Pragmatic Adaptive Trial for Respiratory Infection in Children (PATRIC) Clinical Registry protocol.

INTRODUCTION: Acute respiratory infections (ARI) are the most common cause of paediatric hospitalisation. There is an urgent need to address ongoing critical knowledge gaps in ARI management. The Pragmatic Adaptive Trial for Respiratory Infections in Children (PATRIC) Clinical Registry will evaluate current treatments and outcomes for ARI in a variety of paediatric patient groups. The registry will provide a platform and data to inform a number of PATRIC clinical trials, testing various interventions in ARI treatment and management to optimise paediatric ARI care. METHODS AND ANALYSIS: The PATRIC Clinical Registry is a single-centre, prospective observational registry recruiting from a tertiary paediatric Emergency Department in Western Australia. Through characterising demographic, clinical, treatment and outcome data, the PATRIC Clinical Registry will improve our understanding of antibiotic utilisation and ARI outcomes in children. ETHICS AND DISSEMINATION: The PATRIC Clinical Registry is conducted in accordance with the Declaration of Helsinki, and the International Council for Harmonisation (ICH) Guidelines for Good Clinical Practice (CPMP/ICH/13595) July 1996. Approval is provided by the Child and Adolescent Health Service Human Research Ethics Committee (HREC). Study results will be communicated by presentation and publication (HREC: RGS0000003078.) TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12619000903189. UTN: U1111-1231-3365.

Prevalence of respiratory viruses in community-acquired pneumonia in children: a systematic review and meta-analysis.

BACKGROUND: Respiratory viruses are increasingly detected in children with community-acquired pneumonia but prevalence estimates vary substantially. We aimed to systematically review and pool estimates for 22 viruses commonly associated with community-acquired pneumonia. METHODS: We conducted a systematic review and meta-analysis to determine the prevalence of each of the common respiratory viruses detected by any diagnostic method in children aged up to 18 years with community-acquired pneumonia. We searched MEDLINE, PubMed, Embase, Web of Science, and Scopus databases with no language restrictions for relevant published articles and reports published between Jan 1, 1995, and Dec 31, 2019, restricting the review to pre-COVID-19 pandemic years. Three independent reviewers screened articles and extracted data using a predefined protocol. We calculated the pooled prevalence for each virus in childhood pneumonia using DerSimonian-Laird random-effects models. We assessed bias using the Newcastle-Ottawa Scale. The review protocol was registered in PROSPERO (CRD42016034047). FINDINGS: We identified 186 eligible articles that represented 152 209 children up to age 18 years with community-acquired pneumonia. One or more respiratory viruses were detected in 55·0% (95% CI 50·4-59·7) of paediatric patients with a diagnosis of community-acquired pneumonia; heterogeneity was high (I2=99·4%). Respiratory syncytial virus (22·7%, 20·9-24·5) and rhinovirus (22·1%, 19·5-24·7) were the most commonly detected causes of paediatric pneumonia globally, with other viruses detected in 1-9% of cases. There was non-significant variation in prevalence by the country's national income, under-5 mortality rate, or WHO region. INTERPRETATION: Respiratory viruses are frequently detected in community-acquired pneumonia among children of all ages and geographical regions, with non-significant variation by country's national income or region. Further strategies to limit antibiotic use in children with viral pneumonia and develop treatment and prevention approaches targeting common respiratory viruses are expected to have a substantial effect on the residual burden of childhood pneumonia. FUNDING: None.

Assessing the impact of the 13 valent pneumococcal vaccine on childhood empyema in Australia.

