Friday, July 31, 2015

August Deadlines and Opportunities for Advocacy




Reprinted with the kind permission of Jennie Spotila and Occupy CFS
.

By Jennie Spotila

There are a number of opportunities for ME/CFS advocacy right now – all of which you can do on your own from home! Here are the details:

CFS Advisory Committee Public Comment: The Federal Register notice for the August 18-19th meeting has been published.
  • Registration to attend in person is different this time! You must download a form on the CFSAC website (although it’s not available yet) and email it to CFSACmtg@hhs.gov. Registration for attendance closes August 13th.
  • Public comment registration is required to comment in person or by phone. Request a slot by emailing CFSACmtg@hhs.gov. Comments are limited to three minutes in length, and registration closes August 10th.
  • Written public comment can be submitted, whether you have a speaking slot or not. Comments should be no longer than 5 single spaced pages using 12pt font, and should be in MS Word format. Email your comments to CFSACmtg@hhs.gov by August 13th for inclusion in the public record.
NIH Strategic Plan: Public comment is due August 16th. I‘ve posted details about the plan and my own comments.

Key States Targeted for NIH Funding Petition: MEAction is looking for advocates in twenty-two key states to participate in targeted advocacy with Congress. Even if you don’t live in one of those states, you can still sign the petition.

More advocacy actions will be launched in the near future, so stay tuned HERE.

Monday, June 29, 2015

Study Finds SEID Case Definition Captures Patients With Depression, MS, Lupus

The IOM study - a million dollars down the drain
Leonard Jason has done it again. He has applied the scientific method and come up with something that makes sense.

The IOM has, according to Jason, devised an unworkable case definition. This failure is due to lack of scientific method (coming up with a hypothesis, testing it against evidence, revising the hypothesis, and testing it again to see if it describes all known data and has predictive value).

HHS has a poor track record when it comes to epidemics of new illnesses. They not only came up with an unworkable case definition (and a ridiculous name) for ME a couple of decades ago, they ignored AIDS, are currently ignoring Lyme disease, and have consistently put the interests of the medical/industrial complex ahead of anything that resembles public health.

SEID and the definition that accompanies it are merely one more drop in the ocean of bureaucratic collusion that typifies HHS.

It takes people like Leonard Jason and his colleagues to demonstrate just how negligent HHS has been.

"Empirical methods," he says, "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." This is a gentle way of saying, "you pulled this definition out of your left ear, and it doesn't work."

Here are all the ways it doesn't work, according to the report below:

1) In the first study (60 people) the definition for SEID captured 100% of the people with ME/CFS, but it also captured 33% of patients with MS, and a staggering 47% of patients with lupus.

2) In the second study (45 people), SEID captured 27% of patients with major depression.

3) In the third study (213 people), 75% of the patients who met the Fukuda criteria also met the criteria for SEID. But 44% of those who did not meet the Fukuda criteria were also diagnosed with SEID, and 47% of the patients who had fatigue from other causes - drug and alcohol related causes, psychiatric illnesses, anorexia, chronic diseases - also met the definition for SEID.

4) Using those statistics, and comparing them to the prevalence rate established by the Fukuda definition, Jason's team came up with a prevalence rate that was 2.8 times higher than the current rate. That means if the CDC currently calculates a prevalence of 1 million people with ME/CFS in the US, the estimate would be increased to 2.8 million. And the overwhelming majority of those patients would have other diseases.

Aside from the inability of the new definition to accurately identify a distinct patient population, Jason points out that this definition will ultimately make treatment research impossible: "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."

Jason has called for 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." However, given the abysmal lack of faith shown by HHS, it might be best to leave that department out of any decision making process that involves sick people.

Cited post: The IOM Report: The Good, The Bad, and the Absolutely Hideous

________________________________


Unintended Consequences of not Specifying Exclusionary Illnesses for Systemic Exertion Intolerance Disease

By Leonard A. Jason *, Madison Sunnquist, Bobby Kot, and Abigail Brown

Center for Community Research, DePaul University, Chicago, IL 60614, USA (see end of article for contact information)

Abstract

The Institute of Medicine recently proposed a new case definition for chronic fatigue syndrome (CFS), as well as a new name, Systemic Exertion Intolerance Disease (SEID). Contrary to the Fukuda et al.’s CFS case definition, there are few exclusionary illnesses specified for this new SEID case definition. The current study explored this decision regarding exclusionary illnesses using the SEID criteria with four distinct data sets involving patients who had been identified as having CFS, as well as healthy controls, community controls, and other illness groups. The findings indicate that many individuals from major depressive disorder illness groups as well as other medical illnesses were categorized as having SEID. The past CFS Fukuda et al. prevalence rate in a community based sample of 0.42 increased by 2.8 times with the new SEID criteria. The consequences for this broadening of the case definition are discussed.

Keywords: Myalgic Encephalomyelitis; chronic fatigue syndrome; systemic exertion intolerance disease; case definitions

1. Introduction

The Institute of Medicine (IOM) [1] recently proposed a new case definition, which was intended to replace the Fukuda et al. [2] 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. [2] 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.

2. Methods

2.1. Study 1

2.1.1. Procedure

In the first study, a CFS screening questionnaire had a combination of existing and new measures including: (1) several demographic related items; (2) The Fatigue Scale [10]; and (3) a list of symptoms associated with CFS. Interviewees were asked a series of questions that assessed whether or not they had a number of symptoms commonly experienced by people with CFS. The symptoms needed to be experienced for 6 or more months. The questions were asked by interviewers (for more details of this study, see [11]).

2.1.2. Participants

A total of 60 individuals (15 with CFS, 15 Controls, 15 with Multiple Sclerosis (MS), and 15 with Lupus) were recruited from the greater Chicago area for the present study. Fifteen of the participants were diagnosed by a physician in Chicago with experience in diagnosing and treating CFS. Each of these participants met the Fukuda et al. [2] definition of CFS. To be diagnosed with the CFS Fukuda et al. [2] criteria, participants had to experience persistent or relapsing fatigue for a period of six or more months concurrent with at least four of eight somatic symptoms that do not predate the fatigue. These symptoms are: sore throat, lymph node pain, muscle pain, joint pain, post-exertional malaise, headaches of a new or different type, memory and concentration difficulties, and unrefreshing sleep. Participants also needed to experience substantial reductions in occupational, educational or personal activities as a result of the illness and must not have any exclusionary medical or psychiatric illnesses.

Fifteen healthy control participants had not been diagnosed with CFS or any other illness that could cause significant fatigue. These participants had also been seen by a physician, and no illnesses that could cause fatigue were found (e.g., unresolved cases of hepatitis C virus infection, untreated hypothyroidism).

In addition, fifteen participants with a diagnosis of Multiple Sclerosis (MS) were recruited from self-help groups in the Chicago area. Each of these participants met Poser et al.’s [12] criteria for definite MS. Participants with other chronic medical conditions in addition to MS were excluded. Finally, fifteen participants with a diagnosis of Systemic Lupus Erythematosus (SLE) were recruited from self-help groups in the Chicago area. The participants with Lupus had to meet the SLE criteria as defined by the American Rheumatology Association [13]. There were no significant differences between groups with respect to race, age, education, marital status, and occupation. However, there were significantly fewer women in the healthy control group as compared to the other groups, and significantly more people were on disability in the CFS and MS group compared to the healthy control group.

2.1.3. SEID Diagnosis

To meet the SEID criteria [1] within this sample, a patient needed to have 6 or more months of illness. To meet the substantial reduction from previous levels of functioning criteria, a patient would have needed to have 6 or more months of substantial reduction in functioning. To meet the post-exertional malaise criteria, a patient would need to have indicated presence of at least 1 of our two post-exertional malaise symptoms: sickness/fatigue for >24 h after exercising or experiencing high levels of fatigue after everyday activity. To meet the unrefreshing sleep criteria, a patient would need to indicate unrefreshed sleep that is more frequent than their pre-illness levels. In order to meet the cognitive impairment criteria, a patient would need at least one of the following cognitive items: difficulty concentrating, difficulty finding the right word to say, difficulty with memory, or difficulty remembering things. Due to a lack of items that tapped into orthostatic intolerance criteria, patients would instead need to meet the cognitive impairment criteria to qualify for the SEID criteria. In another study, we found the option to have orthostatic intolerance instead of cognitive impairment typically enabled only approximately 2% more participants to meet SEID criteria [14].

2.1.4. Results

As indicated in Table 1, 100% (n = 15) of those in the CFS group met the SEID criteria, whereas 47% (n = 7) in the Lupus group, 33% (n = 5) in the MS group, and 0% in the control group met the SEID criteria. In an effort to compare this new SEID case definition to the older Fukuda et al. [2] criteria, we computed the sensitivity and specificity. The SEID criteria evidenced a sensitivity of 1.0 (indicating that 100% of participants with CFS were correctly identified by the SEID criteria) and a specificity of 0.73 (indicating that 27% of participants without CFS were classified as meeting the SEID criteria).

Table 1. CFS, MS, Lupus, and Control Sample n = 60.

