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IACFS/ME Board Response to:
Institute of Medicine Report on Chronic Fatigue Syndrome:
Case Definition Issues and Future Directions
A well-validated diagnosis of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is essential for research and clinical care. To that end, the US Department of Health and Human Services (DHHS) tasked the highly respected Institute of Medicine (IOM) to develop “evidence-based clinical diagnostic criteria for ME/CFS for use by clinicians, using a consensus-building methodology”, to “recommend whether new terminology for ME/CFS should be adopted”, and to create plans for disseminating these conclusions to clinicians [1]. IOM recommendations are often accorded high credibility by the US Congress as well as the DHHS and can have a significant impact on funding of federal grant programs. Given the minimal US research funding for the illness, this report may hold promise for new grant initiatives.
In early February, 2015 the IOM released its prepublication report [2] which appropriately emphasized the seriousness of CFS/ME as a debilitating and under-served illness condition. Their recommendations included a new name for CFS/ME as well as a somewhat different case definition in comparison to existing definitions. The new name, Systemic Exertion Intolerance Disease (SEID), requires that the patient have a substantial reduction in pre-illness functioning (occupational, educational, personal activities) for 6 or more months accompanied by new onset of fatigue not alleviated by rest. At least three symptoms are also required: post-exertional malaise, unrefreshing sleep, and either cognitive impairment or orthostatic intolerance. The full IOM report (free download) may be found at: http://www.nap.edu/download.php?record_id=19012#
The advantage of the new name is that it captures the scientific and clinical consensus (with growing empirical confirmation [e.g., 3]) on the importance of the key distinguishing symptom of post-exertional malaise (PEM). Given that this illness name is new, we have no data to guide our evaluation of it. The existing illness name, ME/ CFS, is to be replaced with SEID. Although both the ME and CFS terms are problematic (ME has little evidence behind it and CFS is trivializing), abandoning these terms presents another set of problems.
ME and CFS vs. SEID: Why the differences matter
Both the ME and CFS terms have long histories in the medical literature and capture somewhat different symptom patterns. Also the current definitions (particularly Fukuda et al. [4]) have been specifically linked to significant pathophysiological findings in a number of areas such as energy metabolism, immunology, and neuroendocrinology. Any change in the definition, in this case to SEID, is likely to alter the characteristics of the samples that are studied, the findings that are generated, and the level of comparability with published data. Given the well-known difficulties in replication of findings across studies (even when the same case definition is used), this is more than a minor issue. It remains to be seen if the new illness definition will be adopted in research studies. An official name change, if it occurs, would be made by the US Centers for Disease Control.
Required symptoms in the new definition:
How inclusive/exclusive of ill patients?
In contrast to the broadly inclusive Fukuda et al. definition of CFS which folds in many individuals who are not as severely ill (e.g., cases who do not also meet ME criteria), the new IOM definition (SEID) may narrow the criteria so much that a number of true cases may be excluded. For instance, the requirement of unrefreshing sleep indicates that a patient will be excluded from the IOM definition in the absence of poor sleep. Thus, if an individual with fatigue, PEM, and cognitive impairment does not have poor sleep, he/she would not be diagnosed with the illness. We have no data on the new definition to know how much of a problem this might be.
In support of SEID, empirical studies suggest that the core symptoms distinguishing ME/CFS from controls are PEM, fatigue, unrefreshing sleep, and fatigue [e.g., 3]. Specifically, each SEID-listed symptom occurs in 80-90+% of CFS and/or ME-diagnosed patients. However, when we look at how many patients have two SEID symptoms, the percent will either be the same, or (probably) lower. So with each additional required symptom, more cases are likely to be excluded. This opens up the possibility of potentially inappropriate exclusions of ill individuals -- another perhaps unintended consequence of the new definition.
Importance of uniform standards for case definition assessment
The issue of case definition assessment, although mentioned in the IOM recommendations chapter, was not given the priority that we think it deserves. Importantly the committee did recommend operationalizing the proposed diagnostic criteria so that clinicians have explicit guidance during their assessment of the patient. “The development of clinical questionnaire or history tools that are valid across populations of patients should be an urgent priority.” (IOM report, p. 223) To this end, we support new assessment research on a case definition (whichever one is ultimately used) to create reliable diagnostic guidelines which we do not have now.
To assess symptom domains with consistency, a number of challenges remain. No matter what the case definition is or will be, we still do not have uniform assessment across laboratories or practitioners’ offices. Thus one researcher’s (or clinician’s) method of symptom assessment may be substantively different from another’s. This may be one reason why CFS/ME biomedical studies are so varied and inconsistent in their findings. These are significant concerns that require targeted research to solve.
Uniform assessments for self-report measures of fatigue, pain and other symptoms across illnesses have been developed in a (US) National Institutes of Health funded program called “PROMIS” (Patient Reported Outcomes Measurement Information System) [5]. This project encompassed large scale cooperative efforts across multiple study sites. Similarly, for CFS/ME, multi-site field trials would be needed to establish standard assessment criteria with adequate reliability that can then be adopted by the research and clinical communities. Once such standards are in place, findings are more likely to be replicated and prevalence figures will be more trustworthy. Uniform assessment standards have been proposed for CFS/ME [6].
