Epstein-Barr
Virus
Borysiewicz LK, Haworth SJ, Cohen J, et al. Epstein-Barr virus-specific immune defects in patients with persistent symptoms following infectious mononucleosis. Quarterly Journal of Medicine 1986; 58: 111-21.
Buchwald D, Sullivan JL, Komaroff AL. Frequency of 'chronic active Epstein-Barr virus infection' in a general medical practice. Journal of the American Medical Associatioin 1987; 257: 2303-7.
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.
Cohen JI. Epstein-Barr Virus and the immune system. Journal of the American Medical Association 1997; 278(6): 510.
Editorial. EBV and persistent malaise. Lancet 1985; 1: 1017-18.
Gow PJ. Epstein-Barr virus and persistent malaise [Letter] Lancet 1985; 2: 105.
Halpin D, Wessely S. VP-1 antigen in chronic postviral fatigue syndrome [Letter]. Lancet 1989; 1: 1028-9.
Hellinger WC, 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. Journal of the American Medical Association 1988; 260: 971-3.
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.
Hellinger WC. The Epstein-Barr virus and chronic fatigue syndrome [Letter]. Journal of the American Medical Association 1989; 261: 1278.
Hermann WJ. The Epstein-Barr virus and chronic fatigue syndrome [Letter]. Journal of the American Medical Association 1989 Mar 3; 261: 1277-8.
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? Journal of the American Medical Association 1987; 257: 2297-302.
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.
Hotchin NA, Read R, Smith DG, Crawford DH. Active Epstein-Barr virus infection in post-viral fatigue syndrome. Journal of Infection 1989; 18: 143-50.
Abstract: Serological evidence of active infection with Epstein-Barr virus (EBV) was found in 25 of 124 patients (20%) with the post-viral fatigue syndrome (PVFS). In another study on the same group of patients around 50% were found to have evidence of chronic enterovirus infection. No overlap was found between those patients with enterovirus infection and those with active EBV infection. We suggest that there are multiple causes of PVFS and that, in the absence of coexisting immunosuppressive disease which may itself reactivate the virus, EBV may be the aetiological agent in a predominantly female subgroup of patients with PVFS. Furthermore, the disease process in this subgroup may be immunopathological in nature.
Jones JF, Ray G, Minnich LL, et al. Evidence of active Epstein-Barr virus infection in patients with persistent unexplained illnesses: elevated anti-early antigen antibodies. Annals of Internal Medicine 1985; 102: 1-7.
Abstract: Forty-four patients, including 26 adults and 18 children under 15 years of age, were referred for evaluation of recurrent or persistent illnesses, with symptoms including pharyngitis, lymphadenopathy, fever, headaches, arthralgia, fatigue, depression, dyslogia, and myalgia. Thirty-nine patients were positive for Epstein-Barr virus antibody with antibody levels compatible with active infection for at least 1 year. Antiviral capsid antigen and anti-early antigen titers of patients were significantly greater (p less than 0.001) than age-group-matched controls. The frequency, number, duration, and patterns of symptoms, as well as patient sex, were compared by age in study patients seropositive and seronegative for Epstein-Barr virus. Illness patterns were not associated with changes in specific antibody titers or clinical findings. Lymphocyte phenotype and function analyses were done in 11 of the 39 patients positive for Epstein-Barr virus antibody; no consistent differences from normal were found. Only 1 of 32 patients had circulating interferon, in contrast to 7 of 7 patients with acute infectious mononucleosis. There were many adverse consequences of the illness. Epstein-Barr virus infection may not be self-limiting, and the virus may be associated with clinically recognizable illness other than infectious mononucleosis in children as well as in adults.
Jones JF, Straus SE. Chronic Epstein-Barr virus infection. Annual Review of Medicine 1987; 38: 195-209.
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. Archives of Internal Medicine 1988; 148: 1957-60.
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.
Koo D. Chronic fatigue syndrome - A critical appraisal of the role of Epstein-Barr virus. Western Journal of Medicine 1989; 150: 590-6.
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.
Lerner AM, Zervos M, Dworkin HJ, Chang CH, Fitzgerald JT, Goldstein J. et al. New cardiomyopathy: pilot study of intravenous gangiclovir in a subset of the chronic fatigue syndrome. Infectious Diseases in Clinical Practice 1997; 6(2): 110-117.
