The Institute of Medicine (IOM) [1
] recently proposed a new case definition, which was intended to replace the Fukuda et al.
] chronic fatigue syndrome (CFS) criteria, the most widely used case definition for the past twenty years. The Fukuda et al
. criteria [2
] require four symptoms out of a possible eight, but it is possible that some individuals who meet these diagnostic criteria do not have core symptoms of the illness, such as post-exertional malaise. With the Fukuda et al.
case definition [2
], there are about a million people estimated to have this illness in the US [3
]. In reaction to limitations in the Fukuda et al.
case definition [2
], the Canadian Clinical Criteria Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS) [4
] was developed, and it specified core symptoms, including post-exertional malaise, impairment of memory and concentration, unrefreshing sleep, arthralgia and/or myalgia; and several autonomic, neuroendocrine, and immune manifestations. Still later, the International Consensus Criteria for Myalgic Encephalomyelitis (ME-ICC) criteria [5
] were developed, and these criteria specified eight symptoms within four domains: Post-Exertional Neuroimmune Exhaustion; Neurological Impairments; Immune, Gastro-intestinal, and Genitourinary Impairments; and Energy Production/Transportation Impairments. Others have tried to develop more empiric-based methods [6
]. Each of these case definitions excluded a variety of medical or psychiatric illnesses that might be the cause of the symptoms.
Recently, the IOM [1
] issued a report that proposed a new name (Systemic Exertion Intolerance Disease, SEID) and case definition that included the following four symptoms: substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social or personal activities; post-exertional malaise; unrefreshing sleep; and at least one of the two following symptoms: cognitive impairment or orthostatic intolerance. Whereas the Fukuda et al.
] CFS criteria, the ME/CFS Canadian criteria [4
], and the ME-ICC criteria [5
] excluded other medical and psychiatric conditions that might have produced the fatigue, the new SEID criteria [1
] had a different position regarding exclusionary conditions. The IOM [1
] (p. 186) document defining SEID stated: “Over the years, case definitions of ME/CFS have differed significantly in their classification of exclusionary conditions and comorbidities. As a result, a number of disorders, such as morbid obesity and an array of psychiatric disorders, are listed as exclusionary in one definition and as comorbid in another, despite the lack of scientific evidence that being affected by such disorders precludes having ME/CFS. Indeed, it has become increasingly clear that many patients with ME/CFS have other disorders as well…Some of these other disorders may develop as part of the spectrum of ME/CFS or in response to the burdens of this disorder.” In addition, within the IOM [1
] (p. 185) SEID document, it states that a detailed history and comprehensive physical examination should be used “to determine a differential diagnosis and, where clinically indicated, to exclude other disorders that could cause the patient’s symptoms, as well as to identify any comorbid conditions”. More details on exclusions are provided within the IOM’s SEID Report Guide for Clinicians [7
] (p. 4), where it states: “The presence of other illnesses should not preclude patients from receiving a diagnosis of ME/CFS (SEID) except in the unlikely event that all symptoms can be accounted for by these other illnesses.” The word “unlikely” conveys the impression that most other illnesses would be considered comorbid and not exclusionary as they probably would not account for the unique SEID symptoms.
The problem for diagnosticians in interpreting these guidelines is that the core IOM symptoms are not unique to SEID, as other illnesses have comparable symptoms (e.g., cancer, Hashimoto’s, lupus, chronic heart failure, multiple sclerosis, etc.
). Thus, according to the above IOM guidelines, if these illnesses account for the SEID symptoms, then it is another illness and not SEID. Therefore, many illnesses are now considered a comorbid condition with SEID. However, trying to determine whether an illness is exclusionary vs.
comorbid is a challenging diagnostic task. The IOM [1
] (p. 187) provides the following example that illustrates this complexity: “The committee recognizes that diagnosis and treatment of comorbid conditions is necessary when caring for patients. For example, a patient with ME/CFS with a prominent history of snoring and sleep apnea may have polysomnography diagnostic of sleep apnea. Treatment with continuous positive airway pressure could improve the patient’s overall condition but not resolve all the symptoms of ME/CFS, signifying that in this individual, obstructive sleep apnea is a comorbid condition rather than the cause of the patient’s ME/CFS symptoms.” This suggests that if treatment resolved all the SEID symptoms, then the patient had another illness (in the case above, obstructive sleep apnea); however, if the treatment does not resolve the issues, than the condition is comorbid with SEID. In other words, the ability to determine if an illness is exclusionary rests on its successful treatment, and clearly, many chronic illnesses do not have treatments that cure or alleviate all symptoms.
