Tag: Komaroff

Fecal metagenomic profiles in subgroups of patients with myalgic encephalomyelitis/chronic fatigue syndrome

 

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained persistent fatigue, commonly accompanied by cognitive dysfunction, sleeping disturbances, orthostatic intolerance, fever, lymphadenopathy, and irritable bowel syndrome (IBS). The extent to which the gastrointestinal microbiome and peripheral inflammation are associated with ME/CFS remains unclear. We pursued rigorous clinical characterization, fecal bacterial metagenomics, and plasma immune molecule analyses in 50 ME/CFS patients and 50 healthy controls frequency-matched for age, sex, race/ethnicity, geographic site, and season of sampling.

Results: Topological analysis revealed associations between IBS co-morbidity, body mass index, fecal bacterial composition, and bacterial metabolic pathways but not plasma immune molecules. IBS co-morbidity was the strongest driving factor in the separation of topological networks based on bacterial profiles and metabolic pathways. Predictive selection models based on bacterial profiles supported findings from topological analyses indicating that ME/CFS subgroups, defined by IBS status, could be distinguished from control subjects with high predictive accuracy. Bacterial taxa predictive of ME/CFS patients with IBS were distinct from taxa associated with ME/CFS patients without IBS.

Increased abundance of unclassified Alistipes and decreased Faecalibacterium emerged as the top biomarkers of ME/CFS with IBS; while increased unclassified Bacteroides abundance and decreased Bacteroides vulgatus were the top biomarkers of ME/CFS without IBS. Despite findings of differences in bacterial taxa and metabolic pathways defining ME/CFS subgroups, decreased metabolic pathways associated with unsaturated fatty acid biosynthesis and increased atrazine degradation pathways were independent of IBS co-morbidity. Increased vitamin B6 biosynthesis/salvage and pyrimidine ribonucleoside degradation were the top metabolic pathways in ME/CFS without IBS as well as in the total ME/CFS cohort. In ME/CFS subgroups, symptom severity measures including pain, fatigue, and reduced motivation were correlated with the abundance of distinct bacterial taxa and metabolic pathways.

Conclusions: Independent of IBS, ME/CFS is associated with dysbiosis and distinct bacterial metabolic disturbances that may influence disease severity. However, our findings indicate that dysbiotic features that are uniquely ME/CFS-associated may be masked by disturbances arising from the high prevalence of IBS co-morbidity in ME/CFS. These insights may enable more accurate diagnosis and lead to insights that inform the development of specific therapeutic strategies in ME/CFS subgroups.

 

Source: Dorottya Nagy-Szakal, Brent L. Williams, Nischay Mishra, Xiaoyu Che, Bohyun Lee, Lucinda Bateman, Nancy G. Klimas, Anthony L. Komaroff, Susan Levine, Jose G. Montoya, Daniel L. Peterson, Devi Ramanan, Komal Jain, Meredith L. Eddy, Mady Hornig and W. Ian Lipkin. Fecal metagenomic profiles in subgroups of patients with myalgic encephalomyelitis/chronic fatigue syndrome. Microbiome20175:44. DOI: 10.1186/s40168-017-0261-y https://microbiomejournal.biomedcentral.com/articles/10.1186/s40168-017-0261-y#MOESM1 (Full article)

 

CDC Grand Rounds: Chronic Fatigue Syndrome – Advancing Research and Clinical Education

Abstract:

Chronic fatigue syndrome (CFS) is a complex and serious illness that is often misunderstood. Experts have noted that the terminology “chronic fatigue syndrome” can trivialize this illness and stigmatize persons who experience its symptoms (1). The name was coined by a group of clinicians convened by CDC in the late 1980s to develop a research case definition for the illness, which, at the time, was called chronic Epstein-Barr virus syndrome. The name CFS was suggested because of the characteristic persistent fatigue experienced by all those affected and the evidence that acute or reactivated Epstein-Barr virus infection was not associated with many cases (2).

However, the fatigue in this illness is striking and quite distinct from the common fatigue everyone experiences. A variety of other names have been used, including myalgic encephalomyelitis (ME), ME/CFS, chronic fatigue immune dysfunction, and most recently, systemic exertion intolerance disease (3). The lack of agreement about nomenclature need not be an impediment for advancing critically needed research and education. The term ME/CFS will be used in this article.

