Chronic Fatigue Syndrome Cases Research Articles

Integrated causal inference modeling uncovers novel causal factors and potential therapeutic targets of Qingjin Yiqi granules for chronic fatigue syndrome

Objective: Chronic fatigue syndrome (CFS) is a prevalent symptom of post-coronavirus disease 2019 (COVID-19) and is associated with unclear disease mechanisms. The herbal medicine Qingjin Yiqi granules (QJYQ) constitute a clinically approved formula for treating post-COVID-19; however, its potential as a drug target for treating CFS remains largely unknown. This study aimed to identify novel causal factors for CFS and elucidate the potential targets and pharmacological mechanisms of action of QJYQ in treating CFS. Methods: This prospective cohort analysis included 4,212 adults aged ≥65 years who were followed up for 7 years with 435 incident CFS cases. Causal modeling and multivariate logistic regression analysis were performed to identify the potential causal determinants of CFS. A proteome-wide, two-sample Mendelian randomization (MR) analysis was employed to explore the proteins associated with the identified causal factors of CFS, which may serve as potential drug targets. Furthermore, we performed a virtual screening analysis to assess the binding affinity between the bioactive compounds in QJYQ and CFS-associated proteins. Results: Among 4,212 participants (47.5% men) with a median age of 69 years (interquartile range: 69–70 years) enrolled in 2004, 435 developed CFS by 2011. Causal graph analysis with multivariate logistic regression identified frequent cough (odds ratio: 1.74, 95% confidence interval [CI]: 1.15–2.63) and insomnia (odds ratio: 2.59, 95% CI: 1.77–3.79) as novel causal factors of CFS. Proteome-wide MR analysis revealed that the upregulation of endothelial cell-selective adhesion molecule (ESAM) was causally linked to both chronic cough (odds ratio: 1.019, 95% CI: 1.012–1.026, P = 2.75 e−05) and insomnia (odds ratio: 1.015, 95% CI: 1.008–1.022, P = 4.40 e−08) in CFS. The major bioactive compounds of QJYQ, ginsenoside Rb2 (docking score: −6.03) and RG4 (docking score: −6.15), bound to ESAM with high affinity based on virtual screening. Conclusions: Our integrated analytical framework combining epidemiological, genetic, and in silico data provides a novel strategy for elucidating complex disease mechanisms, such as CFS, and informing models of action of traditional Chinese medicines, such as QJYQ. Further validation in animal models is warranted to confirm the potential pharmacological effects of QJYQ on ESAM and as a treatment for CFS.

A-303 Validation of a Quantitative and Qualitative Molecular Test for the Detection of Epstein-Barr Virus by Real-Time qPCR

Abstract Background The Epstein-Barr virus (EBV, HHV-4) is a human virus of the Herpesviridae family, mainly associated with infectious mononucleosis in adolescence, but it can also be related to other tumors. About 90% of the world's population has been infected by this virus, although the vast majority of these people are asymptomatic. In immunocompromised individuals, such as transplant recipients and HIV-infected patients, high EBV replication is a major predisposing factor to the development of a wide range of B-cell lymphoproliferative disorders such as Burkitt's lymphoma, nasopharyngeal carcinoma, Hodgkin's and non-Hodgkin lymphoma. Early detection of EBV is crucial for the effective management of patients on immunosuppressive therapy after transplantation and immunoproliferative disease. EBV-related diseases, such as in suspected cases of chronic fatigue syndrome and after transplants can be identified by EBV-DNA quantification. Molecular assays, such as Real Time qPCR, have high sensitivity and specificity and are a useful tool for the early diagnosis of EBV infection. This assay differentiates healthy carriers, with low levels of viral load, from ill carriers with a high rate of viral replication. In this way, this work aimed to validate and verify the performance of the alinity m EBV assay. Methods To evaluate the molecular detection of the EBV virus, we used the automated EBV alinity m assay (Abbott). Were evaluated 141 samples from the Molecular Genetics routine of the Pardini Group. Of those, 91 samples (63 plasma and 28 cerebrospinal fluid) were previously tested by in-house PCR for qualitative EBV detection and 50 samples (plasma) were previously tested for quantitative EBV detection by Real-Time PCR (Seegene platform). At the end of the tests, the previous qualitative and quantitative results were compared with the Alinity m EBV test results. Results The range of Alinity m EBV assay detection was <20 IU/mL or <1.30 log(IU/mL) to 200 000 000 IU/ml or 8.30 log(IU/ml). For qualitative analysis, the positive agreement was 100% in both plasma (7/7) and cerebrospinal fluid (6/6) samples, with quantification variation from 2.07 to 4.60 Log(IU/mL) and <1 .30 to 6.30 Log(IU/mL), respectively. The negative agreement was 89% (50/56) for plasma samples, with 6 discordant samples between 1.13 to 3.39 Log(IU/mL) and 91% for cerebrospinal fluid samples (21/23), with two disagreements (1.69 and 2.23 Log(IU/mL), considering the results below the detection range of the assay (<20 IU/mL or <1.30 Log (IU/mL)) as negative because they did not clinical relevance. In quantitative analysis, the negative agreement between comparative methodology (Seegene platform) was 81.0% (33/42), considering as discordant only the samples with a quantifiable detected result. Discordant samples detected by Alinity—and not detected by Seegene platform—presented quantification between 21–791 IU/mL, indicating greater sensitivity of the analyzed methodology. Positive agreement was 100% (5/5). Conclusion The Alinity m EBV Assay demonstrated good performance for molecular detection of EBV. This test can be used as an important tool for clinicians to identify patients with infection, especially in immunosuppressed cases that require a fast, accurate, and reliable diagnosis.

