Respiratory syncytial virus: How, why and what to do

doi:10.1016/j.jinf.2013.09.021

Journal of Infection

Volume 68, Supplement 1, January 2014, Pages S115-S118

https://doi.org/10.1016/j.jinf.2013.09.021 Get rights and content

Summary

Bronchiolitis is the leading cause of hospitalization of infants and young children worldwide. Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis in infants. Studies conducted using molecular diagnostic assays confirmed that RSV accounts for over 50% of bronchiolitis in young children requiring hospitalization. Those studies demonstrate that it is common to identify RSV in association with a second viral agent but it is yet unclear whether the simultaneous detection of two or even three viruses is associated with increased disease severity. Despite extensive efforts, a vaccine for prevention of RSV infection is not yet available. Palivizumab a humanized monoclonal antibody directed against the F protein of RSV is the only agent licensed to prevent severe RSV disease in high-risk children. Among the new antivirals being developed for treatment of RSV infections, an RNA-interference based agent has demonstrated promising results for treatment of lung transplant recipients with acute RSV infection.

Section snippets

The virus

RSV is a member of the Mononegavirales in the Paramyxoviridae family, and Pneumovirinae subfamily. RSV is an enveloped virus with a negative sense, single-stranded RNA genome. These viruses are 150–200 nm in diameter with a helical nucleocapside. RSV has 10 genes encoding 11 proteins—there are 2 open reading frames of M2. The NS1 and NS2 proteins inhibit type I interferon activity. N protein encodes the nucleocapsid protein that associates with the genomic RNA forming the nucleocapsid, and the

Epidemiology and global burden of RSV

Acute lower respiratory infection (ALRI) is the leading cause of global child mortality. Respiratory syncytial virus (RSV) is the most frequent viral pathogen causing ALRI in young children. The global burden of RSV is significant.2, 3 A recent meta-analysis suggests that RSV causes up to 33.8 million ALRIs among children under age 5 (22% of all Lower Respiratory Tract Infections) each year. At least 3.4 million cases required hospital admission, and an estimated 66,000–199,000 of children

Vitamin D and bronchiolitis

Vitamin D status is determined largely from ultraviolet B ray exposure at all ages. Vitamin D also is available from dietary sources, which are more important at higher latitudes at which ultraviolet B ray exposure is inadequate for skin synthesis of vitamin D during winter. The diverse sources of vitamin D, which involve environmental conditions and complex behaviors, complicate vitamin D research. Fortunately, serum 25(OH)D levels provide an excellent measure of overall vitamin D status.

In a

Molecular diagnosis and co-infections

The development of sensitive molecular diagnostic assays has increased the number of viruses detected in respiratory samples compared with conventional methods. A number of studies have used PCR-based assays to study the etiology of bronchiolitis in hospitalized children. Using these methods several investigators have identified viruses in >90% cases of bronchiolitis. In hospitalized infants, RSV was the most frequent agent of bronchiolitis in winter, but other viruses were present in up to 47%

Viral load

The relationships between host factors, virus strain, viral load, and illness severity in respiratory syncytial virus (RSV)-induced bronchiolitis are still poorly defined. In this area studies offer contradictory results.17, 18, 19 Most studies that have attempted to associate viral load measured by quantitative real time PCR with disease severity have failed to establish any significant correlation.20, 21, 22, 23 However, two studies that measured viral load using quantitative cultures and

Etiologic diagnosis of bronchiolitis: is it relevant?

