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Effectiveness of Pneumococcal Vaccination for Elderly People in Catalonia, Spain: A Case-Control Study

  1. Àngela Domínguez1,2,
  2. Lluis Salleras1,3,
  3. David S. Fedsona,
  4. Conchita Izquierdo1,
  5. Laura Ruíz1,
  6. Pilar Ciruela1,
  7. Asunción Fenoll4, and
  8. Julio Casal4
  1. 1Directorate of Public Health, Department of Health, Generalitat of Catalonia, Barcelona
  2. 2Department of Public Health, University of Barcelona, Barcelona
  3. 3Hospital Clínic, Barcelona
  4. 4National Center of Microbiology, Instituto de Salud Carlos III, Madrid, Spain
  1. Reprints or correspondence: Dr. Angela Dominguez, Directorate of Public Health, Dept. of Health, Generalitat of Catalonia, Travessera de les Corts 131-159, 08028, Barcelona, Spain (angela.dominguez{at}gencat.net).
 
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Abstract

Background. Observational studies offer an approach to evaluating the effectiveness of vaccination programs. We evaluated the effectiveness of a 23-valent pneumococcal vaccination program for elderly people in Catalonia, Spain, in a matched-set case-control study.

Methods. We identified 149 cases of invasive pneumococcal disease among patients aged ⩾65 years who were hospitalized in 12 large hospitals in Catalonia during the period of 1 January 2001 through 31 March 2002. We selected 2 hospital control patients and 1 outpatient control subject for each case patient, matching on the basis of age and underlying medical conditions. We obtained their pneumococcal vaccination histories and used conditional logistic regression to determine effectiveness of vaccination.

Results. Among all 149 cases of invasive pneumococcal disease, 131 (87.9%) were caused by vaccine or vaccine-related serotypes. In the adjusted analysis, overall effectiveness of vaccination against infections due to all serotypes was 70% (95% confidence interval [CI], 48%–82%). Among immunocompetent subjects with or without high-risk conditions, effectiveness of vaccination was 76% (95% CI, 51%–88%), but among immunocompromised subjects it was 50% (95% CI, –44% to 82%). Among subjects with infections due to vaccine or vaccine-related serotypes, effectiveness of vaccination was 72% (95% CI, 50%–85%) overall and 78% (95% CI, 50%–90%) in those who were immunocompetent, but it was only 46% (95% CI, –54% to 81%) in those who were immunocompromised. Overall effectiveness of vaccination was 65% (95% CI, 35%–81%) during the noninfluenza period.

Conclusions. Pneumococcal vaccination was effective in preventing invasive pneumococcal disease among all elderly persons in Catalonia. Effectiveness was greater in immunocompetent persons, most of whom had underlying high-risk conditions. The number of subjects was too small to determine whether vaccination was effective in those who were immunocompromised.

Susceptibility to invasive pneumococcal disease varies with age, being highest in children aged <2 years and elderly adults aged ⩾65 years [1, 2]. Although the incidence of disease is lower in the elderly population than it is among children, its health consequences are far more severe, especially in those with underlying high-risk medical conditions. In population-based studies, case-fatality rates for invasive disease among elderly adults vary from 11% to 44%, and similar rates have been reported in case series [2]. The case-fatality rate for pneumococcal pneumonia (nonbacteremic as well as bacteremic cases) is not precisely known, but it is probably 5%–10% [1, 2]

Pneumococcal polysaccharide vaccine was first licensed in 1977, and its 23-valent formulation has been available for 20 years. The efficacy of the vaccine was firmly established in healthy young adults, but many observers doubt its efficacy in elderly adults and in those with medical conditions placing them at high risk, the groups for whom vaccination is recommended [3–5]. Prospective clinical trials have failed to demonstrate efficacy of vaccination in preventing pneumococcal pneumonia in this age group, but the results of individual clinical trials and their meta-analyses should be regarded as inconclusive because of numerous methodological problems [2, 6]. The sample size requirement for a clinical trial of pneumococcal vaccine among elderly people is very large, and it is unlikely that another prospective clinical trial will ever be undertaken.

Observational studies offer another approach to evaluating the effectiveness of pneumococcal vaccination [1, 2, 7–9]. Eight case-control [10–13], indirect cohort [14–17], and retrospective (historical) cohort [18] studies have been published about the effectiveness of pneumococcal vaccination in preventing invasive pneumococcal disease or pneumococcal bacteremia. All but 1 of these studies [14, 19] have shown that pneumococcal vaccination is ∼50%–80% protective for immunocompetent elderly adults and those otherwise at high risk.

