Chronic fatigue syndrome associated with Epstein-Barr virus infection

Abstract:

Epstein-Barr virus (EBV) infection is ubiquitous and may result in multiple and widely different clinical features; the most common of these is infectious mononucleosis (IM). Recently, a group of patients has been included in the chronic EBV infection syndrome (EBVIS), with a sustained nonspecific syndrome consisting of asthenia, anorexia, low grade fever and changes in mood, associated with a viral infection not necessarily caused by EBV; this has been called chronic fatigue syndrome (CFS). We report a patient who fulfilled the criteria for CFS associated with EBV after an acute, well documented EBV infection. We discuss its etiological and pathophysiological implications, emphasizing the need for extreme caution in the diagnosis of CFS. A merely clinical diagnosis may hide severe mistakes.

 

Source: Parras F, Salvá F, Reina J, Gil J, Portela D, Alomar P. Chronic fatigue syndrome associated with Epstein-Barr virus infection. Med Clin (Barc). 1989 Apr 29;92(16):619-22. [Article in Spanish] http://www.ncbi.nlm.nih.gov/pubmed/2545980

 

Chronic fatigue syndrome. A critical appraisal of the role of Epstein-Barr virus

Abstract:

The symptom complex currently designated the chronic fatigue syndrome was previously termed the chronic or chronic active Epstein-Barr virus syndrome or the chronic mononucleosis syndrome, prematurely assuming an etiologic role for the Epstein-Barr virus (EBV). This presumption derived from the fact that some patients with the chronic fatigue syndrome have very high or very low titers of certain antibodies to EBV.

A review of seroepidemiologic patterns of response to EBV and of studies of patients with the chronic fatigue syndrome shows that these antibody titers overlap considerably both with those of controls or other healthy persons and with those of patients with other illnesses.

Given the high prevalence of exposure to EBV, it would be difficult to determine whether the virus caused the syndrome or whether the antibody elevations resulted from the illness, even if distinct differences in titers existed. Other methodologic issues of control selection, laboratory test comparability, and differing case definitions pose problems in studying this syndrome. The recently published working case definition should facilitate the continuing search for causes.

 

Source: D Koo. Chronic fatigue syndrome. A critical appraisal of the role of Epstein-Barr virus. West J Med. 1989 May; 150(5): 590–596. PMCID: PMC1026689 (Full article) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1026689/

 

Chronic fatigue syndrome

I was surprised that CMAJ published the letter from Drs. Gerald H. Ross and Jean A. Monro (Can Med Assoc J 1989; 140: 361) supporting such a vague, descriptive and unscientific term as “chronic fatigue syndrome”. As a practising psychiatrist I have attempted to emphasize that there are also primary psychologic causes of chronic fatigue such as depression and panic disorder (ibid: 361, 364); thus, it is more prudent to consider the relative causes of chronic fatigue than to create a “syndrome” that imposes a diagnostic life sentence of an incurable disease.

That a minuscule percentage of cases of chronic fatigue are due to chronic mononucleosis, other chronic infections and chemical sensitivity is not disputed. What is disputed is the number so diagnosed, particularly now that panic disorder – a primarily psychologic condition that causes chronic fatigue but is more amenable to treatment (antidepressant medication and dynamic insight-oriented psychotherapy) – appears to be reaching epidemic proportions. (1) Therefore, at the risk of considerable ideologic unpopularity, it would seem, I must repeat: “Primum non nocere.”

The statement by Ross and Monro that magnesium deficiency is associated with chemical sensitivity means just that and only that.

Ross and Monro’s six references are not definitive enough, the possible exception being the article of Tosato and colleagues (2) if – and only if – the chronic infectious mononucleosis referred to in the title was confirmed by serologic evidence of an acute attack. (3)

Ross and Monro display psychologic “sympathy” with “empathy” and quote me as referring to the term “psychosomatic” when I used the term “psychologic”.

