Category: Viruses

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

 

No evidence of active infection with human herpesvirus 6 (HHV-6) or HHV-8 in chronic fatigue syndrome

Chronic fatigue syndrome (CFS) is an illness characterized by disabling and long-lasting fatigue and associated with several somatic symptoms such as myalgia, arthralgia, headache, recurrent sore throat, and neurocognitive dysfunction. Frequently, the onset of the illness is preceded by flu-like symptoms, which indicates that immune abnormalities or a viral infection might be involved in the pathogenesis. Although no specific agent has been definitively linked to CFS, several different viruses e.g., herpesviruses, enteroviruses, and retroviruses, have been investigated.

You can read the full article here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC86845/

 

Source: Enbom M, Linde A, Evengård B. No evidence of active infection with human herpesvirus 6 (HHV-6) or HHV-8 in chronic fatigue syndrome. J Clin Microbiol. 2000 Jun;38(6):2457. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC86845/

 

Human herpesviruses 6 and 7 in chronic fatigue syndrome: a case-control study

Abstract:

We conducted this study to determine whether infection with human herpesvirus (HHV) 6A, HHV-6B, or HHV-7 differed between patients with chronic fatigue syndrome and control subjects. We recruited 26 patients and 52 nonfatigued matched control subjects from Atlanta.

Serum samples were tested by enzyme immunoassay for seroreactivity to HHV-6, and all were seropositive. Lymphocyte specimens were cocultivated with cord blood lymphocytes and assayed for HHV-6 and HHV-7; neither virus was isolated. Finally, lymphocytes were tested by use of 3 polymerase chain reaction methods for HHV-6A, HHV-6B, and HHV-7 DNA. HHV-6A or HHV-6B DNA was detected in 17 (22.4%) of 76 samples, and there were no significant differences (by matched analyses) between patients (3 [11.5%] of 26) and control subjects (14 [28%] of 50).

HHV-7 DNA was detected in 14 subjects, and although control subjects (12 [24%]) were more likely than patients (2 [7.7%]) to be positive, the difference was not statistically significant. We found no evidence that active or latent infection with HHV-6A, HHV-6B, HHV-7, or any combination these 3 HHVs is associated with chronic fatigue syndrome.

 

Source: Reeves WC, Stamey FR, Black JB, Mawle AC, Stewart JA, Pellett PE. Human herpesviruses 6 and 7 in chronic fatigue syndrome: a case-control study. Clin Infect Dis. 2000 Jul;31(1):48-52. Epub 2000 Jul 24. http://www.ncbi.nlm.nih.gov/pubmed/10913395

 

Demonstration of borna disease virus nucleic acid in a patient with chronic fatigue syndrome

Comment on: Borna disease virus in human brains with a rare form of hippocampal degeneration but not in brains of patients with common neuropsychiatric disorders. [J Infect Dis. 1999]

 

To the Editor

Czygan et al. [1]reported the detection of Borna disease virus (BDV) nucleic acid in 3 cases of a rare form of hippocampal degeneration, whereas the brains of patients with other neuropsychiatric disorders tested negative for BDV. Chronic fatigue syndrome (CFS) is another, more frequently diagnosed neuropsychiatric disease that is associated with BDV infection. However, the published findings are highly controversial. Nakaya et al. [2, 3] and Kitani et al. [4] showed both BDV-specific antibodies and RNA in a high percentage of Japanese patients with CFS. Bode et al. [5]isolated BDV from peripheral blood mononuclear cells (PBMC) of an American patient with CFS; however, in an earlier publication, Bode et al. [6], as well as Evengård et al. [7] and Yamaguchi et al. [8] in recent publications, did not find serologie evidence for BDV in patients with CFS. A possible explanation for the controversial results is that the term “chronic fatigue syndrome” probably includes several similar clinical conditions that may have different etiologies. In the study by Czygan et al. [1], brain tissue samples from patients who had CFS were not included. Unfortunately, none of the BDV sequences of the CFS cases mentioned above are available in the GenBank database.

You can read the rest of this comment here: http://jid.oxfordjournals.org/content/181/5/1860.long

 

Source: Nowotny N, Kolodziejek J. Demonstration of borna disease virus nucleic acid in a patient with chronic fatigue syndrome. J Infect Dis. 2000 May;181(5):1860-2. http://jid.oxfordjournals.org/content/181/5/1860.long (Full article)

 

Frequent HHV-6 reactivation in multiple sclerosis (MS) and chronic fatigue syndrome (CFS) patients

Abstract:

BACKGROUND: HHV-6 is a ubiquitous virus and its infection usually occurs in childhood and then becomes a latent infection. HHV-6 reactivation has been shown to play a role in the pathogenesis of AIDS and several other diseases.

