Pneumococcal serotypes and risk factors in adult community-acquired pneumonia 2018-20; a multicentre UK cohort study.

Background: Higher-valency pneumococcal vaccines are anticipated. We aimed to describe serotype distribution and risk factors for vaccine-serotype community-acquired pneumonia (CAP) in the two years pre-SARS-CoV-2 pandemic. Methods: We conducted a prospective cohort study of adults hospitalised with CAP at three UK sites between 2018 and 2020. Pneumococcal serotypes were identified using a 24-valent urinary-antigen assay and blood cultures. Risk factors associated with vaccine-type pneumonia caused by serotypes in the 13-, 15- and 20-valent pneumococcal conjugate vaccines (PCV13, PCV15, PCV20) and 23-valent pneumococcal polysaccharide vaccine (PPV23) were determined from multivariable analysis. Findings: Of 1921 adults hospitalised with CAP, 781 (40.7%, 95% confidence intervals (CI) 38.5-42.9%) had pneumococcal pneumonia. A single PCV13-serotype was detected in 242 (31.0%, 95% CI 27.8-34.3%) pneumococcal CAP patients, mostly serotype 3 (171/242, 70.7%, 95% CI 64.5-76.0%). The additional two PCV15-serotypes were detected in 31 patients (4%, 95% CI 2.8-5.6%), and PCV20-non13-serotypes in 192 (24.6%), with serotype 8 most prevalent (123/192, 64.1%, 95% CI 57.1-70.5%). Compared to PCV13-serotype CAP, people with PCV20-non13 CAP were younger (median age 62 versus 72 years, p < 0.001) and less likely to be male (44% versus 61%, p = 0.01). PPV23-non13-serotypes were found in 252 (32.3%, 95% CI 29.1-35.6%) pneumococcal CAP patients. Interpretation: Despite mature infant pneumococcal programmes, the burden of PCV13-serotype pneumonia remains high in older adults, mainly due to serotype 3. PCV20-non13-serotype pneumonia is more likely in younger people with fewer pneumococcal risk factors. Funding: Unrestricted investigator-initiated research grant from Pfizer, United Kingdom; support from National Institute for Health Research (NIHR) Biomedical Research Centre, Nottingham.

Effectiveness of the 23-valent pneumococcal polysaccharide vaccine against vaccine serotype pneumococcal pneumonia in adults: A case-control test-negative design study.

BACKGROUND: Vaccination with the 23-valent pneumococcal polysaccharide vaccine (PPV23) is available in the United Kingdom to adults aged 65 years or older and those in defined clinical risk groups. We evaluated the vaccine effectiveness (VE) of PPV23 against vaccine-type pneumococcal pneumonia in a cohort of adults hospitalised with community-acquired pneumonia (CAP). METHODS AND FINDINGS: Using a case-control test-negative design, a secondary analysis of data was conducted from a prospective cohort study of adults (aged ≥16 years) with CAP hospitalised at 2 university teaching hospitals in Nottingham, England, from September 2013 to August 2018. The exposure of interest was PPV23 vaccination at any time point prior to the index admission. A case was defined as PPV23 serotype-specific pneumococcal pneumonia and a control as non-PPV23 serotype pneumococcal pneumonia or nonpneumococcal pneumonia. Pneumococcal serotypes were identified from urine samples using a multiplex immunoassay or from positive blood cultures. Multivariable logistic regression was used to derive adjusted odds of case status between vaccinated and unvaccinated individuals; VE estimates were calculated as (1 - odds ratio) × 100%. Of 2,357 patients, there were 717 PPV23 cases (48% vaccinated) and 1,640 controls (54.5% vaccinated). The adjusted VE (aVE) estimate against PPV23 serotype disease was 24% (95% CI 5%-40%, p = 0.02). Estimates were similar in analyses restricted to vaccine-eligible patients (n = 1,768, aVE 23%, 95% CI 1%-40%) and patients aged ≥65 years (n = 1,407, aVE 20%, 95% CI -5% to 40%), but not in patients aged ≥75 years (n = 905, aVE 5%, 95% CI -37% to 35%). The aVE estimate in relation to PPV23/non-13-valent pneumococcal conjugate vaccine (PCV13) serotype pneumonia (n = 417 cases, 43.7% vaccinated) was 29% (95% CI 6%-46%). Key limitations of this study are that, due to high vaccination rates, there was a lack of power to reject the null hypothesis of no vaccine effect, and that the study was not large enough to allow robust subgroup analysis in the older age groups. CONCLUSIONS: In the setting of an established national childhood PCV13 vaccination programme, PPV23 vaccination of clinical at-risk patient groups and adults aged ≥65 years provided moderate long-term protection against hospitalisation with PPV23 serotype pneumonia. These findings suggest that PPV23 vaccination may continue to have an important role in adult pneumococcal vaccine policy, including the possibility of revaccination of older adults.

