Evaluation of viral infection as an etiology of ME/CFS: a systematic review and meta-analysis.

BACKGROUND: Myalgic encephalitis/chronic fatigue syndrome (ME/CFS) is a long-term disabling illness without a medically explained cause. Recently during COVID-19 pandemic, many studies have confirmed the symptoms similar to ME/CFS in the recovered individuals. To investigate the virus-related etiopathogenesis of ME/CFS, we conducted a systematic assessment of viral infection frequency in ME/CFS patients. METHODS: We conducted a comprehensive search of PubMed and the Cochrane Library from their inception through December 31, 2022, using selection criteria of viral infection prevalence in ME/CFS patients and controls. Subsequently, we performed a meta-analysis to assess the extent of viral infections' contribution to ME/CFS by comparing the odds ratio between ME/CFS patients and controls (healthy and/or diseased). RESULTS: Finally, 64 studies met our eligibility criteria regarding 18 species of viruses, including a total of 4971 ME/CFS patients and 9221 control subjects. The participants included healthy subjects and individuals with one of 10 diseases, such as multiple sclerosis or fibromyalgia. Two DNA viruses (human herpes virus (HHV)-7 and parvovirus B19, including their co-infection) and 3 RNA viruses (borna disease virus (BDV), enterovirus and coxsackie B virus) showed odds ratios greater than 2.0 compared with healthy and/or diseased subjects. Specifically, BDV exceeded the cutoff with an odds ratio of ≥ 3.47 (indicating a "moderate association" by Cohen's d test) compared to both healthy and diseased controls. CONCLUSION: This study comprehensively evaluated the risk of viral infections associated with ME/CFS, and identified BDV. These results provide valuable reference data for future studies investigating the role of viruses in the causation of ME/CFS.

The effect of concomitant fibromyalgia in HIV infected patients receiving antiretroviral therapy: a prospective cross-sectional study.

BACKGROUND: HIV infected patients receiving antiretroviral therapy (ART) have extensive musculoskeletal system involvement. Arthralgia and myalgia are the most common forms. Fibromyalgia Syndrome (FMS) is a chronic pain syndrome of the musculoskeletal system characterized by diffuse pain including arthralgia and myalgia. These overlapping symptoms are suggested the relationship between HIV and FMS. The primary purpose of this study was to determine the prevalence of FMS in HIV/AIDS patients. The secondary objective was to investigate the effects of FMS on functional status, depression, fatigue, sleep pattern and quality of life. METHODS: A total of 225 HIV infected patients who were receiving ART were included in this cross-sectional prospective study. The demographic data of the participants, CD4 T-lymphocyte count (cells/mm3), viral load (> 40 copy/ml), and ART regimens were recorded. FMS diagnosis was based on 2016 revision of diagnostic criteria. All patients completed the following questionnaires: Fibromyalgia Impact Questionnaire (FIQ), Beck Depression Inventory (BDI), Pittsburgh Sleep Quality Index (PSQI), Fatigue Severity Scale (FSS), and SF-36 scale. RESULTS: FMS was found in 20% of the HIV infected patients (n = 45). The mean duration of disease was 4.74 ± 4.42 years; it was significantly longer in patients with FMS (p = 0.007). The median CD4 T-lymphocyte count was found to be 616.00 ± 303.91 cells/mm3, and it was significantly higher in patients without FMS (p = 0.06). No statistically significant difference was found between the two groups according to the drug regimens used. A statistically significant difference was found in FIQ, BDI, PSQI, FSS and all subgroups of the SF-36 scale between the patients with and without FMS (p = 0.001). CONCLUSIONS: A slightly higher frequency of FMS was determined in HIV infected patients receiving ART compared to previous studies. It was shown that presence of FMS negatively affected the function, depression, fatigue, sleep, and quality of life. Detection of FMS may decrease depression, fatigue, and sleep disorders and increase the quality of life in HIV infected patients. FMS should be distinguished correctly for an accurate treatment management of HIV and for increasing ART compliance.

The role of HHV-6 and HHV-7 infections in the development of fibromyalgia.

