Chronic fatigue syndrome and the diagnostic utility of antibody to Epstein-Barr virus early antigen

Abstract:

Antibody to Epstein-Barr virus (EBV) early antigen has been said to be the most specific indicator of symptomatic chronic EBV infection. We studied the clinical utility of this serologic test in the evaluation of patients with chronic fatigue.

Thirty patients with chronic fatigue and highly elevated titers of antibody to early antigen (greater than or equal to 1:160) were compared with 30 age- and sex-matched controls with no antibody to early antigen.

There were no significant differences noted between patients and controls at the initial evaluation (symptoms, physical examination, laboratory data). Follow-up information, available for 15 matched pairs, showed no differences in outcome between patients and controls. We conclude that the antibody to EBV early antigen is not helpful in the clinical evaluation of patients with chronic fatigue.

 

Source: Hellinger WC1, Smith TF, Van Scoy RE, Spitzer PG, Forgacs P, Edson RS. Chronic fatigue syndrome and the diagnostic utility of antibody to Epstein-Barr virus early antigen. JAMA. 1988 Aug 19;260(7):971-3. http://www.ncbi.nlm.nih.gov/pubmed/2840523

 

Antibodies to Epstein-Barr virus-specific DNase and DNA polymerase in the chronic fatigue syndrome

Abstract:

In an attempt to examine further the association between active Epstein-Barr virus (EBV) infection and the chronic fatigue syndrome (chronic EBV syndrome, or chronic or atypical mononucleosis), antibodies acting against EBV-specific DNase and DNA polymerase, which are expressed only during virus replication, were assayed.

Serum samples from 25 healthy EBV-seropositive individuals neutralized 3.5 +/- 5.1 U (mean +/- SD) of DNase activity and 14.7 +/- 8.5 U of DNA polymerase activity. From these values were selected upper limits of anti-EBV enzyme activity of 17.9 and 31.3 U neutralized in normal individuals, respectively (representing the 95% confidence limit). Serum samples from six groups of subjects representing a variety of EBV-related illnesses were then studied.

Only patients with notably elevated anti-EBV antibody titers to viral capsid antigen (VCA) (greater than 10,000) had elevated levels of anti-EBV DNase (38 to 56 U neutralized) and anti-EBV DNA polymerase (72 to 106 U neutralized). Three additional patients and two geriatric controls with average anti-EBV early antigen/VCA titers had slightly elevated levels of antibody to EBV DNA polymerase. IgA anti-VCA, anti-early antigen antibodies, or both, were also detected in the same patients who had high EBV DNase and polymerase antibody levels.

These antibody profiles are similar to those in patients with nasopharyngeal carcinoma. Since three of the six patients with elevated anti-EBV enzyme antibody levels developed fatal lymphomas, patients with chronic EBV and this antibody profile might be in another illness category at risk for malignant disease.

 

Source: Jones JF, Williams M, Schooley RT, Robinson C, Glaser R. Antibodies to Epstein-Barr virus-specific DNase and DNA polymerase in the chronic fatigue syndrome. Arch Intern Med. 1988 Sep;148(9):1957-60. http://www.ncbi.nlm.nih.gov/pubmed/2843138

 

Chronic mononucleosis syndrome

Abstract:

We present data on 14 patients with chronic symptoms of disabling fatigue in association with serologic evidence of active Epstein-Barr virus (EBV) infection. Two thirds were women, and the average age at onset was 29.6 years. Forty-three percent were known to have had previous infectious mononucleosis, but the usual criteria for that diagnosis were not helpful with the present syndrome.

Eighty-six percent had serologic evidence of cytomegalovirus (CMV) infection. Profound immunodeficiency was not present, but 71% had partial hypogammaglobulinemia, and minor abnormalities of T cell subsets were noted in six of seven patients studied.

Fifty-seven percent achieved temporary serologic and symptomatic remission after an average duration of 33 months. Only one patient has a sustained remission.

Comparison is made with other reported chronic, recurrent, and persistent EBV syndromes, and tentative diagnostic criteria for chronic mononucleosis syndrome are presented. Recently available EBV serologic techniques allow for identification of patients who have reactivated EBV infection, and this reactivation may be related to symptoms.

