Publications

Mari Johnson, Irina Chelysheva, Deniz Öner, Joseph McGinley, Gu-Lung Lin, Daniel O’Connor, Hannah Robinson, Simon B Drysdale, Emma Gammin, Sophie Vernon, Jill Muller, Helen Wolfenden, Sharon Westcar, Lazarus Anguvaa, Ryan S Thwaites, Louis Bont, Joanne Wildenbeest, Federico Martinón-Torres, Jeroen Aerssens, Peter J M Openshaw, Andrew J Pollard on behalf of the PROMISE Investigators

Background

Respiratory syncytial virus (RSV) is a significant cause of infant morbidity and mortality worldwide. Most children experience at least one 1 RSV infection by the age of two 2 years, but not all develop severe disease. However, the understanding of genetic risk factors for severe RSV is incomplete. Consequently, we conducted a genome-wide association study of RSV severity.

Methods

Disease severity was assessed by the ReSVinet scale, in a cohort of 251 infants aged 1 week to 1 year. Genotyping data were collected from multiple European study sites as part of the RESCEU Consortium. Linear regression models were used to assess the impact of genotype on RSV severity and gene expression as measured by microarray.

Results

While no SNPs reached the genome-wide statistical significance threshold (P < 5 × 10⁻⁸), we identified 816 candidate SNPs with a P-value of <1 × 10⁻⁴. Functional annotation of candidate SNPs highlighted genes relevant to neutrophil trafficking and cytoskeletal functions, including LSP1 and RAB27A. Moreover, SNPs within the RAB27A locus significantly altered gene expression (false discovery rate, FDR P < .05).

Conclusions

These findings may provide insights into genetic mechanisms driving severe RSV infection, offering biologically relevant information for future investigations.

Access the article

24 January 2024

Charlotte Vernhes, Louis Bont, Clarisse Demont, Harish Nair 

Access the article 

17 January 2024

Richard Osei-Yeboah, Caroline Klint Johannesen, Amanda Marie Egeskov-Cavling, Junru Chen, Toni Lehtonen, Arantxa Urchueguía Fornes, John Paget, Thea K Fischer, Xin Wang, Harish Nair,  Harry Campbell on behalf of the PROMISE Investigators

Background

Individuals with comorbidities are at increased risk of severe respiratory syncytial virus (RSV) infection. We estimated RSV-associated respiratory hospitalization among adults aged ≥45 years with comorbidities in Denmark and Scotland.

Methods

By analyzing national hospital and virologic data, we estimated annual RSV-associated hospitalizations by 7 selected comorbidities and ages between 2010 and 2018. We estimated rate ratios of RSV-associated hospitalization for adults with comorbidity than the overall population.

Results

In Denmark, annual RSV–associated hospitalization rates per 1000 adults ranged from 3.1 for asthma to 19.4 for chronic kidney disease (CKD). In Scotland, rates ranged from 2.4 for chronic liver disease to 9.0 for chronic obstructive pulmonary disease (COPD). In both countries, we found a 2- to 4-fold increased risk of RSV hospitalization for adults with COPD, ischemic heart disease, stroke, and diabetes; a 1.5- to 3-fold increased risk for asthma; and a 3- to 7-fold increased risk for CKD. RSV hospitalization rates among adults aged 45 to 64 years with COPD, asthma, ischemic heart disease, or CKD were higher than the overall population.

Conclusions

This study provides important evidence for identifying risk groups and assisting health authorities in RSV vaccination policy making.

Access the article

16 November 2023

K Chappin, S B Besteman, M P Hennus, J G Wildenbeest, M Mokry, L J Bont, M van der Vlist, J J A Calis, PROMISE Investigators 

Background

Respiratory syncytial virus (RSV) infection is the primary cause of lower respiratory tract infections in children <5 years of age. Monocytes, especially in the respiratory tract, are suggested to contribute to RSV pathology, but their role is incompletely understood. With transcriptomic profiling of blood and airway monocytes, we describe the role of monocytes in severe RSV infection.

Methods

Tracheobronchial aspirates and blood samples were collected from control patients (n = 9) and those infected with RSV (n = 14) who were admitted to the pediatric intensive care unit. Monocytes (CD14⁺) were sorted and analyzed by RNA sequencing for transcriptomic profiling.

Results

Peripheral blood and airway monocytes of patients with RSV demonstrated increased expression of antiviral and interferon-responsive genes as compared with controls. Cytokine signaling showed a shared response between blood and airway monocytes while displaying responses that were more pronounced according to the tissue of origin. Airway monocytes upregulated additional genes related to migration and inflammation.

Conclusions

We found that the RSV-induced interferon response extends from the airways to the peripheral blood. Moreover, RSV induces a migration-promoting transcriptional program in monocytes. Unraveling the monocytic response and its role in the immune response to RSV infection could help the development of therapeutics to prevent severe disease.

Access the article

06 November 2023

Caren van Roekel, Eero Poukka, Topi Turunen, Hanna Nohynek, Lance Presser, Adam Meijer, Terho Heikkinen, Rolf Kramer, Elizabeth Begier, Anne C Teirlinck,  Mirjam J Knol, PROMISE Investigators

Monitoring the real-life effectiveness of respiratory syncytial virus (RSV) products is of major public health importance. This generic protocol for a test-negative design study aims to address currently envisioned approaches for RSV prevention (monoclonal antibodies and vaccines) to study effectiveness of these products among target groups: children, older adults, and pregnant women. The generic protocol approach was chosen to allow for flexibility in adapting the protocol to a specific setting. This protocol includes severe acute respiratory infection (SARI) and acute respiratory infection (ARI), both due to RSV, as end points. These end points can be applied to studies in hospitals, primarily targeting patients with more severe disease, but also to studies in general practitioner clinics targeting ARI.

Access the article

03 November 2023

Sarah F Hak, Roderick P Venekamp, Marie-Noëlle Billard, Marlies A van Houten, Andrew J Pollard, Terho Heikkinen, Steve Cunningham, Margaret Millar, Federico Martinón-Torres, Ana Dacosta-Urbieta, Louis J Bont, Joanne G Wildenbeest, PROMISE Investigators

Background

During the first year of life, 1 in 4 infants develops a symptomatic respiratory syncytial virus (RSV) infection, yet only half seek medical attention. The current focus on medically attended RSV therefore underrepresents the true societal burden of RSV. We assessed the burden of nonmedically attended RSV infections and compared with medically attended RSV.

Methods

We performed active RSV surveillance until the age of 1 year in a cohort (n = 993) nested within the Respiratory Syncytial Virus Consortium in EUrope (RESCEU) prospective birth cohort study enrolling healthy term-born infants in 5 European countries. Symptoms, medication use, wheezing, and impact on family life were analyzed.

Results

For 97 of 120 (80.1%) nonmedically attended RSV episodes, sufficient data were available for analysis. In 50.5% (49/97), symptoms lasted ≥15 days. Parents reported impairment in usual daily activities in 59.8% (58/97) of episodes; worries, 75.3% (73/97); anxiety, 34.0% (33/97); and work absenteeism, 10.8% (10/93). Compared with medically attended RSV (n = 102, 9 hospital admissions), Respiratory Syncytial Virus NETwork (ReSViNET) severity scores were lower (3.5 vs 4.6, P < .001), whereas duration of respiratory symptoms and was comparable.

Conclusions

Even when medical attendance is not required, RSV infection poses a substantial burden to infants, families, and society. These findings are important for policy makers when considering the implementation of RSV immunization.

Eero Poukka, Caren van Roekel, Topi Turunen, Ulrike Baum, Rolf Kramer, Elizabeth Begier, Lance Presser, Anne Teirlinck, Terho Heikkinen, Mirjam Knol, Hanna Nohynek, PROMISE Investigators

Several immunization products are currently being developed against respiratory syncytial virus (RSV) for children, pregnant females, and older adults, and some products have already received authorization. Therefore, studies to monitor the effectiveness of these products are needed in the following years. To assist researchers to conduct postmarketing studies, we developed a generic protocol for register-based cohort studies to evaluate immunization product effectiveness against RSV-specific and nonspecific outcomes. To conduct a study on the basis of this generic protocol, the researchers can use any relevant databases or healthcare registers that are available at the study site.

Access the article

01 November 2023

Sebastien Kenmoe, Helen Y Chu, Fatimah S Dawood, Jennifer Milucky, Wanitchaya Kittikraisak, Hamish Matthewson, Durga Kulkarni, Piyarat Suntarattiwong, Collrane Frivold, Sarita Mohanty, Fiona Havers, You Li, Harish Nair; for PROMISE investigators.

With the licensure of maternal RSV vaccines in Europe and USA, data are needed to better characterize the burden of respiratory syncytial virus (RSV)-associated acute respiratory infections (ARI) in pregnancy. This study aims to determine among pregnant individuals the proportion of ARI testing positive for RSV and RSV incidence rate, RSV-associated hospitalizations, deaths, and perinatal outcomes.

Read Publication

12 October 2023

Richard Osei-Yeboah, Fuyu Zhu, Xin Wang, Harish Nair, Harry Campbell on behalf of the PROMISE Investigator

Background

Socioeconomic deprivation may predispose individuals to respiratory tract infections. We estimated RSV-associated hospitalizations by socioeconomic deprivation in Scotland.

Methods

Using national routine health care records and virological surveillance from 2010 to 2016, we used a time-series linear regression model and a direct measurement based on ICD-10 coded diagnoses to estimate RSV-associated hospitalizations by Scottish Index of Multiple Deprivation (SIMD) quintile and age in comparison to influenza-associated hospitalizations.

Results

We estimated an annual average rate per 1000 people of 0.76 (95% CI: 0.43–0.90) in the least deprived group to 1.51 (1.03–1.79) for the most deprived group using model-based approach. The rate ratio (RR) was 1.96 (1.23–3.25), 1.60 (1.0–2.66), 1.35 (0.85–2.25), and 1.12 (0.7–1.85) in the 1^st to 4^th quintile versus the least deprived group. The pattern of RSV-associated hospitalization rates variation with SIMD was most pronounced in children 0-2y. The ICD-10 approach provided much lower rates than the model-based approach but yielded similar RR estimates between SIMD. Influenza-associated hospitalization rate generally increased with higher deprivation levels among individuals 1y+.

Conclusions

Higher RSV and influenza hospitalization rates are related to higher deprivation levels. Differences between deprivation levels are most pronounced in infants and young children for RSV, and are more apparent among individuals 1y+ for influenza.

Access the article

05 October 2023

Zakariya Sheikh, Ellie Potter, You Li, Rachel A Cohen, Gaël Dos Santos, Louis Bont, Harish Nair, PROMISE Investigators 

Background

Respiratory syncytial virus (RSV) is a widespread respiratory pathogen, and RSV-related acute lower respiratory tract infections are the most common cause of respiratory hospitalization in children <2 years of age. Over the last 2 decades, a number of severity scores have been proposed to quantify disease severity for RSV in children, yet there remains no overall consensus on the most clinically useful score.

Methods

We conducted a systematic review of English-language publications in peer-reviewed journals published since January 2000 assessing the validity of severity scores for children (≤24 months of age) with RSV and/or bronchiolitis, and identified the most promising scores. For included articles, (1) validity data were extracted, (2) quality of reporting was assessed using the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis checklist (TRIPOD), and (3) quality was assessed using the Prediction Model Risk Of Bias Assessment Tool (PROBAST). To guide the assessment of the validity data, standardized cutoffs were employed, and an explicit definition of what we required to determine a score was sufficiently validated.

Results

Our searches identified 8541 results, of which 1779 were excluded as duplicates. After title and abstract screening, 6670 references were excluded. Following full-text screening and snowballing, 32 articles, including 31 scores, were included. The most frequently assessed scores were the modified Tal score and the Wang Bronchiolitis Severity Score; none of the scores were found to be sufficiently validated according to our definition. The reporting and/or design of all the included studies was poor. The best validated score was the Bronchiolitis Score of Sant Joan de Déu, and a number of other promising scores were identified.

Conclusions

No scores were found to be sufficiently validated. Further work is warranted to validate the existing scores, ideally in much larger datasets.

Access the article

05 October 2023

Amanda Marie Egeskov-Cavling, Caroline Klint Johannesen, Birgitte Lindegaard, Thea Kølsen Fischer, PROMISE Investigators 

Background

Low awareness and lack of routine testing for respiratory syncytial virus (RSV) infections among adults has led to underreporting in hospital records. This study aimed to assess the underreporting and misclassification of RSV infections among adults hospitalized with an respiratory tract infection (RTI)-coded hospitalization.

Methods

This study is an observational cohort study of RSV-associated hospitalizations among Danish adults (≥18 years old) conducted, between 2015 to 2018. Data were extracted from the Danish National Patient Registry (DNPR) and the Danish Microbiology Database. We identified RSV-positive hospitalizations by linking RTI-coded hospitalizations with a positive RSV test.

Results

Using hospital admission registries, we identified 440 RSV-coded hospitalizations, of whom 420 (95%) had a positive RSV test registered. By linking patients with RTI-coded hospital admissions to RSV test result, we found 570 additional episodes of RSV-positive hospitalizations without an RSV-coded diagnosis.

Conclusions

Our study of national register data showed that RSV is underreported among Danish adults. The study showed that the reliability of hospitalization data to estimate the burden of RSV among adults is questionable and are sensitive to changes in practice over time, even with complete nationwide healthcare data. Healthcare data can be useful to observe seasonality but to estimate the disease burden, prospective surveillance is recommended.

