Increased d-lactic Acid intestinal bacteria in patients with chronic fatigue syndrome

Abstract:

Patients with chronic fatigue syndrome (CFS) are affected by symptoms of cognitive dysfunction and neurological impairment, the cause of which has yet to be elucidated. However, these symptoms are strikingly similar to those of patients presented with D-lactic acidosis.

A significant increase of Gram positive facultative anaerobic faecal microorganisms in 108 CFS patients as compared to 177 control subjects (p<0.01) is presented in this report. The viable count of D-lactic acid producing Enterococcus and Streptococcus spp. in the faecal samples from the CFS group (3.5 x 10(7) cfu/L and 9.8 x 10(7) cfu/L respectively) were significantly higher than those for the control group (5.0 x 10(6) cfu/L and 8.9 x 10(4) cfu/L respectively). Analysis of exometabolic profiles of Enterococcus faecalis and Streptococcus sanguinis, representatives of Enterococcus and Streptococcus spp. respectively, by NMR and HPLC showed that these organisms produced significantly more lactic acid (p<0.01) from (13)C-labeled glucose, than the Gram negative Escherichia coli. Further, both E. faecalis and S. sanguinis secrete more D-lactic acid than E. coli.

This study suggests a probable link between intestinal colonization of Gram positive facultative anaerobic D-lactic acid bacteria and symptom expressions in a subgroup of patients with CFS. Given the fact that this might explain not only neurocognitive dysfunction in CFS patients but also mitochondrial dysfunction, these findings may have important clinical implications.

 

Source: Sheedy JR, Wettenhall RE, Scanlon D, Gooley PR, Lewis DP, McGregor N, Stapleton DI, Butt HL, DE Meirleir KL. Increased d-lactic Acid intestinal bacteria in patients with chronic fatigue syndrome. In Vivo. 2009 Jul-Aug;23(4):621-8. http://iv.iiarjournals.org/content/23/4/621.long (Full article)

 

Clinical impact of B-cell depletion with the anti-CD20 antibody rituximab in chronic fatigue syndrome: a preliminary case series

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) is a disease of unknown aetiology. A patient with CFS had unexpected, marked recovery of CFS symptoms lasting for five months during and after cytotoxic chemotherapy for Hodgkin’s disease. We reasoned that the transient CFS recovery was related to methotrexate treatment, which induces immunomodulation in part through B-cell depletion.

METHODS: In a case series, this patient and two additional CFS patients were B-cell depleted by infusion of the monoclonal anti-CD20 antibody rituximab.

RESULTS: All three had improvement of all CFS symptoms. Patients 1 and 2 had major amelioration from 6 weeks after intervention, patient 3 slight improvement from the same time, but then improved markedly from 26 weeks after intervention. The symptomatic effect lasted until weeks 16, 18 and 44, respectively. At relapse, all were retreated with a single (patient 1) or double rituximab infusion (patients 2 and 3). Again, all three had marked symptom improvement, mimicking their first response. After new symptom recurrence, patients 1 and 2 were given weekly oral methotrexate, patient 1 having effect also from this agent. Patients 1 and 2 were again treated for a third rituximab infusion after new relapse, again with a marked clinical benefit. No unexpected toxicity was seen.

CONCLUSION: These observations suggest that B-lymphocytes are involved in CFS pathogenesis for a subset of patients. Benefit for all CFS symptoms, the delayed symptom relief following B-cell depletion, the kinetics of relapses, and the effect also from methotrexate treatment, provide suggestive evidence that B-cells play a significant role in the ongoing clinical features, and that CFS may be amenable to therapeutic interventions aimed at modifying B-cell number and function. More systematic investigations of this therapeutic strategy, and of its biological basis, are now needed.

 

Source: Fluge Ø, Mella O. Clinical impact of B-cell depletion with the anti-CD20 antibody rituximab in chronic fatigue syndrome: a preliminary case series. BMC Neurol. 2009 Jul 1;9:28. doi: 10.1186/1471-2377-9-28. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2711959/ (Full article)

 

A two-year follow-up study of chronic fatigue syndrome comorbid with psychiatric disorders

Abstract:

AIMS: Chronic fatigue syndrome patients often have comorbid psychiatric disorders such as major depressive disorders and anxiety disorders. However, the outcomes of chronic fatigue syndrome and the comorbid psychiatric disorders and the interactions between them are unknown. Therefore, a two-year prospective follow-up study was carried out on chronic fatigue syndrome patients with comorbid psychiatric disorders.

METHODS: A total of 155 patients who met the Japanese case definition of chronic fatigue syndrome were enrolled in this study. Comorbid psychiatric disorders were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders 4th edition criteria. Patients with comorbid psychiatric disorders received psychiatric treatment in addition to medical therapy for chronic fatigue syndrome. Seventy patients participated in a follow-up interview approximately 24 months later.

