Research Digest – October 2014: The Search for Diagnostic Certainty

On Sept. 22nd the Agency for Healthcare Research and Quality (AHRQ) and their Evidence-Based Practice Centers published the draft systematic evidence review on the Diagnosis and Treatment of ME/CFS for comment. This report will be used for the Pathway to Prevention Workshop for ME/CFS to be held on December 9 & 10, 2014. (Read our full response to this draft report HERE.) One of the recommendations of the review is the need to test ME/CFS diagnostic criteria in other populations with diseases similar to ME/CFS where diagnostic uncertainty exists.  This is necessary because ME/CFS is defined by symptoms that are common in many other medical and psychiatric diseases.  Comparing ME/CFS to similar disorders helps determine effective diagnostic criteria to more specifically identify those who have ME/CFS.

Once ME/CFS is diagnosed there are many differences among patients; this is called heterogeneity and is common in most chronic diseases.  Objective biological measures – known as biomarkers – can be helpful for delineating this heterogeneity and identifying ME/CFS subtypes.  Importantly, biomarkers intended to be diagnostic for ME/CFS should be compared to diseases similar to ME/CFS to ensure the accuracy of the biomarker.

While there is more work to be done, in this month’s Research Digest we review three different studies that look at diseases that are common among patients labeled as ME/CFS and to identify more specific biomarkers for ME/CFS.

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 There have been studies published over the years that have looked at whether ME/CFS patients defined by the 1994 Fukuda criteria have other medical and psychiatric diseases that more accurately explain their symptoms.  A study published in the 2013 Journal of Psychosomatic Medicine found that undiagnosed and comorbid disorders were common in people with a presumed diagnosis of ME/CFS.(1) The investigators set up an integrated diagnostic pathway designed to detect known medical and psychiatric diseases that may otherwise go undiagnosed.  There were 377 patients with a presumed ME/CFS diagnosed referred to the study. Of these 279 were eligible for the study.  An unequivocal ME/CFS diagnosis was given to 65 patients.  Another 59 patients had ME/CFS together with a comorbid disorder that did not exclude the ME/CFS diagnosis.  The remaining patients had sleep disorders, medical diseases or psychiatric diagnoses that excluded an ME/CFS diagnosis.  This study highlights the importance of and need for diagnostic criteria that accurately detects ME/CFS and distinguishes it from other disorders.  This will help target treatments appropriately and avoid diagnostic labels that are potentially harmful.

http://www.ncbi.nlm.nih.gov/pubmed/24182640

 

Several studies have used blood gene expression in an attempt to identify biomarkers that delineate ME/CFS subtypes.  Jonathan Kerr has spearheaded many of these studies and in September published a paper in the Journal of Clinical Pathology titled, “Use of single-nucleotide polymorphisms (SNPs) to distinguish gene expression subtypes of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)”.(2) Kerr had previously identified 8 ME/CFS subtypes with different gene expression profiles (measuring the message RNA produced from genes.)  In this study, he used the DNA sequence information of these genes to determine if it could be used to identify the same 8 ME/CFS subtypes and distinguish from people with depression and healthy controls.  Kerr wanted to use the DNA genetic sequence rather than the message RNA because message RNA deteriorates quickly, making it challenging to use as a diagnostic biomarker.  Kerr found that only some of the 8 ME/CFS subtypes were identified using the DNA genetic sequence data but that this method was insufficient to reproducibly differentiate subtypes.  There are several reasons why this method did not delineate ME/CFS subtypes including small sample size and sample heterogeneity.  Nonetheless, these results help inform future studies using genomic technologies to develop objective biomarkers for ME/CFS.

http://www.ncbi.nlm.nih.gov/pubmed/25240059

 

Ekua Brenu and a team from Australia published an interesting paper about the potential for a particular type of biomarker  in PLOS ONE this September titled, “High-throughput sequencing of plasma microRNA in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis”.(3)  What makes this study interesting is the use of plasma – the clear liquid component of blood that is relatively easy and noninvasive to collect to detect microRNA.  Unlike message RNA (discussed in the above study) microRNA are a more readily measured because they are short and can evade destruction, making it intriguing for use as a biomarker.  MicroRNAs use their short sequence structure to regulate gene expression (they do not code for proteins as message RNAs do.)  Brenu and team identified 19 microRNAs that were differentially expressed in the plasma of ME/CFS patients compared to controls.  They confirmed significant up-regulation (increased expression) of three of these microRNAs. More ME/CFS patient samples need to be tested – as do diseases with similar symptoms – to determine the diagnostic utility of these plasma biomarkers for ME/CFS.