As the application of molecular diagnostic assays for respiratory viruses becomes more frequent both in research studies and academic medical centers, physicians raise questions concerning the value of such tests in clinical practice. One argument favoring their use, from the infection control perspective, is the importance, were feasible, of isolating patients according to etiology to prevent hospital-associated infections. In addition, a recent study conducted by Finnish investigators

Palivizumab and motavizumab

Palivizumab, a humanized monoclonal antibody directed against the F protein of RSV, has been used since 1998 in USA and 61 other countries for prevention of severe RSV infection in high-risk children.²⁶ Motavizumab is a neutralizing antibody derived from palivizumab that showed greater neutralization activity against RSV in preclinical studies. A pivotal study assessed the efficacy and safety of motavizumab versus palivizumab for prevention of RSV hospitalization in high-risk infants. Because

Conflict of interest

Dr. Ramilo has served as a consultant for Abbvie, Gilead and Alios.

References (30)

H. Nair
Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis
Lancet
(2010)
E.A. Simoes
Respiratory syncytial virus infection
Lancet
(1999)
E.T. Martin
Clinical disease and viral load in children infected with respiratory syncytial virus or human metapneumovirus
Diagn Microbiol Infect Dis
(2008)
P. Lehtinen
Prednisolone reduces recurrent wheezing after a first wheezing episode associated with rhinovirus infection or eczema
J Allergy Clin Immunol
(2007)
P.L. Collins et al.
Viral and host factors in human respiratory syncytial virus pathogenesis
J Virol
(2008)
H. Zhou
Hospitalizations associated with influenza and respiratory syncytial virus in the United States, 1993–2008
Clin Infect Dis
(2012)
C.G. Garcia
Risk factors in children hospitalized with RSV bronchiolitis versus non-RSV bronchiolitis
Pediatrics
(2010)
C.A. Camargo
Cord-blood 25-hydroxyvitamin D levels and risk of respiratory infection, wheezing, and asthma
Pediatrics
(2011)
T. Jartti
Low serum 25-hydroxyvitamin D levels are associated with increased risk of viral coinfections in wheezing children
J Allergy Clin Immunol
(2010)
M.E. Belderbos
Cord blood vitamin D deficiency is associated with respiratory syncytial virus bronchiolitis
Pediatrics
(2011)

C.A. Camargo

Randomized trial of vitamin D supplementation and risk of acute respiratory infection in Mongolia

Pediatrics

(2012)

D. Miron

Sole pathogen in acute bronchiolitis: is there a role for other organisms apart from respiratory syncytial virus?

Pediatr Infect Dis J

(2010)

N. Richard

The impact of dual viral infection in infants admitted to a pediatric intensive care unit associated with severe bronchiolitis

Pediatr Infect Dis J

(2008)

M.G. Semple

Dual infection of infants by human metapneumovirus and human respiratory syncytial virus is strongly associated with severe bronchiolitis

J Infect Dis

(2005)

C. Calvo

Detection of new respiratory viruses in hospitalized infants with bronchiolitis: a three-year prospective study

Acta Paediatr

(2010)

Cited by (32)

