(CDC) Diagnosis and Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), 2023

(See CDC Treatment Evidence Review - consultation period for discussion of the review during the consultation period)


https://www.cdc.gov/me-cfs/programs/evidence-review.html

Diagnosis and Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

A Systematic Review of the Evidence for Clinical Management of ME/CFS

CDC contracted with the Pacific Northwest Evidence-based Practice Center (EPC) to conduct a systematic review of the scientific literature on treatment and management of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Specifically, the review explored:

• Evidence of the benefits and harms of specific treatments for ME/CFS and its symptoms
• Evidence of the benefits and harms to the patient of diagnosing ME/CFS
• Prevalence of non-ME/CFS conditions in people presenting for evaluation of potential ME/CFS.

The full protocol for the systematic review was registered with PROSPERO (the International Prospective Register of Systematic Reviews).

The final report from this systematic review updates a 2014 review funded by the Agency for Healthcare Research Quality (AHRQ) and its 2016 addendum. It also expands on the prior AHRQ review by including children as well as adults, evaluating harms as well as benefits of diagnosis, and evaluating effects of treatment on depression, anxiety, sleep quality, pain, and other symptoms associated with ME/CFS. In addition, fatigue, function, and quality of life are included in this review by EPC. This review also evaluates the quality of the scientific literature and does not make recommendations or guidelines. The review concludes that there is limited evidence on effective treatments for ME/CFS. While improving clinical care remains a critical issue, the lack of sufficient evidence from the review resulted in the decision not to proceed with developing clinical management guidelines at this time.

The final report of systematic review and supporting materials are available here:

• Final Report of the Systematic Review [40 MB, 174 pages]
• Appendix of the Report [2 MB, 246 pages]
• Summary of Reponses to Public Comments [238 KB, 6 pages]

The full list of public comments can be viewed here: https://www.regulations.gov/docket/CDC-2021-0053/comments.

Systematic Review Summary
Literature searches were conducted in January 2019 and updated through February 2021. Of the 5,525 relevant scientific articles identified, 687 were selected for review, representing 73 studies in 91 publications. Analyses by different case definitions were limited by the small number of trials and the use of less current ME/CFS case definitions. In some instances, trials may have not evaluated patients with more severe ME/CFS. Reporting of harms across trials was also limited. However, no study evaluated benefits or harms of ME/CFS diagnosis compared with non-diagnosis.

In summary, evidence on effective treatments for ME/CFS remains limited. The strength of evidence supporting the use of exercise and cognitive behavioral therapies (CBT) was low. In addition, the magnitude of benefits was small to moderate, with inadequate evidence in patients diagnosed with more current case definitions, limited reporting of harms, and inadequate evaluation in severely affected patients. Methodological and other limitations (imprecision, inconsistency, uncertain generalizability) preclude strong conclusions at this time. Other therapies were shown to be not effective or to require additional evidence to determine effectiveness.

The systematic review has important limitations related to the study design of the clinical trials as well as the methods used to conduct the review. While more details about the limitations of this systematic review can be found in Final Report of the Systematic Review [40 MB, 174 pages], the main limitations are highlighted below:

• Study and Clinical Trial Limitations
  • Lack of blinded outcome assessment: This type of limitation happens when it is not possible to blind (i.e., not let people know) patients or healthcare providers to nonpharmacological interventions such as exercise or CBT. This could potentially result in performance bias or differences in effects based on patient expectations of benefits.
  • Failure to describe randomization, attrition (i.e., leaving a study), and lack of power: Trials in the review often did not describe randomization or allocation concealment methods and experienced high attrition. Most studies were small in sample size and therefore many were underpowered in statistics to detect significant differences.
  • Lack of standardized outcome measures: The ability to compare results across studies was limited because of the different types of outcomes and methods used to measure the outcomes.
• Limitations in Methods Used to Conduct Review
  • Challenges with high statistical heterogeneity (i.e., variation): A number of analyses were characterized by high statistical heterogeneity or variation across studies. Although sensitivity and stratified analyses can be performed to address these differences, the analysis results were limited by a small number of trials and imprecision in measurement.
  • Pooled analyses across inactive therapies: Pooled analyses were performed across different “inactive” therapies (placebo, wait list, usual care, attention control) and then stratified analyses by the type of inactive therapy because each could potentially affect treatment estimates. Although the findings in the stratified analyses were generally consistent and similar across the variety of inactive therapy controls, the small number of trials prevents strong conclusions regarding the impact of type of inactive therapy on findings.

