Invasive pneumococcal infections among persons with and without underlying medical conditions: Implications for prevention strategies

Streptococcus pneumoniae is a leading cause of serious community-acquired infections such as bacteraemia and meningitis and community-acquired pneumonia. The pneumococcal polysaccharide vaccine (PPV23) is recommended for adults aged 18–64 years with certain chronic medical conditions and elderly persons because of high disease rates and increased risk of death [1, 2]. Available information from representative, population-based studies on the outcome of IPD is limited. Case fatality has generally been defined as in-hospital mortality, without extended follow up after discharge from hospital [1, 2].

The estimates of PPV23 effectiveness against IPD are highest among otherwise healthy young adults [3–6], but lower among persons with multiple underlying medical conditions and immunosuppression [7, 8]. In the United States, routine childhood 7-valent pneumococcal conjugate vaccine (PCV7) immunisation program has resulted in dramatic reductions in rates of pneumococcal-related diseases and major changes in the epidemiology of pneumococcal infections in children and adults because of reduced transmission of vaccine types and herd protection in unvaccinated groups [9–11]. In Finland, however, PCV7 has not been introduced in the national immunisation schedule and the uptake of PPV23 in the recommended target groups has been extremely low (3%) [12].

We investigated all first episodes of IPD identified by Finnish microbiology laboratories during 1995–2002 and linked these national, population-based surveillance data to other health registries to evaluate the risk and outcome of IPD among patients with various underlying medical conditions with special emphasis on the general population of working-age adults.

Data from our national, population-based study indicate that about half of all cases and deaths due to IPD occurred among working-age adults and that only 36% of the cases in this age-group had any of the underlying conditions for which PPV23 is currently recommended. To strengthen the efforts to reduce the high burden of IPD among non-elderly adults, policymakers should consider new prevention strategies to supplement the current recommendations for use of PPV23 to reach the almost two-thirds of cases without a vaccine indication.

By linking surveillance data to national vital statistics we were able to estimate all-cause mortality up to 3 months following an episode of IPD. Although the CFP was 9% during the first week, mortality at one month in persons with various underlying conditions ranged from 5% to 30% and increased in most groups up to 3 months after the first positive culture, probably reflecting both the severity of the underlying illness and the effects of long term sequelae [15]. The overall mortality was highest for non-haematological malignancy, chronic liver disease, alcohol-related diseases, cardiac failure and HIV infection. Our findings are consistent with two previous population-based studies on IPD and pneumococcal bacteraemic pneumonia in which mortality among persons with underlying medical conditions ranged from 3% to 13% [2] and 6% to 34% [16], respectively. In both studies the highest mortality was observed among persons with cirrhosis and alcohol abuse, coronary artery disease/congestive heart failure and non-haematological malignancies.

Our survival model for predictors of poor outcome in non-elderly adults indicated that the conditions with highest risk of death were alcohol-related diseases and non-haematological malignancies. The effects of some patient and disease characteristics such as meningitis as the clinical syndrome, age 50–64 years, male sex, ARD and haematological malignancies, seemed time-dependent in predicting death. The hazard ratios for these conditions were either significant only at some time-point in the model or they changed over time. Of all IPD cases, about 5% died during the day of admission and ARD was the most common underlying condition in this group of patients. The hazard ratios for ARD were higher at 0–7 days than at later time points, possibly reflecting delays in hospital admissions and treatment in this patient group.

In our study as much as 64% of IPD cases among working-age adults did not have any of the underlying conditions for which PPV23 is currently recommended. This proportion is substantially higher than previously reported from the U.S. (41%) [1, 17] but there are few comparable data available from European countries. Alcohol-related diseases were the most frequent (11%) underlying condition in the working-age group as they have been in some other previous studies [18]. The incidence of IPD among persons with ARD in our study, however, was lower (21.9) compared with estimates ranging from 62 to 483.4 per 100,000 population in previous population-based studies [2, 19, 20]. However, because of lower base-line incidence in Finland, difficulties in defining the population at risk for ARD as well as evaluating the accuracy and representativeness of the denominator data used in these studies, the interpretation of the observed differences is complex. Our estimated denominator for ARD was an extrapolation based on the 12-month prevalence of persons with alcohol use disorders from a representative sample of Finnish adult (≥ 30 years) population [21].

Among patients with various immunocompromising conditions, the rate of IPD varied from 33.4 to 547.2 per 100,000 and was highest in those with haematological malignancy. In immunocompetent patients (persons with diabetes mellitus, chronic pulmonary disease and cardiac failure) there was less variation in rates (range, 12.0–47.1 per 100,000). Previous population-based studies reported higher rates for solid cancer (216.1 to 300.4 per 100,000), chronic pulmonary disease (62.9 to 503 per 100,000) and HIV (422.9 to 2031.4 per 100,000) [2, 19, 20], likely because of differences in population composition, databases, definitions, sources of denominator data and accuracy and completeness of identifying diagnoses of underlying conditions in IPD patients. Previous studies have included malignancies at any time point [2, 20], whereas we restricted those diagnosed less than five or one year, respectively, before the IPD episode. For chronic pulmonary diseases, some studies incorporated only COPD and emphysema cases [19, 20], but we also included asthma. The relatively low rate of IPD among persons infected with HIV in Finland may reflect good access to antiretroviral therapy, early antibiotic treatment without blood cultures and use of prophylactic antibiotics among those with low CD4⁺ T cell count.

