Although the global burden of IPD is described extensively in the literature, most studies focus on pediatric diseases, and currently available data for Asian countries is lacking. This multicenter study evaluated the IPD disease burden based on laboratory-confirmed cases in adults, stratified by age and underlying conditions. Direct medical costs were estimated by an objective, concrete method to avoid overestimation. These results may be useful for evaluating the cost-effectiveness of pneumococcal vaccines in the future.
Consistent with previous studies [11–13], the proportion of IPD among hospitalized patients and the IPD case fatality rate increased with age. Though patients aged 65 years and older may be more likely to develop IPD compared to younger patients, those aged 50–64 years comprised the largest percentage in this study. A majority of patients aged 50–64 years (73.4%, 239 among 320 subjects) had comorbidities such as diabetes and chronic lung or cardiovascular diseases. Weycker et al. previously found that persons aged 50–64 years comprised the largest proportion of the IPD patients. Considering that this age group is most active socially, indirect medical costs may be greater than corresponding costs for the elderly. In addition, Weycker et al.  reported that the majority of pneumococcal diseases (≥60%), pneumococcal-related death, and pneumococcal-related costs were accounted for by high-risk cases. The high-risk group may be also at greatest risk for IPD. However, contrary to the study by Weycker et al. , the moderate-risk group in our study accounted for more than 40% of IPD cases. Pneumococcal vaccination for the group at moderate risk should be emphasized.
It is also noteworthy that even the low-risk group presented a substantial clinical and economic burden. This may be related to the presence of underlying cerebrovascular, neurocognitive, and neuromuscular disorders and poor performance status in this group of patients. Jain et al. reported that patients with neurologic diseases are at high risk for pneumonia after influenza infection . Though currently not considered high priority for pneumococcal vaccination, patients with neurologic disease were at great risk for IPD. Moreover, several studies have shown that neurologic diseases are risk factors for mortality after pneumococcal infection [15, 16]. This suggests that the definitions for low, moderate, and high risk groups should be reconsidered.
Similar to the findings of Weycker et al. , the direct medical costs per case did not differ significantly between the risk or age groups in the present study; however, our estimates (mean, US$ 5,404-8,756/case) were much lower than those reported by Weycker et al. (US$ 15,402-31,849/case). First, this difference may be related to the methods used for estimation. Weycker et al.  estimated the direct medical costs based on data from the 2004 Healthcare Cost and Utilization Project (HCUP) Nationwide Inpatient Sample (NIS) using mean age- and risk-specific charges, while we calculated them by adding only IPD-related costs for each patient. Second, direct medical costs may potentially be affected by the healthcare system and geographic factors that affect accessibility. In a US study by Huang et al. , mean direct costs per case of pneumococcal bacteremia was estimated to be US $12,667, which is also higher than our estimates.
The patients’ clinical presentations varied significantly by age and risk group. Primary bacteremia was common in the high-risk group, bacteremic pneumonia and peritonitis were most common in the moderate-risk group, and meningitis was prominent in the low-risk group. Bacteremic pneumonia or empyema was more common in older patients, while meningitis and peritonitis were more common in the younger adults. These differences may be related to host-specific serotype distributions, host immunity, or other factors. Previous reports showed that some serogroups with high IPD potential (1, 5 and 7) affected relatively healthy adults, while those with low or intermediate IPD potential (3, 6, 8, 15, 19, 23, 33 and 38) were more likely to affect individuals with immunocompromise due to age and/or comorbidity [17, 18]. Serotypes 3 and 19A pneumococci are more likely to cause pneumonia/empyema , while Serotype 1 is known to cause pneumonia and peritonitis in young adults .
In this study, the overall case fatality rate (30.9%) was higher than in previous reports, which may reflect that the study was composed exclusively of adults. Similarly in a previous Korean study, the case fatality rate for bacteremic pneumonia was 28.6% in adults . In contrast, the case fatality rates for children were reported to be lower than 15% . Independent risk factors for 30-day case fatality include advanced age, poor performance status, bacteremic pneumonia, and nosocomial infection. The case fatality in this study was not related to primary bacteremia, but to bacteremic pneumonia. Previous studies reported advanced age, male sex, comorbidities, alcoholism, sepsis, and meningitis as risk factors for mortality [17, 19]. In this study, meningitis was not related to survival, contrary to previous studies. This may be related to the age of the study population. The risk of meningitis is much higher in pediatric patients than in adults, and infants under one year of age have an especially high case fatality rate .
Since the introduction of the PCV7 vaccine in 2003, a substantial decline in IPD incidence has been reported in the target population aged 5 years and younger . In a study conducted in the Netherlands, however, the overall IPD incidence remained constant in adults . With a serotype shift under the vaccine pressure, the PCV7 coverage rate fell below 25% in Korean patients with pneumococcal pneumonia irrespective of age (unpublished data). Likewise, the proportion of hospitalized adult patients with IPD and the adult case fatality rate did not decrease remarkably over this decade according to this study. Interestingly, the rates of bacterial susceptibility to penicillin and erythromycin decreased around 2010, which may be related to the expansion of the multidrug-resistant serotype 19A [11, 24, 25].
This study has several limitations. First, we could not estimate the incidence of IPD because the study populations were highly mobile and IPD patients were referred from diverse areas of Korea. Second, the serotype distribution could not be investigated. Third, this study was conducted retrospectively, introducing a potential information bias. Uncontrolled confounding factors might exist. To minimize these factors, well-trained research nurses collected data in each hospital using a structured case report form. All data were reviewed and processed without patient-identifying information at the data management center under the supervision of a medical advisor.