 

Source: DuBois RE, Seeley JK, Brus I, Sakamoto K, Ballow M, Harada S, Bechtold TA, Pearson G, Purtilo DT. Chronic mononucleosis syndrome. South Med J. 1984 Nov;77(11):1376-82.  http://www.ncbi.nlm.nih.gov/pubmed/6093268

 

A cluster of patients with a chronic mononucleosis-like syndrome. Is Epstein-Barr virus the cause?

Abstract:

A cluster of 134 patients who had undergone Epstein-Barr virus (EBV) serological testing because of suspected chronic EBV syndrome was investigated in Nevada.

Fifteen case-patients were identified who had severe, persistent fatigue of undetermined etiology for more than two months. When compared with the remaining 119 patients who had less severe illnesses and with 30 age-, sex-, and race-matched control-persons, these 15 patients had significantly higher antibody titers against various components of EBV and against cytomegalovirus and herpes simplex and measles viruses. Epstein-Barr virus serology could not reliably differentiate individual case-patients from the others, and the reproducibility of the tests within and among laboratories was poor.

As a group, the case-patients appear to have had a syndrome that is characterized by chronic fatigue, fever, sore throat, and lymphadenopathy. The relationship of this fatigue syndrome to EBV is unclear; further studies are needed to determine its etiology.

 

Source: Holmes GP, Kaplan JE, Stewart JA, Hunt B, Pinsky PF, Schonberger LB. A cluster of patients with a chronic mononucleosis-like syndrome. Is Epstein-Barr virus the cause? JAMA. 1987 May 1;257(17):2297-302. http://www.ncbi.nlm.nih.gov/pubmed/3033337

 

Frequency of ‘chronic active Epstein-Barr virus infection’ in a general medical practice

Abstract:

Twenty-one percent of 500 unselected patients, aged 17 to 50 years, seeking primary care for any reason were found to be suffering from a chronic fatigue syndrome consistent with “chronic active Epstein-Barr virus (EBV) infection,” They had been experiencing “severe” fatigue, usually cyclic, for a median of 16 months (range, six to 458 months), associated with sore throat, myalgias, or headaches; 45% of the patients were periodically bedridden; and 25% to 73% reported recurrent cervical adenopathy, paresthesias, arthralgias, and difficulty in concentrating or sleeping.

The patients had no recognized chronic “physical” illness and were not receiving psychiatric care. While antibody titers to several EBV-specific antigens were higher in patients than in age- and sex-matched controls subjects, the differences generally were not statistically significant.

A chronic fatigue syndrome consistent with the chronic active EBV infection syndrome was prevalent in our primary care practice. However, our data offer no evidence that EBV is causally related to the syndrome. Indeed, we feel that among unselected patients seen in a general medical practice currently available EBV serologic test results must be interpreted with great caution.

 

Source: Buchwald D, Sullivan JL, Komaroff AL. Frequency of ‘chronic active Epstein-Barr virus infection’ in a general medical practice. JAMA. 1987 May 1;257(17):2303-7. http://www.ncbi.nlm.nih.gov/pubmed/3033338

 

Phenotypic and functional deficiency of natural killer cells in patients with chronic fatigue syndrome

Abstract:

Natural killer (NK)3 cells are large granular lymphocytes that appear to play a significant role in the host’s defense against viral infection. We performed an extensive phenotypic and functional characterization of NK cells on 41 patients with the chronic fatigue syndrome (CFS), or “chronic active Epstein-Barr virus infection” syndrome, and on 23 age- and sex-matched asymptomatic control subjects in an attempt to further characterize this illness.

These studies demonstrated that a majority of patients with CFS have low numbers of NKH1+T3- lymphocytes, a population that represents the great majority of NK cells in normal individuals. CFS patients had normal numbers of NKH1+T3+ lymphocytes, a population that represents a relatively small fraction of NK cells in normal individuals.

When tested for cytotoxicity against a variety of different target cells, patients with CFS consistently demonstrated low levels of killing. After activation of cytolytic activity with recombinant interleukin 2, patients were able to display increased killing against K562 but most patients remained unable to lyse Epstein-Barr virus-infected B cell targets. Additional cytotoxicity experiments were carried out utilizing anti-T3 monoclonal antibody to block killing by NKH1+T3+ cells.