Conclusion and Future Directions
In sum, we hope that the heightened recognition of CFS/ME expressed in the IOM report will lead to new federal grant initiatives that support substantively increased levels of biomedical research on this illness. Key areas for future research, in our view, are the development of an empirically derived case definition of the illness as well as uniform assessments of definitional symptoms with adequate specificity and sensitivity. Achieving these critical endpoints would represent an important advance at the ground level of CFS/ME science with implications for diagnosis, biomarkers, and effective interventions.
More generally, current levels of federal funding are simply not sufficient to meet the challenges of this multifaceted and complex illness. As stated in the IOM report: “Remarkably little research funding has been made available to study the etiology, pathophysiology, and effective treatment of this disease, especially given the number of people afflicted” (page 225). We hope that our federal health agencies will respond positively to this overarching concern.
Fred Friedberg, PhD
Staci Stevens, MA
Rosamund Vallings, MB, MS
Steven Krafchick, MPH, JD
Julia Newton, MD, PhD
Jon Kaiser, MD
References
1. Clayton, E. W. (2015). Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An IOM Report on Redefining an illness. JAMA. Published online February 10, 2015. doi:10.1001/jama.2015.1346
2. Institute of Medicine. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, D.C.: The National Academies Press; 2015. Retrieved from http://www.iom.edu/mecfs
3. Abigail A. Brown & Leonard A. Jason (2014) Validating a measure of myalgic encephalomyelitis/chronic fatigue syndrome symptomatology, Fatigue: Biomedicine, Health & Behavior, 2:3, 132-152.
4. Fukuda, K., Straus, E., Hickie, I., Sharpe, M.C., Dobbins, J.G., & Komaroff, A. (1994). The Chronic Fatigue Syndrome: A comprehensive approach to its definition and study. Annals of Internal Medicine, 121, 953-959.
5. U.S. Department of Health and Human Services. (2009). Food and drug administration guidance for industry on patient reported outcome measures: Use in medical product development to suppose labeling claims. Federal Register.
6. Jason, Unger, Dimitrakoff et al; (2012) Minimum data elements for research reports on CFS. Brain Behav Immun. 2012 Mar;26(3):401-6. doi: 10.1016/j.bbi.2012.01.014. Epub 2012 Jan 28.
Source: National MEFM Action Network on Facebook
Institute of Medicine Report on Chronic Fatigue Syndrome:
Case Definition Issues and Future Directions
A well-validated diagnosis of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is essential for research and clinical care. To that end, the US Department of Health and Human Services (DHHS) tasked the highly respected Institute of Medicine (IOM) to develop “evidence-based clinical diagnostic criteria for ME/CFS for use by clinicians, using a consensus-building methodology”, to “recommend whether new terminology for ME/CFS should be adopted”, and to create plans for disseminating these conclusions to clinicians [1]. IOM recommendations are often accorded high credibility by the US Congress as well as the DHHS and can have a significant impact on funding of federal grant programs. Given the minimal US research funding for the illness, this report may hold promise for new grant initiatives.
In early February, 2015 the IOM released its prepublication report [2] which appropriately emphasized the seriousness of CFS/ME as a debilitating and under-served illness condition. Their recommendations included a new name for CFS/ME as well as a somewhat different case definition in comparison to existing definitions. The new name, Systemic Exertion Intolerance Disease (SEID), requires that the patient have a substantial reduction in pre-illness functioning (occupational, educational, personal activities) for 6 or more months accompanied by new onset of fatigue not alleviated by rest. At least three symptoms are also required: post-exertional malaise, unrefreshing sleep, and either cognitive impairment or orthostatic intolerance. The full IOM report (free download) may be found at: http://www.nap.edu/download.php?record_id=19012#
The advantage of the new name is that it captures the scientific and clinical consensus (with growing empirical confirmation [e.g., 3]) on the importance of the key distinguishing symptom of post-exertional malaise (PEM). Given that this illness name is new, we have no data to guide our evaluation of it. The existing illness name, ME/ CFS, is to be replaced with SEID. Although both the ME and CFS terms are problematic (ME has little evidence behind it and CFS is trivializing), abandoning these terms presents another set of problems.
ME and CFS vs. SEID: Why the differences matter
Both the ME and CFS terms have long histories in the medical literature and capture somewhat different symptom patterns. Also the current definitions (particularly Fukuda et al. [4]) have been specifically linked to significant pathophysiological findings in a number of areas such as energy metabolism, immunology, and neuroendocrinology. Any change in the definition, in this case to SEID, is likely to alter the characteristics of the samples that are studied, the findings that are generated, and the level of comparability with published data. Given the well-known difficulties in replication of findings across studies (even when the same case definition is used), this is more than a minor issue. It remains to be seen if the new illness definition will be adopted in research studies. An official name change, if it occurs, would be made by the US Centers for Disease Control.
