Ding-Ping Liu

Influenza Pandemics: Past, Present and Future

Influenza A virus is well known for its capability for genetic changes either through antigen drift or antigen shift. Antigen shift is derived from reassortment of gene segments between viruses, and may result in an antigenically novel virus that is capable of causing a worldwide pandemic. As we trace backwards through the history of influenza pandemics, a repeating pattern can be observed, namely, a limited wave in the first year followed by global spread in the following year. In the 20th century alone, there were three overwhelming pandemics, in 1918, 1957 and 1968, caused by H1N1 (Spanish flu), H2N2 (Asian flu) and H3N2 (Hong Kong flu), respectively. In 1957 and 1968, excess mortality was noted in infants, the elderly and persons with chronic diseases, similar to what occurred during interpandemic periods. In 1918, there was one distinct peak of excess death in young adults aged between 20 and 40 years old; leukopenia and hemorrhage were prominent features. Acute pulmonary edema and hemorrhagic pneumonia contributed to rapidly lethal outcome in young adults. Autopsies disclosed multiple-organ involvement, including pericarditis, myocarditis, hepatitis and splenomegaly. These findings are, in part, consistent with clinical manifestations of human infection with avian influenza A H5N1 virus, in which reactive hemophagocytic syndrome was a characteristic pathologic finding that accounted for pancytopenia, abnormal liver function and multiple organ failure. All the elements of an impending pandemic are in place. Unless effective measures are implemented, we will likely observe a pandemic in the coming seasons. Host immune response plays a crucial role in disease caused by newly emerged influenza virus, such as the 1918 pandemic strain and the recent avian H5N1 strain. Sustained activation of lymphocytes and macrophages after infection results in massive cytokine response, thus leading to severe systemic inflammation. Further investigations into how the virus interacts with the hosts immune system will be helpful in guiding future therapeutic strategies in facing influenza pandemics.

Public Health Responses to Reemergence of Animal Rabies, Taiwan, July 16–December 28, 2013

Taiwan had been free of indigenous human and animal rabies case since canine rabies was eliminated in 1961. In July 2013, rabies was confirmed among three wild ferret-badgers, prompting public health response to prevent human rabies cases. This descriptive study reports the immediate response to the reemergence of rabies in Taiwan. Response included enhanced surveillance for human rabies cases by testing stored cerebrospinal fluids (CSF) from patients with encephalitides of unknown cause by RT-PCR, prioritizing vaccine use for postexposure prophylaxis (PEP) during periods of vaccine shortage and subsequent expansion of PEP, surveillance of animal bites using information obtained from vaccine application, roll out of preexposure prophylaxis (PrEP) with vaccine stock restoration, surveillance for adverse events following immunization (AEFI), and ensuring surge capacity to respond to general public inquiries by phone and training for healthcare professionals. Enhanced surveillance for human rabies found no cases after testing 205 stored CSF specimens collected during January 2010–July 2013. During July 16 to December 28, 2013, we received 8,241 rabies PEP application; 6,634 (80.5%) were consistent with recommendations. Among the 6,501persons who received at least one dose of rabies vaccine postexposure, 4,953 (76.2%) persons who were bitten by dogs; only 59 (0.9%) persons were bitten by ferret-badgers. During the study period, 6,247 persons received preexposure prophylaxis. There were 23 reports of AEFI; but no anaphylaxis, Guillain-Barré syndrome, or acute disseminated encephalomyelitis were found. During the study period, there were 40,312 calls to the Taiwan Centers for Disease Control hotline, of which, 8,692 (22%) were related to rabies. Recent identification of rabies among ferret-badgers in a previously rabies-free country prompted rapid response. To date, no human rabies has been identified. Continued multifaceted surveillance and interministerial collaboration are crucial to achieve the goal of rabies-free status in Taiwan.

Is a monovalent vaccine against enterovirus 71 sufficient? A review of enterovirus 71 vaccine development based on enterovirus surveillance in Taiwan

Non-polio enteroviruses are among the most common viral infectious agents. More than 60 serotypes of enteroviruses are classified into four groups: coxsackievirus A (CA), coxsackievirus B (CB), echovirus (Echo), poliovirus and new enterovirus. While most enteroviral cases are either asymptomatic or have mild symptoms (e.g., mild upper respiratory problems), some cases exhibit symptoms such as hand-foot-mouth disease (HFMD), herpangina, aseptic encephalitis, viral meningitis and acute hemorrhagic conjunctivitis. Severe complications have potentially lethal consequences. EV71 was first isolated in California in 1969. In the 1970s, two EV71 outbreaks caused a number of deaths in Bulgaria and Hungary, but the enterovirus threat did not receive much attention until epidemics erupted in Malaysia and Taiwan in 1997 and 1998, respectively. Since then, HFMD surveillance systems have been established successively in Malaysia, Singapore, Thailand, China and Vietnam. According to regional surveillance data, EV71 and CA16 are the major pathogenic virus types for HFMD in the Southeast Asian countries.