 

Source: Unger ER, Lin JS, Brimmer DJ, Lapp CW, Komaroff AL, Nath A, Laird S, Iskander J. CDC Grand Rounds: Chronic Fatigue Syndrome – Advancing Research and Clinical Education. MMWR Morb Mortal Wkly Rep. 2016 Dec 30;65(5051):1434-1438. doi: 10.15585/mmwr.mm655051a4. https://www.cdc.gov/mmwr/volumes/65/wr/mm655051a4.htm (Full article)

 

Distinct plasma immune signatures in ME/CFS are present early in the course of illness

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an unexplained incapacitating illness that may affect up to 4 million people in the United States alone. There are no validated laboratory tests for diagnosis or management despite global efforts to find biomarkers of disease. We considered the possibility that inability to identify such biomarkers reflected variations in diagnostic criteria and laboratory methods as well as the timing of sample collection during the course of the illness.

Accordingly, we leveraged two large, multicenter cohort studies of ME/CFS to assess the relationship of immune signatures with diagnosis, illness duration, and other clinical variables. Controls were frequency-matched on key variables known to affect immune status, including season of sampling and geographic site, in addition to age and sex. We report here distinct alterations in plasma immune signatures early in the course of ME/CFS (n = 52) relative to healthy controls (n = 348) that are not present in subjects with longer duration of illness (n = 246).

Analyses based on disease duration revealed that early ME/CFS cases had a prominent activation of both pro- and anti-inflammatory cytokines as well as dissociation of intercytokine regulatory networks. We found a stronger correlation of cytokine alterations with illness duration than with measures of illness severity, suggesting that the immunopathology of ME/CFS is not static. These findings have critical implications for discovery of interventional strategies and early diagnosis of ME/CFS.

 

Source: Hornig M, Montoya JG, Klimas NG, Levine S, Felsenstein D, Bateman L, Peterson DL, Gottschalk CG, Schultz AF, Che X, Eddy ML, Komaroff AL, Lipkin WI. Distinct plasma immune signatures in ME/CFS are present early in the course of illness. Sci Adv. 2015 Feb;1(1). pii: e1400121. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465185/ (Full article)

 

Human endogenous retrovirus-K18 superantigen expression and human herpesvirus-6 and human herpesvirus-7 viral loads in chronic fatigue patients

Abstract:

BACKGROUND: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSIONS: 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.

 

Source: Oakes B, Hoagland-Henefield M, Komaroff AL, Erickson JL, Huber BT. Human endogenous retrovirus-K18 superantigen expression and human herpesvirus-6 and human herpesvirus-7 viral loads in chronic fatigue patients. Clin Infect Dis. 2013 May;56(10):1394-400. doi: 10.1093/cid/cit086. Epub 2013 Feb 13. http://cid.oxfordjournals.org/content/56/10/1394.long (Full article)

 

A multicenter blinded analysis indicates no association between chronic fatigue syndrome/myalgic encephalomyelitis and either xenotropic murine leukemia virus-related virus or polytropic murine leukemia virus

Abstract:

The disabling disorder known as chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) has been linked in two independent studies to infection with xenotropic murine leukemia virus-related virus (XMRV) and polytropic murine leukemia virus (pMLV). Although the associations were not confirmed in subsequent studies by other investigators, patients continue to question the consensus of the scientific community in rejecting the validity of the association. Here we report blinded analysis of peripheral blood from a rigorously characterized, geographically diverse population of 147 patients with CFS/ME and 146 healthy subjects by the investigators describing the original association. This analysis reveals no evidence of either XMRV or pMLV infection. I

MPORTANCE Chronic fatigue syndrome/myalgic encephalomyelitis has an estimated prevalence of 42/10,000 in the United States, with annual direct medical costs of $7 billion. Here, the original investigators who found XMRV and pMLV (polytropic murine leukemia virus) in blood of subjects with this disorder report that this association is not confirmed in a blinded analysis of samples from rigorously characterized subjects. The increasing frequency with which molecular methods are used for pathogen discovery poses new challenges to public health and support of science. It is imperative that strategies be developed to rapidly and coherently address discoveries so that they can be carried forward for translation to clinical medicine or abandoned to focus resource investment more productively. Our study provides a paradigm for pathogen discovery that may be helpful to others working in this field.

