Respiratory syncytial virus infection in adults
BMJ 2019; 366 doi: https://doi.org/10.1136/bmj.l5021 (Published 10 September 2019) Cite this as: BMJ 2019;366:l5021
- Hannah H Nam, senior fellow,
- Michael G Ison, professor
- Division of Infectious Diseases and Organ Transplantation, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Correspondence to: M G Ison mgison{at}northwestern.edu
ABSTRACT
Human respiratory syncytial virus (RSV) belongs to the recently defined Pneumoviridae family, Orthopneumovirus genus. It is a negative sense, single stranded RNA virus that results in epidemics of respiratory infections that typically peak in the winter in temperate climates and during the rainy season in tropical climates. Generally, one of the two genotypes (A and B) predominates in a single season, alternating annually, although regional variation occurs. RSV is a cause of disease and death in children, older people, and immunocompromised patients, and its clinical effect on adults admitted to hospital is clarified with expanded use of multiplex molecular assays. Among adults, RSV produces a wide range of clinical symptoms including upper respiratory tract infections, severe lower respiratory tract infections, and exacerbations of underlying disease. Here we discuss the latest evidence on the burden of RSV related disease in adults, especially in those with immunocompromise or other comorbidities. We review current therapeutic and prevention options, as well as those in development.
Introduction
Human respiratory syncytial virus (RSV) belongs to the recently defined Pneumoviridae family, Orthopneumovirus genus,12 and was discovered more than 60 years ago.3 RSV has since been recognized as one of the most common causes of acute respiratory tract infections in adults. RSV has a particularly significant effect on disease and death in children,4 older people, and immunocompromised adults.56 An estimated 1.5 (95% confidence interval 0.3 to 6.9) million episodes of RSV related acute respiratory illness occurred in older adults in industrialized countries worldwide in 2015, and of these episodes approximately 14.5% involved a hospital admission. Globally, an estimated 14 000 in-hospital deaths in 2015 were associated with RSV related acute respiratory illness.7 Adults infected with RSV can have variable clinical findings that range in severity from mild respiratory symptoms to severe lower respiratory tract infection (LRTI). Host immunity to RSV diminishes over time and can lead to recurrent infections.8 This review will focus on the latest evidence on RSV infections and its effects in adults, including the virology, epidemiology, clinical manifestations, available treatments, and preventive strategies. Although the main focus of this review is on RSV in adults, gaps in research in adults still exist, so data from children will also be used when relevant.
Sources and selection criteria
Our search was broad and included references in PubMed and Medline between 1957 and 2019. We also identified references from the similar items section in PubMed. Search terms included but were not limited to “RSV” and “Orthopneumovirus”, in conjunction with “therapeutics”, “vaccine”, “maternal vaccine”, “epidemiology”, “adults”, and “immunocompromise”. We also searched guidelines and consensus statements. We screened and reviewed more than 200 articles for the preparation of this manuscript. We used relevant review articles and reviewed them for evaluation of references. We individually reassessed and used these references in the review when relevant. As many of the studies on RSV in adults were case series, we included only those with more than 10 patients. Because this was not a formal systematic review, we did not grade the included studies but summarized key outcomes or results. We included observational and animal studies if they were published in peer reviewed journals and clinically relevant. We searched clinical trial information through ClinicalTrials.gov.
Epidemiology
In countries with temperate climates, RSV circulates throughout the winter season and peaks between December and January.9 In tropical countries, outbreaks of RSV still occur during hot, humid, and rainy days in the summer season.10 Generally, one of the two genotypes (A and B) predominates in a single season, and they alternate or co-circulate annually, although regional variation occurs. Whether RSV genotype predicts virulence and disease severity remains unclear owing to conflicting data in children.11121314 Recent methods such as next generation sequencing have provided high resolution understanding of the phylogenetic adaptation that occurs in RSV in the community.15
Most studies of the epidemiology of RSV in adults have important limitations as they focus on selected groups at risk, and older studies used non-molecular techniques with decreased sensitivity for the diagnosis of RSV. Data derived from clinical testing are limited by reduced frequency of testing in the ambulatory setting, particularly among older people and adults who present later to clinical care.1617
Despite most initial and severe infections occurring during early childhood, RSV is increasingly recognized as a common cause of respiratory illness in adults. RSV is the causative agent in up to 12% of medically attended acute respiratory illnesses.18 Although less than 1% of adults affected are estimated to need admission to hospital,19 RSV is the third most commonly identified viral cause of admission, accounting for approximately 177 000 hospital admissions and 17 000 excess deaths, mostly in adults over the age of 65.52021 The average length of stay for patients admitted to hospital with RSV is three to six days, with an overall mortality of 6-8%.18 Among adults admitted to hospital who have a positive RSV test, approximately 10-31% need to be admitted to an intensive care unit, with 3-17% needing mechanical ventilation.18