In Catalonia, a region in the northeast of Spain with a population of ∼6 million people, the reported incidence of invasive pneumococcal disease during 1997–1999 was 27.9 cases per 100,000 persons aged ⩾65 years [20], and invasive disease was recognized as an important problem for elderly people. For this reason, a pneumococcal vaccination program was begun in October 1999 that targeted elderly people and younger persons with medical conditions placing them at increased risk [21, 22]. We undertook a case-control study to evaluate the effectiveness of this program in preventing invasive pneumococcal disease in people aged ⩾65 years.

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Patients and Methods

Study population. We conducted our study in accordance with the general principles for observational studies set forth by the Catalan Department of Health (Barcelona, Spain). We identified cases of invasive pneumococcal disease from reports made to the Department of Health during the period of 1 January 2001 through 31 March 2002. The cases were reported by 12 hospitals that participate in the Microbiological Reporting System of Catalonia. A case patient was defined as a patient from whom Streptococcus pneumoniae was obtained by culture of blood samples, CSF samples, or specimens from other normally sterile sites. All isolates were sent for serotyping to the National Center of Microbiology of the Instituto de Salud Carlos III (Madrid, Spain).

Three control subjects were selected for each case: 2 hospital control subjects and 1 outpatient control subject. The staff who selected control subjects were unaware of their vaccination status. Hospital control subjects were selected from the Basic Minimum Data Set of hospitalized patients reported by each hospital to the Catalan Service of Health. We excluded patients who otherwise qualified as control subjects but whose medical records showed a previous history of invasive pneumococcal disease or an episode of pneumonia of uncertain cause during 1999 or thereafter. Control subjects were matched with case patients on the basis of hospital, age (±3 years), date of hospitalization (±3 months), and the underlying high-risk medical condition considered the most important risk factor. When a satisfactory control subject could not be found, the criteria for age or date of hospitalization were extended (see footnote in table 1). When the case patient had >1 high-risk condition, the control subject was matched on the basis of the condition regarded as the greater risk factor. If several high-risk conditions with similar levels of risk were present, matching was based on the longest-existing condition. Fifty-six matched sets were affected in this way.

Table 1
Table 1

Characteristics of subjects in a case-control study of effectiveness of pneumococcal vaccination among elderly people in Catalonia.

For outpatient control subjects, staff of the primary health care center selected patients who had not experienced an episode of invasive pneumococcal disease and had the same age (±3 years) and risk condition profile as the case patient. Among the 149 outpatient controls, 121 were selected from among persons enrolled in the same health care center as that of the case patient. For 28 case patients, no suitable control subject could be identified in the same health care center, so the control subject was selected from the nearest center.

Risk factors. To ensure that matching was adequate, we divided the 149 case patients and their matched control subjects into 3 strata [12]. Stratum 1 included 39 case patients (26.2%) with conditions associated with immunocompromise: solid-organ or hematological neoplasia, renal failure (dialysis or transplantation), and long-term corticosteroid therapy (⩾20 mg/day). None of these subjects had asplenia. Twenty-six of the 39 stratum 1 case patients were matched with control subjects that had the same high-risk conditions. Stratum 2 included 96 case patients (64.4%) who were immunocompetent but had ⩾1 high-risk condition. All but 8 of these case patients were matched with control subjects who had the same high-risk condition: heart disease, chronic obstructive pulmonary disease (COPD), diabetes mellitus, or chronic liver disease. Stratum 3 included the remaining 14 case patients (9.4%) who had no identified underlying high-risk conditions.

Influenza period. We defined an influenza period as the period during which influenza viruses were isolated from patients in the study area over a period of several weeks. During the first winter (2000–2001), only a few sporadic virus isolates were obtained, and we did not consider this to be an influenza season (unpublished observations). During the second winter, a substantial number of influenza virus isolates were obtained continuously during weeks 2–9 in 2002 (unpublished observations). We considered this 8-week period to be the influenza period.

