10-day-old infant admitted for possible shock

A 10-day-old male infant was admitted to the PICU in late September for evaluation of shock. Over the previous 12 hours, he developed respiratory distress and worsening pallor. This combined with his declining level of interest in and frequency of breast-feeding alarmed his parents. He was transported to the hospital by ambulance. EMS provided the infant with intravenous fluids and oxygen during transport. On arrival to the facility, the infant required additional fluid resuscitation, sedation, intubation and ventilation for stabilization.

Parents denied emesis, diarrhea, cough, rhinorrhea, conjunctival discharge and inconsolability. The male infant was born at term via a precipitous, vaginal delivery. Maternal history was significant for Group B streptococcus colonization, but the infant’s mother did not receive proper intrapartum prophylaxis given the rapid delivery. Other routine prenatal labs were normal. Parents denied any history of oral and genital herpes simplex virus lesions. The infant’s father admitted to having mild upper respiratory tract symptoms around the time of delivery.

The infant’s past medical history was remarkable for a recent ward admission at 6 days of life for evaluation of fever. The infant had an isolated rectal temperature of 101ºF without any other concerning symptoms at that time. He was transferred to the pediatric ward and evaluated for serious bacterial infection to include urine, blood and cerebral spinal fluid (CSF) analysis. The infant received appropriate empiric antibiotic and antiviral therapy with ampicillin, gentamicin and acyclovir.

The infant’s work-up was significant for a leukocytosis (WBC =15,800/µL). His manual differential demonstrated a left shift with 68 polymorphonuclear cells, 18 lymphocytes and 14 monocytes/µL. His CSF protein was elevated at 90 mg/dL and his CSF glucose was 58 mg/dL. His CSF cell counts were 110 red blood cells/µL and 270 white blood cells/µL. The infant’s antimicrobial therapy was discontinued after 48 hours with negative CSF bacterial cultures and a negative CSF polymerase chain reaction (PCR) for herpes simplex virus.

Enterovirus was detected from this infant’s CSF by PCR analysis. He was given a diagnosis of aseptic meningitis, and he was acting, feeding and urinating well at the time of discharge.

On further evaluation in the PICU, the infant’s exam was significant for low blood pressure, muffled heart sounds and decreased capillary refill. After-load reduction with milrinone was required to improve the infant’s perfusion. The infant had an abnormal electrocardiogram. His lab work was significant for elevated troponin levels, but he had no evidence of any other organ involvement. The infant’s transaminases, renal function and brain imaging were all normal. A subsequent echocardiogram demonstrated decreased left-ventricular contractility. A decreased posterior, left ventricular wall motion abnormality was confirmed on cardiac catheterization.

These series of findings were consistent with a diagnosis of infectious myocarditis. The infant was treated with intravenous immunoglobulin (IVIG) and supportive care. Over the following several weeks, he gradually improved and was discharged to home with recovering cardiac function.

Myocarditis can be caused by a variety of viruses to include influenza, Epstein-Barr virus, cytomegalovirus, mumps, measles, HIV, hepatitis C virus and enteroviruses. Enteroviruses are also major common causes of aseptic meningitis. A variety of enteroviruses have been associated with both meningitis and myocarditis. These include poliovirus, echovirus and the coxsackieviruses.

About enteroviruses

There are more than 60 enteroviral serotypes, which are among the small RNA viruses within the Picornaviradae family. Enteroviral genera include the polioviruses, echoviruses, coxsackievirus A and B and newer enteroviruses. In the United States, coxsackieviruses B1-5 and more rarely echovirus and coxsackievirus A have been associated with myopericariditis. Meningitis has been found in a significant number (upward of 50% in some reports) of infantile enteroviral infections with coxsackieviruses B1-5 and echoviruses.

Epidemiology

Human enteroviruses are ubiquitous. They are spread mainly through fecal-oral transmission, but may also be spread from fomites and through inhalation of respiratory secretions.

Respiratory tract shedding occurs only within the first week of infection, but fecal shedding can occur for several weeks after onset. All age groups are affected, but more severe infections occur in young infants. Infants and children younger than 1 year have the highest incidence of infection. The incubation period is usually between three to six days. Infection rates peak in temperate climates during the summer and early fall seasons. Coxsackieviruses B2-5 account for one-third to one-half of sporadic and almost all epidemic cases of myopericarditis. Ninety percent of community-acquired viral, aseptic meningitis are caused by group B coxsackieviruses and echoviruses.

