A Retrospective on the 8th IACFS Conference


by Virginia Teague

This year’s IACFS/ME conference in Fort Lauderdale at the Bahia Mar Resort offered attendees an innovative format focused on the theme of interdisciplinary research and integrative care. The conference began with a two-day session focused on the needs of patients. Patient advocates from international advocacy organizations on CFS, FM, and related illnesses met for the first time to share their ideas in workshops on fundraising fundamentals, empowerment, and media training. Co-hosted by P.A.N.D.O.R.A (Patient Alliance for Neuroendcocrineimmune Disorders Organization for Research and Advocacy, Inc.), these sessions, attended by 350 patients and 222 professionals, provided a unique opportunity for patients to meet and talk with leading international researchers and clinicians.

Tom Sheridan opened the session with insight on how patients and advocates can come together on policy, politics, and press to further understanding and funding for the essential research that will provide long sought answers on causation, markers, and treatment. Quoting Dr. Tony Komaroff, Mr. Sheridan said the debate over whether CFS is actually a disease is over—welcome words for patients, researchers, and clinicians.

Other topics for these sessions include presentations by national and international experts on mold and environmental illness, Lyme Disease, and the role of HHV-6 virus on CFS and fibromyalgia (FM), as well as pediatric CFS, family issues, ergonomics and natural pain relief, sleep disorders, social security concerns, and employment-related legal issues for the disabled and chronically ill.

Of special interest was Montoya’s groundbreaking study on antiviral therapy for CFS patients with elevated antibodies to HHV-6 and EBV, in which 25 CFS patients were treated with the drug valganciclovir, an antiviral often used in treating diseases caused by human herpes viruses. During the past three years, 21 of the patients responded with significant improvement that was sustained even after going off the medication at the end of the treatment regimen, which usually lasted six months. Later this year, with a $1.3 million grant from Roche Pharmaceuticals, Dr. Montoya will replicate his preliminary study among a specific subset of CFS patients who have viral-induceddysfunction of the central nervous system.

This and other research summarized in the first two days of the conference was further expanded on during the three-day professional session, which 169 patients also attended. Each session was introduced by an expert who reviewed methodology and new findings that may hold relevance, followed by presentations on original research, and concluding with a summary by an expert in CFS or FM that emphasized practical clinical applications and priorities for future research. Eliminating separate tracks for clinical and research presentations made it possible for attendees to gain a broader perspective without being forced to choose which presentations they would attend, especially important now when so much new information is changing the way the disease will be diagnosed, evaluated, and treated.

In informal sessions, clinicians also had an opportunity to exchange ideas and share information on what works and what doesn’t with their patients.

On Friday, the professional conference began with a session on various aspects of fatigue, introduced by Watanabe (Osaka, Japan). Tajima’s study using Actigraphy and R-R power spectrum analysis revealed quality of sleep for CFS patients was decreased because of increased wake episodes during the sleep period, leading to a lack of parasympathetic activation during the sleep period and further deterioration of sleep quality. Porter (De Paul University, USA) presented new terms to differentiate five types of fatigue that will help to clarify the amorphous term: wired (over stimulated, tense, agitated), brain fog, molasses fatigue (heaviness), flu fatigue (immunological), and post-exertional. Maloney (Atlanta, Georgia) confirmed the association between CFS and high allostatic load: 56% of CFS patients were found to have high allostatic load (females > males). Moreover, the greater the allostatic load, the greater the prevalence of metabolic syndrome: females with metabolic syndrome were 4 times more likely to have CFS than females without metabolic syndrome. Ciccolella (Stockton, CA) compared serial exercise test results to assess the effects of post-exertional malaise in CFS, and concluded that a single exercise test is insufficient to determine the extent of functional impairment in CFS patients. A second test 24 hours later revealed CFS patients had significantly worse performance than controls, significant support for claims of disability. Nestadt (New York, USA) compared brain metabolites in patients with CFS, those with Generalized Anxiety Disorder, and healthy controls, and discovered a significant proportion of CFS patients had elevated brain ventricular lactate. Marked differences in hippocampal glutamate helped differentiate between CFS patients with and without depression. Those with CFS also had significantly lower N-acetyl-aspartate in the right hippocampus, indicating reduced neuron density or metabolism. These findings support literature suggesting neurobiological distinctions between “pure” CFS and CFS with psychiatric comorbidity. Whistler (Atlanta, Georgia) addressed alterations in apoptosis in post-infection fatigue, and noted the severity of acute infection is related to the likelihood of recovery and affects the fundamental cellular processes. These altered gene expression profiles are manifest in several persistent symptoms of PIFS, indicating many symptoms may be immunologically mediated.