Vaccination history. We determined the pneumococcal vaccination history for each case patient and each control subject from a review of their hospital and health care center records. We considered a subject to have been vaccinated if vaccine had been administered ⩾2 weeks before the onset of invasive pneumococcal disease for case patients and 2 weeks before hospital admission of the hospital control subjects. We considered outpatient control subjects to have been vaccinated if they had been vaccinated ⩾15 days before the date of hospitalization of the case patient with whom they were matched. We excluded from the analysis 33 case patients and 59 control subjects whose vaccination histories could not be determined. The investigators who serotyped the S. pneumoniae isolates were unaware of the vaccination histories of the subjects.

Statistical analysis. We estimated the number of subjects needed for our matched-set analysis by assuming that vaccination coverage among control subjects was 35% [22], and the effectiveness of vaccination for prevention of invasive pneumococcal disease (all serotypes) was 50% [1, 2]. With α = .05 (2-tailed) and a power of 80%, we estimated that we would need 110 case patients and 330 control subjects [23].

We analyzed our data by use of standard statistical techniques. We used the Χ2 test for categorical data and Students' t test for continuous data. All P values were 2-tailed. We evaluated the association between invasive pneumococcal disease and vaccination by determining McNemar's Χ2 test result for matched data. We used conditional logistic regression to control for possible confounding variables [24] and calculated effectiveness of vaccination as 1 - OR. We performed separate analyses to determine effectiveness of vaccination against invasive pneumococcal disease caused by all serotypes and by vaccine and vaccine-related serotypes. We also evaluated effectiveness of vaccination in the noninfluenza period and in each of the 3 risk strata. The statistical software package used was SAS, version 8 (SAS Institute).

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Results

Characteristics of the study subjects. The characteristics of case patients and control subjects are summarized in table 1. The 2 groups were similar in most respects, except for significantly higher rates of renal failure, COPD, and smoking among case patients.

Among all 149 case patients, 121 (81.2%) presented with pneumonia or respiratory symptoms, 13 (8.7%) presented with primary bacteremia, 8 (5.4%) presented with meningitis, and 7 (4.7%) presented with other syndromes (empyema, arthritis, otitis media, orbital cellulitis, and muscle abscesses). The overall hospital case-fatality rate was 16.1%.

The distribution of clinical syndromes among all case patients and among the 131 case patients (87.9%) with infections due to vaccine or vaccine-related serotypes was the same. Among cases in this latter group, 68 (51.9%) were caused by 5 pneumococcal serotypes (3, 14, 1, 4, and 9V), 13 (9.9%) were caused by serotypes 19F and 19A, and 11 (8.4%) were caused by serotypes 6A and 6B. Twelve different serotypes or serogroups accounted for the remaining 39 (29.8%) vaccine and vaccine-related serotypes. of the remaining 18 isolates, 8 were nonserotype organisms, and 10 could not be serotyped.

Effectiveness of vaccination. The vaccination histories of case patients and control subjects are shown in table 2, along with calculations of the unadjusted and adjusted ORs and estimates of effectiveness of vaccination. In the unadjusted analysis of all matched sets, the effectiveness of vaccination was 64% (95% CI, 43%–77%). Effectiveness of vaccination was slightly higher when the analysis was limited to outpatient control subjects and slightly lower when only hospital control subjects were considered. When the unadjusted analysis was limited to the 131 case patients with infections due to vaccine and vaccine-related serotypes, similar estimates of effectiveness of vaccination were obtained (table 2).

Table 2
Table 2

Vaccination histories in cases and control subjects, and unadjusted and adjusted ORs, and estimates of effectiveness of pneumococcal vaccination.

In the adjusted analysis, we used conditional logistic regression and incorporated variables shown in table 1. The factors that were significantly associated with being a case patient were length of hospital stay, hospital period, COPD, use of corticosteroids, and death (data not shown). The resulting adjusted ORs and estimates of effectiveness of vaccination were closely similar to those obtained in the unadjusted analysis (table 2).

Table 3 shows the results of the adjusted analysis of effectiveness of vaccination during the noninfluenza season and according to the 3 risk strata. In the analysis for infections due to all serotypes, the overall analysis included all 149 matched sets and 134 matched sets (excluding 15 matched sets in which the stratum of the case patient and ⩾1 matched control subject were not the same). Overall rates of effectiveness of vaccination were 70% and 72%, respectively. Among the immunocompromised subjects in stratum 1, effectiveness of vaccination was 50%, a rate that was not statistically significant. Among immunocompetent high-risk subjects in stratum 2, vaccination was 75% effective (95% CI, 47%–86%), and it also appeared to be effective for non–high-risk subjects in stratum 3, although the number of subjects available for analysis was small and the result was not statistically significant. When subjects in strata 2 and 3 were analyzed together, vaccination was 76% effective (95% CI, 51%–88%).

