Human Vaccines 7:10, 1037-1047; October 2011; © 2011 Landes Bioscience
ReseaRcH papeR ReseaRcH papeR
*Correspondence to: Gabriela Tannus Branco de Araujo ; Email: gabriela.tannus@axia.bio.br Submitted: 03/21/11; Revised: 07/05/11; Accepted: 07/11/11
DOI: 10.4161/hv.7.10.15987
Introduction
Streptococcus pneumoniae infections are a major cause of illness and death with about 1.6 million cases of fatal pneumococcal disease occurring worldwide annually, mostly in infants and the elderly.41 Streptococcus pneumoniae can cause both non-invasive
and invasive infections.1 In adults and elderly, non-invasive
dis-ease can manifest as pneumonia, whereas bacteremia and men-ingitis are the most common invasive pneumococcal diseases.1
Although, pneumococcal disease can affect all age groups, the elderly and immunocompromised are at highest risk from infec-tion.2 Moreover, since the introduction of pneumococcal
conju-gate vaccination in children in 2000, the epidemiology of invasive pneumococcal disease (IPD) has changed with the reported bur-den of IPD now highest in the elderly population. In the US, the annual incidence of IPD in those ≥65 years of age was recently
Vaccination of adults aged 60 years and older against Streptococcus pneumonia is not recommended in Brazil. The 23-valent polysaccharide pneumococcal vaccine (ppV23) is only available for institutionalized persons or with underlying diseases despite the substantial medical and economic burden related to pneumococcal infections in adults over than 59 years. The study aimed at evaluating the cost efectiveness of implementing a large ppV program in this population.
This analysis was performed using a static decision tree model. Demographic and epidemiological data were ob-tained from Brazilian oicial sources and international literature. economic data were obob-tained from a study performed in 2007 in a public and a private hospital located in sao paulo. Vaccination was assumed to protect for 5 years with 60% efectiveness against bacteremic pneumococcal pneumonia (Bpp) and 21% efectiveness against non bacteremic pneu-mococcal pneumonia (NBpp). Deterministic and sensitivity analyses were performed.
The pneumococcal polysaccharide vaccination saved 5,218 life year gained (LYG). The vaccination program was found to be cost efective in the social security and public health care perspectives with a mean incremental cost-efectiveness ratio of R$10,887 and R$8,281 per LYG respectively. Results were sensitive to the vaccine efectiveness against NBpp, the incidence and case-fatality rate of NBpp. From a societal perspective, ppV23 program for adults 60 and older was found to be cost-saving.
pneumococcal polysaccharide vaccination is clinically and economically favored over the present vaccination strat-egy, in which persons aged over 59 years in sao paulo have not been vaccinated.
Cost-efectiveness analysis of pneumococcal
polysaccharide vaccination from age 60
in São Paulo State, Brazil
Joao Tonolio Neto,1 Gabriela Tannus Branco de araujo,1,2,* anna Gagliardi,1 amanda pinho,3 Laure Durand4 and Marcelo Fonseca1,2
1Federal University of sao paulo; 2axia.Bio consulting; 3sanoi pasteur; são paulo, Brazil; 4sanoi pasteur; Lyon, France
Key words: pneumococcal polysaccharide vaccine, cost-effectiveness analysis, Brazil, elderly
Abbreviations: LYG, life year gained; PPV23, 23-valent polysaccharide pneumococcal vaccine; BPP, bacteremic pneumococcal pneumonia; NBPP, non bacteremic pneumococcal pneumonia; WHO, World Health Organization; GDP, gross domestic product;
QALY, Quality Adjusted Life Year; SUS, Systema Unico de Salud; CAP, Community-Acquired Pneumonia; IPD, Invasive Pneumococcal Disease; CFR, Case-Fatality Rate
reported to be 40/100,000 versus 21/100,000 in children <5 years of age.3 In Europe, there has been a similar shift of the
bur-den of pneumococcal disease to the elderly population.4 Elderly
patients are more vulnerable to infections due to physiological changes associated with aging process, therefore, the risk of an individual to develop pneumonia rises as they grow older. On a yearly basis, approximately one out of twenty persons over the age of 85 will have one episode of pneumonia.5 While in most cases,
the etiological diagnosis of CAP will not have been obtained, the results of a study by Johnstone and co-workers6 showed that in
37% of the cases, Streptoccocus pneumoniae is the causative agent of bacterial pneumonia. In Latin America, S. pneumoniae was demonstrated to be also the most common pathogen implicated in adult CAP, accounting for 35% of cases.7 Consequently,
which has the largest population and the most developed economy (approximately 30% of the Brazilian GDP) of the Brazilian States. Currently, Sao Paulo State offers PPV23 for institutionalized elderly and those with underlying diseases. The aim of this study was to evaluate the health and economic benefits of the PPV23 public funding to the general elderly population in Sao Paulo.
Results
Cost-effectiveness analyses. In the base case scenario where a routine PPV23 vaccination program is implemented in São Paulo State from age 60, vaccination markedly reduced the number of episodes of pneumococcal infections. With a cohort of 3,689,623 individuals, the number of NBPP and BPP cases avoided after 5 years due to pneumococcal vaccination was 12,469 and 2,967 respectively. The number of life years gained (LYG) was 5,218.
The incremental costs related to implementation of PPV23 program in elderly people in São Paulo State was: R$56.8, R$43.2 and R$-5.4 million respectively for scenario 1 using the costs paid by the Brazilian social security SUS, for scenario 2 using the total costs of a public hospitalization, and for scenario 3 taking into account the costs in a private hospital and the absen-teeism costs (Table 1). The averted costs of pneumococcal infec-tions outweighed the costs of a vaccination program in scenario 3. Consequently, the ICER related to a PPV23 vaccination program in São Paulo State in elderly varied according to the scenarios (Table 1): R$10,887 in scenario 1; R$8,281 in scenario 2 and cost-saving in scenario 3 suggesting a return on the investment.
Sensitivity analyses. In the univariate sensitivity analysis, we evaluated the individual effects of epidemiological and vaccina-tion parameters on the cost-effectiveness of the vaccinavaccina-tion strat-egy using the minimum and the maximum of the inputs range (Tables 2–4). As the various inputs should have relatively the same impact on results in each scenario, the univariate sensitivity analysis was performed only on scenario 1 (SUS hospitalization costs). Factors having the greatest impact on ICER were the vac-cine effectiveness against NBPP, the case-fatality rate of NBPP, and the incidence rates of NBPP (Fig. 3).
