total patient-reported life events Major life events related to CF Patient rated Observer rated Major life events not related to CF Patient rated Observer rated
Index appointment
6 months
12 months
18 months
96 6.11 (2.66)
83 5.48 (2.58)
88 4.82 (2.64)
88 4.57 (2.45)
2.45 (1.72) 0.66 (0.61)
2.44 (1.52) 0.62 (0.62)
1.98 (1.21) 0.51 (0.61)
1.76 (1.28) 0.44 (0.52)
0.80 (1.05) 0.13 (0.47)
0.73 (1.02) 0.20 (0.53)
0.63 (1.03) 0.21 (0.53)
0.74 (1.02) 0.22 (0.47)
Table 2 Major life event predictors of clinical status over time. Clinical status
Predictor
t
df
p=
CF symptoms
Research appointment (time) Neuroticism Patient: MLEs related to CF Patient: MLEs not related to CF Observer: MLEs related to CF Observer: MLEs not related to CF Research appointment (time) Neuroticism Patient: MLEs related to CF Patient: MLEs not related to CF Observer: MLEs related to CF Observer: MLEs not related to CF
−3.51 1.86 2.38 −0.96 2.84 0.35 4.44 3.35 −1.24 0.43 −2.86 −1.53
326.73 97.63 294.72 256.72 320.42 236.80 341.70 112.98 334.29 293.39 339.62 260.37
0.00 0.07 0.02 0.34 0.01 0.73 0.00 0.07 0.22 0.67 0.00 0.13
SF-36 vitality
Note: MLE = major life event. Fig. 2. Average SF-36 vitality scores by time and number of observer-rated major life events related to CF. Note: the top, solid line are patients with zero observer-rated CF-related MLEs at each research appointment; the middle line (shorter dashes) are those with one MLE; and the bottom line (longer dashes) are those with two MLEs.
MLEs related to CF with time on vitality such that, over time, fewer MLEs related to CF were associated with increasing vitality. Fig. 2 graphically depicts this effect with the average estimated SF-36 vitality scores at each research appointment across patients, with separate lines for zero, one, and two observer-rated MLEs related to CF. This graph suggests that two MLEs were associated with little change in vitality over time, whereas no MLEs, and to a lesser extent, one MLE, were associated with greater vitality over time. The other interactions of patient rated MLEs related to CF and both observer and patient perceived MLEs not related to CF with time were not significant. Fig. 1. Average cf symptom scores by time and number of patient-rated major life events related to CF. Note: from the bottom to the top of the figure, the bottom four solid lines show average CF symptoms scores for patients who reported zero, one, two, and three major life events related to CF in the six months prior to each research appointment, respectively. The top two dashed lines are those who reported five and six MLEs at each research appointment, respectively. The solid lines suggest decreasing or steady CF symptoms across time for those with zero through four major life events; the dashed lines suggest that five or six major life events are associated with increasing CF symptoms.
4. Discussion This study adds to the literature on the associations of MLEs and CF illness over time, uniquely examining two measures of MLEs by patients and observers, separating MLEs related to CF from those unrelated to CF, and controlling for negative response set. The patients in this sample reported between four and six total life events per six month period, most frequently health- and finance-related events. Of those total events, patients rated between two and three events as significantly undesirable, 70%–77% of which were related to CF. By comparison, observers rated about one event per six month period as having severe impacts, with CF-related events accounting for between 67%–84% of these events. A previous study of patients with alcohol use disorders also assessed MLEs based on both patient reports and observer ratings [31]. The proportions of participants with MLEs in that study can be compared to those of the current study, although there were differences in study methodology. In the current study, six month MLEs unrelated to CF based on patient and observer ratings were more and less common, respectively, compared to three month MLEs
associated with steady or lesser CF symptoms over time. (The graph of this effect based on observer-reported events, which ranged from zero to two, was similar, with the CF symptom values declining across time for those with zero events, increasing for those with two events, and changing little for those with one event.) The HLM analysis of SF-36 vitality was based on 349 observations. Vitality increased significantly over time, as was reported previously [25], and neuroticism was not significantly related to vitality. There was a significant effect of the interaction of observer-rated numbers of 4