The putative glymphatic signature of chronic fatigue syndrome: A new view on the disease pathogenesis and therapy

The underlying pathophysiology of chronic fatigue syndrome remains incompletely understood and there are no curative treatments for this disorder at present. However, increasing neuroimaging evidence indicates that functional and structural abnormalities exist in the brains of chronic fatigue syndrome patients, suggesting that the central nervous system is involved in this disorder and that at least some chronic fatigue syndrome patients may have an underlying neurological basis for their illness. In the present paper, we speculate that glymphatic dysfunction, causing toxic build up within the central nervous system, may be responsible for at least some cases of chronic fatigue syndrome. We further postulate that cerebrospinal fluid diversion such as lumboperitoneal shunting may be beneficial to this subgroup of patients by restoring glymphatic transport and waste removal from the brain. Although recent evidence indicates that at least some chronic fatigue syndrome patients may benefit from cerebrospinal fluid drainage, further studies are needed to confirm this finding and to determine whether this can be attributed to enhancement of glymphatic fluid flow and interstitial fluid clearance. If confirmed, this could offer promising avenues for the future treatment of chronic fatigue syndrome. Clearly, given the relative invasive nature of cerebrospinal fluid diversion, such procedures should be reserved for chronic fatigue syndrome patients who are severely debilitated, or for those with severe headaches. Anyhow, it seems worthwhile to make every effort to identify new therapies for patients who suffer from this devastating disease, especially given that there are currently no effective treatments for this condition.

Changing the name of a syndrome: sympathetic neural hyperalgesia edema syndrome becomes – the increased cellular permeability syndrome

Purpose: To provide examples of other conditions that are improved following treatment with dextroamphetamine sulfate that would not involve hyperalgesia and/or edema. Thus elucidation of such conditions would demonstrate the need to change the name from the sympathetic neural hyperalgesia syndrome to a name that would cover all conditions responding to sympathomimetic amine therapy. Materials and Methods: Cases of chronic fatigue syndrome and various skin and neurologic disorders and temperature regulation conditions are provided as examples of conditions responding well to dextroamphetamine sulfate that do not involve either pain or edema. Results: Examples are provided that show that inherited permeability defects in certain tissues or inherited sympathetic nervous system hypofunction produce symptoms other than pain or swelling yet respond to dextroamphetamine sulfate. Conclusions: Though lacking "pizzazz", the new name given to this condition refers to the main hypothesized defect whether inherited or acquired, and that is increased cellular permeability. Thus, the new name is the increased cellular permeability syndrome in lieu of the sympathetic neural hyperalgesia – edema syndrome which had replaced the name idiopathic edema.

RNA-Seq Analysis of Gene Expression, Viral Pathogen, and B-Cell/T-Cell Receptor Signatures in Complex Chronic Disease.

