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.

Cost of Respiratory Syncytial Virus-Associated Acute Lower Respiratory Infection Management in Young Children at the Regional and Global Level: A Systematic Review and Meta-Analysis.

BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of acute lower respiratory infection (ALRI) in young children aged <5 years. METHODS: We aimed to identify the global inpatient and outpatient cost of management of RSV-ALRI in young children to assist health policy makers in making decisions related to resource allocation for interventions to reduce severe morbidity and mortality from RSV in this age group. We searched 3 electronic databases including Global Health, Medline, and EMBASE for studies reporting cost data on RSV management in children under 60 months from 2000 to 2017. Unpublished data on the management cost of RSV episodes were collected through collaboration with an international working group (RSV GEN) and claim databases. RESULTS: We identified 41 studies reporting data from year 1987 to 2017, mainly from Europe, North America, and Australia, covering the management of a total of 365 828 RSV disease episodes. The average cost per episode was €3452 (95% confidence interval [CI], 3265-3639) and €299 (95% CI, 295-303) for inpatient and outpatient management without follow-up, and it increased to €8591(95% CI, 8489-8692) and €2191 (95% CI, 2190-2192), respectively, with follow-up to 2 years after the initial event. CONCLUSIONS: Known risk factors (early and late preterm birth, congenital heart disease, chronic lung disease, intensive care unit admission, and ventilator use) were associated with €4160 (95% CI, 3237-5082) increased cost of hospitalization. The global cost of inpatient and outpatient RSV ALRI management in young children in 2017 was estimated to be approximately €4.82 billion (95% CI, 3.47-7.93), 65% of these in developing countries and 55% of global costs accounted for by hospitalization. We have demonstrated that RSV imposed a substantial economic burden on health systems, governments, and the society.

Palivizumab and prevention of childhood respiratory syncytial viral infection: protocol for a systematic review and meta-analysis of breakthrough infections.

INTRODUCTION: Childhood respiratory syncytial virus (RSV) infection is a global phenomenon that can lead to fatal respiratory illness. Palivizumab is a drug that is routinely used in affluent countries as a prophylaxis against RSV infection; nevertheless, breakthrough infections are often reported. In light of new findings on potential RSV resistance to palivizumab, an up-to-date synthesis of evidence on effectiveness is needed. Furthering existing reviews, a broadened scope to better reflect effectiveness in a 'real world' clinical context is also important. This systematic review and meta-analysis will enhance our understanding of the effectiveness of palivizumab in varying populations of children. Findings from this review will inform recommendations for best practices regarding palivizumab use for childhood RSV infection as well as research priorities in RSV vaccine development. METHODS AND ANALYSIS: We will conduct a systematic review of primary population-based studies that examine the incidence of palivizumab breakthrough infections in children, published between 1997 to present. In collaboration with a research librarian, four electronic databases (MEDLINE, Embase, Cochrane Library, Web of Science) and additional sources will be searched. Study screening and quality assessment will be performed in duplicate. Data will be extracted by one reviewer, with partial and random verification by a second reviewer. The primary outcomes to assess breakthrough RSV infection will be hospitalisation, length of stay and the need for intensive care unit admission and mechanical ventilation in children receiving palivizumab. The secondary outcome will be RSV-associated mortality. We will conduct a meta-analysis using pooled effectiveness data, and include subgroup analyses by patient comorbidities and drug compliance. Sensitivity analyses for risk of bias and study design will also be performed. ETHICS AND DISSEMINATION: This systematic review will only include data from previously published literature and is therefore exempt from ethics approval. Final results will be disseminated through peer-reviewed publication and presented at academic conferences and scientific meetings engaging paediatric researchers and healthcare providers. Should findings from this review necessitate updates to current clinical practice guidelines, we intend to establish a working group to engage relevant health administrators and decision makers. PROSPERO REGISTRATION NUMBER: CRD42019122120.

Burden of Respiratory Syncytial Virus Disease and Mortality Risk Factors in Argentina: 18 Years of Active Surveillance in a Children's Hospital.