Disclaimer: The findings and conclusions on this web page are those of the authors of the final report of this systematic review, and do not necessarily represent the official position of the Centers for Disease Control and Prevention (CDC). CDC does not endorse specific studies included in this review.


Last Reviewed: January 17, 2023
Source: Centers for Disease Control and Prevention, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Division of High-Consequence Pathogens and Pathology (DHCPP)

 

See also


Source: U.S. Federal Register Vol. 88, #11, pp 2924-2926 Date: January 18, 2023 URL: https://www.federalregister.gov/doc...t-of-myalgic-encephalomyelitischronic-fatigue

https://www.govinfo.gov/content/pkg/FR-2023-01-18/pdf/2023-00813.pdf

[A Notice by the Centers for Disease Control and Prevention]

The Systematic Review Report for Diagnosis and Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS); Notice of Availability

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AGENCY: Centers for Disease Control and Prevention (CDC), Department of Health and Human Services (HHS).

ACTION: Notice.

SUMMARY: The Centers for Disease Control and Prevention (CDC), located within the Department of Health and Human Services (HHS), announces the availability of the final systematic review report titled 'Diagnosis and Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).' The report is accompanied by a summary of public comments.

DATES: The final document is available January 18, 2023.

ADDRESSES: The document may be found in the docket at http://www.regulations.gov, Docket No. CDC-2021-0053 in the Supporting Materials tab and at https://www.cdc.gov/me-cfs/programs/evidence-review.html.

FOR FURTHER INFORMATION CONTACT: Anindita Issa, MD, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifton Road NE, Mailstop H24-12, Atlanta, Georgia 30329; Telephone: 404-718-3959; Email: cfs@cdc.gov.

SUPPLEMENTARY INFORMATION:

In 2022, the systematic review titled 'Diagnosis and Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)' conducted by the Pacific Northwest Evidence-Based Practice Center at Oregon Health and Science University, concluded that there is limited evidence on effective treatments for ME/CFS. The review updates a 2014 Agency for Healthcare Research and Quality (AHRQ)-funded review and its 2016 addendum. It also expands upon the prior AHRQ review by including children as well as adults, evaluating harms as well as benefits of diagnosis, and evaluating effects of treatment on depression, anxiety, sleep quality, pain, and other symptoms associated with ME/CFS in addition to fatigue, function, and quality of life. The report evaluates the quality of the scientific literature and does not make recommendations or guidelines. While improving clinical care remains a critical issue, the lack of sufficient evidence from the review resulted in the decision for CDC not to proceed with developing clinical management guidelines.

On May 17, 2021, CDC published a notice in the Federal Register (87 FR 26733) requesting public comment on the draft report of the systematic review for ME/CFS. One hundred and thirty-five commenters provided feedback including those from academia, professional organizations, advocacy groups, and the public. Some of the comments received were from organizations that represented patient advocacy groups. CDC highly values insights gained from these public comments and especially thanks patients living with ME/CFS, who shared their personal experiences in this public forum.

Comments were centered around several themes. All comments were carefully reviewed and considered by CDC. Themes from the comments included (1) concerns with cognitive behavioral therapy and graded exercise therapy; (2) personal testimonials; (3) inclusion of studies with high risk of bias; (4) exclusion of certain studies on harms evidence; (5) concerns with case definitions and impact on the systematic review; (6) interpretation of results; (7) CDC programmatic concerns and recommendations; and (8) recommended references.

