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Outbreak of hand, foot and mouth disease in Sarawak. Cluster of deaths among infants and young children

Wkly. Epidemiol. Rec., 1997 Jul 11;72(28):211-2.
PMID: 9329278
Matched MeSH terms: Hand, Foot and Mouth Disease/mortality*
Fulltext Deaths in children during an outbreak of hand, foot and mouth disease in Peninsular Malaysia--clinical and pathological characteristics

Shekhar K, Lye MS, Norlijah O, Ong F, Looi LM, Khuzaiah R, et al.

Med J Malaysia, 2005 Aug;60(3):297-304.
PMID: 16379183

From July through December 1997, 11 previously healthy children in Peninsular Malaysia succumbed to an illness clinically characterised by an acute severe refractory left-ventricular failure, following a brief prodromal illness, in the midst of an outbreak of hand, foot and mouth disease (HFMD), similar to the reported experience in Sarawak and Taiwan. Retrospective reviews of the clinical features and results of laboratory, pathological and virological investigations of cases were conducted. The median age of the 11 case-patients was 31 months (range, 13 to 49 months); 6 were males. A brief prodromal illness of 3 days (range, 2 to 5 days) was characterised by fever (axillary temperature > 38 degrees C) (100%), oral ulcers (72%), extremity rashes (45%) and significant vomiting (55%). Upon hospitalisation, 7 of 11 case-patients had features suggestive of cardiogenic shock, while 4 of 11 case-patients developed shock during hospitalisation as evidenced by marked sustained tachycardia (heart rate > or = 180 beats per minute), poor peripheral pulses and peripheral perfusion, mottled extremities, pulmonary oedema (haemorrhagic pulmonary secretions in 8 of 11 cases during tracheal intubation, often precipitated by conservative crystalloid boluses, and radiographic evidence of acute pulmonary oedema in 5 of 7 cases) and markedly impaired left ventricular function on echocardiographic examination (7 of 7 cases). Three of 4 case-patients had aseptic meningitis while one case-patient also had an acute flaccid paraparesis. Despite supportive therapy, death occurred within a median of 13.4 hours following hospitalization. Post-mortem findings (all 8 specimens examined) consistently demonstrated brain-stem encephalitis with foci of neuronal necrosis and micro-abscesses. None of the 11 specimens examined revealed histological evidence of myocarditis. Enterovirus 71 (EV71) was detected in 10 of 11 case-patients, many (7) from various sterile tissue sites (5 from central nervous tissues). No other viruses were isolated or identified. Clinical features and pathological studies closely paralleled the reported experience in Sarawak and Taiwan. The uniform necropsy findings of necrotizing brain-stem encephalitis coupled with essentially normal myocardial histology, in concert with the concurrent and consistent detection of EV71 points to a primary EV71 encephalitis; as yet unclear neurogenic mechanisms may account for the cardiovascular manifestations.

Matched MeSH terms: Hand, Foot and Mouth Disease/mortality*
Complete sequence analyses of enterovirus 71 strains from fatal and non-fatal cases of the hand, foot and mouth disease outbreak in Singapore (2000)

Singh S, Poh CL, Chow VT

Microbiol. Immunol., 2002;46(11):801-8.
PMID: 12516778

Enterovirus 71 (EV71) is a major aetiological agent of hand, foot and mouth disease (HFMD). In recent years, several outbreaks in East Asia were associated with neurological complications and numerous deaths. An outbreak in Singapore in October 2000 afflicted thousands of children, resulting in four fatal cases from three of whom EV71 was isolated. The genomes of two representative EV71 strains isolated from a fatal case and a surviving patient were completely sequenced, and their nucleotide and amino acid sequences compared with known EV71 strains. The two outbreak strains were classified under genogroup B, together with those previously isolated in Singapore, Malaysia and Japan. Comparative sequence analysis of the two Singapore strains revealed 99% nucleotide similarity, while their deduced amino acid sequences were almost identical except for residue 1506 in the 3A non-structural region. Given that the outbreak involved closely related genetic variants of EV71, the broad spectrum of disease severity may be attributed to critical factors such as varying viral inoculation doses or differing host immune responses following infection, but is less likely to be due to the emergence of EV71 strains with heightened virulence.

Matched MeSH terms: Hand, Foot and Mouth Disease/mortality
Identification of enterovirus 71 isolates from an outbreak of hand, foot and mouth disease (HFMD) with fatal cases of encephalomyelitis in Malaysia

AbuBakar S, Chee HY, Al-Kobaisi MF, Xiaoshan J, Chua KB, Lam SK

Virus Res, 1999 May;61(1):1-9.
PMID: 10426204

Thirteen enterovirus 71 (EV71) isolates were obtained from both fatal and non-fatal infections of patients seen in Peninsula Malaysia and in Sarawak during an outbreak of hand, foot and mouth disease (HFMD) in Malaysia in 1997, with incidences of fatal brainstem encephalomyelitis. The isolates were identified using immunofluorescence staining, neutralization assays, and partial sequencing of the 5' untranslated regions (UTR). Assessment of the potential genetic relationships of the isolates using the partial 5'UTR sequences suggested clustering of the isolates into at least two main clusters. Isolates from Peninsula Malaysia were found in both clusters whereas Sarawak-derived isolates clustered only in cluster II. Isolates derived from fatal infections, however, occurred in both clusters and no distinctive nucleotide sequences could be attributed to the fatal isolates. Examination of the nucleotide sequences revealed at least 13 nucleotide positions in all the isolates which differ completely from the previously reported EV71 5'UTR sequences. In addition, at least 11 nucleotide position differences within the 5'UTR were noted which differentiated cluster I from cluster II. Predicted secondary RNA structures drawn using the nucleotide sequences also suggested differences between isolates from the two clusters. These findings suggest the presence of at least two potentially virulent EV71 co-circulating in Malaysia during the 1997 HFMD outbreak.

