Year-Round Respiratory Syncytial Virus Transmission in The Netherlands Following the COVID-19 Pandemic: A Prospective Nationwide Observational and Modeling Study.

We initiated a nationwide prospective study to monitor respiratory syncytial virus (RSV)-related pediatric hospitalizations in 46 hospitals throughout the Netherlands between May 2021 and August 2022. We showed year-round RSV transmission in the Netherlands after an initial 2021 summer outbreak. The pattern was unprecedented and distinct from neighboring countries. We extended a dynamic simulation model to evaluate the impact of waning immunity on pediatric RSV hospitalizations in the Netherlands using 4 different scenarios. Our results suggest that the observed continuous RSV transmission pattern could be associated with waning immunity due to the period of very low RSV circulation during the COVID-19 pandemic.

Nosocomial RSV-related In-hospital Mortality in Children <5 Years: A Global Case Series.

BACKGROUND: According to the World Health Organization, the global burden of nosocomial infections is poorly characterized as surveillance systems are lacking. Nosocomial infections occur at higher rates in low- and lower-middle-income countries (LMICs) than in high-income countries (HICs). Current global RSV burden estimates are largely based on community-acquired infection. We aimed to characterize children with nosocomial RSV-related mortality and to understand the potential impact of RSV immunization strategies. MATERIALS: RSV GOLD is a global registry of children younger than 5 years who died with laboratory-confirmed RSV infection. We compared clinical and demographic characteristics of children with nosocomial and community-acquired RSV in-hospital mortality. RESULTS: We included 231 nosocomial and 931 community-acquired RSV-related in-hospital from deaths from 65 countries. Age at death was similar for both groups (5.4 vs. 6 months). A higher proportion of nosocomial deaths had comorbidities (87% vs. 57%; P < 0.001) or was born preterm (46% vs. 24%; P < 0.001) than community-acquired deaths. The proportion of nosocomial deaths among all RSV deaths was lower in LMICs than in upper-middle-income countries (UMICs) and HICs (12% vs. 18% and 26%, respectively). CONCLUSIONS: This is the first global case series of children dying with nosocomial RSV infection. Future infant-targeted immunization strategies could prevent the majority of nosocomial RSV-related deaths. Although nosocomial RSV deaths are expected to occur at highest rates in LMICs, the number of reported nosocomial RSV deaths was low in these countries. Hospital-based surveillance is needed to capture the full burden of nosocomial RSV mortality in LMICs.

Respiratory syncytial virus prevention within reach: the vaccine and monoclonal antibody landscape.

Respiratory syncytial virus is the second most common cause of infant mortality and a major cause of morbidity and mortality in older adults (aged >60 years). Efforts to develop a respiratory syncytial virus vaccine or immunoprophylaxis remain highly active. 33 respiratory syncytial virus prevention candidates are in clinical development using six different approaches: recombinant vector, subunit, particle-based, live attenuated, chimeric, and nucleic acid vaccines; and monoclonal antibodies. Nine candidates are in phase 3 clinical trials. Understanding the epitopes targeted by highly neutralising antibodies has resulted in a shift from empirical to rational and structure-based vaccine and monoclonal antibody design. An extended half-life monoclonal antibody for all infants is likely to be within 1 year of regulatory approval (from August, 2022) for high-income countries. Live-attenuated vaccines are in development for older infants (aged >6 months). Subunit vaccines are in late-stage trials for pregnant women to protect infants, whereas vector, subunit, and nucleic acid approaches are being developed for older adults. Urgent next steps include ensuring access and affordability of a respiratory syncytial virus vaccine globally. This review gives an overview of respiratory syncytial virus vaccines and monoclonal antibodies in clinical development highlighting different target populations, antigens, and trial results.

Daily intranasal palivizumab to prevent respiratory syncytial virus infection in healthy preterm infants: a phase 1/2b randomized placebo-controlled trial.

Background: Mucosal administration of monoclonal antibodies (mAbs) against respiratory pathogens is a promising alternative for systemic administration because lower doses are required for protection. Clinical development of mucosal mAbs is a highly active field yet clinical proof-of-concept is lacking. Methods: In this investigator-initiated, double-blind, randomized placebo-controlled trial, we evaluated intranasal palivizumab for the prevention of RSV infection in preterm infants (Dutch Trial Register NTR7378 and NTR7403). We randomized infants 1:1 to receive intranasal palivizumab (1 mg/mL) or placebo once daily during the RSV season. Any RSV infection was the primary outcome and RSV hospitalization was the key secondary outcome. The primary outcome was analyzed with a mixed effect logistic regression on the modified intention-to-treat population. Findings: We recruited 268 infants between Jan 14, 2019 and Jan 28, 2021, after which the trial was stopped for futility following the planned interim analysis. Adverse events were similar in both groups (22/134 (16.4%) palivizumab arm versus 26/134 (19.4%) placebo arm). There were 6 dropouts and 168 infants were excluded from the efficacy analyses due to absent RSV circulation during the SARS-CoV-2 pandemic. Any RSV infection was similar in infants in both groups (18/47 (38.3%) palivizumab arm versus 11/47 (23.4%) placebo arm; aOR 2.2, 95% CI 0.7-6.5). Interpretation: Daily intranasal palivizumab did not prevent RSV infection in late preterm infants. Our findings have important implications for the clinical development of mucosal mAbs, namely the necessity of timely interim analyses and further research to understand mucosal antibody half-life. Funding: Funded by the Department of Pediatrics, University Medical Centre Utrecht, the Netherlands.