Abstract: We describe a subset of patients with chronic fatigue syndrome (CFS) as defined by the CDC, a duration of overwhelming fatigue for < 2 years, and oscillating repetitively abnormal aberrant T-waves at 24-hour electrocardiogram (ECG) recordings (Holter monitors). Baseline 12-lead ECG, 2-D echocardiogram, rest/stress myocarial perfusion (thallium 201 or TC-99 sestamibi) and rest/stress multi-gaited acquisition studies, as well as coronary angiography excluded coronary artery disease. Patients in this CFS subset had significant Ig (with or without positive IgM) human cytomegalovirus enzyme-linked immunoassay antibody titers. They had little or no evidence of concurrent Epstein-Barr virus (EBV) multiplication, corroborated by negative viral capsid antigen IgM antibody titer and an EBV total early antigen antibody titer of <="40." Patients were given intravenous ganciclovir (5 mg/kg q12h for 30 days). Before this treatment, none of 18 patients could work or manage a household. At evaluations, 24 weeks after ganciclovir, 13 patients (72%) returned to their premorbid healthy states (P < .05). There were no adverse effects from ganciclovir in these nonimmunosuppressed patients.
Lerner AM, Zervos M, Dworkin HJ, Chang CH, O'Neill W. A unified theory of the cause of chronic fatigue syndrome. Infectious Diseases in Clinical Practice 1997; 6: 239-43.
Lopez-Navidad A, Domingo P, Lopez-Talavera JC, Rabella N, Verger G. Epstein-Barr virus infection associated with interstitial nephritis and chronic fatigue. Scandanavian Journal of Infectious Diseases 1996; 28: 185-187.
Abstract: Severe renal disease in the setting of Epstein-Barr virus (EBV) infection is exceedingly rare. We report here the case of a 22-year-old man with acute EBV infection associated with severe interstitial nephritis. The patient developed chronic fatigue and chronic renal failure with a serological profile typical of primary EBV infection. Clinical improvement with anti-EBNA seroconversion occurred after acyclovir therapy. Our patient illustrates that chronic fatigue with major organ dysfunction and a serological profile of primary infection can be seen in chronic EBV infection. In such a case, acyclovir may prove beneficial.
Lynch S, Seth R. Postviral fatigue syndrome and the VP-1 antigen [Letter]. Lancet 1989; 2: 1160-1.
Marshall GS, Gesser RM, Yamanishi K, Starr SE. Chronic fatigue in children [CFS]: clinical features, Epstein-Barr [EB] virus & [HHV6] human herpesvirus 6 serology & long term follow-up. Pediatric Infectious Diseases Journal 1991; 10(4): 287-90.
Abstract: During a 2-year period, 23 patients (14 girls, 9 boys) with chronic fatigue were referred to the Pediatric Infectious Disease Clinic of a tertiary care center, representing 19% of all out-patients seen in that clinic during that time. The median age was 14 years and the median duration of symptoms before referral was 6 months; 65% had missed at least 2 weeks of school and 30% required a home tutor. There were few positive physical findings and no elevation of white blood cell count (median, 7000/mm3) or erythrocyte sedimentation rate (median, 5 mm/hour). Twenty-five percent had no evidence of Epstein-Barr virus infection, 15% had current or recent infection and 60% had past infection; 33% of the latter had detectable antibody to early antigen but the titers were low. Human herpesvirus 6 titers in 8 patients were similar to those in age- and sex-matched controls. Of 17 patients contacted after a median of 26 months, 76% reported definite improvement, although 38% of these still experienced occasional symptoms. In this referral population chronic fatigue was a common presenting complaint, was associated with marked degrees of dysfunction and bore no relationship to Epstein-Barr virus or human herpesvirus 6 infection. In most children the disorder was self-limited, although a minority were persistently or severely affected.
Morag A, Tobi M, Ravid Z, Schattner A, Revel M. Elevated [2' - 5'] - oligo A synthesase activity in patients with prolonged illness associated with serological evidence of persistent EBV infection. [Letter]. Lancet 1982; 1: 744.
Natelson BH, Ye N, Moul DE, Jenkins FJ, Oren DA, Tapp WN, Cheng YC. High titers of anti-Epstein-Barr virus DNA polymerase are found in patients with severe fatiguing illness. Journal of Medical Virology 1994; 42(1): 42-6.