Diagnosis                                         Percent Who Qualify for SEID

CFS (n = 15)                                    100% (n = 15)
MS (n = 15)                                      33% (n = 5)
Lupus (n = 15)                                  47% (n = 7)
Control (n = 15)                                  0% (n = 0)


2.2. Study 2

2.2.1. Procedure

In the second study, participants were screened by a trained interviewer to determine if they met the inclusion and exclusion criteria for CFS, MDD, or healthy controls (for more details, see [15]). As part of this screening process, all participants were administered the SCID-IV [16] to assess for psychiatric conditions. Participants who met criteria for participation were asked to complete a battery of questionnaires that measured demographics, social, emotional, and physical functioning, activity level, depression, and a comprehensive list of physical, cognitive, and emotional symptoms. Participants were asked to provide data for fatigue and the 8 diagnostic symptoms specified by the Fukuda et al. [2] case definition. They were asked to report if each symptom had been present for 6 months or longer, began before the onset of their fatigue or health problems, how often it was experienced, and rated the intensity of each symptom on the same scale of 0 to 100. A prior study by King and Jason [17] found that the CFS group against the MDD and control group had significant differences for the following items rated on severity: 4 symptoms in the fatigue/weakness group (fatigue, post-exertional malaise, muscle weakness, need to nap each day), 3 symptoms in the neuropsychological category (frequently losing train of thought, difficulty finding the right word, confusion/disorientation), 4 symptoms in the infectious category (sore throat, tender lymph nodes, hot and cold spells, feeling chilled/shivery), 3 symptoms in the rheumatologic category (muscle pain, pain in multiple joints without swelling, night sweats), 1 symptom in the cardiopulmonary category (shortness of breath), 1 symptom in the neurological category (blurred vision) and unrefreshing sleep. Therefore, these items were also used in the present study.

The Structured Clinical Interview for the DSM-IV (SCID) is a valid and reliable semi-structured interview guide that closely resembles a traditional psychiatric interview [16]. The SCID is designed to identify current, past, and lifetime (chronic or recurring, current and past) diagnoses for a majority of DSM-IV, Axis I psychiatric disorders. The SCID is commonly administered during a single session lasting 45 min to an hour. Diagnostic decisions generated by the SCID are based on all possible sources of historical, symptomatic, and behavioral information. The SCID begins with a semi-structured interview portion designed to yield a tentative diagnosis. The tentative diagnosis is then systematically assessed during the structured portion of the interview through the use of embedded questions that conform to the exact, Axis I criteria set forth by the DSM-IV.

The SF-36 is 36-item instrument that is comprised of multi-item scales that assess physical functioning, role limitations, social functioning, bodily pain, general mental health, vitality, and general health perceptions. Higher scores indicate better health, lower disability, or less impact of health on functioning.

Reliability and validity studies have demonstrated that the 36-item version of the SF-36 has high reliability and validity in a wide variety of patient populations [18].

2.2.2. Participants

A total of 45 individuals (15 with CFS, 15 with MDD, and 15 healthy controls) were recruited from the greater Chicago area [15]. Fifteen participants with CFS were solicited to participate in the present study. Participants were drawn from two sources, a local CFS support group in Chicago and previous research studies conducted at DePaul University. Participants were required to have been diagnosed with CFS, using Fukuda et al.’s [2] diagnostic criteria, by a Board-certified physician and were required to have a current (active) case of CFS. All participants had been seen by their physician in the past year. Individuals who reported having uncontrolled or untreated medical illnesses (e.g., untreated anemia) were excluded.

All participants were screened with the SCID-IV to ensure that they did not have any exclusionary psychiatric illnesses as stipulated by the Fukuda et al. [2] case definition.

Fifteen participants with a diagnosis of MDD were solicited from a local chapter of the National Depressive and Manic Depressive support group in Chicago. Participants were required to have been diagnosed with major depression by a licensed psychologist or psychiatrist. All participants were screened with the SCID-IV to ensure that they met criteria for a current (active) case of major depression and did not have any other current psychiatric illnesses. Individuals who had other current psychiatric conditions in addition to major depression were excluded. Individuals who reported having uncontrolled or untreated medical illnesses (e.g., anemia, diabetes) were also excluded. In the MDD group, all 15 (100%) participants met DSM-IV diagnostic criteria for MDD. None of the participants in the MDD group met criteria for MDD with catatonic, melancholic, psychotic, or atypical features. Participants in the MDD group did not meet criteria for any other Axis I disorders.

Finally, fifteen healthy control participants were solicited from the greater Chicago area. Individuals who did not have any medical illnesses or who did not have any uncontrolled or untreated illnesses (e.g., anemia, diabetes) were allowed to participate. All participants were screened with the SCID-IV to ensure that they did not have any current psychiatric illnesses. Individuals with current psychiatric conditions were excluded. Sociodemographic data were compared across the three groups, and there were no significant differences with respect to gender, race, age, SES, education, marital status, occupation, work status, and additional roles [15].

2.2.3. SEID Diagnosis

To meet the SEID criteria [1] within this sample, a patient would need to have 6 or more months of fatigue. Because the SEID criteria do not indicate how to assess substantial reductions, we used criteria that has been published in prior studies with specified cut off points [6,14]. To meet substantial reduction from previous levels of functioning criteria, a patient needed to meet 2 of the following 3 SF-36 criteria: role physical <50, social functioning <62.5, or vitality <35. To meet the post-exertional malaise criteria, a patient needed to have 6 or more months of post-exertional malaise. To meet the unrefreshing sleep criteria, a patient needed to have 6 or more months of unrefreshing sleep. To meet the SEID criteria, the individual needed to have either a cognitive impairment or orthostatic intolerance symptom. In order to meet the cognitive impairment criteria, a patient would need at least one of the following cognitive items: impaired memory present for 6 months or longer, slowness of thought, absent mindedness or forgetfulness, or difficulty focusing. To meet the orthostatic intolerance criteria, a patient would need presence of at least one of the following items: dizziness, wobbling feet when getting up.

2.2.4. Results

As indicated in Table 2, 93% (n = 14) of those in the CFS group, 27% (n = 4) in the MDD group, and 0% in the control group met SEID criteria. In an effort to compare this new SEID case definition to the older Fukuda et al. [2] criteria, we computed the sensitivity and specificity. These criteria resulted in a sensitivity of 0.93 and a specificity of 0.86.

Table 2. CFS vs. MDD Database n = 45.

Diagnosis                              Percent Who Qualify for SEID

CFS (n = 15)                         93% (n = 14)

MDD (n = 15)                       27% (n = 4)

Control (n = 15)                     0% (n = 0)

2.3. Study 3

2.3.1. Procedure

The data were derived from a larger community-based study of CFS that was carried out in three stages [3]. Stage 1 entailed a cross-sectional screening telephone survey of a random sample of 28,673 households, with 18,675 adults completing the screening interview (65.1% completion rate). Of these participants, 780 (4.2%) of the respondents had six or more months of fatigue. Stage 2 involved a structured psychiatric interview for a sample of those respondents from Stage 1 who screened positive for a CFS-like syndrome based on the Fukuda et al. [2] criteria, as well as a screen negative control sample.

In Stage 3, a physician conducted a detailed medical examination to rule out exclusionary medical conditions. All patients underwent detailed reviews of their medical history and a thorough physical and neurological examination to detect evidence of diffuse adenopathy, hepatosplenomegaly, synovitis, neuropathy, myopathy, cardiac or pulmonary dysfunction. All had routine blood tests performed including complete blood count, chemistry screen (including glucose, electrolytes, calcium, magnesium, liver function tests and renal function tests), sedimentation rate, rheumatoid factor, Antinuclear Antibody, triiodothyronine, thyroxine, thyroid-stimulating hormone, Creatine phosphokinase, human immunodeficiency virus, hepatitis screen, B12, red blood cell folate and serum carnitine determinations. All patients had a urinalysis performed.

2.3.2. Participants

According to the Phase 1 screen, of the 18,675 interviewees, 16,453 (88%) had no prolonged or chronic fatigue, 1435 (7.7%) had prolonged fatigue, and 780 (4.2%) had chronic fatigue (seven cases refused to answer the fatigue questions). Among those 780 respondents with chronic fatigue, at Phase 1; 304 had ICF-like illness (e.g., not enough minor symptoms to be eligible for a CFS diagnosis), 68 had a CF-explained-like condition, and 408 had CFS-like profiles. All 408 members of the CFS-like group were invited to participate in Phase 2. Of this group of 408 individuals with CFS-like symptoms, the physician review team reviewed data on 166 individuals, who provided data during the Phase 2 evaluation.

There were 47 individuals who were evaluated in a control group, and these individuals screened negative for CFS-like illness during Phase 1.

A team of four physicians and a psychiatrist were responsible for making a final diagnosis with two physicians independently rating each file using the current U.S. case definition of CFS [2]. Where physicians disagreed, a third physician rater was used [3]. Table 3 shows the number of cases in the control group (Control), individuals who were diagnosed with CFS using the Fukuda et al. [2] case definition (CFS), Idiopathic chronic fatigue (ICF, individuals who did not meet all the Fukuda criteria), and chronic fatigue explained (CF, i.e., melancholic depression, bipolar disorders, anorexia nervosa/bulimia nervosa, psychotic disorders, drug or alcohol related disorders, or medical explanations for their fatigue).

Table 3. Community Epidemiology database n = 213.

