Interferon-induced proteins are elevated in blood samples of patients with chemically or virally induced chronic fatigue syndrome

Abstract:

Overlapping symptomatologies between Chronic Fatigue Syndrome (CFS) and Chemical Sensitivity have been observed by different investigators. Therefore, it is of great importance to develop biomarker(s) for possible differentiation between viral induced CFS (without sensitivity to chemicals) versus chemically induced CFS.

Since interferon induced proteins 2-5A Synthetase and Protein Kinase RNA (PKR) have been implicated in the viral induction of CFS, the objective of this study was to utilize 2-5A and PKR activity for differentiation between CFS induced by either viruses or chemicals.

Based on the CDC definition and criteria, twenty CFS patients who were positive for viral genome(s) (mainly HHV6; HTLVII, EBV, and CMV) and did not have any history of exposure to toxic chemicals were included in this study. As a comparison, the second group of patients consisted of twenty individuals from the same geographical area who were negative for viral genomes but had been exposed to methyl tertiary-butyl ether concentration of up to 70 ppb and benzene concentration up to 14 ppb. All patients complained of fatigue and other symptoms overlapping between the two groups. From all 40 patients, blood was drawn, leukocyte extract was prepared and assayed for 2-5A Synthetase and PKR activity.

Clinical specimens which were positive for viral genomes showed from 2.2-38.7 fold increase in 2-5A activity and 1.3-13.5 fold increase in PKR activities over the background of the healthy controls. Similarly, the second group (negative for viral genomes, but exposed to chemicals) showed a 1.1-29.2 fold increase for 2-5A Synthetase and a 1.3-11.6 fold increase for PKR when they were compared to healthy subjects.

To elucidate mechanisms involved in viral versus chemical induction of 2-5A Synthetase and PKR, MDBK cell lines were cultured either in the presence or absence of HHV6, MTBE, or Benzene, heat shock proteins and interferon-beta. 2-5A and PKR activities were measured in all the above conditions.

A clear induction of 2-5A and PKR was observed when MDBK cells were exposed to HHV6, MTBE, and Benzene. This induction was more significant with HSP90, HSP70, and IFN-beta indicating their involvement in the mechanism of action. However, when MDBK cells were incubated either with MTBE + Benzene or HHV6 in the presence or absence of anti IFN-beta or anti-HSP-70, the activities of both 2-5A and PKR in HHV6 infected cells were inhibited by more than 90% due to addition of anti IFN-beta, and only 20% by addition of anti-HSP70. While in MTBE + Benzene exposed cells anti IFN-beta reduced the activity of these enzymes by 40% and anti-HSP70 by more than 90%.

This variation in the induction of 2-5A and PKR by anti-HSP70 or IFN-beta indicates involvement of IFN-beta in viral induction 2-5A and PKR, and HSP involvement in chemical induction of these enzymes. We conclude that 2-5A and PKR are not only biomarkers for viral induction of CFS, but biomarkers to other stressors that include MTBE and Benzene.

 

Source: Vojdani A, Lapp CW. Interferon-induced proteins are elevated in blood samples of patients with chemically or virally induced chronic fatigue syndrome. Immunopharmacol Immunotoxicol. 1999 May;21(2):175-202. http://www.ncbi.nlm.nih.gov/pubmed/10319275

 

Fibromyalgia, chronic fatigue syndrome, and myofascial pain syndrome

Abstract:

Fibromyalgia was almost completely absent from an urban affluent population compared with poor urban and rural communities. Seventeen percent of Gulf War veterans with soft tissue syndromes had fibromyalgia, a much higher rate than was seen in previous studies of rheumatic disease in the military population. A state of central hyperexcitability in the nociceptive system was reported in fibromyalgia. Altered functioning of the stress-response system has been further documented in fibromyalgia and chronic fatigue syndrome.

