Publications
Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
Chia JK, Chia AYBACKGROUND AND AIMS: The aetiology for chronic fatigue syndrome (CFS) remains elusive although enteroviruses have been implicated as one of the causes by a number of studies. Since most CFS patients have persistent or intermittent gastrointestinal (GI) symptoms, the presence of viral capsid protein 1 (VP1), enterovirus (EV) RNA and culturable virus in the stomach biopsy specimens of patients with CFS was evaluated.
METHODS: 165 consecutive patients with CFS underwent upper GI endoscopies and antrum biopsies. Immunoperoxidase staining was performed using EV-specific monoclonal antibody (mAb) or a control mAb specific for cytomegalovirus (CMV). RT-PCR ELISA was performed on RNA extracted from paraffin sections or samples preserved in RNA later. Biopsies from normal stomach and other gastric diseases served as controls. 75 samples were cultured for EV.
RESULTS: 135/165 (82%) biopsies stained positive for VP1 within parietal cells, whereas 7/34 (20%) of the controls stained positive (p< or =0.001). CMV mAb failed to stain any of the biopsy specimens. Biopsies taken from six patients at the onset of the CFS/abdominal symptoms, and 2-8 years later showed positive staining in the paired specimens. EV RNA was detected in 9/24 (37%) paraffin-embedded biopsy samples; 1/21 controls had detectable EV RNA (p<0.01); 1/3 patients had detectable EV RNA from two samples taken 4 years apart; 5 patient samples showed transient growth of non-cytopathic enteroviruses.
CONCLUSION: Enterovirus VP1, RNA and non-cytopathic viruses were detected in the stomach biopsy specimens of CFS patients with chronic abdominal complaints. A significant subset of CFS patients may have a chronic, disseminated, non-cytolytic form of enteroviral infection, which could be diagnosed by stomach biopsy.
The role of enterovirus in chronic fatigue syndrome.
Chia JK
Two and a half decades after coining of the term chronic fatigue syndrome (CFS), the diagnosis of this illness is still symptom based and the aetiology remains elusive. Enteroviruses are well known causes of acute respiratory and gastrointestinal infections, with tropism for the central nervous system, muscles, and heart. Initial reports of chronic enteroviral infections causing debilitating symptoms in patients with CFS were met with skeptism, and had been largely forgotten for the past decade. Observations from in vitro experiments and from animal models clearly established a state of chronic persistence through the formation of double stranded RNA, similar to findings reported in muscle biopsies of patients with CFS. Recent evidence not only confirmed the earlier studies, but also clarified the pathogenic role of viral RNA through antiviral treatment. This review summarises the available experimental and clinical evidence that supports the role of enterovirus in chronic fatigue syndrome.
Diverse etiologies for chronic fatigue syndrome
Chia JK, Chia AY
SIR—Koelle et al. [1] recently studied 22 pairs of identical twins discordant for chronic fatigue syndrome and concluded that there was no major contribution for viral infections in the perpetuation of chronic fatigue syndrome (CFS). The authors should be commended for their methodology and the use of well-matched control subjects. However, the study raised several issues.
First, similar to previous studies, the approach of Koelle et al. [1] was to look for statistical differences among the well-matched pairs with respect to the presence of viral antibodies and, more specifically, the presence of DNA of the viruses studied. Although these viruses were no more prevalent among the patients with CFS than among their healthy twins, one cannot conclude that these viruses are not the cause of CFS in a small subset of patients. CFS has been described in a small number of patients who had had well-documented acute Epstein-Barr virus (EBV), cytomegalovirus (CMV), and parvovirus B19 infections [2–4], and many of the patients responded to specific antiviral therapy. Of the first 200 patients with CFS who we evaluated for viral etiologies (table 1), only ∼10% had etiologies that were attributed to the viruses studied by Koelle et al. [1]. Chlamydia pneumoniae infection, an uncommon, although treatable, cause of CFS, was also dismissed in a previous, smaller study [5].