BACKGROUND: Respiratory syncytial virus is the leading cause of acute lower respiratory infection in children. We aimed to describe the clinical-epidemiologic pattern and risk factors for mortality associated with RSV infection. METHODS: This is a prospective, cross-sectional study of acute lower respiratory infection in children admitted to the Children's Hospital during 2000 to 2017. Viral diagnosis was made by fluorescent antibody techniques or real-time-polymerase chain reaction. We compared clinical-epidemiologic characteristics of RSV infection in nonfatal versus fatal cases. Multiple logistic regression was used to identify independent predictors of mortality. RESULTS: Of 15,451 patients with acute lower respiratory infection, 13,033 were tested for respiratory viruses and 5831 (45%) were positive: RSV 81.3% (4738), influenza 7.6% (440), parainfluenza 6.9% (402) and adenovirus 4.3% (251). RSV had a seasonal epidemic pattern coinciding with months of lowest average temperature. RSV cases show a case fatality rate of 1.7% (82/4687). Fatal cases had a higher proportion of prematurity (P < 0.01), perinatal respiratory history (P < 0.01), malnourishment (P < 0.01), congenital heart disease (P < 0.01), chronic neurologic disease (P < 0.01) and pneumonia at clinical presentation (P = 0.014). No significant difference between genders was observed. Most deaths occurred among children who had complications: respiratory distress (80.5%), nosocomial infections (45.7%), sepsis (31.7%) and atelectasis (13.4%). Independent predictors of RSV mortality were moderate-to-severe malnourishment, odds ratio (OR): 3.69 [95% confidence interval (CI): 1.98-6.87; P < 0.0001]; chronic neurologic disease, OR: 4.14 (95% CI: 2.12-8.08; P < 0.0001); congenital heart disease, OR: 4.18 (95% CI: 2.39-7.32; P< 0.0001); and the age less than 6 months, OR: 1.99 (95% CI: 1.24-3.18; P = 0.004). CONCLUSIONS: RSV showed an epidemic pattern affecting mostly young children. Malnourishment, chronic neurologic disease, congenital heart disease and the age less than 6 months were the independent risk factors for RSV mortality.

Respiratory syncytial virus seasonality and its implications on prevention strategies.

With maternal and infant vaccines against respiratory syncytial virus (RSV) in development, it is timely to consider how the deployment of these vaccines might vary according to local RSV disease seasonality. In temperate regions RSV infection is predictably limited to a period of 3 to 5 months, while in tropical regions disease seasonality is often both more variable and more prolonged. Accordingly, in tropical regions a year-round immunisation schedule for both maternal and infant immunisation might be appropriate. In contrast, in temperate regions the benefit of year-round maternal immunisation would be heavily dependent on the duration of protection this provided, potentially necessitating a strategy directed at children due to be born in the months immediately prior to the RSV season. This review will consider the impact of seasonality on maternal and infant immunisation strategies against RSV, and the potential of an alternative approach of passive immunisation for all infants immediately prior to the RSV season.

Identifying Gaps in Respiratory Syncytial Virus Disease Epidemiology in the United States Prior to the Introduction of Vaccines.

Respiratory syncytial virus (RSV) causes lower respiratory tract illness frequently. No effective antivirals or vaccines for RSV are approved for use in the United States; however, there are at least 50 vaccines and monoclonal antibody products in development, with those targeting older adults and pregnant women (to protect young infants) in phase 2 and 3 clinical trials. Unanswered questions regarding RSV epidemiology need to be identified and addressed prior to RSV vaccine introduction to guide the measurement of impact and future recommendations. The Centers for Disease Control and Prevention (CDC) convened a technical consultation to gather input from external subject matter experts on their individual perspectives regarding evidence gaps in current RSV epidemiology in the United States, potential studies and surveillance platforms needed to fill these gaps, and prioritizing efforts. Participants articulated their individual views, and CDC staff synthesized individuals' input into this report.

Mortality due to Respiratory Syncytial Virus. Burden and Risk Factors.

