Clinical characteristics of severe neonatal enterovirus infection: a systematic review

Enteroviruses affect millions of people worldwide from all age groups. According to the data from the Center for Disease Control and Prevention in America, non-polio enteroviruses cause 10–15 million infections and tens of thousands of hospitalizations in the United States each year [1]. Disease activity is typically seasonal, and most infections occur in the summer and early fall in temperate parts of the world [2]. Enterovirus infections have variable manifestations. Asymptomatic infections account for approximately 50% of the cases [3]. Symptomatic enterovirus infections range from nonspecific febrile illnesses to life-threatening diseases such as myocarditis or sepsis. The main manifestations include hand-foot-mouth disease, acute hemorrhagic conjunctivitis, herpangina, etc. [3] Infants and people with weak immune systems have a greater chance of developing severe complications.

Enterovirus is a common cause of infections in neonates. Infections in newborns may be acquired vertically before, during, or after delivery, horizontally from family members, or by nosocomial transmission in nurseries [4]. Enteroviruses can seriously affect the nervous and cardiovascular systems in neonates, resulting in myocarditis, meningoencephalitis, and other severe complications. Because of the functionally immature immune system, newborns are at high risk for the development of serious clinical manifestations of infectious diseases [5]. This study systematically reviewed the clinical characteristics of neonates with severe enteroviral infection, with the aim of gathering information for the identification and treatment of neonatal severe enterovirus infections.

A total of 1647 studies were identified through the database search, and 243 of these were retained after screening the titles and abstracts. Subsequently, 177 studies were excluded during the full-text review. Finally, 66 articles with 237 cases of severe neonatal enterovirus infection were included in the analysis. Figure 1 shows the flow diagram of the study selection process. Table s1, s2 and s3 in the supplementary material show the general characteristics of the included neonates and the assessment of the risk of bias. The clinical characteristics of neonates with severe enteroviral infection according to the major complications were showed in Table 1.

Overall, 237 neonates developed severe complications of enterovirus infection, with a male/female ratio of 116/88, and birth weight ranging from 1730 to 4500 g. In total, 51.3% (101/197) of the preterm infants and 52.5% (95/181) of the neonates were delivered by cesarean section. In 70.5% (167 cases) of the cases, the age at the onset of symptoms was less than 7 days. Seventy cases (29.5%) were associated with maternal disease before delivery, while 16 cases (6.8%) reported siblings or friends with symptoms. Maternal amniotic fluid culture revealed scarce Staphylococcus epidermidis in a case of myocarditis [7]. Also, a mother was diagnosed with chorioamnionitis [8] and amnionitis was suspected in another mother [9]. Enterovirus was identified mostly from the rectal or stool samples (118, 49.8%), followed by respiratory samples (101, 42.6%). Additionally, 82.7% (124 cases) of the neonates had coxsackievirus B (CVB) infection, 16.7% (25 cases) had echovirus infection, and 0.7% (1 case) had enterovirus 71 (EV71) infection. The clinical manifestations included temperature abnormalities (127, 53.6%), rash (88, 37.1%), poor feeding (58, 24.5%), respiratory symptoms (45, 19.0%), lethargy (40, 16.9%), jaundice (38, 16.0%), circulatory failure or shock (37, 15.6%), arrhythmias (29, 12.2%), thrombocytopenia (28, 11.8%), poor perfusion (23, 9.7%), irritability (17, 7.2%), hypotonia (9, 3.8%), and diarrhea (9, 3.8%). A total of 127 (53.6%) neonates were treated with empirical antibiotics and 97 (40.9%) neonates with intravenous immunoglobulin (IVIG). Antiviral medications included pocapavir (3, 1.3%) and pleconaril (14, 5.9%). Altogether, the lethality rate was 30.4% (72 cases).

