Surveillance of pneumococcal serotypes in adults hospitalised with acute lower respiratory tract infection in Bristol, UK.

INTRODUCTION: Pneumococcus remains a major cause of adult lower respiratory tract infections (LRTI). Few data exist on the relative contribution of serotypes included in pneumococcal vaccines to community-acquired pneumonia (CAP) and non-pneumonic (NP) LRTI. We measured the burden of all and vaccine-serotype pneumococcal respiratory infection following SARS-CoV-2 emergence to inform evidence-based vaccination policy. METHODS: A prospective cohort study at two Bristol hospitals (UK) including all adults age ≥ 18-years hospitalised with acute lower respiratory tract disease (aLRTD) from Nov2021-Nov2022. LRTI patients were classified as: a) radiographically-confirmed CAP (CAP+/RAD+), b) clinically-diagnosed CAP without radiological confirmation (CAP+/RAD-), or c) NP-LRTI. Pneumococcus was identified by blood culture, BinaxNOW™and serotype-specific urine antigen detection assays (UAD). RESULTS: Of 12,083 aLRTD admissions, 10,026 had LRTI and 2,445 provided urine: 1,097 CAP + RAD+; 207 CAP + RAD-; and 1,141 NP-LRTI. Median age was 71.1y (IQR57.9-80.2) and Charlson comorbidity index = 4 (IQR2-5); 2.7 % of patients required intensive care, and 4.4 % died within 30-days of hospitalisation. Pneumococcus was detected in 280/2445 (11.5 %) participants. Among adults aged ≥ 65y and 18-64y, 12.9 % (198/1534) and 9.0 % (82/911), respectively, tested pneumococcus positive. We identified pneumococcus in 165/1097 (15.0 %) CAP + RAD+, 23/207 (11.1 %) CAP + RAD-, and 92/1141 (8.1 %) NP-LRTI cases. Of the 280 pneumococcal cases, 102 (36.4 %) were due to serotypes included in PCV13 + 6C, 115 (41.7 %) in PCV15 + 6C, 210 (75.0 %) in PCV20 + 6C/15C and 228 (81.4 %) in PPV23 + 15C. The most frequently identified serotypes were 8 (n = 78; 27.9 % of all pneumococcus), 7F (n = 25; 8.9 %), and 3 (n = 24; 8.6 %). DISCUSSION: Among adults hospitalised with respiratory infection, pneumococcus is an important pathogen across all subgroups, including CAP+/RAD- and NP-LRTI. Despite 20-years of PPV23 use in adults ≥ 65-years and herd protection due to 17-years of PCV use in infants, vaccine-serotype pneumococcal disease still causes a significant proportion of LRTI adult hospitalizations. Direct adult vaccination with high-valency PCVs may reduce pneumococcal disease burden.

A review of evidence for pneumococcal vaccination in adults at increased risk of pneumococcal disease: risk group definitions and optimization of vaccination coverage in the United Kingdom.

INTRODUCTION: Pneumococcal disease (PD) significantly contributes to morbidity and mortality, carrying substantial economic and public health burden. This article is a targeted review of evidence for pneumococcal vaccination in the UK, the definitions of groups at particular risk of PD and vaccine effectiveness. AREAS COVERED: Relevant evidence focusing on UK data from surveillance systems, randomized controlled trials, observational studies and publicly available government documents is collated and reviewed. Selected global data are included where appropriate. EXPERT OPINION: National vaccination programs have reduced the incidence of vaccine-type PD, despite the rising prominence of non-vaccine serotypes in the UK. The introduction of higher-valency conjugate vaccines provides an opportunity to improve protection against PD for adults in risk groups. Several incentives are in place to encourage general practitioners to vaccinate risk groups, but uptake is low-suboptimal particularly among at-risk individuals. Wider awareness and understanding among the public and healthcare professionals may increase vaccination uptake and coverage. National strategies targeting organizational factors are urgently needed to achieve optimal access to vaccines. Finally, identifying new risk factors and approaches to risk assessment for PD are crucial to ensure those at risk of PD can benefit from pneumococcal vaccination.

Cost-effectiveness of using a 20-valent pneumococcal conjugate vaccine to directly protect adults in England at elevated risk of pneumococcal disease.