RATIONALE: Respiratory syncytial virus (RSV) is the most frequent cause of hospitalization and an important cause of death in infants in the developing world. The relative contribution of social, biologic, and clinical risk factors to RSV mortality in low-income regions is unclear. OBJECTIVES: To determine the burden and risk factors for mortality due to RSV in a low-income population of 84,840 infants. METHODS: This was a prospective, population-based, cross-sectional, multicenter study conducted between 2011 and 2013. Hospitalizations and deaths due to severe lower respiratory tract illness (LRTI) were recorded during the RSV season. All-cause hospital deaths and community deaths were monitored. Risk factors for respiratory failure (RF) and mortality due to RSV were assessed using a hierarchical, logistic regression model. MEASUREMENTS AND MAIN RESULTS: A total of 2,588 (65.5%) infants with severe LRTI were infected with RSV. A total of 157 infants (148 postneonatal) experienced RF or died with RSV. RSV LRTI accounted for 57% fatal LRTI tested for the virus. A diagnosis of sepsis (odds ratio [OR], 17.03; 95% confidence interval [CI], 13.14-21.16 for RF) (OR, 119.39; 95% CI, 50.98-273.34 for death) and pneumothorax (OR, 17.15; 95% CI, 13.07-21.01 for RF) (OR, 65.49; 95% CI, 28.90-139.17 for death) were the main determinants of poor outcomes. CONCLUSIONS: RSV was the most frequent cause of mortality in low-income postneonatal infants. RF and death due to RSV LRTI, almost exclusively associated with prematurity and cardiopulmonary diseases in industrialized countries, primarily affect term infants in a developing world environment. Poor outcomes at hospitals are frequent and associated with the cooccurrence of bacterial sepsis and clinically significant pneumothoraxes.

Child pneumonia - focus on the Western Pacific Region.

Worldwide, pneumonia is the leading cause of death in infants and young children (aged <5 years). We provide an overview of the global pneumonia disease burden, as well as the aetiology and management practices in different parts of the world, with a specific focus on the WHO Western Pacific Region. In 2011, the Western Pacific region had an estimated 0.11 pneumonia episodes per child-year with 61,900 pneumonia-related deaths in children less than 5 years of age. The majority (>75%) of pneumonia deaths occurred in six countries; Cambodia, China, Laos, Papua New Guinea, the Philippines and Viet Nam. Historically Streptococcus pneumoniae and Haemophilus influenzae were the commonest causes of severe pneumonia and pneumonia-related deaths in young children, but this is changing with the introduction of highly effective conjugate vaccines and socio-economic development. The relative contribution of viruses and atypical bacteria appear to be increasing and traditional case management approaches may require revision to accommodate increased uptake of conjugated vaccines in the Western Pacific region. Careful consideration should be given to risk reduction strategies, enhanced vaccination coverage, improved management of hypoxaemia and antibiotic stewardship.

Respiratory Syncytial Virus Bronchiolitis in Children up to 5 Years of Age in Spain: Epidemiology and Comorbidities: An Observational Study.

This epidemiological survey in Spain estimates the burden of respiratory syncytial virus (RSV) infection in children up to 5 year of age during a 15-year period (1997-2011). Observational retrospective survey was conducted by reviewing data of the National Surveillance System for Hospital Data, including >98% of Spanish hospitals. All hospitalizations related to RSV infection for children up to 5 years, reported during 1997-2011 period, were analyzed. Codes were selected by using the International Classification of Diseases 9th Clinical Modification 466.0-466.19, 480.1, and 079.6. A total of 326,175 and 286,007 hospital discharges for children up to 5 and 2 years of age were reported during the study period. The annual incidence was 1072 and 2413 patients per 100,000, respectively. The average length of hospital stay was 5.7 (standard deviation 8.2) days. Four hundred forty-six deaths were reported; of those, 403 occurred in children <2 years and 355 (80%) occurred in children <12 months of age. Hospitalization and mortality rates were significantly higher in boys and decrease significantly with age. The higher rate of hospitalization and mortality rates were found in the first year of life. Annual average cost for National Health Care System was € 47 M with a mean hospitalization cost of €2162. The average length of hospitalization and costs were significantly higher in high-risk children. RSV infections in children up to 5 year of age still pose a significant health threat in Spain, especially in the infants. The development of preventive, diagnostic, and therapeutic guidelines focused in children with comorbidities may help reduce the hospital and economic burden of the disease.

