Best practice in the prevention and management of paediatric respiratory syncytial virus infection

Abstract

Respiratory syncytial virus (RSV) infection is ubiquitous with almost all infants having been infected by 2 years of age and lifelong repeated infections common. It is the second largest cause of mortality, after malaria, in infants outside the neonatal period and causes up to 200,000 deaths per year worldwide. RSV results in clinical syndromes that include upper respiratory tract infections, otitis media, bronchiolitis (up to 80% of cases) and lower respiratory tract disease including pneumonia and exacerbations of asthma or viral-induced wheeze. For the purposes of this review we will focus on RSV bronchiolitis in infants in whom the greatest disease burden lies. For infants requiring hospital admission, the identification of the causative respiratory virus is used to direct cohorting or isolation and infection control procedures to minimize nosocomial transmission. Nosocomial RSV infections are associated with poorer clinical outcomes, including increased mortality, the need for mechanical ventilation and longer length of hospital stay. Numerous clinical guidelines for the management of infants with bronchiolitis have been published, although none are specific for RSV bronchiolitis. Ribavirin is the only licensed drug for the specific treatment of RSV infection but due to drug toxicity and minimal clinical benefit it has not been recommended for routine clinical use. There is currently no licensed vaccine to prevent RSV infection but passive immunoprophylaxis using a monoclonal antibody, palivizumab, reduces the risk of hospitalization due to RSV infection by 39–78% in various high-risk infants predisposed to developing severe RSV disease. The current management of RSV bronchiolitis is purely supportive, with feeding support and oxygen supplementation until the infant immune system mounts a response capable of controlling the disease. The development of a successful treatment or prophylactic agent has the potential to revolutionize the care and outcome for severe RSV infections in the world’s most vulnerable infants.

Introduction

Respiratory syncytial virus (RSV) infection is the second largest cause of mortality, after malaria, in infants outside the neonatal period and causes up to 200,000 deaths per year worldwide [Nair et al. 2010; Lozano et al. 2012]. In developed nations it is the leading cause of hospitalization in infancy. In the UK there are approximately 30,000 hospitalizations (1–3% of the entire birth cohort) and over 900 paediatric intensive care unit (PICU) admissions per year [Green et al. 2015b], representing a huge healthcare burden and associated cost. In addition, recent data from the USA suggests RSV in older adults has as significant a burden on healthcare services and winter mortality as influenza [McClure et al. 2014a; Widmer et al. 2014; Reed et al. 2015]. In temperate climates, such as the UK, RSV infection occurs in seasonal epidemics, whereas more tropical areas experience RSV activity throughout the year [Welliver, 2007]. RSV infection results in clinical syndromes that include upper respiratory tract infections, otitis media, bronchiolitis and lower respiratory tract infections including pneumonia and exacerbations of asthma- or viral-induced wheeze. For the purposes of this review we will focus on RSV bronchiolitis in infants in whom the greatest disease burden lies. Many studies that investigate RSV and other viral bronchiolitis have only included infants with a very strict set of diagnostic criteria (e.g. no previous episodes of wheezing or less than 1 year of age); however, in the ‘real world’ many infants will be diagnosed with bronchiolitis who do not fulfil these very specific criteria, thus care must be taken when interpreting the results of these studies and in subsequently infant management.

RSV bronchiolitis

Bronchiolitis is an inflammation of the small airways, the bronchioles. In the USA and other developed countries between 50% and 80% of cases of viral bronchiolitis causing hospitalization [Miller et al. 2013; Meissner, 2016] and approximately 20% of emergency department and outpatient visits due to viral bronchiolitis are caused by RSV [Hall et al. 2009]. These estimates vary between countries. RSV bronchiolitis is diagnosed clinically when infants typically present with a short history of coryzal symptoms and reduced feeding. Most have only a low-grade fever but up to 30% may have a fever over 39°C. There is often contact with a family member (especially school age siblings) or a carer who has recently suffered respiratory symptoms. Bronchiolitis can be diagnosed in children up to 2 years old, although most are less than 1 year old. Common differential diagnoses include viral-induced wheeze or asthma, pertussis infection and gastro-oesophageal reflux disease. In particular, differentiating bronchiolitis from viral-induced wheeze or asthma can be very difficult. A trial of a bronchodilator may help with this (see below).