Required symptoms in the new definition:
How inclusive/exclusive of ill patients?
In contrast to the broadly inclusive Fukuda et al. definition of CFS which folds in many individuals who are not as severely ill (e.g., cases who do not also meet ME criteria), the new IOM definition (SEID) may narrow the criteria so much that a number of true cases may be excluded. For instance, the requirement of unrefreshing sleep indicates that a patient will be excluded from the IOM definition in the absence of poor sleep. Thus, if an individual with fatigue, PEM, and cognitive impairment does not have poor sleep, he/she would not be diagnosed with the illness. We have no data on the new definition to know how much of a problem this might be.
In support of SEID, empirical studies suggest that the core symptoms distinguishing ME/CFS from controls are PEM, fatigue, unrefreshing sleep, and fatigue [e.g., 3]. Specifically, each SEID-listed symptom occurs in 80-90+% of CFS and/or ME-diagnosed patients. However, when we look at how many patients have two SEID symptoms, the percent will either be the same, or (probably) lower. So with each additional required symptom, more cases are likely to be excluded. This opens up the possibility of potentially inappropriate exclusions of ill individuals -- another perhaps unintended consequence of the new definition.
Importance of uniform standards for case definition assessment
The issue of case definition assessment, although mentioned in the IOM recommendations chapter, was not given the priority that we think it deserves. Importantly the committee did recommend operationalizing the proposed diagnostic criteria so that clinicians have explicit guidance during their assessment of the patient. “The development of clinical questionnaire or history tools that are valid across populations of patients should be an urgent priority.” (IOM report, p. 223) To this end, we support new assessment research on a case definition (whichever one is ultimately used) to create reliable diagnostic guidelines which we do not have now.
To assess symptom domains with consistency, a number of challenges remain. No matter what the case definition is or will be, we still do not have uniform assessment across laboratories or practitioners’ offices. Thus one researcher’s (or clinician’s) method of symptom assessment may be substantively different from another’s. This may be one reason why CFS/ME biomedical studies are so varied and inconsistent in their findings. These are significant concerns that require targeted research to solve.
Uniform assessments for self-report measures of fatigue, pain and other symptoms across illnesses have been developed in a (US) National Institutes of Health funded program called “PROMIS” (Patient Reported Outcomes Measurement Information System) [5]. This project encompassed large scale cooperative efforts across multiple study sites. Similarly, for CFS/ME, multi-site field trials would be needed to establish standard assessment criteria with adequate reliability that can then be adopted by the research and clinical communities. Once such standards are in place, findings are more likely to be replicated and prevalence figures will be more trustworthy. Uniform assessment standards have been proposed for CFS/ME [6].
Conclusion and Future Directions
In sum, we hope that the heightened recognition of CFS/ME expressed in the IOM report will lead to new federal grant initiatives that support substantively increased levels of biomedical research on this illness. Key areas for future research, in our view, are the development of an empirically derived case definition of the illness as well as uniform assessments of definitional symptoms with adequate specificity and sensitivity. Achieving these critical endpoints would represent an important advance at the ground level of CFS/ME science with implications for diagnosis, biomarkers, and effective interventions.
More generally, current levels of federal funding are simply not sufficient to meet the challenges of this multifaceted and complex illness. As stated in the IOM report: “Remarkably little research funding has been made available to study the etiology, pathophysiology, and effective treatment of this disease, especially given the number of people afflicted” (page 225). We hope that our federal health agencies will respond positively to this overarching concern.
Fred Friedberg, PhD
Staci Stevens, MA
Rosamund Vallings, MB, MS
Steven Krafchick, MPH, JD
Julia Newton, MD, PhD
Jon Kaiser, MD
References
1. Clayton, E. W. (2015). Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An IOM Report on Redefining an illness. JAMA. Published online February 10, 2015. doi:10.1001/jama.2015.1346
2. Institute of Medicine. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, D.C.: The National Academies Press; 2015. Retrieved from http://www.iom.edu/mecfs
3. Abigail A. Brown & Leonard A. Jason (2014) Validating a measure of myalgic encephalomyelitis/chronic fatigue syndrome symptomatology, Fatigue: Biomedicine, Health & Behavior, 2:3, 132-152.
4. Fukuda, K., Straus, E., Hickie, I., Sharpe, M.C., Dobbins, J.G., & Komaroff, A. (1994). The Chronic Fatigue Syndrome: A comprehensive approach to its definition and study. Annals of Internal Medicine, 121, 953-959.
5. U.S. Department of Health and Human Services. (2009). Food and drug administration guidance for industry on patient reported outcome measures: Use in medical product development to suppose labeling claims. Federal Register.
6. Jason, Unger, Dimitrakoff et al; (2012) Minimum data elements for research reports on CFS. Brain Behav Immun. 2012 Mar;26(3):401-6. doi: 10.1016/j.bbi.2012.01.014. Epub 2012 Jan 28.
Source: National MEFM Action Network on Facebook