OBJECTIVES: Despite the current pneumococcal vaccination program in England for older adults and adults with underlying conditions, disease burden remains high. We evaluated cost-effectiveness of 20-valent pneumococcal conjugate vaccine (PCV20) compared to current pneumococcal recommendations for adults in England. METHODS: Lifetime outcomes/costs of invasive pneumococcal disease (IPD) and community-acquired pneumonia (CAP) among adults aged 65-99 years and adults aged 18-64 years with underlying conditions in England were projected using a deterministic cohort model. Vaccination with PCV20 was compared with 23-valent pneumococcal polysaccharide vaccine (PPV23) from the National Health Service perspective. RESULTS: PCV20 was cost saving compared with PPV23 in base case and most sensitivity analyses. In the base case, replacing PPV23 with PCV20 prevented 7,789 and 140,046 cases of IPD and hospitalized CAP, respectively, and 22,199 associated deaths, resulting in incremental gain of 91,375 quality-adjusted life-years (QALYs) and incremental savings of £160M. In probabilistic sensitivity analyses, PCV20 (vs. PPV23) was cost saving in 85% of simulations; incremental cost per QALY was below £30,000 in 99% of simulations. CONCLUSIONS: PCV20 vaccination in adults aged 65-99 years and those aged 18-64 years with underlying comorbidities in England is expected to prevent more hospitalizations, save more lives, and yield lower overall costs than current recommendations for PPV23.

Incidence of community acquired lower respiratory tract disease in Bristol, UK during the COVID-19 pandemic: A prospective cohort study.

Background: The emergence of COVID-19 and public health measures implemented to reduce SARS-CoV-2 infections have both affected acute lower respiratory tract disease (aLRTD) epidemiology and incidence trends. The severity of COVID-19 and non-SARS-CoV-2 aLRTD during this period have not been compared in detail. Methods: We conducted a prospective cohort study of adults age ≥18 years admitted to either of two acute care hospitals in Bristol, UK, from August 2020 to November 2021. Patients were included if they presented with signs or symptoms of aLRTD (e.g., cough, pleurisy), or a clinical or radiological aLRTD diagnosis. Findings: 12,557 adult aLRTD hospitalisations occurred: 10,087 were associated with infection (pneumonia or non-pneumonic lower respiratory tract infection [NP-LRTI]), 2161 with no infective cause, with 306 providing a minimal surveillance dataset. Confirmed SARS-CoV-2 infection accounted for 32% (3178/10,087) of respiratory infections. Annual incidences of overall, COVID-19, and non- SARS-CoV-2 pneumonia were 714.1, 264.2, and 449.9, and NP-LRTI were 346.2, 43.8, and 302.4 per 100,000 adults, respectively. Weekly incidence trends in COVID-19 aLRTD showed large surges (median 6.5 [IQR 0.7-10.2] admissions per 100,000 adults per week), while other infective aLRTD events were more stable (median 14.3 [IQR 12.8-16.4] admissions per 100,000 adults per week) as were non-infective aLRTD events (median 4.4 [IQR 3.5-5.5] admissions per 100,000 adults per week). Interpretation: While COVID-19 disease was a large component of total aLRTD during this pandemic period, non- SARS-CoV-2 infection still caused the majority of respiratory infection hospitalisations. COVID-19 disease showed significant temporal fluctuations in frequency, which were less apparent in non-SARS-CoV-2 infection. Despite public health interventions to reduce respiratory infection, disease incidence remains high. Funding: AvonCAP is an investigator-led project funded under a collaborative agreement by Pfizer.

Public health and budgetary impact of 20-valent pneumococcal conjugate vaccine for adults in England.

