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## Revista de Saúde Pública

*On-line version* ISSN 1518-8787

### Rev. Saúde Pública vol.39 no.1 São Paulo Jan. 2005

#### http://dx.doi.org/10.1590/S0034-89102005000100010

**ORIGINAL
ARTICLES**

**Impact
of influenza vaccination on mortality by respiratory diseases among Brazilian
elderly persons**

**Priscila Maria
Stolses Bergamo Francisco ^{I}; Maria Rita de Camargo Donalisio^{I};
Maria do Rosário Dias de Oliveira Lattorre^{II}**

^{I}Departamento
de Medicina Preventiva e Social. Faculdade de Ciências Médicas.
Universidade Estadual de Campinas. Campinas, SP, Brasil

^{II}Departamento de Epidemiologia. Faculdade de Saúde Pública.
Universidade de São Paulo. São Paulo, SP, Brasil

**ABSTRACT**

**OBJECTIVE: **Respiratory
diseases, especially infectious ones, are becoming increasingly representative
in the morbidity and mortality patterns of elderly persons. The aim of the present
study was to analyze trends in the mortality by respiratory diseases and to
observe the impact of influenza vaccination on mortality rates.

**METHODS: **The study was carried out between 1980 and 2000. Subjects were
elderly persons living in the State of São Paulo, and mortality data
were obtained from the Mortality Information System of the Brazilian Ministry
of Health. This is an ecological time-series study. We analyzed the time trends
of standardized mortality rates by infectious diseases, according to age group
(60-64, 65-69, 70-74, 75-79, and 80+ years) and sex, using polynomial regression.
We estimated confidence intervals for the mean expected response in the years
following the intervention.

**RESULTS: **Rates increased for both sexes among the elderly population.
After the intervention, we observed a declining trend with respect to mortality
indicators. For older males, the mean rate in the 1980-1998 period was 5.08
deaths per thousand men, with a linear, non-constant increase of 0.13 per year;
in 2000, the rate observed was 4.72 deaths per thousand men. The mean annual
rate among women over 60 years was 3.18 deaths per thousand women, with a non-constant
increase of 0.08 per year; in 2000, the rate observed was 2.99 deaths per thousand
women. There was also a significant reduction in mortality rates in all age
groups.

**CONCLUSIONS: **Data indicate the importance of respiratory diseases among
the elderly population and suggest that specific protection against influenza
has a positive effect on the prevention of mortality due to these diseases.

**Keywords: **Aged.
Aging health. Respiratory tract diseases, mortality. Influenza vaccine. Mortality,
trends.

**INTRODUCTION**

Respiratory tract diseases, infectious ones especially, are an
important cause of morbidity and mortality among the elderly
population worldwide.^{4,7,10}

In Brazil, data from the *Sistema de
Informações sobre Mortalidade* (Mortality
Information System) indicates the growing importance of hospital
admissions and deaths due to respiratory diseases among the
elderly, even considering the ageing of the
population.^{6} In 1995, in São Paulo State, the
proportional rate of mortality due to pneumonia among persons
older than 70 years was 9%, with a specific mortality of 594.03
per 100,000 population. In the 60-70 years age group, 1,676
deaths were registered, with a proportional mortality of 4.75%
and a specific rate of 101.39 per 100,000
population.^{6,20}

Influenza epidemics happen more frequently during winter. Such
epidemics account for a mean 20,000 yearly deaths in the United
States.^{21} Influenza outbreaks are associated with
increases in hospital admissions and deaths, mostly due to
complications of the disease and to chronic subjacent
ilnesses.^{2,3}

Vaccination has been the major method for preventing influenza
and its more severe complications. When vaccine composition
coincides with circulating viral strains, vaccine efficacy can be
as high as 70-90% in healthy adults. Among persons older than 60
years, however, efficacy falls to the 30-40%
range.^{2,8,10}

Even considering the greater physiological and immunological
susceptibility of elderly persons to infection, influenza
vaccination has a positive effect on the prevention of severe
influenza, pneumonia, and mortality in this risk
group.^{4,8-10,17}

The aim of the present study is to analyze trends in mortality by respiratory diseases among elderly persons and to observe the impact of influenza vaccination on mortality indicators.

**METHODS**

This is an ecological
time-series study, based on the mortality records of the *Sistema de Informações
sobre Mortalidade do SUS* (Mortality Information System of the Brazilian
Unified Healthcare System - SIM/SUS) for São Paulo State, between the
years 1980 and 2000. Estimates of the elderly population living in the State
were obtained from the *Instituto Brasileiro de Geografia e Estatística*
(Brazilian Institute for Geography and Statistics - IBGE).^{*}
Elderly persons were divided into five age groups: 60 to 64 years, 65 to 69
years, 70 to 74 years, 75 to 79 years, and 80 years and older.

