Prolonged fatigue is a common symptom in primary care.1Chronic fatigue, defined as fatigue of at least 6 months' duration, is associated with diverse physical health conditions. Chronic fatigue syndrome (CFS) is a less prevalent condition of unknown etiology characterized by debilitating, persistent fatigue. Its diagnosis requires at least 4 specified symptoms in the absence of exclusionary medical and psychiatric disorders that could be responsible for the fatigue.2 Thus, medical and psychiatric diagnoses such as cancer, AIDS, multiple sclerosis, schizophrenia, and bipolar disorder are all exclusionary for CFS. Clinically, patients with chronic fatigue and CFS often present with comorbid medical and psychiatric illnesses that are not regarded as part of the exclusion criteria.3–7
The relationship between CFS and several poorly understood nonexclusionary conditions such as fibromyalgia, irritable bowel syndrome, and multiple chemical sensitivity increasingly has been the focus of recent research. For example, although the hallmarks of CFS and fibromyalgia are persistent fatigue and chronic musculoskeletal pain, respectively, up to 90% of patients with fibromyalgia report significant fatigue3–5 and a similar percentage of adults with CFS experience myalgia, headache, and other local or diffuse pain.8 Furthermore, it has been estimated that in referral clinics, 20% to 70% of fibromyalgia patients meet criteria for CFS4,5,7 and, conversely, 35% to 70% of those with CFS have fibromyalgia.4,9 Although the overlap between CFS and fibromyalgia has received the most attention in the literature, several studies have also described symptoms consistent with multiple chemical sensitivity,4,10 irritable bowel syndrome,11,12 and interstitial cystitis in fatigued individuals.13 However, the degree of association of these comorbid clinical conditions with fatigue and CFS is unknown. Furthermore, whether the apparent overlap results from shared underlying mechanisms or coexisting psychiatric disorders remains controversial.
Our primary objective was to determine if there is a significant relationship between chronically fatiguing illness and 10 clinical conditions that appear to be associated with fatigue, adjusting for the potentially confounding effects of psychiatric illness.
- Top of page
- SUBJECTS AND METHODS
- Odds Ratio Analysis
- Regression Analysis of the Count of Comorbid Conditions
The 1994 publication that summarized the CDC criteria for CFS urged investigators to better define the co-occurrence of fatigue with the many other health conditions frequently observed in patients with chronic fatigue, regardless of their apparent relatedness to CFS.2 In the present study, fibromyalgia, irritable bowel syndrome, temporomandibular disorder, tension headache, and chronic low back pain were the conditions most commonly comorbid with chronic fatigue. Over a 70% lifetime prevalence of fibromyalgia was reported by fatigued twins, and fatigued twins were 20 times more likely than their nonfatigued co-twins to suffer from this disorder. These results are consistent with previous studies documenting that among adults with CFS, as many as 90% experience myalgias and other local or diffuse pain,8 and 35% to 70% meet criteria for fibromyalgia.4,9 Similarly, in patients diagnosed with fibromyalgia, up to 90% are fatigued, and 42% actually have CFS.3–5,7,8
While the overlap between fibromyalgia, chronic fatigue, and CFS has been relatively well characterized, the relationship of fatigue to many of the other clinical conditions under study is considerably less clear. The only publication to systematically examine the relationship of chronic fatigue to irritable bowel syndrome24 found that 73% of chronically fatigued adults met the Manning symptom-based irritable bowel syndrome criteria25 over a 1-year retrospective time period. This somewhat higher than the physician-diagnosed lifetime estimates of irritable bowel syndrome reported by our fatigued twins (52%–59%). We previously observed that when the Manning case definition was applied to CFS clinic patients, up to 92% met lifetime criteria for irritable bowel syndrome.26 Although definitions differ across studies, these rates all greatly exceed the estimated prevalence of irritable bowel syndrome in the general population which ranges from 9% to 21%,27 suggesting that chronically fatigued individuals are disproportionately affected with this condition.
Although temporomandibular disorder, tension headache, and low back pain commonly occur in syndromes of chronic painlike fibromyalgia,28,29 and are reported anecdotally among CFS patients, to our knowledge, these relationships have not been investigated in fatigued populations. This is surprising because we noted relatively high lifetime rates and a 2- to 4-fold increase in the likelihood of having these 3 conditions among the fatigued twins compared to their nonfatigued co-twins. Similarly, there has been no information published on the frequency of interstitial cystitis or chronic pelvic pain among chronically fatigued individuals. While interstitial cystitis was not 1 of the more prevalent disorders in the level 3 group, it was associated with an OR of 20 in the level 1 sample. In support of an overlap with chronic fatigue, a recent, large survey found that 9% of interstitial cystitis patients had CFS.13 Finally, with regard to multiple chemical sensitivity, our earlier study noted that 53% to 67% of CFS patients reported a worsening of their multisystem symptoms with exposure to various chemicals.4 The lower prevalence of multiple chemical sensitivity (11%–24%) reported by fatigued twins probably reflects the difference between the frequency of a symptom (hypersensitivity) and a more well-defined syndrome (multiple chemical sensitivity). Alternately, as some have argued, multiple chemical sensitivity may often be unrecognized by affected individuals or treating physicians leading to an underestimation of this disorder among fatigued individuals.30
Given the common perception that manifestations of CFS and related disorders such as fibromyalgia may be explained, at least in part, by underlying psychiatric disorders,31 investigating this association was of great interest. Thus, we examined whether the consistently higher frequency of comorbid conditions among the fatigued twins would be observed when adjusted for the number of lifetime affective and anxiety psychiatric disorders. The OR comparing the frequency of comorbid conditions between fatigued and nonfatigued twins was greater than 10, even after adjusting for psychiatric status, suggesting that the association was not solely the consequence of psychiatric illness.