Abstract: Forty-one patients with chronic fatigue syndrome (CFS), 76 healthy controls matched with the patient group for age range, sex, race, and socioeconomic class, and 22 symptomatic patients with seasonal affective disorder (SAD) had serum sampled for antibodies against 2 Epstein-Barr virus (EBV) replicating enzymes. Abnormal titers of antibodies were found twice as often in CFS patients as controls (34.1% vs. 17.1%), with SAD patients having an intermediate frequency (27.3%). Stratifying for disease severity sharpened the differences considerably, with the sicker CFS and SAD patients having 52% and 50% abnormal tests, respectively; more mildly afflicted CFS and SAD patients had a frequency of abnormal tests in the normal range. Antibodies to EBV DNA polymerase (DNAP) were the more sensitive of the two tests in that they were positive in all cases but one. These findings suggest that antibodies against EBV DNAP may be a useful marker in delineating a subset of patients with severe fatiguing illness for appropriate treatment trials and for monitoring their outcomes.
Pagano JS. Chronic fatigue syndrome [Letter]. New England Journal of Medicine 1989; 321: 188.
Reiss GR. The Epstein-Barr virus and chronic fatigue syndrome. [Letter]. Journal of the American Medical Association 1989; 261: 1278.
Sairenji T, Yamanishi K, Tachibana Y, Bertoni G, Kurata T. Antibody responses to Epstein-Barr virus, human herpesvirus 6 and human herpesvirus 7 in patients with chronic fatigue syndrome. Intervirology 1995; 38(5): 269-73.
Abstract: To test for an association between chronic fatigue syndrome (CFS) and infections with Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7), antibodies to these viruses were tested in the serum from three groups of individuals: (1) 10 CFS patients with chronic fatigue beginning with a clinical pattern of acute infectious mononucleosis [IM; true chronic IM (CIM)]; (2) 10 CFS patients whose illness did not start with acute IM (non-CIM), and (3) healthy controls. High EBV antibody titers were demonstrated in most patients. Antibodies to ZEBRA, a product of the immediate early EBV gene BZLF1, were detected in the serum of CFS patients at a higher frequency than in healthy controls. Antibody titers to HHV-6 and HHV-7 were also higher in the patients with CFS than in the controls. These results are consistent with the view that CFS patients may have reactivations of EBV, HHV-6 and HHV-7.
Schooley RT, Carey RW, Miller G, et al. Chronic Epstein-Barr virus infection associated with fever and interstitial pneumonitus: Clinical and serologic features and response to antiviral chemotherapy. Annals of Internal Medicine 1986; 104: 636-43.
Abstract: Two patients developed fever, interstitial pneumonitis, and pancytopenia associated with extremely high titers of antibody to replicative antigens of the Epstein-Barr virus. In contrast to most patients seropositive for Epstein-Barr virus, neither patient had an antibody response to the Epstein-Barr nuclear antigen K polypeptide. In addition, virus isolated from one patient had a deletion of the B95-8 type in the EcoRI C region of the genome. An etiologic relation between Epstein-Barr virus replication and the clinical manifestations of this syndrome is further shown by the response of each patient to acyclovir therapy. These patients have a new Epstein-Barr-virus-associated syndrome and provide additional evidence that acyclovir may play a role in therapy for selected patients with Epstein-Barr virus infection.
Straus SE, Tosato G, Armstrong G, et al. Persisting illness and fatigue in adults with evidence of Epstein-Barr virus infection. Annals of Internal Medicine 1985; 102: 7-16.
Abstract: Clinical, serologic, virologic, and immunologic evaluations for 31 adults with chronic illness and fatigue suggested that 23 had persisting Epstein-Barr virus infection. Among these 23 patients, cellular immune mechanisms were generally normal, but 4 had mild immunoglobulin deficiencies. However, 20 patients had abnormal serologic profiles specific for Epstein-Barr virus shown by significantly elevated titers of antibodies to the viral capsid antigen or early antigen, or by a deficiency of late-appearing antibodies. In 11 of 15 patients tested, circulating immune complexes were found. Circulating interferon was not found in 18 patients tested, but the activity of 2-5 oligoadenylate synthetase, an interferon-induced enzyme, was increased in 5 patients studied. Of 19 patients, 18 had persisting suppressor T-cell activity typically found in patients recovering from acute infectious mononucleosis. We believe that the Epstein-Barr virus may be associated with chronic illness in adults.