A total of 109 cases of hepatitis or coagulopathy from 17 studies [9‐24] were included (57 boys, 46 girls). Maternal illness in the period from 2 months prepartum to 1 week postpartum was reported in 33 cases (30.3%), including fever in 23, abdominal pain in six, flu-like syndrome in five, and diarrhea in four cases. In three cases, siblings had symptoms of a febrile illness and sore throat a few days before delivery. Neonates presented with the first symptoms between the day of birth and 1 month; 98 (89.9%) presented within 7 days of birth. Eighty-seven records of enterovirus serotypes were extracted, comprising 16 cases of echovirus infection (echovirus 3 in one, echovirus 21 in one, echovirus 11 in four, echovirus 30 in two, echovirus 7 in two, echovirus 6 in two, echovirus 5 in one) and 71 cases of CVB (CVB1 in 22, CVB2 in one, CVB3 in 46, CVB4 in one, CVB5 in one). The most common symptom was temperature abnormalities, with 60 cases of temperature instability, 17 cases of fever, and five cases of hypothermia. Other presenting symptoms were rash (73, 67.0%), jaundice (32, 29.4%), and ascites (27, 24.8%). Complications associated with hepatitis accounted for 23 cases of myocarditis, one case of hypertrophic cardiomyopathy, five cases of intracranial hemorrhage, five cases of encephalitis, eight cases of disseminated intravascular coagulation (DIC), three cases of renal insufficiency, and three cases of pneumonitis. Elevation of aspartate aminotransferase (AST) or alanine transaminase (ALT) was reported in 85 cases. A total of 95 (87.2%) neonates were treated with antibiotics and 56 (51.4%) were treated with IVIG. Antiviral medications utilized were pocapavir (1, 0.9%) and pleconaril (9, 8.3%). Moreover, 94 (86.2%) neonates required blood component transfusions, such as fresh-frozen plasma, platelets, and red blood cell concentrate. Other systematic supportive treatment included mechanical ventilation (17, 15.6%), peritoneal dialysis (4, 3.7%), hemodialysis (1, 0.9%), blood exchange transfusion (4, 3.7%), and continuous venovenous hemofiltration (1, 0.9%). Three (2.8%) neonates received liver transplants. Twenty-nine of the 109 (26.6%) neonates died and were aged between 8 days and 2 months.

A total of 88 neonates in 31 studies [7, 9, 25‐53] developed the major complication of myocarditis, with a male/female ratio of 42/29. In total, 54.7% (35/64) neonates were less than 7 days old at the onset of symptoms. Twenty neonates had a history of maternal disease before delivery, while eight cases reported siblings or friends with symptoms. Thirty-nine neonates had CVB infection (CVB1 in 13, CVB2 in 2, CVB3 in 13, CVB4 in 5, CVB5 in 3, and CVB2 in 1). One neonate had an echovirus 6 infection. Clinical signs of temperature abnormalities (eight neonates with hypothermia, 15 with fever, and one with temperature instability) were observed in 24 neonates. Signs of myocarditis included respiratory symptoms (24, 27.3%), arrhythmias (27, 30.7%), circulatory failure or shock (35, 39.8%), and poor perfusion (11, 12.5%). Myocarditis was reportedly accompanied by other complications including meningoencephalitis (10 cases), renal failure (3 cases), DIC (6 cases), and hepatitis (7 cases). Elevations of troponin and brain natriuretic peptide (BNP) were observed in 30 and 20 cases, respectively. Other primary auxiliary examinations undertaken were electrocardiogram (ECG) for signs of myocardial ischemia (30, 34.1%) and echocardiography for signs of ventricle dilation or function depression (56, 63.6%). Mechanical ventilation was used in 27 neonates, and cardiopulmonary resuscitation was required in five neonates. In addition, 43 neonates received extracorporeal membrane oxygenation (ECMO) support. The medications included antibiotics (16, 18.2%), IVIG (31, 35.2%), pocapavir (2, 2.3%), and pleconaril (5, 5.7%). Moreover, four neonates survived after heart transplantation and one underwent mitral valve replacement. The lethality rate was 38.6% (34/88) in neonates with myocarditis, and 40.7% (22/54) of the survivors had sequelae or required cardiac medication.

Twenty-six cases in 10 studies [8, 54‐62] were diagnosed with meningoencephalitis, with a male/female ratio of 11/10. Manifestations of meningoencephalitis in the mother and other family members were found in five and three cases, respectively. The enterovirus serotypes included four cases of echovirus (echovirus 6 in one, echovirus 30 in two, echovirus 31 in one), seven cases of CVB (CVB1 in four, CVB2 in two, CVB3 in one), and one case of EV71. Signs of central nervous system disease included seizures (10, 38.5%), lethargy (5, 19.2%), irritability (9, 34.6%), tonic–clonic movements of the upper extremities (1, 3.8%), right-sided hemiparesis (1, 3.8%), weak gag reflex (1, 3.8%), and full fontanelle (1, 3.8%). Complications of central diabetes insipidus occurred in one neonate. White matter injury was detected by magnetic resonance imaging (MRI) in 21 cases, while 16 cases exhibited extensive periventricular echogenicity on brain ultrasonography. Four neonates were treated with mechanical ventilation and two were administered IVIG. Altogether, 23 of the 26 neonates survived, with neurological sequelae reported in six.