RESULTS: Of the 70 patients with chronic fatigue syndrome, 33 patients were diagnosed as having comorbid psychiatric disorders including 18 major depressive disorders. Sixteen patients with psychiatric disorders and eight patients with major depressive disorders did not fulfill the criteria of any psychiatric disorders at the follow up. As for chronic fatigue syndrome, nine out of the 70 patients had recovered at the follow up. There is no significant influence of comorbid psychiatric disorders on the outcome of chronic fatigue syndrome.

CONCLUSIONS: Chronic fatigue syndrome patients have a relatively high prevalence of comorbid psychiatric disorders, especially major depressive disorders. The outcomes of chronic fatigue syndrome and psychiatric disorders are independent. Therefore treatment of comorbid psychiatric disorders is necessary in addition to the medical treatment given for chronic fatigue syndrome.

 

Source: Matsuda Y, Matsui T, Kataoka K, Fukada R, Fukuda S, Kuratsune H, Tajima S, Yamaguti K, Kato YH, Kiriike N. A two-year follow-up study of chronic fatigue syndrome comorbid with psychiatric disorders. Psychiatry Clin Neurosci. 2009 Jun;63(3):365-73. doi: 10.1111/j.1440-1819.2009.01954.x. http://onlinelibrary.wiley.com/doi/10.1111/j.1440-1819.2009.01954.x/full (Full article)

 

Chronic fatigue syndrome after infectious mononucleosis in adolescents

Abstract:

OBJECTIVE: The goal was to characterize prospectively the course and outcome of chronic fatigue syndrome in adolescents during a 2-year period after infectious mononucleosis.

METHODS: A total of 301 adolescents (12-18 years of age) with infectious mononucleosis were identified and screened for nonrecovery 6 months after infectious mononucleosis by using a telephone screening interview. Nonrecovered adolescents underwent a medical evaluation, with follow-up screening 12 and 24 months after infectious mononucleosis. After blind review, final diagnoses of chronic fatigue syndrome at 6, 12, and 24 months were made by using established pediatric criteria.

RESULTS: Six, 12, and 24 months after infectious mononucleosis, 13%, 7%, and 4% of adolescents, respectively, met the criteria for chronic fatigue syndrome. Most individuals recovered with time; only 2 adolescents with chronic fatigue syndrome at 24 months seemed to have recovered or had an explanation for chronic fatigue at 12 months but then were reclassified as having chronic fatigue syndrome at 24 months. All 13 adolescents with chronic fatigue syndrome 24 months after infectious mononucleosis were female and, on average, they reported greater fatigue severity at 12 months. Reported use of steroid therapy during the acute phase of infectious mononucleosis did not increase the risk of developing chronic fatigue syndrome.

CONCLUSIONS: Infectious mononucleosis may be a risk factor for chronic fatigue syndrome in adolescents. Female gender and greater fatigue severity, but not reported steroid use during the acute illness, were associated with the development of chronic fatigue syndrome in adolescents. Additional research is needed to determine other predictors of persistent fatigue after infectious mononucleosis.

 

Source: Katz BZ, Shiraishi Y, Mears CJ, Binns HJ, Taylor R. Chronic fatigue syndrome after infectious mononucleosis in adolescents. Pediatrics. 2009 Jul;124(1):189-93. doi: 10.1542/peds.2008-1879. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2756827/ (Full article)

 

A gene signature for post-infectious chronic fatigue syndrome

Abstract:

BACKGROUND: At present, there are no clinically reliable disease markers for chronic fatigue syndrome. DNA chip microarray technology provides a method for examining the differential expression of mRNA from a large number of genes. Our hypothesis was that a gene expression signature, generated by microarray assays, could help identify genes which are dysregulated in patients with post-infectious CFS and so help identify biomarkers for the condition.

METHODS: Human genome-wide Affymetrix GeneChip arrays (39,000 transcripts derived from 33,000 gene sequences) were used to compare the levels of gene expression in the peripheral blood mononuclear cells of male patients with post-infectious chronic fatigue (n = 8) and male healthy control subjects (n = 7).

RESULTS: Patients and healthy subjects differed significantly in the level of expression of 366 genes. Analysis of the differentially expressed genes indicated functional implications in immune modulation, oxidative stress and apoptosis. Prototype biomarkers were identified on the basis of differential levels of gene expression and possible biological significance.

CONCLUSION: Differential expression of key genes identified in this study offer an insight into the possible mechanism of chronic fatigue following infection. The representative biomarkers identified in this research appear promising as potential biomarkers for diagnosis and treatment.

