Risk factors for chronic fatigue syndrome/myalgic encephalomyelitis: a systematic scoping review of multiple predictor studies

Abstract:

BACKGROUND: The aetiology of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is still unknown. The identification of risk factors for CFS/ME is of great importance to practitioners.

METHOD: A systematic scoping review was conducted to locate studies that analysed risk factors for CFS/ME using multiple predictors. We searched for published and unpublished literature in 11 electronic databases, reference lists of retrieved articles and guideline stakeholder submissions in conjunction with the development of a forthcoming national UK guideline. Risk factors and findings were extracted in a concise tabular overview and studies synthesized narratively.

RESULTS: Eleven studies were identified that met inclusion criteria: two case-control studies, four cohort studies, three studies combining a cohort with a case-control study design, one case-control and twin study and one cross-sectional survey. The studies looked at a variety of demographic, medical, psychological, social and environmental factors to predict the development of CFS/ME. The existing body of evidence is characterized by factors that were analysed in several studies but without replication of a significant association in more than two studies, and by studies demonstrating significant associations of specific factors that were not assessed in other studies. None of the identified factors appear suitable for the timely identification of patients at risk of developing CFS/ME within clinical practice.

CONCLUSIONS: Various potential risk factors for the development of CFS/ME have been assessed but definitive evidence that appears meaningful for clinicians is lacking.

 

Source: Hempel S, Chambers D, Bagnall AM, Forbes C. Risk factors for chronic fatigue syndrome/myalgic encephalomyelitis: a systematic scoping review of multiple predictor studies. Psychol Med. 2008 Jul;38(7):915-26. Epub 2007 Sep 25. https://www.ncbi.nlm.nih.gov/pubmed/17892624

 

A longitudinal study of the relationship between psychological distress and recurrence of upper respiratory tract infections in chronic fatigue syndrome

Abstract:

OBJECTIVES: Previous research has found that chronic fatigue syndrome (CFS) patients report increased susceptibility to upper respiratory tract illnesses (URTIs) when compared with healthy volunteers. This study aimed to replicate and extend this research by investigating the role of psychological distress (stress and negative mood) in the recurrence of URTIs in CFS patients as well as its role in the recurrence of CFS symptoms.

DESIGN: A 15-week diary study.

METHODS: Measures of psychological stress, negative mood, recurrence of URTIs and symptoms were recorded each week for a 15-week period. CFS patients (N=21), who had been assessed and diagnosed according to the Oxford criteria, were recruited from the Cardiff Chronic Fatigue Clinic and compared with a matched group of healthy controls (N=18). Frequency of occurrence of infectious illness and the relationship between psychological stress/negative mood and occurrence of illness were assessed.

RESULTS: CFS patients reported more URTIs than the controls. Stress scores (and negative mood) were significantly higher in the week prior to the occurrence of URTIs than in weeks when no subsequent illness occurred. High levels of psychological stress also preceded the severity of reported symptoms of fatigue in the CFS group.

CONCLUSIONS: CFS patients reported more frequent URTIs than healthy controls and these recurrences were preceded by high levels of psychological stress. High levels of stress were also associated with greater subsequent fatigue. Possible explanations of these results are discussed.

 

Source: Faulkner S, Smith A. A longitudinal study of the relationship between psychological distress and recurrence of upper respiratory tract infections in chronic fatigue syndrome. Br J Health Psychol. 2008 Feb;13(Pt 1):177-86. https://www.ncbi.nlm.nih.gov/pubmed/17535488

 

Incidence, prognosis, and risk factors for fatigue and chronic fatigue syndrome in adolescents: a prospective community study

Abstract:

OBJECTIVE: The objective of this study was to describe the incidence, prevalence, risk factors, and prognosis of fatigue, chronic fatigue, and chronic fatigue syndrome in 11- to 15-year-olds.

METHODS: A random general population sample (n = 842) of British adolescents and their parents were assessed at baseline and 4 to 6 months later. The main outcomes were fatigue, chronic fatigue, and chronic fatigue syndrome, operationally defined.