Other rare complications are shown in Table 2, including hemophagocytic lymphohistiocytosis (HLH) [63‐66], pulmonary hemorrhage [67], pulmonary hypoplasia [68], persistent pulmonary hypertension [69], bone marrow failure [70], and congenital skin lesions [71]. Among the six neonates with HLH, four developed fever, abdominal pain, and flu-like symptoms before delivery. All neonates developed the disease within 5 days. Five neonates were treated with IVIG. In the end, one neonate died and another received a liver transplant at the age of 2 months. In four cases consisting of two sets of twins with pulmonary hemorrhage, both the mothers had developed fever and other symptoms on the day of the delivery. The onset ages of the two sets of twins were 7 days and 5 days, respectively. Only one neonate survived with mild disease. There was a single case of pulmonary hypoplasia characterized by a total failure of the development of terminal respiratory units. Echovirus 11 was positive in the amniotic fluid. The neonate was delivered at 38 weeks gestational age and died one hour later. Another case involved intrauterine echovirus 11 infection with persistent pulmonary hypertension and pneumonia. The neonate died 36 h after birth. There was also a case of bone marrow failure and concomitant enteroviral infection. Bone marrow aspiration and biopsy revealed hypocellularity. The neonate finally improved. A boy with congenital disseminated papulovesicular, nodular, bullous, and necrotic ulcerated rash was also reported. He subsequently developed pneumonia, carditis, and hepatitis. CVB3 was identified in the neonate’ s serum. The boy survived with sequelae at 6 months of age.

Manifestations of neonatal enterovirus infections range from asymptomatic, febrile illness to severe disease. A prospective cohort study in 2011–2012 in China reported 131 episodes of neonatal enterovirus infection (39.22%) among the 334 febrile neonates [72]. Xu et al. reported 16 cases of neonatal hand-foot-mouth disease with coxsackievirus A6 infection between 2016 and 2017 in Shanghai, China [73]. In this systematic review, a categorical summary of the most common complications of severe neonatal enterovirus infection was presented, including myocarditis, hepatitis, and encephalitis. In addition, the clinical features of other rare complications were reviewed. Lethality in each of the severe forms of neonatal enterovirus disease is high and varies between 11.5 and 38% depending on the type of disease. The most common severe complication was hepatitis, while myocarditis was the complication with the highest lethality rate. The age of onset in most neonates was less than 7 days and this might be related to the lack of specific transplacental neutralizing antibodies against the infecting serotype in newborns. The main sites of virus detection were the respiratory system, stools, cerebrospinal fluid, blood, and urine. Additionally, enteroviruses have also been detected in tissue samples from dead neonates, such as the heart, lung, spleen, and bone marrow. Isolation of the virus in the amniotic fluid or placenta as evidence of prenatal transmission has also been reported in severe cases. IVIG is frequently used for the treatment of enterovirus infections. Studies suggest that there may be more rapid clearance of viremia after IVIG therapy [74]. A retrospective study from Taiwan, China, evaluating the timing of IVIG administration revealed that early IVIG therapy (within 3 days of illness onset) may be beneficial for the survival of neonates with severe enteroviral infections [12]. The study analyzed 67 cases with culture-confirmed severe enteroviral infection. 41 infants (61%) received IVIG therapy and 29 cases were administered IVIG within 3 days of the illness onset with the mortality rate of 7% (2/29). While among the neonates with late IVIG therapy, the mortality rate was 50% (6/12). In our review, 40.9% of the neonates were treated with IVIG and the dosage of IVIG therapy varied from 0.5–2 g/kg/day. Therefore, more research is needed on the optimal dosage of IVIG treatment. Pleconaril, with activity against the picornaviruses, can bind to the viral capsid, thereby preventing viral uncoating within the cells [9]. A randomized, double-blind, placebo-controlled study of 43 enterovirus-infected neonates in America from 1999 to 2010 supported the potential efficacy of pleconaril [75]. The study enrolled 61 subjects (43 treatment, 18 placebo). Subjects in the treatment group received oral pleconaril of 5 mg/kg per dose 8 hourly for 7 days. Mortality rates in the treatment and placebo groups were 23 and 44%, respectively. They concluded that enterovirus-infected neonates in the treatment group had shorter times to culture, PCR negativity, and better survival.