Corticosteroids as Adjunctive Therapy in the Treatment of Influenza: An Updated Cochrane Systematic Review and Meta-analysis.

OBJECTIVES: Corticosteroids may be beneficial in sepsis, but uncertainty remains over their effects in severe influenza. This systematic review updates the current evidence regarding corticosteroids in the treatment of influenza and examines the effect of dose on outcome. DATA SOURCES: Electronic databases (MEDLINE, EMBASE, CINAHL, LILACS, CENTRAL, and Web of Science) and trial registries were searched to October 2018 for randomized controlled trials, quasi-experimental designs, and observational cohort studies reporting corticosteroid versus no corticosteroid treatment in individuals with influenza. STUDY SELECTION AND DATA EXTRACTION: Two researchers independently assessed studies for inclusion. Risk of bias was assessed using the Cochrane Risk of Bias tool (randomized controlled trials) or Newcastle-Ottawa Scale (observational studies). Where appropriate, we estimated the effect of corticosteroids by random-effects meta-analyses using the generic inverse variance method. Meta-regression analysis was used to assess the association of corticosteroid dose and mortality. DATA SYNTHESIS: We identified 30 eligible studies, all observational apart from one randomized controlled trial. Twenty-one observational studies were included in the meta-analysis of mortality, which suggested an adverse association with corticosteroid therapy (odds ratio, 3.90; 95% CI, 2.31-6.60; 15 studies; adjusted hazard ratio, 1.49; 95% CI, 1.09-2.02; six studies). Risk of bias assessment was consistent with potential confounding by indication. Pooled analysis of seven studies showed increased odds of hospital-acquired infection in people treated with corticosteroids (unadjusted odds ratio, 2.74; 95% CI, 1.51-4.95). Meta-regression of the effect of dose on mortality did not reveal an association, but reported doses of corticosteroids in included studies were high (mostly > 40 mg methylprednisolone [or equivalent] per day). CONCLUSIONS: Corticosteroid treatment in influenza is associated with increased mortality and hospital-acquired infection, but the evidence relates mainly to high corticosteroid doses and is of low quality with potential confounding by indication a major concern.

Pneumococcal serotype trends, surveillance and risk factors in UK adult pneumonia, 2013-18.

BACKGROUND: Changes over the last 5 years (2013-18) in the serotypes implicated in adult pneumococcal pneumonia and the patient groups associated with vaccine-type disease are largely unknown. METHODS: We conducted a population-based prospective cohort study of adults admitted to two large university hospitals with community-acquired pneumonia (CAP) between September 2013 and August 2018. Pneumococcal serotypes were identified using a novel 24-valent urinary monoclonal antibody assay and from blood cultures. Trends in incidence rates were compared against national invasive pneumococcal disease (IPD) data. Persons at risk of vaccine-type pneumonia (pneumococcal conjugate vaccine (PCV)13 and pneumococcal polysaccharide vaccine (PPV)23) were determined from multivariate analyses. FINDINGS: Of 2934 adults hospitalised with CAP, 1075 (36.6%) had pneumococcal pneumonia. The annual incidence of pneumococcal pneumonia increased from 32.2 to 48.2 per 100 000 population (2013-18), predominantly due to increases in PCV13non7-serotype and non-vaccine type (NVT)-serotype pneumonia (annual incidence rate ratio 1.12, 95% CI 1.04 to 1.21 and 1.19, 95% CI 1.10 to 1.28, respectively). Incidence trends were broadly similar to IPD data. PCV13non7 (56.9% serotype 3) and PPV23non13 (44.1% serotype 8) serotypes were identified in 349 (32.5%) and 431 (40.1%) patients with pneumococcal pneumonia, respectively. PCV13-serotype pneumonia (dominated by serotype 3) was more likely in patients in the UK pneumococcal vaccination clinical risk group (adjusted OR (aOR) 1.73, 95% CI 1.31 to 2.28) while PPV23-serotype pneumonia was more likely in patients outside the clinical risk group (aOR 1.54, 95% CI 1.13 to 2.10). INTERPRETATION: The incidence of pneumococcal CAP is increasing, predominantly due to NVT serotypes and serotype 3. PPV23-serotype pneumonia is more likely in adults outside currently identified clinical risk groups.