BACKGROUND: Despite use of 23-valent pneumococcal polysaccharide vaccine (PPV23) in England, disease burden among at-risk adults remains high. We evaluated the public health and budgetary impact of 20-valent pneumococcal conjugate vaccine (PCV20) compared to the current adult pneumococcal vaccination program. METHODS: Five-year outcomes and costs of invasive pneumococcal disease (IPD) and community-acquired pneumonia (CAP) among adults aged 65-99 years and adults aged 18-64 years with underlying conditions in England were projected using a deterministic cohort model. Hypothetical vaccination with PCV20 versus PPV23 was compared from the National Health Service (NHS) perspective. RESULTS: Replacing PPV23 with PCV20 would prevent 785 IPD hospitalizations, 11,751 CAP hospitalizations, and 1,414 deaths over 5 years, and would reduce medical care costs by £48.5 M. With vaccination costs higher by £107.2 M, projected net budgetary impact is £58.7 M. The budgetary impact would be greatest in year 1 (£26.3 M), and would decrease over time (to £1.6 M by year 5). The average budget increase (£11.7 M/year) represents <0.01% of the Department of Health and Social Care total budget and <3% of the vaccine budget. CONCLUSIONS: Use of PCV20 among adults currently eligible for PPV23 in England would substantially reduce the burden of pneumococcal disease, with modest budgetary impact.

A novel approach to estimate the local population denominator to calculate disease incidence for hospital-based health events in England.

While incidence studies based on hospitalisation counts are commonly used for public health decision-making, no standard methodology to define hospitals' catchment population exists. We conducted a review of all published community-acquired pneumonia studies in England indexed in PubMed and assessed methods for determining denominators when calculating incidence in hospital-based surveillance studies. Denominators primarily were derived from census-based population estimates of local geographic boundaries and none attempted to determine denominators based on actual hospital access patterns in the community. We describe a new approach to accurately define population denominators based on historical patient healthcare utilisation data. This offers benefits over the more established methodologies which are dependent on assumptions regarding healthcare-seeking behaviour. Our new approach may be applicable to a wide range of health conditions and provides a framework to more accurately determine hospital catchment. This should increase the accuracy of disease incidence estimates based on hospitalised events, improving information available for public health decision making and service delivery planning.

Hospitalization costs of adult community-acquired pneumonia in England.

OBJECTIVE: Accurate and up-to-date figures of the cost of community-acquired pneumonia (CAP) hospitalization are needed to understand the associated economic burden for public health decision-makers. Recent estimates are lacking, and previously published estimates differ markedly. Our objective was to estimate the current mean cost to the UK National Health Service (NHS) for adult hospitalized CAP. METHODS: All CAP hospitalizations in 2019 for those aged ≥18 years were identified from English Hospital Episode Statistics (HES). Each hospitalization was mapped to the tariff cost paid to the care provider within the NHS, including critical care costs and accounting for length of stay and complexity of the case. Mean hospitalization costs were estimated in total and in individuals with defined underlying comorbidities. RESULTS: A mean cost of £3,904 was estimated for 187,251 CAP admissions providing a total cost of approximately £731 million per annum. The mean cost was £3,402, excluding critical care costs, and £11,654 for critical care episodes in the 4.4% of admissions receiving this care. Groups at high risk of CAP had higher mean costs, ranging from £4,458 for people with diabetes to £5,215 for those with heart disease aged <65 years and £4,356 for those with heart disease to £4,751 for those with liver disease aged >65 years who comprised 74.3% of admissions overall. CONCLUSION: This estimate of the cost of hospitalization for CAP from the total population and in those with certain underlying comorbidities will allow a valid understanding of the cost-benefit of vaccination and evidence-based prioritization of pneumococcal vaccination to those at highest risk.

Community-acquired pneumonia (CAP) is a disease that is most commonly caused in England by the bacterium Streptococcus pneumoniae, which infects patients outside of a hospital. Patients who suffer from CAP often require hospitalization, which incurs a cost to the UK National Health Service (NHS). The goal of this study was to establish the annual cost of hospitalized CAP.The researchers used England's national healthcare database, known as Hospital Episodes Statistics (HES), to select all adults in England who were hospitalized for CAP in 2019. For the 187,251 patients hospitalized, an average cost of £3,904 per person was estimated, amounting to a total cost of £731 million per year to the NHS. Most people admitted to hospital with CAP were at risk for the disease (due to factors such as increased age or presence of another disease) and the cost of treatment for this subgroup was disproportionately larger than that for treatment of patients not at risk. Furthermore, while approximately 5% of patients admitted for CAP received critical care during treatment, the average cost for these patients was over £8,000 higher than for those outside this subsection.The costs of hospitalization reported in this analysis were higher than previously estimated. The researchers highlighted weaknesses in other studies and limitations of the current study which could explain the difference. This work provides up-to-date figures for the cost of treating CAP in hospital in England. Public health decision-makers can use these estimates to determine the cost-benefit of vaccines that can help protect against important causes of CAP, particularly vaccines that target S. pneumoniae.

