Epidemiology of invasive pneumococcal disease in western Sweden during the first 11 years after the introduction of general childhood pneumococcal vaccination

Epidemiology of invasive pneumococcal disease in western Sweden during the first 11 years after the introduction of general childhood pneumococcal vaccination | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Epidemiology of invasive pneumococcal disease in western Sweden during the first 11 years after the introduction of general childhood pneumococcal vaccination Tor Härnqvist, Karin Bergman, Erik Backhaus, Mats Dahl, Helena Kolberg, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5039210/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Invasive pneumococcal disease (IPD) still causes significant morbidity and mortality. In this study, we describe incidence, risk factors, manifestations, and outcome of IPD in Southwest Sweden during the first 11 years following the introduction of pneumococcal conjugate vaccines (PCV) in the childhood vaccination program in 2009. Methods Clinical data from 2,288 consecutive episodes of IPD in Region Västra Götaland, Sweden, during 2009–2019 were retrospectively collected from medical records. Incidence rates were calculated using population data from the same period. The results were compared to data from three previous studies from the same geographical area with a total follow-up of 56 years. Results The incidence of all IPD episodes in 2009–2019 was 12.8/100,000/year. In children < 2 years, this declined from 22.5 in 1996–2008 to 10.7 per 100,000 in 2009–2019, while only a modest reduction was observed in adults. A very high incidence of IPD was seen in patients with multiple myeloma (1,497/100,000) and chronic lymphocytic leukemia (505/100,000). Meningitis occurred in 26% of the IPD episodes in children < 2 years compared to 4.3% in the age group ≥ 65 years (12/46 versus 60/1,403; p < 0.001). An opposing trend was found for pneumonia, which accounted for 22% of the IPD episodes in children < 2 years compared to 77% among the elderly (10/46 vs. 1,085/1,403; p < 0.001). In 604 IPD episodes (26.4%) one or more complications were observed. The case fatality rate increased from 9.9% pre-PCV to 12.9% in the post-PCV period. This was highest among patients with detected bacteremia but with no other clinical manifestations, those admitted to intensive care, and those with hospital-acquired IPD. Conclusions A substantial decrease in IPD incidence was seen in infants and young children but not in the elderly after introduction of PCV in the general childhood vaccination program. The higher IPD mortality post-PCV could be explained by higher age and increased comorbidity among the patients. Patients with hematological malignancies showed a very high risk for IPD. Streptococcus pneumoniae Pneumococcal disease Invasive Meningitis Pneumonia Predisposing factors Mortality Incidence Figures Figure 1 Figure 2 Introduction Streptococcus pneumoniae (the pneumococcus) was estimated to cause more than 800,000 deaths in 2019 worldwide, being the bacterial pathogen associated with the most deaths among children younger than 5 years [ 1 ]. Invasive pneumococcal disease (IPD) with associated bacteremia and/or meningitis most commonly affects individuals of high or very low age. Chronic diseases including pulmonary disease, cardiovascular disease, and various immunosuppressive conditions add to the risk [ 2 , 3 ]. More than 100 serotypes of pneumococci have until now been described with different potential to cause IPD [ 4 , 5 ]. In January 2009, the 7-valent pneumococcal conjugate vaccine (PCV7) was introduced in the Swedish childhood vaccination program, soon replaced by PCV13 and in Southwest Sweden by PCV10 in 2015. Adherence to the childhood immunization program in Sweden is high, with a pneumococcal immunization coverage of 97.1% in children aged 2 years in 2019 [ 6 ]. International studies have shown a decreased incidence of IPD following the introduction of general vaccination of infants [ 7 , 8 ]. In a Swedish context, a herd-immunity effect was observed among older children and adults but not in the elderly during the first eight years after PCV introduction [ 9 ]. This study presents clinical aspects of IPD epidemiology in Southwest Sweden during the first eleven years after the introduction of PCV in the general childhood vaccination program including IPD incidence, risk factors, manifestations, disease severity, complications, and case fatality rate (CFR), with comparison to data obtained from the same region in the pre-PCV era. Methods Study design and patient identification This is a retrospective analysis of invasive pneumococcal infections among all age groups resident in the Region Västra Götaland, Southwest Sweden, between 1 January 2009 and 31 December 2019. The mean population of the area was 1,640,000 during the study period. The patients were identified from the laboratory information systems at four clinical microbiological laboratories serving all hospitals in the region (Sahlgrenska University Hospital, NU Hospital Group, Södra Älvsborg Hospital, and Skaraborg Hospital). An IPD episode was defined by the detection of S. pneumoniae by culture and/or PCR in a specimen from a normally sterile body site including blood, cerebrospinal fluid (CSF), synovial-, pleural-, peritoneal-, or pericardial fluid, or the vitreous body. Medical data and definitions of clinical manifestations Clinical and demographic data were retrieved from the medical records of each patient. Clinical manifestations were defined as follows: Pneumonia and sinusitis required radiological verification or autopsy. Meningitis was defined either by detection of pneumococci from CSF or by a positive blood culture combined with typical clinical symptoms and increased white blood cell count in CSF. Septic arthritis was defined by the detection of pneumococci from synovial fluid whereas osteomyelitis, cellulitis, otitis media, and bronchitis were diagnosed clinically. Patients with growth of pneumococci in blood cultures but presenting without focal manifestation were classified as having bacteremia without a defined focus. Mixed episodes were classified as meningitis if this coexisted with other clinical manifestations. Pneumonia was classified as such if this coexisted with other non-meningeal manifestations. Case fatality rate (CFR) was calculated as the proportion of patients who died within 30 days from the first sample taken in which pneumococci were detected. The mortality rate was calculated as the number of deaths in IPD per 100,000 residents per year. Disease severity was evaluated by rates of admission and length of hospital stay, and by admission and length of stay at an intensive care unit (ICU), respectively. IPD episodes occurring 7 days or later after hospital admission due to any other reason were defined as hospital-acquired infections. Population and prevalence data Population data regarding age, sex, and municipality per year were collected from Statistics Sweden (SCB). Prevalence data regarding underlying diseases and conditions in the population are summarized in Supplementary Table S1 . The number of individuals at risk for IPD was estimated for defined patient groups with known risk factors for IPD based on previous studies [ 10 – 18 ]. For Chronic Obstructive Pulmonary Disease (COPD) the estimate was based on the percentage with a Global Initiative for Obstructive Lung Disease 2019 (GOLD) score ≥ 2 [ 10 ]. The epidemiology of IPD has been studied in Gothenburg along with five adjacent municipalities since 1964 and in Region Västra Götaland since 1996 using the same study protocol [ 19 – 21 ]. Gothenburg is the second-largest city in Sweden with 570,000 inhabitants and the provincial capital of Region Västra Götaland. The results from the present study period 2009–2019 in Region Västra Götaland were compared to data from the same region 1996–2008 [ 21 ] and to data from the Gothenburg area for the periods 1996–2008, 1964–1980, and 1981–1995, respectively [ 19 – 21 ]. Statistical analyses Data categories are presented with numbers and percentages, and age by median, mean, and range. The Mann–Whitney U test was used to compare numerical data, and Fisher’s exact test to compare proportions. Incidence rate and incidence rate ratio (IRR) for the different age groups were calculated. IRR in 1996–2008 was further compared to 2009–2019 assuming Poisson distribution. The risk of IPD among people living with a specific predisposing factor was compared to the risk among all persons in the region without this factor. The risk of death within 30 days of IPD diagnosis among patients with a certain manifestation or predisposing factor was compared to the risk of dying among patients without this manifestation or predisposing factor. The odds ratio of mortality for different covariates was analyzed in univariable analysis followed by multivariable logistic regression corrected for pre- and post-vaccine periods (1996–2008 and 2009–2019), predisposing factors for IPD, age, sex, and admittance to ICU. Statistical analyses were two-sided, with alpha set at 0.05. Descriptive statistics were calculated using Excel 2013 (Microsoft, Redmond, WA). Multivariable analyses were performed using R Statistical Software (v4.2.2; R Core Team 2022), and all other statistical analyses using GraphPad Prism version 10.2 (GraphPad Software, San Diego, CA). Results Study population and pneumococcal vaccine status A total of 2,296 IPD episodes occurred in patients resident in the region between 2009 and 2019. Medical records were available in 2,288 of these episodes, which occurred in 2,232 patients. Pneumococci were isolated from blood in 2,182 episodes (95.4%), from CSF alone in 19 episodes (0.8%), and from another sterile site alone in 45 episodes (2.0%). In 42 episodes (1.8%) pneumococci were detected solely by PCR. Demographics and clinical characteristics of the patients are shown in Table 1 . The median age of the patients was 69 years, with an almost equal distribution between men and women (Table 1 ). Fifty-five patients had more than one episode of IPD during the study period. Table 1 Patient demographics and clinical characteristics in 2,288 episodes of invasive pneumococcal disease. Characteristic Episodes, n (%) Sex Men 1,172 (51.2) Women 1,116 (48.8) Age in years, median (IQR) [mean; range] 69 (58–80) [65; 0–100] Age groups 0–1 year 46 (2.0) 2–17 years 58 (2.5) 18–50 years 309 (13.5) 51–64 years 472 (20.6) ≥ 65 years 1,403 (61.3) Source of infection Community-acquired 2,199 (96.1) Hospital-acquired 1 89 (3.9) Number of IPD episodes per patient (n patients) One episode 2,177 Two episodes 55 Three episodes 1 Disease severity and outcome Length of hospital stay 2 in days, median (mean) [range] 7 (12) [1–227] ICU care 522 (22.8) Length of stay at ICU in days, median (mean) [range] 3 (7) [0–94] Complications 604 (26.4) Sequelae 117 (5.1) 30-day mortality 259 (12.9) ICU, Intensive care unit; IPD, invasive pneumococcal disease; IQR, interquartile range. 1 Defined as IPD episodes occurring 7 days or later after hospital admission due to any other reason. 2 Length of stay in 2,252 IPD episodes, while 36 additional episodes occurred in patients treated as outpatients. Pneumococcal vaccination status was known in 29.2% (651/2,232) of the patients. Of these, 121 patients were previously vaccinated, most frequently with PPV23 ( n = 47) followed by PCV13 ( n = 27). A total of 88 children < 10 years of age, thus potentially included in the Swedish childhood vaccination program during the study period, suffered from IPD. Among the 53 children with known vaccination status, 21 were unvaccinated. Twenty-four of the patients were infants < 12 months of age, and therefore they had not received all three PCV doses by the time of their IPD episode. Overall IPD incidence during 2009–2019 The mean IPD incidence during 2009–2019 was 12.7/100,000 inhabitants/year, without any obvious decreasing or increasing trend during the period (Fig. 1 A). The incidence was highest in the population ≥ 65 years. In this age group, men had a higher incidence than women (44.8 versus 38.2/100,000; p = 0.003) in contrast to the younger age groups, in which there was no difference in incidence between men and women (Fig. 1 B). The incidence among children 0–23 months of age was 10.7/100,000/year (Fig. 1 B). Comorbidity In 1,765 of the IPD episodes (77%), the patient had one or more predisposing factors, most commonly cardiovascular disease (30%), chronic pulmonary disease (21%), or malignancy (20%) (Table 2 ). Patients with multiple myeloma and chronic lymphocytic leukemia (CLL) had the highest incidence rates (1,497/100,000 and 505/100,000, respectively). High incidence rates were also found for patients with lung cancer and asplenia (Table 2 ). Table 2 Predisposing factors in patients with invasive pneumococcal disease: proportion, incidence rates and CFR. Predisposing factor No. of IPD episodes (%) Incidence 1 (No./100,000/year) Odds ratio to get IPD (95% CI) Died 2 (n) CFR 2 (%) Odds ratio of death (95% CI) Cardiovascular disease 690 (30) 142 20.6 2.45 (1.90 – 3.14) *** Pulmonary disease 472 (21) 72 15.3 1.29 (0.97–1.71) COPD 312 (14) 71 6.32 (5.61–7.13) *** 49 15.7 1.31 (0.94–1.83) Asthma 110 (5) 7 0.49 (0.41–0.60) *** 11 10.0 0.74 (0.41–1.38) Malignancy, any 462 (20) 126 12.36 (11.16–13.70) *** 80 17.3 1.57 (1.19–2.08) ** Hematological 232 (10) 289 26.03 (22.68–29.87) *** 32 13.8 1.09 (0.74–1.62) Multiple myeloma 107 (5) 1,497 147.9 (119.7–182.7) *** 17 15.9 1.29 (0.76–2.21) Chronic lymphocytic leukemia 50 (2) 505 43.01 (32.24–57.38) *** 5 10.0 0.75 (0.32–1.81) Solid tumors 246 (11) 86 7.54 (6.60–8.61) *** 51 20.7 1.93 (1.38–2.68) *** Lung 57 (2) 432 36.57 (27.94–47,87) *** 16 28.1 2.73 (1.53–4.86) ** Breast 26 (1) 43 3.43 (2.33–5.05) *** 5 19.2 1.62 (0.66–4.30) Colon 17 (1) 64 5.14 (3.18–8.29) *** 3 17.6 1.45 (0.44–4.78) Prostate 56 (2) 66 5.35 (4.10–6.98) *** 10 17.9 1.48 (0.71–2.91) Diabetes mellitus 359 (16) 36 3.21 (2.87–3.60) *** 49 13.6 1.08 (0.78–1.50) Autoimmune disease 194 (8) 27 13.9 1.10 (0.71–1.67) Rheumatoid arthritis 42 (2) 41 3.29 (2.42–4.47) *** 6 14.3 1.13 (0.51–2.59) Polymyalgia rheumatica 14 (1) 4 28.6 2.73 (0.93–7.97) Systemic lupus erythematosus 18 (1) 154 12.45 (7.80–19.88) *** 2 11.1 0.84 (0.19–3.38) Liver disease 107 (5) 21 19.6 1.70 (1.05 – 2.74) * Renal disease 127 (6) 33 26.0 2.55 (1.66 – 3.87) *** Hemodialysis 11 (0) 202 16.30 (8.96–29.68) *** 2 18.2 1.51 (0.32–5.96) Peritoneal dialysis 3 (0) 163 13.11 (4.18–41.09) *** 0 0.0 N.A. Immune deficiency 107 (5) 12 11.2 0.85 (0.45–1.53) HIV 5 (0) 54 4.30 (1.78–10.37) ** 0 0.0 N.A. Bone marrow transplant 36 (2) 3 8.3 0.61 (0.19–1.78) Hypogammaglobulinemia 15 (1) 0 0.0 N.A. MGUS 40 (2) 10 0.78 (0.57–1.07) 8 20.0 1.71 (0.81–3.74) Immunosuppressive treatment 3 294 (13) 42 14.3 1.15 (0.80–1.63) Asplenia 45 (2) 249 20.57 (15.25–27.75) *** 9 20.0 1.71 (0.82–3.49) Alcohol dependency 164 (7) 32 19.5 1.72 (1.14–2.59) * Smoking 4 412 (18) 45 10.9 0.80 (0.56–1.25) ≥ 1 predisposing factor 1,765 (77) 266 15.1 3.02 (2.04 – 4.55) *** No known risk factor 523 (23) 29 5.5 All episodes 2,288 (100) 12.7 295 12.9 * p < 0.05, ** p < 0.01, *** p < 0.001 CFR, case fatality rate; COPD, chronic obstructive pulmonary disease; HIV, human immunodeficiency virus; IPD, invasive pneumococcal disease; MGUS, monoclonal gammopathy of undetermined significance; N.A., not applicable. 