After RSV infects the upper respiratory tract there is an incubation period of 2–8 days before clinical symptoms occur [Hall, 2001]. Viral replication in the nasopharyngeal epithelium usually leads to mild coryzal symptoms. Within 1–3 days RSV infection spreads to the lower respiratory tract causing cough, dyspnoea and cyanosis. It is not clear why some infants go on to develop lower respiratory tract signs while others do not, but there is some evidence that reduced lung function or a genetic predisposition may play a role in both term and prematurely born infants [Janssen et al. 2007; Drysdale et al. 2011, 2014; Zomer-Kooijker et al. 2014]. Clinical examination findings include prolonged expiration, wheeze, crepitations and signs of respiratory distress [Hall, 2001]. In addition, infants may present with only apnoea, especially those born prematurely, those with bronchopulmonary dysplasia [Meert et al. 1989] or those less than 3 months old [Ralston and Hill, 2009]. Risk factors for more severe disease include premature birth, chronic lung disease, haemodynamically significant congenital heart disease, age less than 3 months, neuromuscular disorders and immunodeficiency [NICE, 2015]. Infants seen in primary care with marked respiratory distress, oxygen saturations less than 92% on air, significantly reduced feeding, clinical dehydration or a history of apnoea require referral to hospital for consideration of hospital admission [NICE, 2015].

Clinical usefulness of respiratory virus testing

For most infants with viral bronchiolitis the course of illness does not progress beyond a mild, self-limiting illness and thus testing for RSV or other respiratory viruses is of limited clinical value. The rapid diagnosis of RSV in primary care and emergency departments via point of care tests can potentially be used to increase confidence in the clinical diagnosis, increase the confidence needed to withhold empirical antibiotics and in communication with parents, although there is limited evidence for this in clinical practice [Thibeault et al. 2007; Flaherman et al. 2010; Mills et al. 2011; Stollar et al. 2014]. In infants requiring hospital admission, the identification of the causative respiratory virus allows for cohorting or isolation and infection control management to minimize nosocomial transmission (see below). In the UK and many other countries cases of confirmed RSV infection are reported routinely by the public health department to build a national epidemiological picture of the high-transmission periods (seasonal epidemics; October–March in the UK) that can then be used to prepare and manage healthcare resources.

Transmission of RSV infection and preventing nosocomial infection in hospital

RSV is highly transmissible with a basic reproduction number (the average number of uninfected people who become infected from one infectious person) estimated to be between 5 and 25 [Weber et al. 2001; Kinyanjui et al. 2015], making the virus a major nosocomial hazard on paediatric wards. RSV from infected infants can survive on fomites (including paper tissues, beds, table tops and toys) for up to 6 h [Hall et al. 1980]. In addition, RSV can survive on contaminated skin (e.g. hands) for up to 25 min [Hall et al. 1980]. Risk factors for patients developing nosocomial RSV infection in hospital include age less than 5 months, prematurity and chronic lung disease of prematurity [Simon et al. 2008]. Nosocomial RSV infections account for 3–13% of cases of hospitalized paediatric respiratory infections during the RSV season [Langley et al. 1997] and are associated with poorer clinical outcomes, including increased mortality, need for mechanical ventilation and longer length of hospital stay [Simon et al. 2008]. While the factors that drive severity in this context are not fully understood it is likely that the increased risk is related to the level and duration of virus exposure on the ward. At the height of an RSV epidemic, paediatric wards are effectively a confluence of RSV-infected infants [Widmer et al. 2014; Reed et al. 2015] and clinical staff [Hall et al. 2009; McClure et al. 2014b] who shed the virus for prolonged periods and collectively establish a continuous exposure risk that is probably greater both in magnitude and duration than community-level exposure. In addition to being a source of nosocomial infection, the enhanced exposure conditions on paediatric wards are likely to increase the risk of super infection with different strains of the virus. There is evidence that up to 10% of RSV-infected infants are at risk of becoming reinfected within several days or weeks of the primary infection [Munywoki et al. 2015].

Several studies have shown that strict infection control practices including hand hygiene, the use of personal protective equipment (gloves, single use aprons, masks and goggles), timely detection and isolating or cohorting infants with RSV infection can reduce nosocomial RSV infection rates by 39–67% [Hall et al. 1978; Doherty et al. 1998; Karanfil et al. 1999; Macartney et al. 2000; Thorburn et al. 2004; Groothuis et al. 2008]. Nosocomial RSV infection has also been shown to have a significant financial cost. One study from Canada showed nosocomial RSV infection added 30% to the total hospitalization costs for the treatment of community-acquired severe RSV infection [Jacobs et al. 2013]. Statistical modelling estimated strict infection control procedures could result in a net saving of Canadian $469 per case of RSV infection [Jacobs et al. 2013]. Another study from the USA showed that for every US$1 spent on infection control practices, US$6 were saved from a reduction in nosocomial RSV infection costs [Macartney et al. 2000].

