Epidemiología de la neumonía neumocócica en adultos mayores de 50 años: estudio de cohortes en Cataluña, 2017-2018 / Epidemiology of pneumococcal pneumonia among middle-aged and older adults in Catalonia, 2017–2018

Objetivo: Analizar la incidencia y letalidad de la neumonía neumocócica (NN) en adultos tras la implementación de la vacunación universal en los niños. Diseño: Estudio de cohortes de base poblacional. Emplazamiento: Atención primaria/hospital, Cataluña. Participantes: 2.059.645 personas≥50 años afiliadas al Institut Català de la Salut, con seguimiento retrospectivo entre 01/01/2017-31/12/2018. Mediciones principales: El Sistema de Información para el Desarrollo de la Investigación en Atención Primaria (SIDIAP) de Cataluña fue usado para establecer las características basales de los miembros de la cohorte, clasificados en 3 estratos de riesgo: bajo (inmunocompetentes sin condiciones de riesgo), medio (inmunocompetentes con alguna condición de riesgo) y alto (inmunocompromiso/asplenia). La ocurrencia de NN entre los miembros de la cohorte fue identificada mediante Conjunto Mínimo Básico de Datos de los 64 hospitales catalanes de referencia. Resultados: Se registraron 3592 episodios de NN, con una incidencia de 90,7 casos por 100.000 personas-año (IC 95%: 85,2-96,5), siendo 11,9 bacteriémicas (IC 95%: 10,8-13,1) y 78,8 no bacteriémicas (IC 95%: 74,0-83,8). La incidencia aumentó sustancialmente según edad (37,3 en 50-64; 98,3 en 65-79 y 259,8 en ≥80 años) y estrato de riesgo basal (42,1; 120,7 y 238,6 en bajo, medio y alto riesgo, respectivamente). La letalidad global fue del 7,6% (10,8% en casos invasivos vs. 7,1%en no invasivos; p=0,004). En modelos multivariantes, estrato de riesgo alto y edad avanzada (>80 años) fueron los más fuertes predictores para padecer episodios invasivos y no invasivos, respectivamente. Conclusión: La incidencia y letalidad de la NN fue moderada en la población>50 años de Cataluña durante 2017-2018.(AU)

Objective: To analyse population-based incidence and lethality of pneumococcal pneumonia (PP) requiring hospitalisation among Catalonian adults after universal vaccination implementation in infants. Design: Population-based cohort study. Setting: Primary care/hospital, Catalonia. Participants: 2,059,645 individuals ≥50 years old affiliated to the Institut Catala de la Salut retrospectively followed between 01/01/2017 and 31/12/2018. Main outcome measures: The Catalonian information system for the development of research in primary care (SIDIAP, Sistema de Información para el Desarrollo de la Investigación en Atención Primaria) was used to establish baseline characteristics and risk-strata of cohort members at study start: low-risk (immunocompetent persons without risk conditions), intermediate-risk (immunocompetent persons with at-risk condition) and high-risk (immunocompromising conditions). PP requiring hospitalisation among cohort members across study period were collected from CMBD (Conjunto Mínimo Básico de Datos) discharge data of 64 reference Catalonian hospitals. Results: An amount of 3592 episodes of HPP were observed, with an incidence density of 90.7 cases per 100,000 person-years (95% CI: 85.2-96.5), being 11.9 bacteremic (95% CI: 10.8-13.1) and 78.8 non-bacteremic (95% CI: 74.0-83.8). Incidence rates substantially increased by age (37.3 in 50-64 years vs. 98.3 in 65-79 years vs. 259.8 in ≥80 years) and baseline-risk stratum (42.1, 120.7 and 238.6 in low-, intermediate- and high-risk stratum, respectively). Overall case-fatality rate was 7.6% (10.8% in invasive cases vs. 7.1% in non-invasive cases; pP=.004). In multivariable analyses, high-risk stratum and oldest age were the strongest predictors for invasive and non-invasive cases, respectively. Conclusion: Incidence and lethality of PP remained moderate among adults >50 years in Catalonia during 2017–2018 (earlier period after universal vaccination introduction for infants).(AU)

Isolation and Characterization of Human Monoclonal Antibodies to Pneumococcal Capsular Polysaccharide 3.

