Nationwide Surveillance of Influenza during the Pandemic (2009–10) and Post-Pandemic (2010–11) Periods in Taiwan

Introduction Although WHO declared the world moving into the post-pandemic period on August 10, 2010, influenza A(H1N1) 2009 virus continued to circulate globally. Its impact was expected to continue during the 2010–11 influenza season. This study describes the nationwide surveillance findings of the pandemic and post-pandemic influenza periods in Taiwan and assesses the impact of influenza A(H1N1) 2009 during the post-pandemic period. Methods The Influenza Laboratory Surveillance Network consisted of 12 contract laboratories for collecting and testing samples with acute respiratory tract infections. Surveillance of emergency room visits and outpatient department visits for influenza-like illness (ILI) were conducted using the Real-Time Outbreak and Disease Surveillance system and the National Health Insurance program data, respectively. Hospitalized cases with severe complications and deaths were reported to the National Notifiable Disease Surveillance System. Results During the 2009–10 influenza season, pandemic A(H1N1) 2009 was the predominant circulating strain and caused 44 deaths. However, the 2010–11 influenza season began with A(H3N2) being the predominant circulating strain, changing to A(H1N1) 2009 in December 2010. Emergency room and outpatient department ILI surveillance displayed similar trends. By March 31, 2011, there were 1,751 cases of influenza with severe complications; 50.1% reported underlying diseases. Of the reported cases, 128 deaths were associated with influenza. Among these, 93 (72.6%) were influenza A(H1N1) 2009 and 30 (23.4%) A(H3N2). Compared to the pandemic period, during the immediate post-pandemic period, increased number of hospitalizations and deaths were observed, and the patients were consistently older. Conclusions Reemergence of influenza A(H1N1) 2009 during the 2010–11 influenza season had an intense activity with age distribution shift. To further mitigate the impact of future influenza epidemics, Taiwan must continue its multifaceted influenza surveillance systems, remain flexible with antiviral use policies, and revise the vaccine policies to include the population most at risk.


Introduction
Influenza pandemic (H1N1) 2009 virus emerged in April 2009 and quickly spread worldwide within 6 weeks. In Taiwan, the first patient infected by the pandemic (H1N1) 2009 virus was identified on 20 May, 2009. This strain of influenza soon became the predominant subtype in circulation and caused 44 confirmed deaths (the mortality rate was 1.9 deaths per million population) in Taiwan during the 2009-10 influenza season. Although WHO declared the world moving into the post-pandemic period on August 10, 2010, the influenza A (H1N1) 2009 virus continued to circulate globally. Its impact, severe complications in younger age and high-risk groups, were expected to continue during the 2010-11 influenza season [1,2].
Taiwan is situated in Eastern Asia with 23 million in population. Since 1998, free influenza vaccines have been provided to targeted groups such as the elderly, patients with catastrophic illnesses as defined by the Bureau of National Health Insurance [3], health care workers, young children aged 0.5-6 years and school-aged children. The annual vaccination coverage for seasonal influenza in the entire population was around 10-15% in recent years.
Influenza surveillance in Taiwan includes the use of sentinel physicians through the Influenza Laboratory Surveillance Network, the Real-time Outbreak and Disease Surveillance (RODS), National Health Insurance (NHI) data, and passive reporting of influenza hospitalized cases with severe complications through the National Notifiable Disease Surveillance System (NNDSS).
The Influenza Laboratory Surveillance Network is coordinated by the Taiwan Centers for Disease Control (TCDC), and comprises of 12 collaborating laboratories aimed to survey and isolate viruses causing respiratory tract infections year round [4]. More than 275 sentinel physicians in private clinics or hospitals voluntarily participated in this surveillance. The physicians were distributed in 21 of the 22 administrative areas of Taiwan. Clinicand hospital-based physicians each contribute to approximately 50% of the specimens collected. The network has been in operation since 1999.
RODS, developed by the University of Pittsburgh (Pittsburgh, PA), was originally designed to detect bioterrorism events or emerging diseases [5]. In Taiwan, RODS has been used to monitor influenza activity through monitoring emergency room (ER) visits [6]. There are more than 160 hospitals that participate in RODS. For the surveillance of outpatient clinics, NHI database is used. Of the 23 million people living in Taiwan, .99% are enrolled in NHI [7], making NHI a comprehensive database to monitor outpatient influenza activity.
According to the Communicable Disease Control Act, physicians are required to report notifiable diseases within the allotted time frame [8]. Influenza with severe complications was made reportable to NNDSS in 2000 [9], requiring reporting within one week. Otherwise, physicians may incur fines approximately USD 3,000-15,000. However, influenza with severe complications was not widely reported until after the 2009 influenza pandemic. Prior to the pandemic, approximately 15-35 confirmed cases were reported in any given influenza season.
Through the use of all these surveillance methods, a nearly complete picture of influenza activity nationwide emerges. This study aimed to describe the nationwide influenza surveillance findings of the pandemic (2009-10) and post-pandemic (2010-11) periods in Taiwan, and to assess the impact of influenza A(H1N1) 2009 during the post-pandemic period.