1 Estimated annual incidence among patients living with this risk factor. For solid tumor malignancies, the estimate is based on 5-year prevalence data. 2 Death within 30 days from sampling with the first detection of pneumococci from a sterile site. 3 Immunosuppressive treatment includes current chemotherapy, immunosuppressants such as tumor necrosis factor inhibitors, and cortisone > 2 weeks in a daily dosage equivalent to prednisone 7.5 mg or higher. 4 Defined as current smoking. Among the 55 patients with two or more IPD episodes, 54 (98%) had an identifiable predisposing condition. Three of these patients had asplenia, while 25 had a hematological malignancy, primarily multiple myeloma ( n = 15). Clinical manifestations Pneumonia was the most frequent IPD manifestation with 1,658 episodes (72%) followed by bacteremia without focus ( n = 281, 12%), and meningitis ( n = 179, 7.8%) (Table 3 ). The annual incidence of IPD with pneumonia during the study period was 9.2/100,000. The annual meningitis incidence was 1.0/100,000 in all age groups and 2.8/100,000 among children < 2 years. The distribution of manifestations varied largely between the age groups. Meningitis occurred in 26% of the IPD episodes in children < 2 years compared to 4.3% of the episodes in the highest age group ≥ 65 years (12/46 vs. 60/1,403; p < 0.001). Almost the opposite was found for pneumonia, which accounted for 22% of the IPD episodes in children < 2 years compared to 77% among the elderly (10/46 vs. 1,085/1,403; p < 0.001). More rarely observed IPD manifestations, including septic arthritis ( n = 80), acute otitis media with or without mastoiditis ( n = 74), sinusitis ( n = 39), endocarditis ( n = 18), and osteitis ( n = 17) are listed in Supplementary Table S2. Table 3 Manifestations in invasive pneumococcal disease: proportions, age distribution and relative risk of death. No. (%) of episodes in different age groups Fatalities Manifestation 1 0–1 year. 2–17 yrs. 18–50 yrs. 51–64 yrs. 65–100 yrs. All ages Died 2 (n) CFR 2 (%) Odds ratio of death (95% CI) Pneumonia without meningitis 10 (22) 22 (38) 230 (74) 316 (67) 1,080 (77) 1,658 (72) 196 11.8% 0.72 (0.56 – 0.93) * …with empyema 2 4 14 17 59 96 6 6.3% …with parapneumonic effusion 0 2 21 23 84 130 12 9.2% Bacteremia with no detectable focus 15 (33) 17 (29) 21 (7) 57 (12) 171 (12) 281 (12) 70 24.9% 2.63 (1.94–3.55) *** Meningitis 12 (26) 9 (16) 39 (13) 59 (13) 60 (4) 179 (8) 17 9.5% 0.69 (0.42–1.16) …without pneumonia 12 9 37 55 55 168 17 …with concurrent pneumonia 0 0 2 4 5 11 0 …with concurrent acute otitis media 1 2 14 16 15 48 4 Other manifestations without pneumonia or meningitis 9 (20) 10 (17) 19 (6) 40 (8) 92 (7) 170 (7) 12 7.1% 0.49 (0.27 – 0.89) * All episodes 46 (100) 58 (100) 309 (100) 472 (100) 1,403 (100) 2,288 (100) 295 12.9% * p < 0.05, *** p < 0.001 CFR, case fatality rate. 1 In 130 episodes more than one manifestation was identified. 2 Death within 30 days from the first sample taken in which pneumococci were identified. A large proportion of patients diagnosed with IPD bacteremia without detectable focus had an underlying malignant disease (42.0%; 118/281), as compared to 18.4% (307/1,669) of patients with IPD and pneumonia. Hospital-acquired IPD occurred in 3.9% of all episodes (Table 1 ). One-third of these patients had an underlying malignant disease (34%, 30/89). Disease severity and complications The patients were treated in hospital in 2,252 of the 2,288 (98.4%) IPD episodes, with a median duration of seven days (range 1–227 days) (Table 1 ). In 22.8% of all episodes, the patient was admitted to the ICU (Table 1 ). Pneumonia was the most frequent manifestation in the ICU admitted patients (326/522; 62.5%), followed by meningitis ( n = 119; 22.8%) and bacteremia without focus ( n = 46; 8.8%). In one-quarter of the IPD episodes one or more specific complications was observed, most commonly parapneumonic effusion ( n = 135), followed by empyema ( n = 98), and myocardial infarction ( n = 24) (Table 1 ). One hundred and sixty-two patients out of 179 with meningitis survived (90.5%). Among these, 57 patients (35.2%), of all ages, had neurological sequelae including paresis, hearing loss, fatigue, and loss of concentration. Among children < 5 years of age with meningitis 12/14 survived, one with a subsequent facial palsy, the others without major sequelae. Case fatality rate Two hundred and ninety-five patients died within 30 days from IPD diagnosis, resulting in an overall CFR of 12.9% (Table 1 ). Of altogether 104 IPD episodes in children and youth < 18 years, four children died (two below 12 months of age, and two 3–4 years) resulting in a CFR of 3.8%. CFR in different age groups is shown in Supplementary Fig. S2. CFR was higher in patients with a known predisposing risk factor or comorbidity compared to those without (15.7% vs. 5.5%, p < 0.001) (Table 2 ). Bacteremia with no detectable focus was associated with the highest CFR (24.9%), followed by pneumonia (11.8%) and meningitis (9.5%) (Table 3 ). Patients with hospital-acquired IPD had a high mortality rate (CFR 36.0%). In patients with complications following their IPD, CFR was 16.9%, and among ICU patients this was 21.1%. Long-term trends: Comparison with previous study periods The annual IPD incidence in Region Västra Götaland was lower during the present study period (2009–2019) compared to the previous period 1996–2008 (12.7 vs. 15.1/100,000; p < 0.001) [ 21 ]. The incidence rate of IPD in the different age groups in 1996–2008 compared to 2009–2019 is shown in Fig. 2 . The incidence was 10/100,000 during the years 1981–1995 and 5/100,000 in 1964–1980 (these study periods included only the city of Gothenburg and surrounding urban areas) (Table 4 ) [ 19 , 20 ]. Table 4 Incidence, CFR, and mortality of IPD in Gothenburg urban area from 1964 to 2019. Age, years Mean population 1 Cases Incidence 2 Died 3 (n) CFR 3 (%) Mortality 4 1964–1980 (17 years) 0–1 15,248 52 23 8 15 3.1 2–17 118,570 32 2 3 9 0.1 18–50 264,282 161 4 28 17 0.6 51-65 a 98,657 129 9 27 21 1.6 66– a 79,387 134 11 34 25 2.5 All ages 576,143 508 5 100 20 1.0 1981–1995 (15 years) 0–1 15,169 67 29 5 7 2.2 2–17 103,624 35 2 3 9 0.2 18–50 280,287 189 4 18 10 0.4 51–64 84,475 167 13 27 16 2.1 65– 99,233 441 30 83 19 5.6 All ages 582,789 899 10 136 15 1.6 1996–2008 (13 years) 0–1 11,636 37 24 1 3 0.66 2–17 118,604 31 2 1 3 0.06 18–50 308,938 257 6 9 4 0.22 51–64 102,280 228 17 10 4 0.75 65– 102,161 530 40 72 14 5.4 All ages 643,620 1,083 13 93 9 1.1 2009–2019 (11 years) 0–1 19,212 21 10 1 5 0.47 2–17 130,413 27 2 1 4 0.07 18–50 353,285 128 3 4 3 0.10 51–64 115,809 170 13 19 11 1.5 65– 115,287 484 38 84 17 6.6 All ages 734,007 830 10 109 13 1.4 CFR, case fatality rate; IPD, invasive pneumococcal disease. 1 Mean population during the period. Values for 1964–1980 are calculated from data obtained from 1968–1980. 2 Number of IPD episodes/100,000 inhabitants/year. 3 Death within 30 days from the first sample taken in which pneumococci were identified. 4 Number of patients who died from IPD/100,000 inhabitants/year. a Data from 1964–1980 include the age groups 51–65 years and 66 years and above. In the region of Västra Götaland, the IPD incidence among children < 2 years decreased by half during the present study period, i.e. the eleven first years after the introduction of pneumococcal vaccine in the childhood vaccination program in Sweden, compared to the previous period (10.7/100,000 in 2009–2019 vs. 22.5/100,000 in 1996–2008; p < 0.001). In the elderly aged 65 years and above, the incidence rate was 41/100,000 in 2009–2019 as compared to 45/100,000 in 1996–2008 ( p = 0.03). The median age at IPD diagnosis increased from 65 in 1996–2008 to 69 years in the present period 2009–2019 ( p < 0.001). During the same periods, the median age at the time of IPD diagnosis among children < 2 years decreased from 414 to 344 days after birth. In the previous study period, data on smoking was not included in the analysis of predisposing factors for IPD. Even after correcting for this, the prevalence of underlying comorbidities or other risk factors for IPD was higher after PCV introduction compared with the previous study period (72% (1,654/2,288) vs. 67% (1,994/2,977); p < 0.001). The annual meningitis incidence has been registered since 1970 and has declined gradually from 1.4/100,000 for all ages in the first study period (1970–1980) to 0.9/100,000 in the present study period. For children < 2 years, the annual meningitis incidence was 12.0/100,000 in 1970–1980, 7.0/100,000 in 1981–1995, 8.6/100,100 in 1996–2008 and 2.8/100,000 in 2009–2019. Overall CFR was higher during the present study period compared to the previous period 1996–2008 (12.9% vs. 9.9%; p < 0.001) but lower than 1964–1980 (20%; p < 0.001). However, after adjusting for age, sex, underlying comorbidity, and ICU care, the difference in mortality between the last two study periods was no longer statistically significant (Supplementary Table S3). Compared to the previous study period 1996–2008, mortality rate has increased among individuals aged 50 and above, whereas in children and younger adults, mortality has steadily decreased over time (Table 4 ). CFR among patients with meningitis showed a decreasing trend compared to previous study periods (9.5% compared to 13.5% in 1996–2008 and 33% in 1964–1980). Discussion This study describes the IPD epidemiology in Southwest Sweden after the introduction of PCV in the general childhood vaccination program and before the onset of the COVID-19 pandemic. It follows a series of IPD studies during 56 years in the same area [ 19 – 21 ]. Overall, 77% of the patients had a known medical condition predisposing to invasive pneumococcal infection. Hematological malignancies, specifically multiple myeloma, and chronic lymphatic leukemia are well-known high-risk factors for IPD [ 22 ]. We found a 118-fold increase in the incidence of IPD among myeloma patients compared to the overall population, and a 40-fold increase among patients with chronic lymphatic leukemia, similar to pre-PCV incidence rates [ 21 ]. Patients with multiple myeloma have impaired B- and T-cell function [ 23 ] and hence an inadequate response to pneumococcal vaccination [ 24 ], which leaves them more vulnerable to pneumococcal infections. Myeloma has been associated with repeated IPD episodes [ 25 ], and our study confirms this. MGUS (monoclonal gammopathy of undetermined significance), which affects approximately 5% of the population > 40 years and may develop into multiple myeloma, has been associated with an increased risk of pneumonia [ 26 ]. We did not find an increased risk of IPD in patients with MGUS, which might reflect an under-diagnosis of the condition in the population. As previously described [ 21 , 22 , 27 ], patients with lung cancer, asplenia, or chronic renal failure undergoing hemodialysis had high incidences of IPD (34-fold, 20-fold, and 16-fold increase, respectively). Only five of the 2,288 recorded IPD episodes occurred in HIV-positive patients, another well-described risk group [ 28 ]. We suggest, however that this is explicable in terms of the known high coverage of anti-retroviral treatment in Sweden (> 95% of HIV patients) resulting in a decreased susceptibility to IPD [ 29 , 30 ]. In almost one-fourth of all patients (23%), no predisposing factor for IPD was found. These patients might have a yet unknown primary or secondary immune deficiency. Other reasons for IPD include viral coinfection, genetic predisposition, or infection by particularly virulent pneumococcal strains. We found an equal incidence of IPD in men and women in all age groups except for the > 65 years group, where men had a higher incidence. This is consistent with data from the previous pre-vaccine study period in the same area [ 21 ] but contrasts with other international studies as well as the earlier study periods in the region, in which men were over-represented [ 19 , 20 , 31 ]. The clinical manifestations of IPD remained largely unchanged after the introduction of PCV in the region [ 21 ]. In children < 2 years, meningitis and bacteremia without focus still comprised almost two-thirds of all episodes. The most common IPD manifestation in the elderly was pneumonia, accounting for 77% of all episodes. The incidence of meningitis decreased with age, as observed in other studies [ 32 , 33 ]. IPD is a severe medical condition and, expectedly, we found