M2-2 gene as a new alternative molecular marker for phylogenetic, phylodynamic, and evolutionary studies of hRSV
2022, Virus Research
Citation Excerpt :
The pivotal cause of ARIs is the human respiratory syncytial virus, hRSV (Nair et al., 2010). A study reported that up to 33.8 million people are affected, mainly children under five years (e.g., especially newborns), with 22% of these infections associated with the lower respiratory tract (Rodriguez and Ramilo, 2014). The hRSV belongs to the Orthopneumovirus genus and the Pneumoviridae family (Adams et al., 2016).
The human Respiratory Syncytial Virus (hRSV) is the main causative agent of acute respiratory infections (ARI), such as pneumonia and bronchiolitis. One of the factors that lead to success in viral replication is the interaction of the M2-2 protein with the ribosomal complex. This interaction is responsible for the phase change of viral activity, acting as an inhibitor or inducer of viral replication, according to the concentration of mRNA. Based on the importance of M2-2 gene and protein have to viral physiology, we performed here evaluations of genetic diversity, phylogenetic reconstructions, phylodynamics, and selection test. Our results suggested an alternative way of classifying this virus in clades A and B, based on a new phylogenetic marker, the M2-2 gene. Therefore, our study is the first one to investigate the dynamics of the evolutionary diversification process of hRSV from the perspective of the M2-2 viral gene. In our study was also identified that the M2-2 gene is under the effect of purifying selection originated by population genetic bottlenecks. Therefore, the M2-2 gene demonstrated an interesting potential to be applied in evolutionary studies involving hRSV, recovering phylogenetic signals and traits of natural selection under the evolution of this virus.
Epicutaneous immunization using synthetic virus-like particles efficiently boosts protective immunity to respiratory syncytial virus
2021, Vaccine
Citation Excerpt :
Respiratory syncytial virus (RSV) is the most common cause of hospitalization in children under 5 years of age [1–3].
Despite the substantial health and economic burden caused by RSV-associated illness, no vaccine is available. The sole licensed treatment (palivizumab), composed of a monoclonal neutralizing antibody, blocks the fusion of the virus to the host cell but does not prevent infection. The development of a safe and efficacious RSV vaccine is therefore a priority, but also a considerable challenge, and new innovative strategies are warranted. Most of the adult population encounter regular RSV infections and can elicit a robust neutralizing antibody response, but unfortunately it wanes over time and reinfections during subsequent seasons are common. One approach to protect the mother and young infant from RSV infection is to administer a vaccine capable of boosting preexisting RSV immunity during pregnancy, which would provide protection to the fetus through passive transfer of maternal antibodies, thus preventing primary RSV infection in newborns during their first months of life. Here, we describe the preclinical evaluation of an epicutaneous RSV vaccine booster that combines epicutaneous patches as a delivery platform and a Synthetic Virus-Like Particles (SVLP)-based vaccine displaying multiple RSV F-protein site II (FsII, palivizumab epitope) mimetic as antigen (V-306). We demonstrated in mice that epicutaneous immunization with V-306 efficiently boosts preexisting immunity induced by the homologous V-306 administered subcutaneously. This boosting was characterized by a significant increase in F- and FsII-specific antibodies capable of competing with palivizumab for its target antigen and neutralize RSV. More importantly, epicutaneous booster immunization with V-306 significantly decreased lung viral replication in experimental mice after intranasal RSV challenge, without inducing enhanced RSV disease. In conclusion, an epicutaneous booster vaccine based on V-306 is safe and efficacious in enhancing RSV preexisting immunity in mice. This needle-free vaccine candidate would be potentially suited as a booster vaccine for vulnerable populations such as young infants via pregnant women, and the elderly.
Developmental plasticity in the neural control of breathing
2017, Experimental Neurology
The respiratory control system undergoes a diversity of morphological and physiological transformational stages during intrauterine development as it prepares to transition into an air-breathing lifestyle. Following birth, the respiratory system continues to develop and may pass through critical periods of heightened vulnerability to acute environmental stressors. Over a similar time course, however, the developing respiratory control system exhibits substantial capacity to undergo plasticity in response to chronic or repeated environmental stimuli. A hallmark of developmental plasticity is that it requires an interaction between a stimulus (e.g., hypoxia, hyperoxia, or psychosocial stress) and a unique window of development; the same stimulus experienced beyond the boundaries of this critical window of plasticity (e.g., at maturity), therefore, will have little if any appreciable effect on the phenotype. However, there are major gaps in our understanding of the mechanistic basis of developmental plasticity. Filling these gaps in our knowledge may be crucial to advancing our understanding of the developmental origin of adult health and disease. In this review, we: i) begin by clarifying some ambiguities in the definitions of plasticity and related terms that have arisen in recent years; ii) describe various levels of the respiratory control system where plasticity can (or has been identified to) occur; iii) emphasize the importance of understanding the mechanistic basis of developmental plasticity; iv) consider factors that influence whether developmental plasticity is permanent or whether function can be restored; v) discuss genetic and sex-based variation in the expression of developmental plasticity; and vi) provide a translational perspective to developmental plasticity.
Non-invasive epicutaneous vaccine against Respiratory Syncytial Virus: Preclinical proof of concept
2016, Journal of Controlled Release
Citation Excerpt :