Sessions on sleep, clinical trials, and pain followed. Of special interest was Clauw’s (Michigan, USA) study on pain processing and treatments in FM and related conditions, in which functional MRI studies revealed a lower threshold of pain and all sensory signals for FM patients.

In a session on epidemiology and case definition, the use of modern statistical information coupled with social and genetic epidemiology is providing new ways to evaluate the disease and determine intervention. Epidemiological studies by Reeves et al. (Atlanta, USA) compared those meeting the current criteria for CFS with those having fatigue but insufficient symptoms (ISF) to be diagnosed with CFS and non-fatigued controls in an attempt to subgroup those with CFS according to their level of impairment and symptom severity. Results suggested that a subset of those with ISF do have a similarly severe illness to CFS, but without at least 4 of the case-defining symptoms. A ten-year follow-up by Kang (Washington, DC) of Gulf War veterans suffering from CFS compared to non-Gulf military peers showed that CFS symptoms decreased significantly in the Gulf veterans compared to non-Gulf sufferers. Jason (DePaul, USA) discussed the economic impact of CFS on society in a community-based versus tertiary-based sample, estimating that the direct and indirect costs of CFS in the United States are between 22 and 28.6 billion dollars annually. Kuratsune estimates an annual economic impact in Japan of 10 billion. The incidence of CFS throughout the world is variable, with estimates in the USA of 2-4 per thousand (c. 800,000 to 1 million people). Jason has also studied the rates of CFS in Nigeria, the first community-based study in a developing country, estimating a prevalence of 0.68%, higher than the United States. In Iceland, Lindal found no positive correlation between the prevalence of CFS today, which is similar to findings in U.S. studies, and the 1947 Iceland Disease.

Saturday’s agenda opened with the brain session, introduced by Lange (New Jersey, USA), who pointed out the strong correlation between low tests of cognition and low physical ability in CFS patients. Tests for measurement include neuropsychological testing, brain imaging, and spinal fluid analysis. Quintana et al. (Barcelona, Spain), in a study using Brain SPET quantification, found a congruent pattern in basal conditions: changes after a stress test suggest inhibitory ways in frontal and especially in anterior temporal lobes. A study by Togo (New Jersey, USA) found that CFS patients have a similar response accuracy compared with controls, but have to work longer and harder in high complexity conditions. Depression had an additive effect in CFS, but does not explain the cognitive dysfunction in CFS. Van Ness (Salt Lake City, USA) showed that CFS patients had slower reaction times compared to sedentary controls. This was compounded by 30 minutes exercise; 24 hours later the CFS patients had definite persisting significant deficits (reinforcing the importance of follow-up testing revealed in Ciccolella’s observations in Friday’s fatigue session). Kuratsune summarized the brain function session, emphasizing that brain dysfunction is a key abnormality in understanding the state of chronic fatigue. Osaka studies have hypothesized that neuro-molecular mechanisms lead to chronic fatigue. Brain dysfunction, metabolic abnormalities, reactivation of viruses, immunological abnormalities and HPS abnormalities are being studied. PET is found to be more sensitive than SPECT and has better spatial resolution. Brain acetylcarnitine uptake is abnormal in CFS, and there is reduced binding power of 5HT in the anterior cingulate cortex (correlating with the pain score). A number of abnormalities with reduced responsiveness on fMRI is an essential feature of CFS.

After a session on behavioral health, focusing on ways to help patients cope with their illness and ways to train healthcare providers to respond to their patients, Jason opened the pediatric session, presenting a new pediatric case definition that should allow for more appropriate identification of children and adolescents with CFS. Jason and his international team of researchers have produced two sliding-scale questionnaires designed for children over the age of twelve and parents/guardians of younger children. A special session devoted to selected oral presentations of poster, another new format at this conference.