Human herpes virus-6 (HHV-6) and human herpes virus-7 (HHV-7) are immunomodulating viruses potentially affecting the nervous system. We evaluated the influence of HHV-6 and HHV-7 infections on fibromyalgia (FM) clinical course. Forty-three FM patients and 50 control group participants were enrolled. 39.50% (n = 17) FM patients had light A delta and C nerve fiber damage, 27.91% (n = 12) had severe A delta and C nerve fiber damage. 67.44% (n = 29) FM patients had loss of warm sensation in feet, loss of heat pain sensation, and increased cold pain sensation (34.90%, n = 15 in both findings). HHV-6 and HHV-7 genomic sequences in peripheral blood DNA in 23/43 (51.00%) and 34/43 (75.50%) of samples from FM patients and in 3/50 (6.00%) and 26/50 (52.00%) of samples from the control group individuals were detected. Active HHV-6 (plasma viremia) or HHV-7 infection was revealed only in FM patients (4/23, 17.40% and 4/34, 11.80%, respectively). A statistically significant moderate positive correlation was found between A delta and C nerve fiber damage severity and HHV-6 infection (p < 0.01, r = 0.410). 23/43 patients from the FM group and control group participants HHV-6 and 34/45 HHV-7 did have infection markers. A statistically significant moderate positive correlation was found between A delta and C nerve fiber damage severity and HHV-6 infection (p < 0.01, r = 0.410). No difference was found between detection frequency of persistent HHV-6 and HHV-7 infection between FM patients and the control group. Statistically significant correlation was observed between quantitation of changes in QST thermal modalities and HHV-6 infection. There was no correlation between A delta and C nerve fiber damage and HHV-7 infection.

Lack of evidence for retroviral infections formerly related to chronic fatigue in Spanish fibromyalgia patients.

BACKGROUND: The etiology of fibromyalgia and chronic fatigue syndrome (FM/CFS) is currently unknown. A recurrent viral infection is an attractive hypothesis repeatedly found in the literature since it would explain the persistent pain and tiredness these patients suffer from. The initial striking link of two distinct orphan retroviruses: the gamma retroviruses murine leukemia virus (MLV)-related virus and the delta retrovirus T-lymphotropic virus type 2 (HTLV-2) to chronic fatigue have not been confirmed to date. RESULTS: Genomic DNA (gDNA) from 75 fibromyalgia patients suffering from chronic fatigue and 79 age-matched local healthy controls were screened for the presence of MLV-related and HTLV-2 related proviral sequences. The XMRV env gene was amplified in 20% of samples tested (24% patients/15% healthy controls). Unexpectedly, no PCR amplifications from independent gDNA preparations of the same individuals were obtained. None of the positive samples showed presence of contaminating murine sequences previously reported by other investigators, neither contained additional regions of the virus making us conclude that the initial env amplification came from spurious air-driven amplicon contaminants. No specific HTLV-2 sequences were obtained at any time from any of the 154 quality-controlled gDNA preparations screened. CONCLUSIONS: Previous associations between MLV-related or HTLV-2 retrovirus infection with chronic fatigue must be discarded. Thus, studies showing positive amplification of HTLV-2 sequences from chronic fatigue participants should be revised for possible undetected technical problems.To avoid false positives of viral infection, not only extreme precautions should be taken when nested-PCR reactions are prepared and exhaustive foreign DNA contamination controls performed, but also consistent amplification of diverse regions of the virus in independent preparations from the same individual must be demanded.The fact that our cohort of patients did not present evidence of any of the two types of retroviral infection formerly associated to chronic fatigue does not rule out the possibility that other viruses are involved in inciting or maintaining fibromyalgia and/or chronic fatigue conditions.

Absence of xenotropic murine leukemia virus-related virus in Italian patients affected by chronic fatigue syndrome, fibromyalgia, or rheumatoid arthritis.

The xenotropic murine leukemia virus-related virus (XMRV) has been recently linked to chronic fatigue syndrome in a US cohort in whom the virus was demonstrated in 67% patients vs 3.7% healthy controls. Albeit this finding was not substantiated by subsequent reports and eventually considered a laboratory contamination, the matter is still the object of intense debate and scrutiny in various cohorts of patients. In this work we examined well-clinically characterized Italian patients affected by chronic fatigue syndrome, and also fibromyalgia and rheumatoid arthritis, two chronic illnesses of basically unknown etiology which show quite a few symptoms in common with chronic fatigue syndrome. Although we used recently updated procedures and controls, the XMRV was not found in 65 patients with chronic fatigue syndrome diagnosis, 55 with fibromyalgia, 25 with rheumatoid arthritis, nor in 25 healthy controls. These results add to the ever-growing number of surveys reporting the absence of XMRV in chronic fatigue syndrome patients and suggest that the virus is also absent in fibromyalgia and rheumatoid arthritis.