Matched MeSH terms: Hand, Foot and Mouth Disease/mortality
Molecular epidemiology of enterovirus 71 in peninsular Malaysia, 1997-2000

Herrero LJ, Lee CS, Hurrelbrink RJ, Chua BH, Chua KB, McMinn PC

Arch Virol, 2003 Jul;148(7):1369-85.
PMID: 12827466

Human enterovirus 71 (EV71) (genus Enterovirus, family Picornaviridae) has been responsible for sporadic cases and outbreaks of hand-foot-and-mouth disease (HFMD), aseptic meningitis, encephalitis and poliomyelitis-like disease in Europe, the U.S.A., Australia and Asia. Recently, there has been an increase in EV71 activity in the Asia-Pacific region, with many outbreaks of HFMD associated with brainstem encephalitis manifesting as neurogenic pulmonary oedema with a high case fatality rate. In 1997, and again in 2000, EV71 outbreaks occurred in peninsular Malaysia. Variations in VP1 gene sequences have been shown to divide all known EV71 field isolates into three distinct genogroups (A, B and C). Consequently we examined the VP1 gene sequences of 43 EV71 strains isolated in peninsular Malaysia between 1997 and 2000 in order to determine the genogroup prevalence over the period. In this study we show that four subgenogroups (B3, B4, C1 and C2) of EV71 circulated in peninsular Malaysia between 1997 and 2000. Subgenogroups B3, B4 and C1 have been identified as the primary cause of the outbreaks of EV71 in peninsular Malaysia. Subgenogroup C1 also displayed endemic circulation from 1997 to 2000 and subgenogroup C2 was present at a low level during the 1997 outbreak.

Matched MeSH terms: Hand, Foot and Mouth Disease/mortality
Fulltext Deaths of children during an outbreak of hand, foot, and mouth disease in Sarawak, Malaysia: clinical and pathological characteristics of the disease. For the Outbreak Study Group

Chan LG, Parashar UD, Lye MS, Ong FG, Zaki SR, Alexander JP, et al.

Clin Infect Dis, 2000 Sep;31(3):678-83.
PMID: 11017815

From April through June 1997, 29 previously healthy children aged <6 years (median, 1.5 years) in Sarawak, Malaysia, died of rapidly progressive cardiorespiratory failure during an outbreak of hand, foot, and mouth disease caused primarily by enterovirus 71 (EV71). The case children were hospitalized after a short illness (median duration, 2 days) that usually included fever (in 100% of case children), oral ulcers (66%), and extremity rashes (62%). The illness rapidly progressed to include seizures (28%), flaccid limb weakness (17%), or cardiopulmonary symptoms (of 24 children, 17 had chest radiographs showing pulmonary edema, and 24 had echocardiograms showing left ventricular dysfunction), resulting in cardiopulmonary arrest soon after hospitalization (median time, 9 h). Cardiac tissue from 10 patients showed normal myocardium, but central nervous system tissue from 5 patients showed inflammatory changes. Brain-stem specimens from 2 patients were available, and both specimens showed extensive neuronal degeneration, inflammation, and necrosis, suggesting that a central nervous system infection was responsible for the disease, with the cardiopulmonary dysfunction being neurogenic in origin. EV71 and possibly an adenovirus, other enteroviruses, or unknown cofactors are likely responsible for this rapidly fatal disease.

Matched MeSH terms: Hand, Foot and Mouth Disease/mortality*
Sentinel surveillance for human enterovirus 71 in Sarawak, Malaysia: lessons from the first 7 years

Podin Y, Gias EL, Ong F, Leong YW, Yee SF, Yusof MA, et al.

BMC Public Health, 2006 Jul 07;6:180.
PMID: 16827926

BACKGROUND: A major outbreak of human enterovirus 71-associated hand, foot and mouth disease in Sarawak in 1997 marked the beginning of a series of outbreaks in the Asia Pacific region. Some of these outbreaks had unusually high numbers of fatalities and this generated much fear and anxiety in the region.
METHODS: We established a sentinel surveillance programme for hand, foot and mouth disease in Sarawak, Malaysia, in March 1998, and the observations of the first 7 years are described here. Virus isolation, serotyping and genotyping were performed on throat, rectal, vesicle and other swabs.
RESULTS: During this period Sarawak had two outbreaks of human enterovirus 71, in 2000 and 2003. The predominant strains circulating in the outbreaks of 1997, 2000 and 2003 were all from genogroup B, but the strains isolated during each outbreak were genetically distinct from each other. Human enterovirus 71 outbreaks occurred in a cyclical pattern every three years and Coxsackievirus A16 co-circulated with human enterovirus 71. Although vesicles were most likely to yield an isolate, this sample was not generally available from most cases and obtaining throat swabs was thus found to be the most efficient way to obtain virological information.
CONCLUSION: Knowledge of the epidemiology of human enterovirus 71 transmission will allow public health personnel to predict when outbreaks might occur and to plan interventions in an effective manner in order to reduce the burden of disease.

Matched MeSH terms: Hand, Foot and Mouth Disease/mortality