Documented evidence of inflammation in ME/CFS Margaret Williams 30th November 2010 Note: although most of the following information is included in Magical Medicine: how to make a disease disappear (http://www.meactionuk.org.uk/magical-medicine.htm), it is presented here as a short 5 page article for ease of access. It may be instructive to consider how the information below has been so consistently ignored by the Wessely School during the 25 years of Professor Peter Whites celebrated Fatigue Service and what impact if any this information will have on the PACE Trial results and on the Principal Investigators consequent recommendations for cognitive restructuring interventions. Some illustrations of published evidence of inflammation in ME/CFS patients include the following: 1955 In this outbreak of ME in Adelaide, Australia, an agent was repeatedly transmitted to monkeys; when the monkeys were killed, microscopically, infiltration of nerve roots with lymphocytes and mononuclear cells was seen and some of the nerve fibres showed patchy damage in the myelin sheaths and axon swellings consistent with neurological involvement. In these monkeys, there were widespread changes involving the dorsal root ganglia, cervical and lumbar nerve roots and peripheral nerves. Perivascular collars of lymphocytes and plasma cells were in the cerebral cortex, brainstem and cerebellum, spinal cord and around blood vessels to nerve roots (Pellew RAA, Miles JAR; Med J Aust:1955:2:13:480-482, cited by J Gordon Parish; Postgraduate Medical Journal 1978:54:711-717). This is particularly significant, given the autopsy evidence presented at the Royal Society of Medicine meeting in the series Medicine and me on 11th July 2009 by Dr Abhijit Chaudhuri, where he showed slides of inflammation of the dorsal root ganglia in three ME/CFS patients. 1970 Innes reported isolation of Coxsackie B2 virus from the cerebrospinal fluid: The isolation of an enterovirus from the cerebrospinal fluid in the fourth month is in itself remarkable (Innes SGB; Lancet:1970:969-971). 1992 Neurologic symptoms, MRI findings, and lymphocyte phenotyping studies suggest that the patients may have been experiencing a chronic, immunologically mediated inflammatory process of the central nervous system (Buchwald, Cheney, Peterson D, Komaroff, Gallo et al; Ann Int Med: 1992:116:103-113). 1994 As with any chronic inflammatory condition affecting the central nervous system, the T2-bright foci on MRI in (ME)CFS may represent a perivascular cellular infiltrate and/or reactive demyelination of the surrounding white matter. Alternatively, these abnormalities may reflect the results of a vasculopathy specifically involving the small vessels of the cerebral white matter. Specifically, on the basis of our observations, the white matter abnormalities seen on MRI images may represent foci of gliosis or chronic demyelination, which appear to be irreversible (Schwartz RE et al; Am J Roentgenology:1994:162:935-941). 1997 It is now evident that this illness is not simply an imaginary one, nor the result of anxiously amplifying normal bodily sensations. Substantial objective evidence of abnormalities in the central nervous system is now available. Magnetic resonance imaging has revealed punctate areas of high signal in the white matter more often in patients with (ME)CFS than in healthy controls. They may represent areas of inflammation or demyelination (Komaroff AL. JAMA:1997:278:14:1179-1184). 2004 These findings are consistent with an activated inflammatory response. Shockingly, the mean QOL (quality of life) scores as regards limitations on physical functioning were very, very low, similar to those found in people with AIDS and multiple sclerosis (Advances in biomedical understanding of ME. Neil Abbot. Vance Spence. InterAction May 2004). 2006 (ME)CFS is a poorly defined medical condition which involves inflammatory and immune activation. The Type I interferon antiviral pathway has been repeatedly shown to be activated in the most afflicted patients. An abnormal truncated form of ribonuclease L (37-kDa RNase L) is also found in (ME)CFS patients and this protein has been proposed as a biological marker for (ME)CFS. The levels of this abnormal protein have been significantly correlated to the extent of inflammatory symptoms displayed by (ME)CFS patients. (Our) results suggest that chronic inflammation due to excess nitric oxide plays a role in (ME)CFS and that the normal resolution of the inflammatory process is impaired (M Fremont, K De Meirleir et al. JCFS 2006:13(4):17-28). 