Diagnosis                             Percent Who Qualify for SEID

CFS (n = 32)                       75% (n = 24)

ICF (n = 45)                        44% (n = 20)

CF (n = 89)                          47% (n = 42)

Control (n = 47)                      6% (n = 3)

2.3.3. SEID Diagnosis

To meet the SEID criteria [1] within this data set, a patient would need to have one of the following indications of 6 or more months of fatigue: fatigue for 6 or more months or fatigue present for more than 50% of the time for a minimum of 6 consecutive months. To meet substantial reduction from previous levels of functioning criteria, a patient needed to meet 2 of the following 3 criteria: role physical <50, social functioning <62.5, or vitality <35. To meet the post-exertional malaise criteria, a patient needed to report the occurrence of one of the following symptoms: prolonged generalized fatigue or malaise following previously tolerable levels of exercise, feeling generally worse than usual or fatigued for 24 h or more after exercise, or exercise brings on my fatigue. To meet the unrefreshing sleep criteria, a patient needed one of the following symptoms: after a night of sleep do you feel rested, after a night of sleep does your fatigue go away temporarily, needing to nap daily, problems falling/staying asleep. To meet the SEID criteria, the individual needed to meet either the cognitive impairment or orthostatic intolerance symptom. In order to meet the cognitive impairment criteria, a patient would need presence of at least one of the following cognitive items: forget recent conversations and events, confusion or distortion in familiar places, inability to concentrate, difficulty retaining information, only able to focus on one thing at a time, or new trouble with math. To meet the orthostatic intolerance criteria, a patient would need presence of at least one of the following items: sharp shooting pains in chest, rapid heartbeat, feeling unsteady on feet, often feeling dizzy, feeling weak or dizzy right after standing up.

2.3.4. Estimating SEID Prevalence

Prevalence, which is the number to be estimated, is represented by P (p). The total number of respondents screened in Phase 1 (18,668) is N (Nt). The proportion of screened positives (408/18,668 = 0.0219) is PI (π), and the proportion of screened negatives (18,260/18,668 = 0.9781) is 1 − PI (1 − π). The proportion of screened positives evaluated in Phase 2 who were diagnosed with SEID (Number of cases with SEID/166) is L1 (λ1), and the proportion of screened negatives evaluated in Phase 2 who were diagnosed with SEID (0/47 = 0.0) is L2 (λ2).

2.3.5. Results

As indicated in Table 3, 75% (n = 24) of those in the CFS group met the SEID criteria, whereas 47% (n = 42) for the CF group, 44% (n = 20) for the ICF group, and 6% (n = 3) for the controls. Within the Chronic Fatigue explained by medical or psychiatric illness (CF), of those 19 with Melancholic Depression, 47% (n = 9) met the SEID criteria. In addition, for those with a medical reason for their fatigue, 48% (n = 16) met SEID criteria. In an effort to compare this new SEID case definition to the older Fukuda et al. [2] criteria, we computed the sensitivity and specificity. In this sample, the SEID criteria had a sensitivity of 0.75 and a specificity of 0.64.

This data set had been previously used to estimate the prevalence of CFS [3], which was 0.42. With the new number of SEID cases, we recalculated the prevalence rate, using methods described elsewhere [19].

This information was then used in the following formula to obtain the estimate of the prevalence [P = L1 × PI + L2 × (1 − PI) = L1 × 0.0219 + 0.0 × 0.9781]. The SEID Prevalence rate = L1 × PI + L2 × (1 − PI) = (89/166) × 0.0219 + 0.0 × 0.9781 = 0.0117. As the prior CFS Fukuda et al. [2] prevalence rate was 0.0042, the new SEID prevalence rate was 2.8 (0.0117/0.0042) times greater.

2.4. Study 4

2.4.1. Procedure

We solicited participants with a diagnosis of MDD and CFS to participate in this study [20]. We administered to all participants the CDC Symptom Inventory, which assesses information about the presence, frequency, and intensity of 19 fatigue related symptoms during the past one month [21]. All eight of the critical Fukuda et al. [2] symptoms were included as well as 11 other symptoms (e.g., diarrhea, fever, sleeping problems, nausea, etc.). For each of the eight Fukuda et al. [2] symptoms, participants were asked to report the frequency (1 = a little of the time, 2 = some of the time, 3 = most of the time, 4 = all of the time) and severity (the ratings were transformed to the following scale: 0.08 = very mild, 1.6 = mild, 2.4 = moderate, 3.2 = severe, 4 = very severe). The frequency and severity scores were multiplied for each of the eight critical Fukuda et al. [2] symptoms and were then summed, in order to determine whether a person met the Fukuda et al. [2] criteria, as operationalized by Reeves et al. [22].

2.4.2. Participants

We recruited 64 individuals, 27 with CFS and 37 with MDD. We obtained our sample of participants with CFS from two sources, local CFS support groups in Chicago and a previous research study conducted at DePaul University. To be included in the study, participants were required to have been diagnosed with CFS, using the Fukuda et al. [2] diagnostic criteria, by a certified physician and were required to currently meet CFS criteria using the Fukuda et al. criteria. We excluded individuals who had other current psychiatric conditions in addition to major depression or who reported having untreated medical illnesses (e.g., diabetes, anemia).

For the MDD group, we found participants from three sources, local chapters of the Depression and Bipolar Support Alliance group in Chicago; Craigslist—a free local classifieds ad forum that is community moderated; and online depression support groups. To be included in the study, all participants were required to have been diagnosed with a MDD by a licensed psychologist or psychiatrist. We excluded individuals who had other current psychiatric conditions in addition to a MDD (e.g., bipolar, schizophrenia) or who reported having untreated medical illnesses were also excluded. We carefully screened participants to ensure that participants from the MDD group did not have CFS as defined by the Fukuda et al. [2] criteria.

2.4.3. SEID Diagnosis

To meet the SEID criteria [1] within this sample, a patient needed to have 6 or more months of illness. To meet substantial reduction from previous levels of functioning criteria, a patient needed to meet 2 of the following 3 criteria: role physical <50, social functioning <62.5, or vitality <35. To meet the post-exertional malaise criteria, a patient would need to have a frequency of at least some of the time and severity score of at least moderate to indicate prolonged levels of malaise following previously tolerated exercise. To meet the unrefreshing sleep criteria, patients would have to have indicated at least 1 of the unrefreshing sleep symptoms: Unrefreshing sleep in the past month, unrefreshing sleep present 6 months or longer, or trouble sleeping through falling or staying asleep. In order to meet the cognitive impairment criteria, a patient would need to have a frequency of at least some of the time and severity score of at least moderate to indicate impaired concentration. Due to a lack of items that tapped into orthostatic intolerance criteria, patients would instead need to meet the cognitive impairment criteria to qualify for this measure. In a prior study by Jason, Sunnquist, Kot, Brown, Newton et al. [14], when using the option to have orthostatic intolerance instead of cognitive impairment, only an additional 2% of participants meet the SEID criteria [14].

2.4.4. Results

As indicated in Table 4, 81% (n = 22) of those in the CFS group met the SEID criteria, whereas 24% (n = 9) of those in the MDD group met SEID criteria. In an effort to compare this new SEID case definition to the older Fukuda et al. [2] criteria, we computed the sensitivity and specificity. The SEID criteria resulted in a sensitivity of 0.81 and a specificity of 0.76.

Table 4. CFS vs. MDD Database n = 64.

Diagnosis                              Percent Who Qualify for SEID

CFS (n = 27)                        81% (n = 22)

MDD (n = 37)                      24% (n = 9)

3. Discussion and Conclusions

Tables 1–4 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 Tables 1 and 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 Tables 2 and 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. [3] community-based epidemiologic study, 32 individuals had been classified as meeting the Fukuda et al. [2] 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. [2] 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. [2] 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. [2] 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. [2] CFS criteria. If there are ambiguities with case definitions, like what has occurred with the Fukuda et al. [2] 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 [24,25]. 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. [19] 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. [22]. Fortunately, few adopted the Reeves et al. [22] 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.

Author Contributions

All authors contributed to the conceptualization of the study, the data analysis, and the writing of this article.

Conflicts of Interest: The authors declare no conflicts of interest.

References

1. IOM (Institute of Medicine). Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness; The National Academies: Washington, DC, USA, 2015.

2. Fukuda, K.; Straus, S.E.; Hickie, I.; Sharpe, M.C.; Dobbins, J.G.; Komaroff, A. The chronic fatigue syndrome: A comprehensive approach to its definition and study. Ann. Intern. Med. 1994, 121, 953–959.

3. Jason, L.A.; Richman, J.A.; Rademaker, A.W.; Jordan, K.M., Plioplys, A.V.; Taylor, R.R.; McCready, W.; Huang, J.C.; Plioplys, S. A community-based study of chronic fatigue syndrome. Arch. Intern. Med. 1999, 159, 2129–2137.

4. Carruthers, B.M.; Jain, A.K.; de Meirleir, K.L.; Peterson, D.L.; Klimas, N.G.; Lerner, A.M.; Bested, A.C.; Flor-Henry, P.; Joshi, P.; Powle, A.C.P.; et al. Myalgic Encephalomyelitis/chronic fatigue syndrome: Clinical working case definition, diagnostic and treatments protocols. J. Chronic Fatigue Syndr. 2003, 11, 7–115.