Second, latent EBV DNA and EBV viruses were often found in the blood and saliva, respectively, of asymptomatic, seropositive individuals [6, 7], and, therefore, by themselves, are not ideal markers of active viral infection or the resultant symptoms of CFS. Would detection of virus-specific mRNA be more indicative of smoldering infection in the PBMCs, and would a positive response to antiviral therapy increase the specificity of the finding? Third, the tissue localization and persistence of viruses may be responsible for the symptoms of CFS, and viruses may not be detected by viral assay of PBMCs or plasma. We have seen 2 patients with CFS who, after acute viral infection, had urine samples positive for EBV DNA and urine cultures persistently positive for CMV growth during a period of 6 months, but whose blood samples tested negative for EBV DNA and CMV DNA, respectively. Both patients improved after receiving intravenous cidofovir therapy.
About one-half of our first 200 patients with CFS had significantly elevated levels of neutralizing antibodies to coxsackievirus B and echoviruses, compared with control subjects from the community. On repeat testing, ∼39% of the patients tested positive for enteroviral RNA in PBMCs, as documented by 3 different PCR techniques [8, 9]. These results are similar to those reported by some investigators [10, 11]. Furthermore, results of a recent animal study and cell culture experiments clearly demonstrated the mechanism of enteroviral persistence [12, 13]. Although no less controversial, it would be interesting to test the twins who participated in the study of Koelle et al. [1] for the presence of enteroviral RNA and neutralizing antibody to enteroviruses.
After 2 decades of extensive research, it is clear that no single virus is responsible for this elusive syndrome. Perhaps we should approach the causes of CFS in the same way that we approach the causes of fever of unknown origin. Many diseases, infectious or noninfectious, can cause fever of unknown origin. There is no single diagnostic test for the entire spectrum of diseases, and the final etiology for each patient can only be ascertained after the meticulous use of reliable tests to eliminate known diseases as causes. We agree with Koelle and colleagues that early evaluation of patients for acute infectious etiology may help document or eliminate common viral infections as causes, perhaps when the fatigue persists for >3 months. Defining the spectrum of infectious and noninfectious causes of this disorder and the relative frequency of various diseases is important since no single treatment strategy will be uniformly effective for diverse infectious etiologies.
Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
Chia JK, Chia AYBACKGROUND AND AIMS: The aetiology for chronic fatigue syndrome (CFS) remains elusive although enteroviruses have been implicated as one of the causes by a number of studies. Since most CFS patients have persistent or intermittent gastrointestinal (GI) symptoms, the presence of viral capsid protein 1 (VP1), enterovirus (EV) RNA and culturable virus in the stomach biopsy specimens of patients with CFS was evaluated.
METHODS: 165 consecutive patients with CFS underwent upper GI endoscopies and antrum biopsies. Immunoperoxidase staining was performed using EV-specific monoclonal antibody (mAb) or a control mAb specific for cytomegalovirus (CMV). RT-PCR ELISA was performed on RNA extracted from paraffin sections or samples preserved in RNA later. Biopsies from normal stomach and other gastric diseases served as controls. 75 samples were cultured for EV.
RESULTS: 135/165 (82%) biopsies stained positive for VP1 within parietal cells, whereas 7/34 (20%) of the controls stained positive (p< or =0.001). CMV mAb failed to stain any of the biopsy specimens. Biopsies taken from six patients at the onset of the CFS/abdominal symptoms, and 2-8 years later showed positive staining in the paired specimens. EV RNA was detected in 9/24 (37%) paraffin-embedded biopsy samples; 1/21 controls had detectable EV RNA (p<0.01); 1/3 patients had detectable EV RNA from two samples taken 4 years apart; 5 patient samples showed transient growth of non-cytopathic enteroviruses.
CONCLUSION: Enterovirus VP1, RNA and non-cytopathic viruses were detected in the stomach biopsy specimens of CFS patients with chronic abdominal complaints. A significant subset of CFS patients may have a chronic, disseminated, non-cytolytic form of enteroviral infection, which could be diagnosed by stomach biopsy.
The role of enterovirus in chronic fatigue syndrome.