One large prospective study conducted over three successive influenza seasons (2006-09) found RSV to be associated with a higher rate of hospital admission than both human metapneumovirus and influenza (15.01, 9.82, and 11.82 per 10 000 residents, respectively).22 Among all adults, RSV attributed mortality is generally estimated to be less than 1%,2324 although RSV may account for as much as 25% of the excess winter mortality that historically was attributed solely to influenza.20
As most RSV infections in adults are not their first infection, most patients experience mild to moderate clinical disease. Risk factors for progression to viral pneumonia and complications include Down’s syndrome, compromised immunity (including patients receiving chemotherapy or chronic immunosuppression for connective tissue disease/vasculitis), underlying lung disease (especially asthma) or heart disease, old age, frailty, living in a long term care facility, and living at high altitude.25262728 Among immunosuppressed patients, the greatest burden is seen in recipients of hematopoietic stem cell transplants (HSCT) and lung transplants, who have an incidence of RSV of 12-16%.2930 Although the rates of medically attended RSV vary depending on season and diagnostic methods, outcomes are generally consistent in showing increased incidence with age, with the highest annual mortality rate from RSV associated pneumonia in adults aged 65 years or above (7.2 per 100 000 person years).1820
Recent studies have identified several genetic markers as being associated with enhanced risk of severe RSV disease. Polymorphisms in cytokine and chemokine related genes including interleukin 4 and its receptor, interleukin 8, interleukin 10, interleukin 13, and chemokine receptor 5, as well as polymorphisms in genes associated with virus cell surface interactions or cell signaling such as toll-like receptor 4, chemokine receptor 1, surfactant protein A, and surfactant protein D, have been associated with severe RSV disease.31
Virology
RSV was reclassified in 2016 into the family Pneumoviridae, genus Orthopneumoviridae. Before this reclassification the taxon Pneumoviridae was a subfamily within the Paramyxoviridae.12 RSV is a medium sized (120-300 nm diameter) pleomorphic enveloped virus with a non-segmented, negative sense, single stranded RNA genome (~15-16 kb), which encodes 11 proteins: two non-structural and nine structural proteins (fig 1). G (attachment), F (fusion), and SH (proposed viroporin) are hydrophobic transmembrane surface glycoproteins that are important for infectivity, as maximally efficient fusion requires participation of all three of these surface glycoproteins.3233 These surface glycoproteins can also serve as the focus of protective antibodies and are therefore potential therapeutic targets. G primarily mediates virus attachment to host cells by targeting ciliated cells of the airways. Following attachment, F undergoes structural changes into a post-triggered form that allows viral penetration by fusing viral and host cellular membranes, as well as facilitating micropinocytosis.3435 This further promotes the fusion of infected cells to adjacent uninfected cells, resulting in the characteristic RSV syncytia from which the name of the virus derives. Both F and G protein are antigens that produce protective immunity and are important in the initial phases of infection as targets for antibody mediated neutralization. G has moderate to high sequence diversity and defines the antigenic groups A and B, whereas F is highly conserved between strains and is recognized by broadly cross neutralizing antibodies; it is therefore an attractive candidate as an RSV vaccine antigen.3637 The pre-fusion form of the F protein is more effective than the post-fusion form in stimulating higher titers of optimally neutralizing antibodies.3438
Structure of human Orthopneumovirus (respiratory syncytial virus)
The M (matrix) protein accumulates at the inner surface of the envelope and is important in viral morphogenesis. Four nucleocapsid associated proteins function as viral transcription factors: N (nucleoprotein), phosphoprotein (P), large (L), and M1-M2 proteins. Two non-structural proteins, NS1 and NS2, can inhibit cellular type I interferon activity.36
RSV isolates are divided into two major antigenic groups, A and B, which are further divided into 13 RSV A genotypes and 20 RSV B genotypes.3940 The major genetic diversity between A and B resides within the G protein, with about 50% genetic differences,41 followed by MH-2 and SH proteins. Strains of both groups can circulate simultaneously during outbreaks, but the proportions of A and B, as well as subtypes, vary yearly.
Transmission
RSV is effectively transmitted by large nasopharyngeal secretion droplets from infected people; aerosolization is less important. Transmission generally occurs when these droplets enter via the mucous membranes of the eyes, nose, and mouth after close contact or by self inoculation through touching contaminated surfaces.4243 Large particle aerosols may transmit within a radius of 3 feet.42 The virus can remain stable for several hours on hard surfaces and hands, transmitting by direct contact with contaminated objects.
