Group B Coxsackie Virus

Etiology

The enterovirus is a positive-sense, single-stranded RNA virus named for its enteric or gastrointestinal route of transmission.[2] Before being reclassified as human enterovirus A-D, the enteroviruses were categorized according to their pathogenesis in humans and laboratory animals into 4 groups: polioviruses, coxsackie A viruses, coxsackie B viruses, and echoviruses.[3] 

Coxsackieviruses are nonenveloped viruses with linear single-stranded RNA. Group A coxsackieviruses primarily cause skin and mucosal infections, most notably hand, foot, and mouth disease and herpangina. Group B coxsackieviruses include 6 recognized serotypes: CVB1, CVB2, CVB3, CVB4, CVB5, and CVB6.[4] In addition to causing mild gastrointestinal and respiratory infections, they can infect cardiac tissue, pleura, pancreas, and liver, leading to pleurodynia, myocarditis, pericarditis, and hepatitis.[5] They can also cause severe, multiorgan, systemic disease in neonates, often leading to critical or fatal illness.[6]

Group B coxsackieviruses are responsible for several syndromes, including:

• Viral prodrome, including fever, fatigue, malaise, myalgia, gastrointestinal upset, eg, nausea, vomiting, diarrhea, and abdominal pain
• Exanthema
• Aseptic meningitis
• Encephalitis
• Pleurodynia 
• Myopericarditis
• Pancreatitis leading to beta-cell destruction and type 1 diabetes.[2][7][8]

Epidemiology

Group B coxsackieviruses have a global distribution and are year-round pathogens, with peak activity during the summer and fall months in temperate climates. They primarily affect infants and young children, often resulting in asymptomatic or mild illness, although they can cause severe disease, primarily in neonates. Group B coxsackieviruses are incredibly common. A seroprevalence study in Italy found that 69% of individuals were positive for at least 1 serotype. Overall, serotype CVB4 was the most prevalent (45%), followed by CVB3 (33%), CVB5 (26%), CVB1 (13%), CVB2 (11%), and CVB6 (2%).[9][10]

Infections peak during the warm summer and fall months in temperate climates. Group B coxsackieviruses account for around 25% of all enterovirus infections, and nearly half of all reported cases occur before age 5 years, with many occurring younger than age 1 year.[11][12] Transmission is primarily through the fecal-oral route, although transmission can also occur through respiratory droplets or via vertical transmission from mother to infant.[13] Group B coxsackieviruses are the most common cause of infectious myocarditis, and frequently cause pancreatitis and aseptic meningitis.[14]

Pathophysiology

Group B coxsackieviruses are transmitted primarily through the fecal-oral route and initially replicate within the gastrointestinal tract and associated lymphoid tissue. Following viral replication and dissemination, these viruses demonstrate marked tropism for the heart, pancreas, and liver, producing direct cytolytic injury and stimulating autoimmune responses that contribute to myocarditis, pericarditis, pancreatitis, and aseptic meningitis. Persistent group B coxsackievirus infection has also been associated with islet autoantibody production, a process believed to contribute to the development of type 1 diabetes.[15] The incubation period generally ranges from 2 to 6 days.

The pathogenesis of group B coxsackievirus infection depends on specific interactions between viral particles and host cell surface receptors. These virus-receptor interactions determine the location and origin of the primary infection while also influencing viral dissemination to distant organs during the post-viremic phase. Two key receptor proteins involved in this process include the coxsackievirus-adenovirus receptor (CAR) and the decay-accelerating factor (DAF), both of which play central roles in viral entry and tissue-specific disease.