Prevalence of xenotropic murine leukemia virus-related virus infection in different risk populations in Spain.

Human infection with the xenotropic murine leukemia virus-related virus (XMRV) has been associated controversially with prostate cancer and chronic fatigue syndrome. Information is lacking about the mechanisms of transmission and potential risk groups for XMRV infection. Plasma and peripheral blood mononuclear cells (PBMCs) from individuals with retroviral infections, chronic viral hepatitis, autoimmune diseases, prostate cancer, chronic fatigue syndrome, and blood donors were tested for XMRV markers. Antibodies to XMRV proteins p15E and gp70 were examined using research assays. DNA extracted from PBMCs was tested for the presence of XMRV gag and env sequences. A total of 1103 specimens belonging to individuals with chronic fatigue syndrome and/or fibromyalgia (437), prostate cancer (69), HIV-1 (149), HTLV-1/2 (31), chronic hepatitis B (81), chronic hepatitis C (72), autoimmune diseases (18), and blood donors (246) were examined. Overall, three samples (0.3%) were p15E seroreactive (two HTLV-1 and one HCV patient). Another 15 (1.4%) were gp70 seroreactive (six chronic fatigue syndrome-fibromyalgia, four blood donors, two HIV-1, one prostate cancer, one HBV, and one HCV). Four specimens were initially positive for XMRV gag sequences, but none could be confirmed by repeated testing. In summary, no evidence of XMRV infection was found in populations with retroviral and viral hepatitis infections in Spain. Likewise, XMRV was not recognized in patients with autoimmune diseases, chronic fatigue syndrome-fibromyalgia, prostate cancer, or healthy blood donors.

Murine gammaretrovirus group G3 was not found in Swedish patients with myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia.

BACKGROUND: The recent report of gammaretroviruses of probable murine origin in humans, called xenotropic murine retrovirus related virus (XMRV) and human murine leukemia virus related virus (HMRV), necessitated a bioinformatic search for this virus in genomes of the mouse and other vertebrates, and by PCR in humans. RESULTS: Three major groups of murine endogenous gammaretroviruses were identified. The third group encompassed both exogenous and endogenous Murine Leukemia Viruses (MLVs), and most XMRV/HMRV sequences reported from patients suffering from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Two sensitive real-time PCRs for this group were developed. The predicted and observed amplification range for these and three published XMRV/HMRV PCRs demonstrated conspicuous differences between some of them, partly explainable by a recombinatorial origin of XMRV. Three reverse transcription real-time PCRs (RTQPCRs), directed against conserved and not overlapping stretches of env, gag and integrase (INT) sequences of XMRV/HMRV were used on human samples. White blood cells from 78 patients suffering from ME/CFS, of which 30 patients also fulfilled the diagnostic criteria for fibromyalgia (ME/CFS/FM) and in 7 patients with fibromyalgia (FM) only, all from the Gothenburg area of Sweden. As controls we analyzed 168 sera from Uppsala blood donors. We controlled for presence and amplifiability of nucleic acid and for mouse DNA contamination. To score as positive, a sample had to react with several of the XMRV/HMRV PCRs. None of the samples gave PCR reactions which fulfilled the positivity criteria. CONCLUSIONS: XMRV/HMRV like proviruses occur in the third murine gammaretrovirus group, characterized here. PCRs developed by us, and others, approximately cover this group, except for the INT RTQPCR, which is rather strictly XMRV specific. Using such PCRs, XMRV/HMRV could not be detected in PBMC and plasma samples from Swedish patients suffering from ME/CFS/FM, and in sera from Swedish blood donors.

[Is fibromyalgia a viral disease?]. / Ist die Fibromyalgie eine Viruserkrankung?