The risk of transmission varies by the target population and care settings, from 6-12% (median 7%) in inpatient units with immunocompromised adults such as those with hematologic cancers and/or HSCT recipients, to 30-32% in other adult care settings.44 To decrease nosocomial transmission, a wide range of multicomponent infection control policies have been studied, including prompt RSV case finding among patients with symptoms, screening all patients on admission, screening staff and/or visitors, isolation policies and/or staff/patient cohorting, restriction of visitors (no young children), and staff training and/or compliance monitoring. Unfortunately, as many of the studies on RSV transmission have used multicomponent measures, assessing the effectiveness of individual components of these control measures is difficult. The guidelines from the Centers for Disease Control recommend contact precautions for the duration of illness, as well as wearing a mask according to standard precautions, and extending the duration of contact precautions in immunocompromised patients owing to prolonged shedding.45 The use of masks with eye-nose goggles may be beneficial in decreasing the rate of RSV illnesses in healthcare workers looking after children.46 Older studies provided conflicting data on the utility of wearing gowns and masks to decrease nosocomial transmission.474849 Two more recent studies show a clearer correlation with more universal mask use, particularly for people in contact with HSCT patients.5051 Data on the use of palivizumab to control nosocomial spread in immunocompromised adults are insufficient.52
Pathogenesis
RSV itself is not cytopathic, as it replicates almost exclusively in the highly differentiated, apical ciliated cells in human airways,53 resulting mainly in superficial damage to the airway lining. This damage to the airway predisposes the patient to secondary bacterial infections.54 It also provides RSV with a mechanism to evade systemic immunity, as the virus avoids exposure to dendritic cells that would be responsible for transporting the RSV antigen to lymph nodes.5355 Increased viral loads are thought to lead to an increase in neutrophilic inflammation of the upper and lower respiratory tracts,56 with the degree of inflammation in part determining the severity of disease. Interestingly, recent data suggest that higher viral load at presentation may be associated with less severe disease, whereas slow viral decay and higher overall viral exposure seem to be associated with more severe disease.57 Particularly severe cases of LRTI have been linked with increased eosinophils as well,58 but the role of eosinophilia is not clear in vaccine enhanced disease.5859
Both the protection and clearance of RSV are mediated by neutralizing antibodies and cytotoxic T cells.1260 Both serum IgG and mucosal IgA antibodies play important roles in protection against subsequent RSV infection. However, RSV is known to evade or suppress B memory cells in humans and suppresses the development of mucosal IgA memory responses in adults.61 The conformational change of pre-fusion to post-fusion F protein also allows RSV to prevent the immune system from creating more potent neutralizing antibodies.8 Both anti-RSV IgG and IgA titers wane rapidly over time in humans, with more than 75% of adults showing a fourfold reduction in neutralizing anti-RSV IgG titers within a year after natural RSV infection.626364 As a result, an antibody response to RSV does not confer lifelong protection, and RSV is able to re-infect the host throughout his or her lifetime.616566 Once infection is established, CD8 T cells are critical for viral clearance in both primary and secondary infections.60 Deficiencies in CD4 and cytotoxic CD8 T cells in patients with severe combined immunodeficiency, allogeneic stem cell transplantation, or lung transplantation have been associated with severe RSV infections.67 Older adults have been found to shed RSV for longer at higher titers, suggesting impaired cellular immunity.68
Diagnosis
RSV can be detected through serology, cell culture, antigen detection tests, and real time polymerase chain reaction (PCR) applied to samples collected from the upper or lower airway (table 1). Real time PCR is favored over other methods because of its superior assay sensitivity, specificity, time to virus identification, and breadth of pathogen detection. Serology (IgM and IgG) is not clinically useful in adults.77 Cell culture has fallen out of favor because of the long time to diagnosis, need for care with samples given the lability of the virus, need for well trained staff, and low sensitivity (17-39%) compared with serology or PCR.7778
Comparison of diagnostic methods for respiratory syncytial virus (RSV) in adults
Enzyme immunoassays for rapid antigen testing were developed as point-of-care tests with results available in 15-30 minutes and do not distinguish RSV serotypes. This method has significantly lower sensitivity in older adults than in children owing to lower viral loads.16 The sensitivity of first generation enzyme immunoassays for RSV in older adults is at best under 20%,79 so they cannot be recommended for general use.16 Second generation enzyme immunoassays were developed with improved sensitivities (~70%) but are still intended for patients under 20 years of age.80
Results of direct fluorescent antibody tests are rapidly available for RSV within about two hours. However, specimens need to be collected appropriately to include an adequate number of epithelial cells. The sensitivity is also low (23-74%), and these tests are not favored in adults.79 Much of the older surveillance data was obtained using direct fluorescent antibody testing, likely underestimating the true incidence of RSV A and RSV B.12
Reverse transcription polymerase chain reaction (RT-PCR) has become the gold standard in respiratory virus detection owing to is higher sensitivity (84-100%).81 Nasopharyngeal swabs are most commonly used and are more sensitive than oropharyngeal swab specimens.82 A recent study has shown that diluted sputum samples may provide a greater yield than nasopharyngeal swabs in adults, but further studies are needed.83 Mid-turbinate swabs have also been proposed but have not yet been studied in adults.84 Lower respiratory samples are preferred for patients with severe disease requiring intubation, as viral replication is higher in the lower respiratory tract in advanced diseases. Most commercial assays are highly multiplexed RT-PCR assays that not only detect RSV in addition to several other respiratory viruses but may also distinguish RSV serotypes (table 2).
