From January 1996 to December 2003, 57,060 specimens were tested for influenza virus, and 51,370 were tested for RSV. The volume of tests performed was noticeably lower in the first 2 years and in the last year of the study (Table 1). There were 9,103 positive results for RSV and 3,829 positive results for influenza. The annual mean number of tests positive for influenza A was 5.8% (range 2.6%–9.5%) and for influenza B, 0.9% (range 0.4%–1.6%). Annually, influenza A (H3N2) was the predominant influenza virus subtype in circulation. During the study period, peaks in influenza A (H3N2) were observed from December 1998 to January 1999 (the predominant circulating strain was A/Sydney/5/97), December 2000 to January 2001 (A/Moscow/10/99), December 2002 to January 2003 (A/Moscow/10/99), and October–November 2003 (A/Fujian/411/2002). Smaller peaks were noted in April–July in 1996, 1997, 1998, and 2002, and from September to November in 1999 and 2003.

During the 8-year period, an annual mean of 15,616 deaths (range 15,301–16,024) occurred in Singapore. An average of 1,798 (range 1,545–2,340) underlying P&I deaths and 8,237 (range 7,833–8,715) underlying C&R deaths occurred each year (Table 2).

The Figure shows the temporal trends for death outcomes as well as influenza virus and RSV activities. Peaks in monthly influenza A viruses corresponded very well with peaks in monthly all-cause deaths, underlying P&I deaths, and underlying C&R deaths.

We tested the Spearman rank correlations between influenza and RSV, and meteorologic variables. Influenza A positivity (Spearman correlation [r] = 0.25) was weakly correlated with relative humidity. However, temperature (r = –0.71) was highly correlated with relative humidity. The influenza A (H3N2) subtype had a high correlation with influenza A (r = 0.75) (data not shown).

The relationship between deaths and each respiratory virus (influenza A, influenza B, and RSV) was examined by using a stepwise sequential approach (Table 3), i.e., first fitting each of the viruses into separate models (models 1–3), then adjusting for 1 of the other 2 viruses (models 4, 5), and finally, adjusting for all viruses in a single model (model 6). Furthermore, potential confounding factors were adjusted for and included in each model.

Influenza A had significant and robust effects on monthly all-cause deaths (RR 1.05 for each 10% change in positive test results, without adjusting for influenza B virus, RSV, and other potential confounding factors; vs. RR 1.05, after adjusting for influenza B, RSV, and other confounding factors), underlying P&I (RR 1.12 vs. RR 1.13), and underlying C&R (1.08 vs. 1.09) deaths.

In Table 4, we used model 6 (as described in Table 3) to further explore the association between influenza A virus subtypes and the 3 death outcomes. We replaced influenza A variable with influenza A subtypes and adjusted for influenza B virus, RSV, and other confounding factors. Only influenza A (H3N2) had significant (all p values <0.001) effects on all-cause deaths (RR 1.04 for each 10% change in positive test results, 95% CI 1.02–1.05), underlying C&R deaths (1.05, 1.04–1.07), and underlying P&I deaths (1.08, 1.04–1.12).

Influenza B also had a significant effect on underlying C&R deaths (RR 1.01 for each 1% change in positive test results, 95% CI 1.00–1.03, p = 0.037) and all-cause deaths (1.01, 1.00–1.02, p = 0.008), but not on underlying P&I deaths (p = 0.878). RSV had no observable impact on all 3 death categories analyzed (RR range 1.00–1.01 for each 10% change in positive test results, p>0.099) (Table 4).

Next, we used the full model to quantify the excess deaths attributable to influenza throughout the year. For deaths from all causes, we estimated an annual mean of 588 influenza-associated deaths (Table 5), representing 3.8% of total deaths. The mean annual estimates of deaths from underlying P&I and C&R associated with influenza were 116 and 475, respectively, representing 6.5% and 5.8% of such deaths.

We observed that the proportion of influenza-associated deaths was higher among the elderly. The annual influenza-associated proportion of deaths from all causes was 11.3 times higher in persons age >65 years (167.8/100,000 person-years) than in the general population (14.8/100,000). For influenza-associated underlying P&I deaths, the annual death rate in those >65 years (46.9/100,000) was 16.2 times higher than those in the general population (2.9/100,000) (Table 5).

Table 6 compares the excess deaths observed in our study with that derived from studies in a subtropical and temperate country (6,7). While we observed a smaller overall impact for all ages than that reported in Hong Kong (6) and the United States (7), we noted a higher proportion of influenza-associated deaths among the elderly in Singapore.

To our knowledge, our findings are the first to demonstrate that influenza activity is associated with excess deaths in a tropical country. Our estimates of annual influenza-associated all-cause deaths, underlying P&I deaths, and underlying C&R deaths in Singapore were 14.8, 2.9, and 11.9 per 100,000 person-years, respectively. This finding would translate to an estimated 588 deaths (3.8% of total deaths) due to influenza annually, which is comparable to the proportion of deaths observed in subtropical Hong Kong (6) and in the United States (7), a temperate country.

Our estimate of 46.9 underlying P&I deaths per 100,000 persons age >65 years each year is lower than the estimate of a local study (21). However, that study acknowledged a possible overestimation of the incidence of influenza in the elderly. Moreover, their estimates were based on the assumption that 40% of P&I deaths were associated with influenza, which was a figure derived from external data from temperate countries. This figure far exceeds our estimate of 6.5% of underlying P&I deaths attributable to influenza. In Hong Kong (6) and the United States (7), influenza-associated deaths represented 7.4% and 9.8% of underlying P&I deaths, respectively.

