Incidence of Hospitalisation and Emergency Department Visits for Pneumococcal Disease in Children, Adolescents, and Adults in Liguria, Italy: A Retrospective Analysis from 2012–2018

Streptococcus pneumoniae infection is responsible for significant morbidity and mortality, particularly in young children and older adults. The aim of this study was to investigate the incidence of hospitalisation and emergency department (ED) visits in relation to episodes of pneumococcal disease (PD) following the introduction of pneumococcal conjugate vaccines (PCVs) into the Liguria region of Italy. Between 2012 and 2018, episodes of all-cause pneumonia (80,152), pneumococcal-specific pneumonia (1254), unspecified pneumonia (66,293), acute otitis media (AOM; 17,040), and invasive PD (IPD; 1788) were identified from in-patient claims, ED and hospital discharge records, and the Liguria Chronic Condition Data Warehouse. In children < 15 years of age, pneumococcal pneumonia-related hospitalisations decreased from 35 to 13 per 100,000 person-years during the study period (p < 0.001); this decrease is potentially related to PCV use in children. All-cause pneumonia hospitalisations remained stable, whereas IPD hospitalisations increased and AOM hospitalisations decreased. In adults, hospitalisations for all-cause pneumonia increased from 5.00 to 7.50 per 1000 person-years (+50%; p < 0.001). Pneumococcal and unspecified pneumonia hospital admissions increased significantly during the study period, considerably affecting those ≥ 65 years of age. IPD hospitalisations varied across all age groups, but a significant change was not observed. Despite pneumococcal vaccination, substantial burden remains for PD in children and adults in Liguria, Italy.


Introduction
S. pneumoniae infections are a major cause of global morbidity and mortality, especially in vulnerable groups, such as older adults, children ≤ 5 years of age, and those at high risk of infection due to comorbidities [1,2]. S. pneumoniae infection can induce invasive and non-invasive pneumococcal disease and is the leading cause of community-acquired pneumonia worldwide [1,3,4].
The frequency of pneumococcal disease in infants has led to the introduction of pneumococcal conjugate vaccines (PCVs) across many regions, and a subsequent decline in vaccine-type paediatric invasive and non-invasive pneumococcal disease has been observed [5]. Young children who carry S. pneumoniae in the nasopharynx are also the main source of transmission to adults, in whom infection with S. pneumoniae can cause pneumococcal disease [6]. Reduction of vaccine serotype nasopharyngeal carriage through the use of PCVs in paediatric populations can indirectly provide protection to adults [6][7][8].

Episode Identification and Definition
For all patients included in the study, pneumonia episodes were identified using pneumococcal-specific ICD-9-CM codes, which indicated that the condition was caused by S. pneumoniae. In addition, codes were included for conditions without pathogen attribution but in which S. pneumoniae is known to have a causative role (unspecified). Furthermore, the definition of all-cause pneumonia comprised all other types of pneumonia, such as bacterial or viral pneumonia (Table S1). IPD episodes were identified with pneumococcal-specific ICD-9-CM codes for pneumococcal bacteraemia, meningitis, bacteraemic pneumonia and other IPD, and unspecified invasive disease (including meningitis, bacteraemia, bacteraemic pneumonia, and other diseases) potentially caused by S. pneumoniae. For patients < 15 years of age, episodes of AOM were also identified through ICD-9-CM codes (Table S1).

Study Endpoints
Episodes of all-cause pneumonia, pneumococcal-specific and unspecified pneumonia, AOM, and IPD (pneumococcal and unspecified) were identified from in-patient claims during the study period, plus ED and hospital discharge records, as well as the Liguria Chronic Condition Data Warehouse, as described above and in Table S1.
The annual incidence of hospital admissions related to IPD and pneumonia was defined as the annual number of inpatient admissions per 1000 or 100,000 person-years.

Statistical Analysis
The clinical burden of pneumonia was stratified according to age, time period, and comorbidity risk factors, reporting the standard deviation for the mean age and frequency distributions with 95% confidence intervals (95% CIs) for the other categoric variables. Trends in incidence were assessed using the chi-squared test; a p-value of <0.05 was considered statistically significant.
Univariate analysis was used for relative risks of comorbidities for pneumococcal pneumonia and IPD. Fisher's exact test was applied for those cases with less than five events in the population with or without a risk factor. Data were analysed using the JMP version 13.0.0 software (SAS Institute, Cary, NC, USA).