BACKGROUND: Empyema is a serious complication of pneumonia frequently caused by Streptococcus pneumoniae (SP). We assessed the impact of the 13-valent pneumococcal conjugate vaccine (13vPCV) on childhood pneumonia and empyema after inclusion in the Australian National Immunisation Program. METHODS: For bacterial pneumonia and empyema hospitalisations, we ascertained incidence rates (IRs) using the National Hospital Morbidity Database International Statistical Classification of Disease discharge codes and relevant population denominators, and calculated incidence rate ratios (IRR) comparing the 13vPCV period (June 2012-May 2017) with the 7vPCV period (June 2007-May 2011). Blood and pleural fluid (PF) cultures and PF PCR of 401 children with empyema from 11 Australian hospitals during the 13vPCV period were compared with our previous study in the 7vPCV period. FINDINGS: Across 7vPCV and 13vPCV periods, IRs per million children (95% CIs) were 1605 (1588 to 1621) and 1272 (1259 to 1285) for bacterial pneumonia, and 14.23 (12.67 to 15.79) and 17.89 (16.37 to 19.42) for empyema hospitalisations. IRRs were 0.79 (0.78 to 0.80) for bacterial pneumonia and 1.25 (1.09 to 1.44) for empyema. Of 161 empyema cases with SP serotypes, 147 (91.3%) were vaccine types. ST3 accounted for 76.4% of identified serotypes in the 13vPCV period, more than double than the 7vPCV period (p<0.001); ST19A decreased from 36.4% to 12.4%. No cases of ST1 empyema were identified in the 13vPCV period versus 14.5% in the 7vPCV period. INTERPRETATION: 13vPCV resulted in a significant reduction in all-cause hospitalisations for bacterial pneumonia but empyema hospitalisations significantly increased, with emergence of pneumococcal ST3 as the dominant serotype in empyema. TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trial Registry ACTRN 12614000354684.

Combination of clinical symptoms and blood biomarkers can improve discrimination between bacterial or viral community-acquired pneumonia in children.

BACKGROUND: Differentiating bacterial from viral pneumonia is important for guiding targeted management and judicious use of antibiotics. We assessed if clinical characteristics and blood inflammatory biomarkers could be used to distinguish bacterial from viral pneumonia. METHODS: Western Australian children (≤17 years) hospitalized with radiologically-confirmed community-acquired pneumonia were recruited and clinical symptoms and management data were collected. C-reactive protein (CRP), white cell counts (WCC) and absolute neutrophil counts (ANC) were measured as part of routine care. Clinical characteristics and biomarker levels were compared between cases with definite bacterial pneumonia (clinical empyema and/or bacteria detected in blood or pleural fluid), presumed viral pneumonia (presence of ≥1 virus in nasopharyngeal swab without criteria for definite bacterial pneumonia), and other pneumonia cases (pneumonia in the absence of criteria for either definite bacterial or presumed viral pneumonia). The area-under-curve (AUC) of the receiver operating characteristic (ROC) curve for varying biomarker levels were used to characterise their utility for discriminating definite bacterial from presumed viral pneumonia. For biomarkers with AUC > 0.8 (fair discriminator), Youden index was measured to determine the optimal cut-off threshold, and sensitivity, specificity, predictive values (positive and negative) were calculated. We investigated whether better discrimination could be achieved by combining biomarker values with the presence/absence of symptoms. RESULTS: From May 2015 to October 2017, 230 pneumonia cases were enrolled: 30 with definite bacterial pneumonia, 118 with presumed viral pneumonia and 82 other pneumonia cases. Differences in clinical signs and symptoms across the groups were noted; more definite bacterial pneumonia cases required intravenous fluid and oxygen supplementation than presumed viral or other pneumonia cases. CRP, WCC and ANC were substantially higher in definite bacterial cases. For a CRP threshold of 72 mg/L, the AUC of ROC was 0.82 for discriminating definite bacterial pneumonia from presumed viral pneumonia. Combining the CRP with either the presence of fever (≥38οC) or the absence of rhinorrhea improved the discrimination. CONCLUSIONS: Combining elevated CRP with the presence or absence of clinical signs/ symptoms differentiates definite bacterial from presumed viral pneumonia better than CRP alone. Further studies are required to explore combination of biomarkers and symptoms for use as definitive diagnostic tool.