Saturday’s agenda concluded with the gender session. Evengard (Stockholm, Sweden) gave an overview, noting that the perception that CFS is a “women’s thing” has severely impacted both research and treatment of the disease. The implications of gender were further explored after the evening awards banquet with a panel discussion on politics and women’s health.

Sunday’s agenda opened with a session on genetics/proteomics where considerable strides are being made that may lead to providing biomarkers and creating personalized therapy for those afflicted. Vernon (Atlanta, USA) introduced the session, noting the challenge of CFS is that it is not a single gene disease, and the gene effect may be epigenetic. The Garcia-Fructuoso research group (Barcelona, Spain) emphasized that CFS and FM are two genetically distinguishable illnesses with extremely high specificity in women, suggesting CFS can be as an exclusion diagnosis for FM. Albright (Salt Lake City, USA) used the Utah Population Data Base to explore a genetic contribution to CFS and associated disorders. Using three techniques to look at risks for CFS in relatives, relatedness among CFS patients, and identification of high risk CFS pedigrees, the study found a relative risk of 7.68 in first degree relatives who share many environmental risks and exposures; in second degree relatives this was less of a factor (relative risk 2.54), suggesting a genetic component which might lead to gene identification predisposing to CFS and related conditions. Evengard noted the sex difference observed in CFS indicates a role for estrogen and estrogen receptors for disease development. Baruniuk (Washington, DC) obtained genetic samples from the cerebrospinal fluid of 52 patients with CFS< FM, and GWI and compared with healthy controls. He found 5 proteins predictive of CFS that were absent in the healthy controls. The specific CFS-related proteome suggests a common pathophysiology for these related illnesses, and detection of at least one of the proteins is predictive of CFS. However, the research presented by Aslakson (Atlanta, USA) showed that a more complete enumeration of altered pathways demonstrated distinct and differing altered biological pathways among CFS subjects, further demonstrating the heterogeneity of CFS. Kerr (London, UK) outlined his team’s research. The precise gene signature and metabolic pathways need to be identified. The utility of genomics/proteomics can involve inheritance, pathogenesis, and diagnosis. Molecules of interest include DNA, RNA, and proteins, and there is potential for future study of lipids and glycans. Kerr emphasized that this illness is a result of psycho-neuro-endocrine-immune interaction. Predispositional genes for CFS have been identified that are associated with Q fever and parvovirus B19.

The Japanese Association for Fatigue Sciences coordinated the session that followed on new methods for evaluating fatigue. Sakudo’s study (Osaka, Japan) of Near-Infrared Spectroscopy as a tool for diagnosing CFS showed near perfect dissemination between healthy controls and CFS patients, suggesting that Vis-NIR spectroscopy for sera combined with chemometrics analysis could provide a promising tool to objectively diagnose CFS. Noninvasive approaches to CFS diagnosis using Vis-NIR spectroscopy are now ongoing. Rokutan (Tokushima, Japan) outlined application of DNA chip for fatigue assessment. Only 2.5 ml of blood is required for samples. Nine CFS genes have been identified by PCR and microarray, and the identified genes may be important for subgrouping CFS. He noted stress assessment was particularly important, and may be a powerful tool to differentiate between stress disorder and CFS. Several of the Japanese researchers mentioned D-Ribose, an anti-fatigue substance prescribed in Japan.