Chronic fatigue syndrome (CFS) remains poorly understood. Although infections are speculated to trigger the syndrome, a specific infectious agent and underlying pathophysiological mechanism remain elusive. In a previous study, we described similar clinical phenotypes in CFS patients and alternatively diagnosed chronic Lyme syndrome (ADCLS) patients—individuals diagnosed with Lyme disease by testing from private Lyme specialty laboratories but who test negative by reference 2-tiered serologic analysis. Here, we performed blinded RNA-seq analysis of whole blood collected from 25 adults diagnosed with CFS and 13 ADCLS patients, comparing these cases to 25 matched controls and 11 patients with well-controlled systemic lupus erythematosus (SLE). Samples were collected at patient enrollment and not during acute symptom flares. RNA-seq data were used to study host gene expression, B-cell/T-cell receptor profiles (BCR/TCR), and potential viral infections. No differentially expressed genes (DEGs) were found to be significant when CFS or ADCLS cases were compared to controls. Forty-two DEGs were found when SLE cases were compared to controls, consistent with activation of interferon signaling pathways associated with SLE disease. BCR/TCR repertoire analysis did not show significant differences between CFS and controls or ADCLS and controls. Finally, viral sequences corresponding to anelloviruses, human pegivirus 1, herpesviruses, and papillomaviruses were detected in RNA-seq data, but proportions were similar (P = .73) across all genus-level taxonomic categories. Our observations do not support a theory of transcriptionally mediated immune cell dysregulation in CFS and ADCLS, at least outside of periods of acute symptom flares.

Mortality of people with chronic fatigue syndrome: a retrospective cohort study in England and Wales from the South London and Maudsley NHS Foundation Trust Biomedical Research Centre (SLaM BRC) Clinical Record Interactive Search (CRIS) Register.

Mortality associated with chronic fatigue syndrome is uncertain. We investigated mortality in individuals diagnosed with chronic fatigue syndrome in secondary and tertiary care using data from the South London and Maudsley NHS Foundation Trust Biomedical Research Centre (SLaM BRC) Clinical Record Interactive Search (CRIS) register. We calculated standardised mortality ratios (SMRs) for all-cause, suicide-specific, and cancer-specific mortality for a 7-year observation period using the number of deaths observed in SLaM records compared with age-specific and sex-specific mortality statistics for England and Wales. Study participants were included if they had had contact with the chronic fatigue service (referral, discharge, or case note entry) and received a diagnosis of chronic fatigue syndrome. We identified 2147 cases of chronic fatigue syndrome from CRIS and 17 deaths from Jan 1, 2007, to Dec 31, 2013. 1533 patients were women of whom 11 died, and 614 were men of whom six died. There was no significant difference in age-standardised and sex-standardised mortality ratios (SMRs) for all-cause mortality (SMR 1·14, 95% CI 0·65-1·85; p=0·67) or cancer-specific mortality (1·39, 0·60-2·73; p=0·45) in patients with chronic fatigue syndrome when compared with the general population in England and Wales. This remained the case when deaths from suicide were removed from the analysis. There was a significant increase in suicide-specific mortality (SMR 6·85, 95% CI 2·22-15·98; p=0·002). We did not note increased all-cause mortality in people with chronic fatigue syndrome, but our findings show a substantial increase in mortality from suicide. This highlights the need for clinicians to be aware of the increased risk of completed suicide and to assess suicidality adequately in patients with chronic fatigue syndrome. National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London.

Early menopause and other gynecologic risk indicators for chronic fatigue syndrome in women.