Cost of management of severe pneumonia in young children: systematic analysis.

BACKGROUND: Childhood pneumonia is a major cause of childhood illness and the second leading cause of child death globally. Understanding the costs associated with the management of childhood pneumonia is essential for resource allocation and priority setting for child health. METHODS: We conducted a systematic review to identify studies reporting data on the cost of management of pneumonia in children younger than 5 years old. We collected unpublished cost data on non-severe, severe and very severe pneumonia through collaboration with an international working group. We extracted data on cost per episode, duration of hospital stay and unit cost of interventions for the management of pneumonia. The mean (95% confidence interval, CI) and median (interquartile range, IQR) treatment costs were estimated and reported where appropriate. RESULTS: We identified 24 published studies eligible for inclusion and supplemented these with data from 10 unpublished studies. The 34 studies included in the cost analysis contained data on more than 95 000 children with pneumonia from both low- and-middle income countries (LMIC) and high-income countries (HIC) covering all 6 WHO regions. The total cost (per episode) for management of severe pneumonia was US$ 4.3 (95% CI 1.5-8.7), US$ 51.7 (95% CI 17.4-91.0) and US$ 242.7 (95% CI 153.6-341.4)-559.4 (95% CI 268.9-886.3) in community, out-patient facilities and different levels of hospital in-patient settings in LMIC. Direct medical cost for severe pneumonia in hospital inpatient settings was estimated to be 26.6%-115.8% of patients' monthly household income in LMIC. The mean direct non-medical cost and indirect cost for severe pneumonia management accounted for 0.5-31% of weekly household income. The mean length of stay (LOS) in hospital for children with severe pneumonia was 5.8 (IQR 5.3-6.4) and 7.7 (IQR 5.5-9.9) days in LMIC and HIC respectively for these children. CONCLUSION: This is the most comprehensive review to date of cost data from studies on the management of childhood pneumonia and these data should be helpful for health services planning and priority setting by national programmes and international agencies.

Economic burden of influenza-associated hospitalizations and outpatient visits in Bangladesh during 2010.

OBJECTIVE: Understanding the costs of influenza-associated illness in Bangladesh may help health authorities assess the cost-effectiveness of influenza prevention programs. We estimated the annual economic burden of influenza-associated hospitalizations and outpatient visits in Bangladesh. DESIGN: From May through October 2010, investigators identified both outpatients and inpatients at four tertiary hospitals with laboratory-confirmed influenza infection through rRT-PCR. Research assistants visited case-patients' homes within 30 days of hospital visit/discharge and administered a structured questionnaire to capture direct medical costs (physician consultation, hospital bed, medicines and diagnostic tests), direct non-medical costs (food, lodging and travel) and indirect costs (case-patients' and caregivers' lost income). We used WHO-Choice estimates for routine healthcare service costs. We added direct, indirect and healthcare service costs to calculate cost-per-episode. We used median cost-per-episode, published influenza-associated outpatient and hospitalization rates and Bangladesh census data to estimate the annual economic burden of influenza-associated illnesses in 2010. RESULTS: We interviewed 132 outpatients and 41 hospitalized patients. The median cost of an influenza-associated outpatient visit was US$4.80 (IQR = 2.93-8.11) and an influenza-associated hospitalization was US$82.20 (IQR = 59.96-121.56). We estimated that influenza-associated outpatient visits resulted in US$108 million (95% CI: 76-147) in direct costs and US$59 million (95% CI: 37-91) in indirect costs; influenza-associated hospitalizations resulted in US$1.4 million (95% CI: 0.4-2.6) in direct costs and US$0.4 million (95% CI: 0.1-0.8) in indirect costs in 2010. CONCLUSIONS: In Bangladesh, influenza-associated illnesses caused an estimated US$169 million in economic loss in 2010, largely driven by frequent but low-cost outpatient visits.