These experiments indicated that the NK cell that appears to be responsible for much of the functional activity remaining in patients with CFS belongs to the NKH1+T3+ subset, which under normal circumstances represents only approximately 20% of the NK cell population.

 

Source: Caligiuri M, Murray C, Buchwald D, Levine H, Cheney P, Peterson D, Komaroff AL, Ritz J. Phenotypic and functional deficiency of natural killer cells in patients with chronic fatigue syndrome. J Immunol. 1987 Nov 15;139(10):3306-13. http://www.ncbi.nlm.nih.gov/pubmed/2824604

 

Scientists Discover Robust Evidence That Chronic Fatigue Syndrome Is a Biological Illness

cytokines
All twenty-four cytokines were altered in both long- and short-term patients compared to controls.

Press Release: NEW YORK (Feb. 27, 2015)—Researchers at the Center for Infection and Immunity at Columbia University’s Mailman School of Public Health identified distinct immune changes in patients diagnosed with chronic fatigue syndrome, known medically as myalgic encephalomyelitis (ME/CFS) or systemic exertion intolerance disease. The findings could help improve diagnosis and identify treatment options for the disabling disorder, in which symptoms range from extreme fatigue and difficulty concentrating to headaches and muscle pain.

These immune signatures represent the first robust physical evidence that ME/CFS is a biological illness as opposed to a psychological disorder, and the first evidence that the disease has distinct stages. Results appear online in the new American Association for the Advancement of Science journal, Science Advances.

With funding to support studies of immune and infectious mechanisms of disease from the Chronic Fatigue Initiative of the Hutchins Family Foundation, the researchers used immunoassay testing methods to determine the levels of 51 immune biomarkers in blood plasma samples collected through two multicenter studies that represented a total of 298 ME/CFS patients and 348 healthy controls. They found specific patterns in patients who had the disease three years or less that were not present in controls or in patients who had the disease for more than three years. Short duration patients had increased amounts of many different types of immune molecules called cytokines. The association was unusually strong with a cytokine called interferon gamma that has been linked to the fatigue that follows many viral infections, including Epstein-Barr virus (the cause of infectious mononucleosis). Cytokine levels were not explained by symptom severity.

“We now have evidence confirming what millions of people with this disease already know, that ME/CFS isn’t psychological,” states lead author Mady Hornig, MD, director of translational research at the Center for Infection and Immunity and associate professor of Epidemiology at Columbia’s Mailman School. “Our results should accelerate the process of establishing the diagnosis after individuals first fall ill as well as discovery of new treatment strategies focusing on these early blood markers.”

There are already human monoclonal antibodies on the market that can dampen levels of a cytokine called interleukin-17A that is among those the study shows were elevated in early-stage patients. Before any drugs can be tested in a clinical trial, Dr. Hornig and colleagues hope to replicate the current, cross-sectional results in a longitudinal study that follows patients for a year to see how cytokine levels, including interleukin-17A, differ within individual patients over time, depending on how long they have had the disease.

Stuck in High Gear

The study supports the idea that ME/CFS may reflect an infectious “hit-and-run” event. Patients often report getting sick, sometimes from something as common as infectious mononucleosis (Epstein-Barr virus), and never fully recover. The new research suggests that these infections throw a wrench in the immune system’s ability to quiet itself after the acute infection, to return to a homeostatic balance; the immune response becomes like a car stuck in high gear. “It appears that ME/CFS patients are flush with cytokines until around the three-year mark, at which point the immune system shows evidence of exhaustion and cytokine levels drop,” says Dr. Hornig. “Early diagnosis may provide unique opportunities for treatment that likely differ from those that would be appropriate in later phases of the illness.”

The investigators went to great lengths to carefully screen participants to make sure they had the disease. The researchers also recruited greater numbers of patients whose diagnosis was of relatively recent onset. Patients’ stress levels were standardized; before each blood draw, patients were asked to complete standardized paperwork, in part to engender fatigue. The scientists also controlled for factors known to affect the immune system, including the time of day, season and geographic location where the samples were taken, as well as age, sex and ethnicity/race.