This study aims to examine whether gynecologic conditions are associated with chronic fatigue syndrome (CFS). This study includes a subset of 157 women from a population-based case-control study in Georgia, United States, conducted in 2004-2009. Gynecologic history was collected using a self-administered questionnaire. Crude odds ratios (ORs) with 95% CIs and ORs adjusted for body mass index and other covariates, where relevant, were estimated for gynecologic conditions between 84 CFS cases and 73 healthy controls. Cases and controls were of similar age. Women with CFS reported significantly more gynecologic conditions and surgical operations than controls: menopause status (61.9% vs 37.0%; OR, 2.37; 95% CI, 1.21-4.66), earlier mean age at menopause onset (37.6 vs 48.6 y; adjusted OR, 1.22; 95% CI, 1.09-1.36), excessive menstrual bleeding (73.8% vs 42.5%; adjusted OR, 3.33; 95% CI, 1.66-6.70), bleeding between periods (48.8% vs 23.3%; adjusted OR, 3.31; 95% CI, 1.60-6.86), endometriosis (29.8% vs 12.3%; adjusted OR, 3.67; 95% CI, 1.53-8.84), use of noncontraceptive hormonal preparations (57.1% vs 26.0%; adjusted OR, 2.95; 95% CI, 1.36-6.38), nonmenstrual pelvic pain (26.2% vs 2.7%; adjusted OR, 11.98; 95% CI, 2.57-55.81), and gynecologic surgical operation (65.5% vs 31.5%; adjusted OR, 3.33; 95% CI, 1.66-6.67), especially hysterectomy (54.8% vs 19.2%; adjusted OR, 3.23; 95% CI, 1.46-7.17). Hysterectomy and oophorectomy occurred at a significantly younger mean age in the CFS group than in controls and occurred before CFS onset in 71% of women with records of date of surgical operation and date of CFS onset. Menstrual abnormalities, endometriosis, pelvic pain, hysterectomy, and early/surgical menopause are all associated with CFS. Clinicians should be aware of the association between common gynecologic problems and CFS in women. Further work is warranted to determine whether these conditions contribute to the development and/or perpetuation of CFS in some women.

Chronic fatigue syndrome and circulating cytokines: A systematic review.

There has been much interest in the role of the immune system in the pathophysiology of chronic fatigue syndrome (CFS), as CFS may develop following an infection and cytokines are known to induce acute sickness behaviour, with similar symptoms to CFS. Using the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analyses) guidelines, a search was conducted on PubMed, Web of Science, Embase and PsycINFO, for CFS related-terms in combination with cytokine-related terms. Cases had to meet established criteria for CFS and be compared with healthy controls. Papers retrieved were assessed for both inclusionary criteria and quality. 38 papers met the inclusionary criteria. The quality of the studies varied. 77 serum or plasma cytokines were measured without immune stimulation. Cases of CFS had significantly elevated concentrations of transforming growth factor-beta (TGF-β) in five out of eight (63%) studies. No other cytokines were present in abnormal concentrations in the majority of studies, although insufficient data were available for some cytokines. Following physical exercise there were no differences in circulating cytokine levels between cases and controls and exercise made no difference to already elevated TGF-β concentrations. The finding of elevated TGF-β concentration, at biologically relevant levels, needs further exploration, but circulating cytokines do not seem to explain the core characteristic of post-exertional fatigue.

Prevalence, Health Care Utilization, and Costs of Fibromyalgia, Irritable Bowel, and Chronic Fatigue Syndromes in the Military Health System, 2006–2010

We compared prevalence, health care utilization, and costs over time for nonelderly adults diagnosed with fibromyalgia syndrome (FMS), irritable bowel syndrome (IBS), and chronic fatigue syndrome (CFS) in relation to timing of federal approvals for FMS drugs. We used military health care claims from October 2006 to September 2010. Retrospective, multiple-year comparisons were conducted using trend analyses, and time series regression-based generalized linear models. Over 5 years, FMS prevalence rates increased from 0.307% to 0.522%, whereas IBS and CFS prevalence rates remained stable. The largest increase in FMS prevalence occurred between 2007 and 2008. Health care utilization was higher for FMS cases compared to IBS and CFS cases. Over 5 years, the total cost for FMS-related care increased $163.2 million, whereas IBS costs increased $14.9 million and CFS cost increased $3.7 million. Between 2006 and 2010, total pharmacy cost for FMS cases increased from $55 million ($3,641/person) to $96.3 million ($3,557/person). Although cause and effect cannot be established, the advent of federally approved drugs for FMS in concert with pharmaceutical industry marketing of these drugs coincide with the observed changes in prevalence, health care utilization, and costs of FMS relative to IBS and CFS.