5. Carruthers, B.M.; van de Sande, M.I.; de Meirleir, K.L.; Klimas, N.G.; Broderick, G.; Mitchell, T.; Stevens, S. Myalgic Encephalomyelitis: International Consensus Criteria. J. Intern. Med. 2011, 270, 327–338.

6. Jason, L.A.; Kot, B.; Sunnquist, M.; Brown, A.; Evans, M.; Jantke, R.; Williams, Y.; Furst, J.; Vernon, S.D. Chronic fatigue Syndrome and myalgic encephalomyelitis: Toward an empirical case definition. Health Psychol. Behav. Med. 2015, 3, 82–93.

7. IOM (Institute of Medicine). Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness; Report Guide for Clinicians; The National Academies: Washington, DC, USA, 2015.

8. Ze-dog, D. A Major Flaw in the IOM’s Definition of ME/CFS. Available online: http://on.fb.me/1vWYv9g (accessed on 18 February 2015).

9. Verrillo, E. Onward through the Fog. The IOM Report: The Good, the Bad, and the Absolutely Hideous. Available online: http://bit.ly/1DcdQ2K (accessed on 16 February 2015).

10. Chalder, T.; Berelowitz, G.; Pawlikowska, T.; Watts, L.; Wessely, S.; Wright, D.; Wallace, E.P. Development of a fatigue scale. J. Psychosom. Med. 1993, 37, 147–153.

11. Jason, L.A.; Ropacki, M.T.; Santoro, N.B.; Richman, J.A.; Heatherly, W.; Taylor, R.R.; Ferrari, J.R.; Haney-Davis, T.M.; Rademaker, A.; Dupuis, J.; et al. A screening instrument for Chronic Fatigue Syndrome: Reliability and validity. J. Chronic Fatigue Syndr. 1997, 3, 39–59.

12. Poser, C.M.; Paty, D.W.; Scheinberg, L.; McDonald, W.I.; Davis, F.A.; Ebers, G.C.; Johnson, K.P.; Sibley, W.A.; Silberberg, D.H.; Toureteliotte, W.W. New diagnostic criteria for multiple sclerosis: Guidelines for research protocols. Ann. Neurol. 1983, 13, 227–231.

13. Tan, E.M.; Cohen, A.S.; Fries, J.F.; Masi, A.T.; McShane, D.J.; Rothfield, N.F.; Schaller, J.G.; Talal, N.; Winchester, R.J. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982, 25, 1271–1277.

14. Jason, L.A.; Kot, B.; Sunnquist, M.; Brown, A.; Newton, J.L.; Strand, E.B.; Vernon, S.D. Chronic Fatigue Syndrome vs. Systemic Exertion Intolerance Disease. Fatigue Biomed. Health Behav. 2015, doi:10.1080/21641846.2015.1051291.

15. Hawk, C.; Jason, L.A.; Torres-Harding, S. Differential diagnosis of chronic fatigue syndrome and major depressive disorder. Int. J. Behav. Med. 2006, 13, 244–251.

16. Spitzer, R.L.; Williams, J.B.W.; Gibbon, M.; First, M.B. Structured Clinical Interview for the DSM-IV—Non-Patient Edition (SCID—NP, Version 2.0); American Psychiatric Press: Washington, DC, USA, 1995.

17. King, C.; Jason, L.A. Improving the diagnostic criteria and procedures for chronic fatigue syndrome. Biol. Psychol. 2005, 68, 87–106.

18. Ware, J.J.; Sherbourne, C.D. The MOS 36-item short-form health survey (SF-36). I. Conceptual frameworkand item selection. Med. Care 1992, 30, 473–483.

19. Jason, L.A.; Porter, N.; Rademaker, A. Epidemiologic approaches to community-based research. In Methodological Approaches to Community-Based Research; Jason, L.A., Glenwick, D.S., Eds.; American Psychological Association: Washington, DC, USA, 1982; pp. 187–204.

20. Jason, L.A.; Najar, N.; Porter, N.; Reh, C. Evaluating the Centers for Disease Control’s empirical chronic fatigue syndrome case definition. J. Disabil. Policy Stud. 2009, 20, 93–100.

21. Wagner, D.; Nisenbaum, R.; Heim, C.; Jones, J.F.; Unger, E.R.; Reeves, W.C. Psychometric properties of the CDC Symptom Inventory for assessment of Chronic Fatigue Syndrome. Popul. Health Metr. 2005, 3, 8. Available online: http://www.pophealthmetrics.com/content/3/1/8 (accessed on 22 July 2005).

22. Reeves, W.C.; Wagner, D.; Nisenbaum, R.; Jones, J.F.; Gurbaxani, B.; Solomon, L.; Papanicolaou, D.A.; Unger, E.R.; Vernon, S.D.; Heim, C.; et al. Chronic fatigue syndrome—A clinical empirical approach to its definition and study. BMC Med. 2005, 3, 19.

23. Brown, M.M.; Jason, L.A.; Kaplan, C.B.; Keys, C.B. Subgroups of chronic fatigue syndrome based on psychiatric disorder onset and current psychiatric status. Health 2010, 2, 90–96.

24. Friedberg, F.; Jason, L.A. Understanding Chronic Fatigue Syndrome: An Empirical Guide to Assessment and Treatment; American Psychological Association: Washington, DC, USA, 1998.

25. Komaroff, A.L.; Fagioli, L.R.; Geiger, A.M.; Doolittle, T.H.; Lee, J.; Kornish, R.J.; Gleit, M.A.; Guerriero, R.T. An examination of the working case definition of Chronic Fatigue Syndrome. Am. J. Med. 1996, 100, 56–64.

26. Regier, D.A.; Boyd, J.H.; Burke, J.D., Jr. One-month prevalence of mental disorders in the United States: Based on five Epidemiological Catchment rea sites. Arch. Gen. Psychiatry 1988, 45, 977–986.

27. Price, J.R.; Mitchell, E.; Tidy, E.; Hunot, V. Cognitive Behaviour Therapy for Chronic Fatigue Syndrome in Adults. Cochrane Database Syst. Rev. 2008, doi: 10.1002/14651858.CD001027.pub2.

28. Jason, L.A.; Sunnquist, M.; Brown, A.; Evans, M.; Vernon, S.D.; Furst, J.; Simonis, V. Examining case definition criteria for chronic fatigue syndrome and Myalgic Encephalomyelitis. Fatigue Biomed. Health Behav. 2014, 2, 40–56.

29. Brown, A.A.; Jason, L.A. Validating a measure of myalgic encephalomyelitis/chronic fatigue syndrome symptomatology. Fatigue Biomed. Health Behav. 2014, 2, 132–152.

30. Jason, L.A. How Disease Names Can Stigmatize. Oxford University Press Blog. Available online: http://blog.oup.com/2015/02/disease-name-chronic-fatigue-syndrome-me/ (accessed on 16 February 2015).

© 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/).

Contact information:

Center for Community Research, DePaul University, Chicago, IL 60614, USA; E-Mails: MSUNNQUI@depaul.edu (M.S.); BKOT@depaul.edu (B.K.); ABROWN57@depaul.edu (A.B.)

* Author to whom correspondence should be addressed; E-Mail: LJASON@depaul.edu;

Tel.: +1-773-325-2018; Fax: +1-773-325-4923.

Academic Editor: Andreas Kjaer

Received: 25 March 2015 / Accepted: 16 June 2015 / Published: 23 June 2015

Diagnostics 2015, 5, 272-286; doi:10.3390/diagnostics5020272

ISSN 2075-4418

www.mdpi.com/journal/diagnostics/

Monday, June 22, 2015

7 Things I Have Learned From Having a Chronic Illness

When you are caught between a rock and a hard place, jumping helps
I am breaking a self-imposed rule today by addressing ME/CFS in the first person. It is not a subject I like talking about, except in the abstract: What research is being done? What treatments are effective? What can we do to pressure the government into taking ME/CFS more seriously? Why must we have so many acronyms?

Those questions are relatively easy to address. "How has ME affected me?" is another matter entirely.

Looking back on my long acquaintance with chronic illness (four of them as of this writing, but who's counting?) I have discovered that these illnesses have changed me - in some respects for the better. No, I am not one of those "glass-is-half-full" people (the glass, by the way, is entirely full; it is half full of water and half full of air). Nor do I experience "gratitude" on a daily basis. It's more a matter of perspective.

This is what I have learned:

1) Most things can be put off. The world seems to run on crises that are to a large extent manufactured. Most things can be delayed - or not done at all. Laundry, for example. And, apparently, my car inspection.

2) The world not only turns without you, it travels in the same ruts. When I got sick there was a war. Two years later, when I sat up and resumed reading the news, there was the same war. It was in a different location, but the basic features were the same: Bombs. Death. Incomprehensible politics.

3) Lots of things aren't important - especially things you might have been doing for the wrong reasons. When I contracted ME I was finishing my PhD. At the time, I thought it was important, and the reasons I had for wanting a career in academia seemed to make sense: "Long vacations," "Academic departments are hiring women,"  "All the other kids on the block have one." The reasons that weren't on my list were: "I like academia," "I like talking with academics," "I am committed to my field of study." It turns out I really don't like close contact with people who think they are saying something meaningful when they are just blathering.

