Viruses – Page 17 – American ME and CFS Society

Chronic Fatigue Syndrome and Herpesviruses: the Fading Evidence

Abstract:

Herpesviruses, in particular Epstein-Barr virus (EBV), cytomegalovirus (CMV) and human herpesvirus 6 (HHV-6), have, for the past two decades, come under considerable scrutiny as aetiological agents of chronic fatigue syndrome (CFS). However, virological findings of herpesviruses in CFS have not been consistent between different studies, and the unusual patterns of serological responses to EBV, CMV and HHV-6 have not been specific for CFS, being observed also in asymptomatic individuals. In addition, patients with symptomatology suggestive of CFS do not appear to have an increased frequency of these herpesviruses, as detected by culture or polymerase chain reaction, compared with controls, which argues against an ongoing active herpetic infection. Studies have also shown that the presumable elevation of antibody titres to EBV, CMV or HHV-6 in CFS are not observed only with these viruses, but also with other organisms such as herpes simplex virus and measles.

Source: Soto NE, Straus SE. Chronic Fatigue Syndrome and Herpesviruses: the Fading Evidence. Herpes. 2000 May;7(2):46-50. http://www.ncbi.nlm.nih.gov/pubmed/11867001

Circulating tumour necrosis factor-alpha and interferon-gamma are detectable during acute and convalescent parvovirus B19 infection and are associated with prolonged and chronic fatigue

Abstract:

To investigate whether cytokine responses may have a bearing on the symptoms and outcome of parvovirus B19 infection, circulating cytokines were measured during acute infection (n=51), follow-up of acute infection (n=39) and in normal healthy controls (n=50).

At acute B19 virus infection (serum anti-B19 IgM-positive), patients ranged in age from 4 to 54 years, with a mean age of 28.2 years. The male:female ratio was 1:4.1 and symptoms were rash (n=15), arthralgia (n=31), fatigue (n=8), lymphadenopathy (n=4), foetal hydrops (n=3), transient aplastic crisis (n=2), neutropenia (n=2), myelodysplasia (n=1), thrombocytopenia (n=1) and pancytopenia (n=1). Of these patients, 39 were contacted after a follow-up period of 2-37 months (mean of 22.5 months).

In comparison with normal controls, detectable IL-6 was associated with acute B19 virus infection (26%; P=0.0003), but not with follow-up (6%; P=0.16). Detection of interferon (IFN)-gamma was associated with acute B19 virus infection (67%; P<0.0001) and follow-up (67%; P<0.0001). Detection of tumour necrosis factor (TNF)-alpha was associated with acute B19 virus infection (49%; P<0.0001) and follow-up (56%; P<0.0001). IL-1beta was detected in acute infection (20%), but not at follow-up. At acute B19 virus infection, detection of serum/plasma IL-6 was associated with rheumatoid factor (P=0.038) and IFN-gamma (> or =7 pg/ml) was associated with fatigue in those patients of > or =15 years of age (P=0.022). At follow-up, fatigue was associated with IFN-gamma (> or =7 pg/ml) and/or TNF-alpha (> or =40 pg/ml) (P=0.0275).

Prolonged upregulation of serum IFN-gamma and TNF-alpha appears to represent a consistent host response to symptomatic B19 virus infection.

Source: Kerr JR, Barah F, Mattey DL, Laing I, Hopkins SJ, Hutchinson IV, Tyrrell DA. Circulating tumour necrosis factor-alpha and interferon-gamma are detectable during acute and convalescent parvovirus B19 infection and are associated with prolonged and chronic fatigue. J Gen Virol. 2001 Dec;82(Pt 12):3011-9. http://www.ncbi.nlm.nih.gov/pubmed/11714978

Antiviral pathway activation in patients with chronic fatigue syndrome and acute infection

Abstract:

Gene expression of key enzymes in 2 antiviral pathways (ribonuclease latent [RNase L] and RNA-regulated protein kinase [PKR]) was compared in 22 patients with chronic fatigue syndrome (CFS), 10 patients with acute gastroenteritis, and 21 healthy volunteers. Pathway activation in the group of patients with infections differed significantly from that of the other 2 groups, in whom there was no evidence of upregulation. Therefore, assay of activation is unlikely to provide the basis for a diagnostic test for CFS.

Comment in: Antiviral pathway activation in chronic fatigue syndrome and acute infection. [Clin Infect Dis. 2002]

Source: Gow JW, Simpson K, Behan PO, Chaudhuri A, McKay IC, Behan WM. Antiviral pathway activation in patients with chronic fatigue syndrome and acute infection. Clin Infect Dis. 2001 Dec 15;33(12):2080-1. Epub 2001 Nov 6. http://cid.oxfordjournals.org/content/33/12/2080.long (Full article)

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