The current pneumococcal capsular polysaccharide (PPS) conjugate vaccine (PCV13) is less effective against Streptococcus pneumoniae serotype 3 (ST3), which remains a major cause of pneumococcal disease and mortality. Therefore, dissecting structure-function relationships of human ST3 pneumococcal capsular polysaccharide (PPS3) antibodies may reveal characteristics of protective antibodies. Using flow cytometry, we isolated PPS3-binding memory B cells from pneumococcal vaccine recipients and generated seven PPS3-specific human monoclonal antibodies (humAbs). Five humAbs displayed ST3 opsonophagocytic activity, four induced ST3 agglutination in vitro, and four mediated both activities. Two humAbs, namely, C10 and C27, that used the same variable heavy (VH) and light (VL) chain domains (VH3-9*01/VL2-14*03) both altered ST3 gene expression in vitro; however, C10 had fewer VL somatic mutations, higher PPS3 affinity, and promoted in vitro ST3 opsonophagocytic and agglutinating activity, whereas C27 did not. In C57BL/6 mice, both humAbs reduced nasopharyngeal colonization with ST3 A66 and a clinical strain, B2, and prolonged survival following lethal A66 intraperitoneal infection, but only C10 protected against lethal intranasal infection with the clinical strain. After performing VL swaps, C10VH/C27VL exhibited reduced ST3 binding and agglutination, but C27VH/C10VL binding was unchanged. However, both humAbs lost the ability to reduce colonization in vivo when their light chains were replaced. Our findings associate the ability of PPS3-specific humAbs to reduce colonization with ST3 agglutination and opsonophagocytic activity, and reveal an unexpected role for the VL in their functional activity in vitro and in vivo. These findings also provide insights that may inform antibody-based therapy and identification of surrogates of vaccine efficacy against ST3. IMPORTANCE Despite the global success of vaccination with pneumococcal conjugate vaccines, serotype 3 (ST3) pneumococcus remains a leading cause of morbidity and mortality. In comparison to other vaccine-included serotypes, the ST3 pneumococcal capsular polysaccharide (PPS3) induces a weaker opsonophagocytic response, which is considered a correlate of vaccine efficacy. Previous studies of mouse PPS3 monoclonal antibodies identified ST3 agglutination as a correlate of reduced ST3 nasopharyngeal colonization in mice; however, neither the agglutinating ability of human vaccine-elicited PPS3 antibodies nor their ability to prevent experimental murine nasopharyngeal colonization has been studied. We generated and analyzed the functional and in vivo efficacy of human vaccine-elicited PPS3 monoclonal antibodies and found that ST3 agglutination associated with antibody affinity, protection in vivo, and limited somatic mutations in the light chain variable region. These findings provide new insights that may inform the development of antibody-based therapies and next-generation vaccines for ST3.

European data sources for computing burden of (potential) vaccine-preventable diseases in ageing adults.

BACKGROUND: To guide decision-making on immunisation programmes for ageing adults in Europe, one of the aims of the Vaccines and InfecTious diseases in the Ageing popuLation (IMI2-VITAL) project is to assess the burden of disease (BoD) of (potentially) vaccine-preventable diseases ((P)VPD). We aimed to identify the available data sources to calculate the BoD of (P)VPD in participating VITAL countries and to pinpoint data gaps. Based on epidemiological criteria and vaccine availability, we prioritized (P) VPD caused by Extra-intestinal pathogenic Escherichia coli (ExPEC), norovirus, respiratory syncytial virus, Staphylococcus aureus, and pneumococcal pneumonia. METHODS: We conducted a survey on available data (e.g. incidence, mortality, disability-adjusted life years (DALY), quality-adjusted life years (QALY), sequelae, antimicrobial resistance (AMR), etc.) among national experts from European countries, and carried out five pathogen-specific literature reviews by searching MEDLINE for peer-reviewed publications published between 2009 and 2019. RESULTS: Morbidity and mortality data were generally available for all five diseases, while summary BoD estimates were mostly lacking. Available data were not always stratified by age and risk group, which is especially important when calculating BoD for ageing adults. AMR data were available in several countries for S. aureus and ExPEC. CONCLUSION: This study provides an exhaustive overview of the available data sources and data gaps for the estimation of BoD of five (P) VPD in ageing adults in the EU/EAA, which is useful to guide pathogen-specific BoD studies and contribute to calculation of (P)VPDs BoD.

Predictors of mortality in invasive pneumococcal disease: a meta-analysis.

OBJECTIVES: To assess risk factors for mortality in invasive pneumococcal disease (IPD). METHODS: We conducted a systemic literature search in January 2019. The main outcome measure included death within 30 days after diagnosis of IPD. The study protocol was registered in PROSPERO (CRD42019120189). RESULTS: After reviewing 2514 potentially relevant records, remaining 190 articles were included in the analysis. A total of 228,782 IPD patients were identified and the mortality rate was 17.2% in the included articles. No significant evidence of publication bias was found according to the funnel plot and Egger's test (t = 1.464, p = 0.145). Male sex, older age, alcohol abuse, previous tuberculosis, meningitis, hospital acquired infections, multilobar infiltrate or effusion, Pitt bacteremia score≥4, Pneumonia Severity Index≥4, clinical conditions requiring intensive care, underlying clinical conditions, disease caused by serotypes 3, 6B, 9 N, 10A, 11A, 16 F, 17 F, 19, 19 F, 22 F, 23A, 23 F, 31 and 35 F, previous antibiotic use, inappropriate initial antibiotic therapy, penicillin resistance, and vancomycin use during the course of treatment were predicators of 30-day mortality. CONCLUSIONS: This meta-analysis highlights important risk factors for IPD-related mortality, many of which may be targeted through preventive measures.