In addition, Ze-dog [8
] pointed out that this new SEID definition lacks exclusion criteria, and as a consequence, it is easier for a person with a primary psychiatric diagnosis to be labeled as having SEID. Verrillo [9
] also commented on these exclusionary SEID ambiguities, and then suggested that because major depression is not exclusionary, patients with a primary psychiatric disorder might be included in the SEID classification. These publications were only commentaries and did not provide data, so it is still unclear whether the SEID case definition [1
] could inappropriately include cases of purely affective disorders, such as Major Depressive Disorder (MDD). It is also unclear whether SEID is more common within other autoimmune illnesses such as MS and Lupus. The present study evaluated whether the SEID case definition distinguished between persons with MDD, and other illnesses, using archival data that were available. We used data from four distinct studies, each with different case ascertainment methods, so we could begin to determine how the new SEID criteria might affect a variety of samples representing tertiary care settings, community based settings, as well as more patient self-diagnosed samples. We hypothesized that individuals with a number of formerly exclusionary illnesses would meet the SEID case definition, thus possibly increasing the prevalence rate of this illness.
3. Discussion and Conclusions
, Table 2
, Table 3
and Table 4
indicate that the SEID criteria will probably select few individuals from healthy control samples, and although a few controls were identified as meeting SEID in Table 3
, that control sample included a large group of individuals from the community, many of whom did have varying levels of fatigue and other problems. In addition, it appears that the SEID criteria do identify most of those who met the Fukuda criteria, as evidenced by the generally high sensitivity statistics; however, rates tend to be lower in Table 3
, which is a community rather than tertiary sample, where symptom rates tend to be lower. Most importantly, the SEID criteria do tend to identify high rates of those with other medical illnesses, as indicated in Table 1
and Table 4
and the low specificity levels, and therefore many individuals with autoimmune and other health illnesses that had been exclusionary with prior case studies will now be comorbidity. In addition, as indicated in Table 2
and Table 4
, many individuals with a purely affective disorder will now be also classified as having SEID.
Rates of SEID could increase due to the reduction of many exclusionary criteria. Based on study 3, using the Jason et al.
] community-based epidemiologic study, 32 individuals had been classified as meeting the Fukuda et al.
] criteria, for a prevalence rate of 0.42, but we estimate that 89 from this sample would now meet the SEID criteria, for a prevalence rate of 1.17, thus, the SEID prevalence rate would be 2.8 times as great. Of course, if our samples had only included those who had been selected patients had met the Fukuda et al.
] criteria, as occurred in a recently published study [14
], then those with many medical and psychiatric illnesses would have already been excluded, so in a study comprised of just those meeting the Fukuda et al.
] criteria, the rates of those meeting the SEID criteria would be much more comparable to those meeting the CFS Fukuda criteria [14
The current study suggests that the core SEID symptoms are not unique to SEID, as some patients with other illnesses, such as those evaluated in this study, have comparable symptoms. As a consequence, some patients with illnesses that had previously been exclusionary under past case definitions such as Fukuda et al.
] will now be comorbid, possibly leading to an expanded number of individuals meeting SEID criteria. Even though the SEID criteria are for a clinical case definition [1
], rather than a research case definition, it is likely that it will be used for research by investigators, as a similar process occurred with the clinical Fukuda et al.
] CFS criteria. If there are ambiguities with case definitions, like what has occurred with the Fukuda et al.
] CFS criteria, there will be difficulties in replicating findings across different laboratories, estimating the prevalence of the illness, consistently identifying biomarkers, and determining which treatments help patients. To develop or validate a reliable case definition, we need to both provide operationally explicit inclusionary and exclusionary criteria as well as develop a consensus within the scientific community for the case definition.
The current study suggests that some patients with MDD, who also have chronic fatigue, sleep disturbances, and poor concentration, will be misdiagnosed as having SEID. MDD can occur for anyone with a serious medical illness. Some patients might have been depressed prior to becoming ill with SEID, and probably others as a reaction to this illness [23
]. However, patients with CFS have symptoms including night sweats, sore throats, and swollen lymph nodes, that are not commonly found in depression, and illness onset with CFS is often sudden, occurring over a few hours or days, whereas primary depression generally shows a more gradual onset [24
]. Hawk, Jason, and Torres-Harding [15
] were 100% successful in differentiating patients with CFS and MDD using the following variables: percent of time fatigue was reported, post-exertional malaise severity, unrefreshing sleep severity, confusion/disorientation severity, shortness of breath severity, and self-reproach.
