In Malaysia, the prevalence, incidence, aetiology and disease burden of HFMD were essentially unknown before May 1997. Interest in the disease and followed by the development of an in-place surveillance system for the disease started following a large outbreak of HFMD in 1997associated with a number of deaths in children due to acute infection of the brain stem [22, 23]. The first documented outbreak of HFMD in Malaysia occurred in April 1997, initially in the state of Sarawak (East Malaysia in Borneo Island) and subsequently spread to peninsular Malaysia by June . The actual number of children who developed HFMD in the outbreak was not known but a total of 4253 cases of HFMD (2113 from Sarawak and 2140 from peninsular Malaysia) were reported by June 1997 . Children aged 4 years and below comprised more than 80% of the HFMD cases with more than 50% of the affected children of aged less than 2 years. As with findings in other parts of the world, HFMD in Malaysia essentially affected children of very young age, particularly those between 1 and 2 years of age. In the 1997 outbreak, 41 deaths (29 from Sarawak and 12 from peninsular Malaysia) were recorded. The mean age of the children who succumbed to the illness was 1.6 years (range 7 months to 6 years) with about 80% below 2 years old [23, 34]. All fatal cases developed signs of shock, including pallor, cold extremities with poor peripheral circulation, delayed capillary refill, and weak peripheral pulses at or soon after admission. Pulmonary oedema was present in many cases as the terminal event and nearly all the fatal cases had sinus tachycardia but no cardiac arrhythmia noted. Echocardiograms obtained on most patients showed a poorly contractile globular left ventricle with low output (ejection fraction under 60%). In most cases, children succumbed to the illness with 6 six days of onset of illness, and death usually ensued within 24 hours following the onset of cardiac instability. Several of the fatal cases also had signs of central nervous system involvement (15% had acute flaccid paralysis and 45% had seizures) [22, 23]. Four fatal cases from peninsular Malaysia had full post-mortem performed and all showed similar pathologic findings. The main histopathological findings were in the brainstem and spinal cord. The entire brainstem including dorsal nucleus of the vagus, tractus solitarius, and reticular formation were inflamed to varying degrees. Inflammation was also present in the pons, midbrain and diencephalons. Severe and widespread inflammation was noted in the grey matter with inflammatory changes that consisted of perivascular culfing by mononuclear cells predominantly and neutrophils occasionally. Cluster of neurons showed degeneration and necrosis with neuronophagia. Microglial nodules were prominent which appeared to form microabscesses. Mild meningitis was noted throughout the CNS but there was no evidence of cerebritis though focal areas of inflammation were noted in the white matter of cerebellum. All cases had histological evidence of pulmonary oedema and the myocardia did not show any inflammation [22, 23]. Both CA16 and EV71 were the major viruses isolated from cases of HFMD but only EV71 was isolated from fatal cases. Other types of enteroviruses, adenovirus and human herpesvirus 1 were isolated in a small proportion of cases of HFMD .
A similar outbreak of HFMD occurred in Malaysia during the latter part of 2000. 8 deaths were reported in peninsular Malaysia with unspecified number of deaths recorded in East Malaysia . The presenting clinical features of children who succumbed to the disease were no different from those seen in the 1997 outbreak. In addition to CA16 and EV71, echovirus 7 (Eo7) was also isolated from cases of HFMD seen at the University of Malaya Medical Centre during the outbreak [16, 21]. Eo7 has previously been implicated as a cause of mild febrile exanthematous diseases in children but has not been reported in association with an HFMD outbreak. During the 2000 HFMD outbreak, besides EV71, Eo7 was also isolated from a few fatal cases of encephalomyelitis. The significance of Eo7 isolation from these fatal cases and its association with EV71 need further study although there have been several earlier reports of fatal infections due to the virus [2, 17, 24, 35].