Non-bacteremic pneumococcal pneumonia: general characteristics and early predictive factors for poor outcome.

Purpose: Nowadays, most cases of pneumococcal community-acquired pneumonia (PCAP) are diagnosed by positive urinary antigen. Our aims were to analyse process of care in patients hospitalised with non-bacteremic PCAP (NB-PCAP) and identify factors associated with poor outcome (PO) in this population.Methods: We conducted a prospective study, including patients hospitalised for NB-PCAP (positive urinary antigen and negative blood culture) over a 15 year period. We performed multivariate analysis of predisposing factors for PO, defined as need for mechanical ventilation and/or shock and/or in-hospital death.Results: Of the 638 patients included, 4.1% died in hospital and 12.8% had PO. Host-related factors were similar in patients with and without PO, but patients with PO had higher illness severity on admission. Adjusted analysis revealed the following independent factors associated with PO: being a nursing home resident (OR: 6.156; 95% CI: 1.827-20.750; p = .003), respiratory rate ≥30 breaths/min (OR: 3.030; 95% CI: 1.554-5.910; p = .001), systolic blood pressure <90 mmHg (OR: 4.789; 95% CI: 1.967-11.660; p = .001), diastolic blood pressure <60 mmHg (OR: 2.820; 95% CI: 1.329-5.986; p = .007), pulse rate ≥125 beats/min (OR: 3.476; 95% CI: 1.607-7.518; p = .002), pH <7.35 (OR: 9.323; 95% CI: 3.680-23.622; p < .001), leukocytes <4000/µL (OR: 10.007; 95% CI: 2.960-33.835; p < .001), and severe inflammation (OR: 2.364; 95% CI 1.234-4.526; p = .009). The area under the curve for predicting PO was 0.890 (95% CI: 0.851-0.929).Conclusions: Since patients with PO seem different and had worse in-hospital course, we identified eight independent risk factors for PO measurable on admission.

Omega-3 fatty acids in contrast to omega-6 protect against pneumococcal pneumonia.

PURPOSE: The aim of this study was to assess if long-term supplementation of omega-3 fatty acids or a diet rich in omega-6 fatty acids ameliorates disease severity in a murine model of pneumococcal pneumonia. We hypothesize that long-term dietary supplementation of omega-3 fatty acids will reduce inflammation, disease severity and improve survival compared to omega-6 fatty acids. METHODS: Mice receiving diets supplemented with Omega-3 or Omega-6 for two months were intranasally infected with Streptococcus pneumoniae. We analyzed survival, bacterial burden, histopathology and inflammatory biomarkers. RESULTS: Our results showed that Omega-3 supplementation had increased survival (p = 0.005), less bacteremia (p = 0.0001) and lower bacterial burden in the lungs (p = 0.0002) when compared to the Omega-6 supplementation. Overall, Omega-3 reduced lung pathology, in particular peribronchial inflammation and cell death. Analyses of lung homogenates showed the Omega-3 cohort had decreased levels of the inflammatory cytokine interleukin-6 and an increase in anti-inflammatory cytokine interleukin-10. CONCLUSIONS: Supplementation of mouse diets with Omega-3 fatty acids improved survival, bacterial invasion in the blood and lungs as well as decreased overall lung tissue inflammation and cell death when compared to the Omega-6 supplemented diets. Translation of these findings in humans may improve outcomes of patients at risk for pneumonia.

Pneumococcal conjugate vaccine modulates macrophage-mediated innate immunity in pneumonia caused by Streptococcus pneumoniae following influenza.

Pneumococcal conjugate vaccination (PCV) may prevent influenza-related pneumonia, including Streptococcus pneumoniae pneumonia. To investigate PCV efficacy against secondary pneumococcal pneumonia following influenza, PCV was administered intramuscularly 2 and 5 weeks before S. pneumoniae serotype-3 colonization of murine nasopharynges followed by intranasal challenge with a sublethal dose of influenza A virus. Bacterial and viral loads, including innate immune responses were compared across conditions. PCV vaccination improved the survival of mice with secondary pneumococcal pneumonia and significantly reduced the pulmonary bacterial burden. Increased monocyte/macrophage influx into the lungs, alleviated loss of alveolar macrophages and decreased neutrophil influx into the lungs occurred in PCV-treated mice irrespective of pneumococcal colonization. Higher monocyte chemoattractant protein 1 levels and lower levels of CXCL1, interferon-γ, interleukin-17A, and IL-10, were detected in PCV-treated mice. Additionally, PCV treatment activated the macrophage intracellular killing of S. pneumoniae. Collectively, PCV potentially modulates the host's innate immunity and specific antibodies induction. Macrophage-related innate immunity should be further explored to elucidate the efficacy and mechanisms of PCV versus influenza-related life-threatening diseases.