Defining influenza seasons
Taiwan has a tropical-to-temperate spectrum of climatic zones. The annual average temperature is 22uC with the lowest temperatures ranging from 12uC to 17uC. Winters are defined as the months of December, January and February. In this study, Taiwan's influenza season was defined as July 1 to June 30 of the following year. For the 2009-10 influenza season, this corresponded to week 26, 2009-week 25, 2010; and for the study period of the 2010-11 influenza season, this corresponded to week 26, 2010-week 13, 2011. Each year, influenza activity usually begins to rise in late October, and peaks sometime during late December to early February the following year.

Influenza Laboratory Surveillance
For the Influenza Laboratory Surveillance Network, clinical specimens obtained from nasal or throat swabs were collected by physicians and sent to TCDC collaborating laboratories for virus isolation and identification using viral culture and/or reverse transcriptase-polymerase chain reaction (RT-PCR). Methods of virus isolation have been described previously [10]. Antigenic characterization of the influenza virus was determined using the hemagglutination inhibition (HI) assays with ferret antisera [11]. Oseltamivir-resistant influenza viruses were detected using DNA sequencing and 50% inhibitory concentration (IC 50 ) analysis of neuraminidase activity [12].

Influenza-like Illness (ILI) Syndromic Surveillance
RODS collected individual patient's International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnostic codes from patient ER visits, covering approximately 85% of all ERs in Taiwan. ICD-9-CM codes were uploaded to RODS in real time, making the data available for daily analysis. ILI cases were detected using RODS predetermined set of ICD-9-CM codes for respiratory syndrome [13].
For the NHI database, all healthcare facilities (clinics and hospitals) submit outpatient department (OPD), ER, and inpatient ICD-9-CM diagnostic codes to the Bureau of National Health Insurance (BNHI) for reimbursement. Because BNHI provided financial incentives for clinics and hospitals to submit good quality claims data electronically within one day of each patient visit, the database had been reliable for insurance claims purposes. On weekdays, aggregated data in prespecified ICD-9-CM diagnostic code groups by age group and geographic location were sent to TCDC electronically. ILI was defined by ICD-9-CM codes 480-487.

Reporting of Influenza Cases with Severe Complications and Deaths
For NNDSS, ILI in a patient who had any pulmonary complications that required hospitalization, neurological complications, myocarditis or pericarditis, invasive bacterial infection, or other severe conditions requiring intensive care unit admission were reported and confirmed by RT-PCR or viral culture [6,14]. All laboratory-confirmed patients reported to NNDSS, with onset dates during July 1, 2009-March 31, 2011, who met the case definition, were included for analysis. In addition, for the 2010-11 influenza season we analyzed characteristics of confirmed patients who died by the end of week 13, 2011, and influenza was contributory as determined by a reviewing physician or recorded on the death certificate. For patients who died, medical records, where available, were reviewed.

Antiviral Prescriptions
Antiviral medications, including oseltamivir, zanamivir, and peramivir, were provided free of charge by TCDC to 1) patients with clinical evidence of severe influenza with complications; 2) ILI patients with danger signs that signal progression to severe disease [15]; 3) ILI patients with critical illness, chronic cardiopulmonary disease, liver disease, renal disease, or diabetes mellitus; 4) ILI patients with body mass index (BMI)$35; and 5) ILI patients in an influenza outbreak. On January 25, 2011, free antivirals were additionally provided to patients with fever for $48 hours and ILI patients who had been in close contact with other ILI patients at home, school, or workplace. Each prescription was registered at the Countermeasure Management Information System operated by TCDC. We compared the weekly number of antiviral prescriptions with the number of ILI visits in RODS from week 1, 2010 through week 13, 2011.

Comparing 2009-10 and 2010-11 Influenza Seasons
We compared the age distribution of influenza outpatient visits (ICD-9-CM code 487) and influenza A(H1N1) 2009 cases with severe complications and deaths between the 2009-10 and 2010-11 influenza seasons. Chi-square tests were used to test whether the two groups of patients were similar in age distribution.