Table 3
Table 3

Adjusted ORs and estimates of overall effectiveness of vaccination during the noninfluenza period and according to risk stratum.

When we limited our analysis to the 118 case patients with infections due to vaccine and vaccine-related serotypes, our overall analysis for all 131 matched sets and for 118 matched sets (excluding 13 matched sets in which the strata of ⩾1 control subject were discordant with those of the case patients) gave us results that were virtually the same as those for all cases of invasive disease (table 3).

Among all 149 cases of invasive disease, 29 (19%) occurred during the influenza period in 2001–2002. We were unable to calculate an adjusted estimate of effectiveness of pneumococcal vaccination for these case patients. However, for the 120 (81%) cases that occurred during the noninfluenza period, when length of hospital stay, COPD, corticosteroid use, and death were adjusted for, overall effectiveness of vaccination was 65% (95% CI, 35%–81%).

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Discussion

Invasive pneumococcal disease is an important health problem for elderly people in Catalonia [20]. The reported incidence (27.9 cases per 100,000 population) is lower than that reported in Valencia and in several other Western European countries [2]. Eighty percent or more of elderly persons with invasive disease have bacteremic pneumococcal pneumonia [2, 11–13] (this study), and differences in reported incidences largely reflect different rates of obtaining blood for culture from patients with pneumonia. In all likelihood, the true incidence of invasive disease in Catalonia, as elsewhere, is closer to 50 cases per 100,000 per year [2].

The pneumococcal vaccination program in Catalonia was begun in 1999 [21], and within 18 months, vaccination coverage among elderly people reached 35% [22]. This coverage level provided an excellent opportunity to undertake a case-control study to determine whether the program was effective. Doing so was thought to be important because of the failure of prospective clinical trials and their meta-analyses to demonstrate vaccine efficacy for elderly and high-risk adults [6] and, consequently, the reluctance of physicians in many Western European countries to use pneumococcal vaccine [2, 25].

In our unadjusted analysis, pneumococcal vaccination was 64% effective in preventing invasive pneumococcal disease (all serotypes) in elderly people, regardless of underlying high-risk conditions. Similar results were obtained in the conditional logistic regression analysis; for example, pneumococcal vaccination was 70% effective in preventing invasive disease (all serotypes, all control subjects; table 2). These results are comparable to those obtained in the case-control studies of Shapiro and Clemens (67%) [10], Shapiro et al. (47%) [12], and Farr et al. (81%) [13]. Moreover, when we limited our analysis to immunocompetent elderly adults (stratum 2 and stratum 3), effectiveness of vaccination was 76% (all serotypes), a result similar to those reported by Shapiro and Clemens (77%) [10], Sims et al. (70%) [11], and Shapiro et al. (53%) [12]. When we considered only cases due to vaccine and vaccine-related serotypes, our estimate of effectiveness of vaccination was slightly higher than it was for all elderly subjects, in keeping with an earlier report [12]. Because the number of study subjects was small, we were unable to demonstrate whether vaccination was effective for persons with conditions associated with immunocompromise (stratum 1), a finding similar to those of previous case-control studies [10, 12].

Our estimate of effectiveness of vaccination and those reported in 4 other case-control studies [10–13] are similar to the estimates of investigators who have used other analytic methods. One retrospective cohort study has shown that vaccination was significantly protective against invasive disease due to all serotypes [18]. Three indirect cohort studies have evaluated effectiveness of vaccination against infections due to vaccine and vaccine-related serotypes. In 2 of these studies, the effectiveness of vaccination in all study subjects was estimated to be 60% and 63% [15–17]. In a third report [14], vaccination was not shown to be effective, but incomplete ascertainment of the vaccination status of study subjects and other methodological problems make it difficult to accept this finding [2, 19]. Indirect cohort and retrospective cohort methods give virtually the same results as the case-control method when applied to the same data set [12, 26]. Thus, no matter which of the 3 analytical methods has been used, the results of all 8 published observational studies and our study can and should be considered together.