a high rate of complications (26.4%), most commonly parapneumonic effusion and empyema. A concurrent myocardial infarction was present in 24 patients. In fact, a strong association between acute myocardial infarction and IPD was found in Tennessee residents in the USA [ 34 ]. Similar to previous reports one-third of the patients with meningitis suffered from neurological sequelae [ 35 ], and this affected all ages. In coherence with multiple studies [ 7 , 36 – 38 ], the overall IPD incidence among children < 2 years declined substantially after PCV introduction. We also observed a general decrease in IPD in the population compared to the previous study period. The reduction of IPD incidence in the elderly was statistically significant, although this was much less pronounced than in infants and younger adults. This limited herd protection of the elderly after introduction of PCV in the childhood vaccination program is consistent with reports from other countries [ 9 , 39 ]. The pneumococcal serotype distribution is highly dynamic and alters over time, geographically, and after the introduction of vaccination [ 40 , 41 ]. We and others have shown that the cause of IPD in persons with known predisposing factors has shifted from PCV13 to non-PCV13 serotypes in Sweden [ 42 , 43 ]. This shift is probably the main driving force behind the lack of substantial IPD decline in the elderly. Despite a reduction of incidence in the present study, the overall incidence of IPD has remained relatively stable in Sweden since the 1990s [ 9 , 20 , 21 ]. Besides the phenomenon of pneumococcal serotype shift this might be explained by an aging population and the increased use of immunosuppressive treatments in various chronic diseases. The number of collected blood cultures has also increased significantly [ 44 ], and in combination with improved blood culture systems, the likelihood of detecting an IPD episode has most likely increased over time. The increase in IPD mortality in the present study as compared to previous periods in the same area was unexpected but could be explained by the increased median age and comorbidity of the patients. However, in comparison with other cohorts, the mortality rate (12.9%) was low. In a meta-analysis of 26 studies from different countries and settings, the overall mortality was 20.8% [ 45 ]. Factors associated with death from IPD in that meta-analysis included age ≥ 65 years, nosocomial infection, underlying chronic diseases, solid organ tumors, and immunosuppressive conditions [ 45 ], i.e. these were similar to our findings. We did not specifically study septic shock, which was also identified as an independent risk factor for mortality, but we observed a high mortality rate in patients admitted to the ICU (20.9%) [ 45 ]. Severe underlying conditions, including hematological malignancies, could also explain the high mortality rates in patients with bacteremia without focus as well as in patients with hospital-acquired IPD (24.6% and 36.0%, respectively). A strength of this study is that almost all IPD episodes during the 11-year study period were included. The use of the same clinical protocol in previous studies allows for long-term follow-up in the study area. Data on clinical manifestations, underlying diseases, and outcomes are solid due to the high quality of the medical records. This study was terminated shortly before the COVID-19 outbreak, and our results are thus not affected by the pandemic. Limitations include the lack of data regarding mechanical ventilation or septic shock management for patients receiving intensive care. Furthermore, occupational exposures linked to a higher IPD risk such as welding were not assessed [ 46 ]. Alcohol abuse and smoking constitute known risk factors for IPD, although the magnitude of their impact is not entirely clear [ 47 ]. Data on alcohol abuse and smoking were most likely underreported in the medical records, hence, the effect of these factors could be underestimated in the analysis. With this study, we present the follow-up data covering 56 years of continuous IPD epidemiology from a geographically relatively large area in Sweden. The present study period adds data from the first eleven years after the introduction of pneumococcal vaccination in the childhood vaccine program. With the addition of PCV15 and PCV20 and the implementation of a national pneumococcal vaccine program for risk groups in Sweden in 2022, further surveillance is warranted on the long-term influence of vaccination on IPD incidence and mortality, including the pneumococcal serotype distribution and the effects on different age groups. Conclusions Following the introduction of a pneumococcal conjugate vaccine in the childhood vaccination program in 2009, IPD incidence has declined among children, but to a much lesser extent in adults > 65 years of age. On the contrary, the overall mortality in IPD was higher than in the pre-vaccine period, with the highest numbers of deaths seen among patients with bacteremia without other clinical manifestations, ICU patients, and patients with hospital-acquired IPD. The increased mortality may be explained by increased age and comorbidity among the patients. Patients with hematological malignancies, especially multiple myeloma, still have a very high risk for IPD. Abbreviations CFR Case fatality rate CLL Chronic lymphocytic leukemia COPD Chronic obstructive pulmonary disease CSF Cerebrospinal fluid GOLD Global Initiative for Obstructive Lung Disease 2019 ICU Intensive care unit IQR Interquartile range IPD Invasive pneumococcal disease MGUS Monoclonal gammopathy of undetermined significance PCR Polymerase chain reaction PCV Pneumococcal conjugate vaccine PPV23 Pneumococcal polysaccharide vaccine SCB Statistics Sweden Declarations Ethics approval and consent to participate The study was approved by the Regional Ethics Committee of Gothenburg (no.123-15, T351-16, and 2020-03453). Informed consent was not obtained due to the retrospective study design. Clinical trial number: not applicable Consent for publication All authors have approved the manuscript for submission. Availability of data and material The dataset used during the current study is available from the corresponding author on request. Competing interests EB and KB are former members of the advisory boards for Pfizer and GSK. The other authors have no competing interests. Funding This work was supported by the Healthcare Committee in Region Västra Götaland [grant no. VGFOUREG-477211 and VGFOUREG-659551], the Local Research and Development Council in Fyrbodal [grant no. VGFOUFBD-964663], and the Department of Research and Development, NU Hospital Group. Authors' contributions RA, EB, and SS designed the study. TH, KB, MD, HK, CST, MO, and JK, collected data from medical records. TH analyzed the data, in close contact with JK and SN. SN performed the multivariate analysis. TH drafted the manuscript, which was finalized together with JK, SS, RA, and KB. All authors have read and approved the final manuscript. Acknowledgements Professor Birger Trollfors, a senior pneumococcal researcher, contributed to the study design and data collection. Unfortunately, he passed away prior to the completion of the study. We wish to thank assistant Malin Karlsson for help with entering data into the database. References Collaborators GBDAR. Global mortality associated with 33 bacterial pathogens in 2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2022;400(10369):2221–48. van Hoek AJ, Andrews N, Waight PA, Stowe J, Gates P, George R, Miller E. The effect of underlying clinical conditions on the risk of developing invasive pneumococcal disease in England. J Infect. 2012;65(1):17–24. Kyaw MH, Rose CE Jr., Fry AM, Singleton JA, Moore Z, Zell ER, Whitney CG. Active Bacterial Core Surveillance Program of the Emerging Infections Program N: The influence of chronic illnesses on the incidence of invasive pneumococcal disease in adults. J Infect Dis. 2005;192(3):377–86. 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Invasive pneumococcal disease: Clinical outcomes and patient characteristics 2–6 years after introduction of 7-valent pneumococcal conjugate vaccine compared to the pre-vaccine period, the Netherlands. Vaccine. 2016;34(8):1077–85. Wiese AD, Mitchel E, Ndi D, Markus TM, Talbot HK, Schaffner W, Grijalva CG. Risk of Acute Myocardial Infarction Among Patients With Laboratory-Confirmed Invasive Pneumococcal Disease: A Self-Controlled Case Series Study. Clin Infect Dis. 2023;76(12):2171–7. Lucas MJ, Brouwer MC, van de Beek D. Neurological sequelae of bacterial meningitis. J Infect. 2016;73(1):18–27. Waight PA, Andrews NJ, Ladhani SN, Sheppard CL, Slack MP, Miller E. Effect of the 13-valent pneumococcal conjugate vaccine on invasive pneumococcal disease in England and Wales 4 years after its introduction: an observational cohort study. Lancet Infect Dis. 2015;15(5):535–43. Ben-Shimol S, Greenberg D, Givon-Lavi N, Schlesinger Y, Miron D, Aviner S, Dagan R, Israel B. Meningitis Active Surveillance G: Impact of PCV7/PCV13 introduction on invasive pneumococcal disease (IPD) in young children: Comparison between meningitis and non-meningitis IPD. Vaccine. 2016;34(38):4543–50. De Wals P, Lefebvre B, Deceuninck G, Longtin J. Incidence of invasive pneumococcal disease before and during an era of use of three different pneumococcal conjugate vaccines in Quebec. Vaccine. 2018;36(3):421–6. van der Linden M, Imohl M, Perniciaro S. Limited indirect effects of an infant pneumococcal vaccination program in an aging population. PLoS ONE. 2019;14(8):e0220453. Harboe ZB, Benfield TL, Valentiner-Branth P, Hjuler T, Lambertsen L, Kaltoft M, Krogfelt K, Slotved HC, Christensen JJ, Konradsen HB. Temporal trends in invasive pneumococcal disease and pneumococcal serotypes over 7 decades. Clin Infect Dis. 2010;50(3):329–37. Stockmann C, Ampofo K, Pavia AT, Blaschke AJ, Mason EO, Presson AP, Forney LJ, Byington CL. Clinical and Epidemiological Evidence of the Red Queen Hypothesis in Pneumococcal Serotype Dynamics. Clin Infect Dis. 2016;63(5):619–26. Bergman K, Harnqvist T, Backhaus E, Trollfors B, Dahl MS, Kolberg H, Ockborn G, Andersson R, Karlsson J, Mellgren A, et al. Invasive pneumococcal disease in persons with predisposing factors is dominated by non-vaccine serotypes in Southwest Sweden. BMC Infect Dis. 2021;21(1):756. Naucler P, Galanis I, Petropoulos A, Granath F, Morfeldt E, Ortqvist A, Henriques-Normark B. Chronic disease and immunosuppression increase the risk for non-vaccine serotype pneumococcal disease - a nationwide population-based study. Clin Infect Dis 2021. Holmbom M, Giske CG, Fredrikson M, Ostholm Balkhed A, Claesson C, Nilsson LE, Hoffmann M, Hanberger H. 14-Year Survey in a Swedish County Reveals a Pronounced Increase in Bloodstream Infections (BSI). Comorbidity - An Independent Risk Factor for Both BSI and Mortality. PLoS ONE. 2016;11(11):e0166527. Chen H, Matsumoto H, Horita N, Hara Y, Kobayashi N, Kaneko T. Prognostic factors for mortality in invasive pneumococcal disease in adult: a system review and meta-analysis. Sci Rep. 2021;11(1):11865. Toren K, Blanc PD, Naidoo RN, Murgia N, Qvarfordt I, Aspevall O, Dahlman-Hoglund A, Schioler L. Occupational exposure to dust and to fumes, work as a welder and invasive pneumococcal disease risk. Occup Environ Med. 2020;77(2):57–63. Cruickshank HC, Jefferies JM, Clarke SC. Lifestyle risk factors for invasive pneumococcal disease: a systematic review. BMJ Open. 2014;4(6):e005224. Additional Declarations Competing interest reported. EB and KB are former members of the advisory boards for Pfizer and GSK. The other authors have no competing interests. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5039210","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":365578012,"identity":"69ccc30a-89be-44db-a9b9-14190a44429f","order_by":0,"name":"Tor Härnqvist","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2klEQVRIiWNgGAWjYJACZgjF2MDAUEGEch4ULQfOkKYFCA62EaHFnr33AXNBzb08vhvJzZ8/zqtNbOA/fAC/LTzHDZhnHCsulryR2CZxcNvxxAaJtAT8WiTSGJh52BISN5wBuurgtmNALTwGRGj5B9bS/OHgHKAW/vMfCGvhbQNqOd7YIHGwoSaxgSEHrw4GnjPHGA7z9iUkzjze2CZx5tgB4zaJNPwOY29vY3zM8y0hse8w++MPFTV1sv38hx/gtwYIDiCRhxnYCKpH01hHvIZRMApGwSgYMQAAeqtK+mMCqiYAAAAASUVORK5CYII=","orcid":"","institution":"University of Gothenburg","correspondingAuthor":true,"prefix":"","firstName":"Tor","middleName":"","lastName":"Härnqvist","suffix":""},{"id":365578013,"identity":"1408c3ca-0b5b-494a-934b-05a434b4b7cd","order_by":1,"name":"Karin Bergman","email":"","orcid":"","institution":"University of Gothenburg","correspondingAuthor":false,"prefix":"","firstName":"Karin","middleName":"","lastName":"Bergman","suffix":""},{"id":365578014,"identity":"c3c5af67-3bd9-4549-a1e8-5d31b547a134","order_by":2,"name":"Erik Backhaus","email":"","orcid":"","institution":"Skaraborg Hospital, Region Västra Götaland","correspondingAuthor":false,"prefix":"","firstName":"Erik","middleName":"","lastName":"Backhaus","suffix":""},{"id":365578015,"identity":"7dc812aa-f4da-4d73-a89d-fb35e1c484bf","order_by":3,"name":"Mats Dahl","email":"","orcid":"","institution":"Närhälsan Management Group, Region Västra Götaland","correspondingAuthor":false,"prefix":"","firstName":"Mats","middleName":"","lastName":"Dahl","suffix":""},{"id":365578016,"identity":"f195ecd7-7768-424d-8fff-6aba6e2a9277","order_by":4,"name":"Helena Kolberg","email":"","orcid":"","institution":"NU Hospital Group, Region Västra Götaland","correspondingAuthor":false,"prefix":"","firstName":"Helena","middleName":"","lastName":"Kolberg","suffix":""},{"id":365578017,"identity":"29d1d9a3-326b-4339-a38b-c2fbfab8c52d","order_by":5,"name":"Caroline Ström Turesson","email":"","orcid":"","institution":"Sahlgrenska University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Caroline","middleName":"Ström","lastName":"Turesson","suffix":""},{"id":365578018,"identity":"5c3361f0-076b-4130-9f55-f38be5fd84f6","order_by":6,"name":"Malin Olander","email":"","orcid":"","institution":"Region Halland","correspondingAuthor":false,"prefix":"","firstName":"Malin","middleName":"","lastName":"Olander","suffix":""},{"id":365578019,"identity":"b73e4ecd-e5a7-46c4-9086-e32c5f85f883","order_by":7,"name":"Staffan Nilsson","email":"","orcid":"","institution":"University of Gothenburg","correspondingAuthor":false,"prefix":"","firstName":"Staffan","middleName":"","lastName":"Nilsson","suffix":""},{"id":365578020,"identity":"3c6fdce1-9fc6-4133-a38b-3477089c0293","order_by":8,"name":"Rune Andersson","email":"","orcid":"","institution":"University of Gothenburg","correspondingAuthor":false,"prefix":"","firstName":"Rune","middleName":"","lastName":"Andersson","suffix":""},{"id":365578021,"identity":"60d0600f-4e61-45d4-9240-5f51c15c9044","order_by":9,"name":"Susann Skovbjerg","email":"","orcid":"","institution":"University of Gothenburg","correspondingAuthor":false,"prefix":"","firstName":"Susann","middleName":"","lastName":"Skovbjerg","suffix":""},{"id":365578022,"identity":"ca292e64-b4b7-4374-86ab-9ef3d057d28f","order_by":10,"name":"Johanna Karlsson","email":"","orcid":"","institution":"University of Gothenburg","correspondingAuthor":false,"prefix":"","firstName":"Johanna","middleName":"","lastName":"Karlsson","suffix":""}],"badges":[],"createdAt":"2024-09-05 15:12:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5039210/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5039210/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":67203991,"identity":"cf0cc726-91f8-49fe-9284-fb6172fabbb7","added_by":"auto","created_at":"2024-10-22 10:33:05","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":991615,"visible":true,"origin":"","legend":"\u003cp\u003ePanel A shows the number of episodes of and deaths from invasive pneumococcal disease per year. Panel B shows the age-specific incidence rates of invasive pneumococcal disease in men and women in different age groups during 2009–2019.