Infectious mononucleosis, Epstein-Barr virus, and chronic fatigue syndrome: a prospective case series

Abstract:

Epstein-Barr viral infection, specifically infectious mononucleosis, typically has a more protracted course than other acute viral illnesses. Some recent observers have additionally suggested the possibility that Epstein-Barr virus (EBV) is the etiologic infectious agent in chronic fatigue syndrome, based on the finding of higher proportions of elevated antibodies to the EBV early antigen in some patients complaining of chronic fatigue.

Straus et al reported on 23 patients with chronic fatigue, 83% of whom exhibited persistently elevated antibodies in modest titer to the early antigen. Ten of these patients had never fully recovered from an episode of acute infectious mononucleosis. Other studies had noted similar associations between persistently elevated antibodies to EBV-specific antigens and chronic symptoms in patients who presented with chronic symptoms after mononucleosis.

Three important antigen complexes, demonstrable by immunofluorescence procedures, are expressed in EBV-infected cells. The early antigen is thought to function perhaps in early replication of viral DNA. A late antigenic complex, the viral capsid antigen, may represent, in addition to structural capsid proteins, components of the viral enzymatic machinery for late phases of replication or transformation. The Epstein-Barr nuclear antigen is felt to function in viral transformation of host cells.

 

Source: Fark AR. Infectious mononucleosis, Epstein-Barr virus, and chronic fatigue syndrome: a prospective case series. J Fam Pract. 1991 Feb;32(2):202, 205-6, 209. http://www.ncbi.nlm.nih.gov/pubmed/1846641

 

Chronic fatigue syndrome

SIR,

Dr Anthony David and colleagues (1) cite our paper (2) as one that makes inflated claims about the chtionic fatigue syndrome.

We first reported retrospectively an association between antibodies to coxsackie virus B and a group of symptoms similar to those previously described as myalgic encephalomyelitis. (3) We were faced with an ever increasing clinical problem of which we had little understanding, and the prospective investigation of coxsackie virus B antibody titres in these patients seemed a reasonable step forward. No widely accepted definition of the chronic fatigue syndrome existed in 1983, and we did not attempt to define it. We approached the problem from the opposite direction in that we had a definable test and we tried to show what happened to the results of this test in a group of ill patients.

Since 1983 much research into this syndrome has been carried out. It has taken a long time for a consensus to be agreed defining the syndrome. We believe that today’s definition that the syndrome cannot be diagnosed before six months has elapsed is acceptable. In our study 72% of our patients were still unwell six months into the illness.

The comparison made by Dr David and colleagues of their paper with ours is invalid. They questioned 611 general practice attenders whereas we reported on a group of 140 patients presenting over six months with what we believe to be the same illness.

In retrospect we think that what we observed was the slow spread of an infective agent through our town in 1983 and through neighbouring towns in our district in 1984 and 1985. The clinical syndrome coincided with a rise in the prevalence of coxsackie virus B antibodies in the general population from 10-12% in 1973-84 (we found 25% in 1983) to 55% in 1985-6. (4) Since then our clinical impression has been one of a return to normal; we see occasional new cases but not as many as in 1983.

The prevalence of this condition seems to depend on the activity of an infective agent of some kind, be it viral or otherwise, in the area of study at the time, and further research is made difficult by the wide fluctuations of prevalence that will be found from place to place and from time to time.

~B D CALDER

~P J WARNOCK Helensburgh G84 8BW

1 David A, Pelosi A, McDonald E, et al. Tired, weak, or in need of rest: fatigue among general practice attenders. BMJ 1990;301:1199-202. (24 November.)

2 Calder BD, Warnock PJ, McCartney RA, Bell EJ. Coxsackie B viruses and post-viral syndrome J R Coll Gen Pract 1987;37: 11-4.

3 Calder BD, Warnock PJ. Coxsackie B infections in Scottish general practice. J R Coll Gen Pract 1984;34:15-9.

4 Miller NA, Carmichael HA, Calder BD, et al. Antibody to coxsackie B virus in diagnosing postviral fatigue syndrome. BMJ (in press).

 

Source: B D Calder and P J Warnock. Chronic fatigue syndrome. BMJ. 1991 Jan 19; 302(6769): 181. PMCID: PMC1668832 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1668832/

 

Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome

Abstract:

OBJECTIVE: To study the association between coxsackie B virus infection and the postviral fatigue syndrome and to assess the immunological abnormalities associated with the syndrome.

DESIGN: Case-control study of patients with the postviral fatigue syndrome referred by local general practitioners over one year.

SETTING: General practitioner referrals in Dunbartonshire, Scotland.

