Trends for Influenza-related Deaths during Pandemic and Epidemic Seasons, Italy, 1969–2001

During epidemics, excess deaths were similar in amplitude and time across 3 regions.

I n Europe and the United States, the geographic pattern of infl uenza epidemics has been studied extensively, yet mostly at the national level with few local studies (1)(2)(3)(4)(5)(6). Description of local infl uenza patterns can contribute to understanding of transmission and seasonality, which are infl uenced by factors such as demographic differences, climatic variability, and virus virulence.
Age patterns and geographic trends for infl uenza are commonly assessed by using data on infl uenza-related deaths, which are indirectly quantifi ed by using statistical methods to estimate seasonal increases in death from pneumonia and infl uenza (P&I) or all causes (AC) (7)(8)(9)(10)(11). This approach has shown that age-specifi c infl uenza death patterns vary according to whether the infl uenza season is epidemic or pandemic. During epidemic seasons, proportion of infl uenza-related deaths is greatest among persons >65 years of age, whereas during all 3 infl uenza A pandemics in the 20th century, persons in this age group accounted for a lower proportion of infl uenza-related deaths in the United States (12) and Europe (8,13).
Although patterns of infl uenza-related deaths have been investigated in many countries (14)(15)(16)(17)(18), few studies have focused on southern Europe. With regard to Italy, these methods have been applied only to death data for elderly persons during 1970-2001 and only at the national level (19). Our objective was to use the above-described approach to assess age patterns and geographic trends for infl uenza-related deaths in Italy; our focus was on differences between epidemic and pandemic seasons.

Death and Population Data
We obtained the monthly number of deaths caused by P&I (9). We calculated the annual number of persons in each age group and the monthly number of deaths per 100,000 population for each age group and standardized these to 30.4-day months.

Virologic Surveillance
To determine which infl uenza viruses were circulating each season, we reviewed publications listing viral subtypes identifi ed in Italian laboratories (21)(22)(23). For the most recent years (1999-2001), we obtained these data from the Italian National Infl uenza Center, which has performed virologic surveillance since 1999.

Statistical Analyses
To estimate age-specifi c excess deaths (an indirect measure of death attributable to infl uenza) from P&I and AC for the 32 infl uenza seasons, we applied a Serfl ing-type regression model to monthly time series of deaths (7,9). As described in previous studies (9,19), we removed the seasonal trend from the time-series data (de-trended) by fi tting a smooth spline function to the average death rates in summer (June-August). Then, we applied a seasonal regression model to the de-trended series, excluding values for December-April, to model the expected mortality rates in the absence of infl uenza activity. Monthly mortality rates were calculated as the observed minus the predicted mortality rates for all epidemic months. We identifi ed epidemic months by applying the above-mentioned procedure to deaths coded specifi cally as infl uenza (ICD-8 code 470-474 and ICD-9 code 487). We defi ned epidemic months as those winter months for which infl uenza-specifi c mortality rates exceeded the upper 95% confi dence limit of the seasonal model.
Seasonal excess deaths were estimated as the sum of monthly excess deaths, after back-adjusting for the true month length and removing the spline transformation. The model was applied to P&I and AC mortality rates separately for each age group. We achieved an excellent fi t for all age groups. All model terms included were statistically significant (p<0.0001), but additional terms were not (p>0.05).

Age Patterns and Geographic Trends
To determine whether variations in age structure biased the geographic comparisons, we generated excess mortality rates for each area and age group and standardized them on the basis of the age distribution of the Italian population in 2001 (the year of the most recent Italian census). This permitted a comparison of age-adjusted P&I and AC excess mortality rate estimates across areas.
To compensate for nondemographic differences among areas (e.g., differences in access to healthcare and in coding for cause-specifi c deaths) (24), we also calculated the percentage increase in mortality rates as the excess deaths divided by the baseline deaths in winter (expected deaths), for P&I and AC, separately. This measure has been used successfully in past research (7,8). To estimate correlations of infl uenza-related death across the 3 geographic regions, we calculated the pairwise Spearman correlation coefficients of seasonal estimates for the 32 years considered.
The highest number of excess deaths was found for the 1969-70 pandemic season; no measurable number of excess deaths was found for 5 seasons (1981-82, 1984-85, 1986-87, 1990-91, 2000-01) ( Figure 1). The 27 seasons that had excess P&I and AC deaths had an average of 2.4 epidemic months per season (range 1-4). The infl uenza seasons with higher excess deaths tended to be characterized by a predominance of infl uenza A (H3N2) viruses ( Figure 1). For these seasons, the average excess deaths from P&I and AC (4.5 and 23.4 per 100,000 population, respectively) was 4× higher than that for the 11 seasons in which infl uenza A (H1N1) or B viruses were predominant (0.8 for P&I and 7.4 for AC, per 100,000 population).
For the overall study period, the excess deaths per 100,000 population from AC was 15 for northern Italy, 14 for central Italy, and 22 for southern Italy; from P&I they were 4, 3, and 3, respectively (online Appendix Figure 1, available from www.cdc.gov/EID/content/13/5/ 694-appG1.htm). Also for these 32 years, no statistical differences among the 3 geographic areas were noted for excess deaths from P&I or AC (Kolmogorov-Smirnov test, p = 0.8 and p = 0.9, respectively). Patterns were similar with the percent increase in excess deaths from P&I and AC. The 95% confi dence intervals for estimates for individual seasons were within 6% of given values (Table 1)