4) People say stupid things all the time, and it doesn't matter. When I first became severely ill, a friend said, "Are you working out?" I confess that at the time I wanted to kill him. (That was a job later performed by excess amounts of alcohol.) And when my daughter contracted ME, another friend said she was just "imitating" me to "get attention." Were those awful things to say? Yes. But people routinely say awful, stupid things, and most of the time they aren't even aware of how awful and stupid they are. That's because they are awfully stupid. You can't fix stupid. But you can ignore it.

5) Doctors don't know jack about the human body, and I don't need to tell them that. At first I wanted help from doctors. Then I realized they didn't know more about what was going on inside me than I did. What was more, they didn't seem to care. So, I began telling them they were full of crap. As the years wore on, I gradually became aware that I was not going to educate doctors - they are, as a profession, unteachable. I now know that GPs are nothing more than glorified drug dealers. So, I only go to one when I need a fix. If I need more than that, I'll go to a vet. (When your patients can't talk, you really have to listen.)

6) Illness doesn't happen for a reason. There is no grand plan, and God gives you plenty you can't handle. (I don't believe in God, but aside from that there is an obvious flaw in that statement: suicide.) There is no path, and we are not on a "journey." I didn't like metaphors when I was studying them, and I like them even less now. If you want to make a comparison, give me a good honest simile.

7) I breathe therefore I am. There is nothing that anybody can do to me that is worse than what I have already experienced. No matter how much weird stuff goes on inside my body, and no matter how many doctors dismiss me, no matter how many government agencies refuse to do a damn thing to stem the tide of what is surely an epidemic, no matter how many friends abandon me, no matter how many jobs I have lost, and no matter how many years I have spent lying in bed wishing it were over, I am still here. True courage is simply this: We are alive. And as long as we are alive, we must persevere.

Thursday, June 4, 2015

Report Finds Graded Exercise Therapy Worsens Symptoms of ME/CFS

Reprinted with permission.


By Russell Fleming


This is the largest and most comprehensive 'patient evidence' report covering ALL aspects of CBT, GET and Pacing – i.e. efficacy, safety and acceptability – that has ever been produced.” ~Dr Charles Shepherd, Medical Advisor, ME Association



On 28th May, The ME Association published Part 1 of the report for public consultation. It is a 294 page document focusing on courses delivered mainly in clinical settings and includes an executive summary, a complete and detailed analysis, relevant patient comments, and extensive conclusions and recommendations.

Part 1 can be downloaded HERE.

Part 2 will focus on self-management and will be published in the near future
.

Introduction

Large numbers of patients with ME/CFS consistently report that prescribed management approaches are not as acceptable, effective, or safe in practice as is often claimed they ought to be.

In 2012 the ME Association decided that a new and more detailed patient survey was required to try and better explain the factors contributing to patient reported outcomes, and this report provides quantitative and qualitative evidence of the patient experience.

The report will be used to lobby the UK National Institute for Health and Care Excellence (NICE) and other authorities, including NHS ME/CFS specialist services, to effect improvements which will hopefully lead to better outcomes for patients in the future.

The Survey

The survey was split into three sections, one each for CBT, GET and Pacing, it asked 228 questions in total and was completed by 1428 respondents. 493 respondents had been on a CBT course, 233 on a GET course and 226 on a Pacing course. Some had been on separate courses for one or more of the interventions; others had been on courses comprising multiple interventions.

The Report

An examination was made of the effect courses were deemed to have had on illness severity, on symptoms, disability benefits, employment and education, the appropriateness of courses in relation to individual patient need, and the effect CBT has on anxiety, depression and stress.

Also considered was course availability within the NHS, suitability of session length, reasons why courses were not completed in full, the provision of course information to patients, the impact of the NICE Guideline on course delivery, effectiveness of courses led by specialists and non-specialists, and a comparison was made between these results and those from previous patient surveys.

Note: The full results can be read in the 294 page report, here are just 3 examples:

Results – Example 1


With regard to the effect courses had on illness severity, we found that GET resulted in the most significant change with more patients who attended such courses reporting their illness had become more severe as a result.

Results – Example 2



Symptoms were reported as having improved or as remaining unaffected by more patients where therapists leading a course recognised ME/CFS to be a physical illness than where therapists believed the illness was psychological.

Symptoms were deemed to have been made notably worse where courses were led by therapists holding this psychological belief even for Pacing.

Results – Example 3



For those who were on benefits, it was most notable that irrespective of the course undertaken, claims remained largely the same with few reducing or stopping their benefits.

However, net overall increases were seen in benefits following courses in CBT and GET compared to a slight decrease from those attending Pacing courses.

Conclusions and Recommendations

Note: Please see Sections 4 and 5 of the report for the full conclusions and recommendations, what follows is a summary:

Cognitive Behavioural Therapy (CBT)

The ME Association concludes that CBT in its current delivered form should not be recommended as a primary intervention for people with ME/CFS.

CBT courses based on the model that abnormal beliefs and behaviours are responsible for maintaining the illness, have no role to play in the management of ME/CFS and increase the risk of symptoms becoming worse.

The belief of some CBT practitioners that ME/CFS is a psychological illness was the main factor which led to less symptoms improving, less courses being appropriate to needs, more symptoms becoming worse and more courses being seen as inappropriate.

Results also indicate that graded exercise therapy should form no part of any activity management advice employed in the delivery of CBT, as this also had a negative effect on outcomes.

However, the results did indicate that, when used appropriately, the practical coping component of CBT can have a positive effect in helping some patients come to terms with their diagnosis and adapt their lives to best accommodate it.

CBT was also seen to have a positive effect in helping some patients deal with comorbid issues – anxiety, depression, stress – which may occur at any time for someone with a long-term disabling illness.

Graded Exercise Therapy (GET)

The ME Association concludes that GET should be withdrawn with immediate effect as a primary intervention for everyone with ME/CFS.

One of the main factors that led to patients reporting that GET was inappropriate was the very nature of GET itself, especially when it was used on the basis that there is no underlying physical cause for symptoms, and that patients are basically ill because of inactivity and deconditioning.

A significant number of patients had been given advice on exercise and activity management that was judged harmful with symptoms becoming worse or much worse and leading to relapse. And it is worth noting that despite current NICE recommendations, a significant number of severe-to-very severe patients were recommended GET by practitioners and/or had taken part in GET courses.

The ME Association recognises that it is impossible for all treatments for a disease to be free from side-effects, but if GET was a licensed medication, it believes the number of people reporting significant adverse effects would lead to a review of the use of GET by regulatory authorities.

Pacing

The ME Association concludes that Pacing is the most effective, safe, acceptable and preferred form of activity management for people with ME/CFS and recommends that it should be a key component of any illness management programme.

For some, improvement may be a slow process so, whilst they may be somewhat better by the end of a course, the improvement is not enough to take them into a better category of severity for some time, perhaps not until they have self-managed their illness for a few years.

The benefit of Pacing may relate to helping people cope and adapt to their illness rather than contributing to a significant improvement in functional status.

Learning coping strategies can help make courses more appropriate to needs even if they do not lead to immediate or even longer term improvement in symptoms. Importantly, it can prevent symptoms from becoming worse.

Next steps...

The ME Association will prepare a paper on illness management that better reflects the patient experience and which utilises the evidence obtained from the results of the 2012 patient survey, and from the ME Association’s 2010 Management Report. It will also reflect those aspects of the 2007 NICE guideline that are felt to be supported by patient evidence but have not found their way into delivered patient care.

The paper will detail a recommended illness management approach for ME/CFS and will focus on issues such as personalised patient care, improved professional education, course accessibility and home visits, and better provision of course information, as well as shared decision making.

The aim is to improve patient reported outcomes with a more encompassing and sympathetic approach to illness management in the absence of a specific treatment.


The ME Association provides information, support and practical advice for people who are affected by ME/CFS/PVFS (myalgic encephalopathy/chronic fatigue syndrome/post-viral fatigue syndrome), their families and carers. They also fund and support research, and offer education and training.

Saturday, May 23, 2015

Conflict of Interest: CDC Accepts Millions from Corporations

Jeanne Lenzer is the associate editor of the The BMJ (British Medical Journal), USA. The BMJ is one of the world's oldest medical journals. As a peer-reviewed publication of the British Medical Association, it has tremendous clout, and is widely read by medical professionals all over the world.

In this BMJ article, Lenzer discusses the conflict of interest generated by an infusion of millions of dollars from private corporations into the CDC. Although she only presents a few cases in which the CDC has shifted policy in order to aid corporate interests, given the enormous amount of money it has received there are obviously many more.

The demise of the CDC as a public institution began in the 1980s during the Reagan-era period of privatization. In 1995 the CDC Foundation, which was created by Congress, began to accept "gifts" on behalf of the CDC. This funding arm has not only led to skewed treatment recommendations - the most recent of which is the narrow window of antibiotic treatment allowed to Lyme disease patients - but has opened the door to strong-arm tactics, such as the NRA's withdrawal of funds after the CDC began an investigation of gun violence.