 

Source: Alter HJ, Mikovits JA, Switzer WM, Ruscetti FW, Lo SC, Klimas N, Komaroff AL, Montoya JG, Bateman L, Levine S, Peterson D, Levin B, Hanson MR, Genfi A, Bhat M, Zheng H, Wang R, Li B, Hung GC, Lee LL, Sameroff S, Heneine W, Coffin J, Hornig M, Lipkin WI. A multicenter blinded analysis indicates no association between chronic fatigue syndrome/myalgic encephalomyelitis and either xenotropic murine leukemia virus-related virus or polytropic murine leukemia virus. MBio. 2012 Sep 18;3(5). pii: e00266-12. doi: 10.1128/mBio.00266-12. Print 2012. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3448165/ (Full article)

 

Retraction for Lo et al., Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors

MEDICAL SCIENCES Retraction for “Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors,” by Shyh-Ching Lo, Natalia Pripuzova, Bingjie Li, Anthony L. Komaroff, Guo-Chiuan Hung, Richard Wang, and Harvey J. Alter, which appeared in issue 36, September 7, 2010, of Proc Natl Acad Sci USA (107:15874–15879; first published August 23, 2010; 10.1073/pnas.1006901107).

Retraction of: Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors. [Proc Natl Acad Sci U S A. 2010]

 

Source: Lo SC, Pripuzova N, Li B, Komaroff AL, Hung GC, Wang R, Alter HJ. Retraction for Lo et al., Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors. Proc Natl Acad Sci U S A. 2012 Jan 3;109(1):346. doi: 10.1073/pnas.1119641109. Epub 2011 Dec 27. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3252929/ (Full article)

 

Role of infection and neurologic dysfunction in chronic fatigue syndrome

Abstract:

Chronic fatiguing illnesses following well-documented infections and acute “infectious-like” illnesses of uncertain cause have been reported for many decades. Chronic fatigue syndrome (CFS) was first formally defined in 1988. There is considerable evidence that CFS is associated with abnormalities of the central and autonomic nervous systems. There also is evidence linking several infectious agents with CFS, although no agent has been proven to be a cause of the illness.

Most of the infectious agents that have been linked to CFS are able to produce a persistent, often life-long, infection and thus are a constant incitement to the immune system. Most also have been shown to be neuropathogens. The evidence is consistent with the hypothesis that CFS, in some cases, can be triggered and perpetuated by several chronic infections that directly or indirectly affect the nervous system, and that symptoms are a reflection of the immune response to the infection.

© Thieme Medical Publishers.

 

Source: Komaroff AL, Cho TA. Role of infection and neurologic dysfunction in chronic fatigue syndrome. Semin Neurol. 2011 Jul;31(3):325-37. doi: http://dx.doi.org/10.1055/s-0031-1287654. Epub 2011 Sep 30. https://www.ncbi.nlm.nih.gov/pubmed/21964849

 

Failure to confirm XMRV/MLVs in the blood of patients with chronic fatigue syndrome: a multi-laboratory study

Abstract:

Murine leukemia viruses (MLVs), including xenotropic-MLV-related virus (XMRV), have been controversially linked to chronic fatigue syndrome (CFS). To explore this issue in greater depth, we compiled coded replicate samples of blood from 15 subjects previously reported to be XMRV/MLV-positive (14 with CFS) and from 15 healthy donors previously determined to be negative for the viruses. These samples were distributed in a blinded fashion to nine laboratories, which performed assays designed to detect XMRV/MLV nucleic acid, virus replication, and antibody. Only two laboratories reported evidence of XMRV/MLVs; however, replicate sample results showed disagreement, and reactivity was similar among CFS subjects and negative controls. These results indicate that current assays do not reproducibly detect XMRV/MLV in blood samples and that blood donor screening is not warranted.