Chia JK
Two and a half decades after coining of the term chronic fatigue syndrome (CFS), the diagnosis of this illness is still symptom based and the aetiology remains elusive. Enteroviruses are well known causes of acute respiratory and gastrointestinal infections, with tropism for the central nervous system, muscles, and heart. Initial reports of chronic enteroviral infections causing debilitating symptoms in patients with CFS were met with skeptism, and had been largely forgotten for the past decade. Observations from in vitro experiments and from animal models clearly established a state of chronic persistence through the formation of double stranded RNA, similar to findings reported in muscle biopsies of patients with CFS. Recent evidence not only confirmed the earlier studies, but also clarified the pathogenic role of viral RNA through antiviral treatment. This review summarises the available experimental and clinical evidence that supports the role of enterovirus in chronic fatigue syndrome.
Diverse etiologies for chronic fatigue syndrome
Chia JK, Chia AY
SIR—Koelle et al. [1] recently studied 22 pairs of identical twins discordant for chronic fatigue syndrome and concluded that there was no major contribution for viral infections in the perpetuation of chronic fatigue syndrome (CFS). The authors should be commended for their methodology and the use of well-matched control subjects. However, the study raised several issues.
First, similar to previous studies, the approach of Koelle et al. [1] was to look for statistical differences among the well-matched pairs with respect to the presence of viral antibodies and, more specifically, the presence of DNA of the viruses studied. Although these viruses were no more prevalent among the patients with CFS than among their healthy twins, one cannot conclude that these viruses are not the cause of CFS in a small subset of patients. CFS has been described in a small number of patients who had had well-documented acute Epstein-Barr virus (EBV), cytomegalovirus (CMV), and parvovirus B19 infections [2–4], and many of the patients responded to specific antiviral therapy. Of the first 200 patients with CFS who we evaluated for viral etiologies (table 1), only ∼10% had etiologies that were attributed to the viruses studied by Koelle et al. [1]. Chlamydia pneumoniae infection, an uncommon, although treatable, cause of CFS, was also dismissed in a previous, smaller study [5].
Second, latent EBV DNA and EBV viruses were often found in the blood and saliva, respectively, of asymptomatic, seropositive individuals [6, 7], and, therefore, by themselves, are not ideal markers of active viral infection or the resultant symptoms of CFS. Would detection of virus-specific mRNA be more indicative of smoldering infection in the PBMCs, and would a positive response to antiviral therapy increase the specificity of the finding? Third, the tissue localization and persistence of viruses may be responsible for the symptoms of CFS, and viruses may not be detected by viral assay of PBMCs or plasma. We have seen 2 patients with CFS who, after acute viral infection, had urine samples positive for EBV DNA and urine cultures persistently positive for CMV growth during a period of 6 months, but whose blood samples tested negative for EBV DNA and CMV DNA, respectively. Both patients improved after receiving intravenous cidofovir therapy.
About one-half of our first 200 patients with CFS had significantly elevated levels of neutralizing antibodies to coxsackievirus B and echoviruses, compared with control subjects from the community. On repeat testing, ∼39% of the patients tested positive for enteroviral RNA in PBMCs, as documented by 3 different PCR techniques [8, 9]. These results are similar to those reported by some investigators [10, 11]. Furthermore, results of a recent animal study and cell culture experiments clearly demonstrated the mechanism of enteroviral persistence [12, 13]. Although no less controversial, it would be interesting to test the twins who participated in the study of Koelle et al. [1] for the presence of enteroviral RNA and neutralizing antibody to enteroviruses.
After 2 decades of extensive research, it is clear that no single virus is responsible for this elusive syndrome. Perhaps we should approach the causes of CFS in the same way that we approach the causes of fever of unknown origin. Many diseases, infectious or noninfectious, can cause fever of unknown origin. There is no single diagnostic test for the entire spectrum of diseases, and the final etiology for each patient can only be ascertained after the meticulous use of reliable tests to eliminate known diseases as causes. We agree with Koelle and colleagues that early evaluation of patients for acute infectious etiology may help document or eliminate common viral infections as causes, perhaps when the fatigue persists for >3 months. Defining the spectrum of infectious and noninfectious causes of this disorder and the relative frequency of various diseases is important since no single treatment strategy will be uniformly effective for diverse infectious etiologies.