Malaysia experienced a smaller outbreak of HFMD in 2003 which appeared to begin in Sarawak and subsequently spread to peninsular Malaysia, a temporal pattern of spread that was similar to the HFMD outbreak in 1997. Again, both EV71 and CA16 were the main causative viruses isolated [6, 9, 25, 28]. On the contrary, the outbreak of HFMD in 2005 started in peninsular Malaysia and later spread to Sarawak in early 2006. The outbreak started in late February with 2 599 cases of HFMD reported in peninsular Malaysia. Eight young children below 5 years old succumbed to the illness, 2 from peninsular Malaysia and 6 from Sarawak. Based on the clinical samples submitted to the National Public Health Laboratory for virological investigation, both EV71 and CA16 were the main aetiological viruses isolated but the isolation of CA16 appeared to precede the isolation of EV71 as the aetiological agent of HFMD (Fig. 1). During the same period, EV71 was also isolated from the blood and stool specimens of a 15 months child who succumbed to febrile illness with clinical presentation of brainstem encephomyelitis with neurogenic pulmonary oedema but without any cutaneous and/or muco-cutaneous manifestations of HFMD (Unpublished data). In 2007, an outbreak of HFMD was only noted in peninsular Malaysia. The outbreak was almost purely due to CA16 though EV71 was isolated from 18 of the 5380 patients' clinical samples submitted for laboratory study. The current on-going outbreak of HFMD started in peninsular Malaysia in epidemiological week 12 (Fig. 2). Up to epidemiological week 33, clinical samples (oral swab or rectal swab) from 1647 patients were submitted to the National Public Health Laboratory for virological confirmation. One hundred and forty eight isolates of CA16 and 123 isolates of EV71 were isolated. As with other HFMD outbreaks in Malaysia, both EV71 and CA16 was the main aetiological viruses isolated. In similarity with the HFMD outbreak in 2005, the isolation of CA16 preceded the appearance of EV71 (Fig. 2).
Figure 1. Temporal relationship on the isolation of coxsackievirus A16 and enterovirus 71 during the outbreak of hand foot and mouth disease in 2005.
Figure 2. Temporal relationship on the isolation of coxsackievirus A16 and enterovirus 71 during the outbreak of hand foot and mouth disease in 2010.
In between outbreaks, EV71 was also known to be isolated intermittently but with low numbers of isolates, by the National Public Health Laboratory since it started to offer diagnostic virological services in 2004. Based on this passive surveillance of HFMD, the number of CA16 and EV71 isolated in the years from 2006 to 2009 is shown in Table 1. The data suggests that both these two enteroviruses causing HFMD underwent low endemic circulation in between outbreaks and led to severe outbreaks when the susceptible paediatric population reached a critical level in an environment for sustained explosive transmission.
Table 1. he number of Coxsackievirus A16 and Enterovirus 71 isolated from clinical samples of respective number of cases of Hand foot and mouth disease (HFMD) submitted to National Public Health Laboratory for laboratory investigation for the years 2006 to 2009.
Enterovirus 71 (EV71) is divided into three distinct genogroups (A, B, C) and 10 sub-genogroups (A, B1-5, C1-4) based on the estimation of the phylogenetic relationship of VP1 gene nucleotide sequences . Based on the analysis of the complete VP1 gene nucleotide sequences of a number of EV71 isolated in Malaysia, 4 sub-genogroups of EV71 (C1, C2, B3 and B4) were co-circulating and caused the outbreak of hand foot and mouth disease in peninsular Malaysia in 1997 where as 2 sub-genogenogroups (B3 and C1) were co-circulating in Sarawak. Two subgenogroups (C1 and B4) appeared to cause the outbreak in 2000 in both peninsular Malaysia and Sarawak. A new subgenogroup B (B5) with minor contribution from subgenogroup C1 were the EV71 strains causing the 2003 HFMD outbreak in Sarawak but the status of the EV71 strains causing the outbreak in peninsular Malaysia were not analyzed. In the 2005 outbreak, besides EV71 strains of subgenogroup C1, EV71 strains belonging to subgenogroup B5 were isolated but formed a cluster which was distinct from EV71 strains of the subgenogroup B5 isolated in 2003 [6, 25, 9]. The four EV71 strains isolated from clinical specimens of patients with hand foot and mouth disease in the Sarawak outbreak in early 2006 also belonged to subgenogroup B5. Phylogenetic analysis of the VP1 gene sequences showed that the four Sarawak EV71 isolates belonged to the same cluster as the EV71 strains that were isolated in peninsular Malaysia as early as May 2005. The data suggested that the EV71 strains causing the outbreak in Sarawak in 2006 could have originated from peninsular Malaysia .