Introducing the viral and immune interactions and health session, Glaser (Ohio, USA) focused on symptoms in CFS that are compatible with a viral etiology, suggesting CFS is associated with endogenous latent viruses such as EBV and HHV-6 that may induce immunopathology by synthesizing viral protein in latently infected cells in which the virus genome is only partially expressed. These proteins could then induce immune dysregulation with effects on cytokines and chemokines and/or T cell or NK function. It is difficult to link a specific virus to CFS if the reactivation is incomplete since virus DNA would not be synthesized. Glaser’s team has shown that EBV encoded dUTPase is able to induce immune dysregulation and associated symptoms in mice, suggesting that at least one protein of the EBV early antigen complex can induce immune regulation and may be involved in the pathology of EBV-associated disease. He noted that stress changes cellular immunity. The cellular immune system in older people is also less effective and thus more prone to another virus or stress. Ablashi (Santa Barbara, USA) described assays that can now be used to detect chronic reactivation of HHV-6 and EBV. Studies have shown there is a positive association between HHV-6 and EBV and CFS, and many viruses could be implicated. Rnase-L was also found to correlate with HHV-6 infection in CFS (65% concordance). Antiviral agents may be effective in treating CFS, as Montoya’s initial study using valganciclovir suggests. Fletcher (Miami, USA) compared GWI and CFS immunologically, and found perforin to be low in both illnesses. NK cell function is low in GWI and moderately low in CFS. CD2 and CD26 activation is high in GWI and moderate in CFS. CD26 cleaves neuropeptide-Y (NPY), and there is significantly reduced NPY in plasma in GWI, but not significantly in CFS. Further studies are underway. Gubaxani (Atlanta, USA) detected elevated IL-6 in the resting state in CFS patients, suggesting that proinflammatory cytokines could be contributing to symptoms and thus be a potential cause or effect of CFS. Levine’s research team (New York, USA) tried to determine if there are biologic markers of active, chronic viral infection in CFS patents, and evidence suggests there is a subset of CFS patients suffering from these infections. Serological assays are useful as long as a high threshold is used.

Tony Komaroff provided an overview of summarized the conference’s findings, noting that great strides are being made to find objective biologic evidence for a disease that has been officially defined by a group of symptoms. Specifically, Komaroff highlighted four areas: the importance of the role of the brain, mitochondrial dysfunction and oxidative stress, new molecular markers, and new methods for epidemiology.

In studies on the role of the brain, Komaroff made special note of functional MRI studies done by Clauw on FM patients, and the new available neuroimaging tools discussed by Lange. He also mentioned Nestadt’s study on increased lactic acid in ventricles of the brain and the many studies done by Watanabe and Kuratsune on diminished blood flow, uptake of acetylcarnitine, and diminished serotonin transceptors in special areas of the brain associated with short-term memory, pain recognition, and autonomic function.

Komaroff mentioned another study by Nestadt on mitochondrial dysfunction and oxidative stress, as well as studies by Ciccolella and Van Ness on impaired oxygen and lowered anaerobic threshold, especially in follow-up tests, which he linked to Kuratsune’s study on impaired brain function; at baseline in either exercise or cognitive testing, function attenuates with repeated testing. He noted Whistler’s study on impaired mitochondrial pathways, Baruniuk’s study on proteins in spinal fluid, Kerr’s and Rokutan’s studies on mitochondrial gene expression, as well as studies by Spence and Belch and Cheney and Lerner.

Of special interest was Sakudo’s near perfect results using near-infrared spectroscopy to differentiate between CFS patients and controls, which Komaroff described as “more beautiful than Elizabeth Taylor when she was young on a good day.” Although this study must replicated, Komaroff considers it most promising.

Certain findings from different studies coalesce in a meaningful way, such as Baruniuk’s study on proteins found in the spinal fluid of Gulf War, FM, and CFS patients. Baruniuk’s proteomic study also is significant in revealing how the immune system reacts to stress. Komaroff also mentioned Kerr’s poster presentation on miRNA control expression of genes, suggesting a possible fingerprint that is potentially very impressive.

New approaches to epidemiology are also providing more insight into subgroups. Statistical methods to collect meticulous data on patients without imposing a bias on it reveal subgroups that are also being defined in laboratories. Of particular note, Komaroff believes, is Maloney’s study on allostatic load, which could tell us a lot about CFS. Presentations by Reeves, Jason, and Kuratsune revealed startling figures on the number of people afflicted with CFS and the cost of the illness to society. Quoting Evengard, Komaroff observed, “The invisible has been made visible.”

Komaroff concluded by saying converging evidence from different investigators using different technologies on different patients is telling us where to look to make scientific advances to understand this illness and, ultimately, to fix it.

Virginia Teague is media liason for the 8th IACFS/ME Conference. A freelance editor and writer, she is an adjunct professor, Liberal Arts, Nova Southeastern University, and former managing editor, Journal of Chronic Fatigue Syndrome.

