Pneumonia is the leading infectious disease and is ranked the fourth most common cause of death in South Korea as of 2017 [1]. Globally, three million people die annually due to pneumonia, exceeding all other infectious causes including tuberculosis, malaria, and human immunodeficiency virus (HIV) infection [2]. With the increase in elderly population with chronic disease, long-term care facilities (LTCF) have expanded in South Korea in the recent decade, and this increase in elderly people living in LTCF could be contributing to the rise in pneumonia-related morbidity and mortality.

Prior to 2005, pneumonia was classified as either community-acquired pneumonia (CAP) or hospital-acquired pneumonia (HAP). Since 2005, healthcare-associated pneumonia (HCAP) was first incorporated into the HAP guidelines of the American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA), considering that HCAP patients might be at high risk for multi-drug resistant (MDR) pathogens through repeated contact with the healthcare system [3]. However, HCAP was removed from the revised HAP guidelines again in 2016, and was supposed to be included in the upcoming CAP guidelines [4]. Similar to patients with CAP, most HCAP cases present from the community followed by frequent emergency room visits during acute disease phase. Furthermore, increasing evidence shows that the causative pathogens of HCAP cases are more closely related to pathogens associated with CAP than HAP [56789].

In the beginning of the new millennium, pneumococcal conjugate vaccine (PCV) was developed and is now in widespread use. In children, PCV7 was first licensed in 2000, and extended to PCV10/PCV13 later in 2010 [10]. In turn, PCV13 was additionally licensed for adults in 2012 as the first conjugate vaccine for adults. PCV13 showed 45% efficacy against vaccine-type non-invasive pneumococcal pneumonia in the community-acquired pneumonia immunization trial in adults (CAPiTA), and 70% real world effectiveness [1112]. Vaccine efficacy could be variable depending on pneumonia types because of different vaccine uptake rates and host factors; therefore, PCVs might affect the epidemiology of pneumonia differentially for CAP and HCAP. This review focuses on the change of epidemiology and etiologic distribution of pneumonia over time after the introduction of PCVs.

The incidence of CAP in adults varies worldwide by country, age, gender, and study period; however, reliable data on the incidence of CAP over a prolonged time period exists only for a few countries in North America and Europe, including the United States (107–370 cases per 100,000 persons aged 18–64 years, 630–5, 697 cases per 100,000 persons aged ≥65 years), the United Kingdom (52–106 cases per 100,000 persons aged 16–64 years, 275–1,006 cases per 100,000 persons aged ≥65 years), and Spain (68–320 cases per 100,000 persons aged 18–64 years, 237–1,400 cases per 100,000 persons aged ≥65 years) (Table 1) [13141516171819202122232425]. A wide variation of CAP incidence, even within the same country, results from distinctions in several factors such as inclusion of HCAP or outpatient pneumonia, and data sources of pneumonia assessment. Among these factors, CAP burden revealed a sharp divergence based on whether the study definition included HCAP. As for retrospective studies, it is difficult to differentiate HCAP from CAP cases by diagnostic codes alone. Thus, the burden in defining CAP using the International Classification of Diseases (ICD) code, which inevitably includes HCAP cases, is generally higher than those defined using clinical and radiological criteria. For example, Jain et al. reported that an annual incidence of CAP in the United States excluding patients with HCAP was 248 cases per 100,000 persons [17]. This result was substantially lower than 649 cases per 100,000 persons in another study by Ramirez et al., which included patients with HCAP [23]. Similarly, two Korean studies showed a large difference in the annual incidence of CAP regarding the inclusion of HCAP: 626 cases per 100,000 persons in one study defined by ICD codes vs. 308 cases per 100,000 persons in another study defined by physician assessment [12]. Both studies included HCAP cases. However, the former study might include most HCAP cases, while the latter study excluded LTCF-associated HCAP cases. Although there was a substantial gap in the burden of CAP based on study method, the incidence of CAP increased consistently with age and is higher in men than in women in all studies. The CAP incidence for persons aged 65 years and older was at least three-fold higher compared to those under the age of 65.

Given the importance of pneumococcal pneumonia in the burden of CAP, both direct and indirect herd effect of PCVs should be considered in predicting the change of CAP incidence among adults. Since the introduction of pediatric PCV vaccination in national immunization programs (NIPs) in several countries, the incidence of invasive pneumococcal disease (IPD) was substantially decreased in both children and adults [2627]. However, although lots of studies were conducted to evaluate the incidence of CAP since the introduction of PCVs, indirect effects on adult CAP have not been conclusively determined [121314172022232425282930313233]. Previous reports in the United States have suggested that the incidence of hospitalized CAP among older adults showed a significant reduction in the last decade [142531]. On the other hand, other studies have not shown any significant decrease in CAP rate in adults [2034]. These inconsistent results might be related to the diverse degree of indirect herd effect on older adults with respect to PCV coverage rates and time interval following PCV NIP implementation.

The case-fatality rate (CFR) of CAP has been published much more than those presented in table 1. Overall CFR ranged from 2.5% to 20%, reaching up to 50% in patients admitted to intensive care unit [3536]. CFR is influenced by several factors including age, sex, treatment regimen, vaccination status, and underlying comorbidities [37]. Although varied by country, approximately 10% of patients required intensive care, and 14% (median) died among hospitalized patients with CAP [38].