Administration of growth hormone to patients with fibromyalgia who have low levels of insulin-like growth factor 1 resulted in improvement in their symptoms and tenderness. An association between chronic fatigue syndrome and initial infections was demonstrated. A correlation between particular immunologic abnormalities and measures of disease severity was documented in chronic fatigue syndrome. Concomitant fibromyalgia in other rheumatic diseases was a major contributor to poor quality of life. A favorable outcome of fibromyalgia in children was reported; the majority of patients improved over 2 to 3 years of follow-up. Treatment of patients with fibromyalgia continues to be of limited success.

 

Source: Buskila D. Fibromyalgia, chronic fatigue syndrome, and myofascial pain syndrome. Curr Opin Rheumatol. 1999 Mar;11(2):119-26. http://www.ncbi.nlm.nih.gov/pubmed/10319215

 

Hypotension: a forgotten illness?

Abstract:

Low blood pressure is a frequently encountered phenomenon in clinical practice. Few practitioners in the Western world however regard chronic low blood pressure as a genuinely pathological disease state. Evidence is emerging that chronic hypotension is associated with considerable morbidity in the community. It has recently been implicated as the causative mechanism in patients with the chronic fatigue syndrome.

Identification of low blood pressure can prove problematic, so ambulatory blood pressure monitoring may prove a more reliable method both for determining mean blood pressure levels and for identifying episodes of marked hypotension. Low blood pressure is broadly divided into two categories, chronic constitutional hypotension and hypotension associated with abnormal postural control. The causes are examined and the clinical presentations are discussed. An approach to investigation and diagnosis is outlined, and current options regarding treatment and management are described. The clinical spectrum of low blood pressure is wide. From young patients with vagally mediated syncope or patients with iatrogenic hypotension to elderly patients with autonomic degenerative conditions, there exists a substantial body of patients with potentially avoidable or treatable morbidity. Such a group requires more rigorous scientific investigation and a more sympathetic clinical approach.

 

Source: Owens PE, O’Brien ET. Hypotension: a forgotten illness? Blood Press Monit. 1997 Dec;2(1):3-14. http://www.ncbi.nlm.nih.gov/pubmed/10234084

 

Immunological response in chronic fatigue syndrome following a graded exercise test to exhaustion

Abstract:

This study was conducted to evaluate the immunological response to an exhaustive treadmill exercise test in 20 female chronic fatigue syndrome patients compared to 14 matched sedentary controls. Venipuncture was performed at baseline and 4 min, 1 hr, and 24 hr postexercise.

White blood cells were labeled for monoclonal antibody combinations and were quantified by FACsan. Cytokines were assayed utilizing quantitative RT/PCR. No group difference was seen in VO2peak (28.6 +/- 1.6 vs 30.9 +/- 1.2 ml.kg-1.min-1; P > 0.05). However, 24 hr after exercise the patients’ fatigue levels were significantly increased (P < 0.05).

The counts of WBC, CD3+ CD8+ cells, CD3+ CD4+ cells, T cells, B cells, natural killer cells, and IFN-gamma changed across time (P’s < 0.01). No group differences were seen for any of the immune variables at baseline or after exercise (P’s > 0.05). The immune response of chronic fatigue syndrome patients to exhaustive exercise is not significantly different from that of healthy nonphysically active controls.

 

Source: LaManca JJ, Sisto SA, Zhou XD, Ottenweller JE, Cook S, Peckerman A, Zhang Q, Denny TN, Gause WC, Natelson BH. Immunological response in chronic fatigue syndrome following a graded exercise test to exhaustion. J Clin Immunol. 1999 Mar;19(2):135-42. http://www.ncbi.nlm.nih.gov/pubmed/10226888

 

Psychological symptoms in chronic fatigue and juvenile rheumatoid arthritis

Abstract:

OBJECTIVE: To determine if psychological morbidity in youth with chronic fatigue is caused by the stress of coping with a chronic illness.

STUDY DESIGN: Case-control study comparing pediatric patients with debilitating chronic fatigue and matched subjects with juvenile rheumatoid arthritis, a chronic medical illness with similar functional sequelae.

SETTING: Pediatric Infectious Diseases Clinic and Juvenile Rheumatoid Arthritis Clinic of Kosair Children’s Hospital.