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-5039210/v1/0e913d60978f510f25582524.png"},{"id":67203990,"identity":"7fe51627-d96f-4825-aec3-0ed86303964e","added_by":"auto","created_at":"2024-10-22 10:33:04","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":492556,"visible":true,"origin":"","legend":"\u003cp\u003eIncidence rate of invasive pneumococcal disease in different age groups in 1996–2008 as compared to 2009–2019 in Region Västra Götaland, Sweden, presented with 95% confidence interval.\u003c/p\u003e\n\u003cp\u003e* \u003cem\u003ep \u003c/em\u003e\u0026lt;0.05; *** \u003cem\u003ep \u003c/em\u003e\u0026lt;0,001\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eIRR, incidence rate ratio.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-5039210/v1/e0a0e3701272c5685ded6acc.png"},{"id":74910227,"identity":"0c874b05-2b51-4908-89cc-bb7cc28885a4","added_by":"auto","created_at":"2025-01-28 08:54:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3268110,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5039210/v1/2196bb26-558f-4793-b396-31c4f45a2081.pdf"},{"id":67203992,"identity":"d81e330a-73ed-41d2-8b96-04afa7e771ca","added_by":"auto","created_at":"2024-10-22 10:33:05","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":160110,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-5039210/v1/4cc6c8660972361d115e94d3.docx"}],"financialInterests":"Competing interest reported. EB and KB are former members of the advisory boards for Pfizer and GSK. The other authors have no competing interests.","formattedTitle":"Epidemiology of invasive pneumococcal disease in western Sweden during the first 11 years after the introduction of general childhood pneumococcal vaccination","fulltext":[{"header":"Introduction","content":"\u003cp\u003e \u003cem\u003eStreptococcus pneumoniae\u003c/em\u003e (the pneumococcus) was estimated to cause more than 800,000 deaths in 2019 worldwide, being the bacterial pathogen associated with the most deaths among children younger than 5 years [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Invasive pneumococcal disease (IPD) with associated bacteremia and/or meningitis most commonly affects individuals of high or very low age. Chronic diseases including pulmonary disease, cardiovascular disease, and various immunosuppressive conditions add to the risk [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMore than 100 serotypes of pneumococci have until now been described with different potential to cause IPD [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In January 2009, the 7-valent pneumococcal conjugate vaccine (PCV7) was introduced in the Swedish childhood vaccination program, soon replaced by PCV13 and in Southwest Sweden by PCV10 in 2015. Adherence to the childhood immunization program in Sweden is high, with a pneumococcal immunization coverage of 97.1% in children aged 2 years in 2019 [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. International studies have shown a decreased incidence of IPD following the introduction of general vaccination of infants [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. In a Swedish context, a herd-immunity effect was observed among older children and adults but not in the elderly during the first eight years after PCV introduction [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e This study presents clinical aspects of IPD epidemiology in Southwest Sweden during the first eleven years after the introduction of PCV in the general childhood vaccination program including IPD incidence, risk factors, manifestations, disease severity, complications, and case fatality rate (CFR), with comparison to data obtained from the same region in the pre-PCV era.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and patient identification\u003c/h2\u003e \u003cp\u003eThis is a retrospective analysis of invasive pneumococcal infections among all age groups resident in the Region V\u0026auml;stra G\u0026ouml;taland, Southwest Sweden, between 1 January 2009 and 31 December 2019. The mean population of the area was 1,640,000 during the study period. The patients were identified from the laboratory information systems at four clinical microbiological laboratories serving all hospitals in the region (Sahlgrenska University Hospital, NU Hospital Group, S\u0026ouml;dra \u0026Auml;lvsborg Hospital, and Skaraborg Hospital). An IPD episode was defined by the detection of \u003cem\u003eS. pneumoniae\u003c/em\u003e by culture and/or PCR in a specimen from a normally sterile body site including blood, cerebrospinal fluid (CSF), synovial-, pleural-, peritoneal-, or pericardial fluid, or the vitreous body.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eMedical data and definitions of clinical manifestations\u003c/h2\u003e \u003cp\u003eClinical and demographic data were retrieved from the medical records of each patient. Clinical manifestations were defined as follows: Pneumonia and sinusitis required radiological verification or autopsy. Meningitis was defined either by detection of pneumococci from CSF or by a positive blood culture combined with typical clinical symptoms and increased white blood cell count in CSF. Septic arthritis was defined by the detection of pneumococci from synovial fluid whereas osteomyelitis, cellulitis, otitis media, and bronchitis were diagnosed clinically. Patients with growth of pneumococci in blood cultures but presenting without focal manifestation were classified as having bacteremia without a defined focus. Mixed episodes were classified as meningitis if this coexisted with other clinical manifestations. Pneumonia was classified as such if this coexisted with other non-meningeal manifestations.\u003c/p\u003e \u003cp\u003eCase fatality rate (CFR) was calculated as the proportion of patients who died within 30 days from the first sample taken in which pneumococci were detected. The mortality rate was calculated as the number of deaths in IPD per 100,000 residents per year.\u003c/p\u003e \u003cp\u003eDisease severity was evaluated by rates of admission and length of hospital stay, and by admission and length of stay at an intensive care unit (ICU), respectively. IPD episodes occurring 7 days or later after hospital admission due to any other reason were defined as hospital-acquired infections.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003ePopulation and prevalence data\u003c/h2\u003e \u003cp\u003ePopulation data regarding age, sex, and municipality per year were collected from Statistics Sweden (SCB). Prevalence data regarding underlying diseases and conditions in the population are summarized in Supplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e. The number of individuals at risk for IPD was estimated for defined patient groups with known risk factors for IPD based on previous studies [\u003cspan additionalcitationids=\"CR11 CR12 CR13 CR14 CR15 CR16 CR17\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. For Chronic Obstructive Pulmonary Disease (COPD) the estimate was based on the percentage with a Global Initiative for Obstructive Lung Disease 2019 (GOLD) score\u0026thinsp;\u0026ge;\u0026thinsp;2 [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe epidemiology of IPD has been studied in Gothenburg along with five adjacent municipalities since 1964 and in Region V\u0026auml;stra G\u0026ouml;taland since 1996 using the same study protocol [\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Gothenburg is the second-largest city in Sweden with 570,000 inhabitants and the provincial capital of Region V\u0026auml;stra G\u0026ouml;taland. The results from the present study period 2009\u0026ndash;2019 in Region V\u0026auml;stra G\u0026ouml;taland were compared to data from the same region 1996\u0026ndash;2008 [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] and to data from the Gothenburg area for the periods 1996\u0026ndash;2008, 1964\u0026ndash;1980, and 1981\u0026ndash;1995, respectively [\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses\u003c/h2\u003e \u003cp\u003eData categories are presented with numbers and percentages, and age by median, mean, and range. The Mann\u0026ndash;Whitney U test was used to compare numerical data, and Fisher\u0026rsquo;s exact test to compare proportions. Incidence rate and incidence rate ratio (IRR) for the different age groups were calculated. IRR in 1996\u0026ndash;2008 was further compared to 2009\u0026ndash;2019 assuming Poisson distribution. The risk of IPD among people living with a specific predisposing factor was compared to the risk among all persons in the region without this factor. The risk of death within 30 days of IPD diagnosis among patients with a certain manifestation or predisposing factor was compared to the risk of dying among patients without this manifestation or predisposing factor. The odds ratio of mortality for different covariates was analyzed in univariable analysis followed by multivariable logistic regression corrected for pre- and post-vaccine periods (1996\u0026ndash;2008 and 2009\u0026ndash;2019), predisposing factors for IPD, age, sex, and admittance to ICU.\u003c/p\u003e \u003cp\u003eStatistical analyses were two-sided, with alpha set at 0.05. Descriptive statistics were calculated using Excel 2013 (Microsoft, Redmond, WA). Multivariable analyses were performed using R Statistical Software (v4.2.2; R Core Team 2022), and all other statistical analyses using GraphPad Prism version 10.2 (GraphPad Software, San Diego, CA).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStudy population and pneumococcal vaccine status\u003c/h2\u003e \u003cp\u003eA total of 2,296 IPD episodes occurred in patients resident in the region between 2009 and 2019. Medical records were available in 2,288 of these episodes, which occurred in 2,232 patients.\u003c/p\u003e \u003cp\u003ePneumococci were isolated from blood in 2,182 episodes (95.4%), from CSF alone in 19 episodes (0.8%), and from another sterile site alone in 45 episodes (2.0%). In 42 episodes (1.8%) pneumococci were detected solely by PCR.\u003c/p\u003e \u003cp\u003eDemographics and clinical characteristics of the patients are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The median age of the patients was 69 years, with an almost equal distribution between men and women (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Fifty-five patients had more than one episode of IPD during the study period.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient demographics and clinical characteristics in 2,288 episodes of invasive pneumococcal disease.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEpisodes, n (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cem\u003eSex\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1,172 (51.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWomen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1,116 (48.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge in years, median (IQR) [mean; range]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e69 (58\u0026ndash;80) \u003c/p\u003e \u003cp\u003e[65; 0\u0026ndash;100]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cem\u003eAge groups\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u0026ndash;1 year\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46 (2.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u0026ndash;17 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58 (2.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u0026ndash;50 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e309 (13.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e51\u0026ndash;64 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e472 (20.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;65 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1,403 (61.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cem\u003eSource of infection\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCommunity-acquired\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2,199 (96.