Tag: subgroups

Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome

Abstract:

OBJECTIVES: To determine mRNA expression differences in genes involved in signalling and modulating sensory fatigue, and muscle pain in patients with chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FM) at baseline, and following moderate exercise.

DESIGN: Forty-eight patients with CFS only, or CFS with comorbid FM, 18 patients with FM that did not meet criteria for CFS, and 49 healthy controls underwent moderate exercise (25 min at 70% maximum age-predicted heart rate). Visual-analogue measures of fatigue and pain were taken before, during and after exercise. Blood samples were taken before and 0.5, 8, 24 and 48 h after exercise. Leucocytes were immediately isolated from blood, number coded for blind processing and analyses and flash frozen. Using real-time, quantitative PCR, the amount of mRNA for 13 genes (relative to control genes) involved in sensory, adrenergic and immune functions was compared between groups at baseline and following exercise. Changes in amounts of mRNA were correlated with behavioural measures and functional clinical assessments.

RESULTS: No gene expression changes occurred following exercise in controls. In 71% of patients with CFS, moderate exercise increased most sensory and adrenergic receptor’s and one cytokine gene’s transcription for 48 h. These postexercise increases correlated with behavioural measures of fatigue and pain. In contrast, for the other 29% of patients with CFS, adrenergic α-2A receptor’s transcription was decreased at all time-points after exercise; other genes were not altered. History of orthostatic intolerance was significantly more common in the α-2A decrease subgroup. FM-only patients showed no postexercise alterations in gene expression, but their pre-exercise baseline mRNA for two sensory ion channels and one cytokine were significantly higher than controls.

CONCLUSIONS: At least two subgroups of patients with CFS can be identified by gene expression changes following exercise. The larger subgroup showed increases in mRNA for sensory and adrenergic receptors and a cytokine. The smaller subgroup contained most of the patients with CFS with orthostatic intolerance, showed no postexercise increases in any gene and was defined by decreases in mRNA for α-2A. FM-only patients can be identified by baseline increases in three genes. Postexercise increases for four genes meet published criteria as an objective biomarker for CFS and could be useful in guiding treatment selection for different subgroups.

© 2011 The Association for the Publication of the Journal of Internal Medicine.

 

Source: Light AR, Bateman L, Jo D, Hughen RW, Vanhaitsma TA, White AT, Light KC. Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome. J Intern Med. 2012 Jan;271(1):64-81. doi: 10.1111/j.1365-2796.2011.02405.x. Epub 2011 Jul 13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3175315/ (Full article)

 

A Comparison of Immune Functionality in Viral versus Non-Viral CFS Subtypes

Abstract:

Participants with CFS were grouped into viral and non-viral onset fatigue categories and assessed for differential immunological marker expression. Peripheral Blood Mononuclear Cells were assessed for differential phenotypic expression of surface adherence glycoproteins on circulating lymphocytes. The flow cytometric analysis employed fluorescent monoclonal antibody labeling.

The viral in comparison to the non-viral group demonstrated significant elevations in several Th1 type subsets including: the percentage and number of CD4+ cells, the percentage and number of CD2+CD26+ cells, the percentage and number of CD2+CD4+CD26+ cells, the percentage and number of CD4+ CD26+ cells, and the percentage of Th2 naïve cells (CD4+ CD45RA+CD62L+).

Of the remaining significant findings, the non viral group demonstrated significant elevations in comparison to the viral group for the following Th1 type subsets: the percentage of CD8+ cells, the percentage of T-cytotoxic suppressor cells (CD3+8+), and the percentage and number of Th1 memory cells (CD8+CD45RA-CD62L-).

The viral group demonstrated a pattern of activation that differed from that of the group with a non-viral etiology, as evidenced by an elevated and out of range percentage and number of CD4+ cells, the percentage of CD2+CD26+, and the percentage of Th2 naïve cells (CD4+CD45RA+CD62L+). Both groups demonstrated reduced and out of range Natural Killer Cell Cytotoxicity and percentage of B-1 cells (CD5+CD19).

In addition, both groups demonstrated an elevated and out of range percentage of CD2+CD8+CD26+, percentage of the Th1 memory subset (CD4+CD45RA-CD62L-), the percentage of Th1 memory and naïve cells (CD8+CD45RA-CD62L-, CD8+CD45RA+CD62L-), the percentage and number of Th2 memory cells (CD4+CD45RA-CD62L+), and the percentage of Th2 memory and naïve cells (CD8+CD45RA-CD62L+, CD8+CD45RA+CD62L+).

These findings imply that the homeostatic mechanism responsible for the regulation of the Th1 (cell mediated) and Th2 (humoral) immune responses is disturbed in CFS. The implications of these findings are discussed.

 

Source: Porter N, Lerch A, Jason LA, Sorenson M, Fletcher MA, Herrington J. A Comparison of Immune Functionality in Viral versus Non-Viral CFS Subtypes. J Behav Neurosci Res. 2010 Jun 1;8(2):1-8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951052/ (Full article)

 

Classification of myalgic encephalomyelitis/chronic fatigue syndrome by types of fatigue

Abstract:

Persons with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often complain of fatigue states (eg, postexertional malaise, brain fog) that are qualitatively different than normal, daily fatigue. Given the heterogeneous nature of ME/CFS, it is likely that individuals with this illness experience these fatigue types differently in terms of severity and frequency. It is also possible that meaningful subgroups of patients exist that exhibit different patterns of the fatigue experience. The purpose of this study was to investigate whether individuals with ME/CFS can be classified in a meaningful way according to the different types of fatigue they experience.

One hundred individuals with ME/CFS participated in the study. Individuals that met inclusion criteria were administered the Multiple Fatigue Types Questionnaire (MFTQ), a 5-factor instrument that distinguishes between different types of fatigue. A cluster analysis was used to classify patients into various clusters based on factor subscale scores. Using a 3-factor solution, individuals were classified according to illness severity (low, moderate, severe) across the different fatigue factors.

However, a 5-cluster solution enabled participants with moderate to severe fatigue levels to fall into more differentiated clusters and demonstrate distinct fatigue state patterns. These results suggest that fatigue patterns of individuals with ME/CFS are heterogeneous, and that patients may be classified into meaningful subgroups.

 

Source: Jason LA, Boulton A, Porter NS, Jessen T, Njoku MG, Friedberg F. Classification of myalgic encephalomyelitis/chronic fatigue syndrome by types of fatigue. Behav Med. 2010 Jan-Mar;36(1):24-31. Doi: 10.1080/08964280903521370. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4852700/ (Full article)

 

Hypocapnia is a biological marker for orthostatic intolerance in some patients with chronic fatigue syndrome

Abstract:

CONTEXT: Patients with chronic fatigue syndrome and those with orthostatic intolerance share many symptoms, yet questions exist as to whether CFS patients have physiological evidence of orthostatic intolerance.

OBJECTIVE: To determine if some CFS patients have increased rates of orthostatic hypotension, hypertension, tachycardia, or hypocapnia relative to age-matched controls.

DESIGN: Assess blood pressure, heart rate, respiratory rate, end tidal CO2 and visual analog scales for orthostatic symptoms when supine and when standing for 8 minutes without moving legs.

SETTING: Referral practice and research center.

PARTICIPANTS: 60 women and 15 men with CFS and 36 women and 4 men serving as age matched controls with analyses confined to 62 patients and 35 controls showing either normal orthostatic testing or a physiological abnormal test.

MAIN OUTCOME MEASURES: Orthostatic tachycardia; orthostatic hypotension; orthostatic hypertension; orthostatic hypocapnia or combinations thereof.

RESULTS: CFS patients had higher rates of abnormal tests than controls (53% vs 20%, p < .002), but rates of orthostatic tachycardia, orthostatic hypotension, and orthostatic hypertension did not differ significantly between patients and controls (11.3% vs 5.7%, 6.5% vs 2.9%, 19.4% vs 11.4%, respectively). In contrast, rates of orthostatic hypocapnia were significantly higher in CFS than in controls (20.6% vs 2.9%, p < .02). This CFS group reported significantly more feelings of illness and shortness of breath than either controls or CFS patients with normal physiological tests.

CONCLUSION: A substantial number of CFS patients have orthostatic intolerance in the form of orthostatic hypocapnia. This allows subgrouping of patients with CFS and thus reduces patient pool heterogeneity engendered by use of a clinical case definition.

 

Source: Natelson BH, Intriligator R, Cherniack NS, Chandler HK, Stewart JM. Hypocapnia is a biological marker for orthostatic intolerance in some patients with chronic fatigue syndrome. Dyn Med. 2007 Jan 30;6:2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1796865/ (Full article)

 

Impaired natural immunity, cognitive dysfunction, and physical symptoms in patients with chronic fatigue syndrome: preliminary evidence for a subgroup?

Abstract:

OBJECTIVE: The diagnostic criteria of chronic fatigue syndrome (CFS) define a heterogeneous population composed of several subgroups. Past efforts to identify subgroup markers have met with mixed success. This study was designed to examine natural killer cell activity (NKCA) as a potential subgroup marker by comparing the clinical presentations of CFS patients with and without clinically reduced NKCA.

METHODS: Forty-one female CFS patients were classified into having either low or normal NKCA levels. These subgroups were then compared on objective measures of cognitive functioning and subjective assessments of fatigue, vigor, cognitive impairment, and daytime dysfunction.

RESULTS: Relative to CFS patients in the normal-NKCA subgroup, low-NKCA patients reported less vigor, more daytime dysfunction, and more cognitive impairment. In addition, low-NKCA patients performed less on objective measures of cognitive functioning relative to normal-NKCA patients.

CONCLUSIONS: The results are offered as preliminary evidence in support of using NKCA as an immunological subgroup marker in CFS. Findings are also discussed in terms of known associations between dysregulated immune functions, somatic symptoms, and psychological stress.

 

Source: Siegel SD, Antoni MH, Fletcher MA, Maher K, Segota MC, Klimas N. Impaired natural immunity, cognitive dysfunction, and physical symptoms in patients with chronic fatigue syndrome: preliminary evidence for a subgroup? J Psychosom Res. 2006 Jun;60(6):559-66. https://www.ncbi.nlm.nih.gov/pubmed/16731230

 

Sub-typing CFS patients on the basis of ‘minor’ symptoms

Abstract:

The diagnosis of chronic fatigue syndrome (CFS), an illness characterized by medically unexplained fatigue, depends on a clinical case definition representing one or more pathophysiological mechanisms. To prepare for studies of these mechanisms, this study sought to identify subtypes of CFS.

In 161 women meeting 1994 criteria for CFS, principal components analysis of the 10 ‘minor’ symptoms of CFS produced three factors interpreted to indicate musculoskeletal, infectious and neurological subtypes. Extreme scores on one or more of these factors characterized about 2/3 of the sample. Those characterized by the neurological factor were at increased risk of reduced scores on cognitive tests requiring attention, working memory, long-term memory or rapid performance.

In addition, the neurological subtype was associated with reduced levels of function. Those characterized by the musculoskeletal factor were at increased risk for the diagnosis of fibromyalgia (chronic widespread pain and mechanical allodynia) and reduced physical function. Those characterized by the infectious factor were less likely to evidence co-occurring fibromyalgia, and showed lesser risk of functional impairment.

The prevalence of disability was increased in those with the highest scores on any of the subtypes, as well as in those with high scores on multiple factors. Depression and anxiety, while frequently present, were not more prevalent in any particular subtype, and did not increase with the severity of specific symptom reports. Results suggest that subtypes of CFS may be identified from reports of the minor diagnostic symptoms, and that these subtypes demonstrate construct validity.

 

Source: Janal MN, Ciccone DS, Natelson BH. Sub-typing CFS patients on the basis of ‘minor’ symptoms. Biol Psychol. 2006 Aug;73(2):124-31. Epub 2006 Feb 10. https://www.ncbi.nlm.nih.gov/pubmed/16473456

 

Heterogeneity of serum tryptophan concentration and availability to the brain in patients with the chronic fatigue syndrome

Abstract:

We assessed the serotonin status of patients with the chronic fatigue syndrome (CFS). Tryptophan (Trp) availability to the brain, expressed as the ratio of concentration of serum Trp to the sum of those of its five competitors (CAA), and other parameters of Trp disposition were compared in 23 patients with the CFS and 42 healthy controls.

The serum [free Trp]/[CAA] ratio was 43% higher in CFS patients, due to a 48% higher [free Trp]. [Total Trp] was also significantly higher (by 19%) in CFS patients, and, although the [total Trp]/[CAA] ratio did not differ significantly between the control and patient groups, the difference became significant when the results were co-varied with age and gender. [CAA] was not significantly different between groups, but was significantly lower in females, compared to males, of the CFS patient group.

We have established normal ranges for Trp disposition parameters and propose criteria for defining the serotonin-biosynthetic status in humans. We have provisionally identified two subgroups of CFS patients, one with normal serotonin and the other with a high serotonin status. The relevance of our findings to, and their implications for, the pharmacological and other therapies of the chronic fatigue syndrome are discussed.

