Qing Zhu,1*† Jason S. McLellan,2† Nicole L. Kallewaard,1 Nancy D. Ulbrandt,1 Susan Palaszynski,1
Jing Zhang,1 Brian Moldt,1 Anis Khan,3 Catherine Svabek,1 Josephine M. McAuliffe,1
Daniel Wrapp,2 Nita K. Patel,1 Kimberly E. Cook,4 Bettina W. M. Richter,1 Patricia C. Ryan,5
Andy Q. Yuan,4 JoAnn A. Suzich1*
Most children with severe RSV infection were previously healthy term children. Palivizumab, the only approved agent for RSV prophylaxis, is limited to high-risk infants, and the cost associated with the requirement for dosing throughout the RSV season makes its use impractical for all infants. This paper describes the development of a monoclonal antibody as potential RSV prophylaxis for all infants with a single intramuscular dose. MEDI8897 has >50-fold higher activity than palivizumab. More than threefold increased half-life. Considering the half-life its use may be an option to protect all infants from RSV disease with once-per-RSV-season dosing.
Terho Heikkinen,1 Emilia Ojala,1 and Matti Waris2
1Department of Pediatrics, University of Turku and Turku University Hospital, and 2Department of Virology, University of Turku, Finland
We analyzed the burden of RSV in a prospective cohort study of children aged ≤13 years during two consecutive respiratory seasons in Turku, Finland (2231 child-seasons of follow-up). Of 6001 medically attended respiratory infections, 302 (5%) were caused by RSV. Per 1000 children, the average annual RSV incidence rates among children aged <3, 3-6, and 7-13 years were 275, 117, and 46, respectively. In children aged <3 years, acute otitis media developed in 58%, and 66% of children in this age group received antibiotics. The mean duration of RSV illness was longest (13.0 days) and the rate of parental work absenteeism highest (136 days per 100 children with RSV) in children aged <3 years. The burden of RSV is particularly great among outpatient children aged <3 years, and young children are an important target group for the development of RSV vaccines and antivirals.
Severity of Respiratory Syncytial Virus Lower Respiratory Tract Infection with Viral Coinfection in HIV-uninfected Children
Natalie I. Mazur,1,2,3 Louis Bont,2,4 Adam L. Cohen,5,6 Cheryl Cohen,7,8 Anne von Gottberg,8,9 Michelle J. Groome,1,10 Orienka Hellferscee,8,9 Kerstin Klipstein-Grobusch,3,7 Omphile Mekgoe,11 Fathima Naby,12 Jocelyn Moyes,7,8 Stefano Tempia,5,6 Florette K. Treurnicht,8 Marietje Venter,13,14 Sibongile Walaza,7,8 Nicole Wolter,8,9 and Shabir A. Madhi1,10; for the South African Severe Acute Respiratory Illness (SARI) Surveillance Group
It is still not clear why some children have life-threatening RSV disease. Molecular diagnostics enable sensitive detection of respiratory viruses but their clinical significance remains unclear in pediatric lower respiratory tract infections (LRTI). We aimed to determine whether viral coinfections increase life-threatening disease in a large cohort. As part of the Severe Acute Respiratory Illness (SARI) hospitalization sentinal surveillance conducted in South Africa from February 2009-December 2013, molecular testing for respiratory viruses was performed in 2.322 HIV-uninfected children with RSV-associated LRTI. We found that RSV and any viral coinfection compared to RSV monoinfection is not associated with more severe disease (OR:0.74, 95%CI 0.39-1.4). However, increased life-threatening disease in RSV-adenovirus (aOR: 3.4, 95%CI: 1.6-7.2, p=0.001)and RSV-Influenza coinfection (aOR: 2.1, 95%CI 1.0-4.5, p=0.05) warrants further study.