Although the UK National Institute for Health and Care Excellence (NICE) bronchiolitis guideline does not include advice on infection control procedures [NICE, 2015], the American Academy of Pediatrics (AAP) guidance [Ralston et al. 2014] recommends using strict infection control practices and isolating or cohorting RSV-positive infants to reduce nosocomial infection. There has, however, been recent debate about the role of cohorting infants with viral bronchiolitis in view of the fact that up to 30% of infants will have multiple viruses detected from their respiratory tract at diagnosis [Mansbach et al. 2012].

Preventing RSV bronchiolitis

Although there is currently no vaccine against RSV, passive immunization is available. Palivizumab is a humanized mouse monoclonal antibody that targets the surface expressed fusion (F) protein of the RSV virus. It has been shown to reduce the risk of hospitalization by 39–78% in various groups of infants predisposed to developing severe RSV disease [e.g. prematurely born infants with or without bronchopulmonary dysplasia (BPD) or infants with haemodynamically significant congenital heart disease] [The IMpact-RSV Study Group, 1998; Feltes et al. 2003]. In addition, palivizumab reduces the relative risk of moderately prematurely born infants with an RSV infection requiring medical attention, but not requiring hospitalization, by nearly 80% [Blanken et al. 2013]. As palivizumab is very expensive (but soon to come off patent) and has a half life of 18–21 days, meaning monthly injections are required to maintain protective titres, cost–benefit analyses limit its use to only the most vulnerable infants; those born prematurely with moderate or severe BPD, haemodynamically significant, acyanotic congenital heart disease, severe combined immunodeficiency or infants with other severe chronic lung conditions or requiring long-term ventilation [Public Health England, 2015]. Another monoclonal antibody, motavizumab, is up to 100 times more potent than palivizumab and has recently been shown to result in an 87% relative reduction in hospitalization due to RSV infection in otherwise healthy term born infants in a phase III clinical trial [O’Brien et al. 2015]. Currently only palivizumab is licensed for RSV prophylaxis; however, motavizumab and other similar products that are in development may become available in the future.

Parental smoking is a known risk factor for RSV infection in infancy and thus parents or carers who smoke should be offered smoking cessation advice. Also breastfeeding offers some protection against RSV infection [Simoes, 2003].

Investigations for viral bronchiolitis

All infants with suspected bronchiolitis, whether in primary care or in hospital, should have their oxygen saturations tested and those with oxygen saturations less than 92% require hospitalization and supplemental oxygen [NICE, 2015]. Blood tests, including blood gas analysis, and chest X-rays should be reserved for infants with severe bronchiolitis requiring high dependency or intensive care or those with atypical features of bronchiolitis [NICE, 2015]. In particular, chest X-rays should not be used to determine if antibiotics are required, as viral bronchiolitis changes may mimic those of bacterial pneumonia [NICE, 2015].

Treatments for viral bronchiolitis

Numerous clinical guidelines for the management of infants with bronchiolitis have been published [Scottish Intercollegiate Guideline Network, 2006; Baraldi et al. 2014; Friedman et al. 2014; Ralston et al. 2014; NICE, 2015], although none are specific for RSV bronchiolitis. One of the most widely used is the AAP guideline ‘The diagnosis, management, and prevention of bronchiolitis’ which was first published in 2006 [American Academy of Pediatrics, 2006] and has recently been updated [Ralston et al. 2014]. In England, NICE published a new bronchiolitis guideline in June 2015 [NICE, 2015]. Numerous interventions have been tried for the treatment of bronchiolitis but large meta-analyses have demonstrated none are beneficial except for supplemental oxygen and feeding support. It is possible, however, some as yet identified subgroups of infants with viral bronchiolitis may benefit from these treatments.

Ribavirin

Ribavirin is an antiviral agent that acts as a guanosine (ribonucleic) analogue. It is currently the only licensed drug for the specific treatment of RSV infection. Due to the side-effect profile (including bone marrow suppression and potential carcinogenicity and teratogenicity) [Turner et al. 2014] and minimal evidence of benefit it is not routinely advised for use in infants with RSV infection [Ventre and Randolph, 2007].

