A comprehensive immunological analysis in chronic fatigue syndrome

Abstract:

A detailed analysis of cell-mediated and antibody-mediated immunity was performed in 20 CDC-defined patients with chronic fatigue syndrome (CFS) and 20 age- and sex-matched healthy controls.

CD3+, CD4+, CD8+, and CD20+ lymphocytes were comparable in two groups. Natural killer cells as defined by CD16, CD56 and CD57 antigens were significantly reduced in CFS. A significant increase in the proportions of CD4+ ICAM 1+ T cells was observed in CFS. Monocytes from CFS displayed increased density (as determined by mean fluorescence channel numbers) of intercellular adhesion molecule 1 (ICAM-1) and lymphocyte function associated antigen 1 (LFA-1), but showed decreased enhancing response to recombinant interferon-gamma in vitro.

The lymphocyte DNA synthesis in response to phytohaemoglobulin (PHA), Concanavalin A (Con A) and pokeweed mitogen (PWM) was normal but the response to soluble antigens was significantly reduced. Serum IgM, IgG, IgA, and IgG subclasses were normal. In vivo specific antibody response to pneumococcus vaccine was depressed in CFS.

Forty percent of patients showed titres of anti-human herpes virus 6 (anti-HHV-6) antibody higher than that in the controls (greater than or equal to 1/80). These data suggest immunological dysfunction in patients with chronic fatigue syndrome. The significance of these observations is discussed.

 

Source: Gupta S, Vayuvegula B. A comprehensive immunological analysis in chronic fatigue syndrome. Scand J Immunol. 1991 Mar;33(3):319-27. http://www.ncbi.nlm.nih.gov/pubmed/1849315

 

Changes in natural killer cell phenotype in patients with post-viral fatigue syndrome

Abstract:

We analysed peripheral blood CD56+ natural killer (NK) cell subsets in 23 carefully characterized patients with post-viral fatigue syndrome (PFS), compared with 19 healthy controls, using fluorochrome-conjugated, specific monoclonal antibodies and the FACScan.

We found significantly increased percentages of CD56+, and especially CD56bright+ NK cells in PFS patients. We also found significantly increased percentages of CD56+ high affinity interleukin-2 (IL-2) receptor (CD25)+ and CD56+ transferrin receptor (CD71+) subsets of cells, most of which also stained brightly for CD56.

Also, we found an increased percentage of CD56+ CD3+ cells, many of which stained brightly for CD56, although there was no increase in the percentage of CD56- CD3+ T cells in these patients. These observations, in conjunction with very low percentage of CD56- CD25+ cells, suggest that there is a preferential involvement of this minor subset of CD56+ CD3+ T cells in PFS.

Finally, a decreased percentage of CD56+ Fc gamma receptor (CD16)+ NK cells was identified, which suggests a reduced capacity of antibody-dependent cellular cytotoxicity in PFS patients. Subsets of CD56+ NK cells co-expressing CD2, CD4 or CD8 did not show any significant difference between PFS patients and healthy controls.

These phenotypic changes provide laboratory evidence of immunological abnormalities in this syndrome, and, we suggest, may be consistent with persistent viral infection.

 

Source: Morrison LJ, Behan WH, Behan PO. Changes in natural killer cell phenotype in patients with post-viral fatigue syndrome. Clin Exp Immunol. 1991 Mar;83(3):441-6. http://www.ncbi.nlm.nih.gov/pubmed/1706238

You can read the full article here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1535328/

 

Chronic fatigue syndrome: I. Epstein-Barr virus immune response and molecular epidemiology

Abstract:

Patients with chronic fatigue syndrome were compared to healthy seropositive control subjects in an open study and a case-control study analyzing spontaneous transformation rates of peripheral blood lymphocytes, EBV viral genome characteristics as determined by DNA restriction fragment polymorphisms, and antibody production by Western blot analysis.

Thirty percent of patients versus 8% of control subjects underwent spontaneous transformation in the two studies. Viral genome patterns were overall similar to one another, with polymorphisms frequently present in BamHI B’, K, H, and Y fragments. Only one line was found with the EBNA-2B genotype.

Nineteen lines were found to contain viral DNA in the linear form suggesting active lytic replication. Western blot studies suggested that ill subjects made antibodies to lytic proteins more frequently than did healthy control subjects. Lack of control of EBV outgrowth in vitro is correlated with antibody evidence of active infection in vivo in some patients with chronic fatigue syndrome.