 

A Retrospective on the 8th IACFS Conference


by Virginia Teague

This year’s IACFS/ME conference in Fort Lauderdale at the Bahia Mar Resort offered attendees an innovative format focused on the theme of interdisciplinary research and integrative care. The conference began with a two-day session focused on the needs of patients. Patient advocates from international advocacy organizations on CFS, FM, and related illnesses met for the first time to share their ideas in workshops on fundraising fundamentals, empowerment, and media training. Co-hosted by P.A.N.D.O.R.A (Patient Alliance for Neuroendcocrineimmune Disorders Organization for Research and Advocacy, Inc.), these sessions, attended by 350 patients and 222 professionals, provided a unique opportunity for patients to meet and talk with leading international researchers and clinicians.

Tom Sheridan opened the session with insight on how patients and advocates can come together on policy, politics, and press to further understanding and funding for the essential research that will provide long sought answers on causation, markers, and treatment. Quoting Dr. Tony Komaroff, Mr. Sheridan said the debate over whether CFS is actually a disease is over—welcome words for patients, researchers, and clinicians.

Other topics for these sessions include presentations by national and international experts on mold and environmental illness, Lyme Disease, and the role of HHV-6 virus on CFS and fibromyalgia (FM), as well as pediatric CFS, family issues, ergonomics and natural pain relief, sleep disorders, social security concerns, and employment-related legal issues for the disabled and chronically ill.

Of special interest was Montoya’s groundbreaking study on antiviral therapy for CFS patients with elevated antibodies to HHV-6 and EBV, in which 25 CFS patients were treated with the drug valganciclovir, an antiviral often used in treating diseases caused by human herpes viruses. During the past three years, 21 of the patients responded with significant improvement that was sustained even after going off the medication at the end of the treatment regimen, which usually lasted six months. Later this year, with a $1.3 million grant from Roche Pharmaceuticals, Dr. Montoya will replicate his preliminary study among a specific subset of CFS patients who have viral-induceddysfunction of the central nervous system.

This and other research summarized in the first two days of the conference was further expanded on during the three-day professional session, which 169 patients also attended. Each session was introduced by an expert who reviewed methodology and new findings that may hold relevance, followed by presentations on original research, and concluding with a summary by an expert in CFS or FM that emphasized practical clinical applications and priorities for future research. Eliminating separate tracks for clinical and research presentations made it possible for attendees to gain a broader perspective without being forced to choose which presentations they would attend, especially important now when so much new information is changing the way the disease will be diagnosed, evaluated, and treated.

In informal sessions, clinicians also had an opportunity to exchange ideas and share information on what works and what doesn’t with their patients.

On Friday, the professional conference began with a session on various aspects of fatigue, introduced by Watanabe (Osaka, Japan). Tajima’s study using Actigraphy and R-R power spectrum analysis revealed quality of sleep for CFS patients was decreased because of increased wake episodes during the sleep period, leading to a lack of parasympathetic activation during the sleep period and further deterioration of sleep quality. Porter (De Paul University, USA) presented new terms to differentiate five types of fatigue that will help to clarify the amorphous term: wired (over stimulated, tense, agitated), brain fog, molasses fatigue (heaviness), flu fatigue (immunological), and post-exertional. Maloney (Atlanta, Georgia) confirmed the association between CFS and high allostatic load: 56% of CFS patients were found to have high allostatic load (females > males). Moreover, the greater the allostatic load, the greater the prevalence of metabolic syndrome: females with metabolic syndrome were 4 times more likely to have CFS than females without metabolic syndrome. Ciccolella (Stockton, CA) compared serial exercise test results to assess the effects of post-exertional malaise in CFS, and concluded that a single exercise test is insufficient to determine the extent of functional impairment in CFS patients. A second test 24 hours later revealed CFS patients had significantly worse performance than controls, significant support for claims of disability. Nestadt (New York, USA) compared brain metabolites in patients with CFS, those with Generalized Anxiety Disorder, and healthy controls, and discovered a significant proportion of CFS patients had elevated brain ventricular lactate. Marked differences in hippocampal glutamate helped differentiate between CFS patients with and without depression. Those with CFS also had significantly lower N-acetyl-aspartate in the right hippocampus, indicating reduced neuron density or metabolism. These findings support literature suggesting neurobiological distinctions between “pure” CFS and CFS with psychiatric comorbidity. Whistler (Atlanta, Georgia) addressed alterations in apoptosis in post-infection fatigue, and noted the severity of acute infection is related to the likelihood of recovery and affects the fundamental cellular processes. These altered gene expression profiles are manifest in several persistent symptoms of PIFS, indicating many symptoms may be immunologically mediated.