The CDC will not bite the hand that feeds it. In the case of ME/CFS the hand is most likely insurance companies, which (as in the case of Lyme disease) don't want to pay for expensive long-term treatments. As long as the CDC promotes criteria for ME/CFS that are vague enough to fit into the generally accepted definition of depression, doctors will prescribe therapy and exercise, patients will be misdiagnosed, and it goes without saying that Ampligen will never be approved.

The concept that the CDC represents the public good needs to be seriously re-evaluated.
_____________________________________


Centers for Disease Control and Prevention: protecting the private good?

By Jeanne Lenzer, associate editor, The BMJ, USA

BMJ 2015;350:h2362 doi: http://www.bmj.com/content/350/bmj.h2362 (Published 15 May 2015)

The Centers for Disease Control and Prevention (CDC) includes the following disclaimer with its recommendations: “CDC, our planners, and our content experts wish to disclose they have no financial interests or other relationships with the manufacturers of commercial products . . . CDC does not accept commercial support.”1

The CDC’s image as an independent watchdog over the public health has given it enormous prestige, and its recommendations are occasionally enforced by law.

Despite the agency’s disclaimer, the CDC does receive millions of dollars in industry gifts and funding, both directly and indirectly, and several recent CDC actions and recommendations have raised questions about the science it cites, the clinical guidelines it promotes, and the money it is taking.

Marcia Angell, former editor in chief of the New England Journal of Medicine, told The BMJ, “The CDC has enormous credibility among physicians, in no small part because the agency is generally thought to be free of industry bias. Financial dealings with biopharmaceutical companies threaten that reputation.”2

Industry funding of the CDC has taken many doctors, even some who worked for CDC, by surprise. Philip Lederer, an infectious diseases fellow at Massachusetts General Hospital and Brigham and Women’s Hospital in Boston, Massachusetts, and a former CDC epidemic intelligence service officer, told The BMJ he was “saddened” to learn of industry funding.

The CDC’s director, Tom Frieden, did not respond to a question about the disclaimer. He told The BMJ by email, “Public-private partnerships allow CDC to do more, faster. The agency’s core values of accountability, respect, and integrity guide the way CDC spends the funds entrusted to it. When possible conflicts of interests arise, we take a hard, close look to ensure that proper policies and guidelines are followed before accepting outside donations.”

Since its inception in 1946, the CDC has had a pivotal role not only in the prevention of infectious diseases but in reducing workplace hazards, motor vehicle injuries, and tobacco related deaths and in ensuring food safety.

One of the CDC’s most important contributions, with an estimated eight million lives saved to date,3 has been its work to educate the public about the dangers of tobacco. CDC spokesperson Thomas Skinner says the surgeon general’s first report on smoking in 1964 was a “tipping point,” when tobacco was first clearly identified as a health hazard by the US government. Skinner said the CDC’s anti-tobacco campaign “serves as an important counter to the more than $950 000 [£630 000; €860 00] that the tobacco industry spends each hour—more than $23m a day—on cigarette advertising and promotion.”

Opening up to private money

Funding of CDC took a turn in 1983, when the CDC was authorised to accept external “gifts” from industry and other private parties. In 1992, Congress passed legislation to encourage relationships between industry and the CDC by creating the non-profit CDC Foundation, which began operations in 1995.

The CDC Foundation raised $52m in fiscal year 2014, of which $12m was from corporations. The CDC itself in fiscal year 2014 received $16m in conditional funding from sources such as corporations, individuals, and philanthropy, including the CDC Foundation. Conditional donations are earmarked for specific projects. For example, in 2012, Genentech earmarked $600 000 in donations to the CDC Foundation for CDC’s efforts to promote expanded testing and treatment of viral hepatitis. Genentech and its parent company, Roche, manufacture test kits and treatments for hepatitis C.

Numerous manufacturers give donations to the CDC Foundation. Janssen also contributed $1.5m in 2012-13,1 and in 2011-12 contributors included Merck ($915 149), Genzyme ($762 000), Sanofi-Aventis ($600 000), and Abbott Laboratories ($550 000).

The CDC has recently issued controversial recommendations for screening tests and drugs,2 4 and is currently overseeing several equally controversial studies.5 Some of these are associated with “conditional” industry funding, as the three examples below show.

Cohort screening for hepatitis C

The CDC issued guidelines in August 2012 recommending expanded (cohort) screening of everyone born from 1945 to 1965 for hepatitis C virus.1 The agency cited new direct acting antiviral drugs and protease inhibitors to treat hepatitis C as part of its rationale for cohort screening, saying the drugs “can halt disease progression and provide a virologic cure (ie, sustained viral clearance following completion of treatment) in most persons.”

The science behind cohort screening has been challenged4 and is said to be “the subject of major debate.”6 The scientific debate along with the price tags of the newer drugs (over $84 000 per treatment course for the new drug sofosbuvir), raise questions about CDC’s industry funding.

In 2010, the CDC, in conjunction with the CDC Foundation, formed the Viral Hepatitis Action Coalition, which supports research and promotes expanded testing and treatment of hepatitis C in the United States and globally. Industry has donated over $26m to the coalition through the CDC Foundation since 2010. Corporate members of the coalition include Abbott Laboratories, AbbVie, Gilead, Janssen, Merck, OraSure Technologies, Quest Diagnostics, and Siemens—each of which produces products to test for or treat hepatitis C infection.

Conflict of interest forms filed by the 34 members of the external working group that wrote and reviewed the new CDC recommendation in 2012 show that nine had financial ties to the manufacturers.1

A report by the Office of the Inspector General in December 2009 found that external advisors to the CDC “play an influential role in decision making for the federal government.” The inspector general evaluated conflicts of interest of advisors and concluded, “CDC has a systemic lack of oversight of the ethics program”: 97% of disclosure forms filed by advisors were incomplete, and 13% of advisors participated in meetings without filing any disclosure at all.7

Although the CDC states it has addressed all of the deficiencies cited in the report, the agency did not restrict participation of the nine conflicted external advisors in the recommendation to broaden hepatitis C screening.1 However, the CDC told The BMJ that external advisors acted in an “individual capacity” and are not designated as “special government employees.” It said that their financial ties to industry didn’t comprise a conflict of interest as the participants “had no relationships directly related to the task-reviewing evidence as a basis for an HCV testing guideline. The reported financial activities represent activities not directly related to this work but involving commercial and non-commercial entities that could be perceived to influence involvement in the task.”

Oseltamivir for flu

Following criticism of the CDC and its foundation for accepting a directed donation from Roche for the agency’s Take 3 flu campaign (Step 3 tells the public to “take antiviral medicine if your doctor prescribes it”),2 the CDC posted an article on its website entitled, “Why CDC Recommends Influenza Antiviral Drugs.”8 The agency cited multiple observational and industry funded studies, including the recent meta-analysis by Dobson and colleagues,9 which it described as an “independent” study. However, the study was sponsored by Roche, and all four authors had financial ties to Roche, Genentech, or Gilead (the first two sell oseltamivir and Gilead holds the patent).10

Despite its extensive list of studies, the CDC did not cite the systematic review and meta-analysis by the Cochrane Collaboration.11

The CDC told The BMJ that it didn’t include the Cochrane review because Cochrane “did not consider any data from uncontrolled observational studies of oseltamivir treatment. While such studies have inherent design limitations, they can inform clinical practice and public health, especially when data from RCTs [randomized controlled trials] are unavailable or have not been conducted among high-risk groups or hospitalized influenza patients, or because having a placebo group would be unethical since antiviral treatment is recommended for these groups.”

The US Food and Drug Administration issued a warning to Roche that it could not claim that oseltamivir reduces pneumonia or deaths since it has never provided evidence to the FDA to support that claim.2 Manufacturers are prohibited by law from making off-label claims about their drugs. However, doctors can legally recommend drugs for off-label uses. By funding the CDC’s Take 3 campaign, Roche and other companies are not claiming their antivirals will reduce pneumonia or death. CDC director, Frieden, however, did make the off-label claim, telling the public that it could “save your life.”2

Shannon Brownlee, senior vice president of the Lown Institute and former journalist covering the CDC, told The BMJ, “This looks like classic stealth marketing, in which industry puts their message in the mouths of a trusted third party, such as an academic or a professional organization.”

CDC and the sugar industry

The CDC has also been criticised for its role in a series of studies into an epidemic of chronic kidney disease among men working in the sugar fields of central America.5 The sugar industry is paying $1.7m to fund the studies, and critics say the fact the research is being funded by the men’s employers raises concerns about how far it will probe industry’s role in the disease outbreak. The CDC states it will provide “technical assistance and subject matter expertise,” for the studies, with the foundation serving as the “grant administrator overseeing the donor funding and facilitating the research activities.”

Researchers think that the epidemic, which has killed over 20 000 mostly young men,12 is most likely to be caused by “two interdependent factors: the misuse of agrochemicals and the working conditions of the labor force.”13 The men are exposed to banned and dangerous pesticides, some of which are known to be nephrotoxic, and the working conditions cited include “regular exposure to very hot temperatures and extreme physical effort, lead[ing] to heat stress and dehydration.”13

Daniel Brooks, associate professor of epidemiology at the Boston University School of Public Health, will lead the CDC research, which includes several observational studies examining genetics and biomarkers in children and a longitudinal study of the sugarcane workers and their families for an as yet undetermined time period. He defends the CDC’s involvement, saying it provides two main benefits, creating a “firewall between donors and researchers” and enlisting the expertise of the CDC.