Sarah Geoghegan1*; Anabella Erviti1*; Mauricio T. Caballero1*; Fernando Vallone2; Stella M. Zanone1; Juan Ves Losada3; Alejandra Bianchi1; Patricio L. Acosta1; Laura B. Talarico1; Adrian Ferretti1; Luciano Alva Grimaldi4; Andrea Sancilio5; Karina Dueñas5; Gustavo Sastre6; Andrea Rodriguez 6 ; Fernando Ferrero7; Edgar Barboza8; Guadalupe Fernández Gago9; Celina Nocito10, Edgardo Flamenco11; Alberto Rodriguez Perez12; Beatriz Rebec13; F. Martin Ferolla1; Romina Libster1; Ruth A. Karron14; Eduardo Bergel1; Fernando P. Polack1,15
Respiratory syncytial virus (RSV) infection during infancy causes enormous mortality in the developing world. However, a good proportion of the mortality data have been derived from studies measuring excess mortality during RSV epidemics. Much of RSV-related deaths probably occur in the community due to lack of access to care. To understand individual characteristics of community-based and hospital-based deaths a prospective multicentre study was performed in Argentina. In hospitalized patients, case fatality was 0.9%. RSV infection explained about 50% of all deaths among infants presenting with lower respiratory tract illness. Death was related to bacterial sepsis and pneumothorax. This study is one of the first to provide insight into clinical characteristics of children dying from RSV and the mechanisms eventually preceding death.
Nasopharyngeal microbiota, host transcriptome and disease severity in children withrespiratory syncytial virus infection
Wouter A.A. de Steenhuijsen Piters1*, Santtu Heinonen2*, Raiza Hasrat1, Eleonora Bunsow2, Bennett Smith2, Maria-Carmen Suarez-Arrabal2, Damien Chaussabel3,4, Daniel M. Cohen5, Elisabeth A.M. Sanders1, Octavio Ramilo2,6, Debby Bogaert1** and Asuncion Mejias2,6**.
From 2010-2014 we conducted a prospective observational study during 4 consecutive RSV seasons at Nationwide Children’s Hospital, Columbus, Ohio, USA. Previously healthy children <2 years of age with a first episode of RSV infection were enrolled either at the outpatient clinics (‘outpatients’) or within 24h [17-39h] (median [IQR]) of admission in the pediatric ward or the pediatric intensive care unit (PICU) (‘inpatients’). Asymptomatic
healthy controls were enrolled during routine primary care visits or elective surgery not involving the respiratory tract. For study criteria see Supplementary methods E1. In addition to the need for hospitalization, RSV disease severity was assessed using a clinical disease severity score (CDSS), and by the need for supplemental oxygen, PICU admission and length of stay.(16)
Incidence of Hospitalization for Respiratory Syncytial Virus Infection amongst Children in Ontario, Canada: A Population-Based Study Using Validated Health Administrative Data
Andrea Pisesky1, Eric I. Benchimol1,2,3,4, Coralie A. Wong4, Charles Hui1, Megan Crowe3, Marc-Andre Belair4, Supichaya Pojsupap1, Tim Karnauchow1, Katie O'Hearn2, Abdool S. Yasseen, III2, James D. McNally1,2*
One in hundred children without comorbidity are hospitalized for RSV lower respiratory tract illness. This is the conclusion from a study performed of a nine year period in Ontario, Canada. Among 1.6 million children 8.7% were born prematurely or suffered congenital heart disease, bronchopulmonary dysplasia or Down syndrome. The incidence of RSV-related admission among these children was 10.2 per 1000 in the first year of life. This was 2.5 times lower than in children with comorbidity. The incidence of RSV-related admissions varied over time between 6,3 and 12 per 1000 showing the critical importance of doing this study over a period of several years. The incidence rates in this report are comparable to those found in a prospective population-based study from the United States (11 per 1000, Hall, NEJM 2007) and the Netherlands (8 per 1000, Zomer, Eur Respir J 2014).
JOHN P. DEVINCENZO, M.D., MATTHEW W. MCCLURE, M.D., JULIAN A. SYMONS, D.PHIL., HOSNIEH FATHI, M.D., CHRISTOPHER WESTLAND, B.A., SUSHMITA CHANDA, PH.D., ROB LAMBKIN WILLIAMS, PH.D., PATRICK SMITH, PHARM.D., QINGLING ZHANG, PH.D., LEO BEIGELMAN, PH.D., LAWRENCE M. BLATT, PH.D., AND JOHN FRY, B.S., R.G.N..
