A small, randomized, placebo-controlled trial of the use of antiviral therapy for patients with chronic fatigue syndrome

Comment on: Editorial response: microbial persistence and idiopathic dilated cardiomyopathy. [Clin Infect Dis. 1999]

 

SIR—We have presented controlled and observational data that are consistent with the hypothesis that subsets of cases of chronic fatigue syndrome (CFS) result from cardiac disease due to a single, persisting infection caused by Epstein-Barr virus (EBV) or, in turn, to a single, persisting infection caused by human cytomegalovirus (HCMV) in immunocompetent patients [1]. Patients who have a separate subset of CFS have simultaneous coinfection with EBV and HCMV. Cardiomyopathic changes are observed in right ventricular endomyocardial biopsy specimens obtained from such patients, and abnormal findings on Holter monitoring (e.g., oscillating abnormal T-wave flattenings and T-wave inversions) are “uniformly” present [2–4]. Left ventricular dysfunction is manifested by sinus tachycardia at rest, abnormal cardiac-wall motion, and decreased left ventricular ejection fractions (rest/stress) in those patients with CFS who are most ill [5]. These findings belie the relatively normal findings observed on standard 12-lead electrocardiograms [6].

In January 1995, a double-blinded, placebo-controlled, phase III crossover study of patients with CFS was initiated. Eleven patients who had CFS (10 of whom were women) were each followed for 18 consecutive months. The mean patient age was 42.7 years, and the mean duration of CFS was 35.1 months. Before antiviral nucleosides were administered, endomyocardial biopsies were performed. Cardiac tissues and blood samples tested negative for isolation of HCMV in cultures of human fibroblast tissues. Two cardiac biopsy specimens that were obtained from patients who had CFS tested positive for HCMV nucleic acids by means of PCR. No cardiac specimen that was obtained from a patient with CFS tested positive for EBV nucleic acids. (Cardiac tissue samples that were obtained from 4 of 21 control patients who had coronary artery disease but who did not have CFS also tested positive for HCMV nucleic acids.) Cardiomyopathic degenerative findings (e.g., myofiber disarray, interstitial fibrosis, increased intracellular granules, and interstitial fat) were noted in patients who had CFS. One patient who had CFS had myocarditis with focal lymphocytic infiltrates.

You can read the rest of this article here: http://cid.oxfordjournals.org/content/32/11/1657.long

 

Source: Lerner AM, Zervos M, Chang CH, Beqaj S, Goldstein J, O’Neill W, Dworkin H, Fitgerald T, Deeter RG. A small, randomized, placebo-controlled trial of the use of antiviral therapy for patients with chronic fatigue syndrome. Clin Infect Dis. 2001 Jun 1;32(11):1657-8. http://cid.oxfordjournals.org/content/32/11/1657.long (Full article)

 

Evaluation of a recombinant line blot for diagnosis of Epstein-Barr Virus compared with ELISA, using immunofluorescence as reference method

Abstract:

A commercial line blot using recombinant antigens was compared with a commercial ELISA and ‘in-house’ IFA (reference test). Two panels were evaluated: Panel A was selected to distinguish between primary infections (89), past infections (20) and seronegatives (8) in immunocompetent individuals. In panel B, patients with a high number of reactivations were included: immunosuppressed patients (37), lymphoma (19), nasopharyngeal carcinoma (10), chronic fatigue syndrome (14). Blood donors (43) and cross-reactive sera (29) were added as controls.

Line blot and IFA were concordant in 94% of primary infections, 100% of seronegatives and 100% of past infections, similar to ELISA. Results differed significantly with regard to reactivations. When compared with IFA, the incidence of reactivations was overestimated by the blot, 24 and 58% in blood donors and cross-reactive sera, respectively. ELISA showed a similar problems with 21 and 34% indeterminate results, respectively.

The line blot is easy to carry out, has a good concordance with the reference IFA for primary infections, and is, therefore, a sufficient choice for distinguishing primary infection from seronegative and past infection. EBV reactivation assessment will require other methods such as EBV viral load.

 

Source: Gärtner BC, Fischinger JM, Roemer K, Mak M, Fleurent B, Mueller-Lantzsch N. Evaluation of a recombinant line blot for diagnosis of Epstein-Barr Virus compared with ELISA, using immunofluorescence as reference method. J Virol Methods. 2001 Apr;93(1-2):89-96. http://www.ncbi.nlm.nih.gov/pubmed/11311347

 

Behavioural effects of infectious mononucleosis

Abstract:

The aim of the present study was to provide preliminary information on the acute and chronic effects of infectious mononucleosis (IM) on memory, attention, psychomotor performance and mood. These issues were examined by comparing individuals with acute IM, those who had the initial illness some months before, and matched healthy controls.