In 2012, W. Ian Lipkin, MD, director of the Center for Infection and Immunity, and colleagues reported the results of a multicenter study that definitively ruled out two viruses thought to be implicated in ME/CFS: XMRV (xenotropic murine leukemia virus [MLV]-related virus) and murine retrovirus-like sequences (designated pMLV: polytropic MLV). In the coming weeks, Drs. Hornig and Lipkin expect to report the results of a second study of cerebrospinal fluid from ME/CFS patients. In separate ongoing studies, they are looking for “molecular footprints” of the specific agents behind the disease—be they viral, bacterial, or fungal—as well as the longitudinal look at how plasma cytokine patterns change within ME/CFS patients and controls across a one-year period, as noted above.

“This study delivers what has eluded us for so long: unequivocal evidence of immunological dysfunction in ME/CFS and diagnostic biomarkers for disease,” says senior author W. Ian Lipkin, MD, also the John Snow Professor of Epidemiology at Columbia’s Mailman School. “The question we are trying to address in a parallel microbiome project is what triggers this dysfunction.”

Co-authors include Andrew F. Schultz, Xiaoyu Che, and Meredith L. Eddy at the Center for Infection and Immunity; Jose G. Montoya at Stanford University; Anthony L. Komaroff at Harvard Medical School; Nancy G. Klimas at Nova Southeastern University; Susan Levine at Levine Clinic; Donna Felsenstein at Massachusetts General Hospital; Lucinda Bateman at Fatigue Consultation Clinic; and Daniel L. Peterson and Gunnar Gottschalk at Sierra Internal Medicine. The authors report no competing interests.

Support for the study was provided by the Chronic Fatigue Initiative of the Hutchins Family Foundation and the National Institutes of Health (AI057158; Northeast Biodefense Center-Lipkin).

About Columbia University’s Mailman School of Public Health

Founded in 1922, Columbia University’s Mailman School of Public Health pursues an agenda of research, education, and service to address the critical and complex public health issues affecting New Yorkers, the nation and the world. The Mailman School is the third largest recipient of NIH grants among schools of public health. Its over 450 multi-disciplinary faculty members work in more than 100 countries around the world, addressing such issues as preventing infectious and chronic diseases, environmental health, maternal and child health, health policy, climate change & health, and public health preparedness. It is a leader in public health education with over 1,300 graduate students from more than 40 nations pursuing a variety of master’s and doctoral degree programs. For more information, please visit www.mailman.columbia.edu.

# # #

Media contact: Tim Paul, Columbia University’s Mailman School of Public Health, 212-305-2676 or tp2111@columbia.edu.

Note: You can read the full text of the Columbia study HERE.

 

Immune Markers in Cerebrospinal Fluid Provide Insights Into the Basis for Symptoms Like “Brain Fog”

Press Release: Mailman School of Public Health, March 30, 2015. Scientists at Columbia University’s Mailman School of Public Health have identified a unique pattern of immune molecules in the cerebrospinal fluid of people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) that provides insights into the basis for cognitive dysfunction—frequently described by patients as “brain fog”—as well as new hope for improvements in diagnosis and treatment.

In the study published in Molecular Psychiatry, Mady Hornig, MD, and colleagues used immunoassay testing methods to measure levels of 51 immune biomarkers called cytokines in the cerebrospinal fluid of 32 people with ME/CFS for an average of seven years, 40 with multiple sclerosis, and 19 non-diseased controls. The researchers found that levels of most cytokines, including the inflammatory immune molecule interleukin 1, were depressed in individuals with ME/CFS compared with the other two groups, matching what was seen in a blood study in patients who had the disease for more than three years. One cytokine—eotaxin—was elevated in the ME/CFS and MS groups, but not in the control group.

“We now know that the same changes to the immune system that we recently reported in the blood of people with ME/CFS with long-standing disease are also present in the central nervous system,” says Dr. Hornig, professor of Epidemiology and director of translational research at the Center for Infection and Immunity at the Mailman School. “These immune differences may contribute to symptoms in both the peripheral parts of the body and the brain, from muscle weakness to brain fog.”

Implications for Diagnosis and Treatment

“Diagnosis of ME/CFS is now based on clinical criteria. Our findings offer the hope of objective diagnostic tests for disease as well as the potential for therapies that correct the imbalance in cytokine levels seen in people with ME/CFS at different stages of their disease,” adds W. Ian Lipkin, MD, John Snow Professor of Epidemiology and director of the Center for Infection and Immunity.