Sessions on sleep, clinical trials, and pain followed. Of special interest was Clauw’s (Michigan, USA) study on pain processing and treatments in FM and related conditions, in which functional MRI studies revealed a lower threshold of pain and all sensory signals for FM patients.

In a session on epidemiology and case definition, the use of modern statistical information coupled with social and genetic epidemiology is providing new ways to evaluate the disease and determine intervention. Epidemiological studies by Reeves et al. (Atlanta, USA) compared those meeting the current criteria for CFS with those having fatigue but insufficient symptoms (ISF) to be diagnosed with CFS and non-fatigued controls in an attempt to subgroup those with CFS according to their level of impairment and symptom severity. Results suggested that a subset of those with ISF do have a similarly severe illness to CFS, but without at least 4 of the case-defining symptoms. A ten-year follow-up by Kang (Washington, DC) of Gulf War veterans suffering from CFS compared to non-Gulf military peers showed that CFS symptoms decreased significantly in the Gulf veterans compared to non-Gulf sufferers. Jason (DePaul, USA) discussed the economic impact of CFS on society in a community-based versus tertiary-based sample, estimating that the direct and indirect costs of CFS in the United States are between 22 and 28.6 billion dollars annually. Kuratsune estimates an annual economic impact in Japan of 10 billion. The incidence of CFS throughout the world is variable, with estimates in the USA of 2-4 per thousand (c. 800,000 to 1 million people). Jason has also studied the rates of CFS in Nigeria, the first community-based study in a developing country, estimating a prevalence of 0.68%, higher than the United States. In Iceland, Lindal found no positive correlation between the prevalence of CFS today, which is similar to findings in U.S. studies, and the 1947 Iceland Disease.

Saturday’s agenda opened with the brain session, introduced by Lange (New Jersey, USA), who pointed out the strong correlation between low tests of cognition and low physical ability in CFS patients. Tests for measurement include neuropsychological testing, brain imaging, and spinal fluid analysis. Quintana et al. (Barcelona, Spain), in a study using Brain SPET quantification, found a congruent pattern in basal conditions: changes after a stress test suggest inhibitory ways in frontal and especially in anterior temporal lobes. A study by Togo (New Jersey, USA) found that CFS patients have a similar response accuracy compared with controls, but have to work longer and harder in high complexity conditions. Depression had an additive effect in CFS, but does not explain the cognitive dysfunction in CFS. Van Ness (Salt Lake City, USA) showed that CFS patients had slower reaction times compared to sedentary controls. This was compounded by 30 minutes exercise; 24 hours later the CFS patients had definite persisting significant deficits (reinforcing the importance of follow-up testing revealed in Ciccolella’s observations in Friday’s fatigue session). Kuratsune summarized the brain function session, emphasizing that brain dysfunction is a key abnormality in understanding the state of chronic fatigue. Osaka studies have hypothesized that neuro-molecular mechanisms lead to chronic fatigue. Brain dysfunction, metabolic abnormalities, reactivation of viruses, immunological abnormalities and HPS abnormalities are being studied. PET is found to be more sensitive than SPECT and has better spatial resolution. Brain acetylcarnitine uptake is abnormal in CFS, and there is reduced binding power of 5HT in the anterior cingulate cortex (correlating with the pain score). A number of abnormalities with reduced responsiveness on fMRI is an essential feature of CFS.

After a session on behavioral health, focusing on ways to help patients cope with their illness and ways to train healthcare providers to respond to their patients, Jason opened the pediatric session, presenting a new pediatric case definition that should allow for more appropriate identification of children and adolescents with CFS. Jason and his international team of researchers have produced two sliding-scale questionnaires designed for children over the age of twelve and parents/guardians of younger children. A special session devoted to selected oral presentations of poster, another new format at this conference.