RESULTS: The incidence over 4 to 6 months was 30.3% for fatigue, 1.1% for chronic fatigue, and 0.5% for chronic fatigue syndrome. The point prevalence was 34.1% and 38.1% for fatigue, 0.4% and 1.1% for chronic fatigue, and 0.1% and 0.5% for chronic fatigue syndrome at time 1 and time 2, respectively. Of participants who were fatigued at time 1, 53% remained fatigued at time 2. The 3 cases of chronic fatigue and 1 case of chronic fatigue syndrome at time 1 had recovered by time 2. Higher risk for development of chronic fatigue at time 2 was associated with time 1 anxiety or depression, conduct disorder, and maternal distress; in multivariate analysis, baseline anxiety or depression remained a significant predictor of chronic fatigue. Increased risk for development of fatigue at time 2 was associated with time 1 anxiety or depression, conduct disorder, and older age; in multivariate analyses, these factors and female gender all were significant predictors of fatigue.

CONCLUSIONS: The incidence rates for chronic fatigue and chronic fatigue syndrome in this adolescent sample were relatively high, but the prognosis for these conditions was good. This prospective study provides evidence for an association between emotional/behavioral problems and subsequent onset of fatigue/chronic fatigue.

 

Source: Rimes KA, Goodman R, Hotopf M, Wessely S, Meltzer H, Chalder T. Incidence, prognosis, and risk factors for fatigue and chronic fatigue syndrome in adolescents: a prospective community study. Pediatrics. 2007 Mar;119(3):e603-9. https://www.ncbi.nlm.nih.gov/pubmed/17332180

 

Premorbid predictors of chronic fatigue

Abstract:

CONTEXT: Chronic fatigue syndrome is a disabling problem characterized by persistent fatigue lasting at least 6 months with a number of ancillary symptoms. Although the etiology of chronic fatiguing illness is unknown, some evidence suggests that stress may confer increased risk for development of the disorder. Moreover, subjects with chronic fatiguing illness may have distinctive personality traits, although this finding could reflect confounding by other mechanisms.

OBJECTIVE: To assess the prospective association of premorbid self-reported stress and personality with chronic fatigue-like illness.

DESIGN: Prospective nested case-control study in a population-based sample.

SETTING: General community.

PARTICIPANTS: From the Swedish Twin Registry, 19,192 twins born between January 1, 1935, and December 31, 1958.

MAIN OUTCOME MEASURES: Information about current chronic fatiguing illnesses was obtained from computer-assisted telephone interviews conducted between 1998 and 2002. Self-reported stress (based on a single question) and personality scales (emotional instability and extraversion in the Eysenck Personality Inventory) were measured from 1972 to 1973 by a mailed questionnaire. Relative risks were estimated with case-control analyses (matched for age and sex) and co-twin control analyses (comparing discordant pairs).

RESULTS: Higher emotional instability and self-reported stress in the premorbid period were associated with higher risk for chronic fatigue-like illness in matched case-control analyses (odds ratios, 1.72 and 1.64, respectively). In co-twin control analyses, relative risk of emotional instability decreased to 1.02 whereas that of stress increased considerably to 5.81. There was no association between extraversion and fatigue.

CONCLUSIONS: Elevated premorbid stress is a significant risk factor for chronic fatigue-like illness, the effect of which may be buffered by genetic influences. Emotional instability assessed 25 years earlier is associated with chronic fatigue through genetic mechanisms contributing to both personality style and expression of the disorder. These findings suggest plausible mechanisms for chronic fatiguing illness.

 

Source: Kato K, Sullivan PF, Evengård B, Pedersen NL. Premorbid predictors of chronic fatigue. Arch Gen Psychiatry. 2006 Nov;63(11):1267-72. https://www.ncbi.nlm.nih.gov/pubmed/17088507

 

Early adverse experience and risk for chronic fatigue syndrome: results from a population-based study

Abstract:

CONTEXT: Chronic fatigue syndrome (CFS) is an important public health problem. The causes of CFS are unknown and effective prevention strategies remain elusive. A growing literature suggests that early adverse experience increases the risk for a range of negative health outcomes, including fatiguing illnesses. Identification of developmental risk factors for CFS is critical to inform pathophysiological research and devise targets for primary prevention.