Access the article

25 September 2023

Zakariya Sheikh, Ellie Potter, You Li, Simon B Drysdale, Joanne G Wildenbeest, Hannah Robinson, Joseph McGinley, Gu-Lung Lin, Deniz Öner, Jeroen Aerssens, Antonio José Justicia-Grande, Federico Martinón-Torres, Andrew J Pollard, Louis Bont, Harish Nair on behalf of the PROMISE Investigators

Background

There is no consensus on how to best quantify disease severity in infants with respiratory syncytial virus (RSV) and/or bronchiolitis; this lack of a sufficiently validated score complicates the provision of clinical care and, the evaluation of trials of therapeutics and vaccines. The ReSVinet score appears to be one of the most promising; however, it is too time consuming to be incorporated into routine clinical care. We aimed to develop and externally validate simplified versions of this score.

Methods

Data from a multinational (the Netherlands, Spain, and United Kingdom) multicenter case-control study of infants with RSV were used to develop simplified versions of the ReSVinet score by conducting a grid search to determine the best combination of equally weighted parameters to maximize for the discriminative ability (measured by area under the receiver operating characteristic curve [AUROC]) across a range of outcomes (hospitalization, intensive care unit admission, ventilation requirement). Subsequently discriminative validity of the score for a range of secondary care outcomes was externally validated by secondary analysis of datasets from Rwanda and Colombia.

Results

Three candidate simplified scores were identified using the development dataset; they were excellent (AUROC >0.9) at discriminating for a range of outcomes, and their performance was not significantly different from the original ReSVinet score despite having fewer parameters. In the external validation datasets, the simplified scores were moderate to excellent (AUROC, 0.7–1) across a range of outcomes. In all outcomes, except in a single dataset for predicting admission to the high-dependency unit, they performed at least as well as the original ReSVinet score.

Conclusions

The candidate simplified scores developed require further external validation in larger datasets, ideally from resource-limited settings before any recommendation regarding their use.

Access the article

15 September 2023

Lance D Presser, Willem M R van den Akker, Adam Meijer, PROMISE Investigators

Respiratory syncytial virus (RSV) is a common pathogen causing mostly cold-like symptoms, but in very young infants and elderly individuals it can lead to severe disease and even death. There are currently promising developments both in vaccine development and in therapeutics that are expected to be approved soon. To get an impression within European countries of the laboratory diagnostics and surveillance activities, in anticipation of these developments, we queried the members of the European Respiratory Syncytial Virus Laboratory Network (RSV-LabNet, under the umbrella of the PROMISE project) via an online survey. The answers from the consortium members showed scattered monitoring and the application of a broad array of techniques in the laboratories. A majority of the members expressed strong interest in harmonization and collaboration for setting up surveillance programs and the need for sharing laboratory protocols. The additional value of RSV whole-genome sequencing is broadly appreciated, but implementation requires further development and closer collaboration. The RSV-LabNet can have an important responsibility in establishing contacts and exchange of expertise and providing a platform for communication to advance diagnostics, preparedness, and surveillance.

Access the article

14 August 2023

Shuyu Deng, Ling Guo, Cheryl Cohen, Adam Meijer, Jocelyn Moyes, Siripat Pasittungkul, Yong Poovorawan, Anne Teirlinck, Michiel van Boven, Nasamon Wanlapakorn, Nicole Wolter, John Paget, Harish Nair, You Li, Respiratory Virus Global Epidemiology Network and the PROMISE Investigators

Background

Previous studies reported inconsistent findings regarding the association between respiratory syncytial virus (RSV) subgroup distribution and timing of RSV season. We aimed to further understand the association by conducting a global-level systematic analysis.

Methods

We compiled published data on RSV seasonality through a systematic literature review, and unpublished data shared by international collaborators. Using annual cumulative proportion (ACP) of RSV-positive cases, we defined RSV season onset and offset as ACP reaching 10% and 90%, respectively. Linear regression models accounting for meteorological factors were constructed to analyze the association of proportion of RSV-A with the corresponding RSV season onset and offset.

Results

We included 36 study sites from 20 countries, providing data for 179 study-years in 1995–2019. Globally, RSV subgroup distribution was not significantly associated with RSV season onset or offset globally, except for RSV season offset in the tropics in 1 model, possibly by chance. Models that included RSV subgroup distribution and meteorological factors explained only 2%–4% of the variations in timing of RSV season.

Conclusions

Year-on-year variations in RSV season onset and offset are not well explained by RSV subgroup distribution or meteorological factors. Factors including population susceptibility, mobility, and viral interference should be examined in future studies.

Access the article

30 May 2023

Xin Wang, PhD * Prof You Li, PhD * Ting Shi, PhD Prof Louis J Bont, MD Helen Y Chu, MD Heather J Zar, PhD Bhanu Wahi-Singh, BMedSci Yiming Ma, MSc Bingbing Cong, BMed Emma Sharland, MBChB Prof Richard D Riley, PhD Jikui Deng, MD Prof Josep Figueras-Aloy, PhD Prof Terho Heikkinen, MD Prof Marcus H Jones, PhD Prof Johannes G Liese, MD Joško Markić, MD Asuncion Mejias, MD Prof Marta C Nunes Prof Bernhard Resch, MD Ashish Satav, MD Kee Thai Yeo, MD Prof Eric A F Simões, PhD Prof Harish Nair, PhD Respiratory Virus Global Epidemiology Network  for theRESCEU investigators

Background

Infants and young children born prematurely are at high risk of severe acute lower respiratory infection (ALRI) caused by respiratory syncytial virus (RSV). In this study, we aimed to assess the global disease burden of and risk factors for RSV-associated ALRI in infants and young children born before 37 weeks of gestation.

Methods

We conducted a systematic review and meta-analysis of aggregated data from studies published between Jan 1, 1995, and Dec 31, 2021, identified from MEDLINE, Embase, and Global Health, and individual participant data shared by the Respiratory Virus Global Epidemiology Network on respiratory infectious diseases. We estimated RSV-associated ALRI incidence in community, hospital admission, in-hospital mortality, and overall mortality among children younger than 2 years born prematurely. We conducted two-stage random-effects meta-regression analyses accounting for chronological age groups, gestational age bands (early preterm, <32 weeks gestational age [wGA], and late preterm, 32 to <37 wGA), and changes over 5-year intervals from 2000 to 2019. Using individual participant data, we assessed perinatal, sociodemographic, and household factors, and underlying medical conditions for RSV-associated ALRI incidence, hospital admission, and three severity outcome groups (longer hospital stay [>4 days], use of supplemental oxygen and mechanical ventilation, or intensive care unit admission) by estimating pooled odds ratios (ORs) through a two-stage meta-analysis (multivariate logistic regression and random-effects meta-analysis). This study is registered with PROSPERO, CRD42021269742.

Findings

We included 47 studies from the literature and 17 studies with individual participant-level data contributed by the participating investigators. We estimated that, in 2019, 1 650 000 (95% uncertainty range [UR] 1 350 000–1 990 000) RSV-associated ALRI episodes, 533 000 (385 000–730 000) RSV-associated hospital admissions, 3050 (1080–8620) RSV-associated in-hospital deaths, and 26 760 (11 190–46 240) RSV-attributable deaths occurred in preterm infants worldwide. Among early preterm infants, the RSV-associated ALRI incidence rate and hospitalisation rate were significantly higher (rate ratio [RR] ranging from 1·69 to 3·87 across different age groups and outcomes) than for all infants born at any gestational age. In the second year of life, early preterm infants and young children had a similar incidence rate but still a significantly higher hospitalisation rate (RR 2·26 [95% UR 1·27–3·98]) compared with all infants and young children. Although late preterm infants had RSV-associated ALRI incidence rates similar to that of all infants younger than 1 year, they had higher RSV-associated ALRI hospitalisation rate in the first 6 months (RR 1·93 [1·11–3·26]). Overall, preterm infants accounted for 25% (95% UR 16–37) of RSV-associated ALRI hospitalisations in all infants of any gestational age. RSV-associated ALRI in-hospital case fatality ratio in preterm infants was similar to all infants. The factors identified to be associated with RSV-associated ALRI incidence were mainly perinatal and sociodemographic characteristics, and factors associated with severe outcomes from infection were mainly underlying medical conditions including congenital heart disease, tracheostomy, bronchopulmonary dysplasia, chronic lung disease, or Down syndrome (with ORs ranging from 1·40 to 4·23).

Interpretation

Preterm infants face a disproportionately high burden of RSV-associated disease, accounting for 25% of RSV hospitalisation burden. Early preterm infants have a substantial RSV hospitalisation burden persisting into the second year of life. Preventive products for RSV can have a substantial public health impact by preventing RSV-associated ALRI and severe outcomes from infection in preterm infants.

Access the Article 

14 February 2024

Anne C. Teirlinck, Caroline K. Johannesen, Eeva K. Broberg, Pasi Penttinen, Harry Campbell, Harish Nair, Rachel M. Reeves, Håkon Bøås, Mia Brytting, Wei Cai, AnnaSara Carnahan, Jean-Sebastien Casalegno, Kostas Danis, Cillian De Gascun, Joanna Ellis, Hanne-Dorthe Emborg, Manuel Gijon, Raquel Guiomar, Siddhivinayak S. Hirve, Helena Jiřincová, Hanna Nohynek, Jesus Angel Oliva, Richard Osei-Yeboah, John Paget, Gatis Pakarna, Richard Pebody, Lance Presser, Marie Rapp, Janine Reiche, Ana Paula Rodrigues, Elina Seppälä, Maja Socan, Karol Szymanski, Ramona Trebbien, Jaromíra Večeřová, Sylvie van der Werf, Maria Zambon, Adam Meijer, Thea K. Fischer

New perspectives on respiratory syncytial virus surveillance at the national level: lessons from the COVID-19 pandemic.

Access the article

3 April 2023

Abraham M. Getaneh, Xiao Li, Zhuxin Mao, Caroline K. Johannesen , Elisa Barbieri, Jojanneke van Summeren, Xin Wang , Sabine Tong, Eugenio Baraldi, Emily Phijffer, Caterina Rizzo, Maarten van Wijhe, Terho Heikkinen, Louis Bont, Lander Willem, Mark Jit, Philippe Beutels, Joke Bilcke, for Respiratory Syncytial Virus Consortium in Europe (RESCEU) investigators

Background

Respiratory syncytial virus (RSV) imposes a substantial burden on pediatric hospital capacity in Europe. Promising prophylactic interventions against RSV including monoclonal antibodies (mAb) and maternal immunizations (MI) are close to licensure. Therefore, we aimed to evaluate the cost-effectiveness of potential mAb and MI interventions against RSV in infants, for six European countries.

Methods

We used a static cohort model to compare costs and health effects of four intervention programs to no program and to each other: year-round MI, year-round mAb, seasonal mAb (October to April), and seasonal mAb plus a catch-up program in October. Input parameters were obtained from national registries and literature. Influential input parameters were identified with the expected value of partial perfect information and extensive scenario analyses (including the impact of interventions on wheezing and asthma).

Results

From the health care payer perspective, and at a price of €50 per dose (mAb and MI), seasonal mAb plus catch-up was cost-saving in Scotland, and cost-effective for willingness-to-pay (WTP) values ≥€20,000 (England, Finland) or €30,000 (Denmark) per quality adjusted life-year (QALY) gained for all scenarios considered, except when using ICD-10 based hospitalization data. For the Netherlands, seasonal mAb was preferred (WTP value: €30,000-€90,000) for most scenarios. For Veneto region (Italy), either seasonal mAb with or without catch-up or MI was preferred, depending on the scenario and WTP value. From a full societal perspective (including leisure time lost), the seasonal mAb plus catch-up program was cost-saving for all countries except the Netherlands.

Conclusions

The choice between a MI or mAb program depends on the level and duration of protection, price, availability, and feasibility of such programs, which should be based on the latest available evidence. Future research should focus on measuring accurately age-specific RSV-attributable hospitalizations in very young children.

Keywords

Respiratory syncytial virus (RSV); Disease burden; Cost-effectiveness analysis; Maternal vaccine; Monoclonal antibody; Seasonal program; Perspective; Expected value of perfect information (EVPI); Expected value of partial perfect information (EVPPI)

Access the article

24 February 2023

Xiao Li, David Hodgson, Julien Flaig, Alexia Kieffer, William L.Herring, Hadi Beyhaghi, Lander Willem, Mark Jit, Joke Bilcke, Philippe Beutels, REspiratory Syncytial virus Consortium in EUrope (RESCEU) Investigators

Objectives

Model-based cost-effectiveness analyses on maternal vaccine (MV) and monoclonal antibody (mAb) interventions against respiratory syncytial virus (RSV) use context-specific data and produce varied results. Through model comparison, we aim to characterize RSV cost-effectiveness models and examine drivers for their outputs.

Methods

We compared 3 static and 2 dynamic models using a common input parameter set for a hypothetical birth cohort of 100 000 infants. Year-round and seasonal programs were evaluated for MV and mAb interventions, using available evidence during the study period (eg, phase III MV and phase IIb mAb efficacy).

Results

Three static models estimated comparable medically attended (MA) cases averted versus no intervention (MV, 1019-1073; mAb, 5075-5487), with the year-round MV directly saving ∼€1 million medical and €0.3 million nonmedical costs, while gaining 4 to 5 discounted quality-adjusted life years (QALYs) annually in <1-year-olds, and mAb resulting in €4 million medical and €1.5 million nonmedical cost savings, and 21 to 25 discounted QALYs gained. In contrast, both dynamic models estimated fewer MA cases averted (MV, 402-752; mAb, 3362-4622); one showed an age shift of RSV cases, whereas the other one reported many non-MA symptomatic cases averted, especially by MV (2014). These differences can be explained by model types, assumptions on non-MA burden, and interventions’ effectiveness over time.

Conclusions

Our static and dynamic models produced overall similar hospitalization and death estimates, but also important differences, especially in non-MA cases averted. Despite the small QALY decrement per non-MA case, their larger number makes them influential for the costs per QALY gained of RSV interventions.