The development of a safe and effective RSV vaccine for infants in the first six months of life is a public health challenge for reducing the severe burden of RSV-associated respiratory diseases, especially bronchiolitis and hospitalizations. Globally, it is estimated that RSV causes > 30 million lower respiratory tract infections each year resulting in > 3 million hospitalizations, making it the most common cause of hospitalizations in children under 5 [1]. Moreover, severe RSV incidence is highest in infants younger than 5 months.
To put a Respiratory Syncytial Virus (RSV) vaccine onto the market, new vaccination strategies combining scientific and technical innovations need to be explored. Such a vaccine would also need to be adapted to the vaccination of young children that are the principal victims of acute RSV infection. In the present project, we describe the development and the preclinical evaluation of an original epicutaneous RSV vaccine that combines two technologies: Viaskin® epicutaneous patches as a delivery platform and RSV N-nanorings (N) as a subunit antigen. Such a needle-free vaccine may have a better acceptability for the vaccination of sensible population such as infants since it does not require any skin preparation. Moreover, this self-applicative vaccine would overcome some issues associated to injectable vaccines such as the requirement of sterile medical devices, the need of skilled health-care professionals and the necessity of stringent store conditions. Here, we demonstrate that Viaskin® patches loaded with a formulation containing N-nanorings (Viaskin®-N) are highly immunogenic in mice and promotes a Th1/Th17 oriented immune response. More importantly, Viaskin®-N epicutaneous vaccine confers a high level of protection against viral replication upon RSV challenge in mice, without exacerbating clinical symptoms. In swine, which provides the best experimental model for the transcutaneous passage of drug/antigen in human skin, we have shown that GFP fluorescent N-nanorings, delivered epicutaneously with Viaskin® patches, are taken up by epidermal Langerhans cells. We have also demonstrated that Viaskin®-N induced a significant RSV N-specific T-cell response in pig. In conclusion, Viaskin®-N epicutaneous vaccine seems efficient to protect against RSV infection in animal model.
Acute bronchiolitis and chest physiotherapy: The end of a reign
2015, Journal Europeen des Urgences et de Reanimation
Chaque hiver, la bronchiolite aiguë du nourrisson est responsable d’un grand nombre d’hospitalisations. Son traitement est avant tout symptomatique et a été codifié lors d’une conférence de consensus de la Haute Autorité de santé (HAS) en 2000. La kinésithérapie respiratoire y avait été mise en avant pour lutter contre l’encombrement et l’obstruction bronchique. Même si les techniques diffèrent d’un pays à l’autre, elle est devenue quasi systématique dans la prise en charge de la bronchiolite aiguë du nourrisson. Mais qu’en est-il réellement de son efficacité ou de sa légitimité ? L’objectif de notre étude était de faire la revue de la littérature sur ce sujet. Peu d’études sont disponibles avec de faibles niveaux de preuve. Elles tendent à montrer que la kinésithérapie respiratoire n’aurait qu’un faible intérêt dans la prise en charge de la bronchiolite aiguë du nourrisson ne modifiant pas l’histoire naturelle de la maladie ou la durée d’hospitalisation. Au total, on ne peut recommander de manière systématique la kinésithérapie chez les nourrissons hospitalisés pour bronchiolite aiguë.
Every winter, numerous infants are hospitalized for acute bronchiolitis. The severity criteria and symptomatic treatment are well known, with chest physiotherapy codified in 2000 by the French Health Authority (HAS) consensus conference (with techniques varying from one country to another) and becoming nearly systematic for the treatment of bronchial obstruction in infants. However, is this treatment really effective and legitimate for acute bronchiolitis? The objective of this study was to review the main studies on this subject. Few studies are available and most have a low level of evidence. However, they all tend to agree that chest physiotherapy does not change the natural history of the disease and most particularly the duration of hospitalization. Therefore, it does not seem that the prescription of chest physiotherapy in infant acute bronchiolitis is recommended.
Acute bronchiolitis and chest physiotherapy: The end of a reign
2015, Archives de Pediatrie
Chaque hiver, la bronchiolite aiguë du nourrisson est responsable d’un grand nombre d’hospitalisations. Son traitement est avant tout symptomatique et a été codifié lors d’une conférence de consensus de la Haute Autorité de santé (HAS) en 2000. La kinésithérapie respiratoire y avait été mise en avant pour lutter contre l’encombrement et l’obstruction bronchique. Même si les techniques diffèrent d’un pays à l’autre, elle est devenue quasi systématique dans la prise en charge de la bronchiolite aiguë du nourrisson. Mais qu’en est-il réellement de son efficacité ou de sa légitimité ? L’objectif de notre étude était de faire la revue de la littérature sur ce sujet. Peu d’études sont disponibles avec de faibles niveaux de preuve. Elles tendent à montrer que la kinésithérapie respiratoire n’aurait qu’un faible intérêt dans la prise en charge de la bronchiolite aiguë du nourrisson ne modifiant pas l’histoire naturelle de la maladie ou la durée d’hospitalisation. Au total, on ne peut recommander de manière systématique la kinésithérapie chez les nourrissons hospitalisés pour bronchiolite aiguë.
Every winter, numerous infants are hospitalized for acute bronchiolitis. The severity criteria and symptomatic treatment are well known, with chest physiotherapy codified in 2000 by the French Health Authority (HAS) consensus conference (with techniques varying from one country to another) and becoming nearly systematic for the treatment of bronchial obstruction in infants. However, is this treatment really effective and legitimate for acute bronchiolitis? The objective of this study was to review the main studies on this subject. Few studies are available and most have a low level of evidence. However, they all tend to agree that chest physiotherapy does not change the natural history of the disease and most particularly the duration of hospitalization. Therefore, it does not seem that the prescription of chest physiotherapy in infant acute bronchiolitis is recommended.