Corticosteroids as adjunctive therapy in the treatment of influenza.

BACKGROUND: Specific treatments for influenza are limited to neuraminidase inhibitors and adamantanes. Corticosteroids show evidence of benefit in sepsis and related conditions, most likely due to their anti-inflammatory and immunomodulatory properties. Although commonly prescribed for severe influenza, there is uncertainty over their potential benefits or harms. This is an update of a review first published in 2016. OBJECTIVES: To systematically assess the effectiveness and potential adverse effects of corticosteroids as adjunctive therapy in the treatment of influenza, taking into account differences in timing and doses of corticosteroids. SEARCH METHODS: We searched CENTRAL (2018, Issue 9), which includes the Cochrane Acute Respiratory infections Group's Specialised Register, MEDLINE (1946 to October week 1, 2018), Embase (1980 to 3 October 2018), CINAHL (1981 to 3 October 2018), LILACS (1982 to 3 October 2018), Web of Science (1985 to 3 October 2018), abstracts from the last three years of major infectious disease and microbiology conferences, and references of included articles. We also searched the World Health Organization International Clinical Trials Registry Platform, ClinicalTrials.gov, and the ISRCTN registry on 3 October 2018. SELECTION CRITERIA: We included randomised controlled trials (RCTs), quasi-RCTs, and observational studies that compared corticosteroid treatment with no corticosteroid treatment for influenza or influenza-like illness. We did not restrict studies by language of publication, influenza subtypes, clinical setting, or age of participants. We selected eligible studies in two stages: sequential examination of title and abstract, followed by full text. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias. We pooled estimates of effect using a random-effects model, where appropriate. We assessed heterogeneity using the I2 statistic and assessed the certainty of the evidence using the GRADE framework. MAIN RESULTS: This updated review includes 30 studies (one RCT with two arms and 29 observational studies) with a total of 99,224 participants. We included 19 studies in the original review (n = 3459), all of which were observational, with 13 studies included in the meta-analysis for mortality. We included 12 new studies in this update (one RCT and 11 observational studies), and excluded one study in the original review as it has been superceded by a more recent analysis. Twenty-one studies were included in the meta-analysis (9536 individuals), of which 15 studied people infected with 2009 influenza A H1N1 virus (H1N1pdm09). Data specific to mortality were of very low quality, based predominantly on observational studies, with inconsistent reporting of variables potentially associated with the outcomes of interest, differences between studies in the way in which they were conducted, and with the likelihood of potential confounding by indication. Reported doses of corticosteroids used were high, and indications for their use were not well reported. On meta-analysis, corticosteroid therapy was associated with increased mortality (odds ratio (OR) 3.90, 95% confidence interval (CI) 2.31 to 6.60; I2 = 68%; 15 studies). A similar increase in risk of mortality was seen in a stratified analysis of studies reporting adjusted estimates (OR 2.23, 95% CI 1.54 to 3.24; I2 = 0%; 5 studies). An association between corticosteroid therapy and increased mortality was also seen on pooled analysis of six studies which reported adjusted hazard ratios (HRs) (HR 1.49, 95% CI 1.09 to 2.02; I2 = 69%). Increased odds of hospital-acquired infection related to corticosteroid therapy were found on pooled analysis of seven studies (pooled OR 2.74, 95% CI 1.51 to 4.95; I2 = 90%); all were unadjusted estimates, and we graded the data as of very low certainty. AUTHORS' CONCLUSIONS: We found one RCT of adjunctive corticosteroid therapy for treating people with community-acquired pneumonia, but the number of people with laboratory-confirmed influenza in the treatment and placebo arms was too small to draw conclusions regarding the effect of corticosteroids in this group, and we did not include it in our meta-analyses of observational studies. The certainty of the available evidence from observational studies was very low, with confounding by indication a major potential concern. Although we found that adjunctive corticosteroid therapy is associated with increased mortality, this result should be interpreted with caution. In the context of clinical trials of adjunctive corticosteroid therapy in sepsis and pneumonia that report improved outcomes, including decreased mortality, more high-quality research is needed (both RCTs and observational studies that adjust for confounding by indication). The currently available evidence is insufficient to determine the effectiveness of corticosteroids for people with influenza.