Ethics
Data obtained for this study was for surveillance purposes; therefore, this study was not reviewed by an institutional review board.

Statistical methods
We used Microsoft Excel (2007) to produce figures and calculate descriptive statistics such as counts and percentages. The chisquare test, median and interquartile range (IQR) were performed using SAS (SAS Institute Inc., Cary, NC, USA), Version 9.2 of the SAS System for Windows 7.  titers. Furthermore, 12 of 1,734 influenza A(H1N1) 2009 viruses tested positive for mutation H275Y in the neuraminidase gene, conferring resistance to oseltamivir. Epidemiologic investigations indicated no clustering. No transmission was found after screening of suspected cases with temporal association or in geographic proximity.

Emergency and Outpatient Illness Surveillance
Following the first documented case of influenza A(H1N1)2009 was imported into Taiwan, patients seeking care for ILI at ERs quickly rose, peaking in week 37, 2009. OPD surveillance had its peak in week 48. This was followed by a much smaller rise during week 7, 2010, occurring in both ER and OPD surveillance because it was during the Lunar New Year, when the majority of the private clinics were closed. While these clinics were closed, patients with ILI sought help at ERs, resulting in the rise in ER surveillance. For OPD surveillance, because patients with chronic diseases stayed away during this period, the relative increase of ILI patients resulted in the small rise.

Hospitalized Cases with Severe Complications and Deaths
Of the 169 (9.7%) patients who died during the 2010-11 influenza season, 128 were directly or indirectly associated with influenza (the mortality rate was 5.5 deaths per million population). By week 50, 2010, deaths were predominantly caused by H3N2 (Fig. 5) (Tables 1 and 2). All three Chi-square tests for the differences in the age distribution between the two groups were statistically significant with p,0.0001.  [19].

Discussion
Among persons who died in association with influenza, 85.9% had underlying diseases, mainly diabetes mellitus and cardiovascular diseases other than hypertension. However, these persons with high-risk underlying diseases were not targeted under the current vaccination program; instead, persons with the 29 groups of diseases listed as ''catastrophic illnesses'' in the NHI program were [3]. Because vaccination is provided free of charge, TCDC has yet to develop a good method to readily verify a person's disease status with known high-risk underlying diseases at vaccination sites. Therefore, persons in high-risk groups not marked for having a ''catastrophic illness'' were not included among the vaccination target groups. Countries such as the United States [20], Australia [21], and the United Kingdom [22] have targeted persons with chronic illnesses, including those with diabetes mellitus, cardiovascular diseases, and chronic respiratory   According to the Taiwan Central Weather Bureau, the average temperature for January 2011 was 13.7uC (56.7uF) in Taipei and 17.5uC (63.5uF) in Kaohsiung, representing the north and south, respectively, making it the coldest January since 1972 [24]. On average, the temperature in January 2011 was 2uC lower than the average of the last 30 years. Because transmission of influenza virus is highly dependent on temperature, unprecedented low   [25,26]. The mortality rate in Taiwan caused by influenza A (H1N1) 2009 during the post-pandemic season was higher than during the pandemic season (5.5 vs. 1.9 deaths per million population, p,0.0001). These two numbers were similar to the death risks of influenza A (H1N1) 2009 in England during the second and the first waves of pandemic in the 2009-10 season (5.4 vs. 1.6 deaths per million population), respectively [27]. Both Taiwan and England reported higher mortality rate during the second wave compared to the first wave. Comparable or even more severe postpandemic period was observed in the same winter in the several European countries [28], such as UK [19,29,30], Greece [31], and Spain [32]. Multiple waves of pandemic influenza were also reported in past pandemics [33].
The findings in this study had some limitations. First, the number of influenza-associated hospitalizations and deaths may be underdiagnosed or underreported because data were derived from a passive surveillance system. Second, using chart review and death certificate to determine whether influenza was contributory to death was subject to misclassification bias. Third, to track ILI activity, we used ICD-9-CM administrative data for syndromic surveillance, which may have lower specificity [34] and coding errors [35].
In conclusion, reemergence of influenza A(H1N1) 2009 during Taiwan's 2010-2011 influenza season had an intense activity with age distribution shift, that during the 2010-11 influenza season, influenza A(H1N1) 2009 patients of all severities were consistently older than those during the 2009-10 season. Most patients with severe disease or died did not receive the current season's influenza vaccine. To further mitigate the impact of future influenza epidemics, Taiwan must continue its multifaceted influenza surveillance systems, remain flexible with antiviral use policies, and revise the vaccine policies to include the population most at risk.