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5. Conclusions
unrelated to alcohol abuse (patient: 46% vs. 27%; observer: 9% vs. 18%) [31]. The numbers of observer-rated MLEs in the present and past [31] studies involving patient samples are greater than an approximate 3% MLE rate in a three-week period in a population-based sample [29]. This study found that greater numbers of major life events related to CF are associated with worse CF clinical status over time. Specifically, more MLEs were associated with increasing CF symptoms and vitality scores lower than the normal range. These results were stronger for standardized observer ratings of life events than for patient-related life events: the effects were found for observer rated life events for both outcome variables but for only one outcome variable for patient rated events. This pattern of results, in consort with the findings that clinical outcome measures were not significantly related to negative response set, suggests that the results are unlikely attributable to reporting biases. Specifically, patients who reported five and six MLEs related to CF, or had two observed-rated MLEs related to CF, appeared to have more CF symptoms over time than those with fewer MLEs (see Fig. 1). Furthermore, this cohort of patients began the study with similar scores on the clinical status variables. These patients' clinical states became increasingly differentiated over time according to the number of MLEs. If the results simply reflected reporting or method biases, this pattern would likely not have emerged. When living with a chronic illness, particularly one with unclear prognosis and treatment options such as CF, attentiveness regarding events with the potential for negative illness consequences is understandable, and consistent with a sensitization model [18]. Although untested in the present study, at a physiological level, others have observed blunted cortisol responses to stress in CF [18,32], which might contribute to sensitivity [18]. At a psychological level, attentiveness appears to be specific to CF-related events – akin to the selective cognitive processing priority sensitization model proposed by Brosschot [33]. Specifically, worse clinical status was related to negative MLEs related to CF more than to generalized negativity (i.e., neuroticism). Stress management may have a useful role in the treatment of CF, as others have recommended [34]. While we are aware of only two clinical trials of stress management for CF thus far, stress management resulted in significantly decreased CF symptom severity in both trials [35,36]. The results of this study suggest several directions for future research, including addressing several limitations. First, there are several methodological limitations. Patient- and observer-rated MLEs could not be compared directly because they involved different methodology. For example, there were cases in which chronic financial stress was rated as extremely negative by patients, but observers rated this difficulty as having moderate impacts, although there was agreement that it was related to CF. The list of life events [28] is relatively more focused on negative than positive life events. Because positive life events were associated with less fatigue severity in a previous study [17], future research should provide a more thorough evaluation of positive events and their association with illness course. A challenge for CF research is its reliance on patient report. The present study included a measure of negative affectivity and used standardized observer ratings of events in order to mitigate the effects of potential reporting biases. The use of objective measures and/or independent reports that complement patient reports will increase confidence in the results. Second, the sample was recruited from a tertiary care center and the results of the study cannot be generalized to all patients with unexplained CF. Third, the study allowed us to model the association of life events and CF over time, but cannot determine if life events play a causal role in CF. The cohort in this study was ill prior to study initiation; future research would need to assess life events and stress sensitivity (e.g., neuroticism) prior to illness onset in order to examine their precipitating functions. In addition to addressing these limitations, future studies could examine the biological underpinnings and associative learning in relating stressful events and CF noted in the present study.
