Coxsackie B virus

Coxsackie B (also written coxsackievirus B) is a group of six types of enterovirus, causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Like other enteroviruses, Coxsackie B viruses have a tropism for muscle cells and have been linked to myalgic encephalomyelitis and chronic fatigue syndrome, as well as Type 1 Diabetes.

Symptoms
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.

Immune system
In a mouse model of myocarditis, Coxsackievirus infection was found to upregulate Toll-like receptor 4 on mast cells and macrophages immediately following infection. It also increased numbers of mast cells.

Mitochondria
Coxsackievirus B3 cleaves Mitochondrial Antiviral Signaling (MAVS) protein to inhibit type I interferon induction. Conversely, upregulation of MAVS inhibits coxsackie B3 by increasing type-1 interferon production.

Exercise
Several studies of a mouse model of Coxsackie B3 myocarditis have found that exercise increases the virulence of the infection and results in poorer outcomes. These studies compare two groups of mice, both infected with CVB3, one that is exercised and the other, sedentary. They found:


 * Exercised mice died of congestive heart failure (the majority while swimming) and had 530X the amount of virus.
 * Exercised mice had increased viral titers, mortality and fiber necrosis.
 * Exercised mice had higher viremia and virus in the hearts and no circulating interferon; non-exercised mice had detectable interferon activity, higher levels of neutralizing antibodies
 * Exercised mice died at much higher rates (52% v. 0 sedentary mice), but not if they were immunosuppressed.
 * Increased T cytotoxic, T suppressor, and T cytotoxic, suppressor/T helper cell ratio, and myocardial inflammatory and necrotic lesions with exercise at 48 hours after infection. "Failure to restrict physical activity in the acute phase of this infection may well contribute to the progression of the disease."

Chronic infection
Some researchers believe that Coxsackie B 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.

In human disease
Viruses in the Coxsackie B family progress to myocarditis or pericarditis, which can result in permanent heart damage or death. Coxsackie B virus infection may also induce aseptic meningitis. As a group, they are the most common cause of unexpected sudden death, and may account for up to 50% of such cases.

Myalgic Encephalomyelitis
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.

Type 1 diabetes
A study of patients with Type 1 Diabetes found that Coxsackie B4 was found to infect β cells and cause inflammation mediated by natural killer cells.

Testing
In the United States, ARUP Laboratories offers a serum microneutralization assay that is designed to measure the concentration of serum antibodies to six serotypes of the virus; B1 through B6. This specific assay has been shown to be sensitive for detection of chronic infections in ME patients. A persistent fourfold or greater rise in antibody titer is often found in these patients, which is not often found in healthy controls.

A complement fixation assay for Coxsackie B serotypes is available in the United States from LabCorp and Quest Diagnostics, however this specific type of assay has not been found to be sensitive for the chronic infections found in ME patients.

Antivirals
There are no approved vaccines or antivirals for Coxsackie viruses, and there have been no human trials. Preliminary research (often in animal models or in vitro) have been shown various compounds to have potential antiviral effects, but it is not known whether these compounds have or could be used to create interventions with any clinical benefit in humans.

John Chia reported that treatment with Interferon and Ribavirin on patients with B3 or B5 appeared to show some benefit, but patients relapsed after discontinuation of treatment. One patient with B4 experienced moderate improvement on Pleconaril but also relapsed.