The nonpolio enteroviruses of the family Picornaviridae were first identified in the 1940s and have since been found to cause a wide spectrum of symptoms, ranging from the common cold to life-threatening myocarditis and meningoencephalitis. The first of these viruses to be discovered was coxsackievirus, which was isolated by Gilbert Dalldorf and Grace Sickles in 1948 while they were attempting to find a cure for polio.1 As the enteroviruses were discovered, they were initially categorized based on disease manifestations into 1 of 4 groups—polioviruses, coxsackieviruses A, coxsackieviruses B, and echoviruses. A fifth group was discovered several years later, sometimes referred to as “new enteroviruses.” The taxonomy of enteroviruses has been constantly evolving over the past 30 years and was most recently revised in 2014. The current classification system denotes 12 species (Enterovirus A, B, C, D, E, F, G, H, and J, and Rhinovirus A, B, and C) of the genus Enterovirus, the family Picornaviridae, and the order Picornavirales.2 These viruses are no longer classified by disease manifestations, but rather based on genetic and molecular similarities. Prior to the new classification system, polioviruses were separate species; however, they are now included in the Enterovirus C species. Due to the distinct and well-studied pathologic features of polioviruses, they will not be discussed in the remainder of this article.
Enteroviruses are very small, nonenveloped viruses with a single-stranded linear RNA genome. Once the virus penetrates and reproduces in a host cell, the viral RNA functions as messenger RNA and creates 3 to 4 proteins. Some of these proteins act as proteases, which interrupt host cell protein synthesis and secretion. By this mechanism, the virus is able to disrupt the normal functioning of host cells and cause malfunction of normal bodily processes.
Although some distinct species of enteroviruses have been found in other primates, humans are thought to be the only natural hosts of enteroviruses.3 They occur worldwide and are thought to be responsible for causing symptomatic disease in approximately 10 to 15 million people each year in the United States alone.4 Infections are seen more often in summer and fall months in temperate climates, and occur year-round in tropical climates.3,5–7 Disease manifestations are often more severe and debilitating in infants, likely due to their immature immune systems and susceptibility to disease. Enteroviruses are most commonly spread by fecal-oral route, but there is also some evidence of respiratory transmission. They can be active at room temperature for several days, which allows for transmission via fomites.
Transmission in Neonates
Neonates can be infected during the prenatal, intrapartum, or postnatal periods. Risk factors for contracting an enterovirus in the neonatal period include maternal illness during pregnancy (especially late in pregnancy), prematurity, low socioeconomic status, and lack of breast-feeding.3,5,8,9 Severe disease has been found to be associated with early age of symptom onset, history of maternal illness, and prematurity.8,10 Several studies have reported enterovirus infections in neonates whose mothers had the same virus, providing compelling evidence to support in-utero transmission, either transplacentally or by ascending infection. There have been a number of case reports and studies in the past 50 years that describe intrauterine infection with both coxsackieviruses and echoviruses, particularly when viruses were contracted by the mother late in pregnancy.8,10,11 Literature regarding transmission in the first and second trimesters remains inconclusive. Fewer data exist to support transmission of nonpolio enteroviruses to infants during birth. Exposure to maternal bodily fluids such as blood, stool, and vaginal fluid during delivery are plausible culprits of transmission by this mechanism, and intrapartum transmission has been described following both vaginal and cesarean delivery.12,13 Symptom onset would likely be within days to weeks after birth in neonates who contracted the virus during birth, whereas those who acquire the disease in-utero often have symptoms only hours after birth. The last and most common way enteroviruses are contracted by neonates is via fecal-oral spread in the postnatal period, typically by mother, other family members, or health care workers. There have been numerous reports of outbreaks of coxsackieviruses and echoviruses in hospital nurseries over the past 50 years, which highlights the infectivity and resiliency of these viruses.10,14–17 In many of these cases, it was thought that a sentinel case occurred due to vertical transmission followed by horizontal transfer to others neonates. In one review of multiple nursery outbreaks, the infants who acquired the disease vertically were found to have more severe disease than those who acquired the virus nosocomially.9,10 Although some studies have found breast-feeding to be protective against enterovirus transmission, enterovirus has been identified by cultures and polymerase chain reaction (PCR) in breast milk, raising the possibility of transmission via breast-feeding.3,5
Disease Symptoms and Complications in Neonates
Neonatal infection with nonpolio enteroviruses can cause a wide range of symptoms, from nonspecific febrile illnesses to life-threatening organ failure. In severe cases, sepsis, meningoencephalitis, myocarditis, pneumonia, hepatitis, and coagulopathy can be seen. Certain viruses can be associated with different disease manifestations, but all have the potential to be quite severe in neonates. In general, coxsackievirus B strains have been the most frequently associated with severe neonatal disease, and echovirus 11 has been increasing in frequency in this population as well.3 Most neonates who contract enteroviruses are typically asymptomatic or have a mild illness that may include fever, irritability, rash, poor feeding, or lethargy.5 These infants usually have a self-limited course and recover fully in only a few days, but some can develop an overwhelming sepsis-like illness. There are many different viruses that can cause a sepsis-like illness, but echovirus 11 has been associated most frequently with fatal septic events.3 One recent study18 performed in Kuwait identified enteroviruses as the cause of sepsis-like illness in 24% of neonates who had negative bacterial cultures; most of these cases were due to coxsackievirus B types.