Incidence of acute lower respiratory tract disease hospitalisations, including pneumonia, among adults in Bristol, UK, 2019, estimated using both a prospective and retrospective methodology.

OBJECTIVES: To determine the disease burden of acute lower respiratory tract disease (aLRTD) and its subsets (pneumonia, lower respiratory tract infection (LRTI) and heart failure) in hospitalised adults in Bristol, UK. SETTING: Single-centre, secondary care hospital, Bristol, UK. DESIGN: We estimated aLRTD hospitalisations incidence in adults (≥18 years) in Bristol, UK, using two approaches. First, retrospective International Classification of Diseases 10th revision (ICD-10) code analysis (first five positions/hospitalisation) identified aLRTD events over a 12-month period (March 2018 to February 2019). Second, during a 21-day prospective review (19 August 2019 to 9 September 2019), aLRTD admissions were identified, categorised by diagnosis and subsequently annualised. Hospital catchment denominators were calculated using linked general practice and hospitalisation data, with each practice's denominator contribution calculated based on practice population and per cent of the practices' hospitalisations admitted to the study hospital. PARTICIPANTS: Prospective review: 1322 adults screened; 410 identified with aLRTD. Retrospective review: 7727 adult admissions. PRIMARY AND SECONDARY OUTCOME MEASURES: The incidence of aLRTD and its subsets in the adult population of Southmead Hospital, Bristol UK. RESULTS: Based on ICD-10 code analysis, annual incidences per 100 000 population were: aLRTD, 1901; pneumonia, 591; LRTI, 739; heart failure, 402. aLRTD incidence was highest among those ≥65 years: 65-74 (3684 per 100 000 adults), 75-84 (6962 per 100 000 adults) and ≥85 (11 430 per 100 000 adults). During the prospective review, 410/1322 (31%) hospitalised adults had aLRTD signs/symptoms and annualised incidences closely replicated retrospective analysis results. CONCLUSIONS: The aLRTD disease burden was high, increasing sharply with age. The aLRTD incidence is probably higher than estimated previously due to criteria specifying respiratory-specific symptoms or radiological change, usage of only the first diagnosis code and mismatch between case count sources and population denominators. This may have significant consequences for healthcare planning, including usage of current and future vaccinations against respiratory infection.

A review of current data to support decision making for introduction of next generation higher valency pneumococcal conjugate vaccination of immunocompetent older adults in the UK.

INTRODUCTION: The burden of pneumococcal disease in older UK adults remains substantial. Higher valency pneumococcal conjugate vaccines (PCVs) are currently in development with adult formulations for two of these anticipated to become available in 2022. This article collates and reviews relevant candidate data now available that may be used to support cost effectiveness assessments of vaccinating immunocompetent UK adults aged ≥65-years with PCVs. AREAS COVERED: This article uses published data from surveillance systems, randomized controlled trials and observational studies. It focuses on local data from the UK but where these are either limited or not available relevant global data are considered. EXPERT OPINION: The body of relevant data now available suggests the UK is well placed to assess the cost effectiveness of vaccinating immunocompetent ≥65-year olds with new generation higher valency PCVs. Recent contemporary data provide important new and robust insights into the epidemiology of pneumococcal disease in older UK adults and help to address much of the uncertainty and data gaps associated with previous analyses. Using these data to make informed decisions about use of new higher valency PCVs for routine use in older adults will be important for public health in the UK.

Identifying UK travellers at increased risk of developing pneumococcal infection: a novel algorithm.