Straus SE. Studies of herpesvirus infection in chronic fatigue syndrome. Ciba Foundation Symposium 1993; 173: 132-9.
Abstract: The relationship of herpesviruses to chronic fatigue syndrome has received considerable attention over the past decade. Data suggesting an association fall into three major categories. First, among acute precipitants of the syndrome are primary infections with some herpesviruses, most notably Epstein-Barr virus and cytomegalovirus. Second, a series of studies have detailed elevations of antibodies to most herpesviruses in selected chronic fatigue syndrome populations, with Epstein-Barr virus and human herpes type 6 being the objects of most scrutiny. Third, one recent study reported a greater ease of recovery of human herpes virus type 6 from chronic fatigue syndrome patients. This review article critically examines the cumulative data regarding an association between one or more herpesviruses and the chronic fatigue syndrome in the context of the known biology and epidemiology of these agents. In view of these, and additional considerations regarding study methodologies, the conclusion is drawn that herpesviruses are not dominant causes of the chronic fatigue syndrome and may not even be necessary to the perpetuation of the illness, but it is premature to dismiss entirely this latter possibility.
Straus SE. EB or not EB - that is the question. Journal of the American Medical Association 1987; 257: 2335-6.
Swanink CM, Van der Meer JWM, Vercoulen JHM, Bleijenberg G, Fennis FM, Galama J MD. Epstein-Barr virus (EBV) and the chronic fatigue syndrome: normal virus load in blood and normal immunologic reactivity in the EBV regression assay. Clinical Infectious Diseases 1995; 20: 1390-2.
Abstract: The etiology of chronic fatigue syndrome (CFS) is unknown. Some patients have high antibody titers to viral capsid antigen (VCA) and early antigen (EA) of Epstein-Barr virus (EBV), suggesting that reactivation of EBV is involved. We investigated virus load (spontaneous transformation) and immunologic regression of EBV-induced transformation in peripheral blood mononuclear cells (PBMCs) from 10 selected patients with CFS who had high antibody titers to VCA and EA. The outcome was compared with that for nine healthy controls and one patient with severe chronic active EBV infection (SCAEBV). There were no significant differences in viral load between patients and healthy controls. Immunologic regression of in vitro-transformed PBMCs was also equally efficient in patients and controls. The SCAEBV-infected patient and two controls, who were all seronegative for EBV, showed impaired regression. In conclusion, we were unable to demonstrate a role for reactivation of EBV in CFS, even in selected patients with high titers of antibody to VCA and EA of EBV.
Tobi M, Morag A, Ravid Z, et al. Prolonged atypical illness associated with serological evidence of persistent Epstein-Barr virus infection. Lancet 1982; 1: 61-4.
Abstract: Seven patients with prolonged atypical illness were followed up for more than a year. Sera taken during that period showed significantly increased titres of IgM antibodies against the viral capsid antigen (VCA) of Epstein-Barr virus (EBV). In four of the patients antibodies to the R component of the early antigen (EA) complex of EBV were clearly detectable. Only one of these seven patients had presented with symptoms of classic infectious mononucleosis. Serological and clinical observations in these patients suggest that the prolonged atypical illness was probably the result of persistent EBV infection.
White PD, Clare AW, Stern H. Epstein-Barr virus and persistent malaise [Letter]. Lancet 1985; 2: 105-6.
Woodward CG, Cox RA. Epstein-Barr virus serology in the chronic fatigue syndrome. Journal of Infection, 1992; 2: 133-9.
Abstract: The antibody profiles against Epstein-Barr virus were studied in 136 patients presenting with chronic fatigue syndromes. These profiles were compared with a panel of sera from blood donors. The patients exhibited higher titres in a combined assay for antibodies to the Restricted (R) and Diffuse (D) components of the Early Antigen complex than controls (P less than 0.001) but titres against these antigens were not useful on an individual patient basis. The patients who displayed elevated titres of antibodies to Early Antigens did not differ clinically from those displaying titres in the control range. Four of nine patients who had increased antibodies to Early Antigens also had evidence of active enterovirus infection.