A probabilistic sensitivity analysis of the cost-effectiveness results using the range or standard deviation of each input (Tables 2–4) is also shown as a cost-effectiveness plane in Figure 2. These results demonstrate that there is a 95% chance that the incremen-tal cost per LYG is contained in the interval R$[6,273; 29,223] for scenario 1 (mean R$13,516); R$[-1,275; 24,653] for scenario 2 (mean at R$10,357), and R$[-76,509; 22,373], for scenario 3 (mean at -R$3,247).
Discussion
Cost-effectiveness evaluations, such as the one described here, are necessary to define population strategies and help decision mak-ers to choose the most relevant options in term of cost/benefit ratio of immunization programs.
In view of the variety of healthcare systems that exist through-out Brazil, the present analysis was performed from three differ-ent scenarios. From the cost study performed in Sao Paulo State, Jackson et al.5 in 2004, 12.5% of the patients over 80 years-old
admitted to hospital for pneumonia die while in the hospital. Resistance of pneumococci to commonly used antimicrobi-als is a serious and increasing problem worldwide, which com-plicates the treatment of infection.8 Antibiotic-resistance causes
an increase in treatment failures and medical costs. Lynch and Zhanel reported in 2009 that worldwide, 15–30% of S. pneu-moniae strains are multidrug resistant (i.e., resistant to ≥3 classes of antibiotics). These investigators also reported that six sero-types (6A, 6B, 9V, 14, 19F, 23F) account for >80% of penicil-lin- or macrolide-resistant S. pneumoniae, worldwide.9 Moreover
in the US, an increase in the isolation of antibiotic resistant 19A strains has been reported, a strain associated with increased inci-dence of IPD.10 Effective immunization against S. pneumoniae is
the most effective method to reduce the impact of pneumococcal infections, including those caused by antibiotic resistant strains. Therefore, physicians and policy-makers have high expectations concerning the value of pneumococcal vaccination of the adults and elderly.
Currently, the pneumococcal vaccine approved in adults is the 23-valent pneumococcal polysaccharide vaccine (PPV23). A growing number of national and international health bodies now recommend pneumococcal vaccination of elderly and at-risk groups. Indeed, PPV23 has been shown to be clinically effective in the reduction of the occurrence of both bacteremic pneumo-coccal pneumonias (BPP) and non-bacteremic pneumopneumo-coccal pneumonias (NBPP).11
The world’s population is progressively aging. This trend is also reflected in Brazilian population where both the proportion of the total population and the real number of elderly people (≥60 years old) have significantly risen for the past few years. Brazilian national statistics data show that the population over 60 years has grown from 8.8% in 1998 to 11.1% in 2008, and should became the sixth largest elderly population in the world by 2020.
In Brazil, presently the public national immunization program recommends PPV23 only for institutionalized elderly, but there is no funding for this vaccination program. As a result, the PPV23 coverage rate in Brazil is low. In fact, data from the Brazilian public health system indicate that only 160,508 doses were used in 2009, which represents a coverage rate of approximately 0.8% if we consider the total demography of adults aged more than 60 in Brazil in 2009. In US, PPV23 has been recommended for all people aged ≥65 years since 1983 and totally financed, and data shows that the coverage increased from 14.1% in 1989 to 60.1% in 2008.12 In the Latin America region, most countries
recommend and finance PPV23 in the general elderly popula-tion considering the health and economic benefit of PPV23. These countries include Argentina, Chile, Ecuador, El Salvador, Mexico, Uruguay, Panama and Venezuela.
diseases, vaccination with PPV23 is again more cost-effective or cost-saving compared to no vaccination strategy among the elderly, considering only direct medical costs.24-27 This economic
benefit increases with age of elderly targeted and vaccination of all individuals above the age 65 years is comparable in terms of cost-effectiveness to many accepted health care interventions.27
The study’s limitations were related to the various inputs used. Firstly, in absence of specific local data, incidence and case-fatal-ity rates were derived from international data. It is likely that the disease epidemiology and health service utilization might be different between US/Europe and Brazil because of differences in prevalent strains, antibiotic resistance within the populations, quality of health care and financial architecture of their respec-tive health-care systems. However, the chosen values were dis-cussed and accepted by local experts to ensure their consistency with the local epidemiology. Moreover, to be sure to not over-estimate the impact of S. pneumoniae in Brazil, we used generally the most conservative value found. Epidemiological data related to pneumonia in Latin America was published just before the finalization of this manuscript.7 These local data were globally
less conservative than those used in the base case and were all included in sensitivity analysis range. Using these data in the SUS base case scenario returned a cost-effectiveness ratio of R$9,709/ LYG. The second limitation is related to the disease costs used in the present analysis. The sample size used to calculate the costs of hospitalization may be considered a limitation. It is enough large for NBPP cost calculation (N = 173 and N = 163 for public and private hospital respectively) but too small for BPP (N = 12 and N = 17 for public and private hospital respectively). Larger stud-ies including larger numbers of patients with BPP will be neces-sary for confirmation. In addition, our analysis considered only the costs of hospitalization and not the outpatient costs and other costs related to pneumococcal infections such as transportation, diet, etc. Including these costs would increase the economic ben-efit of PPV23 vaccination. Thirdly, vaccination costs concerned only vaccine price and transportation. Promotion costs to ensure a high coverage rate also would have been estimated.
three different costs of hospitalization appeared: the lowest cost was that paid by SUS (R$462 for NBPP and R$830 for BPP), the intermediate cost was the amount actually paid by the public hos-pital (R$1,992 for NBPP and R$5,103 for BPP) and the highest was the cost of hospitalization in the private hospital (R$19,764 for NBPP and R$33,320 for BPP). Evaluation of cost-effective-ness ratios using the SUS and the public healthcare costs allowed coverage of the public perspective on the whole. In scenario 3, integrating larger costs (private hospitalization costs and absen-teeism costs) allowed the inclusion of persons who used a private health care system, i.e., 46% of the total elderly population e.g., persons using a managed care organization.
In many developed countries, acceptable cost-effectiveness thresholds have been defined for planning healthcare policies. However, no such definition is available in Brazil, an emerging country facing limited healthcare resources. The World Health Organization (WHO) has suggested an acceptable cost-effective-ness threshold as one that is less than three times the yearly gross domestic product (GDP) per capita and an excellent cost-effec-tiveness threshold as one that is less than one times the yearly GDP per capita.13 In Brazil, where the yearly GDP per-capita
was R$13,720 in 2007 14 at the time of the analysis, an
interven-tion with a cost-effectiveness of up to R$41,160 may therefore be considered as cost-effective by WHO standards. Consequently, in the present analysis, PPV23 vaccination program from age 60 was either extremely cost-effective (inferior to R$13,720 for social security and public health care perspectives) or cost saving (for societal perspective), depending on the scenario considered. This evidence was in favor of a routine PPV23 vaccination pro-gram that would be offered by the government to all adults 60 years of age and older.