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHospital-acquired\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e89 (3.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cem\u003eNumber of IPD episodes per patient (n patients)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOne episode\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2,177\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTwo episodes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThree episodes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cem\u003eDisease severity and outcome\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLength of hospital stay\u003csup\u003e2\u003c/sup\u003e in days, median (mean) [range]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (12) [1\u0026ndash;227]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICU care\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e522 (22.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLength of stay at ICU in days, median (mean) [range]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (7) [0\u0026ndash;94]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComplications\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e604 (26.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSequelae\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e117 (5.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e30-day mortality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e259 (12.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u003cem\u003eICU, Intensive care unit; IPD, invasive pneumococcal disease; IQR, interquartile range.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u003csup\u003e1\u003c/sup\u003e Defined as IPD episodes occurring 7 days or later after hospital admission due to any other reason.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u003csup\u003e2\u003c/sup\u003e Length of stay in 2,252 IPD episodes, while 36 additional episodes occurred in patients treated as outpatients.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003ePneumococcal vaccination status was known in 29.2% (651/2,232) of the patients. Of these, 121 patients were previously vaccinated, most frequently with PPV23 (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;47) followed by PCV13 (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;27). A total of 88 children\u0026thinsp;\u0026lt;\u0026thinsp;10 years of age, thus potentially included in the Swedish childhood vaccination program during the study period, suffered from IPD. Among the 53 children with known vaccination status, 21 were unvaccinated. Twenty-four of the patients were infants\u0026thinsp;\u0026lt;\u0026thinsp;12 months of age, and therefore they had not received all three PCV doses by the time of their IPD episode.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eOverall IPD incidence during 2009\u0026ndash;2019\u003c/h2\u003e \u003cp\u003eThe mean IPD incidence during 2009\u0026ndash;2019 was 12.7/100,000 inhabitants/year, without any obvious decreasing or increasing trend during the period (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). The incidence was highest in the population\u0026thinsp;\u0026ge;\u0026thinsp;65 years. In this age group, men had a higher incidence than women (44.8 versus 38.2/100,000; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003) in contrast to the younger age groups, in which there was no difference in incidence between men and women (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). The incidence among children 0\u0026ndash;23 months of age was 10.7/100,000/year (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eComorbidity\u003c/h2\u003e \u003cp\u003eIn 1,765 of the IPD episodes (77%), the patient had one or more predisposing factors, most commonly cardiovascular disease (30%), chronic pulmonary disease (21%), or malignancy (20%) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Patients with multiple myeloma and chronic lymphocytic leukemia (CLL) had the highest incidence rates (1,497/100,000 and 505/100,000, respectively). High incidence rates were also found for patients with lung cancer and asplenia (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePredisposing factors in patients with invasive pneumococcal disease: proportion, incidence rates and CFR.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePredisposing factor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo. of IPD episodes (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIncidence\u003csup\u003e1\u003c/sup\u003e (No./100,000/year)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOdds ratio to get IPD (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDied\u003csup\u003e2\u003c/sup\u003e (n)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCFR\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eOdds ratio of death (95% CI)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiovascular disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e690 (30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e142\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e20.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e2.45 (1.90\u003c/b\u003e\u0026ndash;\u003cb\u003e3.14) ***\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePulmonary disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e472 (21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e15.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.29 (0.97\u0026ndash;1.71)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCOPD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e312 (14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e6.32 (5.61\u0026ndash;7.13) ***\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e15.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.31 (0.94\u0026ndash;1.83)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAsthma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e110 (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.49 (0.41\u0026ndash;0.60) ***\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e10.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.74 (0.41\u0026ndash;1.38)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMalignancy, any\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e462 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e126\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e12.36 (11.16\u0026ndash;13.70) ***\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e17.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e1.57 (1.19\u0026ndash;2.08) **\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHematological\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e232 (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e289\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e26.03 (22.68\u0026ndash;29.87) ***\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e13.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.09 (0.74\u0026ndash;1.62)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMultiple myeloma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e107 (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1,497\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e147.9 (119.7\u0026ndash;182.7) ***\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e15.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.29 (0.76\u0026ndash;2.21)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic lymphocytic leukemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e505\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e43.01 (32.24\u0026ndash;57.38) ***\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e10.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.75 (0.32\u0026ndash;1.81)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSolid tumors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e246 (11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e7.54 (6.60\u0026ndash;8.61) ***\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e20.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e1.93 (1.38\u0026ndash;2.68) ***\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLung\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e57 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e432\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e36.57 (27.94\u0026ndash;47,87) ***\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e28.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e2.73 (1.53\u0026ndash;4.86) **\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBreast\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e3.43 (2.33\u0026ndash;5.05) ***\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e19.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.62 (0.66\u0026ndash;4.30)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eColon\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e5.14 (3.18\u0026ndash;8.29) ***\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e17.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.45 (0.44\u0026ndash;4.78)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProstate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e56 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e5.35 (4.10\u0026ndash;6.98) ***\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e17.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.48 (0.71\u0026ndash;2.91)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes mellitus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e359 (16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e3.21 (2.87\u0026ndash;3.60) ***\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e13.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.08 (0.78\u0026ndash;1.50)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAutoimmune disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e194 (8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e13.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.10 (0.71\u0026ndash;1.67)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRheumatoid arthritis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e3.29 (2.42\u0026ndash;4.47) ***\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e14.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.13 (0.51\u0026ndash;2.59)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePolymyalgia rheumatica\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e28.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.73 (0.93\u0026ndash;7.97)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSystemic lupus erythematosus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e154\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e12.45 (7.80\u0026ndash;19.88) ***\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e11.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.84 (0.19\u0026ndash;3.38)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e107 (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e19.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e1.70 (1.05\u003c/b\u003e\u0026ndash;\u003cb\u003e2.74) *\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenal disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e127 (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e26.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e2.55 (1.66\u003c/b\u003e\u0026ndash;\u003cb\u003e3.87) ***\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemodialysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e202\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e16.30 (8.96\u0026ndash;29.68) ***\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e18.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.51 (0.32\u0026ndash;5.96)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeritoneal dialysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e163\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e13.11 (4.18\u0026ndash;41.09) ***\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eN.A.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImmune deficiency\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e107 (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e11.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.85 (0.45\u0026ndash;1.53)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e4.30 (1.78\u0026ndash;10.37) **\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eN.A.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBone marrow transplant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e8.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.61 (0.19\u0026ndash;1.78)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypogammaglobulinemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eN.A.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMGUS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.78 (0.57\u0026ndash;1.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e20.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.71 (0.81\u0026ndash;3.74)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImmunosuppressive treatment\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e294 (13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e14.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.15 (0.80\u0026ndash;1.63)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAsplenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e249\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e20.57 (15.25\u0026ndash;27.75) ***\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e20.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.71 (0.82\u0026ndash;3.49)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlcohol dependency\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e164 (7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e19.