The art and science of ME/CFS: A 2016 synopsis
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The art and science of ME/CFS:
A 2016 synopsis
Daniel L. Peterson
Medicine Doktor, Simmaron Research, Sierra Internal Medicine, Incline Village, NV USA.
E-mail: dpeterson@sierrainternalmed.com.
ME/CFS, a complex multisystem disease of diverse etiology, which results
in significant functional and costly impairment, is estimated to affect approx-
imately 40,000 Swedish residents. This synopsis describes developments
by governmental agencies (i.e. the CDC); emerging clinical centers in Stock-
holm and Gothenburg, and the sophisticated Swedish research addressing
basic and translational medicine, and physician education. A model is pre-
sented for Centers of Excellence, additional issues addressed: name chan-
ge controversy, subsetting of patients, Big Data and Precision medicine, the
microbiome, and current treatment challenges. Research obstacles and so-
lutions are outlined including the profound lack of funding and attention af-
forded by government agencies, academic institutions, and pharmaceutical
industry. Development of C.O.E.’s and optimism; based on new science and
technology with worldwide collaboration, suggest hope for the future.
Myalgic Encephalomyelitis (ME/ Current State of Affairs in the
CFS) is a complex multi-system di- U.S. and Sweden
sease of probable diverse etiology and
Centers for Disease Control and Pre-
pathogenesis resulting in significant
vention (CDC) in Atlanta, Georgia, is
functional impairment. Significantly,
embarking on a collaborative innova-
the fatigue is generally worsened by
tive process in order to properly revise
physical or mental exertion. Com-
its educational materials. They have
mon symptoms include cognitive dys-
developed a Technical Development
function, autonomic manifestations
Work group (TDW) to identify the
of dysfunction, sleep abnormalities,
needs and priority topics for educatio-
pain, and GI complaints. Worldwide
nal materials. The emphasis will be
studies have indicated that when app-
on evidence-based, understandable
ropriately screened and diagnosed,
materials that are useful to all stake-
the incidence rates are similar in the
holders. Hopefully, these reports and
developed countries where it has been
efforts will be available in translated
studied. A conservative estimate sug-
form to interested parties including
gests that over 1 million Americans
physicians, patients, and research or-
suffer from ME/CFS and further,
ganizations worldwide. The recent
that a significant proportion (>25%)
efforts by the National Institutes of
are severely affected or disabled.
Socialmedicinsk tidskrift 4/2016 455
English articles
Prevalence in the USA:
Estimated 400/100,000 ≈ over 1 million patients
Prevalence in Sweden:
About 40.000 patients are estimated to have ME in Sweden
Prevalence World Wide:
≈19 million
Prevalence of Severe Cases of ME/CFS:
Approximately 25% of all patients are classified as “severe”
Figure 1. ME/CFS Prevalence and Severity World-wide.
Health (NIH) in the United States to chronic diseases, the driving force for
prioritize the study of ME/CFS are these efforts must come from the pa-
encouraging. Without a significant tient groups and advocates in order
increase in funding for these efforts, to raise awareness in the appropriate
however, it is unlikely that either the government and private agencies to
intramural or extramural programs obtain the priority status and funding
will make rapid or substantial pro- necessary to solve ME/CFS.
gress in this difficult field. Sweden is unique in having a very
There is a certain recognition of well organized and functional na-
ME/CFS in Sweden, it’s effect on the tional patient support organization,
citizenry and cost to society. This has with local groups in the larger cities
resulted in excellent research targeted of Stockholm, Goteborg and Malmo.
at immunological and pathological This patient organization is active in
determinants of ME/CFS. However, lobbying the government for necessa-
access to care at the primary care level ry infrastructure, reform and funding.
remains problematic. The relatively Jonas Bergquist, PhD, at Uppsala
newly established clinic in Stockholm University has been very instrumen-
is an excellent start to remedy this tal in spearheading basic research into
problem. It would appear prudent the biochemical metabolomics and
för researchers and clinicians world- proteomics in the serum and spinal
wide to collaborate in a networking fluid of patients severely affected by
fashion. This would ultimately allow ME/CFS. The Gottfries Clinic in
for targeted research in countries and Molndal, Sweden, continues with its
institutions with special expertise in efforts to meet the demands of pa-
the various aspects of the disease, as tients for diagnosis and treatment of
well as reaching consensus on appro- fibromyalgia as well as ME/CFS. Jo-
priate diagnostic criteria, subsetting nas Blomberg, MD, PhD, a retired
of patient groups, determination of professor of clinical virology, remains
endpoints for study, and appropriate active in his study of the role of viru-
therapeutic strategies. As in all other ses and immunity in the development
456 Socialmedicinsk tidskrift 4/2016English articles
• Direct $9 billion USD
annually
– [approx. $70 billion
Swedish Kronor]
• Indirect $17-$24 bil-
lion USD annually
– [ approx. $140-$200 bil-
lion Swedish Kronor]
Figure 2. Economic Impact of ME/CFS. Annual Economic Loss Due to ME/CFS
of ME/CFS. Dr. Per Julin continues ferent countries and diverse cultures.