Are viruses responsible for the pain in patients with fibromyalgia? Are viruses the trigger for rheumatoid arthritis? Is chronic fatigue syndrome a viral disease? There are many open questions with few or controversial answers. According to the current state of knowledge on the origin of the pain in fibromyalgia the varied symptomatic of fibromyalgia is triggered by peripheral as well as central mechanisms. Despite the broad spectrum of symptoms the disease is a specific entity which is mainly treated with dual reuptake inhibitors, anticonvulsives, tramadol, selective serotonin reuptake inhibitors, gamma-hydroxybutyrate and dopamine agonists in individually selected combinations.

Seroprevalence of parvovirus B19 in fibromyalgia syndrome.

This study was aimed to evaluate the seroprevalence of parvovirus B19 in patients with fibromyalgia syndrome (FS). Seventy-five patients with FS (44.3 +/- 8.3) and 75 healthy controls (44.2 +/- 8.1) were evaluated. Serum anti-B19 IgM and IgG antibodies were measured by ELISA technique. Patients were questioned about duration of symptoms, characteristic features of FS, and symptoms related with viral infection preceding the onset of FS. No significant difference was found regarding the prevalence of anti-B19 IgM antibodies between the groups (p = 0.494). Seropositivity of anti-B19 IgG of the patients was significantly higher than control group (81.3% vs. 64% respectively, p = 0.027). No statistically significant differences were found regarding to the clinical features between fibromyalgia patients with IgG antibody compared to those without IgG antibody. Parvovirus B19 IgG seropositivity was found to be significantly higher in patients with FS. Parvovirus B19 infection might have a role in the etiopathogenesis of FS or might act as a triggering factor.

Hepatitis C virus infection in Italian patients with fibromyalgia.

We evaluated the prevalence of hepatitis C virus (HCV) infection in Italian patients suffering from fibromyalgia (FM), in comparison with patients affected by non-HCV related rheumatic degenerative disorders. Consecutive patients with FM and a statistically comparable group of patients suffering from peripheral osteoarthritis (OA) or sciatica due to L4-L5 or L5-S1 herniated disc were tested for HCV infection with a third-generation microparticle enzyme immunoassay (MEIA). In the positive cases, a third-generation recombinant immunoblot assay (RIBA) confirmatory test and serum HCV-RNA test were performed. Fisher's exact test was performed to compare the prevalence of HCV infection (MEIA- and RIBA-positive results) obtained in the two enrolled groups. Enrolled were 152 subjects suffering from FM and 152 patients with peripheral OA or sciatica. Anti-HCV antibodies were found in 7/152 (4.6%) patients suffering from FM and in 5/152 (3.3%) of control subjects. No statistically significant differences in HCV prevalence were detected between cases and controls. Our present report does not confirm previous data indicating an increased prevalence of HCV in FM patients and does not seem to support a significant pathogenetic role of HCV under this condition.

Higher prevalence of fibromyalgia in patients infected with human T cell lymphotropic virus type I.

OBJECTIVE: . Inflammatory rheumatic conditions including rheumatoid arthritis and Sjögren's syndrome have been reported in individuals infected with human T cell lymphotropic virus type I (HTLV-I). Other chronic lymphotropic virus infections such as hepatitis C and human immunodeficiency virus are associated with fibromyalgia (FM). There are no reports about the association between HTLV-I infection and FM. We evaluated the association between FM and HTLV-I infection. METHODS: We conducted a case-control study with prevalent cases. Ex-blood donation candidates with HTLV-I infection from a blood bank cohort, and healthy blood donors as a control group, were submitted to rheumatologic evaluation to compare the prevalence of FM. The following covariables were also evaluated: other rheumatic diseases, age, sex, personal income, level of education, and depression. RESULTS: One hundred individuals with HTLV-I infection and 62 non-infected blood donors were studied. Thirty-eight (38%) HTLV-I infected individuals and 3 (4.8%) individuals from the control group presented the diagnosis of FM (OR 12.05, 95% CI 3.53-41.17). Other rheumatic diseases were also more prevalent in the infected group (37% vs 12.9%; OR 3.80, 95% CI 1.63-8.86). In multivariate analysis adjusted by the covariables, the association between HTLV-I and FM was statistically significant (OR 9.14, 95% CI 2.42-34.52). CONCLUSION: Our study shows a greater prevalence of FM in HTLV-I infected individuals, suggesting that FM may be associated with this viral infection.

Lack of association of fibromyalgia with hepatitis C virus infection.