13-Valent vaccine serotype pneumococcal community acquired pneumonia in adults in high clinical risk groups.

There is debate regarding the value of vaccinating adults with the 13-valent pneumococcal conjugate vaccine (PCV-13). This analysis was conducted to investigate the risk of PCV-13 serotype community acquired pneumonia (CAP) in hospitalised adults with co-morbid disease and risk factors for pneumococcal disease in the UK. Consecutive adults hospitalised (2008-2013) with a primary diagnosis of CAP, were recruited. Pneumococcal aetiology disease was identified by use of pneumococcal urinary antigen detection and serotype identification using a validated multiplex immunoassay or serum latex agglutination. Adults with PCV-13 serotype CAP were compared to those with non-PCV-13 serotype CAP. Of 2224 patients, PCV-13 serotype CAP was identified in 337 (15.2%) and non-PCV-13 serotype CAP in 250 (11.2%) individuals. Adults aged ≥65 years with one or more clinical risk factors had a significantly lower risk of PCV-13 serotype CAP compared to those aged 16-64 years without clinical risk factors (aOR 0.61, 95%CI 0.41-0.92, p = .018). In a stacked-risk analysis, the presence of incremental clinical risk factors was associated with lower odds of PCV-13 disease (p for trend = .029) Adults with underlying chronic respiratory disease (aOR) 0.56, 95% CI 0.36-0.85, p = .007) and chronic kidney disease (aOR 0.48, 95% CI 0.25-0.92, p = .028) had significantly lower adjusted odds of PCV-13 compared to non-PCV-13 serotype CAP. This analysis suggests that in the UK, the burden of PCV13 disease is greater in adults outside the traditional 'at-risk' groups compared to adults in 'at-risk' groups.

Increased incidence of adult pneumococcal pneumonia during school holiday periods.

Child contact is a recognised risk factor for adult pneumococcal disease. Peaks in invasive pneumococcal disease incidence observed during winter holidays may be related to changes in social dynamics. This analysis was conducted to examine adult pneumococcal community-acquired pneumonia (CAP) incidence during school holiday periods. Between September 2008 and 2013, consecutive adults admitted to hospitals covering the Greater Nottingham area with a diagnosis of CAP were studied. Pneumococcal pneumonia was detected using culture and antigen detection methods. Of 2221 adults studied, 575 (25.9%) were admitted during school holidays and 643 (29.0%) had pneumococcal CAP. CAP of pneumococcal aetiology was significantly more likely in adults admitted during school holidays compared to term time (35.3% versus 26.7%; adjusted OR 1.38, 95% CI 1.11-1.72, p=0.004). Over the 5-year period, the age-adjusted incidence of hospitalised pneumococcal CAP was higher during school holidays compared to term time (incident rate ratio 1.35, 95% CI 1.14-1.60, p<0.001); there was no difference in rates of all-cause CAP or non-pneumococcal CAP. Reported child contact was higher in individuals with pneumococcal CAP admitted during school holidays compared to term time (42.0% versus 33.7%, OR 1.43, 95% CI 1.00-2.03, p=0.046). Further study of transmission dynamics in relation to these findings and to identify appropriate intervention strategies is warranted.