Using pessimistic values in deterministic sensitivity analyses, all ICER also were found to be below the WHO cost-effectiveness threshold of R$41,160 (3 times the GDP per capita). Specifically, the ratio with an effectiveness of PPV23 against NBPP at 0% was R$33,342 which is still under this limit. This means that even with no effectiveness against NBPP, a routine PPV23 vaccination program in elderly in Sao Paulo is a cost-effective option, which is in line with the other published studies in reference 15–17. In addition, in the probabilistic sensitivity analyses, taking into account all uncertainties around parameters and the thresholds of R$41,160, there were a probability of 99.8%, 100% and 100% that the funding of PPV23 vaccination is cost-effective compared to the current situation with no vaccination for scenarios 1, 2 and 3 respectively. If we considered the threshold of R$13,720, the prob-ability would decrease to 60.9%, 74.8% and 87% respectively.
Our results are consistent with those of numerous cost-effec-tiveness analyses performed in US and Europe. As Postma et al.18
concluded in their literature review published in 2003 on the basis of the international literature in the elderly, the cost-effectiveness for the prevention of invasive pneumococcal disease, consider-ing only direct medical costs, varies from cost-savconsider-ing to more than €30,000 per LYG or per QALY.15,19-23 These results would
justify local implementation of a pneumococcal polysaccharide vaccination program from a pharmacoeconomic point of view. In studies concerning both invasive and non invasive pneumococcal
Table 1. Base case results per perspective of the cost-effectiveness analysis of polysaccharide pneumococcal vaccination comparing the non-vaccinated (NV) and vaccinated (V) cohort
Scenario 1 Scenario 12 Scenario 13
NV V NV V NV V
Costs in million R$
cost of NBpp infections 9 8.1 38.7 34.8 198.4 178.6
cost of Bpp infections 6.4 4.4 39.6 27 141.4 96
Vaccination - 59.8 - 59.8 - 59.8
Cost reduction thanks to vaccination, in million R$ (million US$, 1 US$ = R$ 17,955)
Incremental costs (no vaccination-
vaccination)
56.8 43.2 -5.4
Cost effectiveness analysis
analyses (with the most pessimistic incidence values for NBPP and BPP, ICER stayed cost-effective) and regarding a recent anal-ysis performed in US that included this indirect effect.22
Within the Brazilian population aged more than 59 years, a large proportion is still economically active. Indeed 18.8% of people older than 60 years-old are still employed.31 For this
rea-son, the analysis undertaken from the societal perspective was relevant in Brazil. Prevention strategies such as vaccination are extremely important to maintain the economic activity of adults aged 60 and older to maintain functional independence with advancing age. The aging of the population increases health costs and elderly people with acute diseases often require more complex health examinations and treatments. Elderly patients admitted for longer treatments are also much more susceptible to functionality loss. Therefore, a patient with pneumococcal dis-ease can become economically inactive and incur high expenses with the initial disease and any subsequent sequelae.
Methods
Model specification and parameters used for the analysis. A decision-analytic model was developed by Ezus Group (Lyon, France) to estimate the effectiveness and cost-effectiveness of a polysaccharide pneumococcal vaccination program in adult pop-ulation (more than 18 years old) with a possibility to focus the Over the last decade, the importance and benefit of
pneumo-coccal polysaccharide vaccination in adults has been reviewed due to the decrease of pneumococcal incidence rate in countries with a high coverage rate of pneumococcal conjugate vaccines (PCV) in infants. Indeed, in the US, where the coverage rate of the 7-valent pneumococcal conjugate vaccine (PCV7) in children has achieved 80–90% over the last 6 years, herd immunity has globally led to a 38% decrease in the rate of IPD among elderly.28
However, an increase of the incidence of IPD in adults and elderly caused by non-PCV serotypes has been noted in many settings (“serotype replacement”); these increases range from minimal to substantial29 and could reduce the benefits of the PCV
vac-cination.30 Subsequently, PPV23 is the only protection available
against these non-PCV7 serotypes at this time. Our analysis did not take into account the diminution of pneumococcal infec-tions incidence in adults that could result thanks to the use of the 10-valent pneumococcal conjugate vaccine (PCV10), now rou-tinely used in Brazil. The use of PCV10 in Brazil is recent and to date no herd immunity data are available. The future effect of a PCV10 program in Brazil will depend on coverage rates, serotype prevalence and serotype replacement inherent to PCV would not likely to be observed before the program is well established with a high vaccine coverage rate. However, even including an indirect effect of PCV, we can still expect cost-effectiveness results for PPV23 vaccination program regarding our univariate sensitivity
Table 2. epidemiological data used in the model
Item Base case value Range Sources/Comments
NBpp incidence
(per 100,000) 706 425–1099
ament et al. 2000;18 754 hospitalized cap per 100,000 person-years in 65+.
NBpp incidence rate calculated using following assumptions: -40% of cap are pneumococcal pneumonia -80% of pneumococcal pneumonia are NBpp
-NBpp and Bpp hospitalization rates in Brazil are 18.6% and 95.5% respectively Minimum and maximum values also from ament et al. 2000 18 (451 and 1,167 for
incidence of hospitalized pneumonia in France and sweden respectively)
Bpp incidence (per 100,000) 54.5 24–85 WHO WeR 2008: IpD Range in 65+ in industrialized countries.
41 Mean value
calculated from the range
NBpp hospitalization rates 18.6% 10%–30%
Based on the assumption that the
probability of hospitalization varies from 10% for 60–70 yo people to 30% for people more than 70 (mean weighted by sao paulo population size)
Bpp hospitalization rates 95.5% 90–100%
Vila-corcoles et al. 2006;37 found that 4.5% of IpD cases were not hospitalized
(1/22 cases) in spain (hospitalization rate of 95.5%). Range assumed considering the severity of the disease.
NBpp case fatality rates 12.7% 3.6%–18%
Mean from Vila-corcoles 2009 (spain, 65+) 66
Low value from Jackson 2004 (Us, 65+) {Jackson, 2004;6/id}
High value from Luna 2000 (argentina, 18+) 43
Bpp case fatality rate 26.6% 11%–44%
Fedson and Musher in 2004; 1 reported an IpD cFR range from 11% to 44% (mean = 26.6%, 16 studies included) in elderly in developed countries
Middleton 2008 42 reported an IpD cFR of 14.3% for 65–74 yo, 21% in 75–84 yo
and 30.8% for 85+ yo in Us
WHO WeR 2008 41 says that Bpp cFR may reach 30–40% in elderly and in
indus-trialized countries
effectiveness of PPV23 against invasive pneumococcal disease and therefore BPP is largely proven whereas the vaccine effective-ness against NBPP is debatable.