If the relationship between chronic fatigue and the associated clinical conditions assessed here is not primarily attributable to psychiatric factors, what are possible alternative explanations? It seems highly probable that the manifestation of chronic fatigue and a spectrum of comorbid conditions is due to the complex interplay between genes and environmental influences.7,14 Moreover, the “hardwiring” of perception almost certainly has a heritable basis,32 and symptom perception has cognitive and psychological components that depend on information processing by the central nervous system. In this regard, studies have shown that pain perception is related to activation of cortical and subcortical brain structures in patients with fibromyalgia.33 Furthermore, objective similarities among some clinical conditions such as increased pain sensitivity in patients with fibromyalgia and interstitial cystitis suggest a possible common alteration in central processing mechanisms.34 Finally, the high rates of health care utilization among patients with chronic fatigue, CFS, and fibromyalgia35,36 suggest that one consequence of excessively seeking health care may be the receipt of multiple diagnoses.
Clinically, patients with multiple syndromes may be more difficult to treat than those with a single condition. One clinical study observed that temporomandibular disorder patients with poor outcomes had significantly more general health complaints.37 Other investigators have noted that patients with temporomandibular disorder who also have nonmasticatory musculoskeletal complaints were more refractory to treatment than those without auxiliary pain.38 The degree of comorbidity also may have a substantial negative impact on health care utilization and costs. For example, the number of concurrent health conditions among fibromyalgia patients was the most powerful predictor of total health care costs in a recent 7-year, multicenter prospective study.35 In chronically fatigued patients, comorbid clinical conditions may further compound the social cost of an illness already associated with substantial economic consequences in terms of health care, excessive unemployment, and functional disability.36,39 Thus, our findings, in conjunction with others cited here, should alert providers to the potentially devastating cumulative effects of these conditions and argue for early and aggressive intervention.
This co-twin control study had several notable limitations. First, the study relied on self-reported health conditions rather than on a clinical examination and review of medical records for all subjects. This may be particularly problematic for the 10 comorbid clinical conditions under investigation. This methodology could have resulted in either an over- or underestimation of the fatigue-associated conditions we evaluated, depending on the accuracy of the twins' reporting. However, at least for the medical diagnoses exclusionary for CFS, we presented evidence based on written and verbal communication with physicians that self-report appeared to be valid. Second, the method used to identify the sample was not ideal. Solicitation by advertisement resulted in a volunteer sample of twin pairs with the potential for ascertainment problems. However, the more desirable strategy of systematically identifying twins from a well-defined population-based twin registry is not readily accomplished in the United States. Although we emphasized in all recruitment efforts that twins were desired regardless of either the health of their co-twin or a definitive CFS diagnosis, subjects likely screened themselves as eligible or ineligible. This could likely limit the generalizability of our findings to more severely fatigued individuals, such as those found in tertiary care clinics.
A third limitation is related to sample size. Because the clinically diagnosed group consisted of only 22 pairs, we had insufficient power to make definitive statements about the relationship of CFS to specific conditions under study. However, we were able to demonstrate a greater than 90-fold OR between the number of comorbid conditions associated with CFS in the level 3 sample. Other potential problems arise from difficulties in defining and identifying these conditions. Several of the illnesses under study are controversial and do not have a universally agreed upon case definition. Furthermore, the criteria applied by diverse physicians representing many disciplines may have influenced our findings because certain specialties may be more (or less) likely to recognize and diagnose comorbid clinical conditions. Lastly, results from this study cannot ascertain whether their onset came before or after the development of CFS.
In conclusion, this co-twin control study is the first to demonstrate that individuals with a range of fatiguing illnesses have a consistently increased likelihood of experiencing selected comorbid clinical conditions compared to exceedingly well-matched, healthy controls who denied chronic fatigue. These results were independent of the stringency of the case definition for fatigue and the degree of psychiatric morbidity. We relied upon the strengths of a twin design because this method is especially well suited to the study of disorders of unknown etiology and those for which the appropriate comparison groups are not clearly defined.14 Because they control, to a substantial extent, for genetic and environmental factors, twin studies offer a unique approach to the examination of CFS and comorbid conditions—illnesses that represent complex interactions of biological, psychological, and environmental factors. Investigators with access to unselected, population-based twin registries should attempt to replicate our findings to better determine the relative influences of genetic and noninherited factors underlying the relationships between fatigue and related illnesses. Future research should also investigate the temporal relationship of fatigue onset to the appearance of other clinical conditions, and assess the usefulness of early interventions.