Enterovirus

Seventy-one types of enteroviruses have been discovered. Among these are Coxsackie A viruses, Coxsackie B viruses, echoviruses and polioviruses.

The majority of enteroviral infections are subclinical and unlike herpesviruses, usually leave the body after an effective immune response. However, they are also the most common cause of meningitis (responsible for 85-90% of cases), and can cause myocarditis and chronic or life-threatening conditions in certain populations, such as in patients with X-linked agammaglobulinemia (XLA). Most children are exposed to at least one enterovirus by the age of 12 months.

Enteroviruses have a tropism for muscle cells and have been linked to myalgic encephalomyelitis and chronic fatigue syndrome, as well as Type 1 Diabetes.

Coxsackie B viruses
Coxsackie B (also written coxsackievirus B) is a group of six types of enterovirus, causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, headache, sore throat, gastrointestinal distress, extreme fatigue as well as chest and muscle pain. It can also lead to spasms in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the blood, muscle, gut and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.

Persistent infection
Some researchers believe that enteroviruses establish a persistent, intracellular, non-cytolytic infection, that is an infection that does not involve the destruction of infected cells. Non-cytolytic infection is difficult to measure in the serum as viral particles remain in the cell walls of tissues.

The molecular mechanisms of non-cytolytic infection were examined in a small study comparing Coxsackie B2 virus cultured in vitro to RNA extracted via muscle biopsy from eight patients with a chronic fatigue syndrome diagnosis. All patients had symptoms of muscle fatiguability. Four of these samples tested positive for enteroviral RNA. In all four patients with enteroviral-specific RNA, the enteroviral RNA had equal amounts of positive sense and negative sense RNA. By contrast, CVB2 virus in culture produced positive sense RNA at a ratio of 100:1. An equal ratio of positive to negative sense RNA would inhibit the translation of virus-specific gene products, explaining the failure to attract a response from the host immune system, and my account for how CVB2 could establish a persistent infection in these four patients.

Models of persistent infection of the heart and brain have also been studied in mice and in thyroid carcinoma.

Metabolic effects
A study of poliovirus found that polio infection rapidly decreases cellular oxygen consumption (and thus energy production through cellular respiration) by inhibiting succinate dehydrogenase and blocking mitochondrial electron transport.

Myalgic Encephalomyelitis
Ever since the historic outbreaks of ME in the 1930s-1950s, enteroviruses, especially Coxsackie B viruses, have been posited as a key etiological factor in myalgic encephalomyelitis. These frequently coincided with outbreaks of polio, another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse peripheral nervous system damage in monkeys infected with the virus; a stronger response to polio vaccination in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.

There is no consensus regarding the direct evidence for enteroviral persistence in ME patients, in part to different methods of testing and types of tissue samples. Several researchers have indicated that they have failed to find evidence of enteroviruses in the blood and cerebrospinal fluid of ME patients, whereas others maintain that a persistent infection can only be directly measured in tissue samples, for example muscle biopsies, stomach biopsies, or brain tissue.

Some studies have found evidence of enteroviral infection in muscle biopsies in a subset of patients, while others have failed to replicate those results.

Several studies have patients with ME to have persistently elevated levels of Coxsackie B IgM or IgG antibodies, circulating immune complexes containing viral antigen, or presence of enterovirus by PCR or culture, all indicating the possible presence of a persistent infection. Others studies failed to find a difference in rates of positivity between patients and controls. Differences in study outcomes may be due to the criteria used to define study cohorts as well as the techniques used.

Blood testing
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks. In a retrospective cohort study by Melvin Ramsay and Elizabeth Dowsett, 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral IgM, suggesting a persistent infection was present.

Similarly, a study of of 76 patients with postviral fatigue syndrome (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and VP1 antigen was detected in 51%, all pointing to a chronic infection in many post-viral patients. However, a larger study in Scotland of 243 PVFS patients and matched controls found no difference in IgM and IgG positivity between patients and controls.

PCR
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by PCR, compared to only 9% of the comparison group.

Also using PCR, a study of 236 patients by John Chia found enteroviral RNA in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.

Muscle biopsy
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 post-viral fatigue syndrome patients found 53% had enteroviral RNA in muscle compared to 15% of controls. However, a follow-up study comparing CFS patients to patients with other neuromuscular disorders failed to find a statistically significant difference.

Gut biopsy
Research by John Chia and his son, Andrew Chia has looked for enteroviruses in gut biopsies. 82% of samples were positive for viral capsid protein 1 (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of Chronic Fatigue Syndrome patients have a chronic enteroviral infection.

Treatment
There are no FDA-approved treatments for enteroviruses. The drug Pleconaril has been shown to have activity against a number of enteroviruses    but has not been approved by the FDA.

Treatment usually involves supporting the immune response particularly in those with documented immune dysfunction. Dr. Chia treats his patients with enteroviral infection with Equilibrant, gammaglobulin and interferon.

Published Studies

 * 2016, A study on brain tissue samples from a deceased ME patient found evidence of enterovirus specific genomic sequences and enteroviral protein in the patient's cerebral cortex.
 * 2016, A study on stomach tissue samples from CFS patients found that 82% of patients have evidence of chronic enterovirus infection of the stomach.
 * 2010, A longitudinal study found that a percentage of patients presenting to emergency care with acute enterovirus infection would go on to develop symptoms of ME and CFS and had demonstrable evidence of viral persistence.
 * 1996, A Swedish study using the Fukuda criteria was unable to find evidence of any persistent enteroviral infection in fecal samples, muscle biopsies, or cerebrospinal fluid.
 * 1995, In the CFS study group, 42% patients were positive for enteroviral sequences by PCR, compared to only 9% of the comparison group.
 * 1994, A second postmortem tissue study found positive enterovirus PCR sequences in the muscle, heart, brain stem, and hypothalamus of a deceased ME patient.
 * 1990, Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA. "This suggests that entrovirus pesistence in muscle is due to a defect in control of viral RNA synthesis."
 * 1990, A retrospective cohort study found that 31% of ME patients had elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral IgM, indicating the possibility of a persistent infection.
 * 1988, A study of 76 postviral fatigue patients and 30 controls found significantly higher numbers of positive cultures and IgM responses to enteroviruses.
 * 1988, In one study, enterovirus-specific RNA three standard deviations greater than controls was found in muscle biopsies of 20% of ME patients studied.

Talks & interviews

 * 2016, - 86. ‪ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD

Learn More

 * ME/CFS and Polio, chapter from book "ME: The New Plague", Jane Colby.