OBJECTIVES: To determine what role HHV-6 infection or reactivation plays in the pathogenesis of multiple sclerosis (MS) and chronic fatigue syndrome (CFS).

RESULTS: Twenty-one MS and 35 CFS patients were studied and followed clinically. In these patients, we measured HHV-6 IgG and IgM antibody levels and also analyzed their peripheral blood mononuclear cells (PBMCs) for the presence of HHV-6, using a short term culture assay. In both MS and CFS patients, we found higher levels of HHV-6 IgM antibody and elevated levels of IgG antibody when compared to healthy controls. Seventy percent of the MS patients studied contained IgM antibodies for HHV-6 late antigens (capsid), while only 15% of the healthy donors (HD) and 20% of the patients with other neurological disorders (OND) had HHV-6 IgM antibodies. Higher frequency of IgM antibody was also detected in CFS patients (57.1%) compared to HD (16%). Moreover, 54% of CFS patients exhibited antibody to HHV-6 early protein (p41/38) compared to only 8.0% of the HD. Elevated IgG antibody titers were detected in both the MS and the CFS patients. PBMCs from MS, CFS and HD were analyzed in a short term culture assay in order to detect HHV-6 antigen expressing cells and to characterize the viral isolates obtained as either Variant A or B. Fifty-four percent of MS patients contained HHV-6 early and late antigen producing cells and 87% of HHV-6 isolates were Variant B. Isolates from CFS, patients were predominately Variant A (70%) and isolates from HD were predominately Variant B (67%). Moreover, one isolate from OND was also Variant B. Persistent HHV-6 infection was found in two CFS patients over a period of 2.5 years and HHV-6 specific cellular immune responses were detected in PBMCs from ten CFS patients.

CONCLUSION: In both MS and CFS patients, we found increased levels of HHV-6 antibody and HHV-6 DNA. A decrease in cellular immune responses was also detected in CFS patients. These data suggest that HHV-6 reactivation plays a role in the pathogenesis of these disorders.

 

Source: Ablashi DV, Eastman HB, Owen CB, Roman MM, Friedman J, Zabriskie JB, Peterson DL, Pearson GR, Whitman JE. Frequent HHV-6 reactivation in multiple sclerosis (MS) and chronic fatigue syndrome (CFS) patients. J Clin Virol. 2000 May;16(3):179-91. http://www.ncbi.nlm.nih.gov/pubmed/10738137

 

Absence of evidence of Borna disease virus infection in Swedish patients with Chronic Fatigue Syndrome

Abstract:

Chronic Fatigue Syndrome (CFS) is characterized by debilitating fatigue, somatic symptoms and cognitive impairment. An infectious basis has been proposed; candidate agents include enteroviruses, herpesviruses, retroviruses and Borna disease virus (BDV), a novel neurotropic virus associated with neuropsychiatric disorders.

Sera and peripheral blood mononuclear cells (PBMC) from Swedish CFS patients were assayed for evidence of infection using ELISA and Western immunoblot for detection of antibodies to BDV proteins N, P and gp18; and using nested reverse transcriptase polymerase chain reaction (RT-PCR) for detection of BDV N- and P-gene transcripts. No specific immunoreactivity to BDV proteins was found in sera from 169 patients or 62 controls.

No BDV N- or P-gene transcripts were found through RT-PCR analysis of PBMC from 18 patients with severe CFS. These results do not support a role for BDV in pathogenesis of CFS.

 

Source: Evengård B, Briese T, Lindh G, Lee S, Lipkin WI. Absence of evidence of Borna disease virus infection in Swedish patients with Chronic Fatigue Syndrome. J Neurovirol. 1999 Oct;5(5):495-9. http://www.ncbi.nlm.nih.gov/pubmed/10568886

 

Borna disease virus infection in two family clusters of patients with chronic fatigue syndrome

Abstract:

A high rate of Borna disease virus (BDV) infection has been demonstrated in patients with chronic fatigue syndrome (CFS). Herein, we focused on BDV infection in two family clusters of patients with CFS: a father, mother, two sons and one daughter (family #1); and a father, mother, two daughters and one son (family #2).

All members, except for the elder son in family #1 and the father and son in family #2, were diagnosed with CFS. The results supported that all the family members with CFS were infected with BDV, as evidenced by the presence of antibodies to viral p40, p24 and/or gp18 and BDV p24 RNA in peripheral blood mononuclear cells.