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0102783

 

 

(1) Mariman A, Delesie L, Tobback E, Hanoulle I, Sermijn E, Vermeir P, Pevernagie D, Vogelaers D. Undiagnosed and comorbid disorders in patients with presumed chronic fatigue syndrome. J Psychosom Res. 2013 Nov;75(5):491-6.

(2) Shimosako N, Kerr JR. Use of single-nucleotide polymorphisms (SNPs) to distinguish gene expression subtypes of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). J Clin Pathol. 2014 Sep 19.

(3) Brenu EW, Ashton KJ, Batovska J, Staines DR, Marshall-Gradisnik SM. High-Throughput Sequencing of Plasma MicroRNA in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. PLoS One. 2014 Sep 19;9(9):e102783.

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  • Maschelle Mashburn

    I had initially thought this effort was truly a thoroughly informed process, representing true ME patients and that the ‘experts’ on this committee had knowledge and extensive history in the field of both treatment of patients and research of ME. The people on this board have been clearly defined as having no knowledge of or experience in treatment and/or research in the ME field. What a farce this study really was, cloaked under blanket reassurances to an entire community of extremely ill people.
    You eliminated people with certain mental health diagnosis…. Does this allow for those that have been MISDIAGNOSED with a mental health problem? Apparently not. That fact in and of itself renders this study nonrepresentative of the ME community. It is important to include, not exclude, patients flippantly diagnosed with mental health issues simply because a medical diagnosis of ME cannot be made by any test to date. Medical agencies have a very long history of lumping every medical condition science and technology hasn’t learned to identify yet as “all in their head” and psychiatric in nature. Take a peek at the history of MS and how patients have been perceived, misdiagnosed, mistreated, and labled as mentally ill for decades before science caught up enough to diagnose thevvery real physical illness MS truly is. The treatment of MS patients prior to advancenents in imaging technology is abhorrent and a crime against humanity. Once a person has been misdiagnosed, they lose ALL credibility with medical professionals. You needed to look for a physical reason for the patient complaints that would put them in the proper category of body systems malfunctioning as that may be part of the physical illness of ME. A diabetic, or head injury patient can appear to be suffering from mental illness when in physical crisis. Endocrine system abnormalities that would fall under the ME cluster of multiple malfunctioning body systems would explain symptom presentation that appears psychological in nature, when in fact there is a physical problem. Have you learned NOTHING from history’s example of the horrors visited upon medically ill people that were labeled mentally ill and turned over to the psychiatrists? They were tortured. Period. Locked away until they died in assylums and sanatoriums? Shame on all of you for repeating history’s mistakes and selling out ME patients that were erroneously labeled, and handed off to the psychiatric community.
    And you excluded everyone with sleep disorders? Can you possibly be more specific here? FMS patients have a very specific sleep disorder, and most experts in the field of ME and FMS now see them as cross over diagnosis, at the very least they now expect ME patients to be comorbidly diagnosed with FMS as well. This comorbid association is so common, it makes perfect sense to consider them very likely to be cross over diagnosis.
    I am so disappointed in how this study was done. Existing research findings were excluded. Experts in the field were not part of this process. Patients were not properly represented. And now I realize the bumbled, deceptive government studies that offered NO transparency, withheld information and findings to the point of being judged to be in violation of FOIA by our courts is this very study, and the people involved in it are the parties respondible for the mockery of a study I have become very aware of, and I am horrified and beyond disappointed. I feel betrayed, and that I’ve been taken for a fool, as Ive been eagerly, prayerfully, waiting on this study to be completed. Liberating and offering hope and validation of the misery I suffer with every day. I pinned my hopes on you. My children need me. That failure to even try to do this right makes what my family is missing out on, and being denied the return of their mother’s health is on YOU. And you lot are the ones behind the P2P meeting coming up, possibly over with now actually?! I have already gone on record as opposing the whole thing. I have signed the petition. You have done an injustice to people that are suffering horribly and had bought your promises to be responsible in this process. You are counting on us to be to sick to be able to sustain a lengthy protest process. You have underestimated our intelligence and dedication to the search for answers and expectation, no, DEMAND for proper medical treatment. We do fatigue as you drag the battle out, but there are many of us, and when one becomes too ill to continue, there is a recently improved patient ready to take the torch for us while we are miserably, horrifically ill from our efforts, taking months, even years to rejoin the battle, and relieve the patients advocating as we recovered. Then they can rest and recover while it’s our turn on the front lines.
    We are ill. We are suffering. It’s not fair, and we want our lives back. Shame on all of you.

