Trends in Chronic Fatigue Syndrome Research

This paper examines the quantity and focus of CFS research over time and draws some conclusions regarding their implications for CFS patients.

Background

After CFS burst upon the scene in the mid eighties it didn’t take it long to become a major research topic. The first study PubMed cites on CFS (in the 1980’s) was published in 1987* and by 1988/9 the field was up and running. Since 1991 papers with CFS or its equivalent in the title have never numbered less than 100 a year.

Similarly the number of citations PubMed cites for ‘Chronic fatigue syndrome’ are astounding; a search on 2/22/05 brought up 2949 citations with some connection to CFS. These numbers appear at first blush to demonstrate an impressive commitment by the medical establishment to the resolution of CFS.

Progress in our understanding of CFS, however, has been slow. The cause of the disease is still obscure and treatments are still largely ineffective. Instead of addressing the core dysfunctions found in CFS, physicians are often relegated to treat it symptomatically.

There is still no accepted biomarker for this disease and, of course, we still have its unfortunate name. While few in the medical field, at least, appear to believe it has a psychological origin, the role psychology plays in the course of the disease has raised quite controversial. Few findings in this disease, in fact, are without controversy.

The survey was prompted by the discordance between all this activity and the lack of progress in the disease. How could we – 18 years after the ‘advent’ of CFS and some 3000 PubMed citations later – still be saddled with this unfortunate name? Why is there still no test for CFS or an acceptable definition of it?

It is true that CFS is a very complex disease that is difficult to analyze given its changing definitions and the different subsets of patients found within it. But is it THAT mysterious? THAT impervious to investigation? THAT much of an enigma? Or have other factors contributed to the slow pace of knowledge?  This question prompted a survey of how the quantity, focus and ‘potential’ of CFS research has changed over time.

The survey

The papers included in this survey were those cited when ‘chronic fatigue syndrome’ was entered into the search bar at PubMed. PubMed is a search engine sponsored by the National Library of Medicine that accesses over 15 million citations of biomedical papers dating back to the 1950’s (but not the Journal of Chronic Fatigue Syndrome (JCFS)).

A list of titles and abstracts for the JCFS dating back to 1998 on the Haworth Press website were used)  Only those articles (with a very few exceptions) with chronic fatigue syndrome or myalgic encephalitis in the title were included.  (Prior to 1992 when the term CFS was essentially codified citations with pseudonyms for CFS such as postviral fatigue syndrome, EBV syndrome, etc. were included.)

Based either on the title or the abstract provided by PubMed or the Haworth web site the papers were grouped into the following broad categories based on my assessment of their primary orientation; clinical, immune, psychological, brain/CNS. endocrine, metabolic, cardiac, oxidative, cognitive – neuropsychological, sleep, muscles, tilt table, others. A few papers had more than one focus.

The survey examined PubMed citations from 1988/9, 1991, 1994, 1997, 2000, 2003 and 2004 and JCFS papers from 2000, 2003 and 2004.

Quantity

The most surprising finding was that except for very recently over the past 13 years the quantity of PubMed citations has remained more or less stable. One would have thought that as the field matured and became better known the number of citations would increase. Except perhaps for the last year or so this has not occurred. (The number of articles in the table below appears to pick up a bit after 1997.

This was due to the publication of the Journal of Chronic Fatigue Syndrome. This publication may have (a) sparked interest in the field and/or (b) provided a venue for theories, studies, etc. not readily accepted in other publications. The trend in PubMed cited articles was flat.) An average of approximately 130 articles that have CFS or myalgic encephalitis in their title have been published every year for the last 10 years (based on 1994, 97, 00, 03, 04).

Trends in CFS research

*contains citations from the Journal of Chronic Fatigue Syndrome

Trends in research focus

One would expect to see different trends of interest emerge over time in any research area and this has proved true in CFS. The percentage of papers focused on the immune system – the dominant early interest in CFS –  declined from a high of 45% of citations in 1988-89 to about 17% of citations in 2000/03 and 04.

Within the immune category research trends have changed as well; research into viruses, while still a significant topic, has declined markedly since 1991 (1991 – 20 citations; 2003/4 – 5 citations) as interest in bacteria (mycoplasma, chlamydiae, staphylococcus) has picked up (1991/1993 – 0 studies; 2003/2004 – 10 studies).