PARTICIPANTS: Nineteen children and adolescents with debilitating chronic fatigue and 19 age- and sex-matched peers with juvenile rheumatoid arthritis. Outcome. Structured Interview, Kaufman Brief Intelligence Test, Child Behavior Checklist, and Youth Self-Report.

RESULTS: Intellectual functioning on the Kaufman Brief Intelligence Test Composite was average (103, standard score) for both groups. Pediatric patients with chronic fatigue had higher levels of internalizing psychological distress than patients suffering from juvenile rheumatoid arthritis, despite the fact that both groups had a similar pattern of decline in social and physical activities. Duration of illness did not explain the difference in psychological symptoms.

CONCLUSIONS: Psychological factors may play a more active role in debilitating chronic fatigue in pediatric patients than can be explained by the stress of coping with a similar chronic, non-life-threatening illness.

 

Source: Carter BD, Kronenberger WG, Edwards JF, Marshall GS, Schikler KN, Causey DL. Psychological symptoms in chronic fatigue and juvenile rheumatoid arthritis. Pediatrics. 1999 May;103(5 Pt 1):975-9. http://www.ncbi.nlm.nih.gov/pubmed/10224175

 

Acute fatigue in chronic fatigue syndrome patients

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) patients often complain that they are more susceptible to acute mental fatigue. It is important to determine whether this is observed using objective tests of sustained attention and responding.

METHODS: Sixty-seven patients who fulfilled the criteria for CFS proposed by Sharpe et al. (1991) were compared with 126 matched healthy controls. Acute fatigue was assessed by comparing performance at the start and end of a lengthy test session and by examining changes over the course of individual tasks.

RESULTS: CFS patients showed impaired performance compared to the controls and these differences increased as the volunteers developed acute fatigue. In addition, differences between the two groups were larger at the end of the test session.

CONCLUSIONS: The present results show that CFS patients are more susceptible to acute fatigue than healthy controls. This could reflect motor fatigue or an inability to compensate for fatigue with increased effort. This profile is consistent with previous research on fatigue and suggests that interpretation of certain aspects of CFS may be helped by considering it as the end point of a continuum of fatigue rather than a distinct disease.

 

Source: Smith AP, Borysiewicz L, Pollock J, Thomas M, Perry K, Llewelyn M. Acute fatigue in chronic fatigue syndrome patients. Psychol Med. 1999 Mar;29(2):283-90. http://www.ncbi.nlm.nih.gov/pubmed/10218920

 

Is disabling fatigue in childhood influenced by genes?

Abstract:

BACKGROUND: Medically unexplained chronic fatigue in childhood may cause considerable disability and (by definition) its cause remains unclear. A study of fatigue in healthy twins has been undertaken to examine whether or not genetic factors play a part.

METHOD: A questionnaire survey of the main carers of an epidemiological population-based sample of 670 twin pairs who were asked about periods of unexplained and disabling fatigue in their twins. Out of 1340 individuals a period of disabling fatigue was reported for 92 (6.9%). Thirty-three (2.5%) reported disabling fatigue for more than 1 month. Zygosity could be confidently assigned in 98% of the sample providing 278 monozygotic (MZ) and 378 dizygotic (DZ) pairs. These data were analysed using a structural equation modelling approach.

RESULTS: The results showed that disabling fatigue in childhood is highly familial with an MZ tetrachoric correlation (rMZ) of 0.81 and a DZ tetrachoric correlation (rDZ) of 0.59, for fatigue lasting at least a week. The most acceptable model using Akaike’s information criteria, was one containing additive genetic effects (A) and shared environment (C) plus residual (or non-shared) environment (E). For fatigue lasting at least a month rMZ was 0.75 and rDZ 0.47. The most acceptable model included just A and E. However, the role of shared environment could not be conclusively rejected.

CONCLUSIONS: Unexplained disabling fatigue in childhood is substantially familial. Both genetic and shared environmental factors are worth further exploration in a search for the causes.