Corticosteroids as adjunctive therapy in the treatment of influenza.

BACKGROUND: Specific treatments for influenza are limited to neuraminidase inhibitors and adamantanes. Corticosteroids show evidence of benefit in sepsis and related conditions, most likely due to their anti-inflammatory and immunomodulatory properties. Although commonly prescribed for severe influenza, there is uncertainty over their potential benefit or harm. OBJECTIVES: To systematically assess the effectiveness and potential adverse effects of corticosteroids as adjunctive therapy in the treatment of influenza, taking into account differences in timing and doses of corticosteroids. SEARCH METHODS: We searched CENTRAL (2015, Issue 5), MEDLINE (1946 to June week 1, 2015), EMBASE (1974 to June 2015), CINAHL (1981 to June 2015), LILACS (1982 to June 2015), Web of Science (1985 to June 2015), abstracts from the last three years of major infectious disease and microbiology conferences, and references of included articles. SELECTION CRITERIA: We included randomised controlled trials (RCTs), quasi-RCTs and observational studies that compared corticosteroid treatment with no corticosteroid treatment for influenza or influenza-like illness. We did not restrict studies by language of publication, influenza subtypes, clinical setting or age of participants. We selected eligible studies in two stages: sequential examination of title and abstract, followed by full text. DATA COLLECTION AND ANALYSIS: Two pairs of review authors independently extracted data and assessed risk of bias. We pooled estimates of effect using random-effects meta-analysis models, where appropriate. We assessed heterogeneity using the I(2) statistic and assessed the quality of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. MAIN RESULTS: We identified 19 eligible studies (3459 individuals), all observational; 13 studies (1917 individuals) were suitable for inclusion in the meta-analysis of mortality. Of these, 12 studied patients infected with 2009 influenza A H1N1 virus (H1N1pdm09). Risk of bias was greatest in the 'comparability domain' of the Newcastle-Ottawa scale, consistent with potential confounding by indication. Data specific to mortality were of very low quality. Reported doses of corticosteroids used were high and indications for their use were not well reported. On meta-analysis, corticosteroid therapy was associated with increased mortality (odds ratio (OR) 3.06, 95% confidence interval (CI) 1.58 to 5.92). Pooled subgroup analysis of adjusted estimates of mortality from four studies found a similar association (OR 2.82, 95% CI 1.61 to 4.92). Three studies reported greater odds of hospital-acquired infection related to corticosteroid therapy; all were unadjusted estimates and we graded the data as very low quality. AUTHORS' CONCLUSIONS: We did not identify any completed RCTs of adjunctive corticosteroid therapy for treating influenza. The available evidence from observational studies is of very low quality with confounding by indication a major potential concern. Although we found that adjunctive corticosteroid therapy was associated with increased mortality, this result should be interpreted with caution. In the context of clinical trials of adjunctive corticosteroid therapy in sepsis and pneumonia that report improved outcomes, including decreased mortality, more high-quality research is needed (both RCTs and observational studies). Currently, we do not have sufficient evidence in this review to determine the effectiveness of corticosteroids for patients with influenza.

Time to first antibiotic and mortality in adults hospitalised with community-acquired pneumonia: a matched-propensity analysis.

A matched-propensity analysis of national data from the British Thoracic Society community-acquired pneumonia audit was conducted (n=13 725). Overall, time to first antibiotic (TFA) was ≤4 h in 63%. Adjusted 30-day inpatient (IP) mortality was lower for adults with TFA ≤4 h compared with TFA >4 h (adjusted OR 0.84, 95% CI 0.74 to 0.94; p=0.003). Increasing TFA was associated with greater OR of 30-day IP mortality (p value for trend=0.001), but no TFA threshold was evident. Although we found an association between TFA and mortality, we cannot say whether this is causal or whether TFA might just be a quality measure for overall or other processes of care.

British Thoracic Society community-acquired pneumonia care bundle: results of a national implementation project.

