Category: Pathogenesis

Diagnostic evaluation of 2′, 5′-oligoadenylate synthetase activities and antibodies against Epstein-Barr virus and Coxiella burnetii in patients with chronic fatigue syndrome in Japan

Abstract:

To investigate the association of viral infections with chronic fatigue syndrome (CFS), we assayed 2′, 5′-oligoadenylate synthetase (2-5AS) activities in peripheral blood mononuclear cells from CFS patients in Japan. These patients were diagnosed in two hospitals, H1 and H2, located in different areas of the country.

The activities were detected in 19 (86%) and 7 (32%) of each of the 22 patients in H1 and H2, respectively, while they were detected in only four (11%) out of the 38 healthy controls. IFN-alpha was similarly detected in a few CFS patients and healthy controls.

We also assayed the antibody titers against Epstein-Barr virus (EBV) and Coxiella burnetii in these patients. The EBV anti-EA-IgG antibodies were detected in two (9%) and seven (32%) of each of the 22 patients in H1 and H2, respectively. Anti-C. burnetii IgG antibodies were detected in six (27%) out of 22 patients in H1 but not in 22 patients in H2, while they were detected in one (11%) of the nine healthy controls.

Some CFS patients may be associated with EBV or C. burnetii infection. There were some statistical correlations between the 2-5AS activities and antibody titers of EA-IgG (P < 0.05, Student’s t-test) but not to the antibody titers of C. burnetii. The up-regulation of 2-5AS activities suggests immunological dysfunctions with some virus infections in the CFS patients. Our results indicate that 2-5AS activities are useful for a diagnostic marker of CFS and for exploring the complicated pathogenesis of CFS.

 

Source: Ikuta K, Yamada T, Shimomura T, Kuratsune H, Kawahara R, Ikawa S, Ohnishi E, Sokawa Y, Fukushi H, Hirai K, Watanabe Y, Kurata T, Kitani T, Sairenji T. Diagnostic evaluation of 2′, 5′-oligoadenylate synthetase activities and antibodies against Epstein-Barr virus and Coxiella burnetii in patients with chronic fatigue syndrome in Japan. Microbes Infect. 2003 Oct;5(12):1096-102. http://www.ncbi.nlm.nih.gov/pubmed/14554250

 

Modification of the functional capacity of sarcoplasmic reticulum membranes in patients suffering from chronic fatigue syndrome

Abstract:

In chronic fatigue syndrome, several reported alterations may be related to specific oxidative modifications in muscle. Since sarcoplasmic reticulum membranes are the basic structures involved in excitation-contraction coupling and the thiol groups of Ca(2+) channels of SR terminal cisternae are specific targets for reactive oxygen species, it is possible that excitation-contraction coupling is involved in this pathology.

We investigated the possibility that abnormalities in this compartment are involved in the pathogenesis of chronic fatigue syndrome and consequently responsible for characteristic fatigue. The data presented here support this hypothesis and indicate that the sarcolemmal conduction system and some aspects of Ca(2+) transport are negatively influenced in chronic fatigue syndrome.

In fact, both deregulation of pump activities (Na(+)/K(+) and Ca(2+)-ATPase) and alteration in the opening status of ryanodine channels may result from increased membrane fluidity involving sarcoplasmic reticulum membranes.

 

Source: Fulle S, Belia S, Vecchiet J, Morabito C, Vecchiet L, Fanò G. Modification of the functional capacity of sarcoplasmic reticulum membranes in patients suffering from chronic fatigue syndrome. Neuromuscul Disord. 2003 Aug;13(6):479-84. http://www.ncbi.nlm.nih.gov/pubmed/12899875

 

Differences between patients with chronic fatigue syndrome and with chronic fatigue at an infectious disease clinic in Stockholm, Sweden

Abstract:

Background data were collected from patients presenting with fatigue at the clinic of infectious diseases at Huddinge University Hospital, Stockholm. The main purpose was to look for differences as to demographic and functional status for patients fulfilling criteria for chronic fatigue syndrome (CFS) and chronic fatigue (CF).