Objective measures of memory, attention, motor skills and visual functions were obtained, as were subjective reports of mood. The results showed selective effects of acute IM on performance and mood, with the profile of impairments being very similar to those observed in previous studies of influenza.

Different impairments were observed in subjects who had the primary illness several months before, and the effects observed in this group were similar to those observed in recent studies of chronic fatigue syndrome patients.

Both acute and chronic IM subjects reported similar levels of symptoms and psychopathology, with both groups having greater scores than the controls. However, the performance impairments did not reflect symptoms or psychopathology. One may conclude that the study of IM will provide important data on both the acute and longer lasting effects of viral infections on the brain and behaviour.

 

Source: Hall SR, Smith AP. Behavioural effects of infectious mononucleosis. Neuropsychobiology. 1996;33(4):202-9. http://www.ncbi.nlm.nih.gov/pubmed/8840344

 

Epstein-Barr virus infection associated with interstitial nephritis and chronic fatigue

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.

 

Source: López-Navidad A, Domingo P, López-Talavera JC, Rabella N, Verger G. Epstein-Barr virus infection associated with interstitial nephritis and chronic fatigue. Scand J Infect Dis. 1996;28(2):185-7. http://www.ncbi.nlm.nih.gov/pubmed/8792488

 

MMPI profiles of patients with chronic fatigue syndrome

Abstract:

Fifty-three patients with chronic fatigue syndrome (CFS) and 43 healthy nonpatient controls completed the Minnesota Multiphasic Personality Inventory (MMPI). All subjects varied in their degree of seropositivity to active Epstein-Barr virus (EBV) as measured by their anti-early antigen titers. EBV titers were higher among CFS patients and were associated with being more symptomatic.

Differences in patient status were associated with statistically significant elevations on 8 of 9 clinical scales, 4 of which also showed clinically significant elevations (T scores > or = 70): scales 1, 2, 3, and 8. These results are discussed in terms of their implications for intervention strategies associated with MMPI-based CFS subtypes.

 

Source: Schmaling KB, Jones JF. MMPI profiles of patients with chronic fatigue syndrome. J Psychosom Res. 1996 Jan;40(1):67-74. http://www.ncbi.nlm.nih.gov/pubmed/8730646

 

Chronic active Epstein-Barr virus infection in children in Japan

Abstract:

The patients with chronic active Epstein-Barr virus infection (CAEBV) in childhood in Japan are described. Among 39 registered cases, 20 patients were males and 19 were females. Unlike the X-linked lymphoproliferative syndrome, there was no hereditary background.

The incidence of hypersensitivity to mosquito bites was high (31.3%) as a past history. Most patients exhibited hepatomegaly (92.3%), splenomegaly (87.2%) and fever (84.6%). The incidence of absent anti-EB virus nuclear antigen titres was unexpectedly low (17.1%). Lymphoreticular disorders and cardiovascular diseases were major complications.

Twenty-four (61.5%) patients died 6 months to 8 years after the onset, mainly of hepatic failure (eight cases), cardiac failure (five cases), virus-associated haemophagocytic syndrome (three cases) and haematological malignancies (two cases). This study reveals the CAEBV in Japan has several clinical features and should be informative for the pathogenesis of EB virus.

 

Source: Ishihara S, Okada S, Wakiguchi H, Kurashige T, Morishima T, Kawa-Ha K. Chronic active Epstein-Barr virus infection in children in Japan. Acta Paediatr. 1995 Nov;84(11):1271-5. http://www.ncbi.nlm.nih.gov/pubmed/8580625

 

The existence of a fatigue syndrome after glandular fever

Abstract:

This prospective cohort study was designed to test whether a distinct fatigue syndrome existed after the onset of glandular fever.

Two hundred and fifty primary care patients, with either glandular fever or an ordinary upper respiratory tract infection (URTI) were interviewed three times in the 6 months after the clinical onset of their infection. At each interview a standardized psychiatric interview was given and physical symptoms were assessed. There were 108 subjects with and Epstein-Barr virus (EBV) infection; 83 subjects had glandular fever not caused by EBV and 54 subjects had an ordinary URTI. Five subjects were excluded because they had no evidence of an infection.