Respiratory syncytial virus infections in infants and children with congenital heart disease: update on the evidence of prevention with palivizumab.

PURPOSE OF REVIEW: Lower respiratory tract infections multiply morbidity and mortality within patients with significant congenital heart disease (CHD). For respiratory syncytial virus (RSV), one of the most important pathogens, immunoprophylaxis with palivizumab has successfully been introduced. The question is which patients will benefit most from this costly preventive treatment. RECENT FINDINGS: The era after the introduction of palivizumab has revealed a steep decrease in mortality. The markers of success - hospital stays, admission to the intensive care unit, days on mechanical ventilation, and death - consistently favor immunoprophylaxis. The key point of treatment success remains in all cases a careful patient selection, adherence to a time limit of 30 days between the injections and early use after cardiac surgery with cardiopulmonary bypass, as well as avoidance of nosocomial-acquired infections. Preventive therapy with palivizumab in patients with CHD has been investigated in terms of operating efficiency - with the lowest costs per quality-adjusted life years compared with preterm infants with or without bronchopulmonary dysplasia. SUMMARY: The burden of RSV disease will decline, once a vaccine is available. Meanwhile, immunoprophylaxis with palivizumab is a useful tool for high-risk patients to reduce comorbidity and fatal outcome. Pharmacoeconomic considerations measuring quality-adjusted life years indicate important information about cost-effectiveness.

Palivizumab prophylaxis to prevent respiratory syncytial virus mortality after pediatric bone marrow transplantation: a decision analysis model.

OBJECTIVE: Palivizumab, a monoclonal antibody against respiratory syncytial virus (RSV), has been demonstrated to be safe and effective in young children, but evidence is lacking as to whether palivizumab is effective in preventing RSV-induced morbidity and mortality in children who are immunosuppressed after bone marrow transplantation (BMT). As a randomized, double-blind, placebo-controlled trial is lacking, we chose to examine this issue with the use of decision analysis methodology. METHODS: A decision tree was designed to determine mortality from RSV-related lung disease in children who received palivizumab after BMT. Probabilities were derived by meta-analysis methodology on the basis of the available literature. Sensitivity analyses were performed across a broad range of biologically plausible probabilities to judge the robustness of the results of the model. RESULTS: The model revealed that there is a 10% increase in survival in BMT patients who receive palivizumab. The absolute survival rate increased from 83% to 92%. A practitioner would need to treat 12 children to save 1 post-BMT child from dying from RSV-related lung disease. CONCLUSIONS: Decision analysis modeling demonstrates a decrease in mortality in pediatric BMT patients with the addition of palivizumab to protect against RSV-related lung disease. A well-designed, randomized controlled trial is necessary.

Respiratory syncytial virus infections in congenital heart defects--hospitalizations and costs.

AIMS: To register hospitalizations for respiratory syncytial virus (RSV) infections and estimate costs of prophylaxis with humanized monoclonal antibodies (palivizumab) against RSV, compared to hospital care, in cases with congenital heart defects (CHDs). METHODS: Population based study with prospective registration of CHDs. Costs for hospital treatment of RSV-infections in CHD-patients calculated by means of the Norwegian Diagnosis Related Groups system. RESULTS: In 43 470 infants live born in the population through the 18-year period 1987-2004 a structural CHD was diagnosed in 527 (1.2%). A total of 898 (2.1%) hospitalizations for RSV-infections occurred in the study population 1987-2005. The hospital admittance rate was significantly higher for CHD-cases (4.8%) than for children without CHD (2%) (P = 0.002). Severe CHDs (need for surgery or catheter intervention) had a higher admittance rate (9.2%) compared to the group of remaining CHDs (3.3%) (P = 0.01). Number needed to treat with palivizumab to avoid one hospitalization for RSV-infection in cases of severe CHDs was calculated to 24, at costs of US dollar 195,000. The expenses for palivizuamab prophylaxis in severe CHDs were 31 times that of hospital treatment. CONCLUSION: Prophylaxis with palivizumab in severe CHDs is not cost-effective.