Monitoring of community-acquired pneumonia hospitalisations before the introduction of pneumococcal conjugate vaccine into Polish National Immunisation Programme (2009-2016): A nationwide retrospective database analysis.

PURPOSE: Community-acquired pneumonia (CAP) is a common infection with significant morbidity and mortality. In January 2017, Poland introduced pneumococcal conjugate vaccine (PCV) into their national immunisation programme to protect children against invasive pneumococcal disease. This study was designed to investigate pneumonia-related hospitalisation rates and trends from 2009 to 2016 prior to the introduction of nationally funded PCV vaccination. METHODS: Using national public statistic data available from the National Institute of Public Health - National Institute of Hygiene, annual hospitalisation rates for pneumonia were analysed, categorised by aetiology and age (<2, 2-3, 4-5, 6-19, 20-59, 60+ years). Trends over time were assessed, as well as in-hospital mortality. RESULTS: The overall hospitalisation rate due to pneumonia varied between 325.9 and 372.2/100,000 population. Higher rates of hospitalisation were seen in older adults and children ≤5 years. Trends were observed when analysing hospitalisations by pneumonia aetiology within age groups: between 2009 and 2016, Streptococcus pneumoniae hospitalisations significantly increased for children aged <2, 2-3, and 4-5 years, from 5.3 to 12.4, 5.2 to 8.2, and 1.9 to 4.6/100,000 population respectively. Whereas hospitalisations due to Haemophilus influenzae pneumonia decreased significantly from 7.8 to 1.8 and 4.8 to 1.9/100,000 children aged <2 and 2-3 years respectively. The numbers of in-hospital deaths increased from 5578 in 2009 to 8149 in 2016, with >85% of deaths in the 60+ age group. CONCLUSIONS: This is the first national study of pneumonia hospitalisations in Poland, providing the baseline data from which to investigate the impact of the change in vaccination policy on pneumonia hospitalisations in Poland.

Factors influencing long-term survival after hospitalization with pneumococcal pneumonia.

OBJECTIVE: To assess survival and identify predictors of survival more than 30-days after discharge in a cohort of consecutive patients diagnosed with pneumococcal pneumonia. METHODS: Observational study including all consecutive immunocompetent adult patients surviving more than 30-days after hospitalization. The bacteriological diagnosis was based on the results of urinary antigen testing and/or blood culture. Life expectancy was calculated for each patient considering their sex, age and date of discharge. RESULTS: We included 1114 patients that survived more than 30- days after discharge. Of them, 431 (38.6%) died during follow-up (median follow-up of 6.7 years). Age, history of cancer, liver disease, chronic renal disease, chronic obstructive pulmonary disease, cerebrovascular disease, atrial arrhythmia and coronary disease, red cell distribution width (RDW) > 15%, positive blood culture, hematocrit < 30% and living in a nursing home were independent risk factors for reduced long-term survival after hospital discharge. Cumulative 1-, 3- and 5-year survival rates were 93.9%, 85.3% and 76%, respectively. Among non-survivors, 361 (83.8%) died earlier than expected given their life expectancy. CONCLUSIONS: Survival after hospital discharge is mainly associated with age and comorbidities. The findings of bacteremia and elevated RDW on admission could help identify patients at high risk of long-term mortality.

Risk factor profiles and clinical outcomes for children and adults with pneumococcal infections in Singapore: A need to expand vaccination policy?

Invasive pneumococcal infection is a major cause of morbidity and mortality worldwide despite the availability of pneumococcal vaccines. The aim of this study was to re-evaluate the clinical syndromes, prognostic factors and outcomes for pneumococcal disease in adults and children in Singapore during the period before and after the introduction of the pneumococcal vaccine. We retrospectively analyzed a large cohort of patients admitted to the four main public hospitals in Singapore with S. pneumoniae infection between 1997 and 2013. A total of 889 (64% of all isolates identified in the clinical laboratories) cases were included in the analysis; 561 (63.1%) were adult (≥16 years) cases with a median age of 62 years and 328 (36.9%) were paediatric cases with a median age of 3 years. Bacteraemic pneumonia was the most common syndrome in both groups (69.3% vs. 44.2%), followed by primary bacteraemia without pneumonia (14.3% vs. 13.4%), meningitis (6.4% vs. 7.6%) and non-bacteraemic pneumonia (5.2% vs. 21%). The major serotypes in adults were 3, 4, 6B, 14, 19F and 23F whereas in children they were 14, 6B and 19F, accounting both for nearly half of pneumococcal disease cases. No particular serotype was associated with mortality or severity of the pneumococcal disease. Overall mortality rate was 18.5% in adults and 3% in children. Risk factors for mortality included acute cardiac events in adults, meningitis in children and critical illness and bilateral pulmonary infiltrates in both adults and children. Penicillin resistance was not associated with increased mortality. Our results agree with global reports that the course of pneumococcal disease and its clinical outcome were more severe in adults than in children. The main serotypes causing invasive disease were mostly covered by the vaccines in use. The high mortality rates reflect an urgent need to increase vaccination coverage in both adults and children to tackle this vaccine-preventable infection.