 

Source: Gow JW, Hagan S, Herzyk P, Cannon C, Behan PO, Chaudhuri A. A gene signature for post-infectious chronic fatigue syndrome. BMC Med Genomics. 2009 Jun 25;2:38. doi: 10.1186/1755-8794-2-38. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2716361/ (Full article)

 

Sensitive, qualitative detection of human herpesvirus-6 and simultaneous differentiation of variants A and B

Abstract:

BACKGROUND: The current limitations of laboratory testing for the detection of human herpesvirus virus 6 (HHV-6) in clinical specimens with low HHV-6 viral loads make this area a priority for further research and development.

OBJECTIVES: To develop and validate a sensitive qualitative assay for simultaneous HHV-6 detection and variant differentiation.

METHODS: We developed a diagnostic procedure, which combines a magnetic bead-based nucleic acid extraction, PCR amplification, and colorimetric microtiter plate identification (MAG-PCR-EIA), for the sensitive detection of HHV-6 and the simultaneous differentiation of HHV-6A and HHV-6B.

RESULTS: Analytic sensitivities of the MAG-PCR-EIA assay were 10 copies per reaction for both HHV-6A and HHV-6B variants, which is equivalent to 20 copies/ml when 1ml of clinical specimen was processed. A proficiency panel containing 11 blinded specimens covering HHV-6A viral loads from 0 to 100,000 copies was tested, and the MAG-PCR-EIA was able to detect the lowest concentration at one copy in 200microl. A panel of 27 urine specimens, which were collected from patients with and without chronic fatigue syndrome, was tested by the MAG-PCR-EIA. HHV-6 was detected in two (HHV-6A) patients who have chromosomally integrated HHV-6A and in one (HHV-6B) patient who was a healthy control and diagnosed as cervical cancer later on. The HHV-6 results did not correlate with results previously determined by HHV-6 antigenemia in urine.

CONCLUSION: With large specimen volumes processed and an additional signal amplification incorporated, the MAG-PCR-EIA provides a sensitive and qualitative system for HHV-6 detection and simultaneous variant differentiation. Clinical relevance of the assay awaits further investigation.

 

Source: Li H, Meng S, Levine SM, Stratton CW, Tang YW. Sensitive, qualitative detection of human herpesvirus-6 and simultaneous differentiation of variants A and B. J Clin Virol. 2009 Sep;46(1):20-3. doi: 10.1016/j.jcv.2009.05.016. Epub 2009 Jun 21. https://www.ncbi.nlm.nih.gov/pubmed/19540801

 

An integrated approach to infer causal associations among gene expression, genotype variation, and disease

Abstract:

Gene expression data and genotype variation data are now capable of providing genome-wide patterns across many different clinical conditions. However, the separate analysis of these data has limitations in elucidating the complex network of gene interactions underlying complex traits, such as common human diseases. More information about the identity of key driver genes of common diseases comes from integrating these two heterogeneous types of data. We developed a two-step procedure to characterize complex diseases by integrating genotype variation data and gene expression data.

The first step elucidates the causal relationship among genetic variation, gene expression level, and disease. Based on the causal relationship determined at the first step, the second step identifies significant gene expression traits whose effects on disease status or whose responses to disease status are modified by the specific genotype variation. For the selected significant genes, a pathway enrichment analysis can be performed to identify the genetic mechanism of a complex disease. The proposed two-step procedure was shown to be an effective method for integrating three different levels of data, i.e., genotype variation, gene expression and disease status.

By applying the proposed procedure to a chronic fatigue syndrome (CFS) dataset, we identified a list of potential causal genes for CFS, and found an evidence for difference in genetic mechanisms of the etiology between CFS without ‘a major depressive disorder with melancholic features’ (CFS) and CFS with ‘a major depressive disorder with melancholic features’ (CFS-MDD/m). Especially, the SNPs within NR3C1 gene were shown to differently influence the susceptibility of developing CFS and CFS-MDD/m through integrative action with gene expression levels.

 

Source: Lee E, Cho S, Kim K, Park T. An integrated approach to infer causal associations among gene expression, genotype variation, and disease. Genomics. 2009 Oct;94(4):269-77. doi: 10.1016/j.ygeno.2009.06.002. Epub 2009 Jun 18. http://www.sciencedirect.com/science/article/pii/S0888754309001347 (Full article)

 

Chronic fatigue syndrome: comments on deconditioning, blood volume and resulting cardiac function

Abstract:

Cardiovascular and autonomic dysfunction have been suggested to underlie the symptoms accompanying CFS (chronic fatigue syndrome). In the present issue of Clinical Science, Hurwitz and co-workers have investigated whether deficits were present in cardiac output and blood volume in a cohort of patients with CFS and if these were linked to illness severity and sedentary lifestyle. The results clearly demonstrate reduced cardiac stroke volume and cardiac output in more severely afflicted patients with CFS, which is primarily attributable to a measurable reduction in blood volume. Similar findings are observed in microgravity and bed rest deconditioning, in forms of orthostatic intolerance and, to a lesser extent, in sedentary people. The circulatory consequences of reduced cardiac output may help to account for many of the findings of the syndrome.