Mood disorders are the most prevalent psychiatric disorders after anxiety disorders: for major depressive episode, the one-month prevalence is 2.2%, and lifetime prevalence is 5.8% [26
]. The erroneous inclusion of people with primary psychiatric conditions in SEID samples would have detrimental consequences for the interpretation of epidemiologic, etiologic, and treatment efficacy findings for people with this illness. This is what occurred with another CFS case definition developed by the CDC [22
]. Jason et al.
] found that 38% of those with a diagnosis of a MDD were misclassified as having CFS using the CDC empirical case definition of Reeves et al.
]. Fortunately, few adopted the Reeves et al.
] empiric case definition, but the IOM [1
] has considerably more prestige and influence, so their proposed SEID case definition criteria could ultimately have more far reaching effects. In study 3, 47% of those with Melancholic Depression met SEID criteria, whereas rates of MDD meeting SEID criteria in studies 2 and 4 were 27% and 24%, respectively. If individuals with primary affective disorder are misdiagnosed with SEID and provided cognitive behavioral treatment, they will more likely have positive outcomes, and this may create more difficulties in understanding the effects of these interventions for those who have ME (Myalgic Encephalomyelitis). Price, Mitchell, Tidy and Hunot [27
] reviewed 15 studies of CBT with a total of 1043 participants with CFS. At treatment’s end, the CBT group showed more clinical improvement in contrast to those in usual care, but changes were not maintained at a one- to seven-month follow-up when including patients who had dropped out.
There are additional aspects of the IOM [1
] case definition that have problems, besides exclusionary criteria. For example, it is unfortunate that there was a lack of a recommendation for a mental health evaluation, or a structured clinical interview, especially as some of these symptoms can overlap with primary affective or mood disorders. The SEID criteria require a patient to have either cognitive impairment or orthostatic illness, but orthostatic intolerance does not evidence prevalence rates as high as the other proposed core symptoms, whereas cognitive impairment does have higher prevalence rates [28
]. Also, factor analytic studies do not support this system of a choice of cognitive impairment vs.
orthostatic intolerance [29
]. We believe this report did not adequately deal with the issue of whether distinct categories or continuous measures best capture patient differences, as there well might be different groupings of patients, with some having different features or more severity. Finally, empirical methods could have been employed to test the proposed classification system, and the committee members might have benefited from testing out their proposed model with an actual data set, as has recently been done [14
There are a number of limitations in the present study. As we used archival data sets, some of the questions that have been proposed to define SEID were not available. Clearly, the current study needs to be replicated with questions that are now proposed [7
], however, our questionnaires were able to assess that vast majority of issues and domains within SEID. In addition, several of our samples were relatively small, so larger studies are needed. Furthermore, we were only able to identify data sets representing a few illnesses, and more illnesses need to be investigated to assess whether some patients with these diagnoses might be included within the SEID classification system. It should be noted that samples recruited from patient organizations or that do not have an independent physician work up and diagnosis might be less reliable. The new SEID [1
] criteria suggest frequency and severity ratings, many of which were not available from the data sets reported in the current study, so it is possible that some occurrence ratings selected less impaired individuals and inflated the number of patients meeting SEID criteria. Finally, none of the studies included a two-day exercise challenge, and such a test would be a better approach for documenting post-exertional malaise. However, such a test might exclude some of the individuals from a SEID diagnosis, and given that the SEID is a clinical criteria, most medical practitioners will not have access to this expensive two-day exercise test in the diagnostic process.
The recent IOM report [1
] is being widely discussed among academics and the patient community [30
]. There is a need to also consider how these recommendations will affect patients in other countries, given the prestige associated with an IOM report. The present study suggests that there might be a number of illnesses that had been exclusionary, which now might now be considered comorbid. This is a complex diagnostic decision, and there probably is a need for clearer rules regarding whether a person has an exclusionary or comorbid illness. Ultimately, we need investigations to help point to implications of using these new criteria, and ultimately, we need an open and inclusive process where all parties, including key gatekeepers including the patients, scientists, clinicians and government officials, are involved in the decision making process.