Saturday’s agenda concluded with the gender session. Evengard (Stockholm, Sweden) gave an overview, noting that the perception that CFS is a “women’s thing” has severely impacted both research and treatment of the disease. The implications of gender were further explored after the evening awards banquet with a panel discussion on politics and women’s health.

Sunday’s agenda opened with a session on genetics/proteomics where considerable strides are being made that may lead to providing biomarkers and creating personalized therapy for those afflicted. Vernon (Atlanta, USA) introduced the session, noting the challenge of CFS is that it is not a single gene disease, and the gene effect may be epigenetic. The Garcia-Fructuoso research group (Barcelona, Spain) emphasized that CFS and FM are two genetically distinguishable illnesses with extremely high specificity in women, suggesting CFS can be as an exclusion diagnosis for FM. Albright (Salt Lake City, USA) used the Utah Population Data Base to explore a genetic contribution to CFS and associated disorders. Using three techniques to look at risks for CFS in relatives, relatedness among CFS patients, and identification of high risk CFS pedigrees, the study found a relative risk of 7.68 in first degree relatives who share many environmental risks and exposures; in second degree relatives this was less of a factor (relative risk 2.54), suggesting a genetic component which might lead to gene identification predisposing to CFS and related conditions. Evengard noted the sex difference observed in CFS indicates a role for estrogen and estrogen receptors for disease development. Baruniuk (Washington, DC) obtained genetic samples from the cerebrospinal fluid of 52 patients with CFS< FM, and GWI and compared with healthy controls. He found 5 proteins predictive of CFS that were absent in the healthy controls. The specific CFS-related proteome suggests a common pathophysiology for these related illnesses, and detection of at least one of the proteins is predictive of CFS. However, the research presented by Aslakson (Atlanta, USA) showed that a more complete enumeration of altered pathways demonstrated distinct and differing altered biological pathways among CFS subjects, further demonstrating the heterogeneity of CFS. Kerr (London, UK) outlined his team’s research. The precise gene signature and metabolic pathways need to be identified. The utility of genomics/proteomics can involve inheritance, pathogenesis, and diagnosis. Molecules of interest include DNA, RNA, and proteins, and there is potential for future study of lipids and glycans. Kerr emphasized that this illness is a result of psycho-neuro-endocrine-immune interaction. Predispositional genes for CFS have been identified that are associated with Q fever and parvovirus B19.

The Japanese Association for Fatigue Sciences coordinated the session that followed on new methods for evaluating fatigue. Sakudo’s study (Osaka, Japan) of Near-Infrared Spectroscopy as a tool for diagnosing CFS showed near perfect dissemination between healthy controls and CFS patients, suggesting that Vis-NIR spectroscopy for sera combined with chemometrics analysis could provide a promising tool to objectively diagnose CFS. Noninvasive approaches to CFS diagnosis using Vis-NIR spectroscopy are now ongoing. Rokutan (Tokushima, Japan) outlined application of DNA chip for fatigue assessment. Only 2.5 ml of blood is required for samples. Nine CFS genes have been identified by PCR and microarray, and the identified genes may be important for subgrouping CFS. He noted stress assessment was particularly important, and may be a powerful tool to differentiate between stress disorder and CFS. Several of the Japanese researchers mentioned D-Ribose, an anti-fatigue substance prescribed in Japan.

