International Journal of Infectious Diseases
Volume 14, Issue 9 , Pages e775-e780, September 2010

The enterovirus 71 epidemic in 2008—public health implications for Hong Kong

Surveillance and Epidemiology Branch, Centre for Health Protection, Department of Health, 147C Argyle Street, Kowloon, Hong Kong

Received 28 October 2009 published online 05 July 2010.

Corresponding Editor: William Cameron, Ottawa, Canada

Article Outline

Summary 

Objectives

We compared the epidemiological, clinical and laboratory characteristics of enterovirus 71 (EV71) cases recorded in the epidemic year of 2008 with those of the past decade.

Methods

We estimated the annual incidence rates in the general population and in different age groups. We reviewed the clinical and epidemiological information of the cases. The complication and case fatality rates (CFR) were compared with the corresponding average rates for the period 1998–2007. The molecular strains of EV71 isolates were determined.

Results

The estimated annual incidence was 1.4/100 000 in the general population, with the highest incidence (27.9/100 000) reported among children aged under 5 years. The seasonal peak occurred from May to July. The majority (92.9%) presented with hand-foot-mouth disease (HFMD; 90.8%) or herpangina, and 11.2% had complications including meningitis or encephalitis (6.1%), pneumonia (3.1%), acute flaccid paralysis (1.0%), and shock (1.0%). The CFR was 1.0%. Nearly half (45.9%) of school-aged cases had concurrent HFMD outbreaks at their schools/institutions. There was no statistically significant difference in the complications rate and CFR when compared to those of the past decade. Molecular analysis showed that the majority were genogroup C4 strains, similar to the past circulating strains.

Conclusions

The cyclical high activity has had significant public health and social implications. To strengthen public health surveillance and control, EV71 infection was made a statutory notifiable disease in 2009.

Keywords: Enterovirus 71, Communicable disease, Epidemiology, Epidemic, Emerging infection

 

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1. Introduction 

In the past few decades, infection with enterovirus 71 (EV71) has become an emerging infection, especially in areas of Southeast Asia. Although most patients present with a mild illness, such as hand, foot, and mouth disease (HFMD) or herpangina, a small proportion of patients may suffer severe complications such as aseptic meningitis, encephalitis, acute flaccid paralysis, myocarditis, and even death.1, 2, 3, 4, 5 Young children are more susceptible and this is the reason why EV71 infection has captured much attention. A seroepidemiology study conducted in Singapore suggested that the age-specific seroprevalence rate reached a steady state at approximately 50% among children >5 years old.6 Outbreaks occurring among these school-aged children have caused significant social disturbance to both children and their families. In Hong Kong and Singapore, some schools having outbreaks of HFMD associated with EV71 infection have required temporary class suspension or even school closure in order to stop transmission of the disease.7, 8

Epidemics of EV71 have been reported worldwide since the 1970s, in Bulgaria, Hungary and Sweden, resulting in aseptic meningitis, brain stem encephalitis and significant numbers of deaths.9, 10, 11 Over the period 1997–2000, the epidemic wave spread to Southeast Asia affecting Malaysia, Taiwan, Singapore, and Japan.1, 12, 13, 14 The largest HFMD outbreak occurred in Taiwan in 1998 when over 100 000 cases of HFMD were reported; however this was less than 10% of the estimated true figure.1 That outbreak resulted in 400 patients with severe illness and 78 deaths. EV71 was a particular concern since the virus was isolated from 92% of those who died.

An epidemic of EV71 infection was again detected in 2008, involving many areas of Southeast Asia including Hong Kong.7, 15, 16 We assessed the public health implications in Hong Kong by reviewing the epidemiological, clinical and laboratory characteristics of EV71 cases, comparing them to those of the past decade.

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2. Methods 

In Hong Kong, EV71 has mainly been diagnosed by the Public Health Laboratory (PHL) of the Department of Health (DH). Doctors have also been requested to report EV71 infections to the DH on a voluntary basis. All cases diagnosed by the PHL are investigated. We identified cases from the PHL reporting system for the period 1998–2008. A case was defined as a patient who had a compatible clinical presentation and isolation of EV71 or detection of EV71 by polymerase chain reaction (PCR) from a clinical specimen. Upon reporting of the EV71 cases, the patients or next of kin would be interviewed by trained public health doctors or nurses for epidemiological investigation and control purposes, including contact tracing of home or other close contacts and controlling any associated HFMD outbreaks in the child care institutions. Clinical information including the onset date, clinical symptoms and signs, complications, and outcome were obtained from the attending physician or hospital record. These data were retrieved through an electronic database that was reconstructed as the Public Health Information System in 2002.