Another area of diminishing interest have been the clinical aspects of CFS. The clinical category primarily contains doctor to doctor talk; it centers on the diagnosis, treatment, management and prognosis of CFS as well as reviews of CFS and discussions regarding CFS’s validity (controversy).  Still one of the most cited subjects (@20-25%) it makes up substantially smaller portion of the total citations than it used to (30—35%).

Interest in the psychological aspects of CFS has also changed dramatically over time. While no interest was seen early on (0 citations 1988/9 – 0) psychology in CFS rapidly assumed a major focus (1991 – 22). Psychology studies reached a peak in 2001 but have fluctuated dramatically and may have even declined since then.

The two years with the lowest number of psychologically oriented studies were 2000 (16) and 2004 (11). Within the field the focus of interest has changed dramatically. In the early 1990’s depression was a major topic but has been replaced since about 1997 by cognitive behavior therapy (CBT) was a major research interest.

CBT et. al. accounted for from 25% to 60% of psychology citations in 1997, 2000, 2003, 2004.  Aside from these two topics, there appears to be little coherence in this field; research topic range from psychiatric morbidity to the effects of birth order to the radicalization of the self, to parenting, etc.

While interest in the immunological and clinical aspects of CFS appears to have declined, interest in three fields; the brain/CNS, endocrinology and oxidation/metabolism has increased sharply in the last 4 to 7 years. Interest in the brain/CNS has, not surprisingly given the cognitive difficulties associated with CFS, always garnered some interest but in the last two years that interest has jumped markedly with 12 and 14% of all citations devoted to it. Two subtopics, in particular – serotonin and cholinergic function – have gained in popularity lately.

The endocrine system attracted little interest early on. No citations concerning the endocrine system occurred in 1988/91 and only 2 in 1991 and 1994. Since 2000, however, over ten papers have been published on endocrinological topics every year with a dominant focus on cortisol.

Since its discovery in CFS in 1995 by Rowe, orthostatic intolerance has remained a relatively small but nevertheless consistent source of citations. Similarly, while not being a major source of citations, free radicals and the oxidation/antioxidant balance (@4) arrived as a research interest in CFS in the last four years.

It is difficult to discern any trends in muscle activity, metabolic processes or sleep. Interest in each has been present since the early days of CFS research but none has become a major research topic and interest in each has fluctuated greatly. Driven primarily by one research group, interest in cardiology has been consistent but low.

Interestingly alternative health therapies, long a treatment mainstay for CFS patients, were a major source of citations for the first time in 2004 with 8 citations devoted to them. In the past five years genetics has arrived on the scene with several citations devoted to it in 2000, 2003 and 2004.

The implications for CFS patients

What do these numbers mean for CFS patients? Can they be confident that the medical research community has marshalled it’s considerable resources on their behalf?  Even if the numerical trends are flat or only mildly positive one would think 130 or so ‘papers’ a year would be sufficient  to guarantee real progress.

It sounds, after all, like a lot of work is being done – enough one would think to give CFS patients hope that before too many more years pass, significant breakthroughs in the understanding of and treatment of their disease will occur. A closer look at the ‘research’ cited in PubMed indicates this is anything but true. Few of the citations for CFS signify papers that have the potential to make a  difference in the understanding of CFS.

A mixed bag

The papers cited by PubMed vary widely in focus and quality. PubMed citations include everything from letters to reviews, from small one page studies to complex, multi-dimensional studies, from one person treatment ‘trials’ to double- blinded, placebo controlled, multi-group treatment trials.

In PubMed papers on CFS in animals and birth order sit next to large, multi-year studies on prevalence in humans, e.g. a citation in PubMed is not necessarily indicative of a significant contribution to CFS.

What a person suffering from CFS really desires is a breakthrough in our understanding or treatment of CFS. In lieu of that they want to know that significant work is being undertaken to understand CFS. They want to feel that the depth of the research effort into CFS is somehow congruent with the pain caused by CFS; that something that can so overwhelmingly alter their lives is being dealt with seriously by the medical research community.

They want to have an idea that significant progress will occur in CFS before the productive period of their lives is over. The next part of this paper, which examines whether this appears likely to occur, determines how many of the 3000 or so papers PubMed cites have the potential to significantly advance our understanding of CFS.

In order to do that distinctions are made between three categories of papers; insignificant, important but not difference making and potentially difference making papers.