•ThepatientcannotdevelopaBPPandaNBPPinthesame
one year period. However, a patient with a BPP or NBPP event in one period can develop an event in a subsequent period.
•Theevent“DeathduetoothercausesthanBPPorNBPP”is
independent of all events.
•Deathofpatientsoccursuniformlyover1yearperiod. •Everypatientwithapneumococcalinfection(BPPorNBPP)
generates the same costs if they survived or not.
For each cohort, the number of life years experienced and the costs of pneumococcal infections were calculated and compared. To compare the costs and health consequences of PPV23 vacci-nation versus non-vaccivacci-nation, an incremental cost-effectiveness ratio (ICER) was estimated as the incremental cost per life year gained (LYG). Since no health utility data are available in Brazil, the quality-adjusted life year (QALY) due to vaccination was not evaluated. The concept and methodology of cost-utility analyses is not well established in Brazil, the evaluation of LYG can be considered an initial approach in the analysis of cost-utility. analysis on an age-based or a risk-based program. This model also
has been used in Turkey69 and Korea.33 Two identical cohorts,
either vaccinated with the PPV23 or non-vaccinated (since the coverage rate in Brazil in this population is closed to zero), were designed to reflect the São Paulo State elderly population (≥60 years old). Each cohort was followed during a 5-year period divided into 5 periods of 1 year to provide a conservative estimate of the total duration of PPV23 effectiveness. Infections due to S. pneumonia were classified as either BPP or NBPP, which com-prise around 90% of pneumococcal-related outcomes that are preventable by PPV23 vaccination.1 The structure of the model is
illustrated in Figure 1.
Model assumptions are described below:
• Individuals in the “vaccinated” group receive one dose of
PPV23 at the beginning of year 1 according to vaccine coverage rate. They can receive a second dose at the beginning of year 6 if revaccination is considered (not the case in the present study).
• For individuals vaccinated and immunized, the vaccine
effectiveness decreases over the five periods.
• One person vaccinated and immunized against NBPP is
automatically considered immunized against BPP. Indeed, the Table 3. Vaccination data used in the model
Item Base case value Range Sources/Comments
Vaccine effectiveness
against NBpp 21% 0–42%
Vila-corcoles, 2009 (42% in 50+ against NBpp);10 Vila-corcoles, 2006 (39% in 65+
against NBpp and 21% against all cap),37 Maruyama, 2010 (64% against
pneumococ-cal pneumonia and 45% against all cap in nursing home residents);55 Huss, 2009
(11% in elderly and chronically ill patients against all cap from 11 RcT but high het-erogeneity)54
Vaccine effectiveness
against Bpp 64% 44–80%
Mooney, 2008 (61.70% in elderly);51 Vila-corcoles, 2010 (72% in 60+);47 Jackson, 2003
(44% in 65+);52 Domingez, 2005 (70% in all elderly);50 shapiro, 1991 (46% to 80% in
65+);53 Butler, 1993 (75% in 65+)48
Waning rate each year 10% 0–20% sisk, 1997;
38 smith, 2008;21 Middleton, 2008,42 Merito, 2007;23 postma, 2001;20
shapiro, 1991;53
Vaccination coverage rate 60% - Hypothesis in case of ppV-23 100% funding by public system for elderly
Vaccination cost R$27 = Us$15* - Vaccine public price + vaccine transportation door to door = R$27 = Us$15 (from a public payer perspective)
*The 2008 mean exchange rate was used to reflect the monthly rate variation (1 UsD = 1.7955 BRL).
Table 4. cost of hospitalization in R$ per case (direct medical cost in standard police, public health care costs with indirect costs in italic, and private costs with indirect costs underlined)
Item Mean value SD Source/comment
Scenario 1 (i.e., Sistema único de saúde—SUS reimbursement package as defined by Brazilian Ministry of Health)
NBpp 462 293 Vigipneumo retrospective study in public Hospital sao paulo (Hsp). N(NBpp) = 173 and N(Bpp) = 12 64
Bpp 830 575
Scenario 2 (i.e., real hospitalization costs)
NBpp 1,992 3,803 Vigipneumo retrospective study in public Hospital sao paulo (Hsp). N(NBpp) = 173 and N(Bpp) = 12 64
Bpp 5,103 6,506
Scenario 3 (including private costs and absenteeism costs)
NBpp 10,223 = 2,053 x 0.54 + 19,826 x 0.46 43,101 private costs from Vigipneumo study in albert Israelita einstein Hospital—sao paulo N(NBpp) = 163 and N(Bpp) = 17 were included in the societal perspective, assuming
that around 46% of people go to private hospital 64
hospitalized CAP in elderly (65+) in US of 1,150 cases per 100,000. Considering that 40% on average of CAP requiring hospitalization are caused by S. pneumoniae,2 we estimated an
incidence rate of hospitalized pneumococcal pneumonia of 460 cases per 100,000. To determine the incidence of NBPP in gen-eral, we used also the fact that 80% of pneumococcal pneumonia are NBPP (BPp = ¼ NBPP),2 and we used the hospitalization rates
defined above (18.6% of NBPP + 95.5% of ¼ NBPp = 460 cases). We obtained 1,083 of NBPP cases per 100,000. Weycker et al. also recently reported an incidence of 728 NBPP cases/100,000 in 65+ (using a mean of the moderate values weighted by popu-lation size). Another study conducted in five European coun-tries reported a mean incidence of hospitalized pneumonia of 754/100,000 in elderly (65+).19 Using the same calculation as
used by Jackson et al.5 we obtained a total NBPP incidence of
706/100,000. Vila-Corcoles et al.37 reported an incidence of
hos-pitalized pneumonia in Spain of 1,048/100,000 in elderly (65+) that gave a total NBPP incidence rate of 987/100,000. The study from Ament et al.19 was used in the present analysis because it
rep-resents the data of five different countries. The mean European rate was used for the base case, and the minimum and maximum values (451 and 1,167 for incidence of hospitalized pneumonia in France and Sweden respectively) were used for the range. For BPP, range given by the WHO Weekly Epidemiological Record (WER) 2008 41 in people aged more than 65 years and leaving in
Demographic and epidemiological model inputs. Representative demographic data on the São Paulo State elderly population was based on the national statistics data from 2007.34
The total size of the cohort was 3,689,623. The all-cause mortal-ity rate from São Paulo State by age group was obtained from the Brazilian mortality information system.35
In the base case, 18.6% was used for the probability of hos-pitalization due to NBPP. This rate was calculated based on the assumption that the probability of hospitalization varies from 10% for 60–70 years old people to 30% for people more than 70 years old and based on the Sao Paulo population size of these subgroups. In the literature, the hospitalization rate related to CAP was reported to be 50–52.8%.7 Considering this high rate
compared to the rest of the world where 80% of CAP patients are treated as outpatients, and the year of these published data, the value of 18.6% was selected for the analysis.36 For BPP,
Vila-Corcoles et al. (2006) found that 4.5% of IPD cases were not hospitalized (1/22 cases) in Spain which gives a hospitalization rate of 95.5%. Previous reports noted similar rates: 100% from a report by Sisk et al. and 96% from a study by Robinson and co-workers. To be conservative, 95.5% was use in the base case and 90–100% for the range (Table 2).