There is precedent for use of human monoclonal antibodies that regulate the immune response in a wide range of disorders from rheumatoid arthritis to multiple sclerosis. However, the researchers note, additional work will be needed to assess the safety and efficacy of this approach.

The study was supported by a grant from the Chronic Fatigue Initiative of the Hutchins Family Foundation and the Edward P. Evans Foundation.

Additional authors include Andrew F. Schultz, Meredith L. Eddy and Xiaoyu Che at the Mailman School; C. Gunnar Gottschalk and Daniel L. Peterson at Sierra Internal Medicine in Incline Village, NV; and Konstance K. Knox at Coppe Health Care Solutions in Waukesha, WI, and Simmaron Research in Incline Village, NV.

Journal Reference: M Hornig, G Gottschalk, D L Peterson, K K Knox, A F Schultz, M L Eddy, X Che, W I Lipkin. Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome. Molecular Psychiatry, 2015; DOI: 10.1038/mp.2015.29

 

Reduced gait automaticity in female patients with chronic fatigue syndrome: Case-control study

Abstract:

Patients with chronic fatigue syndrome (CFS) report difficulties walking for a prolonged period of time. This study compares gait automaticity between women with CFS and nondisabled controls.

The “stops walking with eyes closed with secondary cognitive task” test is based on the classic “stops walking while talking” test but compares walking with eyes closed while performing a secondary cognitive task in a female CFS population (n = 34) and in female nondisabled controls (n = 38).

When initiating gate, 23.5% of patients with CFS looked toward the ground compared with only 2.6% of nondisabled controls. After 7 m, subjects were asked to close their eyes, and after another 7 m, they were asked, “How much is 100 minus 7?” Of the patients with CFS, 55.9% stopped walking compared with 5.3% of nondisabled controls. Less automated walking was observed in patients with CFS than in nondisabled controls (p < 0.001). The test-retest reliability is moderate for global stopping.

This simple test observed reduced gait automaticity in patients with CFS for the first time. Dual tasking could be helpful to address the functional limitations found in this particular study.

 

Source: Jan b Eyskens, Jo Nijs, Kristien Wouters, Greta Moorkens. Reduced gait automaticity in female patients with chronic fatigue syndrome: Case-control study. Journal of Rehabilitation Research & Development (JRRD), Volume 52 Number 7, 2015, Pages 805 — 814.
Note: You can read the full study HERE.

Epidemic myalgic encephalomyelitis

The letter below, “Epidemic myalgic encephalomyelitis,” was published in the British Medical Journal in 1978. In it, the authors maintain that ME is an organic illness that exists as a distinct clinical entity with recognizable signs and symptoms. The authors propose that the cause may be “a persistent viral infection.

 

Epidemic myalgic encephalomyelitis

Outbreaks of the paralytic disease known as epidemic myalgic encephalomyelitis have puzzled doctors all over the world in the past 30 years. One of the best known of these epidemics was that at the Royal Free Hospital in London in 1955, which affected more than 300 people. (1) Most outbreaks tend to occur in the summer, young adults are predominantly affected, and the incidence is higher in women. The evidence suggests that infection is spread by personal contact, and young hospital personnel seem particularly at risk. The features common to every epidemic include headache, unusual muscular pains (which may be severe), lymphadenopathy-often of the posterior cervical lymph nodes-and low-grade fever.(2, 3) In a minority of cases frank neurological signs can be detected by careful clinical examination: there may be nystagmus, diplopia, myoclonus, bulbar weakness, motor weakness, increased or decreased tendon reflexes, disturbances of the sphincters, and extensor plantar responses.(2-7) Fasciculations, cranial nerve lesions, and extrapyramidal signs have also been reported. Most patients complain of paraesthesiae, and sensory loss is common.”(4) One characteristic feature of the disease is exhaustion, any effort producing generalised fatigue. Often there are psychiatric abnormalities, especially emotional lability and lack of concentration.(1- 3, 4) The clinical outcome may take any of three courses: some patients recover completely, some follow a relapsing course, and some are permanently incapacitated.(3)