2007 A number of symptoms of CFS are linked to inflammatory processes.CFS has been found to be associated with increased immune activation and inflammatory cytokine levels.Our expanded understanding of the genomics of (ME)CFS has reinforced the evidence that the illness is rooted in a biologic pathogenesis that involves cellular dysfunction and interactions between the physiologic stress response and inflammation (Nancy G Klimas and Anne OBrien Koneru ; Curr Rheumatol Rep 2007:9:6:482-487). 2008 In a personal communication, Nancy Klimas, Professor of Medicine at the University of Miami, world-renowned immunologist and expert on ME/CFS, said that 80% of all ME/CFS patients (both severely and not so severely ill) do have evidence of inflammation if the correct scans are employed, and she believes that 100% of ME/CFS patients actually have inflammation. 2008 On 17th December 2008 Emory University School of Medicine issued a press release by Kathi Baker: A new study conducted by researchers from Emory University and the Centres for Disease Control and Prevention (CDC) shows that individuals with (ME)CFS have increased blood levels of the inflammatory chemicals known to increase risk for developing illnesses ranging from cardiovascular disease and dementia to diabetes and cancer. We dont know where the increased inflammation is coming from in patients with (ME)CFS symptoms in our study, and although depression has been associated with increased inflammation, in our study it did not account for the increased inflammation in individuals with (ME)CFS (explained Dr Charles L Raison). The researchers found that subjects with (ME)CFS had higher levels of CRP (c-reactive protein) than did well individuals and also had higher scores on an inflammatory factor that included both CRP and white blood cell levels. 2009 In the study to which the above press release relates, the authors stated: The current study examined plasma concentrations of high-sensitivity c-reactive protein (hs-CRP), white blood cell count (WBC) and a combined inflammation factor in a large (457) population-based sample. Log-transformed mean plasma concentrations of hs-CRP were increased in subjects with (ME)CFS when compared to subjects who were well (Charles L Raison et al; Brain, Behaviour and Immunity 2009:23:3:327-337). 2009 Professor M Maes from Belgium reviewed recent findings on inflammatory and oxidative and nitrosative stress pathways and reported: The psychosomatic symptoms experienced by (ME/CFS patients are caused by intracellular inflammation. Symptoms occurring in (ME)CFS have a genuine organic cause, that is activation of peripheral and central IO and NS pathways and gut-derived inflammation (Curr Opin Psychiatry 2009:22(1):75-83). 2009 Professors Mary Ann Fletcher and Nancy Klimas published yet more confirmatory evidence of immune dysfunction and inflammation in the maintenance of ME/CFS: In this study, 10 of 16 cytokines examined showed good to fair promise as biomarkers. However, the cytokine changes observed are likely to be more indicative of immune activation and inflammationMany of the symptoms are inflammatory in nature. Pro-inflammatory cytokines: A significant elevation in the relative amounts of 4 of 5 pro-inflammatory cytokines in peripheral blood plasma of patients with (ME)CFS was found when compared with the controls. In cases, lymphotoxin (LT) was elevated by 257% and IL-6 by 100% over the controls. Anti-inflammatory cytokines: IL-3 was significantly lower in (ME)CFS patients. The probability of chronic inflammation in (ME)CFS patients is supported by the elevation of four members of the pro-inflammatory cytokine cascade , LT, IL-1, IL-1 and IL-6, in the (ME)CFS samples compared to controls. Interleukin-13, associated with inhibitory effects on inflammatory cytokine production, was lower in cases compared to controls. The results from this study support a TH2 shift, pro-inflammatory cytokine up-regulation and down-regulation of important mediators of cytotoxic cell function. (Journal of Translational Medicine 2009:7:96: doi:10.1186/1479-5876-7-96) 2009 In her lecture in November 2009 at the University of Miami, Professor Nancy Klimas said about viruses and ME/CFS that much of the research at Miami and internationally found that the viruses studied all have several things in common: they infect cells of the immune system and the neurological system; they are capable of causing latent infections and they can reactivate under certain conditions. She also said that their early work at Miami in the late 1980s (published in the Journal of Clinical Microbiology in 1989) showed that ME/CFS patients had