Background Pneumococcal disease is a leading cause of communicable disease morbidity and mortality globally. We aimed to estimate invasive pneumococcal disease (IPD), pneumococcal pneumonia (PP) and all-cause pneumonia (ACP) incidence rates (IRs) in children aged 0–17 years in England from 2003 to 2019. Methods A retrospective study in children ≤17 years old from 2003 to 2019 using the Clinical Practice Research Datalink (CPRD) Gold and Hospital Episodes Statistics Admitted Patient Care (HES APC) databases. IPD episodes were identified in hospital records (HES APC). PP (caused by Streptococcus pneumoniae only) and ACP episodes (caused by any pathogen) were identified in primary care (CPRD) and in hospital records (HES APC). Annual IRs by age-group were calculated as the number of episodes/person-years (PY) at risk, with 95% confidence intervals (95% CI). Interrupted time series analyses were conducted to assess changes in IRs across the post-PCV7 (2007–2009), early post-PCV13 (2011–2014) and late post-PCV13 (2015–2019) periods compared to the pre-PCV7 period (2003–2005) using generalized linear models. Results 170 IPD episodes, 769 PP episodes and 12,142 ACP episodes were identified in 1,500,686 children in 2003–2019. The overall IPD, PP and ACP IRs (per 100,000 PY) were 2.29 (95% CI 1.96–2.66), 10.34 (95% CI 9.62–11.10) and 163.37 (95% CI 160.47–166.30), respectively. The highest IPD, PP and ACP IRs were observed in children aged < 2 years compared to older children (2–4 and 5–17 years). IPD IRs decreased between the pre-PCV7 period and the late post-PCV13 period from 3.28 (95% CI 2.42–4.33) to 1.41 (95% CI 0.80–2.29), IRR 0.28 (95% CI 0.09–0.90), p-value 0.033. PP IRs declined between the pre-PCV7 period and the late post-PCV13 period from 14.65 (95% CI 12.77–16.72) to 3.87 (95% CI 2.81–5.20), IRR 0.19 (95% CI 0.09–0.38), p-value < 0.001. ACP IRs declined between the pre-PCV7 period and the late post-PCV13 period from 167.28 (95% CI 160.78–173.96) to 124.96 (95% CI 118.54–131.63), IRR 0.77 (95% CI 0.66–0.88), p-value < 0.001. Conclusions The clinical burden of IPD, PP and ACP declined in children in England aged 0–17 years between 2003 and 2019, especially in the late post-PCV13 period. This study highlights the importance of PCV vaccination in reducing the burden of PD and ACP in children in England.

Background The 7-valent pneumococcal conjugate vaccine (PCV7) was introduced in 2006 and the 13-valent pneumococcal conjugate vaccine (PCV13) in 2010 in the UK. PCVs are active immunization for the prevention of invasive disease, pneumonia and acute otitis media (AOM) caused by Streptococcus pneumoniae in children. The aim of this observational study was to estimate incidence rates (IRs) of AOM in children ≤17 years from 2003 to 2019 in England, before and after the introduction of pneumococcal conjugate vaccines (PCVs). Methods AOM episodes were identified using Read diagnosis codes in children aged ≤17 years in the Clinical Practice Research Datalink (CPRD) Gold database from 2003 to 2019. Annual IRs with 95% confidence intervals (CI) by age group were calculated as the number of episodes/person-years (PY) at risk. Interrupted time series analyses were conducted to estimate incidence rate ratios (IRR) across post-PCV7 (2007–2009), early post-PCV13 (2011–2014) and late post-PCV13 (2015–2019) periods compared to the pre-PCV7 period (2003–2005) using generalized linear models. Results From 2003 to 2019, 274,008 all-cause AOM episodes were identified in 1,500,686 children. The overall AOM IR was 3690.9 (95% CI 3677.1-3704.8) per 100,000 PY. AOM IRs were highest in children aged < 5 years and decreased by age; < 2 years: 8286.7 (95% CI 8216.8-8357.1); 2–4 years: 7951.8 (95% CI 7902.5-8001.4); 5–17 years: 2184.4 (95% CI 2172.1–2196.8) (per 100,000 PY). Overall AOM IRs declined by 40.3% between the pre-PCV7 period and the late-PCV13 period from 4451.9 (95% CI 4418.1-4485.9) to 2658.5 (95% CI 2628.6-2688.7) per 100,000 PY, and across all age groups. IRRs indicated a significant decrease in AOM IRs in all the post-vaccination periods, compared to the pre-PCV7 period: post-PCV7 0.87 (95% CI 0.85–0.89), early post-PCV13 0.88 (95% CI 0.86–0.91), and late post-PCV13 0.75 (95% CI 0.73–0.78). Conclusions The AOM IRs declined during the 2003–2019 period; however, the clinical burden of AOM remains substantial among children ≤17 years in England.