You can read the rest of this comment here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4236909/

 

Source: Stewart JM. Chronic fatigue syndrome: comments on deconditioning, blood volume and resulting cardiac function. Clin Sci (Lond). 2009 Oct 19;118(2):121-3. doi: 10.1042/CS20090327. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4236909/ (Full article)

 

Does varicella-zoster virus infection of the peripheral ganglia cause Chronic Fatigue Syndrome?

Abstract:

This article posits that infection of the peripheral ganglia causes at least some cases of Chronic Fatigue Syndrome (CFS), with a neurotropic herpesvirus, particularly varicella-zoster virus (VZV), as the most likely cause of the infection. Virtually all CFS symptoms could be produced by an infection of the peripheral ganglia, with infection of the autonomic ganglia causing fatigue, postural hypotension, and sleep disturbances, and infection of the sensory ganglia causing sensory symptoms such as chronic pain. Furthermore, infections of the peripheral ganglia are known to cause long-term nerve dysfunction, which would help explain the chronic course of CFS.

Herpesviruses have long been suspected as the cause of CFS; this theory has recently been supported by studies showing that administering antiherpes agents causes substantial improvement in some CFS patients. VZV is known to frequently reactivate in the peripheral ganglia of previously healthy adults and cause sudden, debilitating illness, making it a likely candidate as a cause of CFS. Moreover, many of the symptoms of CFS overlap with those of herpes zoster (shingles), with the exception that painful rash is not one of the symptoms of CFS.

A model is therefore proposed in which CFS is one of the many manifestations of zoster sine herpete; that is, herpes zoster without rash. Furthermore, re-exposure to VZV in the form of chickenpox has become less common in the past few decades; without such re-exposure, immunity to VZV drops, which could explain the increased incidence of CFS. Co-infection with multiple herpesviruses is a possibility, as some CFS patients show signs of infection with other herpesviruses including Epstein-Barr, Cytomegalovirus, and HHV6. These three herpesviruses can attack immune cells, and may therefore promote neurotropic herpesvirus reactivation in the ganglia.

The possibility of VZV as the causal agent in CFS has previously received almost no attention; the possibility that CFS involves infection of the peripheral ganglia has likewise been largely overlooked. This suggests that the search for a viral cause of CFS has been far from exhaustive. Several antiherpes drugs are available, as is a vaccine for VZV; more research into such agents as possible treatments for CFS is urgently needed.

 

Source: Shapiro JS. Does varicella-zoster virus infection of the peripheral ganglia cause Chronic Fatigue Syndrome? Med Hypotheses. 2009 Nov;73(5):728-34. doi: 10.1016/j.mehy.2009.04.043. Epub 2009 Jun 10. https://www.ncbi.nlm.nih.gov/pubmed/19520522

 

Pharmacological treatment of chronic fatigue syndrome: focusing on the role of antidepressants

Abstract:

Chronic fatigue syndrome (CFS) is characterized by chronic, medically unexplained fatigue associated with effort- and stress-intolerance, widespread pain, and impairment in sleep and concentration. Although this constellation of symptoms is highly prevalent in clinical practice, the pathophysiological mechanisms underlying CFS are poorly understood. Current evidence indicates similarities in symptomatology, and possibly etiology and pathogenesis, between CFS and depression. Additionally, there is significant overlap between CFS and the syndrome of fibromyalgia for which antidepressants have shown consistent efficacy.

Data regarding antidepressant treatment of CFS is less copious and less uniformly positive, such that antidepressant use in CFS remains controversial. The current review aims to summarize available data related to antidepressants and other psychotropic agents in CFS to provide a platform for clinicians to make decisions in their treatment of this challenging syndrome.

We identified relevant studies through a PubMed literature search with a combination of the following search terms: ‘fatigue,’ ‘depression,’ ‘antidepressant,’ ‘etiology’ (e.g., ‘neurobiology,’ ‘neurotransmitter,’ ‘genetic’), ‘diagnosis,’ and ‘treatment’ (e.g., ‘antidepressant’ plus the specific name). In addition, studies were also identified via the reference sections of retrieved articles. The authors thoroughly reviewed major findings from the scanned literatures and eventually synthesized them, providing summary, interpretation, and future directions.

 

Source: Pae CU, Marks DM, Patkar AA, Masand PS, Luyten P, Serretti A. Pharmacological treatment of chronic fatigue syndrome: focusing on the role of antidepressants. Expert Opin Pharmacother. 2009 Jul;10(10):1561-70. Doi: 10.1517/14656560902988510. https://www.ncbi.nlm.nih.gov/pubmed/19514866