Unimportant vs important papers

A certain number of papers cited by PubMed every year have little change of making an important contribution. Chief among these are papers published in a foreign language. These papers are often not abstracted and are probably little read. These papers can be surprisingly abundant; in 2004 they made up about 6% of all PubMed citations on CFS.

Important vs potentially difference-making papers

Some papers are important to the overall understanding and treatment of CFS but have no potential to advance our understanding of the biological processes occurring in CFS. They mostly involve medical professionals talking to medical professionals about peripheral issues common to any disease; i.e. how to characterize, diagnose or treat it, how common it is, what issues its patients face. They mainly occur in the following categories.

Clinical (@20-25%) – A substantial number of papers every year focus on the clinical aspects of CFS (diagnosis, management, prognosis, controversy).

Psychological (@17%) – It is clear, at least to CFS patients, that psychological studies will have little effect on the ultimate resolution of this disease. At their best they may help CFS patients cope with rigors of CFS. At their worst they divert attention and funding from more fundamental aspects of CFS and alienate CFS patients.

Epidemiological (@5%) – Epidemiological papers are vitally important for assessing the prevalence and economic costs of CFS and providing a rationale for more funding. Given the abysmal levels of current funding these papers may, in fact, be the most important papers published. Nevertheless they do not contribute to our understanding of the biological processes operating in CFS.

Neuropsychological/cognitive – (@ 4%) These papers elucidate the problems in cognitive functioning found in CFS patients. As such they provide evidence of brain dysfunction in CFS that is important for disability claims and for promoting more interest in the CFS. They do not, however, advance our knowledge of CFS pathophysiology.

According to this survey about half of the papers PubMed cites every year deal do not have the potential to further our understanding of the biological processes occurring in CFS.

This leaves us with about 70 articles published a year that might make a more less immediate difference in understanding the cause, mapping out its dysfunctions or uncovering a treatment for CFS. Even that sounds like a good number – 70 papers a year should surely offer real hope for CFS patients. Even this number is misleadingly high, however.

Potentially Difference Making Papers – Two general categories of potentially difference making papers can be formed; theoretical papers and studies. While purely theoretical papers have the ability to make a difference in CFS by elucidating creative new approaches to CFS, their impact is always impossible to ascertain at the time of publication. Their impact is further obscured by the fact that many, probably most theoretical papers receive either no or inadequate follow up. Ultimately, the only papers able to have animmediate and significant impact on CFS patients are ones examining the biological processes (the pathophysiology)  present in CFS. In a very real way they are the papers that really matter.

Surprisingly, though, given their fundamental importance, studies addressing CFS pathophysiology are not common. Many more papers are published every year on essentially peripheral subjects such as clinical reviews, psychological studies, etc. In 2004 PubMed listed only 35 studies (not including treatment trials) that actually examined examined  an aspect of CFS pathophysiology. Thus of all the citations that PubMed pulls for CFS only about 15% of them are engaged in uncovering the cause of CFS.

Even within this category there are subcategories and gradations of value. About 30% of all studies of CFS pathophysiology in 2004 simply undertook to confirm or deny prior findings (apoptosis, Th1/Th2 cytokine imbalance, ACTH/cortisol, salivary cortisol, serum erythropoietin). These studies are an important part of the march of science but they are not difference making because they do not forward the science, i.e. they do not bring our understanding of CFS to a deeper level.

A significant number of studies every year are exploratory studies that seek to determine if X occurs in CFS or not (gene expression, brain imaging, EBV, borna virus antibodies, urinary electrophoretic profiles). Is there brain damage in CFS? Is gene expression different? Is X virus present in CFS? Are abnormal levels of sympathetic nervous system activity present in CFS? These studies advance our understanding of CFS but their significance is unclear as well. They open up new avenues for research that may or may not pay off in the future.

The really difference making studies, the ones that might send a jolt of excitement up a patients or researchers spine, are those that have identified an abnormality and are working their way down a chain of causation to its source nd thus to CFS. Only a few papers in 2004, however, actually extended our knowledge of the causal factors of CFS. The corticosteroid gene polymorphism study, for instance, posits a cause for the low cortisol levels present in some CFS patients. The skin vasodilation study examined potential causes of skin vasodilation and by extension orthostatic intolerance.

One reason these papers are so few and much of the emphasis in CFS research is still on exploratory studies is that only a few abnormalities have been consistently found in CFS. Several factors contribute to this including poor funding, different diagnostic criteria over time, the lack of standardization, the occurrence of subsets in CFS, and the waxing and waning nature of the disease.