PATIENTS: 254 Patients referred with the postviral fatigue syndrome (exhaustion, myalgia, and other symptoms referable to postviral fatigue syndrome of fairly recent onset–that is, several months) and age and sex matched controls obtained from same general practitioner; 11 patients were rejected because of wrong diagnoses, resolution of symptoms, and refusal to participate, leaving 243 patients and matched controls.

MAIN OUTCOME MEASURES: Detailed questionnaire (patients and controls) and clinical examination (patients) and blind analysis of blood sample at entry and after six months for determination of coxsackie B virus IgM and IgG antibodies and other variables (including lymphocyte protein synthesis, lymphocyte subsets, and immune complexes).

RESULTS: Percentage positive rates for coxsackie B virus IgM at entry were 24.4% for patients and 22.6% for controls and for coxsackie B virus IgG 56.2% and 55.3% respectively; there were no significant differences between different categories of patients according to clinical likelihood of the syndrome nor any predictive value in a fourfold rise or fall in the coxsackie B virus IgG titre in patients between entry and review at six months. The rates of positive antibody test results in patients and controls showed a strong seasonal variation. Of the numerous immunological tests performed, only a few detected significant abnormalities; in particular the mean value for immune complex concentration was much higher in 35 patients and 35 controls compared with the normal range and mean value for total IgM was also raised in 227 patients and 35 controls compared with the normal range.

CONCLUSIONS: Serological tests available for detecting coxsackie B virus antibodies do not help diagnose the postviral fatigue syndrome. Percentage positive rates of the antibodies in patients simply reflect the background in the population as probably do the raised concentrations of total IgM and immune complexes.

 

Source: Miller NA, Carmichael HA, Calder BD, Behan PO, Bell EJ, McCartney RA, Hall FC. Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome. BMJ. 1991 Jan 19;302(6769):140-3. http://www.ncbi.nlm.nih.gov/pubmed/1847316

 

A supplemental interview for forms of “affective spectrum disorder”

Abstract:

OBJECTIVE: Recent evidence suggests that a number of psychiatric and medical conditions may be members or candidate members of a larger family of conditions, which we have termed “affective spectrum disorder (ASD).” In order to facilitate further research into this concept, we drafted seven interview modules, using the format of the Structured Clinical Interview for DSM-III-R (SCID), designed to diagnose the following psychiatric and medical disorders: irritable bowel syndrome, narcolepsy, Tourette’s disorder, migraine, fibromyalgia, chronic fatigue syndrome, and kleptomania.

METHOD: Published operational diagnostic criteria for these seven disorders were sought in the literature. Questions in SCID format were then drafted in accordance with these operational criteria. Draft modules were then sent to experts familiar with each of the disorders and suggestions and revisions from these experts incorporated into the final modules.

RESULTS: The complete supplemental interview is presented with this report. Preliminary experience with this interview in more than 100 patients tentatively suggests that it is reliable for diagnosing the disorders in question; however, a formal test-retest reliability assessment is still required.

CONCLUSIONS: It is hoped that this supplemental interview, used in conjunction with the SCID, will be helpful in further studies of the epidemiology, pathogenesis, and treatment of these possible forms of affective spectrum disorder.

 

Source: Pope HG Jr, Hudson JI. A supplemental interview for forms of “affective spectrum disorder”. Int J Psychiatry Med. 1991;21(3):205-32. http://www.ncbi.nlm.nih.gov/pubmed/1955274

 

Cognitive and mood-state changes in patients with chronic fatigue syndrome

Abstract:

In this paper the cognitive and psychiatric impairments associated with chronic fatigue syndrome (CFS) and related disorders are reviewed. It is concluded that while acute mononucleosis and infection with Epstein-Barr virus occasionally result in impaired cognition, such changes have not yet been objectively verified in patients with CFS.

However, when patients with CFS are carefully studied, concurrent or premorbid psychiatric disorders are revealed at a greater than chance level. Finally, some suggestions are offered regarding improved neuropsychological assessment of fatigue, concentration, and attention for patients with CFS. The findings to date, while suggesting that psychological predisposition may play a role in the expression of CFS, are still inconclusive regarding the etiology of CFS.