Because the causative pathogen of CAP is unknown on initial presentation, it is important to know the distribution of CAP etiologic agents for the selection of appropriate empirical antibiotics. Streptococcus pneumoniae has been recognized as the most common identifiable pathogen of CAP, followed by Staphylococcus aureus, Haemophilus influenzae, Klebsiella pneumoniae, Mycoplasma pneumoniae, and Chlamydophila pneumoniae in varying order (Table 2). Traditionally, causative agents of CAP were identified using conventional culture methods, so microorganisms were identified in less than 30% of CAP cases during the pre-PCV7 period [3940414243]. With advances in serological and molecular diagnostic tests, the diagnostic yield has improved by up to 40-50%, yet around 50% of CAP pathogens are still unidentified (Table 2) [744454647]. Prior antibiotic use is one of the important reasons for test-negative results. It is unclear to what degree viral pathogens and oral streptococci contribute to the development of pneumonia, and these are points to be further clarified in the future.

Among CAP cases caused by identified bacterial pathogens, S. pneumoniae is the most important causative species, accounting for 26.9–69.4% of pneumonia cases in South Korea (Table 2) [48], and the proportion of pneumococcal pneumonia was higher in studies confined to older adults [749]. However, in a study of severe CAP cases admitted to intensive care units (ICUs), S. aureus infection was more common compared to S. pneumoniae (37.8% vs. 13.5%) [46]. Etiologic distribution might be affected by disease severity, age, and underlying medical conditions.

Although IPDs were already reported as markedly decreased in both children and adults in the PCV13 era, data on pneumococcal CAP is still insufficient [5051]. The introduction of PCVs was expected to affect the etiologic distribution of CAP; however, significant change was not observed after the introduction of the pediatric PCV7 conjugate vaccine [5495253545556]. Even in the early period of PCV13 use, S. pneumoniae still remained as the predominant agent causing CAP in South Korea, at 26.9–43.6% in the pre-PCV7 period, 23.2–69.4% in the post-PCV7 period, and 13.5–46.8% in the post-PCV13 period (Table 2) [744454647]. Similarly, in the etiology of pneumonia in the community study conducted in the United States during the early PCV13 period (2011-2012), S. pneumoniae was the most common causative pathogen of community-acquired bacterial pneumonia (30.1%, 115 cases), followed by S. aureus (9.7%, 37 cases) among the total 382 bacterial pneumonia cases [17]. Considering that about 65% of pediatric PCV13 immunization is required to expect a herd effect in adults and a seven year time period may be required to get the maximal herd effect from childhood immunization, subsequent studies are required to see the PCV13 herd effect [5758]; however, there are several unpredictable uncertainties. First, it is not clear whether pediatric herd effect is enough to decrease non-invasive pneumococcal pneumonia in adults, not confined to IPDs. Second, depending on the degree of serotype replacement, the disease burden of pneumococcal pneumonia would be either persistent or decreased.

During the early 2000s, several studies in the United States reported a high prevalence of MDR pathogens including methicillin-resistant S. aureus (MRSA) and Pseudomonas aeruginosa in HCAP cases, who had recent contact with healthcare systems through nursing homes, hemodialysis, chronic wound care, or recent hospitalization as examples [5960]. Based on this evidence, the 2005 ATS/IDSA guidelines for nosocomial pneumonia included recommendations for HCAP treatment, suggesting empirical coverage of MDR pathogens [3]. Since then, subsequent studies were conducted in South Korea, Japan, and Spain, but most studies showed that S. pneumoniae is the most common causative agent of HCAP, similar to CAP (Table 3) [567894445464954556162636465]. In addition, although the proportion of MDR pathogens is higher in HCAP, some studies revealed indistinguishable etiologic distribution of causative agents between HCAP and CAP [56789]. Prior meta-analysis suggested that higher mortality of HCAP might not be associated with higher frequency of resistant pathogens [66]. Moreover, empirical antibiotic therapy based on HAP guidelines did not show better clinical outcomes compared to CAP regimen, and resulted in higher mortality with inadequate coverage for atypical pathogens in some studies [676869]. Accordingly, HCAP treatment will be covered in the next revised ATS/IDSA CAP guidelines. Given that the HCAP population is heterogeneous and overlaps with that of CAP and HAP, HCAP needs to be further sub-classified, and empirical antibiotic therapy for HCAP should be stratified based on the risk of MDR infection in each subgroup.

Since the introduction of PCV13, community-acquired pneumococcal pneumonia was expected to gradually decrease. In comparison, the disease burden of pneumococcal pneumonia might be persistent among at-risk HCAP populations particularly residing in LTCF with missed opportunity of vaccination [70], as pneumococcal pneumonia outbreaks have been reported among unvaccinated nursing home residents [7172]. In some studies conducted in Japan, the proportion of pneumococcal pneumonia in HCAP was similar or rather higher compared to that of CAP (Table 3) [689]. The concerning point is that MDR S. pneumoniae might be transmitted among LTCF residents with repeated antibiotic exposure. Actually, levofloxacin and ceftriaxone-resistant pneumococcal HCAP cases were recently reported in South Korea [737475] and these MDR pneumococcal pneumonia cases were related to underlying neurological diseases and LTCF residence[737475]. Pneumococcal disease burden among these high-risk populations should be monitored, and targeted vaccination strategy could be considered.

In this review, we summarized the incidence, CFR, and etiologic distribution of CAP since the introduction of PCV use. The incidence and etiologic distribution of this disease might be variable based on study population characteristics (density and age distribution), vaccine uptake rate, and case definitions as whether to include HCAP in the analysis. In the future, pneumonia-related morbidity and mortality could increase with our increasing aged population, and the proportion of HCAP might be higher with the rising prevalence of coexisting medical conditions. The current HCAP definition should be better clarified and further categorized to avoid overtreatment or undertreatment for MDR pathogens. Considering recent reports of MDR pneumococcal HCAP cases in South Korea, pneumococcal vaccination strategy should be tailored to minimize the missed vaccination opportunity in patients with chronic medical conditions [737475].