“Syndromes” like “chronic fatigue syndrome” lessen the burden of introspection. In reverence to the “father” of nosology, Thomas Sydenham, and the “father” of psychiatry, Sigmund Freud, I must state, as a traditionally oriented psychiatrist, that it is nontherapeutic to condone self-defeating behaviour.

~Ray Holland, MD, FRCPC Box 458 Port Colborne, Ont.

References

1. Introduction. In Summary Proceedings of “Panic Disorder – Relative Merits of Pharmacotherapy and Psychotherapy” (satellite symposium of 1988 American Psychiatric Association annual meeting), Medical Group, Mississauga, Ont, 1988
2. Tosato G, Straus SE, Werner H et al: Characteristic T cell dysfunction in patients with chronic active EpsteinBarr virus infection (chronic infectious mononucleosis). J Immunol 1985; 134:3082-3088
3. Evans AS: A virus for all seasons.Buffalo Phys Biomed Sci 1988; 22 (2):14-15

 

Source: R Holland. Chronic fatigue syndrome. CMAJ. 1989 May 1; 140(9): 1016. PMCID: PMC1268972
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1268972/pdf/cmaj00190-0022b.pdf

 

Immunotherapy and enhanced antibody-dependent cell-mediated cytotoxicity using virally-infected target cells

Abstract:

We examined the ability of in vitro addition of Interleukin-2 (IL-2) to differentially enhance antibody-dependent cell mediated cytotoxicity (ADCC) utilizing cultured Epstein-Barr virus infected cells and gammaglobulin (Sandoglobulin). We found significant enhancement of ADCC when IL-2 was added. Chronic Epstein-Barr virus or Chronic Fatigue Syndrome patients in a therapeutic gammaglobulin program may benefit from IL-2 given in vivo.

 

Source: Bosse D, Ades EW. Immunotherapy and enhanced antibody-dependent cell-mediated cytotoxicity using virally-infected target cells. J Clin Lab Immunol. 1989 Jul;29(3):109-10. http://www.ncbi.nlm.nih.gov/pubmed/2561291

 

Chronic fatigue syndrome

Note: This letter was written in response to a letter published in the Canadian Medical Association Journal on May 1, 1989. You can read Holland’s letter here:  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1268972/pdf/cmaj00190-0022b.pdf

 

It is regrettable that the publication of an earlier letter from one of us (G.H.R.) and Dr. Jean A. Monro (Can Med Assocj 1989; 140: 361) generated surprise (and apparent disapproval of CMAJ’s action) on the part of Dr. Ray Holland (ibid 1016).

In expressing his disagreement with the use of the term “chronic fatigue syndrome” Holland also appears to be at odds with the US Centers for Disease Control (CDC), whose case definition for this condition (1) was the main point of the earlier letter. We have no disagreement with Holland that “there are also primary psychologic causes of chronic fatigue”. However, the CDC case definition specifically calls for the exclusion of clinical conditions, including psychiatric disease, that may produce similar symptoms.

The whole issue of what triggers psychologic symptoms or illness, however, is an important related matter. Holland reports, quite rightly, that panic disorder appears to be increasingly common. As physicians we have been led to assume that panic disorder has a psychologic origin rather than identifiable extrinsic causes. At the Environmental Health Center – Dallas we have confirmed that panic attacks and other emotional responses may be reproducibly triggered by double-blind testing for sensitivities to foods, inhalants and chemicals. (2)

Similar behavioural effects have been seen in pesticide poisoning (3) and with exposure to other environmental toxins. (4) Specifically, panic attacks have been cited in the psychiatric literature as being triggered by solvent exposure. (5’6)

Being unable to find physical diagnoses for chronic fatigue does not necessarily mean that psychologic illness is the cause. It may simply be that our understanding of the factors precipitating the illness is far from complete. Medical history teaches us that once physical causes for “psychologic” symptoms are discovered the condition moves, as if by magic, from the psychiatric to the medical realm. A good example of this is the relief of behavioural symptoms by correction of thiamin (7) or cobalamin (8) deficiency.