We analyzed diagnoses referring to pneumonias and influenza
(until 1997, ICD-9 classifications 480-483 and 485-487 were
used), bronchitis (490 and 491) and chronic airway obstruction
(496). For 1998, ICD-10 classifications were used (J10 to J15,
J18, J22, J40 to J42, and J44). These classifications have been
used by a number of authors attempting to measure the impact of
influenza on the community.^{7,17,22} We chose to include
chronic obstructive pulmonary disease (COPD) in light of its
intimate relationship with pulmonary infection among the
elderly.^{22}

We calculated standardized mortality rates using the harmonic
mean of the populations in the 1980-1998 period as a standard
population.^{13}

We calculated the annual ratio between standardized
male/female rates and evaluated changes in this relationship
throughout the years using simple linear regression models. We
considered p-values above 0.05 as indicative of an absence of
change in this ratio within the studied period.^{11}

Initially, we built scatter plots opposing mortality rates and
calendar years in order to better visualize the function that
might better express the relationship between these variables.
Based on the functional relationship observed, we estimated
polynomial regression models, which, in addition to being
statistically powerful, are easy to elaborate and
interpret.^{12,15}

During the modeling process, we considered the rates of
mortality due to selected diagnoses as the dependent variable (Y)
and calendar years as the independent variable (X). The
transformation of variable *year* into variable
*centralized year* (year minus the midpoint of the time
series) was required, since, in polynomial regression models, the
terms in the equation are often self-correlated.^{15}

As a measure of the model's precision, we used the coefficient
of determination (r^{2}). We verified adherence to normal
distribution using the Kolmogorov-Smirnov test; all series were
normally distributed. Residual analysis confirmed the assumed
homocedasticity of the model.^{11,15}

We tested the simple
linear regression model (*U=b _{0}+b_{1}C*)
and then second degree (

*U=b*), third degree (

_{0}+b_{1}C+b_{2}C^{2}*U=b*+

_{0}+b_{1}C+b_{2}C^{2}*b*), and exponential (

_{3}C^{3}*U=e*) models. In light of the statistical similarity of two of the models, we chose that of lower degree. We considered as significant trends whose estimated models obtained p-values below 0.05.

^{b0+b1C}^{11}

In these models,
*b _{0}* is the mean yearly rate,

*b*is the linear effect coefficient (speed), and

_{1}*b*is the quadratic effect coefficient (acceleration). We considered 1989 as the midpoint of the time series.

_{2}For some of the
age groups, variations in the series were smoothed using a moving average centered
on three terms. In this process, the smoothed rate of year *i* (*Y _{ai}*)
corresponds to the arithmetic mean of the coefficients of the previous year
(

*i-1*), of the year itself (

*i*) and of the following year (

*i+1*):

Based upon the models we estimated using data from the 1980-98 period, we calculated confidence intervals for the mean expected response, i.e., the mortality rates referent to the two subsequent years (1999 and 2000). In addition to models and confidence intervals, we also present the rates obtained after vaccination.

We calculated mortality rates and generated graphs using Microsoft Excel (Version 7.0 for Windows 95) spreadsheets. We performed trend analyses using SAS (Statistical Analysis System) Version 8.0 software.

**RESULTS**

Standardized mortality rates by selected respiratory diseases increased among the population 60 years and older in São Paulo State between 1980 and 1998. This was true for both men and women (Figure 1). Among men, the mean rate in the period was 5.08 deaths per thousand men, with a linear non-constant increase of 0.13 per year. Among women, the mean annual rate was 3.18 deaths per thousand women, with a non-constant increase of 0.08 per year. The male to female standardized mortality rate ratio did not change with time (p=0.338). This ratio remained in average 1.55 men for each woman, showing the greater importance of respiratory diseases among men.

An analysis of trends in separate age groups showed that, for men and women alike (Table 1, Figure 2), the older the age group, the greater the magnitude of the annual increment.

The annual linear
non-constant increase (*b _{1}*) was
greater among older males. In the 75-79 years age group, this increase was as
much as three times that of the female population in the same age group. In
both sexes, the population 80 years and older is distinguished by the magnitude
of the mean annual rate (

*b*) (Table 1).

_{0}An analysis of mortality rates after the vaccine intervention shows that, in 1999, there was a significant reduction in these rates among women in the 70-74 years age group. In 2000, there was a steep decline in rates among men in the 70-74 and 80+ years groups, along with a significant reduction in rates among the female population in all age groups (Table 2).