Economic analysis of palivizumab in infants with congenital heart disease.

OBJECTIVE: Palivizumab has been shown to reduce the number of respiratory syncytial virus (RSV)-related hospitalizations by 45% in children with congenital heart disease (CHD). The American Academy of Pediatrics has recommended that infants with hemodynamically significant CHD be considered for palivizumab. However, the economic implications of palivizumab prophylaxis in the CHD population have not been evaluated. In the present study, we sought to examine the cost savings and cost utility of RSV prophylaxis with palivizumab in children with CHD. METHODS: Probabilities of hospitalization and efficacy of prophylaxis were based on published results. Costs of hospitalization were derived from a published analysis of bronchiolitis hospitalization costs from a consortium of children's hospitals. A hypothetical cohort of 10,000 CHD patients (half of whom would receive palivizumab) was created to calculate cost-savings and cost-utility. To assess cost utility, we assumed that by reducing hospitalization, palivizumab would reduce RSV-related hospital mortality, generally reported to be 3% in CHD patients. Sensitivity analysis was performed. RESULTS: On the basis of a protocol of 5 monthly doses of palivizumab, the cost of prophylaxis for 1 RSV season was calculated as 6160 dollars per patient. After accounting for impact on direct and indirect costs of hospitalization, administration of palivizumab to 5000 CHD patients would result in a net loss of 20,415,753 dollars. If one assumes that palivizumab confers a survival benefit, then the cost of life-year saved is 100,338 dollars and cost of quality-adjusted life-year saved is 114,337 dollars. CONCLUSIONS: The cost of palivizumab prophylaxis was high relative to benefits realized. Given the large number of CHD patients who might be considered candidates for RSV prophylaxis (>6000 patients per year in United States) routine use of palivizumab in young children with hemodynamically significant CHD needs to be evaluated further.

Direct cost analyses of palivizumab treatment in a cohort of at-risk children: evidence from the North Carolina Medicaid Program.

OBJECTIVE: Use of palivizumab prophylactic therapy reduces the occurrence of hospitalizations for serious respiratory syncytial virus (RSV) lower respiratory tract infections in at-risk infants. The direct cost-benefit of palivizumab prophylaxis for infants who are born at 32 to 35 weeks' estimated gestational age (EGA) during their first year of life has not been systematically examined. The objective of this study was to compare the direct costs of palivizumab prophylaxis and RSV treatment in infants who were born at 32 to 35 weeks EGA and received and did not receive palivizumab. METHODS: A cohort study was performed of infants who were younger than 1 year and were enrolled in an enhanced primary care case management model within the North Carolina Medicaid Program. Comparisons were made between infants who received (Synagis prophylaxis group) and did not receive palivizumab (nonprophylaxis group) during the study period. Cost was examined using the sum of Medicaid paid services for prophylaxis with palivizumab and treatment for RSV infections that occurred between October 1, 2002, and May 31, 2003. The Anderson framework was used to specify the regression cost models to compare the participants who received (Synagis prophylaxis) and did not receive (nonprophylaxis group) palivizumab. The primary outcomes were actual 7-month seasonal costs and standardized seasonal costs adjusting for the varied months of infant participation. RESULTS: The study sample included 185 Synagis prophylaxis and 182 nonprophylaxis participants who met the inclusion criteria. The average per-person total cost of RSV care and prophylaxis was 5117 dollars for the Synagis prophylaxis group and 371 dollars for the nonprophylaxis group. Five hospitalizations occurred in the prophylaxis group, and 12 occurred in the nonprophylaxis group (odds ratio: 0.27). No deaths occurred in either group. CONCLUSIONS: Palivizumab administered to infants who were born at 32 to 35 weeks' EGA did not provide direct cost savings related to hospitalization or ambulatory care in a Medicaid population. The primary difference in cost between the groups was attributable to the palivizumab prophylaxis.