It is our experience that a substantial percentage of chronic fatigue cases (not a minuscule percentage, as Holland suggests) may arise from or be worsened by adverse reactions to components of the patient’s total environment, such as food, inhalants and chemicals.

~Gerald H. Ross, MD, CCFP Fellow in environmental medicine

~William J. Rea, MD, FACS, FAAEM Medical director

~Alfred R. Johnson, DO, FAAEM Environmental Health Center – Dallas; Dallas, Texas

References

1. Holmes GP, Kaplan JE, Gantz NM et al: Chronic fatigue syndrome: a working case definition. Ann Intern Med 1988; 108: 387-389
2. King DS: Can allergic exposure provoke psychological symptoms? A double-blind test. Biol Psychiatry 1981; 16:3-19
3. Rea Wl, Butler JR, Laseter JL et al: Pesticides and brain function changes in a controlled environment. Clin Ecol 1984; 2:145-150
4. Fein GG, Schwartz PM, Jacobson SW et al: Environmental toxins and behavioral development: a new role for psychological research. Am Psychologist 1983; 38: 1188-1197
5. Dager SR, Holland JP, Cowley DS et al: Panic disorder precipitated by exposure to organic solvents in the work place. Am I Psychiatry 1987; 144:1056-1058
6. Lindstrom K, Ruhimake H, Hamminen K: Occupational solvent exposure and neuropsychiatric disorders. Scand J Work Environ Health 1984; 10: 321-323
7. McLaren DS: Clinical manifestations of nutritional disorders. In Shils ME, Young VR (eds): Modem Nutrition in Health and Disease, Lea and Febiger, Philadelphia, 1988: 733-745
8. Lindenbaum J, Healton EB, Savage DG, et al: Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N EnglJ Med 1988; 318: 1720-1729

 

Source: G H Ross, W J Rea, and A R Johnson. Chronic fatigue syndrome. CMAJ. 1989 Jul 1; 141(1): 11–12. PMCID: PMC1269261  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1269261/

 

Naloxone-reversible monocyte dysfunction in patients with chronic fatigue syndrome

Abstract:

We studied monocyte function in 35 consecutive patients with chronic fatigue syndrome (CFS) and 25 healthy controls. Eighty-five per cent of the patients showed monocyte dysfunction characterized by marked reduction in the number of monocytes displaying immunoreactive cytoskeletal vimentin filaments, a low phagocytosis index, and a reduced expression of HLA-DR antigens. These values increased dramatically after incubation of the patients’ monocytes with the opioid antagonist naloxone.

Other immunological abnormalities also noted in the patients were low lymphocyte blastogenesis and diminished numbers of monocytes displaying receptors for Fc of IgG (FcR) and C3b (CR1). These findings suggest that an increased opioid activity acting through a classical receptor mechanism is active on monocytes from a high proportion of patients with CFS and that this represents a novel example of immunomodulation by opioid peptides in human disease.

We suggest that endogenous opioids are involved in the pathogenesis of the chronic fatigue syndrome.

 

Source: Prieto J, Subirá ML, Castilla A, Serrano M. Naloxone-reversible monocyte dysfunction in patients with chronic fatigue syndrome. Scand J Immunol. 1989 Jul;30(1):13-20. http://www.ncbi.nlm.nih.gov/pubmed/2526966

 

Psychiatric diagnoses in patients who have chronic fatigue syndrome

Abstract:

Patients with persistent fatigue are often suspected of having psychiatric illnesses, particularly depression. The authors used the Diagnostic Interview Schedule to assess the lifetime prevalence of psychiatric disorders in 28 patients who met Centers for Disease Control case definition criteria for chronic fatigue syndrome. Compared with studies of the general population and studies of chronically medically ill patients who received the same structured interview, the rates of psychiatric illness in patients with the chronic fatigue syndrome appeared high. An examination of the medical histories of the 28 patients indicated that psychiatric disorders more often preceded the chronic fatigue than followed it.