In Singapore, we observed that the influenza-associated proportion of deaths was highest in persons >65 years. Again, this finding is consistent with those in the United States where 90% of influenza-associated deaths occurred among the elderly (7). In this population, we estimated an annual number of excess deaths per 100,000 population of 167.8 of all-cause deaths, 46.9 deaths from underlying P&I, and 155.4 deaths from underlying C&R attributable to influenza.

In fact, our estimates for influenza-associated deaths in persons age >65 years were consistently higher than those in Hong Kong and United States, for all 3 mortality outcomes. A possible reason could be the use of influenza vaccines among vulnerable elderly is higher in the United States and Hong Kong than in Singapore. Influenza vaccination for all persons age >65 years is a well-established recommendation of the Advisory Committee on Immunization Practice (ACIP) in the United States (22). Vaccine coverage among elderly persons (>65 years) in the United States increased from 15% to 20% before 1980 to 65% in 2001 (23), and the national target of 60% coverage in this population has been achieved since 1997 (24). In Hong Kong, the use of vaccine has been limited (25). However, the vaccine has been recommended for institutionalized elderly since 1997, and the Department of Health has had a program to vaccinate this population since 1998 (26). In Singapore, influenza vaccine use has been low, and the mean annual quantity used in 2001–2002 was only ≈20,000 doses (Ministry of Health, Singapore, unpub. data). The number of persons age >65 averaged ≈250,000 during that period (27). Even if all 20,000 vaccine doses had been given to this group of persons, vaccination coverage in the elderly would not have exceeded 8% per year.

Annual influenza vaccination for persons age >65 years has been recommended since September 2003 in Singapore by the National Expert Committee on Immunization. Influenza vaccine efficacy for preventing death among people >65 years was estimated to be 68% (28). In a recent study, vaccine effectiveness in those >75 years of age was found to be even greater (29). However, such studies have yet to be conducted in the tropics. We recommend a follow-up study to estimate the impact of vaccination on influenza-associated deaths in this age group in Singapore.

With regard to influenza subtypes, we note that most seasons in the United States were dominated by influenza A (H3N2) virus (30); the greatest number of influenza-associated deaths were associated with influenza A (H3N2), followed by RSV, influenza B, and influenza A (H1N1) virus (31). Influenza A (H3N2) virus accounted for 60% and 77% of positive influenza isolates in the United States (7) and Hong Kong (6), respectively. Our findings were similar. Influenza A (H3N2) was the predominant virus subtype during our study period and had a consistently significant impact on all 3 categories of deaths. Although influenza B was noted to have significant effects on all-cause deaths and underlying C&R deaths, the magnitudes of RRs were relatively small (RR 1.00–1.01, for each 1% change in positive test results). In addition, influenza B virus did not have any significant and observable impact on underlying P&I deaths. We did not observe any significant impact from influenza A (H1N1) virus and RSV on all 3 outcomes.

One limitation of our study may have been that the effect of RSV could have been obscured when we analyzed data on all ages. This virus is known to predominately affect children <2 years of age (8–10), <5% of the population. However, this factor does not negate the main finding that influenza infections are associated with substantial disease in Singapore.

Studies suggest that global interhemispheric circulation of epidemics follows an irregular pathway with recurrent changes in the leading hemisphere (32). As a major travel hub with a high volume of travelers from both hemispheres, Singapore could be a sentinel for detecting changes in the circulating virus strain and contribute toward an understanding of influenza virus circulation pathways. The prevalence of influenza in Singapore illustrates the importance of improving worldwide coverage and quality of virologic and epidemiologic surveillance for influenza, as described in WHO's Global Agenda for Influenza Surveillance and Control (33).

Our findings have a few policy implications. First, they support the recent recommendation by the National Expert Committee on Immunization on annual influenza vaccination for elderly Singaporeans and for persons at high risk of having complications from influenza. Second, the finding that influenza infections account for substantial disease supports our continued investment in strengthening influenza surveillance in our country. Finally, the study provides justification for stockpiling antiviral drugs in our national influenza pandemic preparedness plan. An influenza pandemic can be expected to result in far higher attack and death rates (34,35) than currently observed. The extent of disease and economic impact caused by an influenza pandemic could be greatly reduced by the appropriate use of vaccines and antiviral drugs (36).

In 2003, a new infectious disease, severe acute respiratory syndrome (SARS), emerged, which caused 238 cases and 33 deaths in Singapore (37). The SARS outbreak galvanized public health actions in surveillance and control. Surveillance and plans for containing a resurgence of SARS remain in place, in spite of the low risk of a recurrence. Influenza, in contrast, has caused an average of 588 excess deaths in Singapore annually. Influenza continues to cause an increasing amount of disease in Singapore, particularly in our rapidly aging population. However, available strategies in influenza prevention and control have yet to be optimized, largely because the true impact of influenza has been masked by the lack of a clear seasonal pattern in the tropics. The extent of the infection has remained largely unseen.

Our study is the first to show unequivocally that influenza has a significant impact on proportion of deaths in a tropical country like Singapore. The estimated excess deaths, while less than that observed in subtropical and temperate countries, still constitutes a substantial problem. As influenza-associated deaths are largely preventable through vaccination and the judicious use of antiviral drugs, our findings can influence the public health management of this disease.

We developed 6 negative binomial regression models to examine the relationships between proportion of deaths and the respiratory viruses, namely, influenza A virus, influenza B virus, and respiratory syncytial virus (RSV) (Table 3). The models were written as follows: