Influenza-associated Deaths in Tropical Singapore

We used a regression model to examine the impact of influenza on death rates in tropical Singapore for the period 1996–2003. Influenza A (H3N2) was the predominant circulating influenza virus subtype, with consistently significant and robust effect on mortality rates. Influenza was associated with an annual death rate from all causes, from underlying pneumonia and influenza, and from underlying circulatory and respiratory conditions of 14.8 (95% confidence interval 9.8–19.8), 2.9 (1.0–5.0), and 11.9 (8.3–15.7) per 100,000 person-years, respectively. An estimated 6.5% of underlying pneumonia and influenza deaths were attributable to influenza. The proportion of influenza-associated deaths was 11.3 times higher in persons age >65 years than in the general population. Our findings support the need for influenza surveillance and annual influenza vaccination for at-risk populations in tropical countries.

Influenza virus infections cause excess illness and deaths in temperate countries. In the United States, influenza is responsible for 50 million illnesses and up to 47,200 deaths annually.

However, little is known about the impact of influenza on death rates in tropical regions, where the effect of influenza is thought to be less. In subtropical Hong Kong, deaths from underlying pneumonia and influenza attributable to influenza were estimated to be 4.1/100,000 population per year, higher than the rate (3.1/100,000) reported in the United States.

In tropical Singapore, influenza viruses circulate year round, with a bimodal increase in influenza incidence observed in April–July and November–January. Respiratory syncytial virus (RSV) is also associated with excess deaths. Methods
National Influenza Viral Surveillance

Influenza virus surveillance is carried out throughout the year and has been instituted in Singapore since 1973. We obtained monthly data on influenza A and B viruses and RSV from the WHO-designated National Influenza Centre in Singapore from January 1996 to December 2003. RSV was detected by immunofluorescence tests and virus isolation. Influenza viruses were identified by direct antigen detection with immunofluorescence techniques, serologic tests with complement fixation, and virus isolation. The National Influenza Center provided aggregated data for this study, i.e., monthly numbers of total respiratory specimens tested for influenza virus, positive influenza test results, and influenza virus isolates by subtype, as well as monthly RSV data.

Mortality Data
Three death outcomes were analyzed: underlying pneumonia and influenza (P&I) deaths (ICD-9: 480–487), underlying circulatory and respiratory (C&R) deaths (ICD-9: 390–519), and all-cause deaths (ICD-9: 000–999).
We first applied 6 negative binomial regression models to the monthly number of deaths and monthly proportions of positive influenza virus and RSV tests, to examine the relationships between mortality and the respiratory viruses (namely, models. We also attempted to estimate the excess number of deaths from the viruses.

We estimated the influenza-associated mortality fraction by dividing the number of excess deaths (the difference between observed and expected deaths) by the number of observed deaths, when the proportion of positive influenza results was set to 0 in model 6. The number of excess deaths attributable to influenza was then derived by multiplying the total number of deaths in each mortality category by the respective influenza-associated mortality fraction.

Results
From January 1996 to December 2003, 57,060 specimens were tested for influenza virus, and 51,370 were tested for RSV. 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 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.

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. 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, i.e., first fitting each of the viruses into separate models, then adjusting for 1 of the other 2 viruses (models 4, 5), and finally, adjusting for all viruses in a single model (model 6). 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). 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, 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 6 compares the excess deaths observed in our study with that derived from studies in a subtropical and temperate 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 and in the United States, a temperate country.

This figure far exceeds our estimate of 6.5% of underlying P&I deaths attributable to influenza. In Hong Kong and the United States, 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. 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. 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%. 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; the greatest number of influenza-associated deaths were associated with influenza A (H3N2), followed by RSV, influenza B, and influenza A (H1N1) virus. Influenza A (H3N2) virus accounted for 60% and 77% of positive influenza isolates in the United States and Hong Kong, respectively. 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.

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.

Second, the finding that influenza infections account for substantial disease supports our continued investment in strengthening influenza surveillance in our country. An influenza pandemic can be expected to result in far higher attack and death rates than currently observed. 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. Our study is the first to show unequivocally that influenza has a significant impact on proportion of deaths in a tropical country like Singapore.