 

Source: Kruesi MJ, Dale J, Straus SE. Psychiatric diagnoses in patients who have chronic fatigue syndrome. J Clin Psychiatry. 1989 Feb;50(2):53-6.  http://www.ncbi.nlm.nih.gov/pubmed/2536690

 

Post-viral fatigue syndrome: evidence for underlying organic disturbance in the muscle fibre

Abstract:

Ten patients with post-viral fatigue syndrome and abnormal serological, virological, immunological and histological studies were examined by the single-fibre electromyographic (EMG) technique after excluding concurrent problems in the neuromuscular system. No abnormality of fibre density was noted but all patients had abnormal jitter values. Very high jitter values were not associated with impulse or concomitant blocking. The findings confirm the organic nature of the disease. A muscle membrane disorder probably arising from defective myogenic enzymes is the likely mechanism for the fatigue and the single-fibre EMG abnormalities. This muscle membrane defect may be due to the effects of a persistent viral infection.

 

Source: Jamal GA, Hansen S. Post-viral fatigue syndrome: evidence for underlying organic disturbance in the muscle fibre. Eur Neurol. 1989;29(5):273-6.  http://www.ncbi.nlm.nih.gov/pubmed/2792146

 

Management of chronic (post-viral) fatigue syndrome

Abstract:

Simple rehabilitative strategies are proposed to help patients with the chronic fatigue syndrome. A model is outlined of an acute illness giving way to a chronic fatigue state in which symptoms are perpetuated by a cycle of inactivity, deterioration in exercise tolerance and further symptoms. This is compounded by the depressive illness that is often part of the syndrome. The result is a self-perpetuating cycle of exercise avoidance. Effective treatment depends upon an understanding of the interaction between physical and psychological factors. Cognitive behavioural therapy is suggested. Cognitive therapy helps the patient understand how genuine symptoms arise from the frequent combination of physical inactivity and depression, rather than continuing infection, while a behavioural approach enables the treatment of avoidance behaviour and a gradual return to normal physical activity.

 

Source: S Wessely, A David, S Butler, and T Chalder. Management of chronic (post-viral) fatigue syndrome. J R Coll Gen Pract. 1989 Jan; 39(318): 26–29. PMCID: PMC1711569 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1711569/ (Full article)

 

Acyclovir treatment of the chronic fatigue syndrome. Lack of efficacy in a placebo-controlled trial

Abstract:

Twenty-seven adults with a diagnosis of the chronic fatigue syndrome were enrolled in a double-blind, placebo-controlled study of acyclovir therapy. The patients had had debilitating fatigue for an average of 6.8 years, accompanied by persisting antibodies to Epstein-Barr virus early antigens (titers greater than or equal to 1:40) or undetectable levels of antibodies to Epstein-Barr virus nuclear antigens (titers less than 1:2) or both.

Each course of treatment consisted of intravenous placebo or acyclovir (500 mg per square meter of body-surface area) administered every eight hours for seven days. The same drug was then given orally for 30 days (acyclovir, 800 mg four times daily). There were six-week observation periods before, between, and after the treatments. Three patients had acyclovir-induced nephrotoxicity and were withdrawn from the study.

Of the 24 patients who completed the trial, similar numbers improved with acyclovir therapy and with placebo (11 and 10, respectively). Neither acyclovir treatment nor clinical improvement correlated with alterations in laboratory findings, including titers of antibody to Epstein-Barr virus or levels of circulating immune complexes or of leukocyte 2′,5′-oligoadenylate synthetase. Subjective improvement correlated with various measures of mood.

We conclude that acyclovir, as used in this study, does not ameliorate the chronic fatigue syndrome. We believe that the clinical improvement observed in most patients reflected either spontaneous remission of the syndrome or a placebo effect.

 

Source: Straus SE, Dale JK, Tobi M, Lawley T, Preble O, Blaese RM, Hallahan C, Henle W. Acyclovir treatment of the chronic fatigue syndrome. Lack of efficacy in a placebo-controlled trial. N Engl J Med. 1988 Dec 29;319(26):1692-8. http://www.ncbi.nlm.nih.gov/pubmed/2849717