For the population over 60 years as a whole, without distinction of age group, standardized mean mortality rates by selected respiratory diseases fell within the expected interval for both male and female populations in 1999. In 2000, however, there was a significant reduction in rates, i.e., rates fell below the lower limit of the confidence interval (Table 2, Figure 3).

Among the male population, the absence of impact of vaccination in the years following the intervention was observed only in the 60-64 years group, whereas the remaining groups showed a decreasing trend. In the female population, the decreasing trend is clearer, especially among the 70-74 and 75-79 age groups (Table 2).

**DISCUSSION**

Mortality information registries cover the vast majority (95%)
of deaths in São Paulo State, and thus have sufficient
explanatory power for the construction of satisfactorily reliable
mortality indicators.^{18}

Ecological studies of time series are capable of showing the
evolution of disease rates in a given geographically defined
population, as well as of evaluating the impact of healthcare
interventions, being, therefore, an adequate design for examining
trends in mortality rates with time.^{5,11,14}

In the present study, we found that the trends in mortality by
selected respiratory diseases showed a real increase between 1980
and 1998 in São Paulo State, even after controlling for
the age composition in the period by using standardized rates.
However, the increase in such indicators was asymmetric with
respect to sex and age groups, with a greater annual increase
among males and older groups. Respiratory diseases were confirmed
as an important cause of death among the elderly, corroborating
the findings of other authors.^{6,7,19}

Generally speaking, mortality rates by selected respiratory diseases usually differ between the sexes in the age groups studied, but behave similarly in terms of trends throughout the period.

The peaks in mortality in 1988, 1990, and 1994/95, seen in Figures 1 and 2, could not be explained by the present study. Some hypotheses can be offered for later investigation, including the greater circulation of virulent strains, the circulation of other etiological agents, and climactic factors.

The reduction in mortality rates following vaccine implementation may be due to reductions in the number of cases or in the incidence of more severe cases after vaccination, to the greater sensitivity of healthcare services in the early diagnosis of severe pulmonary conditions, or to an improvement in the specific treatments administered.

When evaluating the impact of influenza vaccination, one must
consider also that virus and bacteria of different etiologies may
be involved in respiratory conditions leading to the
hospitalization and death of elderly persons,^{2,3}
especially during cold and dry seasons, this being a worldwide
phenomenon.^{1}

Our data show that mortality rates in São Paulo State
were lower in 2000 for both sexes. Repeated yearly vaccination is
associated with greater levels of immunological protection and
with reduced mortality compared to the first
immunization.^{1,2} Even considering the weak immune
response of elderly persons to vaccination, a perspective study
conducted in the Netherlands in 1994^{8} showed that
vaccination can reduce clinical and serological influenza by
one-half in non-institutionalized elderly persons.

Nichol et al^{16} (1994), in a cohort study carried
out in the United States between 1990 and 1993 with 25 thousand
subjects aged 65 years and older, found an impact on the
prevention of hospital admissions due to pneumonia and influenza
(48% to 57%) and to all acute and chronic respiratory conditions
(27% to 39%). In a meta-analysis study, Gross et al^{9}
(1995) confirmed the reduction in respiratory diseases, hospital
admissions, and death among institutionalized elderly persons
following vaccination.

The results of the present study also indicate a reduction in
mortality by selected respiratory diseases, varying according to
sex and between different age groups. Nevertheless, a number of
factors must be considered when evaluating the protective effect
of influenza vaccination, including vaccine immunogenicity, the
agreement between the vaccine's antigen content and circulating
viral strains,^{8,9} the prevalence of chronic diseases
in the community, and previous exposure to the Influenza virus.
These factors vary between the seasons, as well as between
different regions.

Apart from these considerations, it is likely that the investments in healthcare directed towards specific anti-influenza immunization of elderly persons in the State of São Paulo are having a positive effect on this populational segment.

In the present study, we sought to draw a general picture of the behavior of mortality due to respiratory tract diseases among elderly persons in the last decades. Continuous evaluation of this trend in years to come may provide more consistent evidence of the impact of successive wide-coverage vaccination campaigns on the Brazilian elderly population.

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**Correspondece to**

Priscila Maria Stolses Bergamo Francisco

Caixa Postal 6111

13083-970 Campinas, SP, Brasil

E-mail: priscila@nepo.unicamp.br

E-mail:iagopric@dglnet.com.br

Received on 3/2/2004.
Approved on 8/6/2004

Based on the Master's dissertation presented at the *Faculdade de Ciências
Médicas da Universidade Estadual de Campinas* in 2002.

* Information obtained online from URL: < http://www.datasus.gov.br/cgi/ibge/popmao.htm>