At a symposium held recently at the Royal Society of Medicine to discuss the disease and plan research there was clear agreement that myalgic encephalomyelitis is a distinct nosological entity. Other terms that have been used to describe the disease were rejected as unsatisfactory for various reasons: the cardinal clinical features show that the disorder is an encephalomyelitis; “Iceland disease” is not specific enough; and “neuromyasthenia” suggests a relation to myasthenia gravis whereas the muscle fatigability is different, as are the electrophysiological findings.(8) Indeed, the exhaustion and tiredness are similar to that described by patients with multiple sclerosis.(9) From the patient’s point of view the designation benign is also misleading, since the illness may be devastating. Originally the term was used because no deaths had been recorded from myalgic encephalomyelitis. Two patients who had had the disease have now been examined post mortem: one was found to have multiple sclerosis. The adjective epidemic is correct, since most cases occur in an epidemic, but the disease may be endemic, and sporadic cases may occur. (10-12)

Some authors have attempted to dismiss this disease as hysterical, (13) but the evidence now makes such a tenet unacceptable. Some purely psychiatric symptoms may well occur, particularly in patients entering the chronic phase. No doubt, too, in an epidemic some hysterical persons will simulate the symptoms of the disease. Nevertheless, the organic basis is clear-from the finding that the putative agent can be transferred to monkeys(14); the detection of an increased urinary output of creatine2 (15); the persistent finding of abnormal lymphocytes in the peripheral blood of some patients (16); the presence of lymphocytes and an increased protein concentration in the cerebrospinal fluid of occasional patients (3); and the neurological findings. At this symposium more evidence was produced to support the organic nature of the disease. Increased serum concentrations of lactic dehydrogenases and transaminases have been found in several patients examined during the acute attack. In a recent outbreak in London immunological studies showed a high incidence of serum anticomplementary activity and the presence of ill-defined aggregates on electron microscopy of acute-phase sera.(17) A perplexing finding, suggesting the possibility of a persistent virus infection, was the ability of lymphocytes from patients to proliferate and survive in vitro for up to 19 weeks. The results of electroencephalographic studies were also stated to be abnormal, confirming other reports. (10)

We still know nothing about the nature and cause of epidemic myalgic encephalomyelitis, but outbreaks are still occurring. Future epidemics should be studied by a collaborative team of neurologists, epidemiologists, virologists, and immunologists. Its findings would be important not only for the study of epidemic myalgic encephalomyelitis but also for other neurological disorders, including multiple sclerosis.

1 British Medical Journal, 1957, 2, 895.

2 White, D N, and Burtch, R B, Neurology, 1954, 4, 506.

3 Acheson, E D, American Journal of Medicine, 1959, 26, 569.

4 Gilliam, A G, Epidemiological Study of an Epidemic, Public Health Bulletin, No 240. US Public Health Service, Washington, 1938.

5 Acheson, E D, Lancet, 1955, 2, 394.

6 Pellew, R A A, Medical Journal of Australia, 1951, 1, 944.

7 Hill, R C J, South African Medical Journal, 1955, 29, 344.

8 Richardson, A T, Annals of Physical Medicine, 1956, 3, 81.

9 McAlpine, D, Compston, N D, and Lumsden, C E, Multiple Sclerosis, chap 5. Edinburgh and London, Livingstone, 1955. ”

10 Ramsay, A M, and O’Sullivan, E, Lancet, 1956, 1, 761.

11 Jelinek, J E, Lancet, 1956, 2, 494.

12 Ramsay, A M, Lancet, 1957, 2, 1196.

13 McEvedey, C P, and Beard, A W, British Medical Journal, 1970, 1, 7.

14 Pellew, R A A, and Miles, J A R, Medical Journal of Australia, 1955, 2, 480.

15 Albrecht, R M, Oliver, V L, and Poskanzer, D C, Journal of the American Medical Association, 1964, 187, 904.

16 Wallis, A L, MD Thesis, Edinburgh University, 1957.

17 Dillon, M J, et al, British Medical Journal, 1974, 1, 301.

 

Source: BRITISH MEDICAL JOURNAL 3 JUNE 1978 1436-1437

You can read and download a PDF file of the letter at:  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1604957/?page=1