A pilot registry of unexplained fatiguing illnesses and chronic fatigue syndrome

BackgroundChronic fatigue syndrome (CFS) has no diagnostic clinical signs or biomarkers, so diagnosis requires ruling out conditions with similar signs and symptoms. We conducted a pilot registry of unexplained fatiguing illnesses and CFS to determine the feasibility of establishing and operating a registry and implementing an education outreach initiative. The pilot registry was conducted in Bibb County, Georgia. Patient referrals were obtained from healthcare providers who were identified by using various education outreach initiatives. These referrals were later supplemented with self-referrals by members of a local CFS support group. All patients meeting referral criteria were invited to participate in a screening interview to determine eligibility. If patients met registry criteria, they were invited to a one-day clinic for physical and laboratory evaluations. We classified patients based on the 1994 case definition.ResultsWe registered 827 healthcare providers. Forty-two providers referred 88 patients, and 58 patients (66%) completed clinical evaluation. Of the 188 CFS support group members, 53 were self-referred and 46 (87%) completed the clinical evaluation. Of the 104 participants completing evaluation, 36% (n = 37) met the criteria for CFS, 17% (n = 18) had insufficient fatigue or symptoms (ISF), and 47% (n = 49) were found to have exclusionary medical or psychiatric illnesses. Classification varied significantly by type of referral but not by previous history of CFS diagnosis. Healthcare providers referred more patients who were classified as CFS as compared to support group referrals in which more exclusionary conditions were identified. Family practice and internal medicine specialties made the most referrals and had the highest number of CFS cases. We conducted three CME events, held three “Meet and Greet” sessions, visited four large clinical health practices and health departments, mailed five registry newsletters, and conducted in-person office visits as part of education outreach, which contributed to patient referrals.ConclusionsReferrals from healthcare providers and self-referrals from the patient support group were important to registry enrollment. The number of potentially treatable conditions that were identified highlights the need for continued medical management in this population, as well as the limitations of registries formed without clinical examination. Education initiatives were successful in part because of partnerships with local organizations.

Human Endogenous Retrovirus-K18 Superantigen Expression and Human Herpesvirus-6 and Human Herpesvirus-7 Viral Loads in Chronic Fatigue Patients

Chronic fatigue syndrome (CFS) is a complex, heterogeneous disease characterized by debilitating fatigue that is not improved with bed rest and worsens after physical activity or mental exertion. Despite extensive research into a cause of CFS, no definitive etiology has been determined; however, a large percentage of CFS patients note an acute infectious event that triggers their fatigue. Blood and saliva were collected from 39 CFS cases and 9 healthy control subjects. Peripheral blood mononuclear cells (PBMCs) were tested for human endogenous retrovirus-K18 (HERV-K18) env transcripts using a TaqMan quantitative polymerase chain reaction (qPCR). In addition, viral copy number of human herpesvirus-6 (HHV-6) and human herpesvirus-7 (HHV-7) were measured in both saliva and PBMCs using TaqMan qPCRs. Transcript levels and viral copy number were compared to patient CFS symptom severity. HERV-K18 env transcripts were not significantly different between healthy control subjects and CFS patients. Also, HERV-K18 env transcripts did not correlate with HHV-6 viral copy number or HHV-7 viral copy number in either PBMCs or saliva. HHV-6 viral copy number and HHV-7 viral copy number in both PBMCs and saliva were not significantly different between healthy control subjects and CFS patients. HERV-K18 env transcripts, HHV-6 viral copy number, and HHV-7 viral copy number did not correlate with CFS symptom severity. We fail to demonstrate a difference in HERV-K18 env transcripts, HHV-6 viral copy number, and HHV-7 viral copy number between CFS patients and healthy controls. Our data do not support the hypothesis of reactivation of HHV-6 or HHV-7 in CFS.

Prevalence, Incidence, and Classification of Chronic Fatigue Syndrome in Olmsted County, Minnesota, as Estimated Using the Rochester Epidemiology Project

ObjectiveTo estimate the prevalence and incidence of chronic fatigue syndrome in Olmsted County, Minnesota, using the 1994 case definition and describe exclusionary and comorbid conditions observed in patients who presented for evaluation of long-standing fatigue. Patients and MethodsWe conducted a retrospective medical record review of potential cases of chronic fatigue syndrome identified from January 1, 1998, through December 31, 2002, using the Rochester Epidemiology Project, a population-based database. Patients were classified as having chronic fatigue syndrome if the medical record review documented fatigue of 6 months' duration, at least 4 of 8 chronic fatigue syndrome–defining symptoms, and symptoms that interfered with daily work or activities. Patients not meeting all of the criteria were classified as having insufficient/idiopathic fatigue. ResultsWe identified 686 potential patients with chronic fatigue, 2 of whom declined consent for medical record review. Of the remaining 684 patients, 151 (22%) met criteria for chronic fatigue syndrome or insufficient/idiopathic fatigue. The overall prevalence and incidence of chronic fatigue syndrome and insufficient/idiopathic fatigue were 71.34 per 100,000 persons and 13.16 per 100,000 person-years vs 73.70 per 100,000 persons and 13.58 per 100,000 person-years, respectively. The potential cases included 482 patients (70%) who had an exclusionary condition, and almost half the patients who met either criterion had at least one nonexclusionary comorbid condition. ConclusionThe incidence and prevalence of chronic fatigue syndrome and insufficient/idiopathic fatigue are relatively low in Olmsted County. Careful clinical evaluation to identify whether fatigue could be attributed to exclusionary or comorbid conditions rather than chronic fatigue syndrome itself will ensure appropriate assessment for patients without chronic fatigue syndrome.

Up-regulation of TGF-β1 mRNA expression in peripheral blood mononuclear cells of patients with chronic fatigue syndrome

It has been shown that the abnormality in immune cells in chronic fatigue syndrome (CFS) patients is closely associated with the participation of TGF-β. In order to study the relationship between TGF-β1 and CFS, we investigated the mRNA levels of TGF-β1 in peripheral blood mononuclear cells (PBMCs) in patients with CFS. Fluorescent quantitative real time reverse-transcription polymerase chain reaction (FQ-RT-PCR) was performed to test TGF-β1 mRNA expression in PBMCs in 63 cases of CFS, 50 cases of disease controls, and 50 cases of healthy controls. The mean value of TGF-β1 mRNA expression in CFS patients was ΔΔCt=1.17±0.58, which was significantly higher than the disease controls (ΔΔCt=0.07±1.08, df=111, p<0.01) and the healthy controls (ΔΔCt=0.00±1.63, df=111, p<0.01). No significant difference was detected between disease and healthy controls (p>0.05). The expression of TGF-β1 in PBMCs is significantly elevated in patients with CFS. It might be correlated to the pathogenesis of the disease.

From XMRV to HIV-1 and back

Xenotropic MLV-related retrovirus (XMRV) was first reported about 5 years ago in a few cases of prostate cancer, but did not attract much attention until its reported association with a large fraction of chronic fatigue syndrome cases about 2 years ago. The publication of the XMRV-CFS connection created a ripple of excitement and interest in the scientific, medical, and patient communities reminiscent of the reports of the association of another retrovirus—HIV-with AIDS some 25 years previously. Although I was not directly involved in either discovery at the time, I was a very interested observer who had been working with various retroviruses and who subsequently became involved in both HIV and research, and I will offer some observations on the parallels and differences between the two. It is noteworthy, that, within 2 years of the first report, in 1983, of the virus we now call HIV, the key findings were widely replicated by virologists using a variety of different assays. By contrast, most of the results of the paper - isolation of infectious virus from patients, frequent detection of virus in plasma and PBMCs by PCR, detection of antiviral antibodies - remain to be replicated outside of the laboratories that authored the original report despite considerable effort worldwide. HIV is now known as the cause of a global pandemic responsible for large numbers of deaths annually and considerable hardship and economic loss. By contrast, is considered by most virologists to be the consequence of a collection of artifacts originating from endogenous murine leukemia viruses prevalent in laboratory and wild mice. In this talk, I will discuss our recent work that uncovered how these associations arose and how even experienced retrovirologists were misled by the initial reports. There are several related, but distinct, issues that need to be considered. First, various mouse (Mus musculus) subspecies carry over a hundred different endogenous proviruses closely (>90%) related to in their DNA. Second, mice are extremely widespread, as is their DNA, which can be found sporadically on laboratory surfaces, as well as contaminants of common reagents and materials. Sensitive PCR assays can detect XMRV related sequences in DNA from tiny fractions of one cell. To detect such contamination, we developed a more sensitive assay based on mouse IAP sequences present in thousands of copies per cell. Third, although only a few of the endogenous MLV proviruses encode infectious virus, it has been known since the 1970s that some of them can give rise to virus that can infect human tumor lines when passaged through nude mice. Indeed, A virus identical to is produced by the 22RV1 prostate cancer line that was derived in just this way In initial reports, however, did not appear to be sufficiently similar to known proviruses to have been derived this way. However, we have recently shown that this is exactly how it did arise, but not from infection of the precursor CWR22 xenograft with a single virus, but rather with a recombinant between the progeny of two previously undescribed proviruses found in the nude mice used for passage. Since the predicted recombinant is ancestral to all isolates, and cannot have arisen more than once, it must have found its way into many laboratories as the 22Rv1 cell line was distributed worldwide and, by means that remain to be worked out, into clinical samples from CFS patients.