A cross-sectional questionnaire survey was performed using a variety of instruments. A thorough medical investigation was performed. No difference was found as to social situation, occupation and illness attributions for patients in the two categories. Patients with CFS reported in general a higher degree of ‘sickness’ with more self-reported somatic symptoms, more self-reported functional impairment and more absence from work. A higher degree of psychiatric comorbidity was observed in CF than in CFS patients. A majority of CFS patients (80%) had an acute infectious onset compared to 43% in the CF group.

Presently used criteria might, according to findings presented here, define two different patient categories in a population characterized by severe, prolonged fatigue. Because CFS patients (compared to patients with CF) have more somatic symptoms, more often report an infectious, sudden onset and have less psychiatric comorbidity, and CF patients seem to have more of an emotional, burn-out-like component one could speculate about the existence of different pathogenetic backgrounds behind the two diagnoses.

 

Source: Evengård B, Jonzon E, Sandberg A, Theorell T, Lindh G. Differences between patients with chronic fatigue syndrome and with chronic fatigue at an infectious disease clinic in Stockholm, Sweden. Psychiatry Clin Neurosci. 2003 Aug;57(4):361-8. http://onlinelibrary.wiley.com/doi/10.1046/j.1440-1819.2003.01132.x/full (Full article)

 

Chronic fatigue and organophosphate pesticides in sheep farming: a retrospective study amongst people reporting to a UK pharmacovigilance scheme

Abstract:

The Department of Health has recently published a report from the CFS/ME Working Group which concluded that chronic fatigue syndrome (CFS) should be recognized as a chronic illness. Symptoms consistent with CFS are often reported by people who consider their health has been affected by exposure to pesticides, but the Working Group concluded that this type of exposure is not a common trigger for the syndrome.

The Veterinary Medicines Directorate (VMD) collects self-assessed reports of ill health in humans associated with veterinary medicines under their Suspected Adverse Reaction Surveillance Scheme. The reporters have mainly been sheep farmers. These reports were used to investigate the possible relationship between chronic fatigue (CF) and exposure to organophosphate pesticides in sheep farming. The overall aim of the study was to investigate a possible association between exposure to organophosphates and the development of CF amongst people who consider their health has been affected by pesticides in sheep farming. The hypothesis investigated was that repeated exposure to organophosphate pesticides in sheep dip may increase the probability of developing CF. A group of mostly sheep farmers who had reported to the VMD surveillance scheme were identified.

We planned to use a retrospective case-control study design but the initial symptoms reports were not sufficiently reliable to enable this. The study population was asked to complete two questionnaires. The first questionnaire was designed to identify the history of exposure of subjects to organophosphate pesticides, and their exposure was then reconstructed using a metric specifically developed for this purpose. The second questionnaire collected detailed information to identify whether the subjects had CF when they originally reported to the VMD and at the time of the survey.

The questionnaire was sent to a total of 206 subjects, of whom 28 had moved home. A total of 37% of the remaining 178 subjects participated. There was a high prevalence of CF amongst those who completed the questionnaire and this has generally persisted since the subjects reported to the VMD. Higher CF scores were associated with higher exposure to organophosphate pesticides.

CF is very common amongst those who consider their health was affected by pesticides and we have shown there is limited evidence of an association between exposure to organophosphates and CF. Further research is needed to investigate the cause of this syndrome amongst farmers exposed to pesticides.

 

Source: Tahmaz N, Soutar A, Cherrie JW. Chronic fatigue and organophosphate pesticides in sheep farming: a retrospective study amongst people reporting to a UK pharmacovigilance scheme. Ann Occup Hyg. 2003 Jun;47(4):261-7. http://annhyg.oxfordjournals.org/content/47/4/261.long (Full article)

 

Chronic fatigue syndrome: new evidence for a central fatigue disorder

Abstract:

Considerable evidence points towards a prominent role for central nervous system (CNS) mechanisms in the pathogenesis of chronic fatigue syndrome (CFS), a disorder characterized chiefly by persistent, often debilitating, fatigue. We wished to characterize circulating profiles of putative amino acid modulators of CNS 5-hydroxytryptamine (5-HT; serotoninergic) and dopaminergic function in CFS patients at rest, as well as during symptom-limited exercise and subsequent recovery.