Keywords

catch-up; cost-utility analysis; high-income country; maternal vaccine; model comparison; monoclonal antibody; RSV; seasonal; year-round program

Access the article

16 November 2022

J G Wildenbeest, M-N Billard, Roy P Zuurbier, K Korsten, A CLangedijk, P Mvan de Ven, M D Snape, S BDrysdale,  A J Pollard FMedSci, H Robinson,T Heikkinen, S Cunningham, T O’Neill, B Rizkalla, A Dacosta-Urbieta, F Martinón-Torres, M Avan Houten, L J Bont, RESCEU Investigators

Background

Respiratory syncytial virus (RSV) is a major cause of hospitalisation in infants. The burden of RSV infection in healthy term infants has not yet been established. Accurate health-care burden data in healthy infants are necessary to determine RSV immunisation policy when RSV immunisation becomes available.

Methods

We performed a multicentre, prospective, observational birth cohort study in healthy term-born infants (≥37 weeks of gestation) in five sites located in different European countries to determine the health-care burden of RSV. The incidence of RSV-associated hospitalisations in the first year of life was determined by parental questionnaires and hospital chart reviews. We performed active RSV surveillance in a nested cohort to determine the incidence of medically attended RSV infections. The study is registered with ClinicalTrials.gov, NCT03627572.

Findings

In total, 9154 infants born between July 1, 2017, and April 1, 2020, were followed up during the first year of life and 993 participated in the nested active surveillance cohort. The incidence of RSV-associated hospitalisations in the total cohort was 1·8% (95% CI 1·6–2·1). There were eight paediatric intensive care unit admissions, corresponding to 5·5% of 145 RSV-associated hospitalisations and 0·09% of the total cohort. Incidence of RSV infection in the active surveillance cohort confirmed by any diagnostic assay was 26·2% (24·0–28·6) and that of medically attended RSV infection was 14·1% (12·3–16·0).

Interpretation

RSV-associated acute respiratory infection causes substantial morbidity, leading to the hospitalisation of one in every 56 healthy term-born infants in high-income settings. Immunisation of pregnant women or healthy term-born infants during their first winter season could have a major effect on the health-care burden caused by RSV infections.

Funding

Innovative Medicines Initiative 2 Joint Undertaking, with support from the EU’s Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations.

Access the article

10 November 2022

Shanshan Zhang, Pia Wahi-Singh, Bhanu Wahi-Singh, Alison Chisholm, Polly Keeling, Harish Nair, RESCEU Investigators

Background

Acute respiratory infections (ARIs) accounted for an estimated 3.9 million deaths worldwide in 2015, of which 56% occurred in adults aged 60 years or older. We aimed to identify the cost of ARI management in older adults (≥50 years) in order to develop an evidence base to assist decision-making for resource allocation and inform clinical practice.

Methods

We searched 8 electronic databases including Global Health, Medline and EMBASE for studies published between January 1, 2000 and December 31, 2021. Total management costs per patient per ARI episode were extracted and meta-analysis was conducted by World Health Organization (WHO) region and World Bank income level. All costs were converted and inflated to Euros (€) (2021 average exchange rate). The quality of included studies and the potential risk of bias were evaluated.

Results

A total of 42 publications were identified for inclusion, reporting cost data for 8 082 752 ARI episodes in older adults across 20 countries from 2001 to 2021. The majority (86%) of studies involved high-income countries based in Europe, North America and Western Pacific. The mean cost per episode was €17 803.9 for inpatient management and €128.9 for outpatient management. Compared with costs reported for patients aged &amp;lt;65 years, inpatient costs were €154.1, €7 018.8 and €8 295.6 higher for patients aged 65-74 years, 75-84 years and over 85 years. ARI management of at-risk patients with comorbid conditions and patients requiring higher level of care, incurred substantially higher costs for hospitalization: €735.9 and €1317.3 respectively.

Conclusions

ARIs impose a substantial economic burden on health systems, governments, patients and societies. This study identified high ARI management costs in older adults, reinforcing calls for investment by global health players to quantify and address the scale of the challenge. There are large gaps in data availability from low-income countries, especially from South East Asia and Africa regions.

Access the article

08 November 2022

Roy P Zuurbier, Koos Korsten, Theo J M Verheij, Chris Butler, Niels Adriaenssens, Samuel Coenen, Olivier Gruselle, Valerie Vantomme, Marlies A van Houten, Louis J Bont, Joanne G Wildenbeest, REspiratory Syncytial Virus Consortium in EUrope (RESCEU) Investigators

Background

Respiratory syncytial virus (RSV) causes a substantial burden in older adults. Viral load in RSV-infected adults is generally lower compared to young children, which could result in suboptimal sensitivity of RSV diagnostics. Although the Xpert® Xpress Flu/RSV assay has been used in routine clinical care, its sensitivity to diagnose RSV infection in older adults is largely unknown. We aimed to compare the performance of the Xpert® Xpress Flu/RSV assay with real-time reverse-transcription polymerase chain reaction (RT-PCR) in home-dwelling older adults (≥60 years of age).

Methods

Nasopharyngeal swabs were tested with Xpert® Xpress Flu/RSV and compared to RSV RT-PCR in older adults with acute respiratory tract infections with different levels of disease severity.

Results

We studied 758 respiratory samples from 561 older adults from 2 consecutive RSV seasons. Thirty-five (4.6%) samples tested positive for RSV by at least 1 of the assays, of which 2 samples were negative by Xpert® Xpress Flu/RSV and 3 samples by real-time RT-PCR. The positive percentage agreement (PPA) was 90.9% (95% confidence interval [CI], 76.4%–96.8%) and negative percentage agreement was 99.7% (95% CI, 99.0%–99.9%). Viral loads were low (≤103 copies/mL or cycle threshold value ≥34) in all cases with discordant results for the 2 assays.

Conclusions

The PPA of Xpert® Xpress Flu/RSV compared to routine RT-PCR is high for RSV detection in home-dwelling older adults. The assay is fast and easy to use at the point of care.

Keywords: Respiratory syncytial virus, diagnosis, molecular, point-of-care test, older adults

04 February 2022

Maarten van Wijhe, Caroline Klint Johannesen, Lone Simonsen, Inger Merete Jørgensen, the RESCEU Investigators , Thea K Fische

Background

Infant respiratory syncytial virus infection (RSV) has been associated with asthma later in life. We explored the risk of recurrent wheeze or asthma in children with infant RSV-associated hospitalization compared to other respiratory infections.

Methods

We performed a retrospective cohort study using Danish national hospital discharge registers. Infants younger than 6 months, born between January 1995 and October 2018, and with a RSV hospital admission were compared to infants hospitalized for injuries, non-RSV acute upper respiratory tract infection (AURTI), pneumonia and other respiratory pathogens, nonpathogen-coded lower respiratory tract infections (LRTI), pertussis, or nonspecific respiratory infections. Infants were followed until recurrent wheeze or asthma diagnosis, death, migration, age 10 years, or study end. We estimated cumulative incidence rate ratios (CIRR) and hazard ratios (HR) adjusted for sex, age at inclusion, hospital length of stay (LOS), maternal smoking, 5-minute APGAR score (APGAR5), prematurity, and congenital risk factors (CRF).

Results

We included 68 130 infants, of whom 20 920 (30.7%) had RSV hospitalization. The cumulative incidence rate of recurrent wheeze or asthma was 16.6 per 1000 person-years after RSV hospitalization, higher than after injury (CIRR, 2.69; 95% confidence interval [CI], 2.48–2.92), AURTI (CIRR, 1.48; 95% CI, 1.34–1.58), or pertussis (CIRR, 2.32; 95% CI, 1.85–2.91), similar to pneumonia and other respiratory pathogens (CIRR, 1.15; 95% CI, .99–1.34) and LRTI (CIRR, 0.79; 95% CI, .60–1.04), but lower than nonspecific respiratory infections (CIRR, 0.79; 95% CI, .73–.87). Adjusted HRs for recurrent wheeze or asthma after RSV hospitalization compared to injuries decreased from 2.37 (95% CI, 2.08–2.70) for 0 to <1 year to 1.23 (95% CI, .88–1.73) for 6 to <10 years for term-born children, and from 1.48 (95% CI, 1.09–2.00) to 0.60 (95% CI, .25–1.43) for preterm-born children. Sex, maternal smoking, LOS, CRF, and APGAR5 were independent risk factors.

Conclusions

Infant RSV hospitalization is associated with recurrent wheeze and asthma hospitalization, predominantly at preschool age. If causal, RSV prophylaxis, including vaccines, may significantly reduce disease burden of wheeze and asthma.

Keywords: RSV, respiratory syncytial virus, asthma, recurrent wheeze, register study, retrospective cohort study, hospitalizations

Access the article

15 April 2022

Guy Berbers, Liesbeth Mollema, Fiona van der Klis, Gerco den Hartog, Rutger Schepp

Background

Respiratory syncytial virus (RSV) generally causes mild disease but can cause severe infections in (premature) infants and elderly adults. Here, we studied RSV-specific antibody concentrations throughout life with emphasis on infants and chronic obstructive pulmonary disease (COPD) patients.

Methods

Sera (N = 2655) from 2 nationwide cross-sectional studies in the Netherlands including individuals aged 0–90 years were analyzed for IgG and IgA antibodies to RSV prefusion F, postfusion F, N, Ga, and Gb proteins and for antibody avidity in 42 COPD patients.

Results

Maternal IgG concentrations declined to age 10–12 months. After the first year of life, approximately 40% of children lacked infection-induced IgA antibodies and may therefore be uninfected. All Dutch children showed serological evidence of RSV infection by age 3 years. Antibody concentrations reached a plateau by age 5–9 years and remains constant throughout life. COPD patients had similar levels and avidity of RSV-specific IgG antibodies compared with age-matched healthy controls.

Conclusions

RSV-IgG antibody patterns throughout life can be used to estimate the degree of immunity acquisition to RSV and to identify groups at increased risk of infection. Seroprevalence of IgA could be a proxy to determine RSV infection in children younger than 1 year.

Keywords: RSV, IgG, IgA, infection, infants, COPD, age

Access the article

15 July 2021

Michiel van Boven, Anne C Teirlinck, Adam Meijer, Mariëtte Hooiveld, Christiaan H van Dorp, Rachel M Reeves, Harry Campbell, Wim van der Hoek, RESCEU Investigators

Background

Respiratory syncytial virus (RSV) is a leading cause of respiratory tract illness in young children and a major cause of hospital admissions globally.

Methods

Here we fit age-structured transmission models with immunity propagation to data from the Netherlands (2012-2017). Data included nationwide hospitalizations with confirmed RSV, general practitioner (GP) data on attendance for care from acute respiratory infection, and virological testing of acute respiratory infections at the GP. The transmission models, equipped with key parameter estimates, were used to predict the impact of maternal and pediatric vaccination.

Results

Estimates of the basic reproduction number were generally high (R0 > 10 in scenarios with high statistical support), while susceptibility was estimated to be low in nonelderly adults (<10% in persons 20-64 years) and was higher in older adults (≥65 years). Scenario analyses predicted that maternal vaccination reduces the incidence of infection in vulnerable infants (<1 year) and shifts the age of first infection from infants to young children.

Conclusions

Pediatric vaccination is expected to reduce the incidence of infection in infants and young children (0-5 years), slightly increase incidence in 5 to 9-year-old children, and have minor indirect benefits.

Keywords

GP consultations; evidence synthesis; hospital data; respiratory syncytial virus; transmission model; vaccination.

Access the article

01 November 2020

Madelief Mollers, Céline Barnadas, Eeva K Broberg, Pasi Penttinen, European Influenza Surveillance Network, Anne C Teirlinck, Thea K Fischer

Background

Respiratory syncytial virus (RSV) is a major contributor to lower respiratory tract infections worldwide and several vaccine candidates are currently in development. Following vaccine introduction, reliable RSV surveillance shoul enable monitoring of vaccination impact. Data on the RSV disease burden in the European Union and European Economic Area (EU/EEA) are sparse.

Aim

The aim of this study was to gather knowledge on current practices of national RSV surveillance in the EU/EEA.

Methods

National Coordinators and National Focal Points for Influenza (epidemiologists and virologists) from the EU/EEA countries (n = 31) were invited to participate in an online survey in August and September 2017. The questionnaire covered questions on epidemiological and laboratory aspects of RSV surveillance.

Results

All EU/EEA countries except Liechtenstein replied to the survey. Eighteen countries reported to have a sentinel surveillance system, 26 countries a non-sentinel surveillance system and three countries to have neither. RSV data collection was mostly done within the context of influenza surveillance. A wide range of diagnostic and characterisation assays was used for the detection of RSV.

Discussion

The majority of EU/EEA countries have some surveillance for RSV in place. The prevailing integration of RSV surveillance into the existing influenza sentinel surveillance system may lead to under-reporting of RSV. The documented variations in existing RSV surveillance systems and their outputs indicate that there is scope for developing guidelines on establishing comparable methods and outcomes for RSV surveillance across the EU/EEA, to ensure the availability of a consistent evidence base for assessing future vaccination programmes.

Keywords

RSV surveillance; EU/EEA

Access the article

2019

Xin Wang, You Li, Ting Shi, Yiming Ma, Bhanu Wahi-Singh, Richard D Riley, Harish Nair

Existing guidelines on respiratory syncytial virus (RSV) prophylaxis differ greatly by gestational age (GA) and other underlying risk factors, highlighting the data gaps in RSV disease burden among preterm infants. We will conduct a systematic review and individual participant data (IPD) meta-analysis of RSV global disease burden among preterm-born children. Three databases, Medline, Embase, and Global Health, will be searched for relevant studies on RSV disease burden for 2019 or before in preterm-born children published between 1 January 1995 and 31 December 2021. IPD will be sought by contacting the investigators identified from published literature and from existing collaboration networks. One-stage and 2-stage random-effects meta-analyses will be used to combine information from IPD and non-IPD studies to produce summary RSV burden estimates of incidence rate, hospital admission rate, and in-hospital case fatality ratio. The framework will be extended to examine subgroup(s) with the most substantial RSV disease burden.