ALS-008176 IS A POTENT ORAL INHIBITOR OF VIRAL REPLICATION WHEN ADMINISTERED EARLY AFTER VIRAL CHALLENGE OF 62 HEALTHY ADULTS. THIS IS THE CONCLUSION BY DEVINCENZO AND COLLEAGUES FROM ALIOS BIOPHARMA AND RETROSCREEN VIROLOGY. TREATMENT WAS STARTED AFTER CONFIRMATION OF RSV INFECTION OR 6 DAYS AFTER INOCULATION. TREATMENT WAS ADMINISTERED EVERY 12 HOURS FOR 5 DAYS. ROBUST AND SURPRISINGLY RAPID INHIBITION OF VIRAL REPLICATION WAS OBSERVED WITHIN 12 HOURS AFTER TREATMENT. NO REBOUND VIRAL REPLICATION WAS OBSERVED. INFECTION-RELATED MUCOUS PRODUCTION WAS ALMOST FULLY PREVENTED BY ALS-008176. NO EVIDENCE OF TOXICITY WAS OBSERVED DURING OR AFTER A 5 DAY TREATMENT. SAFETY AND TOLERABILITY OF SINGLE AND MULTIPLE DOSES OF ALS-008176 IS CURRENTLY TESTED IN INFANTS WITH RSV BRONCHIOLITIS.
Lower respiratory tract infection caused by respiratory syncytial virus: current management and new therapeutics
Natalie I Mazur, Federico Martinón-Torres, Eugenio Baraldi, Brigitte Fauroux, Anne Greenough, Terho Heikkinen, Paolo Manzoni, Asuncion Mejias, Harish Nair, Nikolaos G Papadopoulos, Fernando P Polack, Octavio Ramilo, Mike Sharland, Renato Stein, Shabir A Madhi, Louis Bont, in collaboration with Respiratory Syncytial Virus Network (ReSViNET)
Respiratory syncytial virus (RSV) is a major worldwide cause of morbidity and mortality in children under five years of age. Evidence-based management guidelines suggest that there is no effective treatment for RSV lower respiratory tract infection (LRTI) and that supportive care, ie, hydration and oxygenation, remains the cornerstone of clinical management. However, RSV treatments in development in the past decade include 10 vaccines and 11 therapeutic agents in active clinical trials. Maternal vaccination is particularly relevant because the most severe disease occurs within the first 6 months of life, when children are unlikely to benefit from active immunisation. We must optimise the implementation of novel RSV therapeutics by understanding the target populations, showing safety, and striving for acceptable pricing in the context of this worldwide health problem. In this Review, we outline the limitations of RSV LRTI management, the drugs in development, and the remaining challenges related to study design, regulatory approval, and implementation.
Ruben J. Geerdink, MSc,a Janesh Pillay, MD, PhD,b,c Linde Meyaard, PhD,a and Louis Bont, MD, PhDa,d
Neutrophils are known for their role in fighting bacteria, but they also offer of protecting against viral infections. However, this virtually always occurs at the price of tissue damage. This is also likely to be true for RSV infection, Geerdink and colleagues argue. About 80% of the immunological studies in the published literature focus on the role of lymphocytes, whereas neutrophils dominate the influx of cells in the bronchoalveolar lumen during RSV bronchiolitis. Neutrophils exert antiviral effects through excretion of antiviral proteins, induction of mucus production, phagocytosis and formation of extracellular traps. At the same time, all of these mechanisms may cause deleterious effects on the airways and therefore play a role in the inception of asthma. Geerdink proposes that RSV treatment may be developed by dampening neutrophil activity under an umbrella of currently developed antiviral drugs.
Frequent asymptomatic infections during a respiratory syncytial virus epidemic in a rural Kenyan household cohort
P.K. Munywoki, D.C. Koech, C.N. Agoti, A. Bett, et al
The prevalence of asymptomatic RSV infection is low during infancy (<10%), but high in school age children (50%) and adults (>75%). This is the conclusion from a family-based field study by the RSV Research Group in Kilifi. Researchers determined the presence, load and duration of RSV infection within 40 households in relation to in-house spreading of RSV. The high incidence of asymptomatic RSV infection in older children and adults suggests an important role of asymptomatic RSV infection in within family spread of disease. However, as viral loads were lower and duration of shedding was shorter, asymptomatic infection explained less of within family spread of RSV infection than symptomatic infections. This is the first study quantifying and carefully explaining the role of asymptomatic RSV infection in viral transmission opening the possibility of prevention by hygiene measures.
High quality research is needed to improve patient care.