OBJECTIVE: An association between chronic hepatitis C virus (HCV) infection and fibromyalgia (FM) remains controversial, mainly because previous studies were based on prevalent case series or comparisons with less than optimal control groups. We investigated whether there might be an association between chronic HCV infection and FM. METHODS: We prospectively investigated the prevalence of HCV infection in a series of 115 patients with FM and compared it with the prevalence in the general population of our community reported in the same period. Anti-HCV antibodies were determined by ELISA. In positive cases, infection was confirmed by recombinant immunoblot assay and HCV-RNA was detected by PCR using sera samples. Differences between prevalence rates were assessed by chi-square test. RESULTS: HCV infection was confirmed in 3 of 115 patients with FM (2.6%). Two of these patients (1.74%) had active HCV infection shown by the presence of viral RNA in serum, whereas HCV RNA was undetectable in the third patient. In these cases, liver disease had previously been undiagnosed and HCV infection manifested itself by extrahepatic symptoms. Although the prevalence of HCV infection was slightly higher in patients with FM than in the general population in the age groups 25-44 and 45-64 years, when we compared prevalence rates in the total group and the different age groups, no statistically significant differences were found. CONCLUSION: From our results, it seems unlikely that HCV infection plays a pathogenic role in FM.

Detection of enterovirus in human skeletal muscle from patients with chronic inflammatory muscle disease or fibromyalgia and healthy subjects.

Enterovirus RNA has been found previously in specimens of muscle biopsy from patients with idiopathic dilated cardiomyopathy, chronic inflammatory muscle diseases, and fibromyalgia or chronic fatigue syndrome (fibromyalgia/chronic fatigue syndrome). These results suggest that skeletal muscle may host enteroviral persistent infection. To test this hypothesis, we investigated by reverse transcription-polymerase chain reaction (RT-PCR) assay the presence of enterovirus in skeletal muscle of patients with chronic inflammatory muscle diseases or fibromyalgia/chronic fatigue syndrome, and also of healthy subjects. Three of 15 (20%) patients with chronic inflammatory muscle diseases, 4 of 30 (13%) patients with fibromyalgia/chronic fatigue syndrome, and none of 29 healthy subjects was found positive. The presence of VP-1 enteroviral capsid protein was assessed by an immunostaining technique using the 5-D8/1 monoclonal antibody; no biopsy muscle from any patient or healthy subject was found positive. The presence of viral RNA in some muscle biopsies from patients exhibiting muscle disease, together with the absence of VP-1 protein, is in favor of a persistent infection involving defective viral replication.

Comparison of viral antibodies in 2 groups of patients with fibromyalgia.

OBJECTIVE: The etiologies of fibromyalgia (FM) are unknown. In some cases an acute onset following a flu-like episode is described; in other cases patients report slowly developing disease. We previously found increased prevalence of enterovirus IgM antibodies in patients with acute onset of FM compared to healthy controls. We looked for differences in antimicrobial IgM antibodies in acute versus nonacute onset FM. METHODS: Two well defined, comparable groups of patients with FM (acute 19, nonacute 20) were studied for antibodies in serum to an array of viruses including IgM antibodies. RESULTS: In most viruses no IgM antibodies were found. However, about 50% of the patients with acute FM onset had IgM antibodies against enterovirus compared to only 15% of the slow onset patients. CONCLUSION: The higher prevalence of IgM antibodies against enterovirus in patients with acute onset of FM may indicate a difference in the etiology or the immune response in these patients.

Search for Borna disease virus in Danish fibromyalgia patients.

OBJECTIVE: The purpose of this study was to look for Borna disease virus (BDV) in 18 patients with acute onset of fibromyalgia (FMS) following a "flu-like" episode. BDV is a neurotropic RNA virus affecting horses and sheep. Infections in animals have been reported to cause immune mediated disease characterized by abnormalities in behavior. A possible link between BDV and neuropsychiatric diseases in man has been described, and lately a connection to chronic fatigue syndrome (CFS) has been suggested. METHODS: A BDV-specific nested PCR (RT-PCR) was performed on serum and spinal fluid. RESULTS: The BDV genome was not detected in any of the FMS cases. CONCLUSION: Although BDV was not demonstrated in spinal fluid or serum from the tested patients with FMS, we believe that it is important to report our results, since FMS can exhibit many manifestations in common with CFS. Possible reasons for the discrepant findings are discussed.