 

Source: Jones JF, Streib J, Baker S, Herberger M. Chronic fatigue syndrome: I. Epstein-Barr virus immune response and molecular epidemiology. J Med Virol. 1991 Mar;33(3):151-8. http://www.ncbi.nlm.nih.gov/pubmed/1679118

 

Cognitive behaviour therapy in chronic fatigue syndrome

Abstract:

Fifty patients fulfilling operational criteria for the chronic fatigue syndrome (CFS), and who had been ill for a mean of five years, were offered cognitive behaviour therapy in an open trial. Those fulfilling operational criteria for depressive illness were also offered tricyclic antidepressants. The rationale was that a distinction be drawn between factors that precipitate the illness and those that perpetuate it.

Among the latter are cognitive factors such as the belief that physical symptoms always imply tissue damage, and behavioural factors such as persistent avoidance of activities associated with an increase in symptoms. Therapy led to substantial improvements in overall disability, fatigue, somatic and psychiatric symptoms. The principal problems encountered were a high refusal rate and difficulties in treating affective disorders. Outcome depended more on the strength of the initial attribution of symptoms to exclusively physical causes, and was not influenced by length of illness.

These results suggest that current views on both treatment and prognosis in CFS are unnecessarily pessimistic. It is also suggested that advice currently offered to chronic patients, to avoid physical and mental activity, is counterproductive.

 

Source: Butler S, Chalder T, Ron M, Wessely S. Cognitive behaviour therapy in chronic fatigue syndrome. J Neurol Neurosurg Psychiatry. 1991 Feb;54(2):153-8. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1014351/

 

A report–chronic fatigue syndrome: guidelines for research

Introduction:

Patients who present with a principal complaint of disabling fatigue of uncertain cause have received much attention in recent years. Correspondingly there has been an increasing amount of research into this problem. The findings have however often been contradictory. Resolution of these contradictions depends on the ability to compare research studies, but such constructive comparison has rarely been possible. This is largely because research has been carried out by investigators trained in different disciplines, using different criteria to define the condition. Whilst such an eclectic approach is to be welcomed, agreement on case definition, and assessment methods is necessary if progress is to be made.

You can read the rest of this article here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1293107/pdf/jrsocmed00127-0072.pdf

 

Source: Sharpe MC, Archard LC, Banatvala JE, Borysiewicz LK, Clare AW, David A, Edwards RH, Hawton KE, Lambert HP, Lane RJ, et al. A report–chronic fatigue syndrome: guidelines for research. J R Soc Med. 1991 Feb;84(2):118-21. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1293107/

 

Muscle performance, voluntary activation, twitch properties and perceived effort in normal subjects and patients with the chronic fatigue syndrome

Abstract:

The decrease in maximal force-generating capacity, the degree of central activation of the muscle, and the subjective perception of effort were measured during prolonged submaximal isometric exercise in 12 male patients suffering from the ‘chronic fatigue syndrome’ and 13 naive, healthy male subjects.

Maximal voluntary isometric torque generated by the elbow flexors was measured before, and at 5 min intervals during an endurance sequence of 45 min of repetitive isometric contractions (6 s duration, 4 s rest interval) producing 30% of the initial maximal voluntary torque. Electrical stimuli were also delivered to the elbow flexors to measure the contractile force in the intervals between voluntary contractions. The degree of central motor activation during maximal voluntary contractions was assessed using a sensitive method of twitch interpolation.

In addition, the perceived effort required to achieve the target submaximal contractions was recorded using a standardized self-report scale. A high degree of central activation was achieved in maximal contractions during the endurance sequence both in the patients (mean of maximal force 93.6%; SD 7.8%), and in the control subjects (mean 90.9%; SD 9.5%).

The relative torque produced by either voluntary or electrically stimulated contractions was not significantly different between patients and control subjects throughout the test. There was no significant difference in the perceived exertion between the patients and control subjects.

These findings support the concept that neither poor motivation, nor muscle contractile failure is important in the pathogenesis of ‘fatigue’ in patients with the chronic fatigue syndrome.

 

Source: Lloyd AR, Gandevia SC, Hales JP. Muscle performance, voluntary activation, twitch properties and perceived effort in normal subjects and patients with the chronic fatigue syndrome. Brain. 1991 Feb;114 ( Pt 1A):85-98. http://www.ncbi.nlm.nih.gov/pubmed/1998892

 

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