    • Robert Whaley

      Well said, Maschelle. In 1977, I had a “flu” with 3 days of high (for me) fever. I had just recovered when my 37 year old wife had the same symptoms. She went overnight from a beautiful and powerful woman, to a bed-ridden, suffering person. To rule out a CFS diagnosis based on a “Yes” answer to the question, “Are you depressed?” is almost laughable. A “No” answer would indicate mental illness. Any human who would not quickly become depressed by months of fevers, chills, traveling arthralgia, mental confusion, severe post-exercise malaise, diarrhea, etc., would indeed be mentally strange, not the other way around. I understand that, in England, definition and treatment of this illness was fought over by the Royal providers of allopathic versus psychiatric care. Since Prozac was helpful to some, the psychiatrists stated that CFS must be a psychiatric illness, and therefore fell into their province, and that they should reap the financial benefits of treating it. The patients’ groups fought this battle for about a decade, I believe, before giving in, just to be able to have Prozac prescribed for them. A term used in the U.K. which more clearly describes my wife’s illness is Post-viral encephalitic syndrome. Another is “myalgic encephalomyelitis”. The thing which bothered my wife the most was to have a doctor say, “So, you feel tired a lot?” (As a German, the thought of being considered lazy, was very offensive to her.)
      Her condition fell in line with the concept of cytokine dysregulation espoused by a California psychiatrist. He said that the hypothalamic area was likely damaged by a viral encephalitis, and that this tended to send heavy amounts of cytokines into limited areas in the body, particularly the axillary lymph nodes. In about 1978, my wife’s left axillary node was the size of a baseball, and was removed surgically. One week later, the R axillary node had swollen to the same size, and was also excised. (I never have understood why surgeons believe in cutting out body parts that are doing their job, like tonsils and adenoids.) At any rate, she has been valiantly struggling for 37 years now. She “paints”, lying down, and using a computer program and tablet. She has just finished several exhibits in Chicago. (See RitaWhaleyart.com for her expressions of hope versus despair.)
      All my best to everyone who is fighting this and other illnesses.
      Bob Whaley

      • Maschelle Mashburn

        My very best wishes to your wife. I am amazed and pleased that a doctor recognized the probability of the endocrine system malfunction, and what caused it! I am suffering from the neurological form of this disease as well. I have areas of paralysis that cause incontinence. My endocrine system is so messed up. My ability to write and speak intelligently is severely affected. Hard to believe I was an Editor for a State Governing Office pre-illness. I have a lymphnode just below the back of my right knee that becomes inflammed and swollen from barely using the leg, or bending my leg at the knee. I was advised that if it was removed, the lymphnode in the groin where that leg meets my torso would then become Symptomatic. He said I can expect foot drop (and a lot of pain) if things are left as they are. Remove it and I will end up with a leg that I have to drag. I choose foot drop and the swelling pain and inflammation behind my knee over the alternative. Your wife paints in bed? I’m so glad she still is able! I took up crocheting small projects. I love creating and working with color.
        I commend you on your dedication to remain with your wife. I know it is hard on family. My fiancée left me when I began having episodes of post exertional collapse and horrific pain for days afterwards. He said he was “too young to be somebody’s caregiver”. Ive always been strong and athletic. I like to do things myself, even if it’s usually a man’s task. I just love fixing things. I am not a quitter or lazy person either. Lying in this bed goes against my nature, but the disease put me here.. Not just wanting to lay down. I hope to one day see the finish of Iditarod Sled Dog race again, and run full out through the quiet town of Nome Alaska at night. The night lit by the moon and stars shining and illuminating the snow covered landscape, the cold winter wind howling in my face as I flew down the sidewalks with the pure joy of feeling my body work and feeling so ALIVE! Maybe one day we will be well. I’m in year 10. Your wife is 37 years ill? I hope she is able to heal soon! You never know, of that much we are all certain.

    • Robert Whaley

      In http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2939140/
      the writers discussed the issue in analysis of having to break down everything into its smallest components, and that sometimes this does not work in such a complex syndrome. While it is indeed necessary to limit the number of variables in analysis, in order to limit the number of possibilities, it must be done very carefully. Breaking down “table salt” into sodium and chlorine in an effort to reduce variables to their simplest forms, would simply not be proper. Attempting to have experimental and control groups ingest the 2 different elements would wreak havoc. The myriad worlds populating and making up our bodies are so symbiotically tied in every way, that it is very difficult to separate variables. In such cases, patients’ subjective observations often have much greater weight than laboratory tests. Unfortunately, as doctors age and tire, they often become like Senior Lab Techs. “Alright, we ran this series of tests, and they all look normal. Therefore, there is nothing really wrong with you, except that you might need to de-stress a little, and stop trying to do so much.” (“Oh, you mean like tying my shoelaces?”)