The sugar industry has trumpeted Brooks’ earlier research into the epidemic as proof that conditions in the fields are not the cause of the men’s deaths; Mario Amador, general manager of Nicaragua’s National Committee of Sugar Producers, dismissed the idea that the disease has an occupational origin, telling a reporter with the International Consortium of Investigative Journalists, “We are fully convinced that there is no direct relationship between [chronic kidney disease] and the activities conducted in the sugarcane industry.”5

The Pan American Health Organization has called the outbreak, “a serious public health problem that requires urgent, effective, and concerted multisectoral action.”

Jerome R Hoffman, a methodologist and emeritus professor of medicine at UCLA, told The BMJ, the study was asking the wrong questions. “Epidemiologic studies can of course be tremendously useful in cases like this, but given the human suffering involved, we need to devise and test interventions that have a chance to prevent or ameliorate this substantial harm, as quickly as possible. It’s inappropriate to focus on things that cannot protect these workers, such as identifying an unusual genetic predisposition to kidney failure, or evaluating a biomarker to follow the disease, while ignoring modifiable factors.”

Not just the carrot—but the stick

Corporations have not only been offering gifts to the CDC; they have also used a heavy stick—with consequences that continue to hobble critical research. In 1996, the National Rifle Association, which is underwritten in large part by gun manufacturers, mounted an offensive against CDC’s research into gun violence. The association lobbied Congress, and pro-gun representatives slashed $2.6m from the CDC budget—the exact amount the agency had spent in the previous year on firearm injury research. The funding was later restored, but the bill prohibited any of the restored funds from being used to “advocate or promote gun control.”

Frederick Rivara, one of the team members who conducted gun research for the CDC before the cuts, told The BMJ that firearms research has “plummeted dramatically,” and that gun violence remains a major public health concern in the US, where nearly half a million people have died from gunshot wounds since the funding cuts.

After multiple mass murders, including the shooting of 20 first grade children at the Sandy Hook Elementary School in Newton, Connecticut in 2012, President Obama asked Congress for $10m to fund research into preventing gun violence; however, Congress has not approved the funds to date. The president renewed this request for the 2016 budget.

Professional reaction

Neil Calman, president and chief executive of the Institute for Family Health in New York, a large community health center network in 31 locations with over half a million patient visits a year, says the institute has relied on CDC guidance largely because of its prestige as an independent agency, free of industry relationships. Calman told The BMJ, “Industry funding undermines trust and introduces a bias in the presentation of results and treatment recommendations that is deplorable for a government agency. If the allegations of industry funding and influence are true, we will have to look very carefully at recommendations we are following now and those made in the future by the CDC.”

Calman said, “Industry claims their scientific methodology ensures their studies are unbiased—just as the CDC claims money doesn’t affect their recommendations. Yet multiple studies clearly—and repeatedly—show that who sponsors a study, or issues a guideline, makes a difference.”

Hoffman said, “Most of us were shocked to learn the CDC takes funding from industry. Of course it is outrageous that industry apparently is allowed to punish the CDC if the agency conducts research that has the potential to cut into profits. But it was our government that made this very bad arrangement, so the way to fix it is not to ask the CDC to ‘pretty please be more ethical, and avoid conflicts of interest’; rather, as a society, we have to get the government to reject this devil’s bargain, by changing the rules so this can no longer happen.”

John Mandrola, a cardiologist in Louisville, Kentucky, reacted to the news of industry funding, saying that the CDC “must have the highest of moral ground. For if we are to believe them about public health matters, there can be no conflicts of interest. The public good, pure evidence, that is all.”14

Monday, May 11, 2015

Dr. Kerr Rebuts Assertion That GET and CBT Are Legitimate Treatments for ME/CFS

Unfortunately, PACE isn't admitting anything. 
In a recent editorial published in the British Medical Journal Andrew Lloyd states: "The evidence for graded exercise and cognitive behavioural therapy is already clear, so this treatment should be made widely available."

Dr. Lloyd, an immunologist associated with the University of South Wales, Australia, is a long-time proponent of exercise as the "cornerstone" of treatment for ME/CFS.

The reply by Dr. Jonathan Kerr, who is regarded as one of Britain’s foremost ME/CFS  researchers and an expert in microbiology, inflammation and genetics, lays out the errors in Dr. Lloyd's endorsement of GET and CBT, not the least of which is that Lloyd's "evidence" is based entirely on a study so flawed that it should never have been published. 

In the wake of the Columbia studies documenting progressive immune abnormalities in ME/CFS, and the IOM's unequivocal statement supporting the biogenesis of ME/CFS, it is clear that the proponents of psychological interventions and exercise as legitimate treatments have only one leg to stand on.

And that leg is increasingly in need of a crutch.
________________________________  

The biological pathogenesis of Chronic Fatigue Syndrome / Myalgic Encephalomyelitis

By Jonathan Kerr

This editorial (1) comes from authors from two of three CFS/ME centres whose prolific academic production in CFS/ME provides almost the sole support for a supposed psychiatric basis for the disease; these centres are Kings College London, Nijmegen Medical Centre in the Netherlands, and the University of New South Wales, Sydney, Australia. However, the scientific basis on which the treatments, Cognitive Behavioural Therapy (CBT) and Graded Exercise Therapy (GET), are offered is critically flawed. The original PACE trial conducted by Kings College London, enrolled patients using the 1991 Oxford criteria (2), which allows inclusion of patients with affective disorders. This is in direct conflict with the internationally accepted 1994 CDC criteria which specifically excludes patients with affective disorders. This means that this study was performed using patients whose exact diagnoses are unknown. However, despite this flaw, global insurance companies do not pay sickness benefit to CFS/ME patients on the basis that effective treatments are available. Yet these interventions are not effective in CFS/ME.

CBT helps only a fraction of patients and GET has been shown to exacerbate the symptoms of patients with CFS/ME, which is logical as one of the cardinal symptoms of CFS/ME is post-exertional malaise, and so GET should not be used for CFS/ME patients. Furthermore, the Institute of Medicine in the USA has recently recommended that the name, CFS/ME, should be changed to Systemic Exercise Intolerance Disease (SEID) (3), which again reinforces the truth that exercise therapy should not be used for CFS/ME.

We know that CFS/ME can be triggered by a variety of infections, vaccines, exposure to organophosphate chemicals, and that the pathogenesis involves prolonged immune activation, which results in a flu-like illness that persists for months to years, and we all know how we feel during a flu-like illness, and there is no dispute that flu-like illnesses are caused by viruses. Several infection models have been presented which illustrate very well this progression in patients followed from the time of acute infection to development of CFS/ME. Parvovirus B19 triggers CFS/ME and this is predisposed to by carriage of HLA-DRB1*01, *04 and *07 alleles, is characterised by raised levels of circulating TNF-α and IFN-γ, and CFS/ME triggered by B19 has been cured with intravenous immunoglobulin (IVIG) which is the specific treatment for B19 infection (4). Coxiella burneti also triggers CFS/ME and this is predisposed to by carriage of HLA-DRB1*11 and certain IFN-γ polymorphisms, is associated with chronic immune activation and Q fever-associated CFS/ME is treated successfully with tetracyclines which are the specific treatment for Q fever (5). Epstein-Barr virus triggers CFS/ME, and patients with EBV-triggered CFS/ME have been successfully treated with valacyclovir (6), which is a specific treatment for EBV infection. In all of these models, the infectious agent persists long-term with chronic genomic persistence and antigen presentation, which appears to be important. The diversity of infectious triggers and individual responses likely account for the heterogeneity observed in CFS/ME, and the existence of subtypes, which are recognised to be important for the optimal management of patients.

Maybe the big breakthrough in CFS/ME comes when we are free to apply our significant existing knowledge of CFS/ME towards the best investigation and treatment of INDIVIDUAL patients, whom we know have different pathogenetic processes which account for the existence of disease subtypes. Disease subtypes are a feature of multiple chronic inflammatory autoimmune diseases and are taken into account in their management, and therefore CFS/ME is typical of such a biological disease.

References

1. Lloyd AR, Meer JW. The long wait for a breakthrough in chronic fatigue syndrome. BMJ. 2015;350:h2087. doi: 10.1136/bmj.h2087.

2. Sharpe MC, Archard LC, Banatvala JE, Borysiewicz LK, Clare AW, David A, Edwards RH, Hawton KE, Lambert HP, Lane RJ, et al. A report--chronic fatigue syndrome: guidelines for research. J R Soc Med.1991 Feb;84(2):118-21.

3. Institute of Medicine. Beyond myalgic encephalomyelitis/chronic fatigue syndrome: redefining an illness. Washington, DC: National Academies Pr; 2015

4. Kerr JR, Cunniffe VS, Kelleher P, Bernstein RM, Bruce IN. Successful intravenous immunoglobulin therapy in 3 cases of parvovirus B19-associated chronic fatigue syndrome. Clin Infect Dis. 2003;36(9):e100-6.