to develop and expand the ME/CFS A Nordic coalition, however, might
clinic in Stora Skondal. Other physici- be plausible and should be explored.
ans and centers are striving to deve- The National Center for Neuroim-
lop appropriate institutions or clinics munology and Emerging Diseases at
to serve the approximately 40,000 pa- Griffith University in Australia has
tients with ME/CFS in Sweden. been highly successful in developing
Most of the world’s medical schools the translational medicine concept,
and medical textbooks do not include conducting state of the art basic and
ME/CFS in their curriculum or pu- clinical research while simultaneously
blications, other than perhaps brief engaging in clinical diagnostic and
summaries and suggestions for symp- treatment endeavors.
tomatic therapy.
While education of primary care Name Change Controversy
physicians and other practitioners is
In spite of the extensive publicity
critical to the field, Centers of Ex-
and discussion of the Institute of
cellence appear to be the most cost
Medicine’s (IOM) recommendations
effective and viable approach to ex-
to establish new criteria for ME/CFS,
pediting translational medicine (the
there has not been broad support for
process of bringing bench research to
adopting or endorsing SEID. While
the efficient diagnosis and treatment
the clinical definition is very user
of patients). Worldwide collaboration,
friendly (it can be applied quickly by
as exists in many other diseases such
inexperienced clinicians), it is the ge-
as multiple sclerosis, AIDS, and dia-
neral feeling that it does not capture
betes, would be ideal. It is difficult to
a homogenous population. Leonard
establish the necessary infrastructu-
Jason, psychologist and researcher,
res, particularly in view of differing
has indicated that the SEID defini-
funding mechanisms and distribu-
tion captured most of classically de-
tion systems for medical care in dif-
fined ME/CFS patients but included
Socialmedicinsk tidskrift 4/2016 457English articles Figure 3. SEID Diagnostic Algorithm for ME/CFS a larger and less specifically uniform discussions of the appropriate use of patient cohort. these established and newly proposed Without acceptance by agencies definitions due to the heterogeneous such as the CDC, NIH, or WHO the nature of the patient populations. definition may not be widely adop- Consensus, of course, is the ultimate ted. Additionally, in light of ongoing goal. research initiatives, basic as well as clinical researchers have continued to Research Developments use the long established and accepted Subsetting ME/CFS Patients definitions including the Canadian Consensus Criteria (CCC) and/or the The heterogeneous nature of the po- 1994 CDC Criteria. Certainly there pulations obtained by the various de- will continue to be re-evaluation and finitions suggest that researchers and 458 Socialmedicinsk tidskrift 4/2016
English articles
clinicians must continue efforts at approach utilizing statistical metho-
categorizing patients into subsets in dology and modeling to study ME/
order to determine the etiology and CFS and many other clinical illnesses.
pathogenesis and, ultimately, the most While this approach is clearly of great
appropriate treatment. Examples in- potential, particularly with respect
clude the ongoing clinical trials in to precision medicine, it requires lar-
Norway and the UK with rituximab ge numbers of patients and is a very
in patients presumed to have an au- costly approach to diagnosis. On the
toimmune component to their patho- other hand, there remains a concern
genesis. An example of translational as to whether findings obtained in a
medicine can be found in the work small group of patients, such as the
of professor Carmen Scheibenbogen proposed NIH intramural study of
of Berlin, Germany, describing auto- 40 patients and controls, or the Stan-
antibodies to adrenergic and acetyl- ford Initiative with 20 severely affec-
choline receptors in ME/CFS patients ted patients, will be applicable to the
which has both diagnostic and thera- greater ME/CFS patient population.
peutic implications for the patients. Worldwide, patients, clinicians, and
This may aid in understanding the au- researchers are anxiously awaiting the
toimmune pathophysiology in a sub- results of these preliminary studies
set of patients. Such stimulating and utilizing the Big Data technology ap-
exciting initial results, mandate addi- proach to the study of ME/CFS.