International pneumococcal incidence rates and case-fatal-ity rate (CFR) were used as there were no local data available (Table 2). Jackson et al. (2004) reported an incidence of
developing countries were used. The mean value of the range was used in the base case analysis.
BPP CFR were retrieved from Vaccine 4th
edi-tion1 which reported a CFR range from 11% to
44% (mean = 26.6%, 16 studies included) in elderly in developed countries. This range is con-firmed by many papers: Middleton et al. (2008) showed a CFR of 14.3% for 65–74 years old, 21% in 75–84 year old and 30.8% for 85+ years old in US; the WHO WER of Oct 2008 reported that the CFR attributed to BPP may reach 30–40% in elderly and in industrialized countries; Evers 2007 reported a mean CFR of 21% in 65+ among 10 European countries. For NBPP CFR, the CFR for CAP was used since we could fine no relevant data specific to S. pneumoniae and since assuming that the etiology of CAP to be S. pneumoniae should not impact the mortality rate. In Argentina, a country bordering Brazil, a 18% CFR in 346 patients with CAP (hospitalized or not) aged 18 to 102 years (median age 64) 43 is reported and
a 13.3% in hospitalized patients.44 Other studies
in more industrialized countries reported a CAP-related mortality averaged 10.7% in hospitalized elderly patients in US,45 3.6% in people aged more
than 65+ (hospitalized or not) in US,5 and 12.7%
in people aged more than 65+ in Spain.11 For the
present analysis, a range between 3.6% and 18% was used for the sensitivity analysis and 12.7% (the more recent study-2009) in the base case.
Vaccination model inputs. For this analysis, a one-dose vaccination was simulated. A 60% cov-erage rate was estimated in the case that by the public system and also in consideration that an aged-based program is easier to implement than a risk-based program46-48 (Table 3).
Pneumococcal vaccine effectiveness against IPD is the most firmly established, however the level of effectiveness depends on risk status and age. Meta-analyses of five randomized clinical trials have shown that PPV23 is 68% (95% CI 53–78) effective against IPD among immuno-competent older adults.49 In our analyses, the
val-ues for vaccine effectiveness against were based on multiple observational studies which had the advantage of being conducted in large unselected natural populations11,37,50-55 (Table 3). One of
these recent studies, conducted in Scotland in persons aged ≥65 years, demonstrated a protective effect of PPV23 against IPD of 61.7% (95% CI, 45.1–73.2).54 In Spain, a protective effect of 72%
(95% CI, 46–95) and 70% (95% CI, 48–82) against IPD was reported by Vila-Corcoles et al.53
in persons over 60 years old, and by Dominguez et al.53 in persons over 65. In the US, IPD vaccine
effectiveness of 44% (95% CI, 7–67) in persons
value given in the literature). The mean value of this range was used for the base case: 21% (Table 2).
In addition, as reported in various publica-tions,11,24,37,38,41,42,53,54,56,62,63 a 10% waning rate each year was
applied and a total duration of effectiveness was fixed conserva-tively at 5 years (Table 2).
Vaccination costs including the vaccine public payer price and the door to door transportation cost, was fixed at R$27 Brazilian reais or US$ (US$1 = R$1.7955 - mean exchange rate in 2008) (Table 3). In this analysis, this cost was assumed to be paid entirely by SUS. Adverse events costs were not included as they can be considered negligible. Vaccine administration costs for people aged over 59 years were assumed to be null since it was expected that vaccination would be administered during a regular routine visit to the general practitioner.
Cost of illness and absenteeism data. The Brazilian health system is divided between public and private sector. The public system is called SUS and is a universal system. It means that every Brazilian citizen has the constitutional assured right to receive treatment funded by the government. SUS reimbursement cover-age is based on procedure packcover-ages that are defined in term of value and included services by the Ministry of Health. The fund-ing comes from the federal, state and municipal governments. The private health system (HMOs, Health Plans and Health Insurance Companies) is financed in two ways: fully paid by the patient or partially covered by the patient employer. Although both types of health care cover the treatment of pneumonia, there are differences in terms of access to treatment, medications avail-able, and cost reimbursements routes.
Information about the cost of pneumococcal infections in Brazil was not available in the literature. A retrospective database study was therefore performed in two large hospitals in Sao Paulo 65 and older was reported by Jackson et al.55 in 2003, and 80%
(95% CI, 51–92) in persons 65–74 years old. Shapiro et al.56
1991 values were in accordance with the 14-year nationwide sur-veillance study conducted by the US CDC in the elderly and in persons with underlying chronic disease (effectiveness of 75% in 65+).51 As a result of these studies, effectiveness against BPP in
the base case was assumed to be 64% for all elderly, which is the mean effectiveness of the observational studies. In the sensitivity analyses, the minimum and maximum values given in observa-tional studies were used. These values ranged from 44% from the study by Jackson et al.55 to 80% from reported by Shapiro et al.
The evidence for the effectiveness of PPV23 against NBPP is less firmly established mainly due to the difficulties in identifying S. pneumoniae as etiological agent of pneumonia.49,57 However, the
results of a recent clinical trial conducted in nursing home resi-dents considered at high risk for CAP (mean age: 85 years) showed that PPV23 reduced pneumococcal pneumonia by 64% (95% CI, 32–81) and all-cause pneumonia by 45% (95% CI, 22–61).58 A
systematic review of observational studies,52 which may be
consid-ered to be better estimates of real-life vaccine effectiveness reported an effectiveness of 32% against all pneumonia. In addition, two recent cohort studies conducted in Spain, in which bacteria were identified by radiography, sputum culture, and Binex antigen test, demonstrated an effectiveness against NBPP of 42% (95% CI, 14–61) in persons >50 years old, and 39% (95% CI, -6–65) in elderly >65 irrespective of risk status.11,37 PPV23 has also been
associated with reduced hospitalization of all-cause CAP by 24% (95% CI, 0.9–41) to 26% (95% CI, 8–41),59 lower risk of
hospi-talization and fewer deaths for pneumonia.26,60,61 Consequently in
the current analysis, since our populations were aged ≥60 years, we considered a range of 0–42% effectiveness against NBPP for both populations in the sensitivity analyses (minimum and maximum
State to data collection: one public hos-pital, Hospital São Paulo (HSP), and one private hospital, Hospital Israelita Albert Einstein (HIAE) were included. Both hos-pitals are among the largest in Sao Paulo, each with more than 500 beds (Fig. 4).