Global Respiratory Syncytial Virus-Related Infant Community Deaths.

BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of pediatric death, with >99% of mortality occurring in low- and lower middle-income countries. At least half of RSV-related deaths are estimated to occur in the community, but clinical characteristics of this group of children remain poorly characterized. METHODS: The RSV Global Online Mortality Database (RSV GOLD), a global registry of under-5 children who have died with RSV-related illness, describes clinical characteristics of children dying of RSV through global data sharing. RSV GOLD acts as a collaborative platform for global deaths, including community mortality studies described in this supplement. We aimed to compare the age distribution of infant deaths <6 months occurring in the community with in-hospital. RESULTS: We studied 829 RSV-related deaths <1 year of age from 38 developing countries, including 166 community deaths from 12 countries. There were 629 deaths that occurred <6 months, of which 156 (25%) occurred in the community. Among infants who died before 6 months of age, median age at death in the community (1.5 months; IQR: 0.8-3.3) was lower than in-hospital (2.4 months; IQR: 1.5-4.0; P < .0001). The proportion of neonatal deaths was higher in the community (29%, 46/156) than in-hospital (12%, 57/473, P < 0.0001). CONCLUSIONS: We observed that children in the community die at a younger age. We expect that maternal vaccination or immunoprophylaxis against RSV will have a larger impact on RSV-related mortality in the community than in-hospital. This case series of RSV-related community deaths, made possible through global data sharing, allowed us to assess the potential impact of future RSV vaccines.

Describing global pediatric RSV disease at intensive care units in GAVI-eligible countries using molecular point-of-care diagnostics: the RSV GOLD-III study protocol.

BACKGROUND: Respiratory syncytial virus (RSV) infection is an important cause of hospitalization and death in young children. The majority of deaths (99%) occur in low- and lower-middle-income countries (LMICs). Vaccines against RSV infection are underway. To obtain access to RSV interventions, LMICs depend on support from Gavi, the Vaccine Alliance. To identify future vaccine target populations, information on children with severe RSV infection is required. However, there is a lack of individual patient-level clinical data on instances of life-threatening RSV infection in LMICs. The RSV GOLD III-ICU Network study aims to describe clinical, demographic and socioeconomic characteristics of children with life-threatening RSV infection in Gavi-eligible countries. METHODS: The RSV GOLD-III-ICU Network study is an international, prospective, observational multicenter study and will be conducted in 10 Gavi-eligible countries at pediatric intensive care units and high-dependency units (PICUs/HDUs) during local viral respiratory seasons for 2 years. Children younger than 2 years of age with respiratory symptoms fulfilling the World Health Organization (WHO) "extended severe acute respiratory infection (SARI)" case definition will be tested for RSV using a molecular point-of-care (POC) diagnostic device. Patient characteristics will be collected through a questionnaire. Mortality rates of children admitted to the PICU and/or HDU will be calculated. DISCUSSION: This multicenter descriptive study will provide a better understanding of the characteristics and mortality rates of children younger than 2 years with RSV infection admitted to the PICU/HDU in LMICs. These results will contribute to knowledge on global disease burden and awareness of RSV and will directly guide decision makers in their efforts to implement future RSV prevention strategies. TRIAL REGISTRATION NUMBER: NL9519, May 27, 2021.

Estimated impact of maternal vaccination on global paediatric influenza-related in-hospital mortality: A retrospective case series.

BACKGROUND: Influenza virus infection is an important cause of under-five mortality. Maternal vaccination protects children younger than 3 months of age from influenza infection. However, it is unknown to what extent paediatric influenza-related mortality may be prevented by a maternal vaccine since global age-stratified mortality data are lacking. METHODS: We invited clinicians and researchers to share clinical and demographic characteristics from children younger than 5 years who died with laboratory-confirmed influenza infection between January 1, 1995 and March 31, 2020. We evaluated the potential impact of maternal vaccination by estimating the number of children younger than 3 months with in-hospital influenza-related death using published global mortality estimates. FINDINGS: We included 314 children from 31 countries. Comorbidities were present in 166 (53%) children and 41 (13%) children were born prematurely. Median age at death was 8·6 (IQR 4·5-16·6), 11·5 (IQR 4·3-24·0), and 15·5 (IQR 7·4-27·0) months for children from low- and lower-middle-income countries (LMICs), upper-middle-income countries (UMICs), and high-income countries (HICs), respectively. The proportion of children younger than 3 months at time of death was 17% in LMICs, 12% in UMICs, and 7% in HICs. We estimated that 3339 annual influenza-related in-hospital deaths occur in the first 3 months of life globally. INTERPRETATION: In our study, less than 20% of children is younger than 3 months at time of influenza-related death. Although maternal influenza vaccination may impact maternal and infant influenza disease burden, additional immunisation strategies are needed to prevent global influenza-related childhood mortality. The missing data, global coverage, and data quality in this study should be taken into consideration for further interpretation of the results. FUNDING: Bill & Melinda Gates Foundation.