tional and replicating studies. Precision medicine is yet another
After more than 30 years of stud- trend in medical research. Some suc-
ying ME/CFS worldwide, the prepon- cess has been obtained, for example,
derance of evidence continues to sug- in identifying the correct chemothera-
gest a role of immune perturbation/ peutic agent for treatment of various
dysfunction in the production of the cancers, eliminating the inaccuracy
signs and symptoms of the disease. and potential complications of trial
As molecular biology has become and error therapy even when utilizing
fine tuned, researchers are capable evidence-based studies. The NIH re-
of studying the nuances of B, T and cently awarded $55M for fiscal year
Natural Killer Cell function. Many 2016 to launch the Precision Medicine
of the reported abnormalities such as Initiative (PMI). This is a landmark
impaired Natural Killer Cell function research effort that aims to engage
have been reproduced in independent one million participants to prevent
laboratories. However, there is yet to and treat disease based on lifestyle,
be universal agreement as to the sensi- environment and genetics. Perhaps
tivity and specificity of biomarkers for ME/CFS patients will ultimately be-
diagnosis or treatment. nefit from this effort. It remains to be
determined whether these approaches
Big Data and Precision Medicine utilizing genetic profiles, gene ex-
ME/CFS is a Big Data gold mine. pression studies, metabolomics, etc.,
Big Data has become in vogue as an will have general applicability to the
Socialmedicinsk tidskrift 4/2016 459English articles
diagnosis and treatment of patients engaged in the effort to design app-
with ME/CFS. Precision medicine is ropriate clinical trials and even sup-
certainly a lofty goal with the poten- port their execution. In the interim,
tial for increased sensitivity and spe- clinicians on the front line of patient
cificity of diagnosis and cost effective care must utilize the art of medicine
therapies. in selecting modalities of interven-
The Gut Microbiome and ME/CFS tion that have been demonstrated to
There is increasing evidence that potentially affect quality of life or
the human microbiome is influenced prevent the devastating complications
by many factors and the status of the and comorbidities of chronic disab-
gut microbiome has significant impact ling illness. Large well-funded studies
on immunological function. This is are required for international collabo-
an extremely complex area of study. ration, particularly when studying ge-
The pursuit has been taken up by nu- netics and gene expression of complex
merous well-respected research insti- yet relatively frequent diseases such as
tutions including Columbia and Cor- ME/CFS. These should be conducted
nell Universities in New York. The in well designed and executed studies
potential utility for understanding at multiple sites utilizing only well
the pathogenesis of ME/CFS or for characterized patients.
determining strategies for treatment,
remains to be determined. Hopefully, Obstacles and Solutions
adequate funding for further large
As the P2P and IOM documents
studies will be forthcoming.
clearly point out, ME/CFS research
has been fragmented and fraught with
Treatment of ME/CFS
methodological pitfalls such as use
Treatment of ME/CFS remains chal- of different disease definitions, lack
lenging and problematic. Since the of objective endpoints, small patient
publication of the P2P and IOM do- numbers, lack of control groups, fai-
cuments, there is agreement that ad- lure to replicate results and numerous
ditional work must be done in deter- other short comings. The studies have
mining outcome measures for clinical largely lacked the scientific rigor suf-
trials. In addition, determination of ficient for the world of evidence ba-
appropriate interventions for clinical sed diagnosis and management. Some
trials and execution at multiple sites of these stumbling blocks have been
with well-characterized subsets of overcome by general acceptance of
patient populations are needed. Un- case definitions, emphasis on subsets
fortunately, there has been little inte- and rigorous study designs. Yet, many
rest from the pharmaceutical industry obstacles remain for the nascent re-
which, in general, is the driving force searchers and clinicians in this diffi-
behind well-constructed and funded cult and complex illness.