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e1.72 (1.14\u0026ndash;2.59) *\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking\u003csup\u003e4\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e412 (18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e10.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.80 (0.56\u0026ndash;1.25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;1 predisposing factor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1,765 (77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e266\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e15.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e3.02 (2.04\u003c/b\u003e\u0026ndash;\u003cb\u003e4.55) ***\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo known risk factor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e523 (23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e5.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAll episodes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2,288 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e295\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e12.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003cem\u003e* p\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05, \u003cem\u003e** p\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01, *** \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003cem\u003eCFR, case fatality rate; COPD, chronic obstructive pulmonary disease; HIV, human immunodeficiency virus; IPD, invasive pneumococcal disease; MGUS, monoclonal gammopathy of undetermined significance; N.A., not applicable.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003csup\u003e1\u003c/sup\u003e Estimated annual incidence among patients living with this risk factor. For solid tumor malignancies, the estimate is based on 5-year prevalence data.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003csup\u003e2\u003c/sup\u003e Death within 30 days from sampling with the first detection of pneumococci from a sterile site.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003csup\u003e3\u003c/sup\u003e Immunosuppressive treatment includes current chemotherapy, immunosuppressants such as tumor necrosis factor inhibitors, and cortisone\u0026thinsp;\u0026gt;\u0026thinsp;2 weeks in a daily dosage equivalent to prednisone 7.5 mg or higher.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003csup\u003e4\u003c/sup\u003e Defined as current smoking.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAmong the 55 patients with two or more IPD episodes, 54 (98%) had an identifiable predisposing condition. Three of these patients had asplenia, while 25 had a hematological malignancy, primarily multiple myeloma (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;15).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eClinical manifestations\u003c/h2\u003e \u003cp\u003ePneumonia was the most frequent IPD manifestation with 1,658 episodes (72%) followed by bacteremia without focus (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;281, 12%), and meningitis (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;179, 7.8%) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The annual incidence of IPD with pneumonia during the study period was 9.2/100,000. The annual meningitis incidence was 1.0/100,000 in all age groups and 2.8/100,000 among children\u0026thinsp;\u0026lt;\u0026thinsp;2 years. The distribution of manifestations varied largely between the age groups. Meningitis occurred in 26% of the IPD episodes in children\u0026thinsp;\u0026lt;\u0026thinsp;2 years compared to 4.3% of the episodes in the highest age group\u0026thinsp;\u0026ge;\u0026thinsp;65 years (12/46 vs. 60/1,403; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Almost the opposite was found for pneumonia, which accounted for 22% of the IPD episodes in children\u0026thinsp;\u0026lt;\u0026thinsp;2 years compared to 77% among the elderly (10/46 vs. 1,085/1,403; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). More rarely observed IPD manifestations, including septic arthritis (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;80), acute otitis media with or without mastoiditis (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;74), sinusitis (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;39), endocarditis (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;18), and osteitis (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;17) are listed in Supplementary Table S2.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eManifestations in invasive pneumococcal disease: proportions, age distribution and relative risk of death.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"11\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003eNo. (%) of episodes in different age groups\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c11\" namest=\"c9\"\u003e \u003cp\u003eFatalities\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eManifestation\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u0026ndash;1\u0026nbsp;year.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u0026ndash;17 yrs.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18\u0026ndash;50 yrs.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e51\u0026ndash;64 yrs.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e65\u0026ndash;100 yrs.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eAll ages\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eDied\u003csup\u003e2\u003c/sup\u003e (n)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eCFR\u003csup\u003e2\u003c/sup\u003e (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003eOdds ratio of death (95% CI)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePneumonia without meningitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 (38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e230 (74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e316 (67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1,080 (77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1,658 (72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e196\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e11.8%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e\u003cb\u003e0.72 (0.56\u003c/b\u003e\u0026ndash;\u003cb\u003e0.93) *\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026hellip;with empyema\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e6.3%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026hellip;with parapneumonic effusion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e130\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e9.2%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBacteremia with no detectable focus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21 (7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e57 (12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e171 (12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e281 (12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e24.9%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e\u003cb\u003e2.63 (1.94\u0026ndash;3.55) ***\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMeningitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e39 (13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e59 (13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e60 (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e179 (8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e9.5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0.69 (0.42\u0026ndash;1.16)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026hellip;without pneumonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e168\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026hellip;with concurrent pneumonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026hellip;with concurrent acute otitis media\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther manifestations without pneumonia or meningitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19 (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e40 (8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e92 (7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e170 (7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e7.1%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e\u003cb\u003e0.49 (0.27\u003c/b\u003e\u0026ndash;\u003cb\u003e0.89) *\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAll episodes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e309 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e472 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1,403 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2,288 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e295\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e12.9%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"11\"\u003e\u003cem\u003e* p\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05, *** \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"11\"\u003e\u003cem\u003eCFR, case fatality rate.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"11\"\u003e\u003csup\u003e1\u003c/sup\u003e In 130 episodes more than one manifestation was identified.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"11\"\u003e\u003csup\u003e2\u003c/sup\u003e Death within 30 days from the first sample taken in which pneumococci were identified.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eA large proportion of patients diagnosed with IPD bacteremia without detectable focus had an underlying malignant disease (42.0%; 118/281), as compared to 18.4% (307/1,669) of patients with IPD and pneumonia.\u003c/p\u003e \u003cp\u003eHospital-acquired IPD occurred in 3.9% of all episodes (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). One-third of these patients had an underlying malignant disease (34%, 30/89).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eDisease severity and complications\u003c/h2\u003e \u003cp\u003eThe patients were treated in hospital in 2,252 of the 2,288 (98.4%) IPD episodes, with a median duration of seven days (range 1\u0026ndash;227 days) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn 22.8% of all episodes, the patient was admitted to the ICU (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Pneumonia was the most frequent manifestation in the ICU admitted patients (326/522; 62.5%), followed by meningitis (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;119; 22.8%) and bacteremia without focus (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;46; 8.8%).\u003c/p\u003e \u003cp\u003eIn one-quarter of the IPD episodes one or more specific complications was observed, most commonly parapneumonic effusion (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;135), followed by empyema (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;98), and myocardial infarction (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;24) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOne hundred and sixty-two patients out of 179 with meningitis survived (90.5%). Among these, 57 patients (35.2%), of all ages, had neurological sequelae including paresis, hearing loss, fatigue, and loss of concentration. Among children\u0026thinsp;\u0026lt;\u0026thinsp;5 years of age with meningitis 12/14 survived, one with a subsequent facial palsy, the others without major sequelae.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eCase fatality rate\u003c/h2\u003e \u003cp\u003eTwo hundred and ninety-five patients died within 30 days from IPD diagnosis, resulting in an overall CFR of 12.9% (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOf altogether 104 IPD episodes in children and youth\u0026thinsp;\u0026lt;\u0026thinsp;18 years, four children died (two below 12 months of age, and two 3\u0026ndash;4 years) resulting in a CFR of 3.8%. CFR in different age groups is shown in Supplementary Fig. S2.\u003c/p\u003e \u003cp\u003eCFR was higher in patients with a known predisposing risk factor or comorbidity compared to those without (15.7% vs. 5.5%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Bacteremia with no detectable focus was associated with the highest CFR (24.9%), followed by pneumonia (11.8%) and meningitis (9.5%) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePatients with hospital-acquired IPD had a high mortality rate (CFR 36.0%). In patients with complications following their IPD, CFR was 16.9%, and among ICU patients this was 21.1%.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eLong-term trends: Comparison with previous study periods\u003c/h2\u003e \u003cp\u003eThe annual IPD incidence in Region V\u0026auml;stra G\u0026ouml;taland was lower during the present study period (2009\u0026ndash;2019) compared to the previous period 1996\u0026ndash;2008 (12.7 vs. 15.1/100,000; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The incidence rate of IPD in the different age groups in 1996\u0026ndash;2008 compared to 2009\u0026ndash;2019 is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The incidence was 10/100,000 during the years 1981\u0026ndash;1995 and 5/100,000 in 1964\u0026ndash;1980 (these study periods included only the city of Gothenburg and surrounding urban areas) (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eIncidence, CFR, and mortality of IPD in Gothenburg urban area from 1964 to 2019.