We estimated the annual incidence rates in the general population and different age groups. The incidence was calculated by the number of EV71 cases reported in 2008 divided by population data obtained from the Census and Statistics Department.17 The age-specific incidence was estimated similarly using the populations of the different age groups. The monthly number of reported EV71 cases was calculated to determine seasonality.

The complication and case fatality rates (CFR) were calculated by dividing the number of cases who had complications and the number of fatal cases, respectively, by the total number of cases reported. These rates calculated from cases reported in 2008 were compared with the corresponding rates calculated from cases reported for the period 1998–2007, in order to assess whether the virus was more virulent and associated with more severe clinical presentations and outcomes. We also compared the percentage of cases requiring hospitalization, the median duration of hospital care, and the likelihood of an association with an HMFD outbreak at an institution. These rates were compared using the Chi-square test with Yate's correction whenever appropriate. The Mann–Whitney U-test was used for statistical calculations to compare duration of hospital stay, which was left-skewed.

Diagnosis was laboratory confirmed, either by isolation of EV71 or detection of EV71 by PCR from a clinical specimen. Virus isolation was performed according to conventional methods and the EV71 genome was detected by an in-house real-time reverse-transcriptase PCR (RT-PCR). A phylogenetic tree was constructed using the neighbor-joining method. The molecular epidemiology of EV71 detected in 2008 was compared with that of previous years.

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3. Results 

Ninety-eight EV71 cases were reported in 2008, the highest annual figure in the last decade (Figure 1). The estimated annual incidence was 1.4/100 000 in the general population, with the highest incidence reported in children aged 0–4 years (27.9/100 000) (Figure 2). The seasonal peak was detected in May through July, contributing to 65.3% of the cases, while a small winter peak (October to December) was also noted, which was not seen in the previous 10 years (Figure 3).

More males were affected than females, with a male-to-female ratio of 1.1:1. The age of the patients ranged from 5 months to 42 years with a median age of 3.5 years. Seventy-one cases (72.4%) were aged 5 years or less (Table 1). It was noticed that EV71 also affected four adults (aged from 24 to 42 years), accounting for 4.1%. Among these four adult patients, three were family members of pediatric cases and they were identified during contact tracing. The remaining adult patient also had a history of contact with a child with HFMD, although no laboratory diagnosis was made for that child.

Table 1. Characteristics of enterovirus 71 cases in 2008, compared with cases reported from 1998 to 2007
20081998–2007p-Value
No. of cases98195–
Age distributiona
≤12 years old (%)88 (89.8%)183 (94.3%)0.21
≤5 years old (%)71 (72.4%)156 (80.4%)0.14
Male to female ratioa1.1:1 (52:46)1.6:1 (118:76)0.20
No. of cases with travel history outside Hong Kong during incubation period (%)39 (39.8%): Mainland (38), Taiwan (1)20 (10.3%): Mainland (19), Macao (1)0.00
Clinical presentation 0.28
HFMD89185
Herpangina24
Otherb76
No. of cases requiring hospital care (%)61 (62.2%)98 (50.3%)0.07
Duration of hospital care in days, median (range)c4 (1–42)4 (1–28)0.80
No. of cases with complications11 (11.2%): meningitis/encephalitis (6), acute flaccid paralysis (1), pneumonia (3), shock (1)12 (6.2%): meningitis/encephalitis (10), acute cerebellar ataxia (1), pneumonia (1)0.13
No. of deaths (case fatality rate)1 (1.0%)2 (1.0%)1.00
No. of cases associated with an HFMD outbreak in school (% among school age cases)28 (28.6%)83 (42.6%)0.02

HFMD, hand, foot, and mouth disease.

aAge and sex information was missing for one case in the 1998–2007 group.

bIncludes fever, upper respiratory infection, rash, and pneumonia.

cInformation was missing for four cases in the 1998–2007 group and these patients were excluded from the analysis.