Psychophysical Distress and Alexithymic Traits in Chronic Fatigue Syndrome with and without Comorbid Depression

Patients with chronic fatigue syndrome (CFS) often report a comorbid depressive disorder. Comorbid depression may negatively influence the long-term outcome of CFS therefore it must be correctly diagnosed and treated. The aim of the present study is to provide a clinical and psychometric assessment of CFS patients with and without depressive features. A comparative analysis between 57 CFS subjects (CDC, 1994), 17 of whom with a comorbid depression, and 55 matched healthy volunteers was assessed to evaluate the presence of any psychophysical distress and alexithymic traits, by means of Symptom Checklist-90-R (SCL-90R) and Toronto Alexithymia Scale (TAS-20). The severity of fatigue was also assessed in all CFS patients using the Fatigue Impact Scale (FIS). With regard to psychiatric comorbidity, the SCL-90R scores showed higher levels of somatic complaints in CFS patients than in healthy subjects, whereas augmented depressive and obsessive-compulsive symptoms were observed only in the depressed CFS subgroup. When comparing the TAS-20 scores, we observed a selective impairment in the capacity to identify feelings and emotions, as measured by the Difficulty in Identifying Feelings subscale (DIF), non-depressed CFS patients showing an intermediate score between depressed CFS and healthy controls. Finally, in terms of FIS scores, a statistical trend versus a higher fatigue severity in depressed CFS patients, with respect to non-depressed ones, was observed. In conclusion, comorbid depression in CFS significantly increased the level of psychophysical distress and the severity of alexithymic traits. These findings suggest an urgent need to address and treat depressive disorders in the clinical care of CFS cases, to improve social functioning and quality of life in such patients.

Evidence for a heritable predisposition to Chronic Fatigue Syndrome

BackgroundChronic Fatigue Syndrome (CFS) came to attention in the 1980s, but initial investigations did not find organic causes. Now decades later, the etiology of CFS has yet to be understood, and the role of genetic predisposition in CFS remains controversial. Recent reports of CFS association with the retrovirus xenotropic murine leukemic virus-related virus (XMRV) or other murine leukemia related retroviruses (MLV) might also suggest underlying genetic implications within the host immune system.MethodsWe present analyses of familial clustering of CFS in a computerized genealogical resource linking multiple generations of genealogy data with medical diagnosis data of a large Utah health care system. We compare pair-wise relatedness among cases to expected relatedness in the Utah population, and we estimate risk for CFS for first, second, and third degree relatives of CFS cases.ResultsWe observed significant excess relatedness of CFS cases compared to that expected in this population. Significant excess relatedness was observed for both close (p <0.001) and distant relationships (p = 0.010). We also observed significant excess CFS relative risk among first (2.70, 95% CI: 1.56-4.66), second (2.34, 95% CI: 1.31-4.19), and third degree relatives (1.93, 95% CI: 1.21-3.07).ConclusionsThese analyses provide strong support for a heritable contribution to predisposition to Chronic Fatigue Syndrome. A population of high-risk CFS pedigrees has been identified, the study of which may provide additional understanding.

Adolescent Chronic Fatigue Syndrome: Prevalence, Incidence, and Morbidity

To determine nationwide general practitioner (GP)-diagnosed prevalence and pediatrician-diagnosed incidence rates of adolescent chronic fatigue syndrome (CFS), and to assess CFS morbidity. We collected data from a cross-sectional national sample among GPs and prospective registration of new patients with CFS in all pediatric hospital departments in the Netherlands. Study participants were adolescents aged 10 to 18 years. A representative sample of GPs completed questionnaires on the prevalence of CFS in their adolescent patients. Pediatric hospital departments prospectively reported new cases of CFS in adolescent patients. For every new reported case, a questionnaire was sent to the reporting pediatrician and the reported patient to assess CFS morbidity. Prevalence was estimated through the data from GP questionnaires and incidence was estimated on the basis of cases newly reported by pediatricians from January to December 2008. Prevalence was calculated as 111 per 100 000 adolescents and incidence as 12 per 100 000 adolescents per year. Of newly reported patients with CFS, 91% scored at or above cutoff points for severe fatigue and 93% at or above the cutoff points for physical impairment. Forty-five percent of patients with CFS reported >50% school absence during the previous 6 months. Clinically diagnosed incidence and prevalence rates show that adolescent CFS is uncommon compared with chronic fatigue. The primary adverse impact of CFS is extreme disability associated with considerable school absence.