Recent trends in severe respiratory syncytial virus (RSV) among US infants, 1997 to 2000.

OBJECTIVES: To provide current estimates of the incidence, associated risk factors, and costs of severe respiratory syncytial virus (RSV) infections among infants in the United States, defined as emergency department (ED) visits, hospitalization, and death. STUDY DESIGN: Retrospective analysis of National Hospital Ambulatory Medical Care Survey data 1997 to 2000; National Hospital Discharge Survey data 1997 to 2000; Perinatal Mortality Linked Files 1998 to 1999. The Hospital Cost Utilization Inpatient Sample data 1997 to 2000 were used to estimate hospitalization costs, and the 2001 Medicare fee schedule was used to estimate ED visit costs. Census data were used for population estimates. Between 1997 and 2000, there were 718,008 ED visits by infants with lower respiratory infection diagnoses during the RSV season (22.8/1000), and 29% were admitted. Costs of ED visits were approximately 202 million US dollars. RSV bronchiolitis was the leading cause of infant hospitalization annually. Total hospital charges for RSV-coded primary diagnoses during the 4 years were more than 2.6 billion US dollars. An estimated 390 RSV-associated postneonatal deaths occurred in 1999. Low birth weight and prematurity significantly increased RSV-associated mortality rates. CONCLUSIONS: RSV is a major cause of infant morbidity and mortality. Severe RSV is highest among infants of black mothers and Medicaid-insured infants. Prematurity and low birth weight significantly increase RSV mortality rates.

Respiratory syncytial virus pneumonia in the hospital setting: length of stay, charges, and mortality.

BACKGROUND: Respiratory syncytial virus (RSV) is the most important viral cause of lower respiratory tract infection in infants and young children worldwide. No vaccine against RSV is available, but prophylactic interventions have been shown to be safe and effective in clinical trials. OBJECTIVES: This retrospective analysis was conducted to examine the health and economic burden of hospitalization for RSV pneumonia. METHODS: Nationally weighted hospital discharges for RSV pneumonia among children 4 years old and younger were analyzed by using the Healthcare Cost and Utilization Project National Inpatient Sample. RESULTS: In 1993, there were estimated to be 16,500 hospital discharges with RSV pneumonia, which increased to 19,700 and 20,800 in 1994 and 1995, respectively. Children less than 1 year of age accounted for over 70% of these discharges. Hospital charges (in 1998 dollars) for RSV pneumonia-associated episodes were $295,100,000 in 1993; $392,300,000 in 1994; and $295,800,000 in 1995. CONCLUSIONS: With inpatient charges of $300 to $400 million per year in the United States, the disease burden of RSV pneumonia is very high in terms of both morbidity and economic costs. Emerging prophylactic interventions should have an impact on the high burden of RSV pneumonia.

Respiratory syncytial virus pneumonia among the elderly: an assessment of disease burden.

Respiratory syncytial virus (RSV) is an important cause of acute lower respiratory tract disease among the elderly, but national estimates of the burden of this disease have not been made. To estimate the morbidity, mortality, and medical costs of RSV-associated pneumonia among US elderly, national hospital discharge data, vital statistics, etiologic studies of adult pneumonia hospitalizations, and Medicare cost data were reviewed. In the United States, 687,000 hospitalizations and 74,000 deaths caused by pneumonia occur annually among the elderly; approximately 2%-9% of these are caused by RSV. At a cost of $11,000 per RSV pneumonia hospitalization, the estimated annual cost of RSV pneumonia hospitalizations is $150-$680 million. Exacerbations of congestive heart failure and other chronic conditions may also contribute substantially to RSV disease burden among the elderly. The total RSV disease burden is probably great enough to justify development of an RSV vaccine for use in this group.