 

Source: Grafman J, Johnson R Jr, Scheffers M. Cognitive and mood-state changes in patients with chronic fatigue syndrome. Rev Infect Dis. 1991 Jan-Feb;13 Suppl 1:S45-52. http://www.ncbi.nlm.nih.gov/pubmed/1850543

 

Primary fibromyalgia and the chronic fatigue syndrome

Abstract:

Thirty-three primary fibromyalgia patients were investigated for chronic fatigue syndrome symptoms. Significant fatigue was reported by 21/33 patients (63.6%), and patients reported various flulike symptoms, yet only 7/33 patients (21.2%) fulfilled criteria for the chronic fatigue syndrome. Only one patient reported painful lymph glands and four patients reported fever. Thus, symptoms of painful glands or fever might serve as clinical indicators, distinguishing between fibromyalgia and the chronic fatigue syndrome.

 

Source: Wysenbeek AJ, Shapira Y, Leibovici L. Primary fibromyalgia and the chronic fatigue syndrome. Rheumatol Int. 1991;10(6):227-9. http://www.ncbi.nlm.nih.gov/pubmed/2041979

 

Physiologic measurement of exercise and fatigue with special reference to chronic fatigue syndrome

Abstract:

Oxidative metabolism is the major source of energy for muscle activity, and maximal oxygen uptake (VO2max), the product of maximal cardiac output and maximal arteriovenous oxygen difference, indicates individual capacity for oxidative metabolism and performance of exercise by the large muscles.

Strength, a function of muscle cross-sectional area, motor-unit recruitment, and neuromuscular coordination, is the ability to develop force in a single, brief, maximal-effort voluntary contraction of rested muscle. Weakness is a diminished ability of rested muscle to exert maximal force. Fatigue is a loss of maximal force-generating capacity that develops during muscular activity, likely originates within muscle itself, and persists until muscle is fully recovered. Individual perception of motor effort can be determined with standardized rating scales.

These concepts are discussed in detail, their relevance to the pathophysiology of exercise in chronic fatigue syndrome is analyzed, and a general strategy of exercise evaluation pertinent to chronic fatigue syndrome is presented.

 

Source: Lewis SF, Haller RG. Physiologic measurement of exercise and fatigue with special reference to chronic fatigue syndrome. Rev Infect Dis. 1991 Jan-Feb;13 Suppl 1:S98-108. http://www.ncbi.nlm.nih.gov/pubmed/2020810

 

Validation of biologic markers for use in research on chronic fatigue syndrome

Abstract:

Unresolved aspects of chronic fatigue syndrome can be addressed by research involving biologic markers. These may be any molecular, biochemical, physiological, or other biologic parameter obtainable from biologic specimens. The use of biologic markers in research requires their validation as dependent or independent variables. Additionally, other characteristics of markers such as reliability of assays, background level, confounding factors, interpretations, and legal and ethical implications should be considered before the use of markers in research. A checklist is provided for evaluating a biologic marker before its inclusion in research.

 

Source: Schulte PA. Validation of biologic markers for use in research on chronic fatigue syndrome. Rev Infect Dis. 1991 Jan-Feb;13 Suppl 1:S87-9. http://www.ncbi.nlm.nih.gov/pubmed/2020808

 

Symptoms and signs of chronic fatigue syndrome

Abstract:

This review summarizes the symptoms and signs seen in patients with chronic fatigue syndrome (CFS). It is based on the authors’ experience with two cohorts of approximately 510 patients with chronic debilitating fatigue and on the reported experience of other investigators with similar patients.

The most characteristic symptoms of CFS are the sudden onset of an infectious-type illness, the subsequent chronic and debilitating fatigue, and postexertional malaise; many patients also have recurrent fevers, pharyngitis, adenopathy, myalgias, sleep disorders, and cognitive impairment.

 

Source: Komaroff AL, Buchwald D. Symptoms and signs of chronic fatigue syndrome. Rev Infect Dis. 1991 Jan-Feb;13 Suppl 1:S8-11. http://www.ncbi.nlm.nih.gov/pubmed/2020806

 

Chronic fatigue syndrome: issues in the diagnosis and estimation of incidence

Abstract:

This article critiques the current working definition of chronic fatigue syndrome. The concerns raised about the current working definition are the following: prolonged or excessive exertion is not addressed explicitly; duration and quality of bed rest are not specified; a socioeconomic ascertainment bias is present; data from history and physical findings are not clearly separated and are relegated to minor criteria; and the rigor of neurologic and psychiatric evaluations is not specified.

We propose a flow chart that addresses the possible modes of evolution of chronic fatigue syndrome for patients; this chart may yield more homogeneous subgroups of individuals with this syndrome or enable some patients to avert the syndrome.

 

Source: Armon C, Kurland LT. Chronic fatigue syndrome: issues in the diagnosis and estimation of incidence. Rev Infect Dis. 1991 Jan-Feb;13 Suppl 1:S68-72. http://www.ncbi.nlm.nih.gov/pubmed/2020804