5. Sukocheva OA, Marmion BP, Storm PA, Lockhart M, Turra M, Graves S. Long-term persistence after acute Q fever of non-infective Coxiella burnetii cell components, including antigens. QJM. 2010;103(11):847-63.

6. Lerner AM, Beqaj SH, Deeter RG, Fitzgerald JT. Valacyclovir treatment in Epstein-Barr virus subset chronic fatigue syndrome: thirty-six months follow-up. In Vivo. 2007;21(5):707-13.


_____________________________


Editorial

The long wait for a breakthrough in chronic fatigue syndrome

BMJ 2015; 350 doi: http://dx.doi.org/10.1136/bmj.h2087 (Published 05 May 2015) Cite this as: BMJ 2015;350:h2087

Andrew R Lloyd, professor,
Jos W M van der Meer, professor

Author affiliations

Correspondence to: A R Lloyd a.lloyd@unsw.edu.au

There hasn’t been much good news for patients with the prevalent but enigmatic disorder chronic fatigue syndrome (also referred to as myalgic encephalomyelitis). Over decades, research into the pathophysiology has failed to find convincing evidence of either persistent infection or immunological, endocrine, or metabolic change, and has rejected simplistic notions of depression (typical or atypical) or primary sleep disorder. Several notable “breakthroughs” have failed independent replication. The most noteworthy is the recent rise and fall of xenotropic murine leukaemia virus related virus (XMRV) as the cause, which was ultimately established as a murine DNA laboratory contaminant.1 Similarly, an exhaustive array of randomised controlled trials seeking curative outcomes from antiviral, immunological, hormonal, antidepressant, and many other therapies have failed to show any benefit over placebo, or failed the replication test.

Where then is the progress? Firstly, there is reproducible evidence implicating certain infections as a trigger—notably, infectious mononucleosis caused by Epstein-Barr virus, but also infection with other pathogens.2 Secondly, there is clear evidence that a substantial proportion of patients have a coexisting mood disorder, and sometimes a sleep-wake disorder, and that these conditions may exacerbate or perpetuate the illness.3 Thirdly, independent studies using both structural and functional imaging techniques have identified alterations in the brains of patients with chronic fatigue syndrome, implicating the central nervous system as the site of pathophysiology.4 Fourthly, there is solid evidence from multiple controlled studies that patients can gain control of symptoms and functional improvement through multidisciplinary interventions incorporating graded exercise therapy and cognitive behavioural therapy. These interventions have clearly positive outcomes in systematic reviews and meta-analyses.5 6 7 For instance, the recent Cochrane review of graded exercise therapy5 states that “patients with CFS [chronic fatigue syndrome] may generally benefit and feel less fatigued following exercise therapy, and no evidence suggests that exercise therapy may worsen outcomes. A positive effect with respect to sleep, physical function and self-perceived general health has been observed.”

How therapy works

Plausibly, graded exercise may reverse a perpetuator in the form of physical deconditioning.

However, there is little evidence for loss of aerobic fitness in patients with chronic fatigue syndrome, and limited evidence for improved physical performance after successful graded exercise therapy.8
Instead, graded exercise has been proposed to act by desensitising an exaggerated central nervous system response to the physiological signals associated with exercise.9 In psychological terms, patients may avoid activity because of the prolonged exacerbation of symptoms that follows minor physical activity; this leads to an understandable conclusion that exercise is harmful or to a conditioned fear of such activity.10 In this respect, the recent mediation analysis of the outcomes of the PACE trial is of interest.11 This trial compared standard medical care, cognitive behavioural therapy, graded exercise, and adaptive pacing therapy, concluding that both cognitive behavioural and graded exercise therapy were more effective at reducing fatigue and improving physical disability than standard care or adaptive pacing.12 The mediation analysis suggested that both cognitive behavioural therapy and graded exercise worked by reducing avoidance of activity. This is broadly consistent with findings by others,13 although whether the effect simply relates to the behavioural change itself (that is, exercise) or reconditioning of the associated fear of activity remains unclear. In addition, a substantial proportion of patients do not avoid activity but have repeated boom-bust cycles of overactivity when feeling relatively well (the boom) followed by reduced activity when symptoms are exacerbated thereafter (the bust). These data argue for a personalised approach to both therapies.

Cognitive behavioural therapy for patients with chronic fatigue syndrome is based on the premise that inappropriate cognitive attributions (thinking patterns) and behaviours help perpetuate symptoms. It seeks to alter these attributions and modify the associated behaviour, targeting activity patterns and sleep-wake behaviours. For example, although primary sleep disorders do not explain chronic fatigue syndrome,14 patients typically report that their night-time sleep is unrefreshing, and as fatigue is the dominant symptom, patients may consider that increased sleep will relieve symptoms and aid recovery. This idea commonly leads to frequent daytime naps and a delayed sleep-wake cycle.

Prospects for cure

There has been recent contention about the possibility of cure after graded exercise and cognitive behavioural therapy. An analysis of the PACE trial suggested cure was possible, but recovery outcomes were defined post hoc using population norms with generous thresholds (such as the population mean plus one standard deviation for self reported fatigue).15 This analysis was criticised because of the limited assessments and less than full restoration of health,16 leading to a recommendation that trials use more accurate outcomes (such as clinically relevant improvement) defined in advance and capturing a broad based return to health with assessments of fatigue and function. Trialists must also consider patients’ perceptions of their recovery.17 In this context, the increase in volume of grey matter associated with clinical response to cognitive behavioural therapy, as reported in one study, needs further investigation.18 Even with the unduly liberal designation of recovery, less than one quarter of patients “recovered” in the PACE trial.

What then of the long awaited breakthrough? As is often the case in medical research, progress is predominantly made in modest increments not breakthroughs. The evidence for graded exercise and cognitive behavioural therapy is already clear, so this treatment should be made widely available. The next increments are to find ways to increase the symptom relief and functional improvement achieved by these treatments and to identify factors predicting clinically relevant improvement and non-response in order to increase the proportion of patients who benefit.


Notes
Cite this as: BMJ 2015;350:h2087

Footnotes
Competing interests: We have read and understood BMJ policy on
declaration of interests and have no relevant interests to declare.

Provenance and peer review: Commissioned; not externally peer reviewed.

References

1. Van Kuppeveld FJ, van der Meer JW. XMRV and CFS—the sad end of a story. Lancet2012;379:e27-8.
2. Hickie I, Davenport T, Wakefield D, et al. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. BMJ2006;333:575.
3. Prins JB, van der Meer JW, Bleijenberg G. Chronic fatigue syndrome. Lancet2006;367:346-55.
4. Tanaka M, Ishii A, Watanabe Y. Neural mechanisms underlying chronic fatigue. Rev Neurosci2013;24:617-28.
5. Larun L, Brurberg KG, Odgaard-Jensen J, Price JR. Exercise therapy for chronic fatigue syndrome. Cochrane Database Syst Rev2015;2:CD003200.
6. Reid S, Chalder T, Cleare A, Hotopf M, Wessely S. Chronic fatigue syndrome. BMJ 2000;320:292-6.
7. Knight SJ, Scheinberg A, Harvey AR. Interventions in pediatric chronic fatigue syndrome/myalgic encephalomyelitis: a systematic review. J Adolesc Health2013;53:154-65.
8. Moss-Morriss R, Sharon C, Tobin R, Baldi JC. A randomized controlled graded exercise trial for chronic fatigue syndrome: outcomes and mechanisms of change. J Health Psychol2005;10:245-59.
9. Nijs J, Meeus M, Van Oosterwijck J, et al. In the mind or the brain? Scientific evidence for central sensitisation in chronic fatigue syndrome. Eur J Clin Invest2011;42:203-11.
10. Clark LV, White PD. The role of deconditioning and therapeutic exercise in chronic fatigue syndrome (CFS). J Mental Health2005;14:237-52.
11. Chalder T, Goldsmith KA, White PD, Sharpe M, Pickles AR. Rehabilitative therapies for chronic fatigue syndrome: a secondary mediation analysis of the PACE trial. Lancet Psychiatry2015;2:141-52.
12. White PD, Goldsmith KA, Johnson AL, et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet2011;377:823-36.
13. Wiborg JF, Knoop H, Prins JB, Bleijenberg G. Does a decrease in avoidance behavior and focusing on fatigue mediate the effect of cognitive behavior therapy for chronic fatigue syndrome? J Psychosom Res2011;70:306-10.
14. Jackson ML, Bruck D. Sleep abnormalities in chronic fatigue syndrome/myalgic encephalomyelitis: a review. J Clin Sleep Med2012;8:719-28.
15. White PD, Goldsmith K, Johnson AL, Chalder T, Sharpe M. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychol Med2013;43:2227-35.
16. Kindlon T, Baldwin A. Response to: reports of recovery in chronic fatigue syndrome may present less than meets the eye. Evid Based Mental Health2014. doi:10.1136/eb-2014-101961.
17. Adamowicz JL, Caikauskaite I, Friedberg F. Defining recovery in chronic fatigue syndrome: a critical review. Qual Life Res2014;23:2407-16.
18. De Lange FP, Koers A, Kalkman JS, et al. Increase in prefrontal cortical volume following cognitive behavioural therapy in patients with chronic fatigue syndrome. Brain2008;131:2172-80.
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