Clinical manifestations

Most enteroviral infections are asymptomatic and vary largely depending on the specific serotype of virus responsible for infection. Nonspecific acute febrile illnesses are often the initial presentation of enteroviral infections. In infants, fever can often be associated with poor feeding, irritability, lethargy, emesis, diarrhea, nonspecific rash or common cold symptoms. When more severe infections occur, as with meningitis and myopericarditis, infants can often present with jaundice, cyanosis, neurological symptoms, respiratory distress or a sepsis-like picture. Markers of severe enteroviral disease in infants include:

• an early age of illness onset (especially within the first day of life),
• maternal viral symptoms at delivery,
• absence of fever and irritability,
• tachypnea,
• lethargy,
• abdominal distension,
• hepatomegaly and
• a positive serum viral culture.

Diagnosis

The three major methods of laboratory diagnosis of enterovirus are serologic tests, detection of enteroviral RNA by PCR in body fluids, and isolation and identification in cell culture. Enteroviruses can be isolated from stool, rectal swabs, oropharyngeal secretions and less commonly CSF, blood and urine.

Cultured cells demonstrate a characteristic cytopathic effect within two to six days, at which time a confirmatory monoclonal antibody can be used to identify and serotype the virus. Often, reference laboratories can also perform PCR detection of enterovirus from the CSF, blood and feces, which is more rapid and sensitive than cell culture. The drawback to PCR is the inability to further serotype the virus. Although commercially-available, serologic assays to include enzyme immunoassays are poorly standardized and cross-reactivity among serotypes may lower specificity as well.

Treatment

The mainstay of treatment for most enteroviral infections is supportive care. Some anecdotal evidence exists that in severe infections in immunocompromised hosts, and specifically in acute myopericarditis, IVIG at a dose of 2 g/kg may be of benefit, although there are no comparative data.

Another agent still being tested for the treatment of severe enteroviral disease is pleoconaril.

Pleconaril is a unique compound that integrates into the capsid of picornaviruses and prevents enterovirus from attaching to cellular receptors. It has been studied in a randomized, placebo-controlled multicentered trial for meningitis in adolescents and adults and on a compassionate-release basis for a small number of patients with neonatal sepsis and myocarditis.

Although pleconaril has been shown to shorten the period of viral shedding in some patients, the degree of effect on an individual patient’s clinical course and therapeutic effect is often difficult to ascertain. The NIH/NIAID Collaborative Antiviral Study Group continues to evaluate pleconaril in a randomized, placebo-controlled trial for the treatment of neonatal sepsis. Trial results have not been reported to date.

Prevention

As with most fecal-orally transmitted viruses, good hand washing and hygiene is the most effective way to reduce infection. Passively acquired maternal antibodies are thought to be protective and perhaps the most critical factor in determining the severity of perinatal enteroviral infection. In a hospitalized patient, contact precautions, as well as standard precautions, should be used for infants and young children for the duration of illness.

Michael Rajnik, MD, is a lieutenant colonel in the U.S. Air Force. He is currently the Pediatric Infectious Disease Fellowship Director and Assistant Professor of Pediatrics at the F. Edward Hebert School of Medicine, Uniformed Services University of Health Sciences in Bethesda, Md.

David R. Stagliano, MD, is a major in the U.S. Army. He is currently a Pediatric Infectious Disease Fellow at the F. Edward Hebert School of Medicine, Uniformed Services University of Health Sciences in Bethesda, Md.

For more information:

• Red Book 2006, pages 284-285.
• Long S, Pickering L, Prober C, editors. Chapter 40: Myocarditis. Principles and Practice of Pediatric Infectious Disease. 3^rd ed: Elsevier Science; 2008.
• Long S, Pickering L, Prober C, editors. Chapter 235: Introduction to Picornaviridae. Principles and Practice of Pediatric Infectious Disease. 3^rd ed: Elsevier Science; 2008.
• Long S, Pickering L, Prober C, editors. Chapter 237: Enteroviruses: Coxsackieviruses, Echoviruses, and Newer Enteroviruses. Principles and Practice of Pediatric Infectious Disease. 3^rd ed: Elsevier Science; 2008.
• Am J Clin Pathol. 1970;53: 825–831.
• Clin Infect Dis. 2001; 32: 228-235.
• Pediatr Infect Dis J. 1993; 12(10): 820–824.

Disclaimer: The opinions or assertions contained herein are private views of the authors and are not to be construed as official or as reflecting views of the Department of Defense.