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean population\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCases\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIncidence\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDied\u003csup\u003e3\u003c/sup\u003e (n)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCFR\u003csup\u003e3\u003c/sup\u003e (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMortality\u003csup\u003e4\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003e1964\u0026ndash;1980 (17 years)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u0026ndash;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15,248\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u0026ndash;17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e118,570\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u0026ndash;50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e264,282\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e161\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e51-65\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e98,657\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e129\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e66\u0026ndash;\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e79,387\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e134\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAll ages\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e576,143\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e508\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003e1981\u0026ndash;1995 (15 years)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u0026ndash;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15,169\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u0026ndash;17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e103,624\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u0026ndash;50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e280,287\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e189\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e51\u0026ndash;64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e84,475\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e167\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e65\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e99,233\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e441\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAll ages\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e582,789\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e899\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e136\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003e1996\u0026ndash;2008 (13 years)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u0026ndash;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11,636\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.66\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u0026ndash;17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e118,604\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u0026ndash;50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e308,938\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e257\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e51\u0026ndash;64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e102,280\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e228\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e65\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e102,161\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e530\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAll ages\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e643,620\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1,083\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003e2009\u0026ndash;2019 (11 years)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u0026ndash;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19,212\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.47\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u0026ndash;17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e130,413\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u0026ndash;50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e353,285\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e128\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e51\u0026ndash;64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e115,809\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e170\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e65\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e115,287\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e484\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAll ages\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e734,007\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e830\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e109\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003cem\u003eCFR, case fatality rate; IPD, invasive pneumococcal disease.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003csup\u003e1\u003c/sup\u003e Mean population during the period. Values for 1964\u0026ndash;1980 are calculated from data obtained from 1968\u0026ndash;1980.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003csup\u003e2\u003c/sup\u003e Number of IPD episodes/100,000 inhabitants/year.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003csup\u003e3\u003c/sup\u003e Death within 30 days from the first sample taken in which pneumococci were identified.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003csup\u003e4\u003c/sup\u003e Number of patients who died from IPD/100,000 inhabitants/year.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003csup\u003ea\u003c/sup\u003e Data from 1964\u0026ndash;1980 include the age groups 51\u0026ndash;65 years and 66 years and above.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn the region of V\u0026auml;stra G\u0026ouml;taland, the IPD incidence among children\u0026thinsp;\u0026lt;\u0026thinsp;2 years decreased by half during the present study period, \u003cem\u003ei.e.\u003c/em\u003e the eleven first years after the introduction of pneumococcal vaccine in the childhood vaccination program in Sweden, compared to the previous period (10.7/100,000 in 2009\u0026ndash;2019 vs. 22.5/100,000 in 1996\u0026ndash;2008; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). In the elderly aged 65 years and above, the incidence rate was 41/100,000 in 2009\u0026ndash;2019 as compared to 45/100,000 in 1996\u0026ndash;2008 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03).\u003c/p\u003e \u003cp\u003eThe median age at IPD diagnosis increased from 65 in 1996\u0026ndash;2008 to 69 years in the present period 2009\u0026ndash;2019 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). During the same periods, the median age at the time of IPD diagnosis among children\u0026thinsp;\u0026lt;\u0026thinsp;2 years decreased from 414 to 344 days after birth.\u003c/p\u003e \u003cp\u003eIn the previous study period, data on smoking was not included in the analysis of predisposing factors for IPD. Even after correcting for this, the prevalence of underlying comorbidities or other risk factors for IPD was higher after PCV introduction compared with the previous study period (72% (1,654/2,288) vs. 67% (1,994/2,977); \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003eThe annual meningitis incidence has been registered since 1970 and has declined gradually from 1.4/100,000 for all ages in the first study period (1970\u0026ndash;1980) to 0.9/100,000 in the present study period. For children\u0026thinsp;\u0026lt;\u0026thinsp;2 years, the annual meningitis incidence was 12.0/100,000 in 1970\u0026ndash;1980, 7.0/100,000 in 1981\u0026ndash;1995, 8.6/100,100 in 1996\u0026ndash;2008 and 2.8/100,000 in 2009\u0026ndash;2019.\u003c/p\u003e \u003cp\u003eOverall CFR was higher during the present study period compared to the previous period 1996\u0026ndash;2008 (12.9% vs. 9.9%; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) but lower than 1964\u0026ndash;1980 (20%; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). However, after adjusting for age, sex, underlying comorbidity, and ICU care, the difference in mortality between the last two study periods was no longer statistically significant (Supplementary Table S3).\u003c/p\u003e \u003cp\u003eCompared to the previous study period 1996\u0026ndash;2008, mortality rate has increased among individuals aged 50 and above, whereas in children and younger adults, mortality has steadily decreased over time (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). CFR among patients with meningitis showed a decreasing trend compared to previous study periods (9.5% compared to 13.5% in 1996\u0026ndash;2008 and 33% in 1964\u0026ndash;1980).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study describes the IPD epidemiology in Southwest Sweden after the introduction of PCV in the general childhood vaccination program and before the onset of the COVID-19 pandemic. It follows a series of IPD studies during 56 years in the same area [\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOverall, 77% of the patients had a known medical condition predisposing to invasive pneumococcal infection. Hematological malignancies, specifically multiple myeloma, and chronic lymphatic leukemia are well-known high-risk factors for IPD [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. We found a 118-fold increase in the incidence of IPD among myeloma patients compared to the overall population, and a 40-fold increase among patients with chronic lymphatic leukemia, similar to pre-PCV incidence rates [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Patients with multiple myeloma have impaired B- and T-cell function [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] and hence an inadequate response to pneumococcal vaccination [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], which leaves them more vulnerable to pneumococcal infections. Myeloma has been associated with repeated IPD episodes [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], and our study confirms this.\u003c/p\u003e \u003cp\u003eMGUS (monoclonal gammopathy of undetermined significance), which affects approximately 5% of the population\u0026thinsp;\u0026gt;\u0026thinsp;40 years and may develop into multiple myeloma, has been associated with an increased risk of pneumonia [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. We did not find an increased risk of IPD in patients with MGUS, which might reflect an under-diagnosis of the condition in the population.\u003c/p\u003e \u003cp\u003eAs previously described [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], patients with lung cancer, asplenia, or chronic renal failure undergoing hemodialysis had high incidences of IPD (34-fold, 20-fold, and 16-fold increase, respectively). Only five of the 2,288 recorded IPD episodes occurred in HIV-positive patients, another well-described risk group [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. We suggest, however that this is explicable in terms of the known high coverage of anti-retroviral treatment in Sweden (\u0026gt;\u0026thinsp;95% of HIV patients) resulting in a decreased susceptibility to IPD [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn almost one-fourth of all patients (23%), no predisposing factor for IPD was found. These patients might have a yet unknown primary or secondary immune deficiency. Other reasons for IPD include viral coinfection, genetic predisposition, or infection by particularly virulent pneumococcal strains.\u003c/p\u003e \u003cp\u003eWe found an equal incidence of IPD in men and women in all age groups except for the \u0026gt;\u0026thinsp;65 years group, where men had a higher incidence. This is consistent with data from the previous pre-vaccine study period in the same area [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] but contrasts with other international studies as well as the earlier study periods in the region, in which men were over-represented [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe clinical manifestations of IPD remained largely unchanged after the introduction of PCV in the region [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In children\u0026thinsp;\u0026lt;\u0026thinsp;2 years, meningitis and bacteremia without focus still comprised almost two-thirds of all episodes. The most common IPD manifestation in the elderly was pneumonia, accounting for 77% of all episodes. The incidence of meningitis decreased with age, as observed in other studies [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIPD is a severe medical condition and, expectedly, we found a high rate of complications (26.4%), most commonly parapneumonic effusion and empyema. A concurrent myocardial infarction was present in 24 patients. In fact, a strong association between acute myocardial infarction and IPD was found in Tennessee residents in the USA [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Similar to previous reports one-third of the patients with meningitis suffered from neurological sequelae [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], and this affected all ages.\u003c/p\u003e \u003cp\u003eIn coherence with multiple studies [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan additionalcitationids=\"CR37\" citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e], the overall IPD incidence among children\u0026thinsp;\u0026lt;\u0026thinsp;2 years declined substantially after PCV introduction. We also observed a general decrease in IPD in the population compared to the previous study period. The reduction of IPD incidence in the elderly was statistically significant, although this was much less pronounced than in infants and younger adults. This limited herd protection of the elderly after introduction of PCV in the childhood vaccination program is consistent with reports from other countries [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe pneumococcal serotype distribution is highly dynamic and alters over time, geographically, and after the introduction of vaccination [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. We and others have shown that the cause of IPD in persons with known predisposing factors has shifted from PCV13 to non-PCV13 serotypes in Sweden [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. This shift is probably the main driving force behind the lack of substantial IPD decline in the elderly. Despite a reduction of incidence in the present study, the overall incidence of IPD has remained relatively stable in Sweden since the 1990s [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Besides the phenomenon of pneumococcal serotype shift this might be explained by an aging population and the increased use of immunosuppressive treatments in various chronic diseases. The number of collected blood cultures has also increased significantly [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e], and in combination with improved blood culture systems, the likelihood of detecting an IPD episode has most likely increased over time.