DAF expression occurs on epithelial and endothelial cells, whereas CAR localizes predominantly within the intercalated discs that connect adjacent myocardial cells and facilitate electrical and mechanical communication throughout the myocardium. Binding of group B coxsackieviruses to these receptors promotes viral entry into myocardial cells, initiating cellular injury and inflammatory responses that ultimately contribute to the development of myocarditis.[16]

Central nervous system involvement may develop through hematogenous dissemination or axonal transport of the virus. Viral replication within neural tissues, together with activation of autoimmune mechanisms, contributes to central nervous system injury. Although the precise mechanisms responsible for cellular injury and death remain incompletely understood, proposed pathways include inhibition of host cellular macromolecular synthesis, direct toxicity from viral proteins, and virus-induced apoptosis, all of which likely contribute to the neurologic manifestations associated with group B coxsackievirus infection.[17]

History and Physical

Symptoms of group B coxsackievirus infection frequently include mild, flu-like symptoms, including fever, headache, sore throat, malaise, and myalgia. If gastrointestinal symptoms are present, they may include nausea, vomiting, abdominal pain, and diarrhea. Respiratory symptoms, if present, commonly include upper respiratory tract symptoms, sore throat, and cough. If a rash appears, it typically presents as a maculopapular rash, often first appearing on the face and neck and then spreading to the trunk and extremities, sparing the palms and soles.[18] Severe symptoms vary depending on the site and severity of infection.

Myocarditis/Pericarditis

Symptoms often include chest pain, shortness of breath, dyspnea on exertion, and an irregular heart rate. On physical exam, tachycardia, decreased heart sounds, and a pericardial or pleural friction rub may be present in pericarditis. In severe cases, findings of acute heart failure, eg, a gallop rhythm or elevated jugular venous pressure, may be present.

Pancreatitis

Like other causes of pancreatitis, group B coxsackievirus infection may cause dull to intense abdominal pain, often located in the mid-epigastrium, which may radiate to the back or shoulders. Nausea, vomiting, and diarrhea may be present. On physical exam, individuals may have abdominal tenderness, distention, and guarding. 

Aseptic Meningitis and Encephalitis

Symptoms may include severe headache, fever, vomiting, stiff neck, and confusion. Infants often present with fever and irritability, while children and adults may present with fever, headache, nausea, vomiting, and stiff neck. Encephalitis may present with confusion and seizures. On physical examination, nuchal rigidity may be present in aseptic meningitis, and confusion in encephalitis.

Evaluation

Usually, a clinical diagnosis of a likely enterovirus infection is sufficient, given the self-limiting course of the infection. However, more severe cases, eg, myocarditis, aseptic meningitis, encephalitis, neonatal infections, and infections in immunocompromised individuals, may require the identification of the specific organism. Furthermore, laboratory diagnosis can be epidemiologically useful, especially during epidemics. 

Enterovirus infection, including group B coxsackieviruses, is primarily diagnosed by reverse transcriptase polymerase chain reaction (RT-PCR). Detection of genomic material by RT-PCR from blood, cerebrospinal fluid (CSF), pericardial fluid, or tissue is diagnostic of infection. Detection from respiratory secretions is highly suggestive of infection. A positive RT-PCR test from stool may reflect acute infection, carriage, or shedding from a recent infection. 

Culture-based methods are slower than RT-PCR, more labor-intensive, and more expensive, so they are typically not performed anymore outside of research purposes or for epidemiologic/public health surveillance. In addition, culture has suboptimal sensitivity, around 65% to 75%.[19] Serological tests are reserved for the diagnosis of an enterovirus infection when a particular serovar is suspected, and the diagnosis is often made retrospectively by analyzing both acute and convalescent serum.[20]

Other appropriate diagnostic tests may include:

• Complete blood count (CBC)
• Comprehensive metabolic profile (CMP)
• Erythrocyte sedimentation rate
• Chest x-ray
• Abdominal computed tomography (CT) scan 
• Head CT scan
• Lumbar puncture for cerebrospinal fluid (CSF) cell count, culture and sensitivity, Gram stain, protein, and glucose, and viral PCR 
• Lactic acid
• Procalcitonin

Treatment / Management

No specific antiviral therapy currently targets group B coxsackievirus infection or other enterovirus infections. Management focuses on symptomatic relief and comprehensive supportive care tailored to the patient's clinical presentation and disease severity. Most group B coxsackievirus infections follow a mild, self-limited course and resolve without the need for targeted antiviral treatment.