Myocarditis is a common clinical manifestation of severe neonatal enterovirus infection, and is associated with a high lethality, reaching 38.6% in our review. The principal clinical manifestations of myocarditis include dyspnea, respiratory distress, apnea, arrhythmia, sudden cardiac arrest, and heart failure. Among them, there are a wide variety of arrhythmias, the most common being tachycardia, in addition to bradycardia, atrial flutter, ventricular fibrillation, and conduction block. CVB is the predominant enterovirus type causing myocarditis, especially CVB1 and 3. Weickmann et al. [25] reported a case of myocarditis caused by echovirus 6 in 2020, mainly manifesting as rare junctional ectopic tachycardia. Laboratory tests suggestive of myocarditis generally include elevation of troponin and BNP levels. Most electrocardiograms show myocardial ischemia, and a cardiac ultrasound often shows varying degrees of ventricular dilatation as well as decreased systolic function. We did not calculate the sensitivity and specificity of the diagnostic tests. Since most studies only report the positive result of the diagnostic test, the result of sensitivity and specificity might be overestimated. ECMO has been widely used in children with enterovirus myocarditis, and a total of 43 children who underwent ECMO were included in this study, with a survival rate of 39.5%. Furthermore, a study by Madden et al. [37] in 2011 that evaluated 24 neonates with enterovirus myocarditis receiving ECMO revealed that the survival rate was 33% with a high incidence of renal insufficiency in the children who died. In addition, heart transplantation and valve replacement have also been reported as successful treatments for enterovirus myocarditis.

Hepatitis or coagulopathy is the most common complication of severe neonatal enterovirus infection. It is also a serious complication of neonatal enterovirus infection with a high lethality rate (26.6%), and frequently co-occurs with myocarditis and encephalitis. The main body temperature abnormality in neonates with hepatitis is unstable body temperature, followed by fever. Other common clinical manifestations are rash, ascites, jaundice, hepatosplenomegaly, and thrombocytopenia. Hepatitis can further develop into acute liver failure, liver necrosis, fibrosis, and calcification. The vast majority of children develop the disease within 7 days. A high proportion of enteroviruses were found in the respiratory and stool samples. The proportion of CVB virus infections was high in neonates with hepatitis, with CVB1 and 3 being the most common, although there were also a few echovirus infections. The main supportive treatment for neonates with hepatitis is transfusion of blood components, such as platelets, plasma, and cryoprecipitate. Moreover, treatment with transfusion of maternal plasma has also been reported. Peritoneal dialysis, hemodialysis, blood replacement, and continuous venovenous hemofiltration have been applied in a small number of children; however, their therapeutic effect needs to be further studied.

There were some cases of neonatal enterovirus infection complicated by meningoencephalitis, and most cases had onset within 7 days. 15 cases of meningoencephalitis were accompanied with myocarditis and hepatitis. In these cases, meningoencephalitis was not the main complications or found at autopsy. The lethality rate of neonates with brain injury was low (11.5%), and the common sequelae among surviving neonates were hypotonia and cerebral palsy. Common clinical symptoms are fever and feeding difficulties. Neurological symptoms consist of epilepsy, irritability, hypotonia, and drowsiness. There was a report of a neonate who developed central diabetes insipidus. In most cases, the virus can be isolated from the cerebrospinal fluid and feces. In terms of virus typing, in addition to CVB and echovirus, a brain injury caused by EV71 was also reported. The most common abnormality in MRI is white matter injury. A case report by Hirata et al. [60] in 2011 concluded that diffusion-weighted imaging (DWI) was helpful for the early diagnosis of meningoencephalitis due to neonatal enterovirus infection.

Our article also reviewed some rare complications of neonatal enterovirus infection, such as HLH, pulmonary hemorrhage, pulmonary dysplasia, and bone marrow failure. All children developed the disease within 7 days, and there was a high proportion of mothers with antenatal fever and abdominal pain. Although these complications have only been reported in a few cases, the lethality rate is high and the disease progresses rapidly, often accompanied by damage to multiple organ systems.

However, there were several possible limitations to our study. The first limitation to this review was the small sample sizes within the included studies. Additionally, studies included were mainly case reports and case series, so we conducted a systematic review rather than a meta-analysis.

Our study systematically reviewed the clinical characteristics of severe neonatal enteroviral infections. The results revealed that the lethality rate of severe neonatal enterovirus infections was high. Myocarditis was the complication with the highest lethality rate. The most common symptoms included temperature abnormalities, lethargy, rash, poor feeding, and respiratory symptoms. Additional clinical signs included arrhythmias, circulatory failure or shock, jaundice, and seizures. The main supportive treatment comprised transfusion of blood components, mechanical ventilation, and ECMO. Empirical antibiotics and IVIG were widely used. The antiviral medications used were pocapavir and pleconaril, although more clinical evidence regarding their efficacy is needed.