immune activation and poor anti-viral cell function. She then went on to discuss the importance of the findings of the retrovirus XMRV (evidence of which was published in Science on 8th October 2009), saying that it was very impressive work. She continued: This Science paper was amazing for a number of reasons. First, this team had put together such strong science that they could go for a Science paper. Science is like the Mecca of publication. If you get your stuff in Science, thats the best place you could possibly (get it published). And they dont take just anything and they sure, sure, sure dont take anything unless its extremely well done, validated and tested out. So they took this paper they not only took it, they put it in Science Express. They thought it was so important, they published on a very fast trackThe way (the researchers at the Whittemore Peterson Institute) looked is very sophisticatedThey then tried to find (the virus) in all these other waysthey looked from a whole different angle. Still found it. Backed up and looked from another angle. Still found itthey had five different kinds of ways they looked for this virus. And they were able to find the virus. Thats why Science was so impressedIt is a virus that can infect tissues that arent white blood cellsWeve always thought something like that has to go on in (ME)CFS because you all have some neuro-inflammation. Your brain has a low grade level of inflammation. And you have some inflammation in the tissues that make hormones, particularly in the hypothalamic-pituitary-axis. And this is a virus that infects that type of tissueIts pretty impressive that out of 101 (ME)CFS cases defined by clinical case definition or a research case definition that they found 99 with the virusAnd, oh, by the way, we have a biomarker. Not a small deal. A biomarker the virus itself. No better biomarker than something thats clearly, tightly associated with an illnessSo the conclusion, it really is a big thing. Its a big thingThat work we were already doing plays right into this. All the genomics work and all the immunology work. This is all critical to the better understanding of this illness and how this virus plays into it (with grateful acknowledgement to PANDORA and http://aboutmecfs.org/Rsrch/XMRVKlimas.aspx and http://aboutmecfs.org/Rsrch/XMRVKlimasII.aspx). 2010 On 19th September 2010 in a radio interview (South Florida Spotlite, interviewed by Ron St John), world expert in ME/CFS Professor Nancy Klimas (principal investigator of the National Institute for Healths Centre for Multidisciplinary Studies of (ME)CFS Pathophysiology at the University of Miami) was clear: there is a chronic inflammation, neuro-inflammation, and it upsets the whole balance of your systemsthe patients become terribly ill. The immune system is really cranked up; its a tremendous amount of inflammation. I think that if doctors could get this in their heads that its sort of like lupus or one of these really inflammatory disordersit is that level of inflammation. Theres a tremendous amount of inflammatory stuff going on, and theres a lot of inflammation in the brain itself (http://www.litemiami.com/spotlite/index.aspx) Note on inflammation Following an international meeting on inflammation held in Bordeaux, France, Robert Dantzer et al published a Review entitled Identification and treatment of symptoms associated with inflammation in medically ill patients (Psychoneuroendocrinology 2008:33:18-29). Given the documented evidence of inflammation in ME/CFS, this Review has important implications for people with the disorder. It recommends testing with a standard battery of inflammatory markers in medically ill patients. Quotations that might be relevant for people with ME/CFS include the following: This meeting brought together clinicians and basic scientists with a common interest in understanding inflammation and associated symptoms in medically ill patients (and it) focused on: (a) predominant symptoms associated with inflammation, (b) markers of inflammation at the periphery, (c) possible markers of brain inflammation associated with low-grade peripheral inflammation in humans, (d) animal models of inflammation-associated symptoms, and (e) domains of intervention for controlling inflammation-associated symptoms. The diagnostic tools that are favoured by psychiatrists are clearly not the best ones. As pointed out by Joel Dimsdale (San Diego, CA), the concept of somatisation that is used for characterising symptoms in the absence of any detectable disease is of little operational value, if not misleading. May be reposted.