Food and Drug Administration cleared reverse transcription polymerase chain reaction assays and other molecular assays for respiratory syncytial virus (RSV)85
Clinical presentation
Overall, RSV infection is not clinically distinguishable from other respiratory viruses.86 The clinical presentation of RSV varies from asymptomatic carriage through cold-like symptoms to acute respiratory distress. Asymptomatic infections are rare in adults or older people (<5%).8788 Most patients develop signs of upper respiratory tract infection (URTI) such as nasal congestion and rhinorrhea (22-78%) or sore throat (16-64%) three to five days after infection. Other non-specific symptoms such as asthenia, anorexia, and fever (48-56%) can also occur with varying severity. As the virus progresses to involve the lower respiratory tract, symptoms such as cough (85-95%), wheezing (33-90%), and dyspnea (51-93%) can develop.52381899091
Radiographic studies with computed tomography commonly show pulmonary nodules and ground-glass opacities, and standard chest radiographs may show changes consistent with pneumonia.2192 People infected with RSV more commonly present with nasal congestion, productive cough, and wheezing, and less frequently develop fever, compared with those infected with influenza viruses.2490
Lower respiratory tract infections and pneumonia
RSV causes severe LRTI, with one study from Hong Kong showing that up to 70% of adults admitted to hospital and found to have RSV had LRTI complications including pneumonia, acute bronchitis, or exacerbations of chronic obstructive pulmonary disease (COPD) or asthma.93 LRTI can further result in respiratory failure (8-13%) or death (2-5%).81 The rate of progression has also been associated with certain risk factors, such as tobacco use and lymphopenia.949596 Co-infection is common among adults with RSV infections, with 12.5-23.4% having bacterial co-infections and 21.8% having viral co-infections.2693 Adults with bacterial co-infection or superinfection are more likely to have a more severe disease course and enhanced mortality.2693
Of note, studies show that clinicians may still be hesitant to discontinue antibiotics despite positive respiratory panels, with or without negative procalcitonin values.97 A recent single center epidemiologic study found that clinicians were reluctant to discontinue antibiotics despite lack of cultures showing concomitant bacterial infection; antibiotic overuse was more common among patients with RSV than those with influenza (77% v 69%).98 Future studies will be needed to inform approaches to optimized antimicrobial use in patients with RSV infection.
Patients with comorbidities
Adults admitted to hospital and infected with RSV more often have underlying chronic lung diseases (35.6% v 24.1%) than do patients infected with influenza.93 RSV is a major cause of exacerbation of airway diseases such as asthma or COPD. Patients with multiple comorbidities (for example, COPD and congestive heart failure) are more likely to develop symptomatic RSV illness.99 Although often poorly recognized, cardiovascular disease seems to be a significant risk factor (45-63% of adults admitted to hospital with confirmed RSV).28100101 Among patients with underlying cardiovascular disease, admission is indicated for frequent exacerbations of congestive heart failure, arrhythmias, acute coronary syndromes, and even myocarditis.102103 Of all hospital admissions for congestive heart failure during respiratory viral season, 5.4% are estimated to be attributable to RSV infection.5 Mortality with these cardiovascular exacerbations seems to be higher when RSV infection is also present.93104 This highlights the need to consider RSV as a contributor for patients admitted with these cardiopulmonary complications and may be a focus for future therapeutic interventions.
Immunocompromised patients
Given the effect of RSV on immunocompromised patients, a sizable body of literature exists on the epidemiology, clinical presentation, and management of RSV in this population. Risk of severe disease and mortality from RSV is greatest among recipients of HSCT and lung transplants, although emerging data have highlighted enhanced risk among patients actively undergoing chemotherapy for leukemia and lymphoma as well.105106 Among adult HSCT recipients with RSV infection, progression from URTI to LRTI occurs in 40-60% of cases and LRTI is associated mortality rates of up to 80%.107108109110
Recently, studies have led to the development of two scores to estimate the risk of progressive disease and mortality among HSCT patients infected with RSV, based on recognized risk factors for progression. In the first system, patients are categorized as either having severe immunodeficiency defined as HSCT six months or less before diagnosis of RSV infection, T cell or B cell depletion three months or less before diagnosis, graft-versus-host disease grade 2 or higher, leukopenia (leukocyte count ≤2.0×109 cells/L), lymphopenia (lymphocyte count ≤0.1×109 cells/L), or hypogammaglobulinemia (immunoglobulin ≤6.5 g/L) or having moderate immunodeficiency defined as HSCT more than six months before the diagnosis of RSV infection, graft-versus-host disease grade less than 2, leukocyte count above 2.0×109 cells/L, lymphocyte count above 0.1×109 cells/L, receipt of maintenance immunosuppressive drugs, or T cell or B cell depletion more than three months before diagnosis of RSV infection. Patients with more than two severe immunodeficiency factors were found to have RSV attributed mortality rates of 18%.111 A second immunodeficiency scoring index for HSCT patients infected with RSV (ISI-RSV) was developed to predict risk of progression from URTI to LRTI and RSV associated mortality.112 The score is calculated by developing a total score with 3 points each for absolute neutrophil count under 0.50×109 cells/L and absolute lymphocyte count under 0.20×109 cells/L, 2 points for age 40 years or above, and 1 point each for myeloablative conditioning regimen, acute or chronic graft-versus-host disease, use of any corticosteroids within the previous 30 days, engraftment within 30 days, or pre-engraftment allo-HSCT. Patients are then stratified by total score into three risk groups (low (0-2 points), moderate (3-6 points), or high risk (7-12 points)). Depending on the ISI-RSV risk group, corresponding increased risks of progression (7%, 15%, and 48%) and mortality (0%, 3%, and 29%) exist. These scores have been proposed as tools for determining need for hospital admission and antiviral therapy.