Because rates of invasive pneumococcal disease increase in winter months, some investigators have questioned whether pneumococcal vaccination provides an additional benefit in populations that have high rates of vaccination against influenza [27]. A retrospective cohort study of elderly people with COPD showed that the benefits of influenza and pneumococcal vaccination in preventing hospitalization for pneumonia during the influenza season were additive, but only pneumococcal vaccination was protective during the noninfluenza period [28, 29]. Only 2 of 8 published observational studies that assessed effectiveness of pneumococcal vaccination against invasive disease included influenza vaccination in their adjusted analyses [12, 18]. We did not obtain information on the influenza vaccination status of our study subjects, but we did analyze the effectiveness of pneumococcal vaccination in and out of the influenza period. We were unable to obtain an estimate (adjusted) of effectiveness of vaccination during the influenza period alone, but effectiveness of vaccination (adjusted) was 65% during the noninfluenza period, when 81% of our cases of invasive disease occurred.

Observational studies that use case-control designs and other methods have recognized limitations [8, 23], and not all such studies have shown that pneumococcal vaccination prevents invasive disease. In 1 case-control study conducted among HIV-positive adults, vaccination was protective in white subjects but not in black subjects [30], and in another report, vaccination was not significantly protective in a very-high-risk group of Navajo adults [31]. One case-control study has appeared only as an abstract and has shown a low (30%) and statistically nonsignificant degree of protection [32]. Moreover, in the retrospective cohort study that showed that vaccination was associated with significant protection against invasive disease, vaccination was also associated with a significantly increased risk of all-cause pneumonia and a significantly decreased risk of all-cause mortality, contradictory findings that are difficult to reconcile [18]. Nonetheless, despite these inconclusive findings, 8 of 9 published observational studies [10–13, 15–18] and this study have shown that pneumococcal vaccination offers a significant degree of protection against invasive disease in older people.

Our study had several limitations. We enrolled case patients over a 15-month period, 2–3 years after the vaccination program was begun, and thus were unable to assess long-term protection. Earlier studies showed that both antibody levels and clinical protection decline several years after vaccination [2, 12]. We included immunocompromised subjects in our analysis, a group that, on the whole, responds poorly to vaccination [2]. However, other case-control studies have also included such patients [10, 12, 13]. We did not assess the influenza vaccination status of our case patients and control subjects, and this could have biased our results. We were unable to demonstrate clearly the independent protective effects of pneumococcal and influenza vaccination during influenza seasons, as has been shown previously [28, 29]. Nonetheless, we found that pneumococcal vaccination alone was protective because it reduced the occurrence of invasive disease during periods when influenza viruses were not circulating in the community.

Fifteen years ago, a Technical Advisory Group to the World Health Organization's Regional Office for Europe recommended pneumococcal vaccination for elderly and other high-risk persons [33]. This recommendation was based on evidence of vaccine efficacy in younger adults obtained from clinical trials and evidence of effectiveness of vaccination in elderly persons as shown in case-control studies. Nonetheless, it has taken many years for pneumococcal vaccination to be accepted in some Western European countries, and it is still largely undervalued and underused in many others [2, 25, 34]. This is largely due to misunderstanding about the results of prospective clinical trials in older adults [2, 6] and reluctance to accept the results of observational studies [2, 3–5, 9, 19]. Yet there is neither a theoretical nor an empirical reason for rejecting the findings of well-conducted observational studies [35].

Our demonstration of the clinical effectiveness of pneumococcal vaccination of elderly people provides a sound basis for continuing pneumococcal vaccination programs in Catalonia and in other Western European countries.

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Acknowledgments

We thank the microbiological laboratories that participated in the Microbiological Reporting System of Catalonia and sent isolates for serotyping to the National Center of Microbiology of the Instituto de Salud Carlos III in Madrid and the medical records staffs of the hospitals included in the study. We also thank the Catalan Service of Health and the staffs of the primary health care centers for selecting control subjects and assessing the vaccination status of all study subjects.

Financial support. The study was funded by the Directorate of Public Health, Department of Health, Generalitat of Catalonia. The statistical analysis was funded by a grant from the Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III (Red de Centros de Investigación en Epidemiología y Salud Pública, Epidemiology and Public Health Research Network).

Potential conflicts of interest. D.S.F. was employed until November 2002 by Aventis Pasteur MSD, a European vaccine company that markets pneumococcal vaccine. All other authors: no conflicts.

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Footnotes

  • ↵a Retired, Sergy Haut, France.

  • Received July 19, 2004.
  • Accepted December 12, 2004.
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  1. Clin Infect Dis. (2005) 40 (9): 1250-1257. doi: 10.1086/429236
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