 

Source: Farmer A, Scourfield J, Martin N, Cardno A, McGuffin P. Is disabling fatigue in childhood influenced by genes? Psychol Med. 1999 Mar;29(2):279-82. http://www.ncbi.nlm.nih.gov/pubmed/10218919

 

Unique genetic and environmental determinants of prolonged fatigue: a twin study

Abstract:

BACKGROUND: Prolonged fatigue syndromes have been proposed as prevalent and disabling forms of distress that occur independently of conventional notions of anxiety and depression.

METHODS: To investigate the genetic and environmental antecedents of common forms of psychological and somatic distress, we measured fatigue, anxiety, depression and psychological distress in 1004 normal adult twin pairs (533 monozygotic (MZ), 471 dizygotic (DZ)) over 50 years of age.

RESULTS: Familial aggregation of psychological distress, anxiety and fatigue appeared to be due largely to additive genetic factors (MZ:DZ ratios of 2.12-2.69). The phenotypic correlations between the psychological measures (distress, anxiety and depression) were moderate (0.67-0.79) and higher than that between fatigue and psychological distress (0.38). Multivariate genetic modelling revealed a common genetic factor contributing to the development of all the observed phenotypes (though most strongly for the psychological forms), a second independent genetic factor also influenced anxiety and depression and a third independent genetic factor made a major contribution to fatigue alone. In total, 44% (95% CI 25-60%) of the genetic variance for fatigue was not shared by the other forms of distress. Similarly, the environmental factor determining psychological distress made negligible contributions to fatigue, which was underpinned largely by its own independent environmental factor.

CONCLUSION: This study supports the aetiological independence of prolonged fatigue and, therefore, argues strongly for its inclusion in classification systems in psychiatry.

 

Source: Hickie I, Kirk K, Martin N. Unique genetic and environmental determinants of prolonged fatigue: a twin study. Psychol Med. 1999 Mar;29(2):259-68. http://www.ncbi.nlm.nih.gov/pubmed/10218917

 

Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome

Abstract:

Patients with the chronic fatigue syndrome (CFS) complain consistently of delay in recovery of peripheral muscle function after exercise. The purpose of this study was to try to confirm this observation.

A fatiguing exercise test was carried out on the quadriceps muscle group of ten patients and ten control subjects. The test consisted of 18 maximum voluntary contractions (MVCs) with a 50% duty cycle (10 s contraction, 10 s rest), and the force generated by each contraction was recorded using a KinCom dynamometer. This was followed by a recovery phase lasting 200 min in which quadriceps strength was evaluated at increasing intervals, and a follow-up session at 24 h post-exercise involving three 10 s MVCs.

Throughout the exercise period, the MVCs obtained from the control group were significantly higher than those of the patient group (P = 0.006), but both groups showed a parallel decline in force over the 18 contractions, in keeping with a similar endurance capacity.

Recovery was prolonged in the patient group, however, with a significant difference compared to initial MVCs being evident during the recovery phase after exercise (P = 0.001) and also at 24 h (P < 0.001). In contrast, the control group achieved MVCs which were not significantly different from initial values during the recovery phase, and maintained these at 24 h.

These findings support the clinical complaint of delayed recovery after exercise in patients with CFS.

Copyright 1999 Lippincott Williams & Wilkins

 

Source: Paul L, Wood L, Behan WM, Maclaren WM. Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome. Eur J Neurol. 1999 Jan;6(1):63-9. http://www.ncbi.nlm.nih.gov/pubmed/10209352

 

Managing chronic fatigue syndrome: overview and case study

Abstract:

1. The basic principles of envelope theory are explained. By not overexerting themselves, people with CFS can avoid the setbacks and relapses that commonly occur in response to overexertion while increasing their tolerance to activity. 2. By collecting time series data on fluctuations in energy levels, important clinical observations can be made in respect to a client’s unique condition and experience with CFS.

 

Source: Jason LA, Melrose H, Lerman A, Burroughs V, Lewis K, King CP, Frankenberry EL. AAOHN J. 1999 Jan;47(1):17-21. http://www.ncbi.nlm.nih.gov/pubmed/10205371