Comments: Concerns with cognitive behavioral therapy (CBT) and graded exercise therapy (GET): Commenters expressed concern with inclusion of the CBT and GET in the systematic review, including personal testimony of harms experienced after attempting treatment with CBT or GET, and critiques of the proposed mechanism (or lack of) of CBT or GET.

Response: CDC acknowledges the concerns that commenters have about the inclusion of CBT and GET in this systematic review. The authors of this systematic review report were aware of the criticisms of CBT and GET as treatments for ME/CFS. The studies for CBT and GET were included in the report because they met the inclusion and exclusion criteria of this systematic review protocol, and the limitations of the evidence on these therapies were described in the report as well. The purpose of this systematic review was to provide a summary of available published literature, including limitations. This systematic review does not make treatment recommendations, and therefore, does not recommend GET or CBT.

Comments: Personal testimonials: These testimonials spoke to the sincere frustration and desperation experienced by many patients with ME/CFS, including difficulty finding providers familiar with ME/CFS, struggles during and after attempted treatment with GET or CBT, and the impact of ME/CFS on their daily lives.

Response: CDC appreciates the patients living with ME/CFS to share their stories and acknowledges the struggles that they face on a daily basis. CDC highly values insights gained from these public comments. Some patients felt that this systematic review was recommending treatment with GET or CBT. However, the purpose of this systematic review was to provide a summary of available published literature, including limitations. This systematic review does not make treatment recommendations, and therefore, does not recommend GET or CBT.

Comments: Inclusion of studies with high risk of bias: Commenters expressing concern that unblinded trials and studies reporting participant-reported outcomes should have been rated high risk of bias or should be downgraded unless there were other methodological limitations.

Response: CDC recognizes commenters' concerns about such studies. For interventions where blinding is not possible, we followed the standard approach used in many other systematic evidence reviews and downgraded for open-label design, but did not necessarily downgrade to high risk of bias unless there were other methodological limitations.

Comments: Exclusion of certain studies on harms evidence: Commenters suggest that the review missed potentially relevant evidence on harms by excluding observational studies and patient surveys.

Response: CDC understands commenters' concern about exclusion of these studies. We will take them into consideration for future systematic reviews. This review focused on randomized controlled trials (RCT) for evaluation of benefits and harms of treatments because observational studies and non-RCTs are susceptible to bias and confounding, particularly for more subjective outcomes like those evaluated in this report.

Comments: Concerns with case definitions and impact on the systematic review: Some commenters suggested the removal of studies that used older case definitions for the inclusion of this review.

Response: CDC respects the reasons for commenters' concerns with the case definitions used in the report, as many case definitions have emerged over the past several decades. To address the issue of the multitude of case definitions, regrouped analyses were performed for various case definitions.

Comments: Interpretation of results: Commenters questioned the use and interpretation of meta-analysis in the systematic review, due to high heterogeneity, low strength of evidence, and high risk of bias studies.

Response: CDC appreciates commenters' concerns with meta-analysis methodology. In the revision we incorporated some of these comments and added more details to address these concerns. Essentially, the meta-analysis results were restructured for visualization and to facilitate the interpretation of results, thus overcoming this challenge and allowing for useful information to be reviewed.

Comments: CDC programmatic concerns and recommendations: Commenters included requests or recommendations to the CDC ME/CFS program regarding future research and/or guidelines.

Response: CDC appreciates the comments for improving the CDC ME/CFS program and will address them with leadership during program planning activities.

Comments: Recommended references: Commenters suggested additional information available on websites and in scientific publications.

Response: CDC recognizes the importance of reviewing these suggested references. Each suggested reference was assessed for this current review with pre-established inclusion/exclusion criteria. For future systematic reviews CDC may consider different criteria, which may allow for taking the suggested references into further consideration.

Based on public comments, CDC revised the final report to include (1) information about the decision not to proceed with developing clinical management guidelines; (2) regrouping of plots for the meta-analysis by case definition to facilitate the interpretation of results by various case definitions; (3) regrouping limitations into two major categories (study and clinical trial limitations and limitation in methods used to conduct the review); and (4) adding a description about the importance of collecting common data elements via standardized instruments or other assessment tools. The final report and a thematic summary of responses to public comments can be found in the Supporting Materials tab of the docket and at https://www.cdc.gov/me-cfs/programs/evidence-review.html.