OBJECTIVE: To examine the relationship between early adverse experience and risk for CFS in a population-based sample of clinically confirmed CFS cases and nonfatigued control subjects.

DESIGN, SETTING, AND PARTICIPANTS: A case-control study of 43 cases with current CFS and 60 nonfatigued controls identified from a general population sample of 56 146 adult residents from Wichita, Kan.

MAIN OUTCOME MEASURES: Self-reported childhood trauma (sexual, physical, and emotional abuse and emotional and physical neglect) and psychopathology (depression, anxiety, and posttraumatic stress disorder) by CFS status.

RESULTS: The CFS cases reported significantly higher levels of childhood trauma and psychopathology compared with the controls. Exposure to childhood trauma was associated with a 3- to 8-fold increased risk for CFS across different trauma types. There was a graded relationship between the degree of trauma exposure and CFS risk. Childhood trauma was associated with greater CFS symptom severity and with symptoms of depression, anxiety, and posttraumatic stress disorder. The risk for CFS conveyed by childhood trauma increased with the presence of concurrent psychopathology.

CONCLUSIONS: This study provides evidence of increased levels of multiple types of childhood trauma in a population-based sample of clinically confirmed CFS cases compared with nonfatigued controls. Our results suggest that childhood trauma is an important risk factor for CFS. This risk was in part associated with altered emotional state. Studies scrutinizing the psychological and neurobiological mechanisms that translate childhood adversity into CFS risk may provide direct targets for the early prevention of CFS.

 

Source: Heim C, Wagner D, Maloney E, Papanicolaou DA, Solomon L, Jones JF, Unger ER, Reeves WC. Early adverse experience and risk for chronic fatigue syndrome: results from a population-based study. Arch Gen Psychiatry. 2006 Nov;63(11):1258-66. https://www.ncbi.nlm.nih.gov/pubmed/17088506

 

Salivary cortisol as a predictor of postoperative fatigue

 Abstract:

OBJECTIVE: Some patients with chronic fatigue syndrome (CFS) exhibit low basal cortisol levels, but it is not known whether low cortisol is a cause of CFS, predates the onset of CFS symptoms, or is an epiphenomenon caused by the behavioral changes typical of CFS. Because elective surgery is one of the few predictable risk factors for chronic fatigue, in this study, we followed a cohort of surgery patients from before to 6 months after their operation to test these theories.

METHOD: One hundred sixty-one patients completed fatigue questionnaires and provided salivary cortisol samples before undergoing an elective inpatient surgical procedure, and then 2 days, 3 weeks, and 6 months afterward.

RESULTS: Controlling for relevant demographic and surgical variables and for preoperative fatigue, low preoperative cortisol did not predict postoperative fatigue severity on any occasion (p > .05). Similarly, there was no correlation between low postoperative cortisol and postoperative fatigue severity at 3 weeks or 6 months (p > .05). Although 16 patients met our case definition for “chronic fatigue” at the 6-month follow up, low preoperative and low postoperative cortisol did not significantly predict fatigue caseness (p > .05).

CONCLUSIONS: Any association between chronic fatigue and low cortisol would seem to develop after the onset of fatigue symptoms. Low cortisol is therefore unlikely to be the primary cause of chronic fatigue states.

 

Source: Rubin GJ, Hotopf M, Papadopoulos A, Cleare A. Salivary cortisol as a predictor of postoperative fatigue. Psychosom Med. 2005 May-Jun;67(3):441-7. http://www.ncbi.nlm.nih.gov/pubmed/15911908 

 

Association between chronic fatigue syndrome and the corticosteroid-binding globulin gene ALA SER224 polymorphism

Abstract:

Chronic fatigue syndrome (CFS) is characterized by idiopathic fatigue of greater than 6 months’ duration with postexertional exacerbation and many other symptoms. A trend toward relative hypocortisolism is described in CFS. Twin and family studies indicate a substantial genetic etiologic component to CFS. Recently, severe corticosteroid-binding globulin (CBG) gene mutations have been associated with CFS in isolated kindreds. Human leukocyte elastase, an enzyme important in CBG catabolism at inflammatory sites, is reported to be elevated in CFS. We hypothesized that CBG gene polymorphisms may act as a genetic risk factor for CFS.