The majority (90.8%) of cases presented with hand-foot-mouth disease, while two cases suffered from the milder course of herpangina. Others presented with non-specific symptoms including fever, upper respiratory illness, non-specific skin rash, and pneumonia. Sixty-one cases (62.2%) required hospital care with a median duration of stay of 4 days. The majority of the cases recovered uneventfully, while 11.2% of the cases suffered complications including meningitis or encephalitis (6.1%), pneumonia (3.1%), acute flaccid paralysis (1.0%), and shock (1.0%). There was only one fatal case and the CFR was 1.0%. An 11-month-old boy who had a history of good past health, presented with fever and shortness of breath in August 2008; his clinical condition deteriorated rapidly and he was certified dead at the emergency department despite resuscitation attempts. The cause of death was attributed to interstitial pneumonitis, and a throat swab, tracheal aspirate and rectal swab were all positive for EV71 by RT-PCR. His three-year-old elder sister was also diagnosed to have EV71 infection, but she recovered without any complications.

Among the 61 cases who were known to attend schools or child care institutions, 28 (45.9%) of them had concurrent HFMD outbreaks at their schools or institutions. These 21 HFMD outbreaks affected a range of 2 to 25 persons. Most outbreaks could be controlled with stepped-up infection control measures, including the observation of strict personal hygiene practices by frequent hand washing, thorough cleansing and disinfection of the contaminated surfaces and soiled items, and excluding children with HFMD from schools until fever had subsided and all the vesicular lesions had dried and crusted. However, there was evidence of sustained transmission of EV71 in six schools despite implementation of these stepped-up measures. They required temporary class suspension for 14 days in order to halt the transmission of disease.

There were no statistical differences in the complication rate or CFR when compared with the corresponding rates for the past 10 years (p-value=0.12 and 1.00, respectively). There was no statistical difference in the percentage requiring hospital care or in the duration of stay in hospital in EV71 cases reported in 2008 compared to those reported in the past 10 years. Regarding the proportion of associated HFMD outbreaks, the cases reported in 2008 were apparently less likely to be associated with an HFMD outbreak when compared with the relevant figures of the past decade. It was noted that a significantly higher proportion of cases in 2008 reported a travel history outside Hong Kong (mainly to Mainland China) during the incubation period. However, it was difficult to ascertain the exact source of infection for these cases as EV71 infection is endemic in both Hong Kong and the other areas that the cases had visited.

Figure 4 illustrates the results of phylogenetic analysis for 1998–2008. It was found that the majority of the cases reported in 2008 were C4 strains, which were also the predominant circulating strains in the past 10 years. C1, C2, B3 and B4 strains were detected in previous years, but only constituted a small proportion. In 2008, the rectal swab of a tourist from Taiwan was positive for EV71 by PCR, and gene sequencing results showed it was a B5 strain. The fatal case reported in 2008 belonged to C4, while the other two fatal cases were C4 (reported in 2000) and B3 (reported in 1999).

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4. Discussion 

Our estimated incidence of EV71 infection in Hong Kong for 2008 was 1.4/100 000 in the general population, with the highest incidence reported in children aged 0–4 years (27.9/100 000). The true incidence was probably much higher because many patients could have presented with only mild HFMD and been managed in the out-patient setting and not tested. The bias due to under-reporting by doctors was considered to be minimal, since not all laboratories in Hong Kong have the capacity to isolate the EV71 virus or detect EV71 by PCR. In fact, the PHL of the DH is the reference laboratory, which receives referral specimens from public hospitals and private practitioners. Essentially, all EV71 cases were diagnosed by the PHL and the current review has captured all laboratory confirmed cases.

Apart from the usual EV71 peak season detected in the summer months, we also noticed that there was an increase in EV71 activity in the winter months of 2008 (from October to December). This is consistent with the findings of other surveillance systems for HFMD reported in Hong Kong since 2006, including the number of institutional HFMD outbreaks reported to the DH, the sentinel surveillance systems based at general practitioners and child care centres.18 EV71 contributed to a higher proportion of circulating enteroviruses throughout the whole year of 2008 compared to 2006 and 2007, although according to the laboratory surveillance in these 3 years coxsackie A viruses were still predominant. It is interesting to note that such a bimodal peak for HFMD has also been observed in other Asian countries including Singapore but not in Taiwan in recent years.19, 20