No association of xenotropic murine leukemia virus-related virus with prostate cancer or chronic fatigue syndrome in Japan

BackgroundThe involvement of xenotropic murine leukemia virus-related virus (XMRV) in prostate cancer (PC) and chronic fatigue syndrome (CFS) is disputed as its reported prevalence ranges from 0% to 25% in PC cases and from 0% to more than 80% in CFS cases. To evaluate the risk of XMRV infection during blood transfusion in Japan, we screened three populations--healthy donors (n = 500), patients with PC (n = 67), and patients with CFS (n = 100)--for antibodies against XMRV proteins in freshly collected blood samples. We also examined blood samples of viral antibody-positive patients with PC and all (both antibody-positive and antibody-negative) patients with CFS for XMRV DNA.ResultsAntibody screening by immunoblot analysis showed that a fraction of the cases (1.6-3.0%) possessed anti-Gag antibodies regardless of their gender or disease condition. Most of these antibodies were highly specific to XMRV Gag capsid protein, but none of the individuals in the three tested populations retained strong antibody responses to multiple XMRV proteins. In the viral antibody-positive PC patients, we occasionally detected XMRV genes in plasma and peripheral blood mononuclear cells but failed to isolate an infectious or full-length XMRV. Further, all CFS patients tested negative for XMRV DNA in peripheral blood mononuclear cells.ConclusionOur data show no solid evidence of XMRV infection in any of the three populations tested, implying that there is no association between the onset of PC or CFS and XMRV infection in Japan. However, the lack of adequate human specimens as a positive control in Ab screening and the limited sample size do not allow us to draw a firm conclusion.

Serologic and PCR testing of persons with chronic fatigue syndrome in the United States shows no association with xenotropic or polytropic murine leukemia virus-related viruses

In 2009, a newly discovered human retrovirus, xenotropic murine leukemia virus (MuLV)-related virus (XMRV), was reported by Lombardi et al. in 67% of persons from the US with chronic fatigue syndrome (CFS) by PCR detection of gag sequences. Although six subsequent studies have been negative for XMRV, CFS was defined more broadly using only the CDC or Oxford criteria and samples from the US were limited in geographic diversity, both potentially reducing the chances of identifying XMRV positive CFS cases. A seventh study recently found polytropic MuLV sequences, but not XMRV, in a high proportion of persons with CFS. Here we tested blood specimens from 45 CFS cases and 42 persons without CFS from over 20 states in the United States for both XMRV and MuLV. The CFS patients all had a minimum of 6 months of post-exertional malaise and a high degree of disability, the same key symptoms described in the Lombardi et al. study. Using highly sensitive and generic DNA and RNA PCR tests, and a new Western blot assay employing purified whole XMRV as antigen, we found no evidence of XMRV or MuLV in all 45 CFS cases and in the 42 persons without CFS. Our findings, together with previous negative reports, do not suggest an association of XMRV or MuLV in the majority of CFS cases.

Fatigue Scales and Chronic Fatigue Syndrome: Issues of Sensitivity and Specificity

Few studies have explored issues of sensitivity and specificity for using the fatigue construct to identify patients meeting chronic fatigue syndrome (CFS) criteria. In this article, we examine the sensitivity and specificity of several fatigue scales that have attempted to define severe fatigue within CFS. Using Receiver Operating Characteristic (ROC) curve analysis, we found most scales and sub-scales had either significant specificity and/or sensitivity problems. However, the post-exertional subscale of the ME/CFS Fatigue Types Questionnaire (Jason, Jessen, et al., 2009) was the most promising in terms of specificity and sensitivity. Among the more traditional fatigue scales, Krupp, LaRocca, Muir-Nash, and Steinberg's (1989) Fatigue Severity Scale had the best ability to differentiate CFS from healthy controls. Selecting questions, scales and cut off points to measure fatigue must be done with extreme care in order to successfully identify CFS cases.