27 April 2022

van Wijhe M, Johannesen CK, Simonsen L, Jørgensen IM; RESCEU Investigators, Fischer TK

Background

Infant respiratory syncytial virus infection (RSV) has been associated with asthma later in life. We explored the risk of recurrent wheeze or asthma in children with infant RSV-associated hospitalization compared to other respiratory infections.

Methods

We performed a retrospective cohort study using Danish national hospital discharge registers. Infants younger than 6 months, born between January 1995 and October 2018, and with a RSV hospital admission were compared to infants hospitalized for injuries, non-RSV acute upper respiratory tract infection (AURTI), pneumonia and other respiratory pathogens, nonpathogen-coded lower respiratory tract infections (LRTI), pertussis, or nonspecific respiratory infections. Infants were followed until recurrent wheeze or asthma diagnosis, death, migration, age 10 years, or study end. We estimated cumulative incidence rate ratios (CIRR) and hazard ratios (HR) adjusted for sex, age at inclusion, hospital length of stay (LOS), maternal smoking, 5-minute APGAR score (APGAR5), prematurity, and congenital risk factors (CRF).

Results

We included 68 130 infants, of whom 20 920 (30.7%) had RSV hospitalization. The cumulative incidence rate of recurrent wheeze or asthma was 16.6 per 1000 person-years after RSV hospitalization, higher than after injury (CIRR, 2.69; 95% confidence interval [CI], 2.48–2.92), AURTI (CIRR, 1.48; 95% CI, 1.34–1.58), or pertussis (CIRR, 2.32; 95% CI, 1.85–2.91), similar to pneumonia and other respiratory pathogens (CIRR, 1.15; 95% CI, .99–1.34) and LRTI (CIRR, 0.79; 95% CI, .60–1.04), but lower than nonspecific respiratory infections (CIRR, 0.79; 95% CI, .73–.87). Adjusted HRs for recurrent wheeze or asthma after RSV hospitalization compared to injuries decreased from 2.37 (95% CI, 2.08–2.70) for 0 to <1 year to 1.23 (95% CI, .88–1.73) for 6 to <10 years for term-born children, and from 1.48 (95% CI, 1.09–2.00) to 0.60 (95% CI, .25–1.43) for preterm-born children. Sex, maternal smoking, LOS, CRF, and APGAR5 were independent risk factors.

Conclusions

Infant RSV hospitalization is associated with recurrent wheeze and asthma hospitalization, predominantly at preschool age. If causal, RSV prophylaxis, including vaccines, may significantly reduce disease burden of wheeze and asthma.

Keywords

RSV, respiratory syncytial virus, asthma, recurrent wheeze, register study, retrospective cohort study, hospitalizations

Access the article

15 April 2022

Li X, Bilcke J, Vázquez Fernández L, Bont L, Willem L, Wisløff T, Jit M, Beutels P; REspiratory Syncytial virus Consortium in EUrope (RESCEU) Investigators.

Background

Every winter, respiratory syncytial virus (RSV) disease results in thousands of cases in Norwegian children under 5 years of age. We aim to assess the RSV-related economic burden and the cost-effectiveness of upcoming RSV disease prevention strategies including year-round maternal immunization and year-round and seasonal monoclonal antibody (mAb) programs.

Methods

Epidemiological and cost data were obtained from Norwegian national registries, while quality-adjusted life-years (QALYs) lost and intervention characteristics were extracted from literature and phase 3 clinical trials. A static model was used and uncertainty was accounted for probabilistically. Value of information was used to assess decision uncertainty. Extensive scenario analyses were conducted, including accounting for long-term consequences of RSV disease.

Results

We estimate an annual average of 13 517 RSV cases and 1572 hospitalizations in children under 5, resulting in 79.6 million Norwegian kroner (~€8 million) treatment costs. At €51 per dose for all programs, a 4-month mAb program for neonates born in November to February is the cost-effective strategy for willingness to pay (WTP) values up to €40 000 per QALY gained. For higher WTP values, the longer 6-month mAb program that immunizes neonates from October to March becomes cost-effective. Sensitivity analyses show that year-round maternal immunization can become a cost-effective strategy if priced lower than mAb.

Conclusions

Assuming the same pricing, seasonal mAb programs are cost-effective over year-round programs in Norway. The timing and duration of the cost-effective seasonal program are sensitive to the pattern of the RSV season in a country, so continued RSV surveillance data are essential.

Keywords

cost-utility analysis; disease burden; expected value of perfect information; maternal immunization; monoclonal antibody; respiratory syncytial virus; seasonal program; vaccines.

Access the article

16 March 2022

McGinley JP, Lin GL, Öner D, Golubchik T, O’Connor D, Snape MD, Gruselle O, Langedijk AC, Wildenbeest J, Openshaw P, Nair H, Aerssens J, Bont L, Martinón-Torres F, Drysdale SB, Pollard AJ; RESCEU Investigators

Abstract

Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in infants and young children worldwide. Here we evaluated host demographic and viral factors associated with RSV disease severity in 325 RSV-infected infants under 1 year of age from 3 European countries during 2017-2020. Younger infants had a higher clinical severity (ReSViNET) score and were more likely to require hospitalization, intensive care, respiratory support, and/or mechanical ventilation than older infants (<3 months vs 3 to <6 months and 3 to <6 months vs ≥6 months). Older age (≥6 months vs <3 months), higher viral load, and RSV-A were associated with a greater probability of fever. RSV-A and RSV-B caused similar disease severity and had similar viral dynamics. Infants with a more severe RSV infection, demonstrated by having a higher ReSViNET score, fever, and requiring hospitalization and intensive care, were more likely to have developed subsequent wheezing at 1 year of age.

Clinical trials registration

NCT03756766.

Keywords

disease severity; respiratory syncytial virus; subgroup; viral load; wheezing.

Access the article

28 July 2022

Billard MN, Wildenbeest J, Bont LJ, Nair H, McCracken JP, Oude Rengerink K; RESCEU Investigators

Objectives

Year-to-year variation in respiratory viruses may result in lower attack rates than expected. We aimed to illustrate the impact of year-to-year variation in attack rates on the likelihood of demonstrating vaccine efficacy (VE).

Study design and setting

We considered an individually randomized maternal vaccine trial against respiratory syncytial virus (RSV)-associated hospitalizations. For 10 RSV-associated hospitalizations per 1,000 infants, sample size to have 80% power for true VE of 50% and 70% was 9,846 and 4,424 participants. We reported power to show VE for varying attack rates, selected to reflect realistic year-to-year variation using observational studies. Eight scenarios including varying number of countries and seasons were developed to assess the influence of these trial parameters.

Results

Including up to three seasons decreased the width of the interquartile range for power. Including more seasons concentrated statistical power closer to 80%. Least powered trials had higher statistical power with more seasons. In all scenarios, at least half of the trials had <80% power. For three-season trials, increasing the sample size by 10% reduced the percentage of underpowered trials to less than one-quarter of trials.

Conclusion

Year-to-year variation in RSV attack rates should be accounted for during trial design. Mitigation strategies include recruiting over more seasons, or adaptive trial designs.

Keywords

Attack rate; Incidence; RSV; Sample size; Seasonality; Statistical power.

Access the article

26 February 2022

Johannesen CK, van Wijhe M, Tong S, Fernández LV, Heikkinen T, van Boven M, Wang X, Bøås H, Li Y, Campbell H, Paget J, Stona L, Teirlinck A, Lehtonen T, Nohynek H, Bangert M, Fischer TK; RESCEU Investigators.

Background

Knowledge on age-specific hospitalizations associated with RSV infection is limited due to limited testing, especially in older children and adults in whom RSV infections are not expected to be severe. Burden estimates based on RSV coding of hospital admissions are known to underestimate the burden of RSV. We aimed to provide robust and reliable age-specific burden estimates of RSV-associated hospital admissions based on data on respiratory infections from national health registers and laboratory-confirmed cases of RSV.

Methods

We conducted multiseason regression analysis of weekly hospitalizations with respiratory infection and weekly laboratory-confirmed cases of RSV and influenza as covariates, based on national health registers and laboratory databases across 6 European countries. The burden of RSV-associated hospitalizations was estimated by age group, clinical diagnosis, and presence of underlying medical conditions.

Results

Across the 6 European countries, hospitalizations of children with respiratory infections were clearly associated with RSV, with associated proportions ranging from 28% to 60% in children younger than 3 months and we found substantial proportions of admissions to hospital with respiratory infections associated with RSV in children younger than 3 years. Associated proportions were highest among hospitalizations with ICD-10 codes of “bronchitis and bronchiolitis.” In all 6 countries, annual incidence of RSV-associated hospitalizations was >40 per 1000 persons in the age group 0-2 months. In age group 1-2 years the incidence rate ranged from 1.3 to 10.5 hospitalizations per 1000. Adults older than 85 years had hospitalizations with respiratory infection associated to RSV in all 6 countries although incidence rates were low.

Conclusions

Our findings highlight the substantial proportion of RSV infections among hospital admissions across different ages and may help public health professionals and policy makers when planning prevention and control strategies. In addition, our findings provide valuable insights for health care professionals attending to both children and adults presenting with symptoms of viral respiratory infections.

Keywords

RSV; burden of disease; public health; respiratory syncytial virus; time series analysis; viral hospitalizations.

24 June 2022

Reeves RM, van Wijhe M, Lehtonen T, Stona L, Teirlinck AC, Vazquez Fernandez L, Li Y, Osei-Yeboah R, Fischer TK, Heikkinen T, van Boven M, Bøås H, Donà D, Barbieri E, Campbell H; RESCEU Investigators.

Background

Since the widespread adoption of palivizumab prophylaxis in Europe, there have been a number of clinical practice guidelines (CPGs) published for the prevention of respiratory syncytial virus (RSV) infection in children. The aim of this systematic review was to identify CPGs for the prevention of RSV infection across Europe.

Methods

We performed a systematic literature search and contacted European influenza and respiratory virus networks and public health institutions, to identify national CPGs for the prevention of RSV infection. The Reporting Items for practice Guidelines in Healthcare (RIGHT) Statement checklist was applied to extract data and review the quality of reporting.

Results

A total of 20 national CPGs were identified, all published between 2000 and 2018. The greatest discrepancy between guidelines was the recommendations for palivizumab prophylaxis for premature infants, with recommendations varying by gestational age. All guidelines recommended or considered the use of palivizumab in infants with bronchopulmonary dysplasia, 85% (n = 17) in children with congenital heart disease (CHD), and 60% (n = 12) in children with severe combined immunodeficiency.

Conclusions

We recommend that agencies publishing RSV prevention guidelines adopt the RIGHT reporting requirements when updating these guidelines to improve the presentation of the evidence-base for decisions.

Keywords

RSV guidelines Europe; palivizumab; prophylaxis.

Access the article 

25 March 2022

Mao Z, Li X, Korsten K, Bont L, Butler C, Wildenbeest J, Coenen S, Hens N, Bilcke J, Beutels P; RESCEU Investigators.

Background

Respiratory syncytial virus (RSV) and influenza virus infections result in a considerable mortality and morbidity among the aging population globally. Influenza vaccination for older adults before the seasonal influenza epidemic has been evaluated to be cost-effective in many countries. Interventions against RSV in older adults are in the pipeline, and evaluating their cost-effectiveness is crucial for decision making. To inform such evaluations, our aim was to estimate average costs and health-related quality of life (HRQoL) in older adults with RSV and influenza infection.

Methods

The European RESCEU observational cohort study followed 1040 relatively healthy community-dwelling older adults aged 60 years and older during 2 consecutive winter seasons. Health care resource use and HRQoL were collected and analyzed during RSV episodes, and also during influenza episodes. Country-specific unit cost data were mainly obtained from national databases. Direct costs were estimated from a patient, health care provider, and health care payers’ perspective, whereas indirect costs were estimated from a societal perspective. Due to small sample size, no formal statistical comparisons were made.

Results

Thirty-six RSV and 60 influenza episodes were reported, including 1 hospitalization. Means (median; first-third quartile) of €26.4 (€5.5; 0-47.3) direct and €4.4 (€0; 0-0) indirect costs were reported per nonhospitalized RSV episode, and €42.5 (€36; 3.3-66.7) direct and €32.1 (€0; 0-0) indirect costs per nonhospitalized influenza episode. For RSV episodes, the utility value decreased from 0.896 (0.928; 0.854-0.953) to 0.801 (0.854; 0.712-0.937) from preseason to 1 week after symptom onset; for influenza, the change was from 0.872 (0.895; 0.828-0.953) to 0.664 (0.686; 0.574-0.797).

Conclusions

The average costs and HRQoL estimates of older adults treated outside the hospital can be used to inform the design of future studies and the decision making regarding interventions to prevent RSV infection in older adults. Larger studies are needed to provide better country-specific and complementary cost estimates and to allow for formal statistical comparison of costs between RSV and influenza.

Clinical trials registration

NCT03621930.

Keywords

EQ5D; RSV; cost; elderly; flu; health-related quality of life; influenza; outpatients; productivity loss; prospective study.