clinical trials. It is hoped that agencies The largest of these obstacles is the
such as the FDA and others might be failure of the scientific world (and in
460 Socialmedicinsk tidskrift 4/2016English articles some cases the patient community) to these goals. accept the existence of ME/CFS as a In just the last few months the NIH real, organically based disease, and as- has funded projects aimed at training sociated with extreme disability. Fled- patients to recognize exhaustion (pre- gling efforts have been further ham- cision medicine) and a broadly based pered by profound lack of funding of large study to determine biomarkers the magnitude necessary to conduct (big data analysis and high tech mole- even the basic rigorous studies and cular biological techniques). treatment interventions. Govern- Longitudinal studies to determine ment agencies, academic institutions the natural history of ME/CFS are and the pharmaceutical industry have being conducted by the CDC at multi- ignored the call to action, leaving fun- ple sites using common data elements, ding to small grants and private do- standardized testing and data analysis. nations. The International Association for Ch- It may be useful to remind oursel- ronic Fatigue Syndrome/Myalgic En- ves of the magnitude of ME/CFS in cephalomyelitis (IACFS/ME) is again the world in human and economic hosting their biannual meeting at the terms. Clearly such large numbers Weston Fort Lauderdale, October 27- should justify the resources necessary 30. Participation by researchers and to intensely study the disease and al- clinicians, and patients are of course leviate the concomitant disability and welcomed and encouraged. economic cost to all societies. One of the most unique and ubiqui- Using basic patient’s samples tous symptoms of ME/CFS is post- such as blood, urine, saliva and CSF exertional fatigue following physical sophisticated research can be done on or cognitive challenge. Many centers DNA, RNA, epigenetic markers, pro- are now studying this symptom to de- teins, metabolites and immune cells termine its cause, to seek a potential and their messenger cytokines and unique (sensitive and specific) biomar- chemokines. ker and determine potential therapeu- New technology such as high out- tic interventions for this very disab- put sequencing, big data mining, etc. ling symptom. will provide the necessary tools to sol- A few large, classically designed tre- ve these problems, but adequate fun- atment studies are being conducted ding must be obtained. It has been while compassionate, empiric treat- guesstimated that with adequate fun- ment protocols remain the standard ding such as that allocated to other of care. comparable old and emerging disease Recently major strides have been (e.g. Zika virus related disorders) ME/ taken to achieve common goals in CFS could be fully understood and Europe. Phenomenal progress has treated in 3-5 years. While it is unlike- been made over the past ten years in ly that a single country or agency will the UK through the effort of the In- step up to the financial plate, world- vest in ME UK Charity to stimulate wide collaboration could accomplish research and patient and physician Socialmedicinsk tidskrift 4/2016 461
English articles
education. As an example, the Invest Conclusion
in ME Research Charity has launched
Throughout the world, access to care
the foundation for a translational
remains problematic for patients with
biomedical research Centre of Excel-
ME/CFS. There remains a lack of
lence. It also sponsored a state of the
knowledge on the part of most phy-
art scientific meeting, affording invi-
sicians at both the primary care and
ted scientists and clinicians the opp-
specialty level with respect to ME/
ortunity to share research and stra-
CFS in general and particularly in
tegies while providing education and
the area of diagnosis and appropriate
hope to patients and treating clinici-
treatment. Strategies implemented to
ans. The recent IIMEC11 conference
date have had limited success in en-
presented stimulating new studies on
couraging clinicians to specialize in
case definitions, sub setting patient
the area of ME/CFS or to even make
groups, the human, viral and bacterial
an appropriate diagnosis. Given the
gut microbiome, potential genetic and
long duration of this gaping hole in
metabolomic biomarkers, and second
the provision of medical care, many
generation research on a wide variety
experts feel that the appropriate fun-
of immune markers including NK
ding and establishment of Centers of
cells, B cells and cytokines. With pro-
Excellence may be the most viable
per support and leverage these areas
approach for educating physicians
all present viable and promising po-
and ancillary personnel. Alas, while
tential for future clinical researchers
there is widespread support amongst
and clinicians.
patient groups and clinicians, the fun-
Representatives of 13 countries in
ding and infrastructure is not endor-
Europe have joined the European ME
sed or supported for this approach.
Research Group (EMERG) for inter-
And yet, never before have the tools
national collaboration. This repre-
been so efficient and available for the
sents a major step in the development
study of complex diseases and the fu-
of a necessary regional infrastructure
ture is optimistic if the obstacles afo-
to support new research initiatives.
rementioned and the many others can
Such collaborative efforts will maxi-
be uniformly overcome.
mize research speed and efficiency.
References
IOM (Institute of Medicine). 2015. Beyond Myalgic National Institutes of Health Pathways to Preven-
Encephalomyelitis/Chronic Fatigue Syndro- tion Workshop: Advancing the Research on
me: Redefining an illness. Washington, DC: Myalgic Encephalomyelitis/ Chronic Fatigue
The National Academies Press. Syndrome. Ann Intern Med. 2015: 162 (12):
860-865. doi: 10.7326/M15-0338.
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