Low Seroprotection against Preseasonal Influenza Local Strains in Children Might Predict the Upcoming Epidemic Influenza Strains

BACKGROUND. Our objective was to determine the serological signals that indicated the possible dominant circulating influenza virus subtypes for the coming influenza seasons. METHODS. Healthy children 6 months through 5 years of age, adults 18-60 years of age, and elderly adults >60 years of age were recruited to receive seasonal trivalent inactivated influenza vaccinations from October through December during the 2006-2007 and 2008-2009 seasons. Paired serum samples were collected at baseline and at 3 weeks after vaccination. Using a hemagglutination inhibition (HAI) assay, we measured antibody responses to local influenza strains circulating early in October, before each winter influenza season. RESULTS. A total of 301 subjects were tested for antibody to local strains (80, 120, and 101 subjects in the 2006-2007, 2007-2008, and 2008-2009 seasons, respectively). The dominant winter influenza strains in Taiwan were B/Malaysia/2506/2004-like in the 2006-2007 season, A/Brisbane/59/2007-like virus (H1N1) in the 2007-2008 season, and A/Brisbane/59/2007-like virus (H1N1) in the 2008-2009 season. The group with the lowest number of subjects with an HAI titer of 40 at baseline was children with antibody against the B/Taiwan/0050/2006 in the 2006-2007 season, A/Taiwan/785/2006 (H1N1) in 2007-2008 season, and A/Taiwan/951/2007 (H1N1) in 2008-2009 season. The emergence of these viruses correlated well with the circulating influenza subtype in the following winter peak seasons. CONCLUSIONS. Low seroprotection rate among children against a specific locally circulating influenza strain might predict the dominantly circulating subtype of influenza virus in the coming winter season. A year-end preseasonal serological survey of children could provide valuable information about the possible circulating strain and tailor the disease-control strategy accordingly.

Low Seroprevalence of Parvovirus B19 in Taiwanese Children and Young Adults

BACKGROUND This study aimed to evaluate the prevalence of parvovirus B19 antibodies in children and young adults aged=30 years old in Taiwan. METHODS Stored serum samples from healthy volunteers aged 1-29 years in Taipei were randomly selected and tested for antiparvovirus B19 immunoglobulin G by enzyme immunoassay. RESULTS A total of 277 serum samples were tested. The overall seroprevalence of parvovirus B19 in Taiwanese children and young adults was 23.1% (64/277) in 2004. The positive rate increased slightly with age; it ranged from 15.0% in those aged 1-4 years to 30.8% in those aged 25-29 years (trend test, p=0.01). The age-adjusted anti-B19 immunoglobulin G seropositive rate was slightly higher in males (27.8%) than in females (18.8%; adjusted odds ratio: 0.56; 95% confidence interval: 0.32-0.99). CONCLUSION Most children and young adults in Taipei City are not immune to parvovirus B19, suggesting that no parvovirus B19 epidemic has occurred in the last few decades.

Disease burden of enterovirus infection in Taiwan: Implications for vaccination policy

OBJECTIVES This study aimed to assess the disease burden and economic impacts of human nonpolio enteroviruses (NPEV) and enterovirus A71 (EV-A71) infection in Taiwan. MATERIALS AND METHODS We included children under five years old (n=983,127-1,118,649) with ICD-9-CM codes 0740 (herpangina) or 0743 (hand-foot-and-mouth disease) from the 2006 to 2010 National Health Insurance Database. Severity of enterovirus infection was assessed from outpatient/emergency visits, hospitalization (with/without intensive care unit [ICU] admission), infection with severe complications, and death. We estimated medical costs and indirect costs from the societal perspective. RESULTS The annual rates of NPEV events for children under five years old ranged from 13.9% to 38.4%, of which 5.1-8.8% were hospitalized. EV-A71 accounted for 7.8% of all NPEV medical costs, but 79.1% of NPEV ICU costs. Travel costs and productivity loss of caregivers were

Risk assessment of human infection with avian influenza A (H7N9) virus in Taiwan.

37.1 (range:

Influenza in Taiwan: seasonality and vaccine strain match.

24.5-

A Review of Prevention and Control for Enterovirus Infections in Asia

64.7) million per year. These costs were not higher in the EV-A71 dominant year (

Influenza in Taiwan: Seasonality and vaccine strain match

34.4 million) compared with those in the other years. Productivity losses resulting from premature mortality by NPEV infection were