BACKGROUND: In 2016, the travel subcommittee of the UK Joint Committee on Vaccination and Immunisation (JCVI) recommended that 13-valent PCV (PCV13) could be offered to travellers aged over 65 years, visiting countries without infant PCV immunization programmes. This study aimed to identify, collate and review the available evidence to identify specific countries where UK travellers might be at an increased risk of developing pneumococcal infection. The data were then used to develop an algorithm, which could be used to facilitate implementation of the JCVI recommendation. METHODS: We conducted a systematic search of the published data available for pneumococcal disease, PCV vaccine implementation, coverage data and programme duration by country. The primary data sources used were World Health Organization databases and the International Vaccine Access Centre Vaccine Information and Epidemiology Window-hub database. Based on the algorithm, the countries were classified into 'high overall risk', 'intermediate overall risk' and 'low overall risk' from an adult traveller perspective. This could determine whether PCV13 should be recommended for UK adult travellers. RESULTS: A data search for a total of 228 countries was performed, with risk scores calculated for 188 countries. Overall, 45 countries were classified as 'high overall risk', 86 countries as 'intermediate overall risk', 57 countries as 'low overall risk' and 40 countries as 'unknown'. CONCLUSION: To our knowledge this is the first attempt to categorize the risk to UK adult travellers of contracting pneumococcal infection in each country, globally. These findings could be used by national travel advisory bodies and providers of travel vaccines to identify travellers at increased risk of pneumococcal infection, who could be offered PCV immunization.

Clinical and financial burden of hospitalised community-acquired pneumonia in patients with selected underlying comorbidities in England.

BACKGROUND: Hospitalised pneumonia may have long-term clinical and financial impact in adult patients with underlying comorbidities. METHODS: We conducted a retrospective cohort study using the Hospital Episode Statistics (HES) database to determine the clinical and financial burden over 3 years of hospitalised community-acquired pneumonia (CAP) to England's National Health Service (NHS). Subjects were adults with six underlying comorbidities (chronic heart disease (CHD); chronic kidney disease (CKD); chronic liver disease (CLD); chronic respiratory disease (CRD); diabetes mellitus (DM) and post bone marrow transplant (post-BMT)) with an inpatient admission in 2012/2013. Patients with CAP in 2013/2014 were followed for 3 years and compared with similarly aged, propensity score-matched adults with the same comorbidity without CAP. FINDINGS: The RR of hospital admissions increased after CAP, ranging from 1.08 (95% CI 1.04 to 1.12) for CKD to 1.38 (95% CI 1.35 to 1.40) for CRD. This increase was maintained for at least 2 years. Mean difference in hospital healthcare costs (£) was higher for CAP patients in 2013/2014; ranging from £1115 for DM to £8444 for BMT, and remained higher for 4/6 groups for 2 more years, ranging from £1907 (95% CI £1573 to £2240) for DM to £11 167 (95% CI £10 847 to £11 486) for CRD.) The OR for mortality was significantly higher for at least 3 years after CAP, ranging from 4.76 (95% CI 4.12 to 5.51, p<0.0001) for CLD to 7.50 (95%CI 4.71 to 11.92, p<0.0001) for BMT. INTERPRETATION: For patients with selected underlying comorbidities, healthcare utilisation, costs and mortality increase for at least 3 years after being hospitalised CAP.

Co-diagnoses of acute myeloid leukaemia and COVID-19: presentation and management implications.

We report a case of concurrent new diagnoses of confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and acute myeloid leukaemia (AML). We review the existing literature on coronavirus disease 2019 (COVID-19) in the immunocompromised patient and the implications for managing our patient's haematological neoplasm. The implications of severe immunocompromise are unclear in the context of infection with SARS-CoV-2. Respiratory and viral systemic symptoms remained mild in this patient and this is consistent with the existing literature on COVID-19 in immunocompromised patients. To our knowledge, this is the first description of a case of SARS-CoV-2 infection with AML.

Community-acquired pneumonia in the United Kingdom: a call to action.

Pneumococcal disease has a high burden in adults in the United Kingdom (UK); however, the total burden is underestimated, principally because most cases of community-acquired pneumonia (CAP) are non-invasive. Research into pneumonia receives poor funding relative to its disease burden (global mortality, disability-adjusted life years, and years lived with disability), ranking just 20 out of 25 for investment in infectious diseases in the UK. The current accuracy of data for establishing incidence rates is questionable, and it is a reflection of the paucity of research that much of the background information available derives from nearly 30 years ago. Given the relationship between CAP and mortality (pneumonia accounts for 29,000 deaths per annum in the UK, and 5-15% of patients hospitalised with CAP die within 30 days of admission), and the increasing threat of antimicrobial resistance associated with inappropriate antibiotic prescribing, such neglect of a highly prevalent problem is concerning. In this Call to Action, we explore the poorly understood burden of CAP in the UK, discuss the importance of an accurate diagnosis and appropriate treatment, and suggest how national collaboration could improve the management of an often life-threatening, yet potentially preventable disease.