Bronchodilators

Many infants with bronchiolitis have wheeze and thus are often prescribed bronchodilators, including β2 agonists (e.g. salbutamol, albuterol) and anticholinergics (e.g. ipratropium bromide). A large meta-analysis [Gadomski and Scribani, 2014] including 30 clinical trials and nearly 2000 infants found bronchodilators did not reduce hospital admissions, length of hospital stay or the length of the course of the illness. In addition, side effects after bronchodilators were common and included tachycardia, tremor and oxygen desaturation. Bronchodilators are thus not routinely recommended for infants with bronchiolitis. In infants with a strong personal or family history of atopy with wheeze as the predominate symptom (without crackles on auscultation), and thus viral-induced-wheeze or asthma is a likely differential diagnosis, a trial using bronchodilators may be beneficial; however, if there is no clear response it should be discontinued [NICE, 2015]. A clear response includes a sustained improvement in oxygen saturations or reduction in respiratory distress.

Nebulized adrenaline (epinephrine)

There is some evidence that nebulized adrenaline may reduce hospital admissions in the short term (within 24 h) but this difference is no longer significant at 7 days [Hartling et al. 2011], and thus overall, nebulized adrenaline does not reduce hospital admissions. One randomized controlled trial [Plint et al. 2009] demonstrated a reduction in hospitalization if nebulized adrenaline and corticosteroids were used simultaneously; however, this was only found in an underpowered subanalysis. At present, therefore, there is insufficient evidence to support the routine use of nebulized adrenaline (with or without corticosteroids) in infants with bronchiolitis [NICE, 2015].

Corticosteroids

A recent meta-analysis including over 2500 infants found no benefit of systemic or inhaled corticosteroids in viral bronchiolitis either in reducing admission to hospital or reducing length of stay [Fernandes et al. 2010]. Considering the potential side effects of corticosteroids (including reduced growth and bone mineral density) their routine use should be avoided, although worryingly we have recently demonstrated 19% of general practitioners in the UK routinely prescribe oral steroids for infants with bronchiolitis (unpublished observation).

Nebulized hypertonic saline

Nebulized hypertonic saline acts as a mucolytic and theoretically could reduce airway secretions. Several large trials have demonstrated some benefit of nebulized hypertonic saline on reducing hospital length of stay [Zhang et al. 2015]. However, this benefit is only apparent in infants who have been hospitalized for more than 72 h, and the vast majority of infants are hospitalized for less than 48 h. A large randomized controlled trial and economic evaluation in the UK found no evidence for the benefit of hypertonic saline [Everard et al. 2015]. Recent NICE guidance suggests hypertonic saline should not routinely be used [NICE, 2015] and the AAP guidance suggests its use should only be considered in those infants with a prolonged length of stay [Ralston et al. 2014].

Leukotriene receptor antagonists

Few studies [Liu et al. 2015] have investigated the role of leukotriene receptor antagonists (e.g. montelukast) in infants with bronchiolitis and none have demonstrated a benefit of montelukast over placebo. At present there is insufficient evidence to support their routine use.

Antibiotics

One large prospective study in the USA demonstrated only 1.2% of infants with severe RSV bronchiolitis developed proven secondary bacterial infection [Hall et al. 1988]. Infants with a clear diagnosis of viral bronchiolitis, whether or not RSV is proven virologically, should not receive prophylactic antibiotics [Farley et al. 2014]. Antibiotics should be considered for infants with signs of a secondary bacterial infection.

Heliox

Although heliox may reduce clinical scores in the first few hours after starting, it has not been shown to reduce hospital admissions, length of stay or need for mechanical ventilation [Liet et al. 2010]. The routine use of heliox is, therefore, not recommended but more research is needed in this area.

Physiotherapy

Otherwise well infants with bronchiolitis who are not mechanically ventilated should not receive physiotherapy as it has no impact on outcomes [Roque I Figuls et al. 2012]. However, for those infants with difficulty in clearing secretions (e.g. cystic fibrosis and neuromuscular disorders), physiotherapy should be considered [NICE, 2015].

As a result of the lack of evidence of efficacy for these interventions, the current routine management of viral bronchiolitis is purely supportive with feeding support and oxygen supplementation. Infants who are unable to take sufficient fluid orally (at least 50% of normal) should be commenced on either naso- or orogastric feeding or intravenous fluid [Ralston et al. 2014; NICE, 2015].

In infants who have been hospitalized, discharge criteria include the triad of the infant being clinically stable, taking sufficient oral fluids and persistent oxygen saturation greater than 92% on air [NICE, 2015].