It is often a worry that a high circulation of EV71 will result in worse clinical presentations and outcomes. In the epidemic of HFMD in Taiwan in 1998, EV71 was isolated in 78 patients with various complications and in 34 of the fatal cases.1 Our analysis showed that both the complications rate and the CFR were not statistically significant when compared to the data of past years. The complication rate in 2008 was 11.2%, slightly higher than the average of 6.2% during the period 1998–2007. A similar higher proportion of cases required hospitalization in 2008 (62.2% in 2008 vs. 50.3% in 1998–2007). This might be partly attributed to the enhanced hospital-based surveillance system for HFMD implemented in early May 2008 in Hong Kong in view of the HFMD outbreak occurring in Mainland China.15 To facilitate early detection of severe infections of HFMD and implement public health actions, from May 2008 doctors in Hong Kong were requested to report clinical cases of HFMD with severe complications admitted to hospitals, even without laboratory confirmation. Among the 98 cases reported in 2008, five were reported through this system and were subsequently confirmed to be EV71 infections.

In 2008, the majority (63.6%) of cases with clinical complications occurred in children aged 5 years or younger. Meningitis and encephalitis were the most commonly reported complications. One patient suffered from acute flaccid paralysis, which was also seen in the outbreak in Perth, Australia in 1999 and in the Taiwan outbreak in 1998.1, 21 In contrast to the previous two reported fatal cases in Hong Kong, the fatal case reported in 2008 did not have any documented evidence of central nervous system complications. In the first fatal case reported in 1999, a 2-year-old boy suffered from brainstem encephalomyelitis with rapid cardiovascular decompensation.22 The second fatal case reported in 2000 resembled the death cases experienced in Taiwan in the 1998 outbreak; a 5-year-old girl presented with meningoencephalitis, complicated by pulmonary edema and pulmonary hemorrhage. The cause of death in the 2008 case was interstitial pneumonitis. Pulmonary complications due to EV71, although rare, are also reported in the literature.23 After reviewing the 78 cases with severe infections caused by EV71 in Taiwan, Ho et al. found that there were nine cases with pulmonary edema or hemorrhage without any neurological complications.1

Our epidemiological data suggest that there was a 3- to 4-year cycle of high activity of EV71 infection in Hong Kong. Similar surveillance findings have been reported in Malaysia, Taiwan, and Japan.24, 25, 26 In fact, it has been suggested that there have been three separate waves of EV71 activity worldwide, one in each decade between 1970 and 2000, with the last wave occurring from 1997 to 2000.27 Interestingly, about 10 years after the last wave, an epidemic of EV71 again occurred in 2008, with many areas of Asia, including Malaysia, Singapore, Taiwan and Mainland China, reporting high activity of the disease. There are different postulations for why the epidemics occur cyclically. The emergence of new circulating strains has often been a focus.28 However, our findings do not suggest that there has been a major change in the molecular epidemiology of EV71 in Hong Kong. In 2008, C4 was still the predominant circulating strain in Hong Kong. Another postulation for the high cyclical activity is the accumulation of a susceptible population. Lu et al. showed that before the large epidemic in Taiwan in 1998, 40% to some 60% of the study population was seropositive for EV71 in the period 1989–1993.29 However, in 1994 and 1997, a notably drop in seroprevalence (20% to some 30%) of EV71 infection was detected in the community. Such a buildup of a non-immune population may facilitate a more efficient transmission of the virus in the community.

Although the clinical presentation and predominant strain of EV71 in Hong Kong in 2008 were similar to those in past years, the cyclical high activity has had significant public health and social implications. Currently there is no effective chemoprophylaxis or vaccine for EV71. While we are waiting for an effective vaccine to be developed, early case detection and prevention of secondary spread appear to be the most effective public health measures for controlling EV71 infection.30 To strengthen public health surveillance and control, EV71 infection has been a statutory notifiable disease in Hong Kong since March 2009.

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Acknowledgements 

We would like to thank the health professionals of the Public Health Laboratory Centre for carrying out the laboratory tests for EV71 and all the medical and nursing staff of the Epidemiology Section, Surveillance and Epidemiology Branch, Centre for Health, HKSAR, for investigating the cases in this series.

Conflict of interest: We declare that we do not have any conflict of interest in writing this article.

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References 

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PII: S1201-9712(10)02400-8

doi:10.1016/j.ijid.2010.02.2265

International Journal of Infectious Diseases
Volume 14, Issue 9 , Pages e775-e780, September 2010

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