By contrast, studies involving solid organ transplant recipients have shown higher mortality in lung transplant patients, in whom LRTIs with RSV can be a risk factor for chronic rejection (bronchiolitis obliterans syndrome (BOS)/chronic lung allograft dysfunction) and for death (mortality rate up to 20%).113114 Local inflammation and enhanced exposure of the immune system to pulmonary antigens lead to injury in the airway epithelial cells and subepithelial structures, leading to obliteration of the small airways and subsequently chronic lung allograft dysfunction.115
Recent studies show that RSV is independently associated with a broader definition of immunocompromise as well, including patients receiving cancer chemotherapy and long term immunosuppression. The FLUVAC trial is a large prospective observational study of influenza vaccine conducted in six hospitals over three influenza seasons in France, which showed that among adults admitted to hospital with influenza-like illness, those with solid cancer and immunosuppressive treatment had increased risk of RSV infection (adjusted odds ratio 2.1 (95% confidence interval 1.1 to 4.1) and 2.0 (1.1 to 3.8), respectively).100
Treatment
The standard of care for the management of RSV infection in adults is mainly limited to supportive care with bronchodilators, supplemental oxygen, intravenous fluid, and antipyretics.116 The US Food and Drug Administration (FDA) has approved two drugs for prevention or treatment of RSV LRTI in children: palivizumab for prophylaxis and aerosolized ribavirin for treatment. Antiviral therapy is considered and used more frequently in the setting of HSCT and lung transplant.
Ribavirin
Ribavirin is a guanosine analog that is FDA approved, in its aerosolized formulation, for the treatment of RSV in infants and young children but not in adults. The approval in the pediatric population was based on two small placebo controlled trials in non-mechanically ventilated infants after treatment groups showed statistically significant differences in mean symptom scores.117118 Subsequent meta-analyses cite multiple methodological errors in these studies, drawing the conclusion that aerosolized ribavirin had no clinically significant effect.119 Nevertheless, ribavirin is still commonly used in adult patients with HSCT and lung transplants on the basis of mainly observational data (see supplementary table).120 Intravenous ribavirin is not commercially available in most parts of the world. Owing to challenges in drug delivery and exceptional cost, many centers use oral ribavirin off-label for the treatment of immunocompromised patients despite a lack of prospective efficacy data.120121122
Multiple studies suggest that early treatment with ribavirin can help to prevent progression of URTI into LRTI,123124 but use of ribavirin in LRTI has been shown to be less effective.125 A pooled analysis of HSCT recipients suggests that early treatment with aerosolized ribavirin is more effective than placebo, but studies have been limited by small numbers and do not account for multiple risk factors including disease severity.126
Furthermore, a comprehensive review of the available literature shows that patients treated with aerosolized ribavirin and an antibody preparation, including standard intravenous immune globulin (IVIG), RSV Ig, or palivizumab, had the lowest risk of progression to lower tract disease and death.110127 If aerosolized ribavirin is used, continuous dosing (6 g over 18 hours daily) has been shown to be as effective as intermittent dosing (2 g over 3 hours every 8 hours) in preventing progression to LRTI.128 As outlined above, because of challenges in using aerosolized ribavirin and its extreme cost, many centers have begun using oral ribavirin, although the dose and duration used varies considerably.120 Most studies that have compared oral and inhaled ribavirin have shown similar efficacy, although none has been randomized or included a placebo arm.120121129130 On the basis of these findings, many centers are using either aerosolized or oral ribavirin with or without an antibody preparation to prevent progression in patients with RSV URTI who are at high risk and to prevent mortality in patients with LRTI.105120131132 In a survey of US Midwestern transplant centers in 2016, eight of 12 centers were using inhaled ribavirin in selected patient populations.120
Similarly, clinical studies in lung transplant recipients have generally been limited to single arm observational studies. The earliest study used intravenous ribavirin, which was associated with 100% survival rate (total 18 patients) with only 5% (one patient) developing post-RSV BOS.133 Several retrospective observational studies on oral ribavirin have consistently shown similar outcomes with oral therapy and intravenous or inhaled ribavirin.110122134135136137
Intravenous immunoglobulin and monoclonal antibodies
Intravenous immunoglobulins and monoclonal antibodies such as palivizumab can be used alone or in combination with ribavirin to treat and prevent RSV disease, although most data on efficacy are limited to pediatric and HSCT patients (see section on Antibody based therapies for RSV).138139
Although no head-to-head comparisons between various antibody preparations have been conducted, the relative benefit seems to be similar between formulations, especially when combined with ribavirin. Furthermore, as palivizumab is priced on weight based doses for small children, the cost for an adult is exceptionally high. A new formulation of IVIG with high RSV titers (Asceniv, ADMA Biologics, Ramsey, NJ) was approved in the US, and compassionate use experience in RSV infected patients showed safety and good outcomes.140
Guidelines
No formal guidelines specific to the management of RSV in adults are available. The Infectious Disease Society of America (IDSA) practice guidelines (2007) do not recommend using antivirals in the treatment of RSV in the setting of community acquired pneumonia.141 Similarly, European Respiratory Society (ERS) Task Force/European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines on lower respiratory tract infections (2005) recommend consideration of molecular testing for RSV (as well as influenza) during the winter season but do not make specific recommendations on treatment.142 Guidelines for the HSCT and SOT population review available therapies (as discussed above) but do not formally recommend a particular therapy in specific patients.105131132
Emerging drug treatments
RSV is thought to be a viable target for the development of antiviral agents, given the relatively prolonged duration of viral shedding at up to eight days post-infection.143 Furthermore, several potential targets for novel agents exist, and some are in preclinical development or advanced clinical development against RSV (table 3 and fig 2).