Objective To estimate healthcare resource utilisation (HCRU) and costs associated with pneumococcal disease (PD) in children aged ≤17 years in England from 2003–2019. Methods A retrospective study in children aged ≤17 years was conducted using the Clinical Practice Research Datalink Gold primary care database and Hospital Episodes Statistics Admitted Patient Care database from 2003–2019. Episodes of invasive pneumococcal disease (IPD) were identified in hospital, pneumococcal pneumonia (PP) and all-cause pneumonia (ACP) episodes in primary care and in hospital, and acute otitis media (AOM) episodes in primary care. General practitioner (GP) visits and inpatient admission yearly rates were calculated per 1,000 persons. The average inpatient and primary care cost per episode were calculated. The Mann-Kendall test was used to assess monotonic time trends. Results 1,500,686 children were followed from 2003–2019. The highest average inpatient cost per episode [£34,255 (95%CI 27,222–41,288)] was in IPD, followed by ACP [£3,549 (95%CI 3,405–3,693)] and PP [£1,498 (95%CI 1,153–1,843)]. The highest primary care costs per episode were in AOM [£48.7 (95%CI 48.7–48.7)], followed by PP [£38.4 (95%CI 37.0–39.7)] and ACP [£28.6 (95%CI 28.2–29.1)]. The highest inpatient admission and GP visits yearly rates were observed in children aged <2 years. Across years, a significant decrease in GP visits yearly rates was observed for PP, ACP and AOM in children overall (p-value<0.001). A decrease in primary care costs was observed for ACP (p-value<0.001). There was an increasing trend in AOM primary care costs (p-value<0.001). No significant trends were observed in inpatient admission yearly rates in PP, ACP or IPD and inpatient costs per episode in PP, ACP and IPD. Conclusion From 2003–2019, primary care HCRU and costs decreased (except for PP cost), but no trends in inpatient HCRU and costs were observed. The economic burden of pneumonia, IPD and AOM remains substantial in children aged ≤17 years in England.

Background: Early observational studies suggested that tocilizumab might produce clinical improvement in covid-19 patients leading to the use of tocilizumab. Early underpowered randomised controlled trials (RCTs) however did not show benefit until the most recent largest trial. RECOVERY trial. We aimed to compare the evidence from RCTs and observational studies of the effect of tocilizumab on in-hospital mortality in patients with covid-19. Materials and Methods: Embase and PubMed were searched from July 2020 until 1 March 2021. Observational studies and RCTs assessing in-hospital mortality in patients receiving tocilizumab compared with standard care or placebo were included. The primary outcome was in-hospital mortality closest to 30 days. The risk of bias in observational studies was assessed using the ROBINS-I tool. A fixed effect meta-analysis was used to combine relative risks, with random effects and risk of bias as a sensitivity analysis. Results: Of 5,792 publications screened for inclusion, eight RCTs and 33 observational studies were identified. The RCTs showed an overall relative risk reduction in in-hospital mortality at 30 days of 0.86 (95% confidence interval (CI) 0.78 to 0.96) with no statistically significant heterogeneity. 23 of the observational studies had a severe risk of bias, 10 of which did not adjust for potential confounders. The 10 observational studies with moderate risk of bias reported a larger reduction in mortality at 30-days (relative risk 0.72, 95% CI 0.64 to 0.81) but with significant heterogeneity (P<0.01). Conclusion: This meta-analysis provides strong evidence from RCTs that tocilizumab reduces the risk of mortality in hospitalised covid-19 patients. Observational studies with moderate risk of bias exaggerated the benefits on mortality two-fold and showed heterogeneity. Collectively observational studies provide a less reliable evidence base for evaluating treatments for covid-19.