Mortality and costs of pneumococcal pneumonia in adults: a cross-sectional study. / Mortalidade e custos da pneumonia pneumocócica em adultos: um estudo transversal.

OBJECTIVE: Pneumococcal pneumonia is a significant cause of morbidity and mortality among adults. The study's main aim was to evaluate the in-hospital mortality and related costs of community-acquired pneumococcal pneumonia in adults. METHODS: This cross-sectional study used medical records of adult patients with pneumococcal pneumonia hospitalized in a university hospital in Brazil from October 2009 to April 2017. All patients aged ≥ 18 years diagnosed with pneumococcal pneumonia were included. Risk factors, intensive care unit admission, length of hospital stay, in-hospital mortality, and direct and indirect costs were analyzed. RESULTS: In total, 186 patients were selected. The mean in-hospital mortality rate was 18% for adults aged < 65 years and 23% for the elderly (≥ 65 years). Bacteremic pneumococcal pneumonia affected 20% of patients in both groups, mainly through chronic respiratory disease (adjusted OR: 3.07, 95% CI: 1.23-7.65, p < 0.01). Over 7 years, annual total direct and indirect costs were USD 28,188 for adults < 65 years (USD 1,746 per capita) and USD 16,350 for the elderly (USD 2,119 per capita). CONCLUSION: Pneumococcal pneumonia remains an important cause of morbidity and mortality among adults, significantly affecting direct and indirect costs. These results suggest the need for prevention strategies for all adults, especially for patients with chronic respiratory diseases.

OBJETIVO: A pneumonia pneumocócica é uma causa significativa de morbimortalidade entre adultos. Desta maneira, o objetivo principal deste estudo foi avaliar a mortalidade intra-hospitalar e os custos relacionados à doença adquirida em adultos. MÉTODOS: Este estudo transversal utilizou prontuários de pacientes adultos com pneumonia pneumocócica internados em um hospital universitário no Brasil, de outubro de 2009 a abril de 2017. Todos os pacientes com idade ≥ 18 anos e diagnosticados com pneumonia pneumocócica foram incluídos. Dados como os fatores de risco, a internação em unidade de terapia intensiva, o tempo de internação, a mortalidade hospitalar e os custos diretos e indiretos foram analisados. RESULTADOS: No total, 186 pacientes foram selecionados. A taxa média de mortalidade intra-hospitalar foi de 18% para adultos com idade < 65 anos e 23% para os idosos (≥ 65 anos). A pneumonia pneumocócica bacterêmica acometeu 20% dos pacientes em ambos os grupos, principalmente por doença respiratória crônica (OR ajustada: 3,07; IC95%: 1,23­7,65; p < 0,01). Após levantamento das internações ocorridas no período de sete anos de tratamento, verificou-se que os custos diretos e indiretos totais anuais foram de US$ 28.188 para adultos < 65 anos (US$ 1.746 per capita) e US$ 16.350 para os idosos (US$ 2.119 per capita). CONCLUSÃO: A pneumonia pneumocócica continua sendo uma importante causa de morbimortalidade entre adultos, afetando significativamente os custos diretos e indiretos. Esses resultados sugerem a necessidade de estratégias de prevenção para todos os adultos, especialmente para pacientes com doenças respiratórias crônicas.

23-valent pneumococcal polysaccharide vaccine improves survival in dialysis patients by preventing cardiac events.