Groups of 12 CFS patients and 11 age- and sex-matched sedentary controls, with similar physical activity histories, underwent ramp-incremental exercise to the limit of tolerance. Plasma amino acid concentrations, oxygen uptake and ratings of perceived exertion were measured at rest, and during exercise and recovery.

Peak oxygen uptake was significantly lower in the CFS patients compared with controls. Rating of perceived exertion in the patients was higher at all time points measured, including at rest, relative to controls. Levels of free tryptophan (free Trp), the rate-limiting 5-HT precursor, were significantly higher in CFS patients at exhaustion and during recovery, whereas concentrations of branched-chain amino acids (BCAA) and large neutral amino acids (LNAA) were lower in CFS patients at exhaustion, and for LNAA also during recovery. Consequently, the [free Trp]/[BCAA] and [free Trp]/[LNAA] ratios were significantly higher in CFS patients, except at rest.

On the other hand, levels of tyrosine, the rate-limiting dopaminergic precursor, were significantly lower at all time points in the CFS patients. The significant differences observed in a number of key putative CNS 5-HT and dopaminergic modulators, coupled with the exacerbated perception of effort, provide further evidence for a potentially significant role for CNS mechanisms in the pathogenesis of CFS.

 

Source: Georgiades E, Behan WM, Kilduff LP, Hadjicharalambous M, Mackie EE, Wilson J, Ward SA, Pitsiladis YP. Chronic fatigue syndrome: new evidence for a central fatigue disorder. Clin Sci (Lond). 2003 Aug;105(2):213-8. http://www.ncbi.nlm.nih.gov/pubmed/12708966

 

Analysis of 16S rRNA gene sequences and circulating cell-free DNA from plasma of chronic fatigue syndrome and non-fatigued subjects

Abstract:

BACKGROUND: The association of an infectious agent with chronic fatigue syndrome (CFS) has been difficult and is further complicated by the lack of a known lesion or diseased tissue. Cell-free plasma DNA could serve as a sentinel of infection and disease occurring throughout the body. This type of systemic sample coupled with broad-range amplification of bacterial sequences was used to determine whether a bacterial pathogen was associated with CFS. Plasma DNA from 34 CFS and 55 non-fatigued subjects was assessed to determine plasma DNA concentration and the presence of bacterial 16S ribosomal DNA (rDNA) sequences.

RESULTS: DNA was isolated from 81 (91%) of 89 plasma samples. The 55 non-fatigued subjects had higher plasma DNA concentrations than those with CFS (average 151 versus 91 ng) and more CFS subjects (6/34, 18%) had no detectable plasma DNA than non-fatigued subjects (2/55, 4%), but these differences were not significant. Bacterial sequences were detected in 23 (26%) of 89. Only 4 (14%) CFS subjects had 16S rDNA sequences amplified from plasma compared with 17 (32%) of the non-fatigued (P = 0.03). All but 1 of the 23 16S rDNA amplicon-positive subjects had five or more unique sequences present.

CONCLUSIONS: CFS subjects had slightly lower concentrations or no detectable plasma DNA than non-fatigued subjects. There was a diverse array of 16S rDNA sequences in plasma DNA from both CFS and non-fatigued subjects. There were no unique, previously uncharacterized or predominant 16S rDNA sequences in either CFS or non-fatigued subjects.