This study examined the associations of MLEs and CF illness over time and examined MLEs related to CF and non-CF as rated by patients and by observers. As judged by both patients and observers, MLEs related to CF were associated with worse CF clinical status over time, which was not related to patients' negative response set. This study adds to the literature regarding specific types of life events' relationship to illness course. A clinical implication of the results is that stress management may be relevant and helpful in the treatment of CF. Funding This work was supported by the National Institutes of Health, U19AI38429. Declaration of Competing Interest None. Acknowledgements The authors wish to extend their sincere thanks to the patients who participated in this study, and to those who helped with data collection. References [1] K. Fukuda, S.E. Straus, I. Hickie, M.C. Sharpe, J.G. Dobbins, A. Komaroff, the International Chronic Fatigue Syndrome Study Group, The chronic fatigue syndrome: a comprehensive approach to its definition and study, Ann. Intern. Med. 121 (1994) 953–959, https://doi.org/10.7326/0003-4819-121-12-199412150-00009. [2] D. Buchwald, T. Pearlman, P. Kith, W. Katon, K. Schmaling, Screening for psychiatric disorders in chronic fatigue and chronic fatigue syndrome, J. Psychosom. Res. 42 (1997) 87–94, https://doi.org/10.1016/S0022-3999(96)00234-6. [3] D. Buchwald, T. Pearlman, J. Umali, K. Schmaling, W. Katon, Functional status in patients with chronic fatigue syndrome, other fatiguing illnesses, and healthy individuals, Am. J. Med. 171 (1996) 364–370, https://doi.org/10.1016/S00029343(96)00234-3. [4] P.F. Sullivan, P. Kovalenko, T.P. York, C.A. Prescott, K.S. Kendler, Fatigue in a community sample of twins, Psychol. Med. 33 (2003) 263–281, https://doi.org/10. 1017/S0033291702007031. [5] W.D.A. Bruce-Jones, P.D. White, J.M. Thomas, A.W. Clare, The effect of social adversity on the fatigue syndrome, psychiatric disorders and physical recovery, following glandular fever, Psychol. Med. 24 (1994) 651–659, https://doi.org/10. 1017/S003329170002780X. [6] L.A. Jason, B.Z. Katz, Y. Shiraishi, C.J. Mears, Y. Im, R.R. Taylor, Predictors of postinfectious chronic fatigue syndrome in adolescents, Health Psychol. Behav. Med. 2 (1) (2014) 41–51, https://doi.org/10.1080/21642850.2013.869176. [7] L.A. Jason, R.R. Taylor, C.L. Kennedy, S. Song, D. Johnson, S. Torres, Chronic fatigue syndrome: occupation, medical utilization, and subtypes in a communitybased sample, J. Nerv. Ment. Dis. 188 (9) (2000) 568–576. [8] I.E. Salit, Precipitating factors for the chronic fatigue syndrome, J. Psychiatr. Res. 31 (1997) 59–65, https://doi.org/10.1016/S0022-3956(96)00050-7. [9] S. Hatcher, A. House, Life events, difficulties and dilemmas in the onset of chronic fatigue syndrome: a case-control study, Psychol. Med. 33 (2003) 1185–1192, https://doi.org/10.1017/S0033291703008274. [10] T. Theorell, V. Blomkvist, G. Lindh, B. Evengard, Critical life events, infections, and symptoms during the year preceding chronic fatigue syndrome (CFS): an examination of CFS patients and subjects with a nonspecific life crisis, Psychosomatic Medicine 61 (1999) 304–310 doi. [11] I. Gimno Pi, M.L. Guitard Sein-Echaluce, L. Rosselló Aubach, J. Torres Puig-Gros, J. Fernández Solà, Stressful events in the onset of chronic fatigue syndrome, Revista Española de Salud Pública (Spanish J. Public Health) 18 (2016) e1–e7. [12] A. Clements, M. Sharpe, S. Simkin, J. Borrill, K. Hawton, Chronic fatigue syndrome: a qualitative investigation of patients’ beliefs about the illness, J. Psychosom. Res. 42 (6) (1997) 615–624, https://doi.org/10.1016/S0022-3999(97)00087-1. [13] S. Lewis, C.L. Cooper, D. Bennett, Psychosocial factors and chronic fatigue syndrome, Psychol. Med. 24 (1994) 661–671, https://doi.org/10.1017/ S0033291700027811. [14] F. Friedberg, J. Coronel, V. Seva, J.L. Adamowicz, A. Napoli, Participant attributions for global change ratings in unexplained chronic fatigue and chronic fatigue syndrome, J. Health Psychol. 21 (2016) 690–698, https://doi.org/10.1177/ 1359105314535458. [15] S.K. Lutgendorf, M.H. Antoni, G. Ironson, M.A. Fletcher, F. Penedo, A. Baum, N. Schneiderman, N. Klimas, Physical symptoms of chronic fatigue syndrome are exacerbated by the stress of Hurricane Andrew, Psychosom. Med. 57 (1995) 310–323, https://doi.org/10.1097/00006842-199507000-00002.
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