Access the article

12 August 2022

You Li, Xin Wang, Diana M. Blau, Mauricio T. Caballero, Daniel R. Feikin, Cristopher J. Gill, Shabir A Madhi, Saad B. Omer, Eric A. F. Simoes, et al

Image

Abstract

Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory infection in young children. We previously estimated that in 2015, 33·1 million episodes of RSV-associated acute lower respiratory infection occurred in children aged 0–60 months, resulting in a total of 118 200 deaths worldwide. Since then, several community surveillance studies have been done to obtain a more precise estimation of RSV associated community deaths. We aimed to update RSV-associated acute lower respiratory infection morbidity and mortality at global, regional, and national levels in children aged 0–60 months for 2019, with focus on overall mortality and narrower infant age groups that are targeted by RSV prophylactics in development. RSV contributes substantially to morbidity and mortality burden globally in children aged 0–60 months, especially during the first 6 months of life and in LMICs. We highlight the striking overall mortality burden of RSV disease worldwide, with one in every 50 deaths in children aged 0–60 months and one in every 28 deaths in children aged 28 days to 6 months attributable to RSV. For every RSV-associated acute lower respiratory infection in-hospital death, we estimate approximately three more deaths attributable to RSV in the community. RSV passive immunisation programmes targeting protection during the first 6 months of life could have a substantial effect on reducing RSV disease burden, although more data are needed to understand the implications of the potential age-shifts in peak RSV burden to older age when these are implemented.

Keywords

RSV, disease burden, ALRI, low-income countries, middle-income countries, LMICs

Access the article

19 May 2022

Nicole D Derksen-Lazet, Corline E J Parmentier, Joanne G Wildenbeest, Louis J Bont, RESCEU Investigators

Abstract

Respiratory syncytial virus (RSV) causes a substantial disease burden among children, elderly and immunocompromised adults. Recognition of patient involvement in research is gradually increasing. Most research is being carried out without active patient involvement other than patients participating as study subjects, and most knowledge gained through research only partially reaches the general public. Since 2016, the RSV Patient Advisory Board has officially been involved as an advisory group in the Respiratory Syncytial Virus Consortium in Europe (RESCEU). What started as a small single-center initiative, is now growing towards an international organization providing patient perspectives as inputs to scientists, and improving awareness of RSV. This article summarizes the history, current role, and future aims of the RSV Patient Advisory Board as an advocate to improve patient involvement in research. RSV patients and their representatives are important stakeholders in setting the global research agenda, and educating patients, professionals, and the general public.

Keywords

patient involvement, awareness, patient network, patient perspective, patient participation.

Access the article

2022

Thomas C Williams, Mark D Lyttle, Steve Cunningham, Ian Sinha, Olivia V Swann, Abigail Maxwell-Hodkinson, Robin Marlow, Damian Roland, Paediatric Emergency Research in the UK and Ireland (PERUKI)

Background

Bronchiolitis (most frequently caused by respiratory syncytial virus; RSV) is a common winter disease predominantly affecting children under one year of age. It is a common reason for presentations to an emergency department (ED) and frequently results in hospital admission, contributing to paediatric units approaching or exceeding capacity each winter. During the SARS-CoV-2 pandemic, the circulation of RSV was dramatically reduced in the United Kingdom and Ireland. Evidence from the Southern Hemisphere and other European countries suggests that as social distancing restrictions for SARS-CoV-2 are relaxed, RSV infection returns, causing delayed or even summer epidemics, with different age distributions. 

Study question

The ability to track, anticipate and respond to a surge in RSV cases is critical for planning acute care delivery. There is an urgent need to understand the onset of RSV spread at the earliest opportunity. This will influence service planning, to inform clinicians whether the population at risk is a wider age range than normal, and whether there are changes in disease severity. This information is also needed to inform decision on the timing of passive immunisation of children at higher risk of hospitalisation, intensive care admission or death with RSV infection, which is a public health priority. 

Methods and likely impact

This multi-centre prospective observational cohort study will use a well-established research network (Paediatric Emergency Research in the UK and Ireland, PERUKI) to report in real time cases of RSV infection in children aged under two years, through the collection of essential, but non-identifying patient information. Forty-five centres will gather initial data on age, index of multiple deprivation quintile, clinical features on presentation, and co-morbidities. Each case will be followed up at seven days to identify treatment, viral diagnosis and outcome. Information be released on a weekly basis and used to support clinical decision making.

Keywords

Bronchiolitis; COVID-19; Children; Infants; Palivizumab; Respiratory Syncytial Virus.

Access the article

21 January 2022

Wang X, Li Y, Vazquez Fernandez L, Teirlinck AC, Lehtonen T, van Wijhe M, Stona L, Bangert M, Reeves RM, Bøås H, van Boven M, Heikkinen T, Klint Johannesen C, Baraldi E, Donà D, Tong S, Campbell H

Background

Respiratory syncytial virus (RSV) is a leading cause of respiratory tract infections (RTIs) in young children. High-quality country-specific estimates of bed days and length of stay (LOS) show the population burden of RSV-RTI on secondary care services and the burden among patients, and can be used to inform RSV immunization implementation decisions.

Methods

We estimated the hospital burden of RSV-associated RTI (RSV-RTI) in children under 5 years in 7 European countries (Finland, Denmark, Norway, Scotland, England, the Netherlands, and Italy) using routinely collected hospital databases during 2001-2018. We described RSV-RTI admission rates during the first year of life by birth month and assessed their correlation with RSV seasonality in 5 of the countries (except for England and Italy). We estimated average annual numbers and rates of bed days for RSV-RTI and other-pathogen RTI, as well as the hospital LOS.

Results

We found that infants born 2 months before the peak month of RSV epidemics more frequently had the highest RSV-RTI hospital admission rate. RSV-RTI hospital episodes accounted for 9.9-21.2 bed days per 1000 children aged <5 years annually, with the median (interquartile range) LOS ranging from 2 days (0.5-4 days) to 4 days (2-6 days) between countries. Between 70% and 89% of these bed days were in infants aged <1 year, representing 40.3 (95% confidence interval [CI], 40.1-40.4) to 91.2 (95% CI, 90.6-91.8) bed days per 1000 infants annually. The number of bed days for RSV-RTI was higher than that for RTIs associated with other pathogens in infants aged <1 year, especially in those <6 months.

Conclusions

RSV disease prevention therapies (monoclonal antibodies and maternal vaccines) for infants could help prevent a substantial number of bed days due to RSV-RTI. “High-risk” birth months should be considered when developing RSV immunization schedules. Variation in LOS between countries might reflect differences in hospital care practices.

Keywords

Europe; bed days; birth month; hospital admission; respiratory syncytial virus.

Access the article

12 Jan 2022

Koos Korsten, Niels Adriaenssens, Samuel Coenen, Chris C Butler, Jean-Yves Pirçon, Theo J M Verheij, Louis J Bont, Joanne G Wildenbeest, RESCEU Investigators

Background

Knowledge about how older adults get a respiratory infection is crucial for planning preventive strategies. We aimed to determine how contact with young children living outside of the household affects the risk of acute respiratory tract infections (ARTI) in community-dwelling older adults.

Methods

This study is part of the European RESCEU older adult study. Weekly surveillance was performed to detect ARTI throughout 2 winter seasons (2017-2018, 2018-2019). Child exposure, defined as having regular contact with children under 5 living outside of the subject’s household, was assessed at baseline. The average attributable fraction was calculated to determine the fraction of ARTI explained by exposure to these children.

Results

We prospectively established that 597/1006 (59%) participants experienced at least 1 ARTI. Child exposure increased the risk of all-cause ARTI (adjusted odds ratio [aOR], 1.58; 95% confidence interval [CI], 1.21 -2.08; P = .001). This risk was highest in those with the most frequent contact (aOR, 1.80; 95% CI, 1.23-2.63; P = .003). The average attributable fraction of child exposure explaining ARTI was 10% (95% CI, 5%-15%).

Conclusions

One of 10 ARTI in community-dwelling older adults is attributable to exposure to preschool children living outside of the household.

Clinical trials registration

NCT03621930.

Keywords

child exposure; community; elderly; respiratory infection.#

Access the article

15 December 2021

Koos Korsten, Niels Adriaenssens, Samuel Coenen, Chris C Butler, Theo J M Verheij, Louis J Bont, Joanne G Wildenbeest, RESCEU Investigators

Background

Respiratory syncytial virus (RSV) surveillance is heavily dependent on the influenza-like illness (ILI) case definition from the World Health Organization (WHO). Because ILI includes fever in its syndromic case definition, its ability to accurately identify acute respiratory tract infections (ARTI) caused by RSV in older adults is uncertain.

Methods

The accuracy of the WHO ILI and a modified ILI (requiring only self-reported fever) case definitions in identifying patients with PCR-confirmed RSV-ARTI was evaluated in community-dwelling older adults (≥60 years) from the prospective European RESCEU cohort study.

Results

Among 1040 participants, 750 ARTI episodes were analyzed including 36 confirmed RSV-ARTI. Due to a general lack of fever, sensitivity for RSV-ARTI was 33% for modified ILI and 11% for ILI. The area under the curve for both ILI definitions was 0.52 indicating poor discrimination for RSV. RSV-ARTI could not be distinguished from all other ARTI based on clinical symptoms.

Conclusions

The use of ILI underestimated the occurrence of RSV-ARTI in community-dwelling older adults up to 9-fold (11% sensitivity). Because worldwide RSV surveillance depends largely on ILI, there is an urgent need for a better approach to measure the occurrence of RSV disease and the impact of future RSV vaccine introduction. Clinical Trials Registration. NCT03621930.

Keywords

ILI; RESCEU; RSV; case definition; older adults; respiratory syncytial virus.

Access the article

14 December 2021

Teirlinck AC, Broberg EK, Stuwitz Berg A, Campbell H, Reeves RM, Carnahan A, et al.

Respiratory syncytial virus (RSV) is a common cause of acute lower respiratory tract infections and hospitalisations among young children and is globally responsible for many deaths in young children, especially in infants aged <6 months. Furthermore, RSV is a common cause of severe respiratory disease and hospitalisation among older adults. The development of new candidate vaccines and monoclonal antibodies highlights the need for reliable surveillance of RSV. In the European Union (EU), no up-to-date general recommendations on RSV surveillance are currently available. Based on outcomes of a workshop with 29 European experts in the field of RSV virology, epidemiology and public health, we provide recommendations for developing a feasible and sustainable national surveillance strategy for RSV that will enable harmonisation and data comparison at the European level. We discuss three surveillance components: active sentinel community surveillance, active sentinel hospital surveillance and passive laboratory surveillance, using the EU acute respiratory infection and World Health Organization (WHO) extended severe acute respiratory infection case definitions. Furthermore, we recommend the use of quantitative reverse transcriptase PCR-based assays as the standard detection method for RSV and virus genetic characterisation, if possible, to monitor genetic evolution. These guidelines provide a basis for good quality, feasible and affordable surveillance of RSV. Harmonisation of surveillance standards at the European and global level will contribute to the wider availability of national level RSV surveillance data for regional and global analysis, and for estimation of RSV burden and the impact of future immunisation programmes.

Access the article

01 October 2021

Joseph McGinley, Ryan Thwaites, Will Brebner, Lewis Greenan-Barrett, Jeroen Aerssens, Deniz Öner, Louis Bont, Joanne Wildenbeest, Federico Martinón-Torres, Harish Nair, Andrew J Pollard, Peter Openshaw, Simon Drysdale, RESCEU Investigators

Background

Respiratory syncytial virus (RSV) infections occur in human populations around the globe, causing disease of variable severity, disproportionately affecting infants and older adults (>65 years of age). Immune responses can be protective but also contribute to disease. Experimental studies in animals enable detailed investigation of immune responses, provide insights into clinical questions, and accelerate the development of passive and active vaccination. We aimed to review the role of antibody and T-cell responses in relation to RSV disease severity in animals.

Methods

Systematic review and meta-analysis of animal studies examining the association between T-cell responses/phenotype or antibody titers and severity of RSV disease. The PubMed, Zoological Record, and Embase databases were screened from January 1980 to May 2018 to identify animal studies of RSV infection that assessed serum antibody titer or T lymphocytes with disease severity as an outcome. Sixty-three studies were included in the final review.

Results

RSV-specific antibody appears to protect from disease in mice, but such an effect was less evident in bovine RSV. Strong T-cell, Th1, Th2, Th17, CD4/CD8 responses, and weak Treg responses accompany severe disease in mice.

Conclusions

Murine studies suggest that measures of T-lymphocyte activity (particularly CD4 and CD8 T cells) may be predictive biomarkers of severity. Further inquiry is merited to validate these results and assess relevance as biomarkers for human disease.

Keywords

RSV; RSV antibody; T lymphocyte; animal model; disease severity; meta-analysis; systematic review.

Access the article

15 September 2021

Wang X, Li Y, Nair H, Campbell H; RESCEU Investigators

Background

Early-life severe respiratory syncytial virus (RSV) infection has been associated with subsequent risk of asthma and recurrent wheeze. However, changes in the association over time and the interaction effect of the age at first RSV infection are less well understood. We aimed to assess the time-varying association between RSV and subsequent asthma and wheeze admission and explore how the association was affected by the age at RSV infection.

Methods

We retrospectively followed up a cohort of 23 365 children for a median of 6.9 years using Scottish health databases. Children who were born between 2001 and 2013 and had RSV-associated respiratory tract infection (RTI) admissions under 2 years were in the exposed group; those with unintentional accident admissions under 2 years comprised the control group. The Cox proportional-hazards model was used to report adjusted hazard ratios (HRs) of RSV admissions on subsequent asthma and wheeze admissions. We did subgroup analyses by follow-up years. We also explored how this association was affected by the age at first RSV admission.

Results

The association was strongest in the first 2 years of follow-up and decreased over time. The association persisted for 6 years in children whose first RSV-RTI admission occurred at 6-23 months of age, with an adjusted HR of 3.9 (95% confidence interval [CI], 3.1-4.9) for the first 2 years, 2.3 (95% CI, 1.6-3.2) for 2 to <4 years, and 1.9 (95% CI, 1.2-2.9) for 4 to <6 years of follow-up. In contrast, the association was only significant for the first 2 years after first RSV-RTI admissions occurring at 0-5 months.