In 2013, 16 U.K. hospital trusts participated in a quality improvement programme involving implementation of a community-acquired pneumonia (CAP) care bundle. High-level data were collected on 14,962 patients admitted with CAP; bundle implementation increased from 1% in October 2012 to 20% by September 2013. Analysis of patient-level data on 2118 adults (median age 75.3 years) found that in the bundle-implementation group, significantly more patients received antibiotics within 4 h of admission (adjusted OR 1.52, 95% CI 1.08 to 2.14, p=0.016) and 30-day inpatient mortality was lower (8.8% vs. 13.6%; adjusted OR 0.59, 95% CI 0.37 to 0.95, p=0.03).

Impact of infant 13-valent pneumococcal conjugate vaccine on serotypes in adult pneumonia.

Infant 13-valent pneumococcal conjugate vaccination (PCV13) was introduced to the UK in 2010. Its impact on serotypes implicated in adult non-bacteraemic pneumococcal pneumonia is not known. Beginning in 2008, a 5-year prospective cohort study of adults admitted to hospital with community-acquired pneumonia (CAP) was conducted. Pneumococcal serotype was established using a validated multiplex immunoassay (Bio-Plex; Bio-Rad, Hercules, CA, USA). The overall incidence for hospitalised CAP and pneumococcal CAP was 79.9 (95% CI 76.6-83.3) and 23.4 (95% CI 21.6-25.3) per 100,000 population, respectively. A decline in CAP (incidence rate ratio (IRR) per year 0.96, 95% CI 0.94-0.99; p=0.016) and pneumococcal CAP (IRR per year 0.84, 95% CI 0.80-0.89; p<0.001) was observed over the 5-year period of the study. Between the pre- and post-PCV13 periods of the study, the incidence of CAP due to serotypes included in the PCV7 declined by 88% (IRR 0.12, 95% CI 0.08-0.20; p<0.001), and CAP due to the additional 6 serotypes in PCV13 declined by 30% (IRR 0.70, 95% CI 0.51-0.96; p=0.024). Incidence of adult pneumococcal pneumonia declined over the last 5 years, with serotypes included in PCV13 declining post-PCV13 introduction, indicating early herd protection effects from PCV13 infant vaccination on adult non-bacteraemic disease. These effects may accrue over the coming years with implications for national pneumococcal vaccination policies in adults.

Effect of corticosteroid therapy on influenza-related mortality: a systematic review and meta-analysis.

BACKGROUND: Most studies have reported that corticosteroid therapy adversely influences influenza-related outcomes. METHODS: Electronic databases were searched from inception to March 2013 for experimental and observational studies investigating systemic corticosteroid therapy for presumed influenza-associated complications. Meta-analysis of Observational Studies in Epidemiology guidelines were adopted. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using random-effects models, and heterogeneity was assessed using the I(2) statistic. Quality of evidence was assessed using the Grading Assessment, Development, and Evaluation system. RESULTS: We identified 16 eligible studies (3039 individuals), all of which were observational; 10 (1497 individuals) were included in the meta-analysis of mortality, of which 9 studied patients with 2009 pandemic influenza A virus subtype H1N1. Risk of bias was greatest in the comparability domain of the Newcastle-Ottawa scale, consistent with potential confounding by indication, and data specific to mortality were of low quality. Meta-analysis found an increased odds of mortality (OR, 2.12; 95% CI, 1.36-3.29) associated with corticosteroid therapy. Subgroup analysis of adjusted estimates from 4 studies with very low statistical heterogeneity found a similar association (OR, 2.58; 95% CI, 1.39-4.79). CONCLUSIONS: No completed clinical trials were identified. Evidence from observational studies, with important limitations, suggests that corticosteroid therapy for presumed influenza-associated complications is associated with increased mortality.

Admission via the emergency department in relation to mortality of adults hospitalised with community-acquired pneumonia: an analysis of the British Thoracic Society national community-acquired pneumonia audit.

