Fatal cases have been identified in the UK
Cases of fulminant hepatitis have been described in premature infants in the UK and they are remarkably similar to the circumstances described for Child E and Child P.
In a multi-study analysis of cases of severe neonatal enterovirus infection, it was found that of the 237 infants identified, all of the neonates developed severe complications. Among them, 46.0% hepatitis or coagulopathy, 37.1% had myocarditis, 11.0% had meningoencephalitis, and 5.9% had other complications such as hemophagocytic lymphohistiocytosis and pulmonary haemorrhage. The mortality rate in this population was extremely high, at 30.4%. The highest risk of mortality was observed for infants with myocarditis, who had a mortality rate of 38.6%. In 70.5% neonates, the age at the onset of symptoms was less than 7 days. The most common symptoms associated with infection were temperature abnormalities (53.6%), rash (37.1%), poor feeding (24.5%) and respiratory symptoms (21.9%). In many cases, the infants presented as healthy before suddenly collapsing. This is similar to the cases of males at CoCH and twin births were disproportionately affected. There is no discussion or exploration of other common causes of the symptoms observed in the neonates. However, enteroviral infection outbreaks are common in neonatal units (Fuchs et al., 2013; Yuri et al., 2011) and the spread typically occurs through an infected mother passing the virus on in utero. Where transmission occurs in-utero, the symptoms are typically severe and the mortality rate is very high (Zhang et al., 2019).
Disseminated intravascular coagulation (DIC) is a condition characterised by abnormal blood clotting and bleeding throughout the body. It can occur as a complication of various infectious diseases, including coxsackievirus infections. Coxsackieviruses are a group of viruses belonging to the enterovirus family, in infants these viruses can cause myocarditis (inflammation of the heart), hepatitis and viral meningitis. In the context of a coxsackievirus infection, DIC may occur due to Coxsackievirus directly damaging blood vessels, leading to the release of substances that activate the clotting cascade. This excessive activation of clotting factors can result in the formation of blood clots throughout the body. Activation of the immune response due to coxsackievirus infection can cause the immune system to become overactive and release inflammatory substances that can trigger DIC. These substances can disrupt the balance between clotting factors and anticoagulant mechanisms, leading to abnormal clot formation. There were a number of instances of spontaneous bleeding and haemorrhage comorbid with gastric bloating. This is a common finding in Coxsackievirus B and Echovirus 11 infection. These two strains of enterovirus are responsible for numerous outbreaks in neonatal units and they are associated with pulmonary haemorrhage and hepatitis. There is some indication that the infants at CoCH may have been subject to an invading pathogen that went untested and undiscovered (Gando et al., 2016). In unrelated studies, researchers assessed the blood clotting capacity of preterm neonates. The group conducted several haemostasis tests, including PT, aPTT, fibrinogen, thrombin-antithrombin complex, antithrombin III activity and fibrinolytic markers (d-dimer, plasminogen activator inhibitor, and plasminogen tissue activator), using blood samples from ill preterm infants with respiratory distress syndrome (RDS), sepsis or asphyxia and compared them to a group of healthy preterm infants. Their findings were consistent with the activation of the coagulation cascade and the fibrinolytic system in ill preterm infants at the initial phase of RDS and at the active phase of sepsis. It is believed that the limited reserve capacity of the immature haemostatic system in preterm infants renders them more vulnerable and at risk for thromboembolic events (Mautone et al., 1997). Thus, neonates are at risk of two specific events relating to blood clotting; thrombosis and haemorrhage.
A recent study into the outbreak of echovirus 11 on a neonatal unit found that in premature infants receiving TPN at onset, thrombocytopenia and decreased haemoglobin levels in the early stage of illness were associated with haemorrhage-hepatitis syndrome in neonates with E-11 infection. It was speculated that intestinal immune insufficiency could play a key role in the development of haemorrhage-hepatitis syndrome in neonates infected with Echovirus 11. It is essential, given the core similarities between variables described in the Echovirus 11 outbreak in China, and the findings at CoCH, that greater scrutiny should be placed on the possible contribution of infectious disease as an explanation for the sudden collapse among the infants in this case. Dr Evans does not appear to have made any effort to investigate viral infections as a cause of sudden collapse in the infants, despite the fact that the symptoms observed in the infants overlapped with those described in cases of enterovirus outbreaks.
Neonates with E-11 infection who were admitted to one NICU in Hubei province and three NICUs in Guangdong province in China between April and October 2019 were included. A confirmed neonatal case was defined with laboratory evidence of E-11 infection detected by reverse transcription polymerase chain reaction (RT-PCR). Patients were categorised into two groups (mild and severe) based on the absence or presence of haemorrhage-hepatitis. In this cohort, the most common initial symptoms of E-11 infection were fever (52%) and tachypnoea (21%). During the course of illness, haemorrhage (including petechiae, gastric bleeding or bloody stools) were the most common clinical symptoms (46%). The most common complications included acute myocardial injury (41%, as evidenced by elevated myocardial enzyme levels and decreased cardiac function on echocardiography), pneumonia (22%), acute respiratory distress syndrome (ARDS; 16%, excluding RDS owing to surfactant deficiency), DIC (10%), acute renal injury (9%, with elevated creatinine levels with or without oliguria/anuria) and shock (9%) syndrome (Wang et al., 2023). It should be noted that a number of the infants at CoCH exhibited some of these same symptoms, which should at least have warranted further investigation by Dr Evans.
Ryan et al., 1986 described six preterm infants born at the Royal Alexandria Hospitals, Edmonton, Canada who experienced the rupturing of a subcapsular liver haematoma. The diagnosis of a ruptured SHL was made between 4 and 18 days of life by means of clinical and sonographic findings in four of the infants; an intact SHL was diagnosed at autopsy in the other two. Contrary to the expert opinion of Dr Marnerides, the “relevant antecedent events included mechanical ventilation (in all six), administration of indomethacin (in all six), hypoxia (in five), bilateral pneumothorax necessitating repeated pleural drainage (in three), external cardiac massage (in three) and septicaemia (in two) “ (Ryan et al., 1987). These reports are by no means isolated and one is left to wonder how Dr Marnerides was so unaware of the body of published peer-reviewed findings which essentially disprove his claims. Given the tendency for the expert witnesses to rely on dated scientific publications, one would assume the findings of Ryan et al., would meet this requirement. It is not being suggested, however, that the only evidence for the occurrence of SLH in the neonatal period is limited to the past three decades. Subcapsular Liver Haematoma (SLH) has been repeatedly identified in preterm neonates. In a 2013 case study, SLH was described in an infant whose symptoms bore a significant similarity to those observed in Child O. Namely, that the infant presented with systemic non-specific symptoms which were followed by progressive abdominal distention, accompanied by a bluish colouration of the overlying skin (Gonçalves et al., 2013). In this case study, the infant survived the SLH due to clinicians taking swift action to identify the cause of the abdominal distention. In the case of Child O, despite observing clear changes in the child’s abdomen, they focused only on the diagnosis of NEC, which was highly unlikely given the infant was only days old.