Nearly half of neonates infected with enteroviruses experience respiratory symptoms such as rhinorrhea, cough, tachypnea, and respiratory distress. Pneumonia has been reported and can be rapidly progressing and severe, but generally, severe respiratory complications are very rare. Similarly, skin involvement is quite common as nearly half of patients develop a nonspecific rash, but the rash is generally self-limiting with no sequelae.3,5,9
Although most neonates infected with enteroviruses have mild illnesses without complications, enteroviruses can severely affect many organ systems in neonates, most notably the central nervous, cardiovascular, and gastrointestinal systems. Infants with central nervous system (CNS) disease (meningoencephalitis) caused by enteroviruses often present with lethargy, hypotonia, poor feeding, fever, vomiting, and seizures.6,7,9 Coxsackievirus B1–B5 and many echoviruses have most commonly been identified in cases of enteroviral meningoencephalitis in neonates.3 Few data exist regarding outcomes of those affected by enteroviral meningoencephalitis, but one case report described periventricular white matter necrosis and delay in myelination after an infection with an echovirus, resulting in mild-persistent hemiparesis.19 Another case series6 of six infants with enterovirus meningoencephalitis who presented with seizures and hypotonia described severe periventricular echogenicity in 5 of the 6 on initial ultrasonography, and abnormal magnetic resonance imaging in all six patients. After 2 years, 3 of 6 patients had lasting effects related to their illnesses, including cerebral palsy, epilepsy, behavioral disorder, and cerebral visual impairment. The authors report a similarity of brain lesion distribution to that seen in periventricular leukomalacia.6
Like CNS complications, cardiac complications from enterovirus infections are thought to be very rare in neonates. However, myocarditis can be much more severe and even lethal in this population. Coxsackievirus B viruses are the most common enteroviruses associated with myocarditis in neonates, and they act by inducing direct lysis of infected myocytes.3,20,21 Myocarditis can present with symptoms of respiratory distress, temperature instability, anorexia, and lethargy, and clinical signs including cardiomegaly, arrhythmias, congestive heart failure, and ventricular dysfunction.9,21 A recent retrospective study found that of 35 infants diagnosed with enteroviral myocarditis, there was a 31% mortality rate and 66% of survivors developed severe cardiac damage. Only 23% of infants fully recovered from their illness with no sequelae.20 Many of these infants have required extracorporeal membrane oxygenation (ECMO) due to rapid decline of cardiopulmonary functioning. In 2011, a cohort study22 combining data from 116 ECMO centers reported that 24 neonates with enteroviral myocarditis were placed on ECMO over the past 8 years. Of these, 33% survived to hospital discharge, which is much lower than the survival rate of those supported by ECMO for all types of myocarditis. The reason for this relative low survival rate is currently unknown.22 It was also suggested that ECMO may be a good intermediate bridging step to heart transplantation for these infants.