 

Source: Simmons G, Glynn SA, Komaroff AL, Mikovits JA, Tobler LH, Hackett J Jr, Tang N, Switzer WM, Heneine W, Hewlett IK, Zhao J, Lo SC, Alter HJ, Linnen JM, Gao K, Coffin JM, Kearney MF, Ruscetti FW, Pfost MA, Bethel J, Kleinman S, Holmberg JA, Busch MP; Blood XMRV Scientific Research Working Group (SRWG). Failure to confirm XMRV/MLVs in the blood of patients with chronic fatigue syndrome: a multi-laboratory study. Science. 2011 Nov 11;334(6057):814-7. doi: 10.1126/science.1213841. Epub 2011 Sep 22. Collaborators (25) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3299483/ (Full article)

 

Chronic fatigue syndrome: understanding a complex illness

Abstract:

Chronic fatigue syndrome (CFS) is a debilitating illness that affects many people. It has been marred by controversy, from initial scepticism in the medical community about the existence of the condition itself to continuing disagreements–mainly between some patient advocacy groups on one side, and researchers and physicians on the other–about the name for the illness, its aetiology, its pathophysiology and the effectiveness of the few currently available treatments. The role of the CNS in the disease is central in many of these discussions. Nature Reviews Neuroscience asked four scientists involved in CFS research about their views on the condition, its causes and the future of research aimed at improving our understanding of this chronic illness.

 

Source: Holgate ST, Komaroff AL, Mangan D, Wessely S. Chronic fatigue syndrome: understanding a complex illness. Nat Rev Neurosci. 2011 Jul 27;12(9):539-44. doi: 10.1038/nrn3087. https://www.ncbi.nlm.nih.gov/pubmed/21792218

 

EEG spectral coherence data distinguish chronic fatigue syndrome patients from healthy controls and depressed patients–a case control study

Abstract:

BACKGROUND: Previous studies suggest central nervous system involvement in chronic fatigue syndrome (CFS), yet there are no established diagnostic criteria. CFS may be difficult to differentiate from clinical depression. The study’s objective was to determine if spectral coherence, a computational derivative of spectral analysis of the electroencephalogram (EEG), could distinguish patients with CFS from healthy control subjects and not erroneously classify depressed patients as having CFS.

METHODS: This is a study, conducted in an academic medical center electroencephalography laboratory, of 632 subjects: 390 healthy normal controls, 70 patients with carefully defined CFS, 24 with major depression, and 148 with general fatigue. Aside from fatigue, all patients were medically healthy by history and examination. EEGs were obtained and spectral coherences calculated after extensive artifact removal. Principal Components Analysis identified coherence factors and corresponding factor loading patterns. Discriminant analysis determined whether spectral coherence factors could reliably discriminate CFS patients from healthy control subjects without misclassifying depression as CFS.

RESULTS: Analysis of EEG coherence data from a large sample (n = 632) of patients and healthy controls identified 40 factors explaining 55.6% total variance. Factors showed highly significant group differentiation (p < .0004) identifying 89.5% of unmedicated female CFS patients and 92.4% of healthy female controls. Recursive jackknifing showed predictions were stable. A conservative 10-factor discriminant function model was subsequently applied, and also showed highly significant group discrimination (p < .001), accurately classifying 88.9% unmedicated males with CFS, and 82.4% unmedicated male healthy controls. No patient with depression was classified as having CFS. The model was less accurate (73.9%) in identifying CFS patients taking psychoactive medications. Factors involving the temporal lobes were of primary importance.

CONCLUSIONS: EEG spectral coherence analysis identified unmedicated patients with CFS and healthy control subjects without misclassifying depressed patients as CFS, providing evidence that CFS patients demonstrate brain physiology that is not observed in healthy normals or patients with major depression. Studies of new CFS patients and comparison groups are required to determine the possible clinical utility of this test. The results concur with other studies finding neurological abnormalities in CFS, and implicate temporal lobe involvement in CFS pathophysiology.

 

Source: Duffy FH, McAnulty GB, McCreary MC, Cuchural GJ, Komaroff AL. EEG spectral coherence data distinguish chronic fatigue syndrome patients from healthy controls and depressed patients–a case control study. BMC Neurol. 2011 Jul 1;11:82. doi: 10.1186/1471-2377-11-82. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3146818/ (Full article)