Although ultimately, at this time, CDC did not find sufficient evidence from the review to proceed with the development of clinical management guidelines for ME/CFS, the review was instrumental in spotlighting the research gaps in the currently available literature, and consequently, possible improvements for future clinical trial design and ways to leverage funding resources for clinical trials.

Dated: January 11, 2023. Tiffany Brown, Acting Executive Secretary, Centers for Disease Control and Prevention. [FR Doc. 2023-00813 Filed 1-17-23; 8:45 am] BILLING CODE 4163-18-P

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To me this is mincing words. I would like to see something much more rigorous.

It is not that the strength of evidence supporting CBT is low. It is that it is not good enough to use for clinical policy and if anything the most plausible analysis is that CBT doesn't work. I think it is particularly unfortunate that they say that the magnitude of benefits was small to moderate. What they should have said is that the claimed benefit was small to moderate. It is highly likely that these 'benefits' are merely apparent. The bit about diagnostic categories is irrelevant. All that needs to be said is that there is no good evidence (for any group). The evidence does not preclude a strong conclusion. It allows the very strong conclusion that there is no reliable evidence for the efficacy of these treatments. Period.

And how come then that for 'other therapies' they can reach the strong conclusion that they are not effective or require further evidence? The situation is exactly the same. This is the point I spelled out in the introduction to my NICE testimony.

I admit that the UK has spawned the problem of poor quality evidence, but at least we have also managed to debunk it. We have the support of an admirable US health journalist but I see little evidence that the health worthies have grasped the nature of the problem. Sorry to be partisan, but if they have read my report to NICE I don't see how they can come up with this grey-washing.

 

Thanks for posting, @Tom Kindlon

What's especially frustrating is that this group knows all the issues - outcome switching, high bias, unblinded trials with subjective outcomes, nonspecific criteria, etc. They are the same group that conducted the 2014 review and the 2016 reanalysis that downgraded evidence for CBT and GET. They've received extensive input on how to formulate their review protocols and hundreds of public comments on their 2014 review and again in 2021. But with the exception of downgrading evidence for CBT and GET in their 2016 reanalysis, the input and feedback barely seems to penetrate.

@Jonathan Edwards - I appreciate the overwhelming impact of study conduct. But IMO, the diagnostic categories is also highly relevant. If an ME/CFS exercise study is perfectly conducted but uses criteria that don't require PEM, then claims of applicability to those who do experience PEM - are problematic. I imagine we could see this same situation in Long COVID exercise studies if they don't consider PEM status in patient selection. One example from ClinicalTrials.gov - the online protocol for this study doesn't mention PEM as an exclusion.

 

The nail on the head.

 

For sure. And it's not just pwME. It's LC and Lyme patients as well.

There's history for you. It speaks to the democratization of medicine - the majority count more than the minority. We are literally talking millions of sick people here that are being kicked to the curbside, but our maelstrom doesn't register when compared, not just to the majority not afflicted, but to the vested interests who lobby against our plight.

But hey, let's take one for the team. Why not.

 

"In summary, evidence on effective treatments for ME/CFS remains limited."

Nope there are no objective, real world benefits of any treatments.

"The strength of evidence supporting the use of exercise and cognitive behavioral therapies (CBT) was low."

Nope, there are no real world, objective benefits. Trials using subjective outcome measures in unblinded trials need to demonstrate objective changes. Not been demonstrated. Zero objective evidence.

"In addition, the magnitude of benefits was small to moderate,"

This is regarding subjective outcome measures. Largely meaningless statement. It's expected that in unblinded trials patients will report small to moderate positive changes. It's the placebo effect.

"with inadequate evidence in patients diagnosed with more current case definitions, limited reporting of harms, and inadequate evaluation in severely affected patients."

Yup, we have known this for a long time. Nothing new to add here. Move along. Patients, advocates, charities, academics and researchers been making these points for a long while.