Principal components analyses of symptoms supported the existence of a fatigue syndrome, particularly in the two glandular fever groups. The addition of symptoms not elicited by the standard interviews gave the full syndrome. This included physical and mental fatigue, excessive sleep, psychomotor retardation, poor concentration, anhedonia, irritability, social withdrawal, emotional lability, and transient sore throat and neck gland swelling with pain. A fatigue syndrome probably exists after glandular fever.

 

Source: White PD, Thomas JM, Amess J, Grover SA, Kangro HO, Clare AW. The existence of a fatigue syndrome after glandular fever. Psychol Med. 1995 Sep;25(5):907-16. http://www.ncbi.nlm.nih.gov/pubmed/8588009

 

Antibody responses to Epstein-Barr virus, human herpesvirus 6 and human herpesvirus 7 in patients with chronic fatigue syndrome

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.

 

Source: 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. http://www.ncbi.nlm.nih.gov/pubmed/8724857

 

The Epstein-Barr virus and chronic fatigue syndrome

Abstract:

Lately discovered chronic fatigue syndrome is associated with Epstein-Barr virus infection. The objective of this paper was to detect this syndrome in our patients. 31 patients with cured acute infective mononucleosis were examined by questionnaire, physical check-up and laboratory analyses in order to detect disorders characteristic for chronic fatigue syndrome. Six months after they had been cured, out of 7 patients 5 patients complained of frequent sore throat, fatigue and exhaustion, and a year later, all 5 patients were sleepy and tired all the time. More than a year after the acute illness 19 patients were examined and in 5.6% frequent sore throat and enlarged neck lymph nodes occurred. The gathered results point to disorders characteristic for chronic fatigue syndrome in a high percentage. This pilot study should only be the beginning of examinations of this kind.

 

Source: Jovanović J, Cvjetković D, Brkić S, Madle-Samardzija N. The Epstein-Barr virus and chronic fatigue syndrome. Med Pregl. 1995;48(11-12):391-3. [Article in Croatian] http://www.ncbi.nlm.nih.gov/pubmed/8643052

 

Simultaneous measurement of antibodies to Epstein-Barr virus, human herpesvirus 6, herpes simplex virus types 1 and 2, and 14 enteroviruses in chronic fatigue syndrome: is there evidence of activation of a nonspecific polyclonal immune response?

Abstract:

As a test of the hypothesis that elevated titers of viral antibodies in patients with chronic fatigue syndrome (CFS) are due to a nonspecific polyclonal immune response, antibodies to Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), and 14 enteroviruses in 20 patients with CFS and 20 age- and gender-matched controls were simultaneously measured.

Similarly, titers of IgG to herpes simplex virus (HSV) types 1 and 2 were measured in 18 of these cases and in the respective controls. IgG to EBV viral capsid antigen (VCA) was present at titers > or = 1:320 in 55% of cases vs. 15% of controls (P = .02).

The geometric mean titers of early antigen antibody to EBV, HHV-6 IgG, and HSV-1 and HSV-2 IgG were not significantly different among cases and controls. Of the 14 enteroviral antibodies tested for, only those to coxsackieviruses B1 and B4 were present at significant titers (> or = 1:8) in cases vs. controls (P = .02 and P = .001, respectively).

Of the cases, 19 (95%) had either an EBV VCA IgG titer > or = 1:320 or a coxsackievirus B1 or B4 antibody titer > or = 1:8, a percentage significantly higher than that of controls (40%; P = .0004). Titers of EBV VCA IgG and coxsackievirus B1 and B4 antibodies were simultaneously elevated in only 20% of cases.

There was no correlation between elevated titers of EBV VCA IgG and IgG to HHV-6, HSV-1, and HSV-2 or antibody to coxsackieviruses B1 and B4 in the cases. The prevalence of reported allergies to medications or other substances was identical in both groups (60%). These findings suggest that in the majority of cases of CFS, elevation of viral antibody titers is not due to a nonspecific polyclonal immune response.

Comment in: Viral antibodies in chronic fatigue syndrome. [Clin Infect Dis. 1995]

 

Source: Manian FA. Simultaneous measurement of antibodies to Epstein-Barr virus, human herpesvirus 6, herpes simplex virus types 1 and 2, and 14 enteroviruses in chronic fatigue syndrome: is there evidence of activation of a nonspecific polyclonal immune response? Clin Infect Dis. 1994 Sep;19(3):448-53. http://www.ncbi.nlm.nih.gov/pubmed/7811864