The healthy members, except for the father of family #2 who was positive for antibody to p24, were all negative by both assays. Follow-up studies in family #1 continued to reveal BDV antibodies and BDV RNA, except in the mother, who lost the RNA upon slight recovery from the disease.

 

Source: Nakaya T, Takahashi H, Nakamur Y, Kuratsune H, Kitani T, Machii T, Yamanishi K, Ikuta K. Borna disease virus infection in two family clusters of patients with chronic fatigue syndrome. Microbiol Immunol. 1999;43(7):679-89. http://onlinelibrary.wiley.com/doi/10.1111/j.1348-0421.1999.tb02456.x/full (Full article)

 

Detection of borna disease virus-reactive antibodies from patients with psychiatric disorders and from horses by electrochemiluminescence immunoassay

Abstract:

The prevalence of Borna disease virus (BDV)-specific antibodies among patients with psychiatric disorders and healthy individuals has varied in several reports using several different serological assay methods. A reliable and specific method for anti-BDV antibodies needs to be developed to clarify the pathological significance of BDV infections in humans.

We developed a new electrochemiluminescence immunoassay (ECLIA) for the antibody to BDV that uses two recombinant proteins of BDV, p40 and p24 (full length). Using this ECLIA, we examined 3,476 serum samples from humans with various diseases and 917 sera from blood donors in Japan for the presence of anti-BDV antibodies.

By ECLIA, 26 (3.08%) of 845 schizophrenia patients and 9 (3.59%) of 251 patients with mood disorders were seropositive for BDV. Among 323 patients with other psychiatric diseases, 114 with neurological diseases, 75 with chronic fatigue syndrome, 85 human immunodeficiency virus-infected patients, 50 with autoimmune diseases including rheumatoid arthritis and systemic lupus erythematosis and 17 with leprosy, there was no positive case except one case each with alcohol addiction, AIDS, and dementia.

Although 19 (1.36%) of 1,393 patients with various ocular diseases, 10 (1.09%) of 917 blood donors, and 3 (4.55%) of 66 multitransfused patients were seropositive for BDV-specific antigen, high levels of seroprevalence in schizophrenia patients and young patients (16 to 59 years old) with mood disorders were statistically significant.

The immunoreactivity of seropositive sera could be verified for specificity by blocking with soluble p40 and/or p24 recombinant protein. Anti-p24 antibody was more frequent than p40 antibody in most cases, and in some psychotic patients antibody profiles showed only p40 antibody. Although serum positive for both p40 and p24 antibodies was not found in this study, the p40 ECLIA count in schizophrenia patients was higher than that of blood donors.

Furthermore, we examined 90 sera from Japanese feral horses. Antibody profiles of control human samples are similar to that of naturally BDV-infected feral horses. We concluded that BDV infection was associated in some way with psychiatric disorders.

 

Source: Yamaguchi K, Sawada T, Naraki T, Igata-Yi R, Shiraki H, Horii Y, Ishii T, Ikeda K, Asou N, Okabe H, Mochizuki M, Takahashi K, Yamada S, Kubo K, Yashiki S, Waltrip RW 2nd, Carbone KM. Detection of borna disease virus-reactive antibodies from patients with psychiatric disorders and from horses by electrochemiluminescence immunoassay. Clin Diagn Lab Immunol. 1999 Sep;6(5):696-700. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC95757/ (Full article)

 

Stealth adaptation of an African green monkey simian cytomegalovirus

Abstract:

DNA extracted from cultures of a cytopathic virus isolated from a patient with chronic fatigue syndrome was cloned into pBluescript plasmid. The nucleotide sequences of the plasmid inserts were analyzed using the BlastN and BlastX programs of the National Center for Biotechnology Information.

In confirmation of earlier studies, many of the sequences show partial homology to various regions within the genome of human cytomegalovirus (HCMV). The matching regions were unevenly distributed throughout the HCMV genome. No matches were seen with either the UL55 or the UL83 genes, which provide the major antigenic targets for anti-HCMV cytotoxic T-cell-mediated immunity.

This finding is consistent with the notion that certain viruses can avoid immune elimination by deleting genes required for effective antigenic recognition by the cellular immune system. The term “stealth” has been applied to such viruses. Comparisons were also made between the sequences of the stealth virus and the limited sequence data available on cytomegaloviruses from rhesus monkeys and from African green monkeys. These comparisons unequivocally establish that the virus was derived from an African green monkey simian cytomegalovirus.

 

Source: Martin WJ. Stealth adaptation of an African green monkey simian cytomegalovirus. Exp Mol Pathol. 1999 Apr;66(1):3-7. http://www.ncbi.nlm.nih.gov/pubmed/10331958