Patient Demographics
In children < 15 years of age, a total of 9750 episodes of all-cause pneumonia were identified, including 287 episodes of pneumococcal pneumonia and 5964 episodes of unspecified pneumonia that were potentially caused by S. pneumoniae. A larger proportion of these episodes was observed in children 0-4 years of age compared with children 5-14 years of age (Table 1).
In addition, 17,040 episodes of AOM and 878 episodes of IPD and unspecified invasive disease potentially caused by S. pneumoniae were identified in children < 15 years of age, including 695 episodes of bacteraemia, 172 cases of other invasive pneumococcal diseases (e.g., pneumococcal septicaemia), and 11 episodes of meningitis. In children 0-4 years of age, 10,562 episodes of AOM, 578 episodes of bacteraemia, and nine episodes of meningitis were identified (Table 1).
In patients ≥ 15 years of age, a total of 70,402 episodes of all-cause pneumonia were identified; of these, 60,529 episodes were unspecified pneumonia and 967 were pneumococcal pneumonia. In addition, 1082 episodes of IPD were identified, including 129 episodes of meningitis and 953 episodes of bacteraemic pneumonia (pneumococcal-specific), pneumococcal septicaemia, pneumococcal infection, and empyema or pleural effusion ( 3) † The "Other" category comprised pneumococcal-specific conditions including pneumococcal arthritis, pneumococcal peritonitis, and the following disease manifestations with and without the presence of pneumococcal infection: infective pericarditis, acute and subacute bacterial endocarditis, acute and subacute endocarditis, spontaneous bacterial peritonitis, acute or unspecified osteomyelitis, and pyogenic/unspecific arthritis. IPD: invasive pneumococcal disease; PCV: pneumococcal conjugate vaccine; SD: standard deviation.
Annual incidence of IPD hospitalisation in children < 15 years of age showed an increase over the study period, with values ranging from 1.70 cases per 100,000 personyears in 2012 to 4.85 cases per 100,000 person-years in 2018 (p < 0.001) ( Table 3).
In addition, the annual incidence of AOM hospitalisation showed a decreasing trend, from 0.447 to 0.327 cases per 1000 person-years (p = 0.94) from 2012 to 2018, peaking in 2017 at 0.460 cases per 1000 person-years (Table 4). An increasing trend in the annual incidence of AOM ED visits, not followed by hospitalisation, was observed, from 6.506 to 7.208 cases per 1000 person-years (p = 0.34) from 2012 to 2018. 100,000 person-years (p = 0.53, R 2 = 0.03). In children 2-4 and 5-14 years of age dence significantly decreased from 2012 to 2018 (from 69 to 22 cases per 100,00 years [p < 0.01, R 2 = 0.7] and from 21 to 8 cases per 100,000 person-years [p < 0.001 respectively) ( Table 3). Hospitalisations for unspecified pneumonia also decre hough not significantly, in children <15 years of age ( Figure 1B).

Adolescents and Adults ≥ 15 Years of Age
The incidence of all-cause pneumonia, pneumococcal pneumonia, and unspecified pneumonia hospital admissions increased between 2012 and 2018 in all age groups but was more apparent in those 65-84 and ≥85 years of age. In adults diagnosed with allcause pneumonia, an increase in the annual incidence of hospitalisation was observed, increasing from 5.00 to 7.50 per 100,000 person-years (+50%, p < 0.001; Figure 2A). The annual incidence rate of hospitalisation for all-cause pneumonia increased significantly in the 65-84 years age group (from 8.95 to 12.70 per 1000 person-years; +42%, p < 0.001) Vaccines 2022, 10, 1375 8 of 14 and in adults ≥ 85 years of age (from 26.63 to 38.58 per 1000 person-years; +45%, p < 0.001; Figure 3).

Adolescents and Adults ≥15 Years of Age
The incidence of all-cause pneumonia, pneumococcal pneumonia, and unspecified pneumonia hospital admissions increased between 2012 and 2018 in all age groups but was more apparent in those 65-84 and ≥85 years of age. In adults diagnosed with all-cause pneumonia, an increase in the annual incidence of hospitalisation was observed, increasing from 5.00 to 7.50 per 100,000 person-years (+50%, p < 0.001; Figure 2A). The annual incidence rate of hospitalisation for all-cause pneumonia increased significantly in the 65-84 years age group (from 8.95 to 12.70 per 1000 person-years; +42%, p < 0.001) and in adults ≥85 years of age (from 26.63 to 38.58 per 1000 person-years; +45%, p < 0.001; Figure 3).    In those diagnosed with pneumococcal pneumonia, hospitalisation rates also increased significantly during the study period, from 0.5 to 1.2 per 10,000 person-years (+140%, p < 0.001; Figure 2B). Most notably, significant increases were observed in adults In those diagnosed with pneumococcal pneumonia, hospitalisation rates also increased significantly during the study period, from 0.5 to 1.2 per 10,000 person-years (+140%, p < 0.001; Figure 2B). Most notably, significant increases were observed in adults 65-84 years of age (from 0.10 to 0.22 per 1000 person-years; +120%, p < 0.001), whereas non-significant increases were seen in adults ≥ 85 years of age (from 0.21 to 0.45 per 1000 person-years; +114%, p = 0.25; Figure S1).
The overall incidence of IPD hospitalisation did not increase significantly over time, showing high variability in all age groups analysed. However, IPD incidence was significantly higher in the older (65-84 and ≥85 years) age groups ( Figure S2).