Although our estimates from national laboratory-based surveillance are representative of the entire population of Finland, the observed IPD incidence was low compared with reports from some other European countries [22–24], and the United States [1]. Our previous report from Finland found that the overall average annual incidence of IPD increased by 35.1% during a 8-year study period and increased in all adult age groups [25]. In that study temporal increase and higher regional IPD rates were significantly associated with higher blood culturing rates suggesting that the true incidence of IPD may be higher. Furthermore, although IPD is the most severe manifestation of pneumococcal infections, it represents only a small proportion of the overall burden of pneumococcal disease.

Of the national registries we used to define the co-morbidities for IPD cases and acquire population-based denominators, the Finnish Cancer Registry has almost 100% coverage [26, 27], and the comprehensiveness of hospital discharge data has been validated previously [28–31]. However, our study also has several limitations. First, due to the registry-based study design, our analysis of the clinical outcome lacked chart review data to assess the effect of severity of illness indicators on IPD-related mortality. Information on some underlying conditions may also have been missed. Second, the denominator data for persons with co-morbidities were only available in aggregated form and did not allow estimating age-specific rates in various groups of patients with co-morbidities. Third, it is well known that ICD-coding in hospital discharge data may be incomplete and could be subject to misclassification. For this reason, we used hospital discharge data only to identify underlying conditions (ARD, chronic liver diseases, diseases of the spleen and CSF leakage) for which data were not available in the two other registries where standardised criteria and definitions are used. The standardised reimbursement criteria for underlying conditions in the National Social Insurance Institution's database may have excluded mild cases of certain underlying conditions such as COPD and asthma and diabetes mellitus type 2. Fourth, we did not have information on receipt of pneumococcal polysaccharide vaccination and cigarette smoking habits of patients as some of the associations we found with higher risk of IPD (e.g. alcohol-related diseases and COPD) may be confounded by smoking. About half of invasive pneumococcal disease in immunocompetent non-elderly adults has been previously attributed to cigarette smoking [32].

In Finland, the coverage of PPV23 among the elderly and high risk groups is about 3% and would not be expected to impact our results. Despite of the existing vaccine recommendation, PPV23 is not included in the government-funded national vaccination program, and the expense is covered by the treating clinical unit or the individual. Two clinical trials have been conducted in Finland to assess the efficacy of PPV23 against pneumonia [33, 34]. The conflicting results from these trials regarding the efficacy in the aged of PPV23 against mainly serologically diagnosed pneumococcal pneumonia, or pneumonia in general probably have also had a major influence on the vaccination coverage.

The patient groups with highest rates of IPD (e.g. haematological malignancy, organ and bone marrow transplantation, HIV infection) were different from those at highest risk of death (e.g. ARD, non-haematological malignancy and cardiac failure). The almost two-thirds of working-age cases without PPV23 indication, as well as those with alcohol-related diseases may be difficult to reach with public health interventions and acceptability of vaccination may be low among healthy persons. One proposed strategy includes lowering the recommended age for universal PPV23 vaccination to include all persons aged 50 years and older which might result in moderately increased number of IPD cases prevented compared with the current high risk indications [35, 36]. However, given the increasing risk of IPD and mortality with age and the unknown duration of protection after primary immunisation, the optimal timing and frequency of revaccination with PPV23 will need to be determined before this strategy can be implemented. Currently, there are no data available on the clinical effectiveness of revaccination and serologic studies suggest that antibody responses may by lower after revaccination that after primary vaccination [37–39].

Routine childhood immunisation with PCV7 has not yet been introduced in Finland. However, increasing evidence has been accumulating about the substantial indirect effects of childhood PCV7 immunisation in reducing rates of adult pneumococcal disease in the U.S. and elsewhere [40, 41], although early reports from some European countries have had inconsistent results [42–45]. The serotypes included in PCV7 cause approximately 50% of IPD in Finnish adults, a proportion similar to the U.S. before PCV7 introduction [25]. Therefore, introducing routine childhood immunisation in Finland would provide an opportunity to substantially reduce the disease burden among the difficult-to-reach groups of working-age adults without PPV23 indications [11].

In addition to young children and elderly persons, the burden of invasive pneumococcal infections is also substantial among working-age persons without high risk conditions. In the general population of non-elderly adults, two-thirds of invasive infections and one half of fatal cases occur in persons without a recognised PPV23 indication. Policymakers should therefore consider additional prevention strategies to reduce the burden of pneumococcal disease in the overall population.