Safety and Efficacy of Anidulafungin for Fungal Infection in Patients With Liver Dysfunction or Multiorgan Failure.

BACKGROUND: The objective of this study was to review our clinical experience on the safety and efficacy of anidulafungin, an echinocandin antifungal, in the treatment of invasive fungal infections (IFIs) in patients with moderate to severe abnormal liver function tests or multiorgan failure and IFI, in a large United Kingdom Liver Centre. METHODS: The clinical records of the first 50 consecutive patients treated for IFI with anidulafungin between January 7, 2009 and March 2, 2011 were analyzed. Data were collected on demographics, underlying disease, disease characteristics, hematological and biochemical parameters, IFI, concomitant bacterial and viral infections, response to anidulafungin, and anidulafungin-related adverse events. RESULTS: The patients' median age was 54.3 years (range, 19.6-75.9); 60% were male. Twenty-two (44%) patients were liver transplant recipients. Others had hepatopancreaticobiliary disease (n = 15, 30%) or chronic liver disease (n = 11, 22%). Invasive fungal infection (predominantly Candida spp) was proven in 36 (72%) patients, probable in 14 (28%). Of 46 evaluable patients, 35 (76%) had a favorable anidulafungin treatment outcome. Forty-nine (98%) had abnormal liver function tests (LFTs) pretreatment; 31 (62%) had ≥1 LFT raised to ≥2× baseline during anidulafungin treatment. CONCLUSIONS: In this highly specialized group of patients, anidulafungin treatment was efficacious and well tolerated by those with decompensated liver disease, multiorgan failure, and high-risk liver transplant with proven or probable IFI.

A systematic review of the burden of vaccine preventable pneumococcal disease in UK adults.

BACKGROUND: Invasive pneumococcal disease (IPD) and pneumococcal pneumonia are common and carry a significant morbidity and mortality. Current strategies to prevent pneumococcal disease are under review in the United Kingdom (UK). We conducted a systematic review to evaluate the burden of vaccine type adult pneumococcal disease specifically in the UK. METHODS: A systematic review conducted and reported according to MOOSE guidelines. Relevant studies from 1990 to 2015 were included. The primary outcome was the incidence of vaccine type pneumococcal disease, focussing on the pneumococcal polysaccharide vaccine (PPSV), the 13-valent conjugate vaccine (PCV13) and the 7-valent conjugate vaccine (PCV7). RESULTS: Data from surveillance in England and Wales from 2013/14 shows an incidence of 6.85 per 100,000 population across all adult age groups for IPD, and an incidence of 20.58 per 100,000 population in those aged >65 years. The corresponding incidences for PCV13 serotype IPD were 1.4 per 100,000 and 3.72 per 100,000. The most recent available data for community-acquired pneumonia (CAP) including non-invasive disease showed an incidence of 20.6 per 100,000 for adult pneumococcal CAP and 8.6 per 100,000 population for PCV13 serotype CAP. Both IPD and CAP data sources in the UK suggest an ongoing herd protection effect from childhood PCV13 vaccination causing a reduction in the proportion of cases caused by PCV13 serotypes in adults. Despite this, applying the incidence rates to UK population estimates suggests more than 4000 patients annually will be hospitalised with PCV13 serotype CAP and more than 900 will be affected by IPD, although with a trend for these numbers to decrease over time. There was limited recent data on serotype distribution in high risk groups such as those with chronic respiratory or cardiac disease and no data available for vaccine type (VT) CAP managed in the community where there is likely to be a considerable unmeasured burden. CONCLUSION: The most recent available data suggests that VT pneumococcal disease continues to have a high burden in UK adults despite the impact of childhood PCV13 vaccination. IPD estimates represent only a fraction of the total burden of pneumococcal disease. STUDY REGISTRATION: PROSPERO CRD42015025043.