A total of 248 patients with CFS defined by Centers for Disease Control criteria, and 248 controls were recruited. Sequencing and restriction enzyme testing of the CBG gene coding region allowed detection of severe CBG gene mutations and a common exon 3 polymorphism (c.825G–>T, Ala-Ser224).

Plasma CBG levels were measured in 125 CFS patients and 198 controls by radioimmunoassay. Total and free (calculated and measured) cortisol levels were ascertained in single samples between 8-10 a.m. The age of onset (mid 30s) and gender ratio (2.2:1, female:male) of the patients were similar to those reported in U.S. epidemiologic studies.

A trend toward a preponderance of serine224 homozygosity among the CFS patients was noted, compared with controls (chi2 = 5.31, P = 0.07). Immunoreactive-CBG (IR-CBG) levels were higher in Serine/Alanine (Ser/Ala) than Ala/Ala subjects and higher again in Ser/Ser subjects, this effect was strongest in controls; Ser/Ser: 46.1+/-1.8 (n = 31, P = 0.03) vs. Ser/Ala: 42.4+/-1.0 (n = 56, P = 0.05) vs. Ala/Ala: 40.8+/-1.7 microg/mL (n = 21). Despite higher CBG levels, there was a nonsignificant trend toward lower total and free plasma cortisol in serine allele positive patients, total cortisol: Ser/Ser: 13.3+/-1.4 (n = 34) vs. Ser/Ala: 14.0+/-0.7 (n = 66) vs. Ala/Ala: 15.4+/-1.0 (n = 23).

Homozygosity for the serine allele of the CBG gene may predispose to CFS, perhaps due to an effect on hypothalamic-pituitary-adrenal axis function related to altered CBG-cortisol transport function or immune-cortisol interactions.

 

Source: Torpy DJ, Bachmann AW, Gartside M, Grice JE, Harris JM, Clifton P, Easteal S, Jackson RV, Whitworth JA. Association between chronic fatigue syndrome and the corticosteroid-binding globulin gene ALA SER224 polymorphism. Endocr Res. 2004 Aug;30(3):417-29. http://www.ncbi.nlm.nih.gov/pubmed/15554358

 

Childhood predictors of self reported chronic fatigue syndrome/myalgic encephalomyelitis in adults: national birth cohort study

Abstract:

OBJECTIVE: To study childhood risk factors for chronic fatigue syndrome in adult life.

DESIGN: Examination of data from the 1970 British birth cohort.

PARTICIPANTS: 16,567 babies born 5-11 April 1970, followed up at 5, 10, 16, and 29-30 years.

MAIN OUTCOME MEASURES: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) identified by self report at age 30 years. Data from childhood from questionnaires given to parents and teachers. Maternal mental health assessed with the malaise inventory.

RESULTS: 93 (0.8%, 95% confidence interval 0.7 to 1.0) of 11 261 participants reported ever having CFS/ME, and 48 (0.4%, 0.3 to 0.6) had the condition currently. Higher risk of CFS/ME was associated with having a limiting longstanding condition in childhood (odds ratio 2.3, 1.4 to 3.9), female sex (2.3, 1.4 to 2.6), and high social class in childhood (2.2, 1.4 to 3.5). Higher levels of exercise in childhood were associated with lower risk (0.5, 0.2 to 0.9). Maternal psychological disorder, psychological problems in childhood, birth weight, birth order, atopy, obesity, school absence, academic ability, and parental illness were not associated with risk of CFS/ME.

CONCLUSIONS: We identified no association between maternal or child psychological distress, academic ability, parental illness, atopy, or birth order and increasing risk of lifetime CFS/ME. Sedentary behaviour increased the risk.