View all citing articles on Scopus

View full text

Respiratory syncytial virus: How, why and what to do

Summary

Section snippets

The virus

Epidemiology and global burden of RSV

Vitamin D and bronchiolitis

Molecular diagnosis and co-infections

Viral load

Etiologic diagnosis of bronchiolitis: is it relevant?

Palivizumab and motavizumab

Conflict of interest

Lancet

Lancet

Diagn Microbiol Infect Dis

J Allergy Clin Immunol

Viral and host factors in human respiratory syncytial virus pathogenesis

J Virol

Hospitalizations associated with influenza and respiratory syncytial virus in the United States, 1993–2008

Clin Infect Dis

Risk factors in children hospitalized with RSV bronchiolitis versus non-RSV bronchiolitis

Pediatrics

Cord-blood 25-hydroxyvitamin D levels and risk of respiratory infection, wheezing, and asthma

Pediatrics

Low serum 25-hydroxyvitamin D levels are associated with increased risk of viral coinfections in wheezing children

J Allergy Clin Immunol

Cord blood vitamin D deficiency is associated with respiratory syncytial virus bronchiolitis

Pediatrics

Randomized trial of vitamin D supplementation and risk of acute respiratory infection in Mongolia

Pediatrics

Sole pathogen in acute bronchiolitis: is there a role for other organisms apart from respiratory syncytial virus?

Pediatr Infect Dis J

The impact of dual viral infection in infants admitted to a pediatric intensive care unit associated with severe bronchiolitis

Pediatr Infect Dis J

Dual infection of infants by human metapneumovirus and human respiratory syncytial virus is strongly associated with severe bronchiolitis

J Infect Dis

Detection of new respiratory viruses in hospitalized infants with bronchiolitis: a three-year prospective study

Acta Paediatr