"Methodological and other limitations (imprecision, inconsistency, uncertain generalizability) preclude strong conclusions at this time."

The main issue of lack of objective measures in unblinded trials is glossed over, why?

"Other therapies were shown to be not effective or to require additional evidence to determine effectiveness."

All therapies including exercise and CBT included, it should read and conclude

 

Now that the CDC have spent decades going nowhere, what, if anything is the plan and leadership to bring about change?

Patients really cannot be expected to wait another decade for another report like this

 

Frankly seems cowardly. Those treatments used to be recommended, and they admit they don't even have evidence for it. That's scandalous, and they can't even acknowledge that wrong. They still dither, giving far too much respect to the mindlessly obsessive attempt to psychologize this. And in the end they abdicate any responsibility for this wrong having endured for decades without any possibility in the foreseeable future to actually do better.

They basically say more research is needed, and we know that more BPS research will be published than actual scientific research, it's cheap and mindlessly easy, it will be presented as legitimate all over again, and we are still decades into this, with nothing to show for it as a result of cowardly dereliction of duty... and they just do it again anyway.

The fact that useless treatments have been the exclusive and obsessive focus for so long doesn't really bother anyone, still zero urgency, zero concern for patients and even less interest to find any more. It's just paralysis and complete indifference to the patients, to the principles of medicine and even the damn law.

It doesn't matter that the evidence is of low quality. They know it's low quality. Low quality evidence is the bulk of evidence-based medicine. They don't care and no one's responsible for anything. So even after 3 years of Long Covid, everything is still locked firmly in place with no one even interested to do anything serious.

What a complete disaster of choice, cowardly dereliction of duty is the tradition and the norm.

 

There are potential problems but if the study is perfectly conducted and gives a positive result the assumption is that it is applicable unless there is a well argued reason not. There may well be but we know so little that we cannot be sure. That leaves the door wide open for those with other ideas about diagnostic grouping to say they are just as entitled to use them.

A couple of weeks ago I had a chat about ME politics with Bob Souhami. Bob is regarded as something of a gold standard in UK medicine for rigorous thinking (now in his eighties). His question was what was the evidence for a specific ME category within chronic fatigue being clinically useful. The answer is that nobody knows. I think it is likely to be useful, but I have to admit we don't yet have the evidence.

We can only win the argument by sticking to hard evidence and admitting where it is missing.

 

No, wrong question, imho. Fatigue is a sidebar, same as it is with the flu or cancer or MS. I would be loathe to qualify ME as a "fatigueing illness," no slight to Straus and company. God the CDC has a dark history in our circles. Focus on the package and PEM.

 

I see it as a step in the right direction for the CDC, they know they are losing the argument for more exercise.

I'm assuming somewhere in the background Dr Nath at NIH, the research teams at various esteemed colleges, and the expanse of long covid are causing the CDC to pivot.

Welcome to the starting line, after how many years?

 

That's really it. This flaw is in the foundations of modern medicine. Not the scientific medicine part, just the modern practice part. The foundations of what is health, what is illness and how it influences people are crooked, flawed, barely existent. The fundamentals are the weakest point, but addressing them requires reworking the foundations and there is no appetite for that, the system is broken but everyone keeps it going, exactly the same way as politics don't work for us but people keep voting for it anyway.

 

I think we are well past that point. We may not know the exact etiology and how all the strands of research fit together. And we need more studies/replication - using well-characterized cohorts. But IMO, there's substantial research evidence across multiple systems of an abnormal response to exertion in ME. Because of that evidence, researchers often use an exertion challenge to provoke the disease. And bth the US and the UK now require PEM for an ME diagnosis and even WHO recognizes the need to identify it in Long COVID patients clinically.

I can't imagine any justification to continue to lump ME into an undifferentiated mass of chronically fatiguing, medically unexplained conditions as done historically.

One good thing is that CDC did not support the article being submitted for publication in a journal because of the extensive feedback they received. It shouldn't have been released at all but at least it doesn't have that stamp of approval.