Tag: Komaroff

Inflammation correlates with symptoms in chronic fatigue syndrome

It is not unusual for patients who say they are sick to have normal results on standard laboratory testing. The physician often concludes that there is no “real” illness and that the patients’ symptoms likely stem from a psychological disorder. An alternative conclusion, often honored in the breach, is that the standard laboratory tests are measuring the wrong things.

Chronic fatigue syndrome (CFS)―also called myalgic encephalomyelitis/chronic fatigue syndrome―is such an illness. Often, the condition begins suddenly, following an “infectious-like” illness.

For years, patients do not return to full health. The illness waxes and wanes, and at its worst leads patients to be bedridden or unable to leave their homes. A report from the National Academies estimates that CFS affects up to 2.5 million people in the United States and generates direct and indirect expenses of $17–24 billion annually (1). The most widely used case definition (2) consists only of symptoms. This, along with typically normal results on standard laboratory tests, has raised the question of whether there are any “real” objective, biological abnormalities in CFS. In PNAS, Montoya et al. report the latest evidence that there are such abnormalities.

Indeed, research over the past 30 y has discovered pathology involving the central nervous system (CNS) and autonomic nervous system (ANS), energy metabolism (with associated oxidative and nitrosative stress), and the immune system, as described in a detailed review (4). This Commentary will briefly summarize the evidence, providing citations only to work published since this review. I will then place the report by Montoya et al. (3) in context, and speculate about the pathophysiology of the illness.

Source: Anthony Komaroff. Inflammation correlates with symptoms in chronic fatigue syndrome. PNAS  2017 ; published ahead of print August 15, 2017 doi: 10.1073/pnas.1712475114  http://www.pnas.org/content/early/2017/08/14/1712475114.extract

Incidence of myalgic encephalomyelitis/chronic fatigue syndrome in a large prospective cohort of U.S. nurses

Abstract:

Background: The incidence of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), the rates of both under-diagnosis and over-diagnosis, and the nature of the onset of the condition have not been assessed in large studies of health professionals.

Purpose: To determine the cumulative incidence of ME/CFS in a large population of health professionals, to examine the nature of the onset of the illness, and to estimate the frequency of both over-diagnosis and under-diagnosis of ME/CFS.

Methods: We sent an email questionnaire to participants in the Nurses’ Health Study II (NHS II), a large prospective cohort of female nurses. Forty-two thousand three hundred and ninety-four women completed the questionnaire, which included the 1994 Centers for Disease Control and Prevention (CDC) criteria for ME/CFS.

Results: One-hundred and two women (240 per 100,000 surveyed) developed an illness that met criteria for ME/CFS between 1989 and 2009. The onset of ME/CFS was gradual in 40.6%, sudden (following flu-like illness or other precipitating events) in 18.8%, followed emotional or physical trauma in 32.3%, and was uncertain in the rest. Under-diagnosis was common: only 15 (15%) of the women who met criteria for ME/CFS reported having been diagnosed. Over-diagnosis also was common: four times as many subjects had been diagnosed with ME/CFS by community doctors as actually met criteria. The distribution of symptoms was not different in comparing cases with a sudden onset to those with a gradual onset.

Conclusions: In this large cohort of female nurses, we found a low cumulative incidence of ME/CFS. Over-diagnosis and under-diagnosis were high, even in this medically sophisticated population.

Source: Natalia Palacios, Kathryn C. Fitzgerald, Anthony L. Komaroff & Alberto Ascherio. Incidence of myalgic encephalomyelitis/chronic fatigue syndrome in a large prospective cohort of U.S. nurses .Fatigue: Biomedicine, Health & Behavior. Pages 1-8 Received 08 Mar 2017, Accepted 24 Apr 2017, Published online: 18 May 2017. http://www.tandfonline.com/doi/full/10.1080/21641846.2017.1323576

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