Introducing the viral and immune interactions and health session, Glaser (Ohio, USA) focused on symptoms in CFS that are compatible with a viral etiology, suggesting CFS is associated with endogenous latent viruses such as EBV and HHV-6 that may induce immunopathology by synthesizing viral protein in latently infected cells in which the virus genome is only partially expressed. These proteins could then induce immune dysregulation with effects on cytokines and chemokines and/or T cell or NK function. It is difficult to link a specific virus to CFS if the reactivation is incomplete since virus DNA would not be synthesized. Glaser’s team has shown that EBV encoded dUTPase is able to induce immune dysregulation and associated symptoms in mice, suggesting that at least one protein of the EBV early antigen complex can induce immune regulation and may be involved in the pathology of EBV-associated disease. He noted that stress changes cellular immunity. The cellular immune system in older people is also less effective and thus more prone to another virus or stress. Ablashi (Santa Barbara, USA) described assays that can now be used to detect chronic reactivation of HHV-6 and EBV. Studies have shown there is a positive association between HHV-6 and EBV and CFS, and many viruses could be implicated. Rnase-L was also found to correlate with HHV-6 infection in CFS (65% concordance). Antiviral agents may be effective in treating CFS, as Montoya’s initial study using valganciclovir suggests. Fletcher (Miami, USA) compared GWI and CFS immunologically, and found perforin to be low in both illnesses. NK cell function is low in GWI and moderately low in CFS. CD2 and CD26 activation is high in GWI and moderate in CFS. CD26 cleaves neuropeptide-Y (NPY), and there is significantly reduced NPY in plasma in GWI, but not significantly in CFS. Further studies are underway. Gubaxani (Atlanta, USA) detected elevated IL-6 in the resting state in CFS patients, suggesting that proinflammatory cytokines could be contributing to symptoms and thus be a potential cause or effect of CFS. Levine’s research team (New York, USA) tried to determine if there are biologic markers of active, chronic viral infection in CFS patents, and evidence suggests there is a subset of CFS patients suffering from these infections. Serological assays are useful as long as a high threshold is used.

Tony Komaroff provided an overview of summarized the conference’s findings, noting that great strides are being made to find objective biologic evidence for a disease that has been officially defined by a group of symptoms. Specifically, Komaroff highlighted four areas: the importance of the role of the brain, mitochondrial dysfunction and oxidative stress, new molecular markers, and new methods for epidemiology.

In studies on the role of the brain, Komaroff made special note of functional MRI studies done by Clauw on FM patients, and the new available neuroimaging tools discussed by Lange. He also mentioned Nestadt’s study on increased lactic acid in ventricles of the brain and the many studies done by Watanabe and Kuratsune on diminished blood flow, uptake of acetylcarnitine, and diminished serotonin transceptors in special areas of the brain associated with short-term memory, pain recognition, and autonomic function.

Komaroff mentioned another study by Nestadt on mitochondrial dysfunction and oxidative stress, as well as studies by Ciccolella and Van Ness on impaired oxygen and lowered anaerobic threshold, especially in follow-up tests, which he linked to Kuratsune’s study on impaired brain function; at baseline in either exercise or cognitive testing, function attenuates with repeated testing. He noted Whistler’s study on impaired mitochondrial pathways, Baruniuk’s study on proteins in spinal fluid, Kerr’s and Rokutan’s studies on mitochondrial gene expression, as well as studies by Spence and Belch and Cheney and Lerner.

Of special interest was Sakudo’s near perfect results using near-infrared spectroscopy to differentiate between CFS patients and controls, which Komaroff described as “more beautiful than Elizabeth Taylor when she was young on a good day.” Although this study must replicated, Komaroff considers it most promising.

Certain findings from different studies coalesce in a meaningful way, such as Baruniuk’s study on proteins found in the spinal fluid of Gulf War, FM, and CFS patients. Baruniuk’s proteomic study also is significant in revealing how the immune system reacts to stress. Komaroff also mentioned Kerr’s poster presentation on miRNA control expression of genes, suggesting a possible fingerprint that is potentially very impressive.

New approaches to epidemiology are also providing more insight into subgroups. Statistical methods to collect meticulous data on patients without imposing a bias on it reveal subgroups that are also being defined in laboratories. Of particular note, Komaroff believes, is Maloney’s study on allostatic load, which could tell us a lot about CFS. Presentations by Reeves, Jason, and Kuratsune revealed startling figures on the number of people afflicted with CFS and the cost of the illness to society. Quoting Evengard, Komaroff observed, “The invisible has been made visible.”

Komaroff concluded by saying converging evidence from different investigators using different technologies on different patients is telling us where to look to make scientific advances to understand this illness and, ultimately, to fix it.

Virginia Teague is media liason for the 8th IACFS/ME Conference. A freelance editor and writer, she is an adjunct professor, Liberal Arts, Nova Southeastern University, and former managing editor, Journal of Chronic Fatigue Syndrome.