An outbreak of enterovirus 71 infection in Taiwan 1998: A comprehensive pathological, virological, and molecular study on a case of fulminant encephalitis

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Abstract

Background: In a recent enterovirus outbreak in Taiwan, serotype 71 was the culprit of encephalitis causing rapid clinical deterioration and death among young children. Objectives: Since knowledge of enterovirus 71 (EV71) infection in the central nervous system is still limited, the purpose of the present case study was attempted to uncover the pathogenesis of the virus. Study design: We performed a detailed pathological examination, virological and molecular studies on a case of EV71 infection with a rapidly fatal outcome. In addition, the whole genome of the virus was sequenced to determine the genetic relationships to other enteroviruses and two other EV71 strains (a prototype BrCr and a neurovirulent MS strain), and to provide the genetic basis of its neurovirulence of the new isolate, NCKU9822 strain. Results: Characteristic features of acute encephalomyelitis were observed, with most prominent lesions in the spinal cord and brain stem. Mild myocarditis and pancreatitis were also noticed. EV71 antigen was localized to neurons on immunohistochemical staining. EV71 was recovered from all organs with inflammatory reaction. Sequence analysis showed that overall NCKU9822 and the two EV71 strains shared 80% nucleotide identity and 95% amino acid identity. It had only 45% amino acid and 52% nucleotide identities with polioviral P1 capsid region. Conclusion: The spinal cord and brain stem were the main targets of EV71 in the fatal cases in this outbreak, however, heart and pancreas might also be involved. Since the amino acid sequences in the P1 region are conserved (97% identity) among the three EV71 strains as compared to other enteroviruses and polioviruses, these EV71 neurovirulent strains might share the same mechanisms of neurovirulence, and the mechanisms might be different from those in polioviruses.

Introduction

Enterovirus 71 (EV71) has been associated with an array of clinical diseases including hand, foot and mouth disease (HFMD), aseptic meningitis, encephalitis, and poliomyelitis-like paralysis (Alexander et al., 1994, Melnick, 1996). There have been two EV71 outbreaks resulting in rapid clinical deterioration and death among young children; one outbreak occurred in Bulgaria during May–September 1975 (Shindarov et al., 1979), and another in Malaysia during April–June 1997 (Lum et al., 1998a). However, knowledge of the mechanisms of the viral neurovirulence is still limited.

Between April and October 1998 in Taiwan, an EV71 outbreak characterized by rapid onset of central nervous system disease and fatal outcome occurred (Centers for Disease Control and Prevention, 1998, Chang et al., 1998). In this outbreak, more than 90 000 children with HFMD have been reported. Among these patients, more than 320 children have been hospitalized with suspected meningitis, encephalitis, or acute flaccid paralysis, and at least 55 died, suggesting neurovirulence of the pathogen.

In the present report, we describe a case of EV71 infection with CNS involvement and rapidly fatal course. Comprehensive pathological, virological, and molecular studies have been performed on this case in order to unearth the pathogenesis of the virus.

Section snippets

Patient and clinical course

On October 26 1998, fever and oral ulcers developed in a 3-year-old boy from Tainan County. On October 28, he had a vesicular rash on his hands and feet, and several episodes of myoclonus seizures. He was admitted to a local hospital for suspected HFMD on October 29. It was not long after this admission when vomiting, cold sweating, ataxia, dyspnea, and hypotension occurred. He was immediately transferred to the National Cheng Kung University Hospital on the same day. On physical examination,

Autopsy findings and immunohistochemistry

The brain appeared normal grossly. On microscopic examination, typical features of acute encephalitis, including perivascular cuffing by mixed inflammatory cells (Fig. 1A) and neuronophagia or inflammatory nodules (Fig. 1B), were noticed. Mixed inflammatory infiltrates in the brain substance and histological evidence of acute neuron injury were observed extensively. Occasionally, devastated and cavitary appearance can be found in the areas with notable inflammation. The most prominent

Discussion

The EV71 epidemic in 1998 in Taiwan is the third known EV71 outbreak resulting in rapid clinical deterioration and death among young children (Shindarov et al., 1979, Centers for Disease Control and Prevention, 1998, Chang et al., 1998, Lum et al., 1998a). The autopsy findings of this case, together with those reported elsewhere (Shindarov et al., 1979, Centers for Disease Control and Prevention, 1998, Chang et al., 1998, Lurn et al., 1998b, Komatsu et al., 1999), indicate that the brain stem

Acknowledgements

The study was supported by the grant NHRI-CN-CR8804 from the National Health Research Institute, Taiwan.

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