\u003c/p\u003e \u003cp\u003eThe increase in IPD mortality in the present study as compared to previous periods in the same area was unexpected but could be explained by the increased median age and comorbidity of the patients. However, in comparison with other cohorts, the mortality rate (12.9%) was low. In a meta-analysis of 26 studies from different countries and settings, the overall mortality was 20.8% [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. Factors associated with death from IPD in that meta-analysis included age\u0026thinsp;\u0026ge;\u0026thinsp;65 years, nosocomial infection, underlying chronic diseases, solid organ tumors, and immunosuppressive conditions [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e], \u003cem\u003ei.e.\u003c/em\u003e these were similar to our findings. We did not specifically study septic shock, which was also identified as an independent risk factor for mortality, but we observed a high mortality rate in patients admitted to the ICU (20.9%) [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. Severe underlying conditions, including hematological malignancies, could also explain the high mortality rates in patients with bacteremia without focus as well as in patients with hospital-acquired IPD (24.6% and 36.0%, respectively).\u003c/p\u003e \u003cp\u003eA strength of this study is that almost all IPD episodes during the 11-year study period were included. The use of the same clinical protocol in previous studies allows for long-term follow-up in the study area. Data on clinical manifestations, underlying diseases, and outcomes are solid due to the high quality of the medical records. This study was terminated shortly before the COVID-19 outbreak, and our results are thus not affected by the pandemic.\u003c/p\u003e \u003cp\u003eLimitations include the lack of data regarding mechanical ventilation or septic shock management for patients receiving intensive care. Furthermore, occupational exposures linked to a higher IPD risk such as welding were not assessed [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. Alcohol abuse and smoking constitute known risk factors for IPD, although the magnitude of their impact is not entirely clear [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. Data on alcohol abuse and smoking were most likely underreported in the medical records, hence, the effect of these factors could be underestimated in the analysis.\u003c/p\u003e \u003cp\u003e With this study, we present the follow-up data covering 56 years of continuous IPD epidemiology from a geographically relatively large area in Sweden. The present study period adds data from the first eleven years after the introduction of pneumococcal vaccination in the childhood vaccine program. With the addition of PCV15 and PCV20 and the implementation of a national pneumococcal vaccine program for risk groups in Sweden in 2022, further surveillance is warranted on the long-term influence of vaccination on IPD incidence and mortality, including the pneumococcal serotype distribution and the effects on different age groups.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eFollowing the introduction of a pneumococcal conjugate vaccine in the childhood vaccination program in 2009, IPD incidence has declined among children, but to a much lesser extent in adults\u0026thinsp;\u0026gt;\u0026thinsp;65 years of age. On the contrary, the overall mortality in IPD was higher than in the pre-vaccine period, with the highest numbers of deaths seen among patients with bacteremia without other clinical manifestations, ICU patients, and patients with hospital-acquired IPD. The increased mortality may be explained by increased age and comorbidity among the patients. Patients with hematological malignancies, especially multiple myeloma, still have a very high risk for IPD.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCFR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCase fatality rate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCLL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eChronic lymphocytic leukemia\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCOPD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eChronic obstructive pulmonary disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCSF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCerebrospinal fluid\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGOLD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGlobal Initiative for Obstructive Lung Disease 2019\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eICU\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eIntensive care unit\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIQR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInterquartile range\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIPD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInvasive pneumococcal disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMGUS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMonoclonal gammopathy of undetermined significance\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePCR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePolymerase chain reaction\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePCV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePneumococcal conjugate vaccine\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePPV23\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePneumococcal polysaccharide vaccine\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSCB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eStatistics Sweden\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Regional Ethics Committee of Gothenburg (no.123-15, T351-16, and 2020-03453). Informed consent was not obtained due to the retrospective study design.\u003c/p\u003e\n\u003cp\u003eClinical trial number: not applicable\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eAll authors have approved the manuscript for submission.\u003c/p\u003e\n\u003cp\u003eAvailability of data and material\u003c/p\u003e\n\u003cp\u003eThe dataset used during the current study is available from the corresponding author on request.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eEB and KB are former members of the advisory boards for Pfizer and GSK. The other authors have no competing interests.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Healthcare Committee in Region V\u0026auml;stra G\u0026ouml;taland [grant no. VGFOUREG-477211 and VGFOUREG-659551], the Local Research and Development Council in Fyrbodal [grant no. VGFOUFBD-964663], and the Department of Research and Development, NU Hospital Group.\u003c/p\u003e\n\u003cp\u003eAuthors\u0026apos; contributions\u003c/p\u003e\n\u003cp\u003eRA, EB, and SS designed the study. TH, KB, MD, HK, CST, MO, and JK, collected data from medical records. TH analyzed the data, in close contact with JK and SN. SN performed the multivariate analysis. TH drafted the manuscript, which was finalized together with JK, SS, RA, and KB. All authors have read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eProfessor Birger Trollfors, a senior pneumococcal researcher, contributed to the study design and data collection. Unfortunately, he passed away prior to the completion of the study.\u003c/p\u003e\n\u003cp\u003eWe wish to thank assistant Malin Karlsson for help with entering data into the database.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCollaborators GBDAR. Global mortality associated with 33 bacterial pathogens in 2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2022;400(10369):2221\u0026ndash;48.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan Hoek AJ, Andrews N, Waight PA, Stowe J, Gates P, George R, Miller E. The effect of underlying clinical conditions on the risk of developing invasive pneumococcal disease in England. J Infect. 2012;65(1):17\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKyaw MH, Rose CE Jr., Fry AM, Singleton JA, Moore Z, Zell ER, Whitney CG. Active Bacterial Core Surveillance Program of the Emerging Infections Program N: The influence of chronic illnesses on the incidence of invasive pneumococcal disease in adults. J Infect Dis. 2005;192(3):377\u0026ndash;86.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSjostrom K, Spindler C, Ortqvist A, Kalin M, Sandgren A, Kuhlmann-Berenzon S, Henriques-Normark B. 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Am J Med Sci. 2012;343(4):303\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKristinsson SY, Tang M, Pfeiffer RM, Bjorkholm M, Goldin LR, Blimark C, Mellqvist UH, Wahlin A, Turesson I, Landgren O. Monoclonal gammopathy of undetermined significance and risk of infections: a population-based study. Haematologica. 2012;97(6):854\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKang JM, Kim EH, Ihn K, Jung I, Han M, Ahn JG. Risk of invasive pneumococcal disease in patients with asplenia/hyposplenism: A nationwide population-based study in Korea, 2009\u0026ndash;2018. Int J Infect Dis. 2020;98:486\u0026ndash;93.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGarcia Garrido HM, Mak AMR, Wit F, Wong GWM, Knol MJ, Vollaard A, Tanck MWT, Van Der Ende A, Grobusch MP, Goorhuis A. 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Occupational exposure to dust and to fumes, work as a welder and invasive pneumococcal disease risk. Occup Environ Med. 2020;77(2):57\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCruickshank HC, Jefferies JM, Clarke SC. Lifestyle risk factors for invasive pneumococcal disease: a systematic review. BMJ Open. 2014;4(6):e005224.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Streptococcus pneumoniae, Pneumococcal disease, Invasive, Meningitis, Pneumonia, Predisposing factors, Mortality, Incidence","lastPublishedDoi":"10.21203/rs.3.rs-5039210/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5039210/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eInvasive pneumococcal disease (IPD) still causes significant morbidity and mortality. In this study, we describe incidence, risk factors, manifestations, and outcome of IPD in Southwest Sweden during the first 11 years following the introduction of pneumococcal conjugate vaccines (PCV) in the childhood vaccination program in 2009.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eClinical data from 2,288 consecutive episodes of IPD in Region V\u0026auml;stra G\u0026ouml;taland, Sweden, during 2009\u0026ndash;2019 were retrospectively collected from medical records. Incidence rates were calculated using population data from the same period. The results were compared to data from three previous studies from the same geographical area with a total follow-up of 56 years.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe incidence of all IPD episodes in 2009\u0026ndash;2019 was 12.8/100,000/year. In children\u0026thinsp;\u0026lt;\u0026thinsp;2 years, this declined from 22.5 in 1996\u0026ndash;2008 to 10.7 per 100,000 in 2009\u0026ndash;2019, while only a modest reduction was observed in adults. A very high incidence of IPD was seen in patients with multiple myeloma (1,497/100,000) and chronic lymphocytic leukemia (505/100,000). Meningitis occurred in 26% of the IPD episodes in children\u0026thinsp;\u0026lt;\u0026thinsp;2 years compared to 4.3% in the age group\u0026thinsp;\u0026ge;\u0026thinsp;65 years (12/46 versus 60/1,403; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). An opposing trend was found for pneumonia, which accounted for 22% of the IPD episodes in children\u0026thinsp;\u0026lt;\u0026thinsp;2 years compared to 77% among the elderly (10/46 vs. 1,085/1,403; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). In 604 IPD episodes (26.4%) one or more complications were observed. The case fatality rate increased from 9.9% pre-PCV to 12.9% in the post-PCV period. This was highest among patients with detected bacteremia but with no other clinical manifestations, those admitted to intensive care, and those with hospital-acquired IPD.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eA substantial decrease in IPD incidence was seen in infants and young children but not in the elderly after introduction of PCV in the general childhood vaccination program. The higher IPD mortality post-PCV could be explained by higher age and increased comorbidity among the patients. Patients with hematological malignancies showed a very high risk for IPD.\u003c/p\u003e","manuscriptTitle":"Epidemiology of invasive pneumococcal disease in western Sweden during the first 11 years after the introduction of general childhood pneumococcal vaccination","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-22 10:33:00","doi":"10.21203/rs.3.rs-5039210/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c6300e5e-c40a-47a0-8202-76ab21d80910","owner":[],"postedDate":"October 22nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-01-28T08:53:54+00:00","versionOfRecord":[],"versionCreatedAt":"2024-10-22 10:33:00","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5039210","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5039210","identity":"rs-5039210","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}