The inclusion criteria were patients aged over 60 years and patients hospital-ized for diagnosis of NBPP or BPP due to S. pneumoniae with a laboratory con-firmation. In these patients, resources consumed were retrieved from their files. Theses resources included: procedures, laboratory tests, medical examinations, treatments (medications and other ther-apies), and their length of stay in the intensive care unit and general ward. No outpatient resources were collected. As the cost data were not available with the medical records, official data sources were used to estimate the costs in both hospi-tals. For the public health care setting, procedures, hospitalization and medical test costs were taken from SUS (Sistema Único de Saúde-Unique Health System) reimbursement Table,64 and devices and
drugs costs from Ministry of Health prices data banking.65 Since these two
Tables present reference values of reim-bursement and acquisition values in the public health care market displaying both individual and combined (packages) val-ues, two methods for building costs were performed. The first was from the SUS payer perspective and the second from the hospital perspective. For the private health care setting, Brazilian Medical Association Table (LPM99) was used for procedures, hospitalization and tests costs66 and SIMPRO Brazil Magazine
(wholesales list price 2007; 2009 number 51) for devices and drugs costs. Costs, expressed in Brazilian reais, were calcu-lated and detailed in the Figure 4.
In the public hospital, two separate costs of hospitalization due to pneumo-coccal infections were retrieved. These included; (1) the cost paid by SUS cor-responding to the reimbursement pack-age as defined by the Brazilian Ministry of Health and; (2) the total cost of hos-pitalization corresponding to the exact cost for the hospital. As these two costs were very different (total hospitaliza-tion costs were approximately five times higher than SUS costs), we decided to
deterministic sensitivity analysis, 0% and 10% were used respec-tively for the low and high value.
Conclusion
As recently described by Rijkers et al.32 pneumococcal vaccines
may become the most important vaccines for adults and children worldwide in the future years. Healthcare providers and key deci-sion makers should recognize the serious health impact of pneu-mococcal disease in adults, closely monitor the epidemiology of pneumococcal serotypes, particularly ‘serotype replacement’ and ensure increased vaccine coverage.
Allocation of public funds is one important recognized way to increase the coverage rate, facilitating people’s access to vaccina-tion. In Sao Paulo State, PPV23 vaccination program from age 60 would be highly cost-effective considering total public hospi-talization costs as well as the public hospihospi-talization costs reim-bursed by SUS. It is even likely to be cost-saving and to generate a return on investment when private health-care and absenteeism costs are considered as suggested by the present analysis. This paper supports therefore a universal vaccination program funded by the Brazilian public system.
Disclosure of Financial or Ethical conflicts
sanofi pasteur funded the cost of illness study.
Joao Tonolio Neto M.D., Ph.D.: Medical Doctor from Federal University of Sao Paulo, consultant for several other pharmaceu-tical industries;
Gabriela Tannus M.Sc.: independent researcher from Axia. Bio Consulting, consultant for several other pharmaceutical industries;
Anna Gagliardi M.D.: Medical Doctor from Federal University of Sao Paulo, consultant for several other pharmaceu-tical industries;
Amanda Pinho: employee from sanofi pasteur, Brazil; Laure Durand, M.Sc.: employee from sanofi pasteur, France. Marcelo Fonseca M.D., M.Sc.: Medical Doctor from Federal University of Sao Paulo and independent researcher from Axia. Bio Consulting, consultant for several other pharmaceutical industries.
test the impact of these costs in two different scenarios. The cost difference between the SUS reimbursement and the total hospitalization cost represents a deficit for the public hospital.
In addition to these two scenarios, another one was also con-sidered, which included the total public health care costs (not only the SUS reimbursement package), the private costs of hos-pitalization, and the cost of absenteeism. Of persons over 60 years old, 18.8% were considered active31 with a daily salary
esti-mated at R$37.59 (GDP per capita in 2007 divided by 365).14
Absenteeism duration was considered to be equivalent to length of stay in hospital.
Cost of illness data was that previously presented to a Latin America congress.67Table 4 shows the final costs according to
each scenario and to the type of pneumococcal infections (NBPP and BPP).
Sensitivity analyses. Under base case assumptions, parameter values were varied individually in a one-way sensitivity analysis to identify which variables would have a major impact on the cost-effectiveness results. A variety of inputs were tested and their values are shown in Tables 2–4. Additional details pertaining to the values of the ranges are found in the epidemiological and vac-cination inputs section.
In addition, parameters listed in Tables 2 and 3 (NBPP inci-dence, BPP inciinci-dence, NBPP case fatality rate, BPP case fatality rate, vaccine effectiveness against NBPP and vaccine effective-ness against BPP) were varied simultaneously in probabilistic sensitivity analyses, where random draws from each parameter’s distribution were performed and the effectiveness and incremen-tal cost calculated. This procedure was repeated 1,000 times. Parameter distributions were chosen based on the parameter type and level of certainty. Those parameters whose distribu-tions were least certain (epidemiological and case-fatality rate data from international literature) were assigned uniform dis-tributions, where all values in a range are equally likely to be chosen. Parameters whose distributions were most certain (cost data from local cost of illness study) were assigned log-normal distributions.
A 5% discount rate on costs and lives was used in base case as described in the Brazilian’s health economics guidelines.68 In the
References
1. Fedson DS, Musher DM. Pneumococcal polysac-charide vaccine, In: Plotkin SA, Orenstein WA, Eds. Vaccines. Philadelphia: Elsevier 2004; 529-88. 2. Fedson DS, Musher DM, Eskola J. Pneumococcal
vaccine, In: Plotkin SA, Orenstein WA, Eds. Vaccines. Philadelphia: WB Saunders 1999; 553-607.
3. Active Bacterial Core Surveillance (ABCs) Report Emerging Infections Program Network Streptococcus
pneumoniae 2008; 2011.
4. Annual Epidemiological Report on Commuicable Diseases in Europe 2009; 166-8.
5. Jackson ML, Neuzil KM, Thompson WW, Shay DK, Yu O, Hanson CA, et al. The burden of community-acquired pneumonia in seniors: results of a population-based study. Clin Infect Dis 2004; 39:1642-50. 6. Johnstone J, Majumdar SR, Fox JD, Marrie TJ.