Possibly one of the most severe and often fatal complications of neonatal enterovirus infections is hepatitis, often resulting in hepatic necrosis with subsequent coagulopathy. In a literature review of multiple nursery outbreaks of echovirus infections, 83% of infants with severe hepatitis syndrome died.10 Two other more recent studies8,23 reported a mortality rate of 24% to 31% for hepatic necrosis with coagulopathy, although this was significantly higher than any other complication of enteroviral infections. Approximately half of infants with enteroviral infections have some evidence of hepatitis during their illness, although most do not progress to hepatic necrosis. Hepatic necrosis is most commonly seen with coxsackievirus B and echovirus 11 infections and can be manifested by lethargy, poor feeding, and jaundice. In some cases, this necrosis can advance to fulminant liver failure, thrombocytopenia, and disseminated intravascular coagulation (DIC).5,8 Other gastrointestinal symptoms/complications of enteroviral infections in neonates may include generalized vomiting, abdominal distention, and diarrhea, as well as pancreatitis and necrotizing enterocolitis.3
Hematologic complications, often resulting from hepatic necrosis, can be devastating in neonates with enteroviral complications. Hematologic involvement is most often demonstrated by thrombocytopenia, prolonged clotting times/coagulation studies, and clinical bleeding. In addition to DIC, coagulopathy resulting from liver failure can result in intracranial hemorrhage and renal and adrenal hemorrhagic necrosis.9,23 Aside from hemorrhagic complications, it has also been suggested that neonatal enterovirus infections may present with clinical and laboratory features consistent with hemophagocytic lymphohistiocytosis (HLH). Fever, splenomegaly, and coagulopathy may be present in both disease processes, and elevated ferritin and hemophagocytosis on bone marrow biopsy, which are two of the most specific features of HLH, can also be seen with neonatal enterovirus infections.24 The significance of these results remains unclear, but it has been recently suggested that enterovirus may be a causative factor of neonatal HLH.25
Diagnosing and Treating Enterovirus
Diagnosing neonatal enterovirus infections generally begins with a clinical suspicion based on time of the year, history of exposure, presence of risk factors, and clinical symptoms. In a patient with any of the symptoms described above, other sources of neonatal sepsis including Group B Streptococcus, Escherichia coli, Listeria, herpes simplex virus, and congenital infections must also be considered as possible etiologies. The standard laboratory test to diagnose enterovirus infections has traditionally been isolation of the virus in a cell culture. The cells used for this culture are typically monkey kidney cells or human fibroblasts. Rectal/stool cultures have the highest yield in neonatal enteroviral infections, followed by cerebrospinal fluid (CSF), oral mucosa, and lastly, serum and urine. Because serum and urine cultures are often unreliable if negative, PCR has gained popularity as a tool to identify enteroviruses from these sites. PCR has also been proven more rapid and sensitive than culture for isolation of enterovirus from CSF. Enterovirus PCR primers detect most strains of enterovirus responsible for neonatal disease with a sensitivity of >80%, and they have nearly 100% specificity. For these reasons, PCR is often preferred over culture for diagnosis of neonatal enterovirus infections.3,9,13,26 In addition to confirming the diagnosis by virus identification, a thorough laboratory evaluation should be performed. This should include checking blood counts to assess for thrombocytopenia or hemolysis, liver function enzymes to assess for hepatic injury, chemistries to assess for electrolyte imbalances and renal impairment, and CSF studies to assess for meningitis including cell counts, glucose, and protein. If there is hepatic involvement, coagulation studies and ammonia levels should be followed, and a renal ultrasound may be considered if clinically indicated. If there is concern for cardiac or pulmonary involvement, a chest radiograph, electrocardiogram, or echocardiogram may be of benefit. Finally, if the patient presents with lethargy and altered mental status, head imaging may be warranted to assess for intracranial hemorrhage associated with coagulopathy or white matter changes associated with meningoencephalitis.
Treatment for neonatal enterovirus infections has traditionally involved only supportive care, as no curative agent has yet been approved. Oftentimes, hydration, respiratory support, and close monitoring of clinical status are sufficient to assist neonates with overcoming the illness. In severe cases, intensive care support may be required, including mechanical ventilation, ECMO, cardiovascular medications, and possible organ transplantation.13 Immunoglobulin is sometimes used in severe cases in attempt to neutralize the virus, as infected neonates did not likely receive protective antibodies against enteroviruses while in-utero. Data supporting use of immunoglobulin for neonatal enteroviruses are currently lacking, and outcomes remain unknown.13 There are currently clinical trials underway in China for a new type of intravenous immunoglobulin, which may be effective against Enterovirus 71, a serotype that has caused several devastating outbreaks throughout the world with a particularly high mortality rate.27 Other therapeutic agents are currently being investigated, which act by binding viral capsids, interrupting viral replication, or targeting viral proteases. Pleconaril is an antiviral drug created in the late 1990s that has received the most attention as a potential therapy for neonatal enterovirus infections. It integrates into the capsid of these viruses and prevents release of the viral RNA.13 When it was first released for use, there were several studies that made pleconaril seem promising as a therapy for neonatal enterovirus infections. One case study28 reported use of pleconaril in four preterm infants who had myocarditis, fulminant hepatitis, meningoencephalitis, and DIC due to coxsackievirus B, and all recovered completely with no adverse effects. Another report described three neonates with enteroviral hepatitis who were treated with pleconaril. Two recovered slowly after initiation of pleconaril, and the third died of fulminant hepatitis.29 A double-blinded, placebo-controlled study in 2003 revealed that pleconaril was well tolerated with no side effects, but there was no significant difference in duration of hospitalization or symptoms.30 The medication was rejected by the US Food and Drug Administration in 2002 due to safety concerns, but has continued to be studied. A phase II clinical trial assessing pleconaril for treatment of neonates with enteroviral sepsis syndrome has been completed, but data have not yet been released.31 No other antivirals have been approved for use at this time, although there are several currently being studied.