The lack of standardization is puzzling given the sophistication of the medical research establishment but is a very real problem. Two recent overviews of immune and neuroendocrine research in CFS cited  the lack of standardization and poor study methodology as reasons for the conflicting results sometimes seen in CFS research studies. Nancy Klimas was able to explain away several inconsistencies concerning cytokine studies simply by noting the different laboratory techniques used. This problem has been frequently noted by the NIH yet it has taken no steps to address it.

Funding woes

The greatest problem facing CFS research, however, is inadequate funding. This is a disease, after all, that can affect the immune, cardiovascular, endocrine and nervous systems.. In how many diseases are brain scans and spinal taps as well as hormonal, immune, orthostatic,  metabolic, sleep and exercise tests part of the research protocol? In how many diseases do psychological studies take up a significant amount of research funds?

Despite its needs CFS remains one of the most poorly funded diseases in the United States. Despite productivity losses to the US economy from disabled  CFS patients totaling some $9,000,000,000 a year, the National Institutes of Health (NIH) saw fit last year to fund CFS research to the tune of only $6,000,000. Of the 175 research areas funded by the NIH in 2004 CFS was 170th in funds awarded.

The NIH gave temporal mandibular joint (TMJ) researchers 3’xs as much money as CFS; Lyme’s disease was given 5 x’s the money CFS was; Crohn’s disease 9 x’s, anthrax research 17 x’s. asthma 50 x’s and AIDS 500 x’s as much  money. Just theincrease in asthma funding over the past two years – the increase! – was five times the total funding given CFS last year. This does not take into account the fact that a significant proportion of the funds the NIH says were devoted to ‘CFS research’ did not investigate CFS pathophysiology.

It is clear there is simply too little money and too many areas of interest for research in any one area to move ahead rapidly in CFS. Research into serotonin activity in CFS provides a case study of how slowly even a ‘major research effort’ proceeds in CFS.

Serotonin: A Case Study: Bakheit et. al. first uncovered evidence of increased serotonergic HPA axis activity in response to busiprone in CFS patients in 1992. In the same year Demitrack et. al. found evidence of increased serotonin activity in the spinal fluid. Since 1992 seven studies (about one every other year) have assessed serotonergic levels or activity in the spinal fluid, hypothalamus and brain in CFS using different serotonin agonists and different techniques (PET scan, CSF levels, provocation). Some heterogeneous findings have been found but for the most part studies have indicated increased serotonin activity in CFS.

Thirteen years after serotonin levels were first seen to be abnormal in CFS researchers now appear to beapproaching a consensus that serotonergic activity is increased in CFS. That is a long time in the life of a CFS patient. It is about third of ones productive years. It is a very long time to wait for researchers to reach an agreement about the importance of one substance – and researchers are still not there yet. That consensus may still be several years and several studies away.

What is most unsettling about this situation is that serotonin is not an obscure compound. One of the major neurotransmitters in the body, serotonin is involved in gastric secretion, and smooth muscle (vascular) and central nervous system activity.

A whole class of drugs, selective serotonin reuptake inhibitors (SSRI’s) has been developed to battle depression and other mood disorders. Because serotonin has the potential to effect so many different systems, one would think serotonin activity in CFS would have been assessed extensively once studies indicating a possible upregulation was present.

Instead the ‘serotonin question’ has been attacked in a piecemeal fashion by researchers using different protocols. Remember we have hardly even begun to assess the cause of a possible serotonergic up regulation in CFS; it has taken over a decade just to arrive at a consensus that it probably exists.

The same story plays out regarding cortisol, the most important adrenal hormone. Thirteen years after low cortisol levels were first noted cortisol levels are still being assessed in CFS. While heterogeneous cortisol findings do complicate matters to some degree, this slow progress cannot simply be laid at the feet of a wildly heterogeneous patient population.

Instead it is largely a function of a poorly funded and poorly organized research community. When researchers take a decade or more to assess the levels of one major substance in the body, can CFS patients any confidence that the resolution of their disease is anywhere in sight?

CFS is a complex disease. Understanding it will undoubtedly require venturing out into new ground and piecing together findings in novel ways. A new disease process will most likely need to be explicated. Cortisol and serotonin, however, hardly constitute ‘new ground’.