Respiratory Syncytial Virus-related Death in Children With Down Syndrome: The RSV GOLD Study.

BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of mortality in children younger than 5 years worldwide. Systematic reviews have shown that Down syndrome (DS) is an independent risk factor for severe RSV infection. We aimed to describe demographic and clinical characteristics of children with DS who died with RSV infection. METHODS: We performed a retrospective case series in which data were shared by individual researchers, research networks and physicians worldwide as part of the RSV Global Online Database study. We included children with DS who died when younger than 5 years of age with laboratory-confirmed RSV infection. RESULTS: We included 53 children with DS and RSV-related mortality from 20 countries in 5 continents. Five (9.4%) children were from low-income or lower-middle-income countries. Median age at time of death was 6.0 months [interquartile range (IQR): 3.00-12.0]. Thirteen (24.5%) children were born term and had no other risk factors for severe RSV disease. In total, 36 (67.9%) children had congenital heart disease, 8 (15.1%) had chronic lung disease and 1 (1.9%) had congenital immunodeficiency. Duration of hospitalization was significantly longer for children with DS compared with children without DS [median length of stay, 13 days (IQR: 6.8-21.0) vs. 8 days (IQR: 3.0-18.5), P=0.005]. CONCLUSIONS: One-fourth of children with DS and RSV-confirmed death did not have risk factors for severe RSV disease, indicating that DS is an important risk factor for RSV-related mortality. Age distribution at time of death demonstrates that maternal vaccination would not be sufficient to protect children with DS against RSV-related mortality.

Birth asphyxia following delayed recognition and response to abnormal labour progress and fetal distress in a 31-year-old multiparous Malawian woman.

Reducing neonatal mortality is one of the targets of Sustainable Development Goal 3 on good health and well-being. The highest rates of neonatal death occur in sub-Saharan Africa. Birth asphyxia is one of the major preventable causes. Early detection and timely management of abnormal labour progress and fetal compromise are critical to reduce the global burden of birth asphyxia. Labour progress, maternal and fetal well-being are assessed using the WHO partograph and intermittent fetal heart rate monitoring. However, in low-resource settings adherence to labour guidelines and timely response to arising labour complications is generally poor. Reasons for this are multifactorial and include lack of resources and skilled health care staff. This case study in a Malawian hospital illustrates how delayed recognition of abnormal labour and prolonged decision-to-delivery interval contributed to birth asphyxia, as an example of many delivery rooms in low-income country settings.

Increasing the dose of oral vitamin K prophylaxis and its effect on bleeding risk.

Vitamin K prophylaxis in infancy aims to prevent life-threatening vitamin K deficiency bleeding (VKDB). The Dutch prophylactic oral daily regimen was increased sixfold from 25 to 150 µg because of a high failure rate. To evaluate the efficacy of this new regimen, incidences of intracranial VKDB under both regimens were compared using both general and targeted surveillance. Late VKDB in the general pediatric population was identified by the Netherlands Pediatric Surveillance Unit, between 1 October 2014 and 31 December 2016. Additionally, infants with intracranial vitamin K deficiency bleeding were identified using the Dutch Pediatric Intensive Care Evaluation registry. The incidence of intracranial VKDB as assessed by general and targeted surveillance decreased from 1.6 per 100,000 (95% CI, 0.4-5.1) to 1.3 per 100,000 (95% CI, 0.5-3.2) and from 3.1 per 100,000 live births (95% CI, 1.9-5.0) to 1.2 per 100,000 live births (95% CI, 0.6-2.3), respectively. Median time between consecutive cases in the latter increased from 24 to 154 days (p < 0.001).Conclusion: A sixfold increase in oral vitamin K prophylaxis was associated with a surprisingly modest reduction in the incidence of intracranial VKDB, indicating that factors other than the dose need addressing to improve efficacy. What is Known: • The efficacy of intramuscular vitamin K prophylaxis is threatened by an increasing number of parents opting out. • Oral prophylaxis represents an attractive and less invasive alternative but is inferior, especially in infants with malabsorption of vitamin K due to cholestasis. What is New: • Increasing the daily oral dose of vitamin K sixfold had a surprisingly modest effect on the incidence of late vitamin K deficiency bleeding. • This finding indicates that factors other than the dose must play an important role.