Chronic respiratory morbidity after RSV bronchiolitis

Infants who are recovering from RSV bronchiolitis can continue to have respiratory symptoms including cough and wheeze for several weeks (‘post-bronchiolitis wheeze’). Up to 50% of those admitted to hospital for RSV bronchiolitis will continue to have episodes of recurrent wheeze for several years [Nenna et al. 2015]. There is no evidence for the use of steroids, montelukast or other medications in preventing these symptoms but the acute episodes often respond to anti-asthma medication. Most children will eventually grow out of these symptoms, although in some they will persist [Stein et al. 1999]. The odds ratio for a hospital admission for asthma between the ages of 2 and 14 years in those who were hospitalized with severe bronchiolitis (all causes) in infancy is estimated at 2.8 in the UK [Green et al. 2015b]. One recent study has demonstrated a significant reduction in parent-reported wheezing days in premature infants in the first year of life with palivizumab prophylaxis, implying a causal relationship between RSV infection early in life and the development of wheeze [Blanken et al. 2013]. Contrary to this, however, the recent motavizumab study found no reduction in post-RSV bronchiolitis wheezing in those term-born infants who received motavizumab despite a reduction in RSV infections [O’Brien et al. 2015].

Future horizons in RSV vaccines and other anti-RSV therapeutics

The last 10 years have seen renewed interest in the development of clinical interventions against RSV [PATH, 2015]. Trials of novel antivirals such as GS-5806, an oral viral entry inhibitor [DeVincenzo et al. 2014b], ALN-RSV01, an siRNA based therapy [DeVincenzo et al. 2010] and ALS-008176, a nucleoside analogue [DeVincenzo et al. 2014a] have been shown to effectively restrict virus replication in controlled human infection studies while novel technologies such as Llama-derived single domain antibodies (nanobodies) provide protection from infection in murine studies and have now progressed to clinical development [Schepens et al. 2011]. These encouraging results have increased optimism that a clinically effective antiviral therapy targeted at high-risk groups may be on the horizon and could become available for clinical use within a few years.

Development of RSV vaccines continues apace with the adoption of novel platforms of antigen delivery. Previous difficulties with RSV vaccine development have included concerns over safety, particularly with live-attenuated vaccines after the unsuccessful RSV vaccine trial in the 1960s [Kapikian et al. 1969] and include enhanced disease, nasal congestion (young infants being obligate nasal breathers), genetic instability, vaccine virus transmission and limited immunogenicity, and an incomplete understanding of the immune correlates of protection [Green et al. 2015b]. These issues are, however, slowly being overcome. In the last 3 years live virus vectored vaccines [Green et al. 2015a] and nanoparticle based vaccines [Glenn et al. 2013] have been tested in phase I and II clinical trials and have exhibited excellent safety and immunogenicity profiles with some early evidence of efficacy [Glenn et al. 2015]. As these products progress into later phase clinical evaluation there is hope that an effective vaccine for populations at risk of developing severe RSV disease (including infants and older people) may become available within a decade. Palivizumab remains the only research development success available to clinicians facing the burden of RSV disease. In spite of its demonstrated effectiveness, the high cost of this intervention precludes its systematic use in all but the highest risk patients, even in the most resource rich settings. There is, however, renewed hope that this proven prophylactic approach may soon come into widespread use. With the recent expiry of MedImmune’s patent on palivizumab the opportunity has now arisen for the development of cost-effective biosimilar versions of palivizumab. The World Health Organization has recently established a new technology transfer hub with the aim of developing a platform for the accelerated production and deployment of biosimilar products to the market at an affordable cost [Humphreys, 2015]. If successful, this and similar initiatives are likely to have a huge impact on the global mortality burden by establishing access to immunoprophylaxis for high-risk infants in resource-poor settings where the vast majority of RSV attributable deaths occur [Nair et al. 2011].

Summary

RSV is a ubiquitous infection that is associated with huge morbidity and mortality and associated healthcare use and cost, especially in infants. Although currently there are no active treatments, and thus routine management is purely supportive care, there are new RSV vaccines and antiviral medications on the horizon. The development of a successful treatment or prophylactic agent has the potential to revolutionize the care and outcome for severe RSV infections in the world’s most vulnerable infants.

Funding

The authors received no financial support for the research, authorship, or publication of this article.

Conflict of interest statement

The authors declared no potential conflicts of interest with respect to the research, authorship, or publication of this article.