OBJECTIVE: To determine the association between 30-day inpatient mortality and route of admission to hospital, for adults with community acquired pneumonia (CAP). METHODS: We studied 16 313 adults included in the British Thoracic Society (BTS) national CAP audit dataset. Comparisons were made between adults admitted via emergency departments (ED) with non-ED routes of admission, with regard to 30-day inpatient mortality. Secondary outcome measures were adherence to national CAP guidelines (time to first chest X-ray ≤4 h from admission; time to first antibiotic dose ≤4 h from admission; antibiotic choice; and antibiotic route of administration) by route of admission. RESULTS: Of adults hospitalised with CAP, 75.6% were admitted via ED; these adults had a greater prevalence of comorbid illness and higher disease severity in comparison with non-ED admissions. Adjusted 30-day inpatient mortality was similar for ED versus non-ED route of admission (OR 1.10, 95% CI 0.96 to 1.25). Admissions via ED were associated with faster processes of care (time to chest X-ray ≤4 h, adjusted OR 3.39, 95% CI 2.79 to 4.12; time to first antibiotic ≤4 h, adjusted OR 1.62, 95% CI 1.42 to 1.84) and greater use of intravenous antibiotics regardless of disease severity (adjusted OR 1.58, 95% CI 1.43 to 1.74). CONCLUSIONS: Adults with CAP admitted via EDs have more comorbid illness and greater disease severity compared to those admitted via non-ED routes. Following adjustment for these differences, 30-day inpatient mortality was not associated with route of admission.

The relevance of pneumococcal serotypes.

Pneumococcal disease leads to considerable mortality, morbidity and healthcare cost worldwide, and disease rates are predicted to increase due to an aging population. There are over 90 different pneumococcal serotypes identified to date, each with unique capsular characteristics capable of eliciting serotype-specific immunity in its host. Several recent studies have demonstrated important differences in invasiveness, disease severity, complications from disease and antibiotic resistance patterns that are specific to individual serotypes. This knowledge is particularly pertinent given the ongoing seroepidemiological changes worldwide, partly due to the introduction of pneumococcal conjugate vaccination to childhood immunization schedules. Further characterization of pneumococcal serotype-specific clinical features, and continued surveillance of serotypes in nasopharyngeal carriage and disease, will help guide treatment and prevention strategies in pneumococcal disease.

Clinical features of adults with seven-valent-conjugated-vaccine-serotype pneumococcal pneumonia.

BACKGROUND: Despite the reduction in adult invasive pneumococcal disease through 'herd protection' consequent to the introduction of childhood pneumococcal conjugate vaccination (PCV), a significant proportion of adults continue to develop pneumococcal pneumonia caused by one of the seven serotypes included in the seven-valent conjugated pneumococcal vaccine (PCV7). The clinical features and outcomes of these adults have not been previously reported. METHODS: Adults recruited over a three year period to a large prospective cohort study of community acquired pneumonia (CAP) were investigated for pneumococcal serotypes using a validated multiplex immunoassay (Bio-plex). The baseline characteristics and outcomes of adults with PCV7-serotype CAP in comparison to those with non-PCV7-serotype CAP were established. RESULTS: Pneumococcal aetiology was identified in 415 of 1166 (35.6%) individuals, and a serotype determined in 287 (69.2%). Following exclusion of three individuals with both a PCV7 and non-PCV7 serotype, 77 of the remaining 284 (27.1%) adults had CAP due to PCV7 serotypes. Adults with PCV7-serotype CAP were older (median years (inter-quartile range) 73.3 (60.8-84.4) versus 65.0 (46.1-78.0); p=0.001) and were more likely to have a World Health Organisation performance status ≥1 (odds ratio (OR) 2.05, 95% confidence interval (CI) 1.21-3.50).The presence of stroke (adjusted OR 2.84, 95% CI 1.36-5.95) and dementia (adjusted OR 3.55, 95% CI 1.26-9.94) as underlying co-morbid illnesses were independently associated with PCV7-serotype CAP; 30-day mortality was significantly greater in adults with PCV7-serotype CAP (adjusted OR 4.38, 95% CI 1.85-10.34). CONCLUSION: A significant proportion of adults continue to develop PCV7-serotype CAP in the era of childhood pneumococcal conjugate vaccination. These adults are more likely to have stroke and dementia as underlying co-morbid illnesses, and have a higher 30-day mortality. A combination of pneumococcal transmission factors, host factors and pneumococcal serotype specific characteristics are likely to explain these findings.