BACKGROUND: Immunodeficient patients are recommended to receive pneumococcal vaccination. However, there is limited evidence showing effectiveness of the polysaccharide vaccine. Polysaccharide vaccination has shown an association with cardiovascular event risk reduction. We assessed the efficacy of the 23-valent pneumococcal polysaccharide vaccine (PPSV23) in relation to the risk of hospitalization and death due to pneumonia and acute cardiac events. METHODS: The medical records of all dialysis patients attending our 8 study centers in 2010 were studied, and we selected 1038 consecutive patients. One-to-one propensity score matching was used to correct for potential selection bias in a PPSV23-vaccinated group versus a non-vaccinated group, and a total of 510 patients were identified for outcome analysis. Time to first admission, or deaths due to all-cause pneumonia or cardiac events until 2015 were compared between both groups. RESULTS: The all-cause death rate was significantly decreased in the PPSV23-vaccinated group, (hazard ratio [HR] 0.62, 95% confidence interval [CI]; 0.46-0.83, P = 0.002). All-cause death was considered to be a competing risk for the other outcomes. Further outcomes were evaluated by competing risk analysis adjusting for mortality. There was no statistically significant difference in the hospitalization rate for pneumonia; however, the hospitalization rate due to cardiac events was significantly lower in the PPSV23-vaccinated group than in the non-vaccinated group (HR 0.44, 95% CI; 0.20-0.96, P = 0.040). There was no statistically significant difference in the death rate due to pneumonia; however, the rate of cardiac death was significantly lower in the PPSV23-vaccinated group than in the non-vaccinated group (HR 0.36, 95% CI; 0.18-0.71, P = 0.003). CONCLUSIONS: The PPSV23 vaccination is associated with a good prognosis and a low-risk of cardiac events in dialysis patients; however, there was no evidence indicating enhanced protective efficacy against pneumonia, suggesting the PPSV23 vaccination might improve the prognosis by directly preventing cardiovascular events.

Rethinking results from the Japanese 23-valent pneumococcal polysaccharide vaccine randomized clinical trial.

We review a previously published randomized clinical trial of 23-valent pneumococcal polysaccharide vaccine (PPSV23) that has been used extensively globally to support PPSV23 use among adults. We argue that serious issues with internal and external validity exist that affect the usefulness of these data when evaluating pneumococcal vaccines for the general adult population. As one example of internal data inconsistency, the values reported for the percent of all pneumonia cases due to pneumococcus and the vaccine efficacy (VE) for all cause pneumonia are mutually inconsistent, even based on unrealistically high values for PPSV23 VE against vaccine serotypes and the proportion of pneumococcal pneumonias due to vaccine serotypes.

Risk modelling the mortality impact of antimicrobial resistance in secondary pneumococcal pneumonia infections during the 2009 influenza pandemic.

OBJECTIVES: The aim of this study was to estimate the impact of antimicrobial resistance (AMR) in secondary pneumococcal pneumonia infections on global mortality during the 2009 influenza pandemic, to estimate future pandemic mortality risk and to inform pandemic preparedness. METHODS: Risk analysis modelling was conducted using a multivariate risk formula. Literature reviews were conducted to generate global central estimates for each of the parameters of the risk formula in relation to the 2009 influenza pandemic, secondary pneumococcal pneumonia, rates of AMR, and pneumococcal vaccine efficacy as a component of pandemic preparedness. RESULTS: Global Streptococcus pneumoniae AMR was estimated at 21.8% to 27.6%, and contributed to 1.8% to 2.3% of deaths during the 2009 influenza pandemic. When directly applied to mortality due to multidrug resistance, pneumococcal vaccination could potentially prevent 1277 to 3754 deaths and could have reduced mortality from multidrug-resistant S. pneumoniae to 1% to 1.2%. CONCLUSIONS: AMR in secondary pneumococcal infections contributed towards a small percentage of the global mortality during the 2009 influenza pandemic. Increased S. pneumoniae AMR could result in a three- to four-fold rise in mortality due to secondary pneumococcal infections in future influenza pandemics. Pneumococcal vaccination has an important role in preventing pneumococcal co-infections and combating AMR in all populations, and should be considered a key component of influenza pandemic preparedness or early action plans.

Pneumonia hospitalisation and case-fatality rates in older Australians with and without risk factors for pneumococcal disease: implications for vaccine policy.

Community-acquired pneumonia (CAP) results in substantial numbers of hospitalisations and deaths in older adults. There are known lifestyle and medical risk factors for pneumococcal disease but the magnitude of the additional risk is not well quantified in Australia. We used a large population-based prospective cohort study of older adults in the state of New South Wales (45 and Up Study) linked to cause-specific hospitalisations, disease notifications and death registrations from 2006 to 2015. We estimated the age-specific incidence of CAP hospitalisation (ICD-10 J12-18), invasive pneumococcal disease (IPD) notification and presumptive non-invasive pneumococcal CAP hospitalisation (J13 + J18.1, excluding IPD), comparing those with at least one risk factor to those with no risk factors. The hospitalised case-fatality rate (CFR) included deaths in a 30-day window after hospitalisation. Among 266 951 participants followed for 1 850 000 person-years there were 8747 first hospitalisations for CAP, 157 IPD notifications and 305 non-invasive pneumococcal CAP hospitalisations. In persons 65-84 years, 54.7% had at least one identified risk factor, increasing to 57.0% in those ⩾85 years. The incidence of CAP hospitalisation in those ⩾65 years with at least one risk factor was twofold higher than in those without risk factors, 1091/100 000 (95% confidence interval (CI) 1060-1122) compared with 522/100 000 (95% CI 501-545) and IPD in equivalent groups was almost threefold higher (18.40/100 000 (95% CI 14.61-22.87) vs. 6.82/100 000 (95% CI 4.56-9.79)). The CFR increased with age but there were limited difference by risk status, except in those aged 45 to 64 years. Adults ⩾65 years with at least one risk factor have much higher rates of CAP and IPD suggesting that additional risk factor-based vaccination strategies may be cost-effective.