Viral infection in adults hospitalized with community-acquired pneumonia: prevalence, pathogens and pre-sentation. Chest 2008; 134:1141-8.
7. Isturiz RE, Luna CM, Ramirez J. Clinical and eco-nomic burden of pneumonia among adults in Latin America. Int J Infect Dis 2010; 14:852-6.
8. van der PT, Opal SM. Pathogenesis, treatment and prevention of pneumococcal pneumonia. Lancet 2009; 374:1543-56.
9. Lynch JP, III, Zhanel GG. Streptococcus pneumoniae: does antimicrobial resistance matter? Semin Respir Crit Care Med 2009; 30:210-38.
10. Linares J, Ardanuy C, Pallares R, Fenoll A. Changes in antimicrobial resistance, serotypes and genotypes in
Streptococcus pneumoniae over a 30-year period. Clin Microbiol Infect 2010; 16:402-10.
11. Vila-Corcoles A, Salsench E, Rodriguez-Blanco T, Ochoa-Gondar O, de Diego C, Valdivieso A, et al. Clinical effectiveness of 23-valent pneumococcal poly-saccharide vaccine against pneumonia in middle-aged and older adults: a matched case-control study. Vaccine 2009; 27:1504-10.
12. Lu PJ, Nuorti JP. Pneumococcal polysaccharide vac-cination among adults aged 65 years and older, US 1989–2008. Am J Prev Med 2010; 39:287-95.
13. World Health Organization. Macroeconomics and Health: Investing in Health for Economic Development 2001.
14. IBGE. National accounts. Brazilian PIB per capita 2010.
15. Evers SM, Ament AJ, Colombo GL, Konradsen HB, Reinert RR, Sauerland D, et al. Cost-effectiveness of pneumococcal vaccination for prevention of invasive pneumococcal disease in the elderly: an update for 10 western European countries. Eur J Clin Microbiol Infect Dis 2007; 26:531-40.
16. Ament A, Fedson DS, Christie P. Pneumococcal vac-cination and pneumonia: even a low level of clinical effectiveness is highly cost-effective. Clin Infect Dis 2001; 33:2078-9.
54. Mooney JD, Weir A, McMenamin J, Ritchie LD, Macfarlane TV, Simpson CR, et al. The impact and effectiveness of pneumococcal vaccination in Scotland for those aged 65 and over during winter 2003/2004. BMC Infect Dis 2008; 8:53.
55. Jackson LA, Neuzil KM, Yu O, Benson P, Barlow WE, Adams AL, et al. Effectiveness of pneumococcal poly-saccharide vaccine in older adults. N Engl J Med 2003; 348:1747-55.
56. Shapiro ED, Berg AT, Austrian R, Schroeder D, Parcells V, Margolis A, et al. The protective efficacy of polyvalent pneumococcal polysaccharide vaccine. N Engl J Med 1991; 325:1453-60.
57. Huss A, Scott P, Stuck AE, Trotter C, Egger M. Efficacy of pneumococcal vaccination in adults: a meta-analysis. CMAJ 2009; 180:48-58.
58. Maruyama T, Taguchi O, Niederman MS, Morser J, Kobayashi H, Kobayashi T, et al. Efficacy of 23-valent pneumococcal vaccine in preventing pneumonia and improving survival in nursing home residents: double blind, randomised and placebo controlled trial. BMJ 2010; 340:1004.
59. Dominguez A, Izquierdo C, Salleras L, Ruiz L, Sousa D, Bayas JM, et al. Effectiveness of the pneumococcal polysaccharide vaccine in preventing pneumonia in the elderly. Eur Respir J 2010; 36:608-14.
60. Johnstone J, Marrie TJ, Eurich DT, Majumdar SR. Effect of pneumococcal vaccination in hospitalized adults with community-acquired pneumonia. Arch Intern Med 2007; 167:1938-43.
61. Johnstone J, Eurich DT, Minhas JK, Marrie TJ, Majumdar SR. Impact of the pneumococcal vaccine on long-term morbidity and mortality of adults at high risk for pneumonia. Clin Infect Dis 2010; 51:15-22. 62. Fedson DS, Liss C. Precise answers to the wrong
ques-tion: prospective clinical trials and the meta-analyses of pneumococcal vaccine in elderly and high-risk adults. Vaccine 2004; 22:927-46.
63. Postma MJ, Bos JM, van Gennep M, Jager JC, Baltussen R, Sprenger MJ. Economic evaluation of influenza vaccination. Assessment for The Netherlands. Pharmacoeconomics 1999; 16:33-40.
64. Unified public health Table—SIGTAP/SUS 2011.
65. Ministry of Health. Prices prices databanking 2011. 66. Brazilian Medical Assocation (AMB). Procedures
reim-bursement table 2011.
67. Toniolo J, Araujo GTB, Gagliardi AM, Fonseca MCM, Pinho AS, Durand L. Cost of pneumonia hospitaliza-tion in elderly people from two large Brazilian hosp-tials, ISPOR 2nd Latin America Conference, Rio de Janeiro, Brazil, September 2009; 2009: PIH7. 68. Tarn TYH, Smith MD. Pharmacoeconomic Guildelines
Around the World 2004.
69. Akin L, Kaya M, Altinel S, Durand L. Cost of pneu-mococcal infections and cost effectiveness analysis of pneumococcal vaccination in at risk adults and elderly in Turkey. Hum Vaccin 2011; 7:441-450.
37. Vila-Corcoles A, Ochoa-Gondar O, Hospital I, Ansa X, Vilanova A, Rodriguez T, et al. Protective effects of the 23-valent pneumococcal polysaccharide vaccine in the elderly population: the EVAN-65 study. Clin Infect Dis 2006; 43:860-8.
38. Sisk JE, Moskowitz AJ, Whang W, Lin JD, Fedson DS, McBean AM, et al. Cost-effectiveness of vaccina-tion against pneumococcal bacteremia among elderly people. JAMA 1997; 278:1333-9.
39. Robinson KA, Baughman W, Rothrock G, Barrett NL, Pass M, Lexau C, et al. Epidemiology of invasive
Streptococcus pneumoniae infections in the United States 1995–1998: Opportunities for prevention in the con-jugate vaccine era. JAMA 2001; 285:1729-35. 40. Weycker D, Strutton D, Edelsberg J, Sato R, Jackson
LA. Clinical and economic burden of pneumococcal disease in older US adults. Vaccine 2010; 28:4955-60. 41. 23-valent pneumococcal polysaccharide vaccine. WHO
position paper. Wkly Epidemiol Rec 2008; 83:373-84. 42. Middleton DB, Lin CJ, Smith KJ, Zimmerman RK,
Nowalk MP, Roberts MS, et al. Economic evaluation of standing order programs for pneumococcal vaccination of hospitalized elderly patients. Infect Control Hosp Epidemiol 2008; 29:385-94.