If it takes so long to simply assess the levels of these substances, how long will it take to investigate the lesser known or still unknown substances or processes that most likely lie at the heart of CFS? If the research community is this poor at assessing the ‘easy’ stuff how in the world will it be able to muster the ability to tackle the more problematic stuff?

Innovation quenched

Benjamin Natelson’s recent travails concerning finding funding for a spinal fluid gene/protein expression study are illustrative of the funding travails that confront CFS researchers. Dr. Natelson has been the most prolific CFS researcher in the world over the past five years and gene and protein expression studies are arguably the two most potentially helpful research field concerning CFS.

They have the potential  to fundamentally alter our understanding of CFS. Despite Dr. Natelson’s reputation and the NIH’s recognition of the urgent need to break new ground in this disease it has refused to even partially fund his gene/protein expression CSF study.

This was notwithstanding the fact that Dr. Natelson recently co-authored a study finding abnormal cytokine levels in the spinal fluid of CFS patients, or the fact that he already has the spinal fluid. Perhaps not surprisingly a year after Dr. Natelson was denied funding a proteomics study by another researcher found a potential protein biomarker in the CSF of CFS patients.

One is tempted to ask if this eminent researcher cannot get funding for such a worthwhile project then what chance do lesser known researchers CFS have? The history of CFS research is littered with promising studies that had positive outcomes but received  little or no follow up (hypercoagulation, PKR, adenosine levels, G-actin, etc.).

Innovative theories regarding CFS pathophysiology are regularly advanced but are rarely adequately tested. Despite demonstrating tie-ins with several other theories of CFS and being the topic of much discussion, Pall’s nitric oxide/peroxynitrite theory has been the object of only one small study in six years.

This petty pace

The 3000 papers so often cited with regards to CFS research is misleading as only a small portion of those papers actually involve research efforts.  Even the small amount of research done on CFS might be sufficient if we had a clear focus on CFS pathophysiology – if we knew what part of the body to zero in on, but we don’t. Research into CFS is spread all over the body. This means, given the small amount of research funding CFS receives, our progress in understanding this disease is doomed to be achingly slow.

The funding is simply not available for research teams to target an area and quickly and exhaustively investigate it. An examination of the CFS research ‘groups’ of the past five years indicates that most are very small groups that are able to produce a study once every year and a half or so.

These groups, always subject to a tenuous funding environment, manage to slowly chip away at their subject of interest over time but given their resources the amount of progress they can make is limited. Stewart, for instance, lists 16 different possible causes of the microcirculatory difficulties found in a subset (low-flow POTS) of a subset of CFS patients.

Similarly Spence and Khan list 9+ items that could be affecting acetylcholinesterase activity in CFS. Given the current pace of CFS research it can take many years for a consensus to form around any positive findings. A research effort that could take a year or two in a well funded disease can easily take ten years or more in CFS.

By under funding CFS research the powers that be have essentially decreed it will move forward at a petty pace. They have decided there are more important things for them to focus on. While researchers scramble for funding CFS patients watch the decades and their lives and dreams dribble away.

Shakespeare’s description of the human condition in Macbeth never resonated more strongly than it does with both CFS researchers and patients who seem, at times, relegated to irrelevance while the great public research institutions entrusted with the nation’s health look away.

“To-morrow, and to-morrow, and to-morrow,
Creeps in this petty pace from day to day,
To the last syllable of recorded time…
Life’s but a walking shadow; a poor player…”

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*The first two papers on CFS in the eighties were

Buchwald D, Sullivan JL, Komaroff AL..Frequency of ‘chronic active Epstein-Barr virus infection’ in a general medical practice. JAMA. 1987 May 1;257(17):2303-

Caligiuri M, Murray C, Buchwald D, Levine H, Cheney P, Peterson D, Komaroff AL, Ritz J. Phenotypic and functional deficiency of natural killer cells in patients with chronic fatigue syndrome. J Immunol. 1987 Nov 15;139 (10):3306-13.

It’s amazing how quickly what would become an important cadre of researchers and physicians congealed around CFS. Of the authors of the first two papers on CFS Buchwald has co-authored 69 papers on CFS, Komaroff 63, Levine 32 and Peterson 30. Dr. Cheney became one of the most creative CFS clinicians. CFS was not only a defining moment for their patients; it changed the lives of many of the earliest physicians on the scene as well. Several have dedicated their careers to understanding and treating CFS.