Conclusions

We found a more persistent association for subsequent asthma and wheeze in children whose first severe RSV infection occurred at 6-23 months compared to those whose first severe RSV infection occurred at 0-6 months. This provides new evidence for further assessment of the association and RSV intervention programs.

Keywords

age at first RSV infection; asthma; severe RSV infections; time since RSV infection; wheeze.

Access the article

15 September 2021

Shi T, Vennard S, Jasiewicz F, Brogden R, Nair H; RESCEU Investigators

Background

Respiratory syncytial virus related acute respiratory infection (RSV-ARI) constitutes a substantial disease burden in adults with comorbidities. We aimed to identify all studies investigating the disease burden of RSV-ARI in this group.

Methods

We estimated the incidence, hospitalization rate, and in-hospital case fatality ratio (hCFR) of RSV-ARI in adults with comorbidities based on a systematic review of studies published between January 1996 and March 2020. We also investigated the association between RSV-ARI and any comorbidity in adults. Meta-analyses based on random effects model were carried out.

Results

Overall, 20 studies were included. The annual incidence rate of RSV-ARI in adults with any comorbidity was 37.6 (95% confidence interval [CI], 20.1-70.3) per 1000 persons per year in industrialized countries and the seasonal incidence rate was 28.4 (11.4-70.9) per 1000 persons per season. The hCFR in industrialized countries was 11.7% (5.8%-23.4%). There were no studies in developing countries. There were insufficient data to generate the meta-estimate of hospitalization rate. The likelihood of experiencing RSV-ARI for those with any comorbidity compared to those without was estimated to be 4.1 (odds ratio [OR], 1.6-10.4) and 1.1 (OR, 0.6-1.8) from studies using univariable and multivariable analysis respectively.

Conclusion

The disease burden of RSV-ARI among adults with comorbidity is substantial with limited data available.

Keywords

acute respiratory infection; adults; comorbidity; respiratory syncytial virus.

Access the article

15 September 2021

Gu-Lung Lin, Simon B Drysdale, Matthew D Snape, Daniel O’Connor, Anthony Brown, George MacIntyre-Cockett, Esther Mellado-Gomez, Mariateresa de Cesare, David Bonsall, M Azim Ansari, Deniz Öner, Jeroen Aerssens, Christopher Butler, Louis Bont, Peter Openshaw, Federico Martinón-Torres, Harish Nair, Rory Bowden, RESCEU Investigators; Tanya Golubchik, Andrew J Pollard

Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection in young children globally, but little is known about within-host RSV diversity. Here, we characterised within-host RSV populations using deep-sequencing data from 319 nasopharyngeal swabs collected during 2017-2020. RSV-B had lower consensus diversity than RSV-A at the population level, while exhibiting greater within-host diversity. Two RSV-B consensus sequences had an amino acid alteration (K68N) in the fusion (F) protein, which has been associated with reduced susceptibility to nirsevimab (MEDI8897), a novel RSV monoclonal antibody under development. In addition, several minor variants were identified in the antigenic sites of the F protein, one of which may confer resistance to palivizumab, the only licensed RSV monoclonal antibody. The differences in within-host virus populations emphasise the importance of monitoring for vaccine efficacy and may help to explain the different prevalences of monoclonal antibody-escape mutants between the two subgroups.

Access the article

26 August 2021

Rosalie S Linssen, Anne C Teirlinck, Michiel van Boven, Dominique Biarent, Luca Stona, Angela Amigoni, Rosanna I Comoretto, Stephane Leteurtre, Amélie Bruandet, Gunnar K Bentsen, Inger Marie Drage, Xin Wang, Harry Campbell, Job B M van Woensel, Louis Bont, Reinout A Bem

Purpose

Viral bronchiolitis is a major cause of pediatric intensive care unit (PICU) admission. Insight in the trends of bronchiolitis-associated PICU admissions is limited, but imperative for future PICU resource and capacity planning.

Materials and methods

We retrospectively studied trends in PICU admissions for bronchiolitis in six European sites, including three full national registries, between 2000 and 2019 and calculated population-based estimates per 100,000 children where appropriate. Information concerning risk factors for severe disease and use of invasive mechanical ventilation was also collected when available.

Results

In total, there were 15,606 PICU admissions for bronchiolitis. We observed an increase in the annual number, rate and estimates per 100,000 children of PICU admissions for bronchiolitis at all sites over the last two decades, while the proportion of patients at high risk for severe disease remained relatively stable.

Conclusions

The international increased burden of bronchiolitis for the PICU is concerning, and warrants further international attention and investigation.

Keywords

Bronchiolitis; Critical care; Pediatrics.

Access the article

22 July 2021

Rosalie S Linssen, Reinout A Bem, Berber Kapitein, Katrien Oude Rengerink, Marieke H Otten, Bibiche den Hollander, Louis Bont, Job B M van Woensel

Abstract

Respiratory syncytial virus (RSV) bronchiolitis causes substantial morbidity and mortality in young children, but insight into the burden of RSV bronchiolitis on pediatric intensive care units (PICUs) is limited. We aimed to determine the burden of RSV bronchiolitis on the PICUs in the Netherlands. Therefore, we identified all children ≤ 24 months of age with RSV bronchiolitis between 2003 and 2016 from a nationwide PICU registry. Subsequently we manually checked their patient records for correct diagnosis and collected patient characteristics, additional clinical data, respiratory support modes, and outcome. In total, 2161 children were admitted to the PICU for RSV bronchiolitis. The annual number of admissions increased significantly during the study period (β 4.05, SE 1.27, p = 0.01), and this increase was mostly driven by increased admissions in children up to 3 months old. Concomitantly, non-invasive respiratory support significantly increased (β 7.71, SE 0.92, p < 0.01), in particular the use of high flow nasal cannula (HFNC) (β 6.69, SE 0.96, p < 0.01), whereas the use of invasive ventilation remained stable.Conclusion: The burden of severe RSV bronchiolitis on PICUs has increased in the Netherlands. Concomitantly, the use of non-invasive respiratory support, especially HFNC, has increased. What is Known: • RSV bronchiolitis is a major cause of childhood morbidity and mortality and may require pediatric intensive care unit admission. • The field of pediatric critical care for severe bronchiolitis has changed due to increased non-invasive respiratory support options. What is New: • The burden of RSV bronchiolitis for the Dutch PICUs has increased. These data inform future strategic PICU resource planning and implementation of RSV preventive strategies. • There was a significant increase in the use of high flow nasal cannula at the PICU, but the use of invasive mechanical ventilation did not decrease.

Keywords

Airway management; Bronchiolitis; Child; High flow nasal cannula; Non-invasive ventilation; Respiratory syncytial viruses; Vaccination.

Access the article

23 April 2021

Korsten K, Adriaenssens N, Coenen S, Butler C, Ravanfar B, Rutter H, Allen J, Falsey A, Pirçon JY, Gruselle O, Pavot V, Vernhes C, Balla-Jhagjhoorsingh S, Öner D, Ispas G, Aerssens J, Shinde V, Verheij T, Bont L, Wildenbeest J; RESCEU investigators 

Background

Respiratory syncytial virus (RSV) infection in older adults is recognised as an important health issue. We aimed to assess the community burden of RSV in Europe in older adults aged ≥60 years.

Methods

This international, prospective, observational cohort study is part of work by the REspiratory Syncytial virus Consortium in EUrope (RESCEU). Participants were recruited through general practitioners’ (GPs) offices before two independent RSV seasons. Participants reported weekly about symptoms of acute respiratory tract infection (ARTI) during one RSV season. ARTI patients were tested for RSV during home visits and completed a daily symptom diary. RSV illness included PCR-confirmed ARTI and those showing seroconversion over the season. RSV ARTI was based on PCR alone (ClinicalTrials.gov, NCT03621930).

Results

We recruited 1040 participants (527 in season 2017–2018 and 513 in season 2018–2019) with a median age of 75 years (range 60–100 years). Of these, 1023 (99%) lived independently at home at baseline. RSV illness incidence was 22 out of 527 (4.2%) and 37 out of 513 (7.2%) in the respective seasons. RSV illness did not affect frailty or cardiopulmonary status during the course of the study. No patients were hospitalised or died from RSV illness. In the 36 patients with PCR confirmed RSV ARTI, symptom duration averaged 19 days, while a doctor’s visit took place in 11 out of 36 cases (31%). RSV ARTI could not be differentiated clinically from all other ARTIs based on symptoms.

Conclusion

This European study showed that RSV is prevalent in community-dwelling older adults and rarely causes severe disease. This suggests that watchful waiting, using a continuity of care approach to identify those who do need more intensive care, is often justified when RSV is suspected in family practice.

Access the article 

01 April 2021

F Zeevat, J Luttjeboer, J H J Paulissen, J van der Schans, P Beutels, C Boersma, M J Postma, RESCEU Investigators

Background

In older adults, the burden of respiratory syncytial virus (RSV) resembles that of influenza and may even be considered worse due to the lack of preventive interventions. This study was performed to identify the available literature on RSV infection in older adults, and to provide updated exploratory results of the cost-effectiveness of a hypothetical RSV vaccine in the Netherlands and the United Kingdom.

Methods

A literature search was performed in Medline and EMBASE on 11 November 2019, which served as input for a static decision-tree model that was used to estimate the EJP, for an RSV vaccine applying different willingness-to-pay (WTP) thresholds. WTP thresholds applied were €20 000 and €50 000 per quality-adjusted life-year for the Netherlands, and £20 000 and £30 000 per quality-adjusted life-year for the United Kingdom. Analyses were-in line with country-specific guidelines-conducted from a societal perspective for the Netherlands and a third-party payer perspective for the United Kingdom. The robustness of the cost-effectiveness results was tested in sensitivity analysis.

Results

After screening the literature, 3 studies for the Netherlands and 6 for the United Kingdom remained to populate the country-specific models. In the base case analysis for the Netherlands (mean RSV incidence, 3.32%), justifiable vaccine prices of €16.38 and €50.03 were found, based on applying the lower and higher WTP thresholds, respectively. Similarly, for the United Kingdom (mean incidence, 7.13%), vaccine prices of £72.29 and £109.74 were found, respectively.

Conclusion

RSV vaccination may well be cost-effective in both the Netherlands and the United Kingdom, depending on the exact RSV incidence, vaccine effectiveness and price. However, sensitivity analysis showed that the results were robust based on varying the different parameter estimates and assumptions. With RSV vaccines reaching the final stages of development, a strong need exists for cost-effectiveness studies to understand economically justifiable pricing of the vaccine.

Keywords

Cost-effectiveness; Elderly; Older adults; Respiratory Syncytial Virus; The Netherlands; United Kingdom.

Access the Article

01 April 2021

Ting Shi, Sophie Vennard, Sara Mahdy, Harish Nair

Respiratory syncytial virus associated acute lower respiratory infection (RSV-ALRI) constitutes a substantial disease burden in young children. We aimed to identify all studies investigating the risk factors of RSV-ALRI poor outcome or mortality in young children.We carried out a systematic literature review across 7 databases with data from studies published from January 1995 to December 2019. We defined poor outcome as need for prolonged hospital stay, oxygen supplementation, mechanical ventilation or intensive care unit (ICU) admission. Quality of all eligible studies was assessed according to modified GRADE criteria. We conducted meta-analyses to estimate odds ratio (OR) with 95% confidence intervals (CI) for individual risk factors. We identified 27 eligible studies, which investigated 20 risk factors for RSV-ALRI poor outcome and/or mortality in children younger than 5 years old, in comparison to those with RSV-ALRI who did not have poor outcome or mortality. Among those risk factors, 6 had statistically significant associations with RSV-ALRI poor outcome: any comorbidity (OR 2.69 (95% CI 1.89-3.83)), congenital heart disease (3.40 (95% CI 2.14-5.40)), prematurity with gestational age (GA) <37 weeks (1.75 (95% CI 1.31-2.36)), prematurity with GA ≤32 weeks (2.68 (95% CI 1.43-5.04)), age <3 months (4.91 (95% CI 1.64-14.71)), age <6 months (2.02 (95% CI 1.73-2.35)). Apart from age <3 months, the meta-estimate ORs for all other risk factors were based on studies using multivariable analysis. For mortality, only prematurity with GA <37 weeks had a significant meta-estimate of OR 3.81 (95% CI 1.68-8.63) based on univariable analysis.This study represents a comprehensive report of the association between various risk factors and RSV-ALRI poor outcome and mortality in young children. More research should be carried out to elucidate risk factors associated with poor outcome and mortality using multivariable analysis.

Access the article

12 February 2021

Rutger M. Schepp, Cornelis A. M. de Haan, Deidre Wilkins, Hans Layman, Barney S. Graham, Mark T. Esser, Guy A. M. Berbers

Abstract

Human respiratory syncytial virus (RSV) is a major cause of severe respiratory disease in (premature) newborns and causes respiratory illness in the elderly. Different monoclonal antibody (MAb) and vaccine candidates are in development worldwide and will hopefully become available within the near future. To implement such RSV vaccines, adequate decisions about immunization schedules and the different target group(s) need to be made, for which the assessment of antibody levels against RSV is essential. To survey RSV antigen-specific antibody levels, we developed a serological multiplex immunoassay (MIA) that determines and distinguishes antibodies against the five RSV glycoproteins postfusion F, prefusion F, Ga, Gb, and N simultaneously. The standardized RSV pentaplex MIA is sensitive, highly reproducible, and specific for the five RSV proteins. The preservation of the conformational structure of the immunodominant site Ø of prefusion F after conjugation to the beads has been confirmed. Importantly, good correlation is obtained between the microneutralization test and the MIA for all five proteins, resulting in an arbitrarily chosen cutoff value of prefusion F antibody levels for seropositivity in the microneutralization assay. The wide dynamic range requiring only two serum sample dilutions makes the RSV-MIA a high-throughput assay very suitable for (large-scale) serosurveillance and vaccine clinical studies.IMPORTANCE In view of vaccine and monoclonal development to reduce hospitalization and death due to lower respiratory tract infection caused by RSV, assessment of antibody levels against RSV is essential. This newly developed multiplex immunoassay is able to measure antibody levels against five RSV proteins simultaneously. This can provide valuable insight into the dynamics of (maternal) antibody levels and RSV infection in infants and toddlers during the first few years of life, when primary RSV infection occurs.