Novel respiratory syncytial virus (RSV) antiviral agents in clinical development
Therapeutic options and mechanism of action of available antiviral agents for respiratory syncytial virus
Fusion inhibitors
One of the primary antiviral targets is the RSV F protein. Inhibition of the F protein may prevent the entry of RSV into the host cells and subsequent infection, and it could therefore serve as a target for therapeutic intervention.144
Presatovir (oral GS-5806) is an oral small molecule fusion inhibitor that has completed phase II studies. In the human challenge study, treatment of otherwise healthy patients experimentally infected with RSV resulted in significant reductions in the viral load, total weight of mucus produced, and total symptom score.145 In the phase IIb studies in lung transplant recipients (https://clinicaltrials.gov/ct2/show/NCT02534350), presatovir did not result in improved viral or clinical outcomes.146 Likewise, in a phase IIb study in adults admitted to hospital with RSV, presatovir did not shorten the time weighted average change in viral load or number of admission-free days.147 Phase II trials conducted in HSCT recipients with either URTI or LRTI have shown trends toward potential benefit of treatment in patients who are at a high risk for poor RSV related outcomes presenting early in the treatment course.146148
JNJ-53718678 is a small molecule that binds to the pre-fusion F protein and was the second fusion inhibitor to go through advanced development. Human challenge studies showed excellent safety, and it was effective in reducing viral load and severity of clinical disease.149 Preliminary reports of a phase Ib study in infants admitted to hospital with RSV likewise showed safety and suggested virologic benefit.148150 Two phase II studies of JNJ-53718678 in adults and infants have begun (https://clinicaltrials.gov/ct2/show/NCT03379675; https://clinicaltrials.gov/ct2/show/NCT03656510).
RV521 is an oral small molecule fusion inhibitor that showed safety and reduced viral load and disease severity in a phase IIa study.151 Before further studies on efficacy, RV521 is being studied to determine any interactions with other drugs that may have specific effects on enzymes and transporter proteins influencing the absorption of the drug (https://clinicaltrials.gov/ct2/show/NCT03782662).
MDT-637 is a fusion inhibitor that can be delivered as a dry inhaled powder. Preclinical data show that it can be delivered into the upper and lower airways, and achievable human concentrations in respiratory secretions were hundreds to thousands of times greater than those of ribavirin.152 Future studies are planned.153
Nucleoside analogs
Nucleoside analogs that inhibit RNA polymerase are being developed for prevention and treatment of RSV. Oral lumicitabine (ALS-008176; https://clinicaltrials.gov/ct2/show/NCT02094365) is a putative N inhibitor that directly binds the N-terminal region of the nucleocapsid protein in vitro, presumed to act before viral replication complex formation.154 This molecule was investigated in HSCT recipients as well as in a human challenge model (https://clinicaltrials.gov/ct2/show/NCT00416442). Clinical development is currently on hold.
Small interfering RNA
RNA interference is a natural biologic process whereby small interfering RNAs (siRNAs) can direct sequence specific degradation of mRNA, leading to reduced expression of corresponding proteins.155 ALN-RSV01 is a small interfering RNA that targets RSV and has shown promise in prevention of BOS in lung transplant patients. Two studies in lung transplant patients have been completed, and use was associated with a numerical but statistically non-significant decrease in new or progressive BOS at day 180 (13.6% v 30.3%; P=0.058). The effect was enhanced when treatment started early at less than five days from onset of symptoms.156 However, no significant effect on viral parameters or symptom scores was observed, and the drug is no longer being studied.
Challenges to drug development
Although development of new agents against RSV is needed, several challenges have been identified at two recent important meetings: one at the Wellcome Trust in 2012 and one with the Global Virology Foundation in 2013.157 Main concerns include an under-appreciation of the burden of disease resulting in a misinterpretation of the potential market size, difficulties in point of care diagnostics for RSV in adults, and relatively low infection rates in adults complicating recruitment for large clinical trials. Another challenge to consider in the development of RSV related drugs is that RSV may undergo viral genetic changes and mutations that may allow for viral escape of antiviral therapies and even vaccines. Furthermore, disappointing results in recent studies of agents active against RSV in patients with clinical disease raise the question of the ability to use antiviral therapies effectively at the time when most patients present with clinical illness. Many adults present to medical care late in the disease process at day four to six or after significant disease progression, which may render many of the therapeutics that decrease viral load less efficacious.
Antibody based therapies for preventing RSV
Monoclonal antibodies
Passive infusion of antibodies, either through standard polyclonal immunoglobulins or RSV-IVIG, with a high concentration of RSV neutralizing antibodies, may prevent acquisition of RSV.
Palivizumab is an RSV specific monoclonal antibody derived from murine antibodies and is directed against the F (both pre-fusion and post-fusion) protein. It has been approved by the FDA and European Medicines Agency for the prevention of RSV only in pediatric patients at high risk of RSV disease. In infants at high risk, palivizumab used as prevention is 55% effective at reducing rates of hospital admission and has been shown to reduce morbidity but not mortality.158 Given cost constraints, data on the use of palivizumab as preventive therapy in immunosuppressed and older patients are limited (cost per adult dose up to $10 000 (£8247; €8975) in the US).159 Palivizumab has been successfully used to prevent an outbreak of nosocomial RSV transmission in a single HSCT unit with adults.52
Limited data on treatment in adults suggest reduced progression to lower respiratory tract disease with early use of the combination of intravenous palivizumab and ribavirin.127160161 The largest single center study using palivizumab in younger adults (median age 16 years) with HSCT failed to show a significant effect on outcome as assessed by progression to LRTI, early mortality rate, and one year overall survival rate.160
Several other monoclonal antibodies are in development. MEDI8897 is a recombinant human immunoglobulin G1 κ monoclonal antibody derived from D25 that targets the pre-fusion conformation of the RSV F protein. It has been shown to be safe in phase I studies in adults and phase II studies in infants and children.162 MEDI8897 binds to a highly conserved epitope on RSV F protein and neutralizes a diverse panel of RSV A and B strains with greater than 50-fold higher activity than palivizumab.