Comment in: What causes chronic fatigue syndrome? [BMJ. 2004]

 

Source: Viner R, Hotopf M. Childhood predictors of self reported chronic fatigue syndrome/myalgic encephalomyelitis in adults: national birth cohort study. BMJ. 2004 Oct 23;329(7472):941. Epub 2004 Oct 6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC524102/ (Full article)

 

 

Development of the chronic fatigue syndrome in severely fatigued employees: predictors of outcome in the Maastricht cohort study

Abstract:

STUDY OBJECTIVE: To identify risk factors of the development of the chronic fatigue syndrome (CFS), the persistence or recurrence of fatigue, or recovery from fatigue in a large sample of fatigued employees.

DESIGN: Analyses were based on the Maastricht cohort study (MCS), a prospective population based cohort study among more than 12 000 employees. Multiple regression models were used to identify predictors of CFS-like caseness (meeting research criteria for CFS), non-CFS fatigue caseness, or no fatigue caseness.

SETTING: The working population in the Netherlands.

PARTICIPANTS: 1143 employees with medically unexplained fatigue were followed up prospectively for 44 months.

MAIN RESULTS: At 44 month follow up, 8% of the employees were CFS-like cases (none of who reported to have received a CFS diagnosis), 40% were non-CFS fatigue cases, and 52% were no longer fatigue cases. Factors that predicted CFS-like caseness compared with non-CFS fatigue caseness were high age, exhaustion, female sex, low education, and visits to the general practitioner. Factors that predicted CFS-like caseness compared with no fatigue caseness were fatigue, exhaustion, low education, visits to the GP and occupational physician, and bad self rated health. Factors that predicted non-CFS fatigue caseness compared with no fatigue caseness were fatigue, low self perceived activity, exhaustion, anxious mood, and bad self rated health.

CONCLUSIONS: Unexplained fatigue among employees in some instances is a precursor of the development of CFS. The prognostic role of self rated health suggests that prevention and treatment of chronic fatigue should be aimed at changing the perception of health or illness. Less clear is the role of health care seeking or receiving a CFS diagnosis.

 

Source: Huibers MJ, Kant IJ, Knottnerus JA, Bleijenberg G, Swaen GM, Kasl SV. Development of the chronic fatigue syndrome in severely fatigued employees: predictors of outcome in the Maastricht cohort study. J Epidemiol Community Health. 2004 Oct;58(10):877-82. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1763327/

 

Temporal relations between unexplained fatigue and depression: longitudinal data from an international study in primary care

Abstract:

OBJECTIVE: Unexplained fatigue syndromes, such as chronic fatigue syndrome and neurasthenia, are strongly associated with depression, but the temporal nature of this association is not clear.

METHODS: The authors examined this issue by using data from the World Health Organization collaborative study of psychological problems in general health care. Three thousand two hundred one subjects from 15 primary care centers in 14 countries were followed up for 12 months. The Composite International Diagnostic Interview was the main instrument used. Odds ratios and their 95% confidence intervals (CI) were calculated using logistic regression models adjusted for sociodemographic variables, physical morbidity and intercenter variability.

RESULTS: Cases of depression were found to have an increased risk of developing a new episode of unexplained fatigue at follow-up with an adjusted odds ratio of 4.15 (95% CI = 2.64-6.54). Similarly, cases of unexplained fatigue were found to have an increased risk of developing a new episode of depression at follow-up with an adjusted odds ratio of 2.76 (95% CI = 1.32-5.78). Further adjustment for subthreshold symptoms at baseline weakened the reported associations, especially between fatigue and development of a new episode of depression, but these remained significant.

CONCLUSIONS: The findings support the view that unexplained fatigue and depression might act as independent risk factors for each other.

 

Source: Skapinakis P, Lewis G, Mavreas V. Temporal relations between unexplained fatigue and depression: longitudinal data from an international study in primary care. Psychosom Med. 2004 May-Jun;66(3):330-5. http://www.ncbi.nlm.nih.gov/pubmed/15184691