OVERVIEW: What every practitioner needs to know

Are you sure your patient has neonatal enteroviral infection? What are the typical findings for this disease?

Although enteroviruses generally cause mild and self-limited disease, newborns – especially those infected at the time of delivery – are susceptible to overwhelming infection. Severely affected infants typically present during the first week of life, with symptoms that are difficult to distinguish from those of bacterial sepsis, including fever, poor feeding, lethargy, respiratory distress, and cardiovascular collapse. Echoviruses and parechoviruses typically cause a syndrome characterized by hepatic necrosis and coagulopathy, whereas coxsackie B viruses are more likely to cause myocarditis and meningoencephalitis.

Infants with perinatal enterovirus infections may also have diarrhea, pulmonary symptoms, exanthems, and necrotizing enterocolitis.

What other disease/condition shares some of these symptoms?

Enteroviral sepsis may closely resemble infections caused by bacteria such as Group B streptococci and E. coli. Disseminated herpes simplex virus infection also causes hepatic necrosis and coagulopathy, often accompanied by pneumonia. Congenital heart disease can cause a sepsis-like picture, and metabolic diseases may cause hepatic failure.

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What caused this disease to develop at this time?

Protection against enterovirus infections depends on serotype-specific neutralizing antibodies; placental transfer of maternal neutralizing antibodies protects the newborn against those viruses to which the mother is immune. However, when a mother is infected just before the time of delivery, the virus can be transmitted to the infant before antibodies have been produced. In many infants with severe enteroviral sepsis, the mothers experienced fever and abdominal pain shortly before or just after delivery.

The typical infant with echovirus hepatitis presents several days after birth, often after discharge from the newborn nursery. However, some cases have occurred in the first day of life, suggesting that intrauterine transmission is possible. Coxsackievirus B myocarditis is seen in older infants, as well as newborns.

Enterovirus outbreaks in nurseries have been reported, with some fatal cases.

Risk factors for severe disease include maternal illness near the time of delivery, prematurity, and onset within the first week of life.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Enterovirus- and parechovirus-specific PCR tests can detect viral RNA in blood, CSF, and urine of infants with disseminated infection. Sensitivity is greatest when multiple sites are sampled.

The CBC may show elevated leukocyte counts, left shift, or thrombocytopenia. CSF pleocytosis with lymphocyte predominance is typical of enteroviral meningitis.

Elevated liver enzymes and bilirubin, as well as abnormal PT/PTT are typical of enteroviral sepsis.

Would imaging studies be helpful? If so, which ones?

Chest X-ray, EKG, and echocardiogram may show evidence of myocarditis or pneumonia. In infants with focal neurologic signs, ultrasound imaging may reveal intracranial hemorrhage.

If you are able to confirm that the patient has neonatal enteroviral infection, what treatment should be initiated?

Infants that appear septic should be treated with antibiotics (ampicillin plus cefotaxime) and acyclovir until bacterial infection and HSV have been excluded.

There is no specific treatment for enteroviral sepsis, and care is essentially supportive. Replacement of clotting factors may be helpful in managing coagulopathy; respiratory and blood pressure support may be needed.

Intravenous immunoglobulin (IVIG) may contain neutralizing antibodies active against common enterovirus serotypes; it has been used in some patients, but there is no evidence that it is effective.

An antiviral drug, pleconaril, has been tried in patients with enteroviral sepsis, but the results of a recently completed randomized trial have not been reported as of June, 2012, and the drug is not commercially available.

What are the possible outcomes of neonatal enteroviral infection?

Echovirus hepatitis with coagulopathy is a life-threatening illness (with mortality in a third or more cases). Many survivors recover without sequelae, but some suffer intracranial hemorrhage or other complications. In some cases, liver transplantation may be needed.

Infants who do not acquire infection from infected mothers generally have an uncomplicated course. Post-natally acquired enteroviral meningitis in infants does not result in neurologic sequelae.

What causes this disease and how frequent is it?

Severe infections are caused by a variety of enteroviruses: echoviruses (and others); coxsackie B viruses; and parechoviruses. Severe infections with coxsackie A viruses are less well described (but these viruses are harder to culture).

Enterovirus infections occur primarily in the summer and early autumn.

In a report from Denver, city-wide surveillance for enteroviral infections in infants less than 2 weeks old identified 29 cases over a 2-year period, of whom five had severe disease, and none died. At Children’s Hospital of Philadelphia, we generally see one newborn with life-threatening enteroviral disease each year.

What is the evidence?

Tebrueugge, M, Curtis, N. “Enterovirus infections in neonates”. Semin Fetal Neonatal Med.. vol. 14. 2009. pp. 222-227. (This is the most up-to-date review of this topic.)

Modlin, JF. “Perinatal echovirus infection: insights from a literature review of 61 cases of serious infection and 16 outbreaks in nurseries”. Rev Infect Dis. vol. 8. 1986. pp. 918-926. (This article suggests the role of late maternal infection in severe disease and the protective effect of antibody transferred to the newborn.)

Abzug, MJ. “Prognosis for neonates with enterovirus hepatitis and coagulopathy”. Pediatr Infect Dis J. vol. 20. 2001. pp. 758-763. (This article describes survival for infants provided with supportive care.)

Abzug, MJ, Levine, MJ, Rotbart, HA. “Profile of enterovirus disease in the first two weeks of life”. Pediatr Infect Dis J. vol. 12. 1993. pp. 820-824. (Description of the experience at Denver Children's Hospital during a period of city-wide surveillance.)

Rorabaugh, ML, Berlin, LE, Heldrich, F, Roberts, K, Rosenberg, LA, Doran, T, Modlin, JF. “Aseptic meningitis in infants younger than 2 years of age: acute illness and neurologic complications”. Pediatr. vol. 92. 1993. pp. 206-211. (When acquired post-natally, enterovirus meningitis in the young infant does not lead to long-term neurologic sequelae.)