Analysis of Comorbidities Adolescents and Adults ≥ 15 Years of Age
The prevalence of comorbid conditions in the Liguria population demonstrated an increasing trend with age. Generally, the incidence of hospitalization for all-cause pneumonia was highest in patients with chronic respiratory illness and chronic cardiovascular disease (Figure 3).
Across most age groups in the adult population, the relative risk of contracting pneumococcal-related pneumonia in patients with comorbidities was statistically significant in comparison with patients without a comorbidity, with the highest relative risk ob-  The hospitalisation rates for IPD among adults with comorbidities 65-84 and ≥85 years of age were also numerically higher than in adolescents and adults < 65 years of age during the study period (2012-2018).

Discussion
The aim of this study was to investigate the incidence of hospitalisation and ED visits in relation to episodes of pneumococcal disease following the introduction of PCVs into the Liguria region of Italy. In this retrospective analysis, there was an observed decrease in annual pneumonia-related hospital admissions for children < 15 years of age between 2012 and 2018. Overall, a greater decrease in pneumococcal pneumonia hospital admissions was observed compared with unspecified pneumonia admissions, with similar rates observed for children < 5 years of age and those 5-14 years of age. The decrease in the incidence of pneumococcal-related hospitalisation observed in this study corroborates findings from other trials and observational studies that report a decrease in a similar trend in IPD and pneumonia episodes in young children, following the successful implementation of PCV13 vaccination in infants [21,22]. However, within the decreasing trend observed in our study, there was an anomaly in 2016, when the incidence of hospitalisation was significantly lower in comparison with other years assessed. There are two potential factors that could contribute to this outlier. First could be the update to the indications contained in the Ligurian Vaccine Prevention Plan, implemented at the start of 2016, which offered the pneumococcal vaccine free of charge to high-risk subjects of all ages [23]. This could have led to a decrease in the incidence of severe disease and explain the low values observed in 2016. A second variable that could have led to the decrease in incidence could be related to the low circulation of influenza-like illness and symptoms reported in the 2015-2016 season, which was the lowest peak recorded between 2012 and 2018 [24].
In addition, there was a decreasing trend observed in AOM hospitalisation and ED visits for children < 15 years of age, which supports the findings of other studies in Italian regions. During 2002 to 2014 in Tuscany, Boccalini et al. observed a decrease in hospitalisations due to AOM in children and an increase in hospitalisations for potentially associated pneumococcal diseases in older subjects > 64 years of age [25].
In contrast to the decreasing trend in AOM hospitalisation, a generally stable trend in IPD hospitalisations was observed in the analysis, with a slight overall increase in cases in children < 5 years of age, peaking in 2017.
In adults and adolescents, the incidence of all-cause pneumonia-related hospitalisation increased across all age groups throughout the study period but was more apparent in those ≥ 65 years of age. Unspecified pneumonia comprised the majority (~80%) of pneumonia cases.
In adults and adolescents, the incidence of IPD hospitalisation showed an increasing trend across the study period but was not significant, apart from in the group ≥ 65 years of age. This increase in cases is mirrored in a national Italian study that analysed general IPD incidence from 2007-2017, highlighting the largest increase in IPD observed in individuals > 64 years of age [26]. Despite this general increasing trend in IPD observed in our study, high variability across all the adult age groups was observed; this could be due to two potential factors. Age groups with a low incidence of IPD hospitalisation may receive indirect protection against pneumococcal disease following the introduction of PCVs into paediatric immunisation programmes [27]. In age groups in which a high incidence in IPD hospitalisation was observed, the phenomenon of immunosenescence, associated with older age, could increase the disease burden linked with IPD, leading to a higher incidence of hospitalisation [28]. Comorbidities of a respiratory, renal, or cardiovascular nature were associated with an increase in the burden of pneumonia and IPD in adults ≥ 65 years of age, supporting the rationale for vaccine recommendation in older adults.
The findings of this study are likely to be a direct result of the introduction and uptake of PCV13 vaccination in infants in the Liguria region [21]. However, despite the decrease in incidence of pneumococcal pneumonia-related hospital admissions reported here, pneumonia is still a major burden in children globally [29]. Similar to this, the clinical burden of ED access and hospitalisations due to pneumonia has increased in adolescents and adults since the introduction of PCV13 in 2010; yet, of these episodes, pneumococcal pneumonia only accounted for approximately 1% of all pneumonia cases. However, inaccurate diagnosis could have contributed to the small number of cases, which may not accurately reflect the true incidence of pneumococcal pneumonia. This highlights the current unmet need to distinguish between S. pneumoniae pathogens colonising the upper respiratory tract and S. pneumoniae causative of pneumonia [30].
The results of our study confirm that the burden of pneumococcal disease remains substantial, particularly in older age groups, even with under-reporting and under-coding by hospital discharge records. In order to attain broader protection against pneumococcal disease and reduce the burden in the adult population, it would be necessary to strike a balance between maintaining disease reduction for current vaccine serotypes, while expanding the additional serotype coverage through research and development.