Procalcitonin is not an independent predictor of 30-day mortality, albeit predicts pneumonia severity in patients with pneumonia acquired outside the hospital.

BACKGROUND: Procalcitonin (PCT) is a useful marker for pneumonia. However, its clinical usefulness in elderly patients has not been studied extensively. This study aimed to assess the relationship between PCT and prognosis and pneumonia severity in elderly patients with pneumonia acquired outside the hospital. METHODS: Data considered relevant to pneumonia severity and prognosis were retrospectively obtained from clinical charts of all patients with pneumonia who were admitted to our hospital from 2010 to 2017. The primary outcome was 30-day mortality in elderly patients (aged ≥75 years), and the relationship between PCT levels and pneumonia severity, as determined by the pneumonia severity index (PSI) was also examined. RESULTS: Data were collected from 667 patients, of which 436 were elderly patients. Multivariate and receiver operating characteristic curve analysis revealed that albumin, body mass index, and PSI class rather than PCT are important factors related to 30-day mortality in elderly patients. PCT was also not an independent prognostic factor in younger patients. PCT levels significantly differed by pneumonia severity (mild, moderate, and severe) in both younger (p < 0.001) and elderly (p < 0.0001) patients, with levels increasing as severity increased. In contrast, C-reactive protein (CRP) levels and white blood cell counts did not significantly differ by pneumonia severity in younger and elderly patients. A subgroup analysis focused on Streptococcus pneumoniae pneumonia revealed that PCT levels differed by severity in elderly patients (p = 0.03), with levels increasing as severity increased. CONCLUSION: PCT was not an independent predictor of 30-day mortality in both of elderly and younger patients. PCT levels, but not CRP levels, significantly increased with increasing pneumonia severity in younger and elderly patients, although the degree of increase tended to be lower in elderly patients compared to younger patients for the same severity. PCT levels also significantly increased with increasing pneumonia severity in elderly patients with Streptococcus pneumoniae pneumonia.

Effect of pneumococcal conjugate vaccine introduction on childhood pneumonia mortality in Brazil: a retrospective observational study.

BACKGROUND: Understanding the real-world effect of pneumococcal conjugate vaccines (PCVs) on pneumonia mortality is crucial because of the expectation that increased PCV use will substantially reduce the burden of pneumonia deaths in children younger than 5 years. However, few post-vaccine introduction studies have estimated the benefits of PCV use on childhood mortality and results have been inconsistent. Therefore, we set out to assess the effect of introduction of ten-valent pneumococcal conjugate vaccine (PCV10) on pneumonia mortality in children in Brazil. METHODS: In this retrospective observational study, we used publicly available mortality data of children aged 3-59 months in Brazil. We separated data by age group (3-11 months, 3-23 months, and 3-59 months) and stratified data by three different socioeconomic factors of Brazilian municipalities (in 2010): Human Development Index, proportion of children living in extreme poverty, and proportion of mothers with no primary education. We first examined long-term trends in childhood pneumonia mortality in Brazil (from 1980 to 2014). We then assessed the effect of PCV10-introduced in Brazil in 2010-both nationally and in municipalities stratified by socioeconomic status, with a synthetic control approach as our primary analytical method. FINDINGS: Between 1980 and 2010, a period during which Brazil's Human Development Index rose substantially, national pneumonia mortality in children younger than 5 years decreased from about 150 to 15 deaths per 100 000 children younger than 5 years. Despite rapid uptake of PCV10 after its introduction in 2010, we observed a further vaccine-associated decline of about 10% in national childhood pneumonia mortality with our primary analytical method, with a high degree of uncertainty in the estimates. We observed larger reductions in municipal childhood pneumonia mortality in all three age groups (3-11 months, 3-23 months, and 3-59 months) in municipalities with a high percentage of extreme childhood poverty and mothers with no primary education, with the largest decrease observed in children aged 3-23 months in municipalities with low maternal education (24%, 95% credible interval 7-35). INTERPRETATION: The large reduction observed from 1980 to 2010 in national pneumonia mortality in children younger than 5 years underscores that improvements in nutrition, hygiene, education, and health care have an important role in reducing pneumonia mortality. Although the PCV-associated reduction in childhood pneumonia mortality at the national level was modest, we found that PCV led to larger reductions in low-income municipalities. Similarly, large benefits might occur when PCVs are introduced in other low-income settings. FUNDING: Bill & Melinda Gates Foundation and National Institute of Allergy and Infectious Diseases.