Magnitude and Trends of Infl uenza-related Deaths during Pandemic and Epidemic Seasons, by Age
During epidemic seasons, most infl uenza-related deaths at the national level (84%) occurred in persons >65 years of age, for P&I and AC; by contrast, during the 1969-70 infl uenza A (H3N2) pandemic season, deaths markedly affected all age groups, especially the 45-64 group.
In Italy the proportion of excess deaths from AC in persons <65 years of age was 3-fold higher during the pandemic season than during all other epidemic seasons. In particular, when the pandemic season was compared with the season with the second highest number of deaths (1974-75), the number of infl uenza-related deaths was 7× higher for persons 0-14, 4× higher for persons 15-44 and 45-64, and 2× higher for persons >65 years of age. Similar results were obtained for all 3 geographic areas ( Table 2). The number of excess deaths from AC during the infl uenza A (H3N2) pandemic season was 1-to 9-fold higher in Italy than in other European countries (France, England, and Wales), in North American countries (United States, Canada), and in Asian countries (Japan, Australia) ( Table 3).

Discussion
This study showed a high level of correlation in the amplitude of infl uenza epidemics (i.e., peaks in rates were similar) in the 3 Italian regions during a 32-year period spanning epidemic and pandemic seasons. The analysis of local infl uenza-related death patterns did not show differences in mean mortality rates among geographic areas These fi ndings are consistent with the high level of synchrony found in other area-level studies in Europe and in the United States (1,2,5,6).
The fi rst season analyzed was the 1969-70 pandemic season. In Italy, as in other European countries (8), the pandemic season was more destructive in the second season of circulation of infl uenza A (H3N2) virus (i.e., in 1969-70), 1 year after the pandemic strain was fi rst introduced to Italy (25-27). The pandemic season seems to have had a greater effect in Italy; excess mortality rates were estimated to be 38 (20,000 deaths) for P&I and 107 (57,000 deaths) for AC. These unexpectedly large excess mortality rates were 3-fold higher than that in the United States and 1-fold higher than those in other European countries. The increase in percentage of deaths reduced but did not eliminate these differences. However, the percentage of deaths in persons <65 in Italy (29%) was lower than the percent-  age in that age group in the United States (34%) but similar to the percentages in other European countries, especially France (27%) ( Table 3). Future studies could address these differences in numbers of deaths that may stem from underlying differences in baseline mortality rates or perhaps in infl uenza transmission. During the pandemic seasons, compared with epidemic seasons, the relative increase in mortality rates was lower for elderly than for younger persons in Italy, confi rming that during pandemics, children and young adults have a greater relative risk for death than the elderly (12). A possible explanation is the partial immune protection of elderly persons who may have been exposed before 1891 to H3 antigens (28), whereas persons born after 1891 would not have been exposed to these antigens.
Several limitations should be mentioned. First, deaths from P&I were not always confi rmed by laboratory methods, which could have resulted in misclassifi cation of deaths. However, patterns of death from P&I were very similar to those from AC, which are not subject to this bias. A second limitation was that demographic and nondemographic differences could have biased the geographic com-parison. However, we performed age standardization and calculated the percentage increase in deaths over the winter baseline, which reduces baseline differences in deaths, unrelated to infl uenza.
A third, more critical, caveat stems from the surveillance of viral subtypes. The proportion of laboratory-confi rmed cases has only been available since 1999 (i.e., for only 2 years of the study period). However, in the latest years the proportion of laboratory-confi rmed cases was ≈15% (range 11%-28%), with >3,000 samples tested (29), which could have affected the accuracy of infl uenza diagnoses over time and perhaps across regions. For example, during the 1998-99 season, when infl uenza B viruses were predominant, the death rate was high compared with that found for the other infl uenza B seasons, which indicates that the characterization of viral subtypes is limited by the geographic distribution of the sites participating in virologic surveillance.
Our fi ndings suggest that infl uenza epidemics are strongly correlated in amplitude across the 3 regions of Italy. Different factors have been reported to drive the spatial and temporal correlations of epidemics: population move-  ments and environmental factors such as climate or weather conditions (5,30,31). Although population movements are assumed to play a key role in the global spread of infl uenza epidemics, they have been quantifi ed only in the United States (5,32,33). The role of environmental factors and differences in circulating viruses among the geographic areas in Italy also remains to be clarifi ed.
In conclusion, our results suggest that geographic synchrony of infl uenza in Italy is high and that for persons <65 years of age, death rates are likely to be substantially elevated in a future pandemic as compared with other epidemic seasons. Our study adds to others that have found strong spatiotemporal patterns in illness and death from infl uenza in the United States, France, Australia, and across Europe (1,3,5,34). Such results provide insight for the Italian pandemic preparedness and response efforts (35,36) and could be used in mathematical models for infl uenza spread at the national level.