 

Source: Vernon SD, Shukla SK, Conradt J, Unger ER, Reeves WC. Analysis of 16S rRNA gene sequences and circulating cell-free DNA from plasma of chronic fatigue syndrome and non-fatigued subjects. BMC Microbiol. 2002 Dec 23;2:39. Epub 2002 Dec 23. http://www.ncbi.nlm.nih.gov/pubmed/12498618

 

Predictions and associations of fatigue syndromes and mood disorders that occur after infectious mononucleosis

Abstract:

BACKGROUND: Certain infections can trigger chronic fatigue syndromes (CFS) in a minority of people infected, but the reason is unknown. We describe some factors that predict or are associated with prolonged fatigue after infectious mononucleosis and contrast these factors with those that predicted mood disorders after the same infection.

METHODS: We prospectively studied a cohort of 250 primary-care patients with infectious mononucleosis or ordinary upper-respiratory-tract infections until 6 months after clinical onset. We sought predictors of both acute and chronic fatigue syndromes and mood disorders from clinical, laboratory, and psychosocial measures.

FINDINGS: An empirically defined fatigue syndrome 6 months after onset, which excluded comorbid psychiatric disorders, was most reliably predicted by a positive Monospot test at onset (odds ratio 2.1 [95% CI 1.4-3.3]) and lower physical fitness (0.35 [0.15-0.8]). Cervical lymphadenopathy and initial bed rest were associated with, or predicted, a fatigue syndrome up to 2 months after onset. By contrast, mood disorders were predicted by a premorbid psychiatric history (2.3 [1.4-3.9]), an emotional personality score (1.21 [1.11-1.35]), and social adversity (1.7 [1.0-2.9]). Definitions of CFS that included comorbid mood disorders were predicted by a mixture of those factors that predicted either the empirically defined fatigue syndrome or mood disorders.

INTERPRETATION: The predictors of a prolonged fatigue syndrome after an infection differ with both definition and time, depending particularly on the presence or absence of comorbid mood disorders. The particular infection and its consequent immune reaction may have an early role, but physical deconditioning may also be important. By contrast, mood disorders are predicted by factors that predict mood disorders in general.

 

Source: White PD, Thomas JM, Kangro HO, Bruce-Jones WD, Amess J, Crawford DH, Grover SA, Clare AW. Predictions and associations of fatigue syndromes and mood disorders that occur after infectious mononucleosis. Lancet. 2001 Dec 8;358(9297):1946-54. http://www.ncbi.nlm.nih.gov/pubmed/11747919

 

Antioxidant status and lipoprotein peroxidation in chronic fatigue syndrome

Abstract:

The aetiology and pathogenesis of the Chronic Fatigue Syndrome (CFS) are still largely unresolved. Accompanying metabolic disorders such as selective n-6 fatty acid depletion suggest that oxidative stress and more specifically lipid peroxidation might play a role in its pathogenesis.

In order to investigate this hypothesis, oxidant-antioxidant status and its impact on lipoprotein peroxidation in vitro was examined in 61 patients with unexplained fatigue lasting more than 1 month. They were subdivided into 2 groups: group CFS+ (33 subjects) fulfilled the 1988 Center of Disease Control criteria for CFS and group CFS- did not but was similar as regards age, sex distribution and clinical characteristics.

Antioxidant status was similar in the 2 groups except for lower serum transferrin in the CFS + (mean (95 % CI) 2.41 (2.28-2.54) versus 2.73 (2.54-2.92) g/L in the CFS-, p = 0.009) and higher lipoprotein peroxidation in vitro: 6630 (5949-7312) versus 5581 (4852-6310) nmol MDA/mg LDL and VLDL cholesterol x minutes, p = 0.035). CFS intensified the influence of LDL cholesterol (p = 0.012) and of transferrin (p = 0.045) on peroxidation in vitro, suggesting additional pro-oxidant effects.

These results indicate that patients with CFS have increased susceptibility of LDL and VLDL to copper-induced peroxidation and that this is related both to their lower levels of serum transferrin and to other unidentified pro-oxidising effects of CFS.