Keywords

assay development; immunoassays; multiplex; respiratory syncytial virus.

Access the article

24 April 2019

Gu-Lung Lin, Joseph P. McGinley, Simon B. Drysdale, Andrew J. Pollard

Abstract

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis can be caused by a broad range of pathogens; however, bacterial infections represent the majority of sepsis cases. Up to 42% of sepsis presentations are culture negative, suggesting a non-bacterial cause. Despite this, diagnosis of viral sepsis remains very rare. Almost any virus can cause sepsis in vulnerable patients (e.g., neonates, infants, and other immunosuppressed groups). The prevalence of viral sepsis is not known, nor is there enough information to make an accurate estimate. The initial standard of care for all cases of sepsis, even those that are subsequently proven to be culture negative, is the immediate use of broad-spectrum antibiotics. In the absence of definite diagnostic criteria for viral sepsis, or at least to exclude bacterial sepsis, this inevitably leads to unnecessary antimicrobial use, with associated consequences for antimicrobial resistance, effects on the host microbiome and excess healthcare costs. It is important to understand non-bacterial causes of sepsis so that inappropriate treatment can be minimised, and appropriate treatments can be developed to improve outcomes. In this review, we summarise what is known about viral sepsis, its most common causes, and how the immune responses to severe viral infections can contribute to sepsis. We also discuss strategies to improve our understanding of viral sepsis, and ways we can integrate this new information into effective treatment.

Keywords

dengue virus; epidemiology; herpes simplex virus; human enterovirus; human parechovirus; immune pathogenesis; influenza virus; viral sepsis.

Access the article

27 September 2018

Li X, Willem L, Antillon M, Bilcke J, Jit M, Beutels P.

Background

Respiratory syncytial virus (RSV) frequently causes acute lower respiratory infection in children under 5, representing a high burden in Gavi-eligible countries (mostly low-income and lower-middle-income). Since multiple RSV interventions, including vaccines and monoclonal antibody (mAb) candidates, are under development, we aim to evaluate the key drivers of the cost-effectiveness of maternal vaccination and infant mAb for 72 Gavi countries.

Methods

A static Multi-Country Model Application for RSV Cost-Effectiveness poLicy (MCMARCEL) was developed to follow RSV-related events monthly from birth until 5 years of age. MCMARCEL was parameterised using country- and age-specific demographic, epidemiological, and cost data. The interventions’ level and duration of effectiveness were guided by the World Health Organization’s preferred product characteristics and other literature. Maternal vaccination and mAb were assumed to require single-dose administration at prices assumed to align with other Gavi-subsidised technologies. The effectiveness and the prices of the interventions were simultaneously varied in extensive scenario analyses. Disability-adjusted life years (DALYs) were the primary health outcomes for cost-effectiveness, integrated with probabilistic sensitivity analyses and Expected Value of Partially Perfect Information analysis.

06 April 2018

Lin GL, Golubchik T, Drysdale S, O’Connor D, Jefferies K, Brown A, de Cesare M, Bonsall D, Ansari MA, Aerssens J, Bont L, Openshaw P, Martinón-Torres F, Bowden R, Pollard AJ; RESCEU Investigators.

Abstract

Targeted metagenomics using strand-specific libraries with target enrichment is a sensitive, generalized approach to pathogen sequencing and transcriptome profiling. Using this method, we recovered 13 (76%) complete human respiratory syncytial virus (RSV) genomes from 17 clinical respiratory samples, reconstructed the phylogeny of the infecting viruses, and detected differential gene expression between 2 RSV subgroups, specifically, a lower expression of the P gene and a higher expression of the M2 gene in RSV-A than in RSV-B. This methodology can help to relate viral genetics to clinical phenotype and facilitate ongoing population-level RSV surveillance and vaccine development. Clinical Trials Registration. NCT03627572 and NCT03756766.

Keywords

RNA sequencing; differential gene expression; respiratory syncytial virus; transcriptome profiling; whole-genome sequencing.

Access the article

07 October 2020

Li Y, Reeves RM, Wang X, Bassat Q, Brooks WA, Cohen C, Moore DP, Nunes M, Rath B, Campbell H, Nair H; RSV Global Epidemiology Network; RESCEU investigators.

Background

Influenza virus, respiratory syncytial virus, parainfluenza virus, and metapneumovirus are the most common viruses associated with acute lower respiratory infections in young children (<5 years) and older people (≥65 years). A global report of the monthly activity of these viruses is needed to inform public health strategies and programmes for their control.

Methods

In this systematic analysis, we compiled data from a systematic literature review of studies published between Jan 1, 2000, and Dec 31, 2017; online datasets; and unpublished research data. Studies were eligible for inclusion if they reported laboratory-confirmed incidence data of human infection of influenza virus, respiratory syncytial virus, parainfluenza virus, or metapneumovirus, or a combination of these, for at least 12 consecutive months (or 52 weeks equivalent); stable testing practice throughout all years reported; virus results among residents in well-defined geographical locations; and aggregated virus results at least on a monthly basis. Data were extracted through a three-stage process, from which we calculated monthly annual average percentage (AAP) as the relative strength of virus activity. We defined duration of epidemics as the minimum number of months to account for 75% of annual positive samples, with each component month defined as an epidemic month. Furthermore, we modelled monthly AAP of influenza virus and respiratory syncytial virus using site-specific temperature and relative humidity for the prediction of local average epidemic months. We also predicted global epidemic months of influenza virus and respiratory syncytial virus on a 5° by 5° grid. The systematic review in this study is registered with PROSPERO, number CRD42018091628.

Access the article

August 2019

Korsten K, Adriaenssens N, Coenen S, Butler C, Ravanfar B, Rutter H, Allen J, Falsey A, Pirçon JY, Gruselle O, Pavot V, Vernhes C, Balla-Jhagjhoorsingh S, Öner D, Ispas G, Aerssens J, Shinde V, Verheij T, Bont L, Wildenbeest J; RESCEU investigators.

Background

Respiratory syncytial virus (RSV) infection in older adults is recognized as an important health issue. We aimed to assess the community burden of RSV in Europe in older adults aged ≥60 years.

Methods

This international prospective observational cohort study is part of REspiratory Syncytial virus Consortium in EUrope (RESCEU). Participants were recruited before two independent RSV-seasons through general practitioner’s offices. Participants reported weekly about symptoms of acute respiratory tract infection (ARTI) during one RSV-season. . ARTI patients were tested for RSV during home visits and completed a daily symptom diary. RSV-illness included PCR-confirmed ARTI and those showing seroconversion over the season. RSV-ARTI was based on PCR alone (ClinicalTrials.gov, NCT03621930).

Results

We recruited 1040 participants (527 in season 2017-2018, 513 in season 2018-2019) with a median age of 75 years (range 60-100). 1023 (99%) lived independently at home at baseline. RSV-illness incidence was 4.2% (22/527) and 7.2% (37/513) in the respective seasons. RSV-illness did not affect frailty or cardiopulmonary status during the course of the study. No patients were hospitalized or died from RSV-illness. In the 36 patients with PCR confirmed RSV-ARTI, symptom duration averaged 19 days, while a doctor’s visit took place in 11/36 (31%) of cases. RSV-ARTI could not clinically be differentiated from all other ARTI based on symptoms.

Conclusion

This European study showed that RSV is prevalent in community-dwelling older adults and rarely causes severe disease. This suggests that watchful waiting, using a continuity of care approach to identify those who do need more intensive care is often justified when RSV is suspected in family practice.

Access the article

15 October 2020

Rachel M Reeves, Maarten van Wijhe, Sabine Tong, Toni Lehtonen, Luca Stona, Anne C Teirlinck, Liliana Vazquez Fernandez, You Li, Carlo Giaquinto, Thea Kølsen Fischer, Clarisse Demont, Terho Heikkinen, Irene Speltra, Michiel van Boven, Håkon Bøås, Harry Campbell, RESCEU Investigators

Background

Respiratory syncytial virus (RSV) is a leading cause of respiratory tract infection (RTI) in young children. Registries provide opportunities to explore RSV epidemiology and burden.

Methods

We explored routinely collected hospital data on RSV in children aged < 5 years in 7 European countries. We compare RSV-associated admission rates, age, seasonality, and time trends between countries. Results We found similar age distributions of RSV-associated hospital admissions in each country, with the highest burden in children < 1 years old and peak at age 1 month. Average annual rates of RTI admission were 41.3–112.0 per 1000 children aged < 1 year and 8.6–22.3 per 1000 children aged < 1 year. In children aged < 5 years, 57%–72% of RTI admissions with specified causal pathogen were coded as RSV, with 62%–87% of pathogen-coded admissions in children < 1 year coded as RSV. Conclusions Our results demonstrate the benefits and limitations of using linked routinely collected data to explore epidemiology and burden of RSV. Our future work will use these data to generate estimates of RSV burden using time-series modelling methodology, to inform policymaking and regulatory decisions regarding RSV immunization strategy and monitor the impact of future vaccines. 

Access the article

Alexandria Chung, Rachel M Reeves, Harish Nair, Harry Campbell, RESCEU investigators

Background

Bronchiolitis is the commonest cause of respiratory related hospital admissions in young children. This study aimed to describe temporal trends in bronchiolitis admissions for children under 2 years of age in Scotland by patient characteristics, socioeconomic deprivation, and duration of admission.

Methods

The national hospital admissions database for Scotland was used to extract data on all bronchiolitis admissions (International Classification of Disease, Tenth Revision, code J21) in children <2 years of age from 2001 to 2016. Deprivation quintiles were classified using the 2011 Scottish Index of Multiple Deprivation.

14 August 2020

Michiel van Boven, Anne C Teirlinck, Adam Meijer, Mariëtte Hooiveld, Christiaan H van Dorp, Rachel M Reeves, Harry Campbell, Wim van der Hoek, RESCEU Investigators

Background

Respiratory syncytial virus (RSV) is a leading cause of respiratory tract illness in young children and a major cause of hospital admissions globally.

Methods

Here we fit age-structured transmission models with immunity propagation to data from the Netherlands (2012-2017). Data included nationwide hospitalizations with confirmed RSV, general practitioner (GP) data on attendance for care from acute respiratory infection, and virological testing of acute respiratory infections at the GP. The transmission models, equipped with key parameter estimates, were used to predict the impact of maternal and pediatric vaccination.

Results

Estimates of the basic reproduction number were generally high (R0 > 10 in scenarios with high statistical support), while susceptibility was estimated to be low in nonelderly adults (<10% in persons 20-64 years) and was higher in older adults (≥65 years). Scenario analyses predicted that maternal vaccination reduces the incidence of infection in vulnerable infants (<1 year) and shifts the age of first infection from infants to young children.

Conclusions

Pediatric vaccination is expected to reduce the incidence of infection in infants and young children (0-5 years), slightly increase incidence in 5 to 9-year-old children, and have minor indirect benefits.

Keywords

GP consultations; evidence synthesis; hospital data; respiratory syncytial virus; transmission model; vaccination.

Access the article

21 August 2020

You Li, Harry Campbell, Harish Nair, RESCEU Investigators

Background

Respiratory syncytial virus (RSV)–related acute lower respiratory infection is an important cause of death in infants and young children. However, little is known about the risk period for RSV-related deaths after presentation to health services with an RSV illness.

Methods

Using the Scottish national mortality database, we identified deaths from respiratory/circulatory causes (hereafter “respiratory/circulatory deaths”) in young children aged <5 years during 2009–2016, whose medical history and records of laboratory-confirmed RSV infections were obtained by linking the mortality database to the national surveillance data set and the Scottish Morbidity Record. We used a self-controlled case series (SCCS) design to evaluate the relative incidence of deaths with respiratory/circulatory deaths in the first year after an RSV episode. We defined the risk interval as the first year after the RSV episode, and the control interval as the period before and after the risk interval until 5 years after birth. Age-adjusted incidence ratio and attributable fraction were generated using the R software package SCCS.

Access the article

14 August 2020

Deniz Öner, Simon B Drysdale, Calum McPherson, Gu-Lung Lin, Sophie Janet, Jonathan Broad, Andrew J Pollard, Jeroen Aerssens, RESCEU Investigators

Background

Clinical manifestations of respiratory syncytial virus (RSV) infection vary widely from mild, self-limiting illness to severe life-threatening disease. There are gaps in knowledge of biomarkers to objectively define severe disease and predict clinical outcomes.

Methods

A systematic search was performed, 1945–March 2019 in databases Ovid Medline, Embase, Global health, Scopus, and Web of Science. Risk of bias was assessed using the Cochrane tool.

Access the article

14 August 2020

Joanne G Wildenbeest, Roy P Zuurbier, Koos Korsten, Marlies A van Houten, Marie N Billard, Nicole Derksen-Lazet, Matthew D Snape, Simon B Drysdale, Hannah Robinson, Andrew J Pollard, Terho Heikkinen, Steve Cunningham, Amanda Leach, Federico Martinón-Torres, Carmen Rodríguez-Tenreiro Sánchez, Alberto Gómez-Carballa, Louis J Bont, Respiratory Syncytial Virus Consortium in Europe (RESCEU) Investigators

Background

Respiratory syncytial virus (RSV) causes significant morbidity and mortality in infants worldwide. Although prematurity and cardiopulmonary disease are risk factors for severe disease, the majority of infants hospitalized with RSV are previously healthy. Various vaccines and therapeutics are under development and expected to be available in the near future. To inform the use of these new vaccines and therapeutics, it is necessary to determine the burden of RSV disease in Europe. We will prospectively follow-up a birth cohort to obtain incidence data on RSV acute respiratory tract infection (ARTI).