Effect of Combined ß-Lactam/Macrolide Therapy on Mortality According to the Microbial Etiology and Inflammatory Status of Patients With Community-Acquired Pneumonia.

BACKGROUND: Antibiotic combinations that include macrolides have shown lower mortality rates than ß-lactams in monotherapy or combined with fluoroquinolones in patients with community-acquired pneumonia (CAP). However, this effect has not been studied according to the levels of C-reactive protein in CAP with identified microbial cause. In patients with CAP and known microbial cause we aimed to evaluate 30-day mortality of a ß-lactam plus macrolide (BL + M) compared with a fluoroquinolone alone or with a ß-lactam (FQ ± BL). METHODS: We analyzed a prospective observational cohort of patients with CAP admitted to the Hospital Clinic of Barcelona between 1996 and 2016. We included only patients with known microbial cause. RESULTS: Of 1,715 patients (29%) with known etiology, a total of 932 patients (54%) received BL + M. Despite lower crude mortality in the BL + M group in the overall population (BL + M, 5% vs FQ ± BL, 8%; P = .015), after adjustment by a propensity score and baseline characteristics, the combination of BL + M had a protective effect on mortality only in patients with high inflammatory response (C-reactive protein, > 15 mg/dL) and pneumococcal CAP (adjusted OR, 0.28; 95% CI, 0.09-0.93). No benefits on mortality were observed for the population without high inflammatory response and pneumococcal CAP or with other etiologies. CONCLUSIONS: The combination of a ß-lactam with a macrolide was associated with decreased mortality in patients with pneumococcal CAP and in patients with high systemic inflammatory response. When both factors occurred together, BL + M was protective for mortality in the multivariate analysis.

Mortalidade e custos da pneumonia pneumocócica em adultos: um estudo transversal / Mortality and costs of pneumococcal pneumonia in adults: a cross-sectional study

RESUMO Objetivo A pneumonia pneumocócica é uma causa significativa de morbimortalidade entre adultos. Desta maneira, o objetivo principal deste estudo foi avaliar a mortalidade intra-hospitalar e os custos relacionados à doença adquirida em adultos. Métodos Este estudo transversal utilizou prontuários de pacientes adultos com pneumonia pneumocócica internados em um hospital universitário no Brasil, de outubro de 2009 a abril de 2017. Todos os pacientes com idade ≥ 18 anos e diagnosticados com pneumonia pneumocócica foram incluídos. Dados como os fatores de risco, a internação em unidade de terapia intensiva, o tempo de internação, a mortalidade hospitalar e os custos diretos e indiretos foram analisados. Resultados No total, 186 pacientes foram selecionados. A taxa média de mortalidade intra-hospitalar foi de 18% para adultos com idade < 65 anos e 23% para os idosos (≥ 65 anos). A pneumonia pneumocócica bacterêmica acometeu 20% dos pacientes em ambos os grupos, principalmente por doença respiratória crônica (OR ajustada: 3,07; IC95%: 1,23‐7,65; p < 0,01). Após levantamento das internações ocorridas no período de sete anos de tratamento, verificou-se que os custos diretos e indiretos totais anuais foram de US$ 28.188 para adultos < 65 anos (US$ 1.746 per capita) e US$ 16.350 para os idosos (US$ 2.119 per capita). Conclusão A pneumonia pneumocócica continua sendo uma importante causa de morbimortalidade entre adultos, afetando significativamente os custos diretos e indiretos. Esses resultados sugerem a necessidade de estratégias de prevenção para todos os adultos, especialmente para pacientes com doenças respiratórias crônicas.

ABSTRACT Objective Pneumococcal pneumonia is a significant cause of morbidity and mortality among adults. The study's main aim was to evaluate the in-hospital mortality and related costs of community-acquired pneumococcal pneumonia in adults. Methods This cross-sectional study used medical records of adult patients with pneumococcal pneumonia hospitalized in a university hospital in Brazil from October 2009 to April 2017. All patients aged ≥ 18 years diagnosed with pneumococcal pneumonia were included. Risk factors, intensive care unit admission, length of hospital stay, in-hospital mortality, and direct and indirect costs were analyzed. Results In total, 186 patients were selected. The mean in-hospital mortality rate was 18% for adults aged < 65 years and 23% for the elderly (≥ 65 years). Bacteremic pneumococcal pneumonia affected 20% of patients in both groups, mainly through chronic respiratory disease (adjusted OR: 3.07, 95% CI: 1.23-7.65, p < 0.01). Over 7 years, annual total direct and indirect costs were USD 28,188 for adults < 65 years (USD 1,746 per capita) and USD 16,350 for the elderly (USD 2,119 per capita). Conclusion Pneumococcal pneumonia remains an important cause of morbidity and mortality among adults, significantly affecting direct and indirect costs. These results suggest the need for prevention strategies for all adults, especially for patients with chronic respiratory diseases.