 

Source: Manuel y Keenoy B, Moorkens G, Vertommen J, De Leeuw I. Antioxidant status and lipoprotein peroxidation in chronic fatigue syndrome. Life Sci. 2001 Mar 16;68(17):2037-49. http://www.ncbi.nlm.nih.gov/pubmed/11388705

 

Role of impaired lower-limb venous innervation in the pathogenesis of the chronic fatigue syndrome

Abstract:

BACKGROUND: In patients with acute orthostatic hypotension, there is excessive pooling of blood in the legs, which may result from the strikingly subnormal compliance that is demonstrable in the pedal veins during norepinephrine infusion. The common occurrence of delayed orthostatic hypotension and/or tachycardia in the chronic fatigue syndrome (CFS) led to the present studies of foot vein compliance in CFS patients with a linear variable differential transformer.

METHODS: Seven patients with CFS were compared with 7 age- and gender matched healthy control subjects in their blood pressure, heart-rate, and plasma norepinephrine responses to prolonged standing and in measurements of their foot vein contractile responses to intravenous norepinephrine infusions with the linear variable differential transformer.

RESULTS: Excessive, delayed (usually after 10 min) orthostatic reductions in systolic and diastolic blood pressure (P < 0.01) and inconsistently excessive increases in heart rate were found in the CFS patients, in whom venous compliance in response to infused norepinephrine was significantly reduced (P < 0.05).

CONCLUSIONS: In these patients with CFS, delayed orthostatic hypotension was clearly demonstrable, and, as in previously reported patients with orthostatic hypotension of acute onset, this was associated with reduced pedal vein compliance during norepinephrine infusion, implying impaired sympathetic innervation of foot veins. The rapid symptomatic improvement demonstrated in previous studies of CFS patients during correction of orthostatic venous pooling by inflation of military antishock trousers (MAST) to 35 mm Hg may suggest that excessive lower body venous pooling, perhaps by reducing cerebral perfusion, is involved in the orthostatic component of fatigue in these patients.

 

Source: Streeten DH. Role of impaired lower-limb venous innervation in the pathogenesis of the chronic fatigue syndrome. Am J Med Sci. 2001 Mar;321(3):163-7. http://www.ncbi.nlm.nih.gov/pubmed/11269790

 

Results of isoproterenol tilt table testing in monozygotic twins discordant for chronic fatigue syndrome

Abstract:

BACKGROUND: The pathogenesis of chronic fatigue syndrome (CFS) is unknown. Neurally mediated hypotension (NMH) has been suggested as a common comorbid condition or a potential underlying cause.

METHODS: We conducted a cotwin control study of 21 monozygotic twins who were discordant for CFS. One twin met the 1994 Centers for Disease Control and Prevention criteria for CFS, and the other twin was healthy and denied chronic fatigue. The twins were selected from a volunteer twin registry in which at least 1 member reported persistent fatigue. As part of a 7-day clinical evaluation, all 21 twin pairs were evaluated with a 3-stage tilt table test with isoproterenol hydrochloride for the assessment of NMH. The presence of NMH was defined as syncope or presyncope associated with a decrease of 25 mm Hg in blood pressure and no associated increase in heart rate.

RESULTS: A positive tilt table test result was observed in 4 twins with CFS (19%) and in 4 healthy twins (19%). This difference was not statistically significant (matched pair odds ratio, 1.0; 95% confidence interval, 0.2-5.4; P>.90). Compared with the healthy twins, the twins with CFS reported more severe symptoms of CFS and NMH both in the week before and during the tilt table test.

CONCLUSIONS: These results do not support a major role for NMH in CFS. They highlight the importance of selecting well-matched control subjects, as well as the unique value of the monozygotic cotwin control design in the study of this illness. Arch Intern Med. 2000;160:3461-3468.

 

Source: Poole J, Herrell R, Ashton S, Goldberg J, Buchwald D. Results of isoproterenol tilt table testing in monozygotic twins discordant for chronic fatigue syndrome. Arch Intern Med. 2000 Dec 11-25;160(22):3461-8. http://www.ncbi.nlm.nih.gov/pubmed/11112240