A subset of patients develops severe disease, including systemic neonatal infection, severe myocarditis, encephalitis, chronic infection in immunocompromised individuals, and disseminated infection with multiorgan involvement. These presentations often require hospitalization, close clinical monitoring, and intensive supportive management to address organ dysfunction and prevent further complications. Despite the potential severity of these infections, no antiviral agents have received approval from the United States Food and Drug Administration (FDA) for the treatment of group B coxsackievirus infection in the United States. Consequently, optimal management depends on early recognition, appropriate supportive interventions, vigilant monitoring for complications, and timely involvement of relevant medical specialists when indicated.

Differential Diagnosis

As most Group B coxsackievirus infections are mild, significant overlap with other common viral infections is noted, including:

• Other enteroviruses (eg, echoviruses and group A coxsackieviruses, eg, HFMD and herpangina)
• Epstein-Barr virus 
• Cytomegalovirus 
• Lyme disease
• Rocky Mountain spotted fever
• Other causes of gastrointestinal symptoms (eg, acute hepatitis A, B, or C, viral gastroenteritis, acute pancreatitis)
• Myocarditis/pericarditis
  • Acute myocardial infarction
  • Human immunodeficiency virus (HIV) cardiomyopathy
  • Lupus erythematosus
  • Rheumatic fever
• Aseptic meningitis/encephalitis
  • Herpes simplex virus (HSV)
  • HIV
  • Lymphocytic choriomeningitis virus
  • Arboviruses
  • Bacterial meningitis
• Systemic neonatal disease
  • Bacterial sepsis
  • HSV encephalitis
  • Necrotizing enterocolitis 

Prognosis

Group B coxsackievirus infections are usually self-limited, with most resulting in complete recovery, though a few exceptions occur. While aseptic meningitis due to group B coxsackievirus infection has an excellent prognosis and is rarely life-threatening, the majority recover without any long-term neurologic problems.[21]

Myocarditis and pericarditis from group B coxsackievirus are generally favorable, with the majority of individuals recovering completely.[22] However, outcomes vary with the degree of inflammation and age, with newborns faring worse than older children and adults.[23] Severe pancreatitis due to group B coxsackievirus can lead to pancreatic beta-cell destruction and the development of type 1 diabetes.[8]

Complications

Although most Group B coxsackievirus infections resolve without sequelae, severe complications may develop because of the virus's tropism for the heart, central nervous system, pancreas, liver, and other organs. Cardiac involvement may result in myocarditis or myopericarditis, progressing to arrhythmias, acute heart failure, cardiogenic shock, or fulminant heart failure in severe cases.[24][25][24] Central nervous system infection can lead to aseptic meningitis or encephalitis, with complications including seizures, altered mental status, persistent neurologic deficits, and, rarely, death.[2][7] Pancreatic involvement may cause acute pancreatitis, and evidence suggests that viral-mediated beta-cell injury and autoimmune activation may contribute to the development of type 1 diabetes in susceptible individuals. Neonates face the greatest risk of severe disease, with disseminated infection causing sepsis-like illness, multiorgan dysfunction, and high morbidity and mortality.

Complications occur more frequently in neonates, immunocompromised individuals, and patients with significant cardiac or neurologic involvement, making early recognition and close monitoring essential. Delayed diagnosis or failure to identify evolving organ dysfunction may result in preventable adverse outcomes, prolonged hospitalization, intensive care admission, or permanent organ damage. Careful clinical assessment, appropriate diagnostic testing in severe presentations, and timely referral to cardiology, neurology, infectious disease, critical care, or neonatology facilitate prompt supportive management, reduce the risk of disease progression, and improve patient outcomes.