RSV immunoglobulins
Before the development of palivizumab, passive prophylaxis was achieved with the use of conventional RSV-IVIG (Respigam), which was approved by the FDA in 1996.163 Studies in children at high risk showed that RSV-IVIG reduced total days in hospital for RSV related disease, incidence of hospital admission, number of days of oxygen supplementation, and scores for moderate or severe respiratory tract disease.163 Subsequently, data suggested a trend toward increased deaths in pediatric patients with cyanotic heart disease who were undergoing corrective surgery.164 Studies of RSV-IVIG for HSCT recipients at high risk (both children and adults), when given at two separate doses following HSCT, did not show significant effects, although the study was underpowered and included few patients with documented RSV.165 After approval of palivizumab, RSV-IVIG was no longer manufactured.
A similar RSV immunoglobulin, IVIG RI-001, has also been studied, but phase I studies were suspended owing to slow accrual rates (https://clinicaltrials.gov/ct2/show/NCT00632463). RI-001 has been studied in HSCT patients with a wide range of ages (2 months to 71 years) in compassionate use settings with a 73% (11/15) survival rate.140 IVIG RI-002 is a similar RSV immunoglobulin preparation that was studied in children with primary immunodeficiencies (https://clinicaltrials.gov/ct2/show/NCT01814800) with the goal of reducing the number of serious bacterial infections per patient per year.166 It was recently approved by the FDA without a specific indication for RSV.
Inhaled nanobodies
Inhaled nanobodies are the next generation of monoclonal antibodies to be used for local pulmonary delivery of antibodies for a variety of respiratory diseases.167 Nanobodies are derived from camelids (llamas, camels, and dromedaries), which make only heavy chains that are different from those of human antibodies. When fragments of the antibodies are expressed alone, they retain specific antigen binding capacity and are called nanobodies.
An inhaled nanobody called ALX-0171 has been developed against the RSV F protein for treatment of RSV.168 The inhaled formulation allows for a high concentration of drug to be delivered to the respiratory tract, and studies in HSCT recipients (https://clinicaltrials.gov/ct2/show/NCT03468829) and infants admitted to hospital (https://clinicaltrials.gov/ct2/show/NCT03418571) were started but then stopped owing to insufficient evidence of efficacy in the infant population.
RSV vaccines
The goal of RSV vaccination would be to prevent severe disease and its subsequent complications in target populations at higher risk such as young infants, older children, pregnant women, and people aged over 65 years.37169 Although efforts to develop RSV vaccines had been unsuccessful for decades, recent efforts have yielded dozens of vaccine candidates that show promise (table 4).
Respiratory syncytial virus (RSV) vaccines and monoclonal antibodies in development (April 2019, adapted from PATH, https://path.org/resources/rsv-vaccine-and-mab-snapshot/)
Initial attempts in the 1960s to develop a whole virus vaccine inactivated by heat and formalin were unsuccessful owing to the observed phenomenon of enhanced disease in children who received the vaccine. A successful vaccination strategy would need to improve on the immunity provided by natural infection but avoid the deleterious effects seen with formalin inactivated virus.170171 To induce a protective vaccine response without immune enhancement, several approaches have been tried, including the use of live attenuated or live chimeric virus vaccines, gene based vectors, or nucleic acid approaches.60172173174175176
The most common vaccine target for RSV is the F protein, with the pre-fusion F protein identified as having most epitopes for neutralizing antibodies.177 Although purified F protein vaccines have failed to confer protection from RSV infection in children,178 pre-fusion F protein strategies have been found to elicit 10-fold to 100-fold more potent neutralizing antibodies than palivizumab.36 Vaccine development using the pre-fusion F protein can be challenging owing to its structural instability. The pre-fusion F protein is likely to prematurely refold into the more stable post-fusion conformation both in solutions and on the surface of virions. Efforts to mitigate this problem include use of structure stabilized versions of RSV F protein that maintain its metastable antigenic sites (such as antigenic site Ø) despite extremes in pH, osmolality, and temperature.179
The G protein has also been increasingly recognized as a critical target for vaccine development.65 Whereas the F protein remains highly conserved between RSV-A and RSV-B subgroups, the G protein is significantly more variable except for a highly conserved area known as the central conserved domain. One recent study has shown that elevated concentrations of both anti-G and anti-pre-fusion F antibodies were associated with lower scores for clinical disease severity.180 Difficulties in creating a G protein based vaccine include its heterogeneous glycosylation and sequence variability outside of the central conserved domain.181 One approach to achieving a vaccine against both A and B strains is to consider creating a fusion peptide comprising central conserved domain peptides from both strains.