Pneumococcal serotypes in adult non-invasive and invasive pneumonia in relation to child contact and child vaccination status.

BACKGROUND: On a population level, pneumococcal conjugate vaccination in children has reduced the incidence of vaccine-type disease in all age groups, including older adults. Few individual level studies have been performed describing the pneumococcal serotypes associated with adult community acquired pneumonia (CAP) and quantifying associations with child contact and child vaccination status. METHODS: Pneumococcal serotypes were determined using a validated multiplex immunoassay (Bio-Plex) in a large prospective cohort of adults hospitalised with CAP. Child (<16 years old) contact history and child pneumococcal vaccination status were obtained from patients and public health records, respectively. RESULTS: Of 1130 participants, 329 (29.1%) reported child contact, and pneumococcal infection was identified in 410 (36.3%). Pneumococcal CAP was commoner in adults with child contact (148/329 (45.0%) vs 262/801 (32.7%); adjusted OR 1.63, CI 1.25 to 2.14; p<0.001). A serotype was determined in 263 of 410 (64.1%) adults with pneumococcal CAP; 112 (42.6%) reported child contact, 38 (33.9%) with a vaccinated child. Adults in contact with a vaccinated child were significantly less likely to have vaccine-type CAP compared with adults in contact with an unvaccinated child (6 of 38 (15.8%) vs 25 of 74 (33.8%), respectively; OR 0.37, 95% CI 0.14 to 0.99; p=0.044). CONCLUSIONS: Pneumococcal aetiology in adult CAP is independently associated with child contact and implicated serotypes are influenced by child vaccination status. This is the first study to demonstrate these associations at an individual rather than population level; it affirms that 'herd protection' from childhood vaccination extends beyond adult invasive disease to pneumococcal CAP.

Single versus combination antibiotic therapy in adults hospitalised with community acquired pneumonia.

The benefits of ß-lactam/macrolide combination therapy over ß-lactam therapy alone for the treatment of hospitalised community-acquired pneumonia (CAP) in relation to pneumonia severity are uncertain. We studied 5240 adults hospitalised with CAP from 72 secondary care trusts across England and Wales. The overall 30-day inpatient (IP) death rate was 24.4%. Combination therapy was prescribed in 3239 (61.8%) patients. In a multivariable model, combination therapy was significantly associated with lower 30-day IP death rate in patients with moderate-severity CAP (adjusted OR 0.54, 95% CI 0.41 to 0.72) and high-severity CAP (adjusted OR 0.76, 95% CI 0.60 to 0.96) but not low-severity CAP.

NPY augments the proliferative effect of FGF2 and increases the expression of FGFR1 on nestin positive postnatal hippocampal precursor cells, via the Y1 receptor.

We have shown that neuropeptide Y (NPY), a peptide neurotransmitter released by hippocampal interneurons, is proliferative for hippocampal neural stem progenitor cells (NSPCs) via the Y1 receptor. Fibroblast growth factor (FGF) 2, released predominantly by astrocytes, is also a powerful mitogen for postnatal and adult NSPCs, via the FGFR1 receptor. Knockout studies show that NPY and FGF2 are individually necessary, but not sufficient, for seizure-induced neurogenesis, suggesting a possible interaction. Here, we examined for interactions between NPY and FGF2 on NSPCs from the postnatal hippocampus and report that the combination of NPY and FGF2 significantly shortens the cell cycle time of nestin positive NSPCs, more than either factor alone. This augmentation of proliferation rate is NPY Y1 receptor mediated, and Y1 receptor activation increases both FGFR1 mRNA and protein in NSPC cultures. NSPCs immunostain for both Y1 and FGFR1 receptors and the interaction is specific for dentate NSPCs. This is the first report of a proliferative factor that augments the proliferative effect of FGF2 and is the first evidence of a positive proliferative interaction between a glial growth factor and a neuronal transmitter, identifying a novel neural activity driven mechanism for modulating the proliferation of hippocampal NSPCs.