Strengths of the Study
One strength of this study is that it considered multiple clinical manifestations of pneumonia, including both IPD and pneumococcal-specific pneumonia episodes in addition to unspecified pneumonia. This study also provides two estimates of the clinical burden of pneumonia: one that is highly specific, with a degree of certainty that episodes included in the analysis are caused by S. pneumoniae, and one that would capture additional undetected episodes of pneumococcal pneumonia associated with other pathogens, describing instances of co-infection. Furthermore, our analysis is based on real-world data from the Liguria Regional Administrative Database, including and assessing numerous records on hospitalisation and ED visits.

Limitations of the Study
Within the study design, there is a limitation regarding the assignment of diagnosis codes, such as ICD-9-CM. The assignment of these codes does not necessarily indicate disease presence, due to the possibility of incorrect coding. A further limitation is the uncertainty of the aetiology of the diseases that required hospitalisation, making it difficult to fully attribute the increasing trends in the hospitalisation to pneumococcal disease. However, hospital discharge records that describe the final diagnosis of a patient could be a reliable proxy for the circulation of S. pneumoniae in the Ligurian population.

Conclusions
Following the introduction of PCV13 into the infant immunisation programme throughout Italy since 2010, the annual incidence of pneumococcal pneumonia-related hospitalisation decreased significantly in children < 15 years of age. However, the general incidence of all-cause and pneumococcal pneumonia significantly increased in patients 65-84 and >85 years of age in the Liguria region of Italy. This reinforces the belief that, despite protection in children through the use of PCVs, and subsequent indirect protection in adults, there is an unmet need for increased vaccination uptake in older adults. The impact of new and future PCVs on the incidence of pneumococcal disease will depend on the proportion of disease caused by S. pneumoniae and the prevalence of vaccine-type serotypes in children and adults, substantiating the view that further PCV development with a wider range of serotypes is also warranted.
Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/vaccines10091375/s1, Table S1: Search terms and diagnoses of IPD and pneumonia used to identify episodes all patients in Liguria, Italy (2012-2018); Figure S1: Age-stratified annual incidence of (A) unspecified pneumonia and (B) pneumococcal pneumonia in adolescents and adults ≥ 15 years of age following the introduction of PCV13 in Liguria, Italy  Institutional Review Board Statement: Data collected in the administrative healthcare data regional service are transmitted by the Ligurian Local Health Units and hospitals to the regional health agency of Liguria "Azienda Ligure Sanitaria" (A.Li.Sa.). Thus, ethical review and approval were waived for this study because the institutional activities of A.Li.Sa. include handling regional healthcare administrative data and conduct epidemiological studies, projects, and research to support strategical choices of healthcare Regional Law (29 July 2016, n.17. Istituzione dell'Azienda Ligure Sanitaria della Regione Liguria (A.Li.Sa.) e Indirizzi per il Riordino delle Disposizioni Regionali in Materia Sanitaria e Sociosanitaria. Bollettino Ufficiale n.15, 30 July 2016 Available online: http://lrv.regione.liguria.it/liguriass_prod/articolo?urndoc=urn:nir:regione.liguria:legge: 2016-07-29;17&pr=idx,0;artic, 1;articparziale,0 (accessed on 22 November 2021)). The current regulation on privacy allows professionals belonging to the regional A.Li.Sa. access to healthcare administrative data routinely transmitted by the public funded LHUs and hospitals of the Liguria region. Data are anonymous and have been evaluated in an aggregate manner. Finally, patients who access to regional public health services give consent to the use of healthcare data also for scientific purpose.
Informed Consent Statement: Administrative healthcare data or Data Warehouse is a regional service that collects Hospital Discharge Records (HDRs), the flow of outpatient visits, and pharmaceuticals and was used as a data source. HDR data are recorded with the consent of the patient and can be used for scientific studies in the form of aggregated and de-identified data.