43. Luna CM, Famiglietti A, Absi R, Videla AJ, Nogueira FJ, Fuenzalida AD, et al. Community-acquired pneu-monia: etiology, epidemiology and outcome at a teach-ing hospital in Argentina. Chest 2000; 118:1344-54. 44. Caberlotto OJ, Cadario ME, Garay JE, Copacastro CA,
Cabot A, Savy VL. [Community-acquired pneumonia in patients in 2 hospital populations]. Medicina 2003; 63:1-8.
45. Kaplan V, Angus DC. Community-acquired pneumo-nia in the elderly. Crit Care Clin 2003; 19:729-48. 46. Honkanen PO, Keistinen T, Kivela SL. The impact of
vaccination strategy and methods of information on influenza and pneumococcal vaccination coverage in the elderly population. Vaccine 1997; 15:317-20. 47. Pebody RG, Hellenbrand W, D’Ancona F, Ruutu P.
Pneumococcal disease surveillance in Europe. Euro Surveill 2006; 11:171-8.
48. Jimenez-Garcia R, Rodriguez-Rieiro C, Hernandez-Barrera V, Lopez dA, Rivero CA, Rodriguez LA, et al. Effectiveness of age-based strategies to increase influ-enza vaccination coverage among high risk subjects in Madrid. Vaccine 2011; 29:2840-5.
49. Moberley SA, Holden J, Tatham DP, Andrews RM. Vaccines for preventing pneumococcal infection in adults. Cochrane Database Syst Rev 2008; 422. 50. Vila-Corcoles A, Ochoa-Gondar O, Guzman
JA, Rodriguez-Blanco T, Salsench E, Fuentes CM. Effectiveness of the 23-valent polysaccharide pneumo-coccal vaccine against invasive pneumopneumo-coccal disease in people 60 years or older. BMC Infect Dis 2010; 10:73. 51. Butler JC, Breiman RF, Campbell JF, Lipman HB,
Broome CV, Facklam RR. Pneumococcal polysaccha-ride vaccine efficacy. An evaluation of current recom-mendations. JAMA 1993; 270:1826-31.
52. Conaty S, Watson L, Dinnes J, Waugh N. The effec-tiveness of pneumococcal polysaccharide vaccines in adults: a systematic review of observational studies and comparison with results from randomised controlled trials. Vaccine 2004; 22:3214-24.
53. Dominguez A, Salleras L, Fedson DS, Izquierdo C, Ruiz L, Ciruela P, et al. Effectiveness of pneumococcal vaccination for elderly people in Catalonia, Spain: a case-control study. Clin Infect Dis 2005; 40:1250-7. 18. Postma MJ, Heijnen ML, Beutels P, Jager JC.
Pharmacoeconomics of elderly vaccination against invasive pneumococcal infections: cost-effectiveness analyses and implications for The Netherlands. Expert Rev Vaccines 2003; 2:477-82.
19. Ament A, Baltussen R, Duru G, Rigaud-Bully C, de Graeve D, Ortqvist A, et al. Cost-effectiveness of pneumococcal vaccination of older people: a study in 5 western European countries. Clin Infect Dis 2000; 31:444-50.
20. Melegaro A, Edmunds WJ. The 23-valent pneumococ-cal polysaccharide vaccine. Part II. A cost-effectiveness analysis for invasive disease in the elderly in England and Wales. Eur J Epidemiol 2004; 19:365-75. 21. Postma MJ, Heijnen ML, Jager JC. Cost-effectiveness
analysis of pneumococcal vaccination for elderly indi-viduals in The Netherlands. Pharmacoeconomics 2001; 19:215-22.
22. Smith KJ, Zimmerman RK, Lin CJ, Nowalk MP, Ko FS, McEllistrem MC, et al. Alternative strategies for adult pneumococcal polysaccharide vaccination: a cost-effectiveness analysis. Vaccine 2008; 26:1420-31. 23. Smith KJ, Zimmerman RK, Nowalk MP, Roberts
MS. Age, revaccination and tolerance effects on pneu-mococcal vaccination strategies in the elderly: a cost-effectiveness analysis. Vaccine 2009; 27:3159-64. 24. Merito M, Giorgi RP, Mantovani J, Curtale F, Borgia
P, Guasticchi G. Cost-effectiveness of vaccinating for invasive pneumococcal disease in the elderly in the Lazio region of Italy. Vaccine 2007; 25:458-65. 25. de Graeve D, Lombaert G, Goossens H.
Cost-effectiveness analysis of pneumococcal vacci-nation of adults and elderly persons in Belgium. Pharmacoeconomics 2000; 17:591-601.
26. Nichol KL, Baken L, Wuorenma J, Nelson A. The health and economic benefits associated with pneumo-coccal vaccination of elderly persons with chronic lung disease. Arch Intern Med 1999; 159:2437-42. 27. Baltussen RMPM, Ament AJHA, Leidl RM, Van Furth
R. Cost-effectiveness of vaccination against pneumo-coccal pneumonia in The Netherlands. Eur J Public Health 1997; 7:153-61.
28. Jackson ML, Nelson JC, Weiss NS, Neuzil KM, Barlow W, Jackson LA. Influenza vaccination and risk of com-munity-acquired pneumonia in immunocompetent elderly people: a population-based, nested case-control study. Lancet 2008; 372:398-405.
29. Changing epidemiology of pneumococcal serotypes after introduction of conjugate vaccine: July 2010 report. Wkly Epidemiol Rec 2010; 85:434-6. 30. Hanage WP. Serotype-specific problems associated with
pneumococcal conjugate vaccination. Future Microbiol 2010; 3:23-30.
31. Brazilian Institute Geographics and Statistics— IBGE—Employment Research 2008: available in www. ibge.gov.br/home/estatistica/populacao/trabalhoerendi-mento/pnad2008/brasilpnad2008.pdf
32. Rijkers GT, van Mens SP, Velzen-Blad H. What do the next 100 years hold for pneumococcal vaccination? Expert Rev Vaccines 2010; 9:1241-4.
33. Kim SA, Lee SY, Batmunkh N, Kilgore PE, Ki MR. Cost-effectiveness of pneumococcal vaccination in the elderly: a study using national health insurance database in South Korea, ISPOR 3rd Aisia-Pacific Conference, Seoul, South Korea 2008.
34. IBGE-Population by state and age. Population and development. Population and social indicators coordi-nation 2010.
35. MS/SVS/DASIS—Sistema de Informações sobre Mortalidade—SIM 2010.