Maternal vaccines
Although most vaccines have been targeted at infants and children, the ability to effectively vaccinate infants early enough to prevent disease has led to studies targeting the mother. Maternal immunization is a strategy that has been used successfully to protect infants from other diseases such as pertussis and influenza.182183 For RSV, studies have shown transplacental transfer of RSV neutralizing antibody in natural infection,184 as well as in clinical studies of an RSV vaccine candidate.185
With maternal vaccine studies, sterilizing immunity with PCR negative RSV disease in the infant will likely not be achievable. Rather, the goal would be to either delay or reduce the severity of RSV disease within the first few months of the infant’s life. Expert opinion is that enhanced disease is highly unlikely in the setting of maternal vaccination.186 Current candidate vaccine approaches for maternal immunization are subunit proteins based on the pre-fusion F protein structure. An RSV F nanoparticle vaccine (Novavax) is in phase III trials in healthy women in their third trimester of pregnancy, which will assess the prevention of medically significant RSV LRTI through 90 days of life (https://clinicaltrials.gov/ct2/show/NCT02624947).187
RSV vaccines for older people
The basis for severe RSV associated disease in older people with comorbidities is more complex than that of primary infection in the pediatric population. The immunologic factors required to supplement pre-existing RSV immunity in older people are not well understood, and the immunologic pathways leading to severe disease are likely multifactorial and more nuanced than in infants. Live attenuated or live chimeric vaccines likely cannot be used owing to pre-existing immunity that will reduce replication, which will likely be too limited to generate adequate immunogenicity. Current approaches include subunit proteins based on pre-fusion F protein conformation or more complex virus-like particles or virosomes.
GSK3844766A (GlaxoSmithKline) is a vaccine candidate that was produced on the basis of low seroprevalent human adenovirus serotypes 26 and 35 encoding the RSV F gene. It has been found to produce a durable antibody response in animal models,175 and it is currently in phase I trials in adults aged 60-80 years (https://clinicaltrials.gov/ct2/show/NCT03814590). Adjuvant formulations such as AS01, which is a recombinant gD protein for varicella zoster, are also available for the adult population and can potentially provide larger and more durable antibody responses.60 Although the overall burden of RSV disease in older adults is high, rates of infection are relatively low (~5%), with even lower rates of medically attended LRTI (~1%) and hospital admission (~0.1%), which will make designing and testing vaccine candidates challenging.186
Challenges to vaccine development
Despite the prospect of RSV vaccines becoming more realistic with several vaccines entering advanced clinical development, many gaps in knowledge remain. If a vaccine is approved, studies will be needed to understand the effect of the vaccine on rates of hospital admission, complications, and mortality attributed to RSV. Concomitant stable and reproducible immunogenicity assays matching the vaccine may need to be developed to adequately evaluate the effect of the vaccine. Although multiple studies have been done to further understand the pathophysiology behind enhanced respiratory disease, the exact mechanism behind the phenomenon is still not fully understood. Future work in these systems would better inform risk mitigation strategies for vaccine candidates. No consensus exists on the best clinical endpoints to use for clinical trials. Although RSV related hospital admission and severe disease with LRTI is a useful and easily ascertainable endpoint, it is not ideal as the rate of admissions for RSV may be insufficient for a preventive vaccine and may not be assessed appropriately without designing a very large trial. Furthermore, hospital admissions are the result of a heterogeneous decision making process, with substantial variation among providers. Finally, careful characterization of circulating viral strains will be necessary to detect the emergence of mutants escaping therapeutics and vaccination once they are available.
Conclusions
RSV is an important pathogen in immunocompromised patients and older adults. The morbidity and mortality of RSV infection in populations at risk are comparable to those of influenza. Recent advances in molecular diagnostics have made rapid identification of RSV infection possible. Several new antiviral therapies and vaccines are being investigated and are needed to prevent RSV infection and reduce the effects of the virus on patients. Most importantly, despite research on the epidemiology and outcomes of RSV in children, immunocompromised patients, and older adults, large contemporary studies of the epidemiology and outcomes of RSV in adults admitted to hospital are needed to define the full spectrum of disease and identify areas in which novel antiviral agents and vaccines can be applied to improve the outcomes of patients.
Research questions
Which host and virus factors are associated more severe respiratory syncytial virus (RSV) disease?
Can we use RSV sequence monitoring to establish the true incidence of RSV across diverse ages, populations, and pathogens?
What are the best endpoints for clinical trials in severe RSV, as well as vaccine development?
Can we develop safer and more effective vaccines if we are able to fully understand the underlying mechanism behind RSV enhanced disease with formalin inactivated vaccine?
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Footnotes
Series explanation: State of the Art Reviews are commissioned on the basis of their relevance to academics and specialists in the US and internationally. For this reason they are written predominantly by US authors
Contributors: Both authors contributed to the idea for the article, review of primary literature, and writing of the manuscript. Both are guarantors.
Funding: HHN is supported through T32 AI095207.
Competing interests: We have read and understood BMJ policy on declaration of interests and declare the following interests: MGI is a paid member of DSMB for GlaxoSmithKline and Shionogi, has received personal consulting fees from Celltrion, Genentech/Roche, Janssen, Seqirus, Shionogi, Viracor Eurofins, and VirBio, and has served as a non-paid consultant for GlaxoSmithKline, Romark, and Vertex; Northwestern University has received payments for research from AiCuris, Chimerix, Emergent BioScience, Genentech/Roche, Gilead, Janssen, and Shire.
Provenance and peer review: Commissioned; externally peer reviewed.
Patient involvement: No patients were involved in the drafting or review of this manuscript.