 

Source: Badawy AA, Morgan CJ, Llewelyn MB, Albuquerque SR, Farmer A. Heterogeneity of serum tryptophan concentration and availability to the brain in patients with the chronic fatigue syndrome. J Psychopharmacol. 2005 Jul;19(4):385-91. http://www.ncbi.nlm.nih.gov/pubmed/15982993

 

Chronic fatigue syndrome: the need for subtypes

Abstract:

Chronic fatigue syndrome (CFS) is an important condition confronting patients, clinicians, and researchers. This article provides information concerning the need for appropriate diagnosis of CFS subtypes. We first review findings suggesting that CFS is best conceptualized as a separate diagnostic entity rather than as part of a unitary model of functional somatic distress. Next, research involving the case definitions of CFS is reviewed.

Findings suggest that whether a broad or more conservative case definition is employed, and whether clinic or community samples are recruited, these decisions will have a major influence in the types of patients selected. Review of further findings suggests that subtyping individuals with CFS on sociodemographic, functional disability, viral, immune, neuroendocrine, neurology, autonomic, and genetic biomarkers can provide clarification for researchers and clinicians who encounter CFS’ characteristically confusing heterogeneous symptom profiles.

Treatment studies that incorporate subtypes might be particularly helpful in better understanding the pathophysiology of CFS. This review suggests that there is a need for greater diagnostic clarity, and this might be accomplished by subgroups that integrate multiple variables including those in cognitive, emotional, and biological domains.

 

Source: Jason LA, Corradi K, Torres-Harding S, Taylor RR, King C. Chronic fatigue syndrome: the need for subtypes. Neuropsychol Rev. 2005 Mar;15(1):29-58. http://www.ncbi.nlm.nih.gov/pubmed/15929497

 

IgM serum antibodies to Epstein-Barr virus are uniquely present in a subset of patients with the chronic fatigue syndrome

Abstract:

BACKGROUND: A unique subset of patients with chronic fatigue syndrome (CFS) and IgM serum antibodies to cytomegalovirus (HCMV) non-structural gene products p52 and CM2 (UL 44 and UL 57) has been described.

PATIENTS AND METHODS: Fifty-eight CFS patients and 68 non-CFS matched controls were studied. Serum antibodies to EBV viral capsid antigen (VCA) IgM and EBV Early Antigen, diffuse (EA, D) as well HVCMV(V), IgM and IgG; VP (sucrose, density purified V); p52 and CM2 IgM serum antibodies were assayed.

RESULTS: Mean age of CFS patients was 44 years (75% women). Control patients were 9 years older (73% women). Serum EBV VCA IgM positive antibody titers were identified in 33 CFS patients (Group A subset EBV VCA IgM 62.3+/-8.3, neg. <20), but were not present in other CFS patients, (Group B subset EBV VCA IgM 6.8+/-0.7) controls (p<0.0001). EBV VCA IgM titers remained positive in CFS patients from Group A for 24-42 months.

CONCLUSION: Serum antibody to EBV VCA IgM may be a specific diagnostic test for a second subset of CFS patients.

 

Source: Lerner AM, Beqaj SH, Deeter RG, Fitzgerald JT. IgM serum antibodies to Epstein-Barr virus are uniquely present in a subset of patients with the chronic fatigue syndrome.  In Vivo. 2004 Mar-Apr;18(2):101-6. http://iv.iiarjournals.org/content/18/2/101.long (Full article)

 

Integration of gene expression, clinical, and epidemiologic data to characterize Chronic Fatigue Syndrome

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) has no diagnostic clinical signs or diagnostic laboratory abnormalities and it is unclear if it represents a single illness. The CFS research case definition recommends stratifying subjects by co-morbid conditions, fatigue level and duration, or functional impairment. But to date, this analysis approach has not yielded any further insight into CFS pathogenesis. This study used the integration of peripheral blood gene expression results with epidemiologic and clinical data to determine whether CFS is a single or heterogeneous illness.

RESULTS: CFS subjects were grouped by several clinical and epidemiological variables thought to be important in defining the illness. Statistical tests and cluster analysis were used to distinguish CFS subjects and identify differentially expressed genes. These genes were identified only when CFS subjects were grouped according to illness onset and the majority of genes were involved in pathways of purine and pyrimidine metabolism, glycolysis, oxidative phosphorylation, and glucose metabolism.

CONCLUSION: These results provide a physiologic basis that suggests CFS is a heterogeneous illness. The differentially expressed genes imply fundamental metabolic perturbations that will be further investigated and illustrates the power of microarray technology for furthering our understanding CFS.

 

Source: Whistler T, Unger ER, Nisenbaum R, Vernon SD. Integration of gene expression, clinical, and epidemiologic data to characterize Chronic Fatigue Syndrome. J Transl Med. 2003 Dec 1;1(1):10. http://www.ncbi.nlm.nih.gov/pubmed/14641939