Methods

Multicenter prospective study of a birth cohort consisting of 10 000 healthy infants, recruited during 3 consecutive years. RSV associated hospitalization in the first year of life will be determined by questionnaires and hospital chart reviews. A nested cohort of 1000 infants will be actively followed. In case of ARTI, a respiratory sample will be collected for RSV molecular diagnosis.

Access the article

14 August 2020

Kimberley Jefferies, Simon B Drysdale, Hannah Robinson, Elizabeth Ann Clutterbuck, Luke Blackwell, Joseph McGinley, Gu-Lung Lin, Ushma Galal, Harish Nair, Jeroen Aerssens, Deniz Öner, Annefleur Langedijk, Louis Bont, Joanne G Wildenbeest, Federico Martinon-Torres, Carmen Rodríguez-Tenreiro Sánchez, Simon Nadel, Peter Openshaw, Ryan Thwaites, Myra Widjojoatmodjo, et. al

Respiratory syncytial virus (RSV) is the leading viral pathogen associated with acute lower respiratory tract infection and hospitalization in children < 5 years of age worldwide. While there are known clinical risk factors for severe RSV infection, the majority of those hospitalized are previously healthy infants. There is consequently an unmet need to identify biomarkers that predict host response, disease severity, and sequelae. The primary objective is to identify biomarkers of severe RSV acute respiratory tract infection (ARTI) in infants. Secondary objectives include establishing biomarkers associated with respiratory sequelae following RSV infection and characterizing the viral load, RSV whole-genome sequencing, host immune response, and transcriptomic, proteomic, metabolomic and epigenetic signatures associated with RSV disease severity. Six hundred thirty infants will be recruited across 3 European countries: the Netherlands, Spain, and the United Kingdom. Participants will be recruited into 2 groups: (1) infants with confirmed RSV ARTI (includes upper and lower respiratory tract infections), 500 without and 50 with comorbidities; and (2) 80 healthy controls. At baseline, participants will have nasopharyngeal, blood, buccal, stool, and urine samples collected, plus complete a questionnaire and 14-day symptom diary. At convalescence (7 weeks ± 1 week post-ARTI), specimen collection will be repeated. Laboratory measures will be correlated with symptom severity scores to identify corresponding biomarkers of disease severity.

Clinical Trials Registration NCT03756766.

Access the article

14 August 2020

Roy P Zuurbier, Louis J Bont, Annefleur C Langedijk, Mirjam Hamer, Koos Korsten, Simon B Drysdale, Matthew D Snape, Hannah Robinson, Andrew J Pollard, Federico Martinón-Torres, Carmen Rodríguez-Tenreiro Sánchez, Alberto Gómez-Carballa, Ana Isabel Dacosta-Urbieta, Terho Heikkinen, Steve Cunningham, Marlies A van Houten, Joanne G Wildenbeest, for the RESCEU Investigators. 

Background

Respiratory syncytial virus (RSV) is a major cause of hospitalization in infants. Early detection of RSV can optimize clinical management and minimize use of antibiotics. BinaxNOW RSV (BN) is a rapid antigen detection test that is widely used. We aimed to validate the sensitivity of BN in hospitalized and nonhospitalized infants against the gold standard of molecular diagnosis.

Methods

We evaluated the performance of BN in infants with acute respiratory tract infections with different degrees of disease severity. Diagnostic accuracy of BN test results were compared with molecular diagnosis as reference standard.

Access the article

30 March 2020

Dexter J Wiseman, Ryan S Thwaites, Simon B Drysdale, Sophie Janet, Gavin C Donaldson, Jadwiga A Wedzicha, Peter J Openshaw, the RESCEU Investigators.

Background

Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis in young infants. However, it is also a significant pathogen in older adults. Validated biomarkers of RSV disease severity would benefit diagnostics, treatment decisions, and prophylactic interventions. This review summarizes knowledge of biomarkers for RSV disease in adults.

Methods

A literature review was performed using Ovid Medline, Embase, Global health, Scopus, and Web of Science for articles published 1946–October 2016. Nine articles were identified plus 9 from other sources.

Access the article

30 March 2020

Shanshan Zhang, Lily Zainal Akmar, Freddie Bailey, Barbara A Rath, Maren Alchikh, Brunhilde Schweiger, Marilla G Lucero, Leilani T Nillos, Moe H Kyaw, Alexia Kieffer, Sabine Tong, Harry Campbell, Philippe Beutels, Harish Nair.

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.

Access the article

30 March 2020

Pa Saidou Chaw, Lei Hua, Steve Cunningham, Harry Campbell, Rafael Mikolajczyk, Harish Nair, et al.

Background

Respiratory syncytial virus (RSV) is among the most important causes of acute lower respiratory tract infection (ALRI) in young children. We assessed the severity of RSV-ALRI in children less than 5 years old with bronchopulmonary dysplasia (BPD).

Methods

We searched for studies using EMBASE, Global Health, and MEDLINE. We assessed hospitalization risk, intensive care unit (ICU) admission, need for oxygen supplementation and mechanical ventilation, and in-hospital case fatality (hCFR) among children with BPD compared with those without (non-BPD). We compared the (1) length of hospital stay (LOS) and (2) duration of oxygen supplementation and mechanical ventilation between the groups.

Access the article

11 December 2019

Pa Saidou Chaw, Stephanie Wen Lan Wong, Steve Cunningham, Harry Campbell, Rafael Mikolajczyk, Harish Nair, RESCEU Investigators.

Background

Respiratory syncytial virus (RSV) is the most common viral pathogen associated with acute lower respiratory infections (ALRIs), with significant childhood morbidity and mortality worldwide. Estimates reporting RSV-associated ALRI (RSV-ALRI) severity in children with congenital heart disease (CHD) are lacking, thus warranting the need to summarize the available data. We identified relevant studies to summarize the findings and conducted a meta-analysis of available data on RSV-associated ALRI hospitalizations in children aged <5 years, comparing those with underlying CHD to those without CHD.

Methods

We conducted a systematic search of existing relevant literature and identified studies reporting hospitalization of children aged <5 years with RSV-ALRI with underlying or no CHD. We summarized the data and conducted (where possible) a random-effects meta-analysis to compare the 2 groups.

Access the article

10 October 2019

Amir Kirolos, Sara Manti, Rachel Blacow, Gabriel Tse, Thomas Wilson, Martin Lister, Stseve Cunningham, Alasdair Campbell, Harish Nair, Rachel M Reeves, Ricardo M Fernandes, Harry Campbell, RESCEU Investigator.

Background

Bronchiolitis is the leading cause of hospital admission for respiratory disease among infants aged <1 year. Clinical practice guidelines can benefit patients by reducing the performance of unnecessary tests, hospital admissions, and treatment with lack of a supportive evidence base. This review aimed to identify current clinical practice guidelines worldwide, appraise their methodological quality, and discuss variability across guidelines for the diagnosis and management of bronchiolitis.

Methods

A systematic literature review of electronic databases EMBASE, Global Health, and Medline was performed. Manual searches of the gray literature, national pediatric society websites, and guideline-focused databases were performed, and select international experts were contacted to identify additional guidelines. The Appraisal of Guidelines for Research and Evaluation assessment tool was used by 2 independent reviewers to appraise each guideline.

Access the article

14 August 2019

Ting Shi, Yujing Ooi, Ei Mon Zaw, Natasa Utjesanovic, Harry Campbell, Steve Cunningham, Louis Bont, Harish Nair, RESCEU Investigators.

Background

Recurrent wheeze and asthma in childhood are commons causes of chronic respiratory morbidity globally. We aimed to explore the association between respiratory syncytial virus (RSV) infection in early life and subsequent respiratory sequelae up to age 12 years.

Methods

We estimated the strength of association by 3 control groups and 3 follow-up age groups, with data from studies published between January 1995 and May 2018. We also estimated associations by diagnostic criteria, age at infection, and high-risk population.

Access the article

01 August 2019

Ting Shi, Angeline Denouel, Anna K Tietjen, Iain Campbell, Emily Moran, Xue Li, Harry Campbell, Clarisse Demont, Bryan O Nyawanda, Helen Y Chu, Sonia K Stoszek, Anand Krishnan, Peter Openshaw, Ann R Falsey, Harish Nair.

Respiratory syncytial virus–associated acute respiratory infection (RSV-ARI) constitutes a substantial disease burden in older adults aged ≥65 years. We aimed to identify all studies worldwide investigating the disease burden of RSV-ARI in this population. We estimated the community incidence, hospitalization rate, and in-hospital case-fatality ratio (hCFR) of RSV-ARI in older adults, stratified by industrialized and developing regions, using data from a systematic review of studies published between January 1996 and April 2018 and 8 unpublished population-based studies. We applied these rate estimates to population estimates for 2015 to calculate the global and regional burdens in older adults with RSV-ARI in the community and in hospitals for that year. We estimated the number of in-hospital deaths due to RSV-ARI by combining hCFR data with hospital admission estimates from hospital-based studies. In 2015, there were about 1.5 million episodes (95% confidence interval [CI], .3 million–6.9 million) of RSV-ARI in older adults in industrialized countries (data for developing countries were missing), and of these, approximately 14.5% (214 000 episodes; 95% CI, 100 000–459 000) were admitted to hospitals. The global number of hospital admissions for RSV-ARI in older adults was estimated at 336 000 hospitalizations (uncertainty range [UR], 186 000–614 000). We further estimated about 14 000 in-hospital deaths (UR, 5000–50 000) related to RSV-ARI globally. The hospital admission rate and hCFR were higher for those aged ≥65 years than for those aged 50–64 years. The disease burden of RSV-ARI among older adults is substantial, with limited data from developing countries. Appropriate prevention and management strategies are needed to reduce this burden.

Access the article

18 March 2019

Ting Shi, Andrew Arnott, Indre Semogas, Ann R Falsey, Peter Openshaw, Jadwiga A Wedzicha, Harry Campbell, Harish Nair.

Acute respiratory tract infections (ARI) constitute a substantial disease burden in adults and elderly individuals. We aimed to identify all case-control studies investigating the potential role of respiratory viruses in the etiology of ARI in older adults aged ≥65 years. We conducted a systematic literature review (across 7 databases) of case-control studies published from 1996 to 2017 that investigated the viral profile of older adults with and those without ARI. We then computed a pooled odds ratio (OR) with a 95% confidence interval and virus-specific attributable fraction among the exposed (AFE) for 8 common viruses: respiratory syncytial virus (RSV), influenza virus (Flu), parainfluenza virus (PIV), human metapneumovirus (HMPV), adenovirus (AdV), rhinovirus (RV), bocavirus (BoV), and coronavirus (CoV). From the 16 studies included, there was strong evidence of possible causal attribution for RSV (OR, 8.5 [95% CI, 3.9–18.5]; AFE, 88%), Flu (OR, 8.3 [95% CI, 4.4–15.9]; AFE, 88%), PIV (OR, not available; AFE, approximately 100%), HMPV (OR, 9.8 [95% CI, 2.3–41.0]; AFE, 90%), AdV (OR, not available; AFE, approximately 100%), RV (OR, 7.1 [95% CI, 3.7–13.6]; AFE, 86%) and CoV (OR, 2.8 [95% CI, 2.0–4.1]; AFE, 65%) in older adults presenting with ARI, compared with those without respiratory symptoms (ie, asymptomatic individuals) or healthy older adults. However, there was no significant difference in the detection of BoV in cases and controls. This review supports RSV, Flu, PIV, HMPV, AdV, RV, and CoV as important causes of ARI in older adults and provides quantitative estimates of the absolute proportion of virus-associated ARI cases to which a viral cause can be attributed. Disease burden estimates should take into account the appropriate AFE estimates (for older adults) that we report.

Access the article

17 November 2020

Ting Shi, Angeline Denouel, Anna K Tietjen, Jen Wei Lee, Ann R Falsey, Clarisse Demont, Bryan O Nyawanda, Bing Cai, Robert Fuentes, Sonia K Stoszek, Peter Openshaw, Harry Campbell, Harish Nair.

Pneumonia constitutes a substantial disease burden among adults overall and those who are elderly. We aimed to identify all studies investigating the disease burden among older adults (age, ≥65 years) admitted to the hospital with pneumonia. We estimated the hospital admission rate and in-hospital case-fatality ratio (CFR) of pneumonia in older adults, stratified by age and economic status (industrialized vs developing), with data from a systematic review of studies published from 1996 through 2017 and from 8 unpublished population-based studies. We applied these rate estimates to population estimates for 2015 to calculate the global and regional burden in older adults who would have been admitted to the hospital with pneumonia that year. We estimated the number of in-hospital pneumonia deaths by combining in-hospital CFRs with hospital admission estimates from hospital-based studies. We identified 109 eligible studies; 73 used clinical pneumonia as the case definition, and 36 used radiologically confirmed pneumonia as the case definition. We estimated that, in 2015, 6.8 million episodes (uncertainty range [UR], 5.8–8.0 episodes) of clinical pneumonia resulted in hospital admissions of older adults worldwide. The hospital admission rate increased with advancing age and was higher in men. The total disease burden was likely underestimated when using the definition of radiologically confirmed pneumonia. Based on data from 52 hospital studies reporting data on pneumonia mortality, we estimated that about 1.1 million in-hospital deaths (UR, 0.9–1.4 in-hospital deaths) occurred among older adults. The burden of pneumonia requiring hospitalization among older adults is substantial. Appropriate prevention and management strategies should be developed to reduce its impact.

Access the article

08 March 2019