Introduction

Human respiratory syncytial virus (RSV) was discovered in 1956, following the isolation of the pathogen from respiratory samples of chimpanzees with coryza.[1] Soon after, the virus was recognized as a cause of respiratory tract infections in infants and young children.[2] Please see StatPearls' companion resource, "Respiratory Syncytial Virus Infection in Children", for further information. Despite early reports of its association with respiratory illness in the adult population, RSV was not recognized as a common cause of adult infection for 2 more decades.[3][4][5] 

Infection with RSV in adults can directly cause several respiratory tract ailments, including viral pneumonia and bronchiolitis in susceptible individuals.[6] Additionally, RSV infection in older adults and those with underlying comorbidities can indirectly compromise cardiovascular and neurocognitive function.[7][8] Immunocompromised adults and those older than 70 are at the highest risk of developing severe illness and life-threatening complications due to RSV.[9] Recently, the landscape of RSV infection in children and adults has experienced significant change with the development of rapid and sensitive diagnostic tools and effective immunization strategies. 

Etiology

RSV is a single-stranded, enveloped ribonucleic acid (RNA) virus approximately 15.2 kb in length. This virus belongs to the genus Pneumovirus, subfamily Pneumovirinae, and order Mononegavirales; filamentous forms of the virions can range up to 10 μm in length and 300 μm in diameter.[10] Structural features unique to RSV include helical striations surrounding its core, located internally within its envelope. The viral envelope contains glycoproteins G, F, and SH, which participate in viral attachment (protein-G), fusion and syncytia formation (protein-F), and ion channel function (protein-SH). Protein-F is the antigen target for currently approved RSV vaccines and monoclonal antibodies. Antigenic virus subtypes A and B do not appear to differ significantly in pathogenicity or protein-F antigenicity.[11][12] The viral matrix protein plays a crucial role in forming stable virion structures.[13] The viral replication and transcription process is mediated through the RNA polymerase complex, a target for antivirals.[14]

Epidemiology

RSV has a worldwide distribution. The incidence ranges from 7.3 to 13.5 per 100,000 population in Africa and Asia, to as high as 1790 per 100,000 population in the United States (US).[15] In Europe, RSV is estimated to account for up to 11% of influenza-like illness presentations. In temperate climates, infection tends to peak during winter, where RSV infections overlap with those of influenza and other respiratory pathogens. In tropical climates, RSV remains endemic throughout the year.

The epidemiology of RSV infection in adults has not been as extensively studied as that in children.[16][17] Established case definitions and the historical lack of routine testing significantly underestimate rates of RSV infection in adults. However, the recent development of rapid and sensitive diagnostic tests is beginning to contribute to a better understanding of RSV epidemiology, morbidity, and mortality. Approximately 12% of adult respiratory tract infection cases that come to medical attention in the US are due to RSV.[18] RSV-attributed mortality among all adults is less than 1%; however, attributed mortality in those requiring hospitalization is approximately 4% to 7%.[11] Moreover, approximately 75% of deaths due to RSV occur in people aged 65 years and older. An estimated global reproductive number of RSV is approximately 3 across all seasons, meaning each infected case produces 3 secondary cases in a completely susceptible population.[19] The incubation period ranges from 2 to 8 days.[20]

In the US, annual RSV infection in adults causes approximately 180,000 hospitalizations and 14,000 deaths.[9][21] In 2023, results from a study conducted in Spain identified RSV as the third most prevalent cause of viral respiratory tract infections requiring hospitalization in adults older than 60; RSV prevalence was exceeded by SARS-CoV-2 and influenza, respectively.[22] The study's results demonstrated that those admitted to a hospital with RSV as the cause of their respiratory tract infection were at the highest risk for transfer to intensive care, had longer hospital stays, and had the highest rate of mortality. Results from a recent study from China identified RSV infection in hospitalized adults older than 18 as having greater mortality than influenza A.[23] Persons older than 60 are at increased risk of hospitalization due to RSV, and the risk significantly increases in those individuals older than 70.

Adults with underlying health conditions, including chronic obstructive pulmonary disease, asthma, diabetes, Down syndrome, cardiovascular disease, including congestive heart failure, chronic renal failure, and immunocompromised individuals (including those with neutropenia and lymphopenia) are at high risk for severe RSV infection and hospitalization.[24] Those individuals with a history of lung transplantation or hematologic stem cell transplantation are at the highest risk.[11][17] RSV transmission rates are high in adults residing in long-term care facilities, thus posing a significant risk to this population.[18][25] 

Pathophysiology

Like many respiratory viruses, RSV is transmitted by respiratory droplets and contaminated surfaces to mucous membranes. The virus attaches to respiratory epithelial cells, where it undergoes cell fusion followed by nucleocapsid entry and replication. The viral protein G allows RSV virions to bind to endothelial cell surfaces, using the virulence factor annexin II. The protein G can also interact with the host chemokine receptor C-X3-C motif chemokine receptor 1 (CX3CR1), facilitating cell adhesion and entry.[26] 

Host immune mechanisms are triggered to produce cytokines and chemokines, including interferon. The cytokines stimulate specific genes, leading to the production of RNase, which possesses antiviral activity. At the site of infection, the RSV protein F triggers activation of toll-like receptors, which initiate an inflammatory cascade of various host innate immune cells, including macrophages, neutrophils, and natural killer cells. Macrophage production of tumor necrosis factor and interferon activates the adaptive immune response.

RSV is capable of suppressing B memory cells and IgA memory responses. Additionally, both anti-RSV immunoglobulin (Ig) G and IgA responses decline rapidly over time. Thus, multiple RSV infections can occur throughout an individual’s lifetime. Patients with underlying immunodeficiency and older adults experiencing immunosenescence are at risk for severe infection.[11][12][27]

The viral infection and host immune response result in inflammatory changes and damage to the respiratory epithelial cells. The presence of edema, desquamated epithelial cellular debris, neutrophils, and mononuclear cells obstructs the infected airways. The resulting RSV infection can cause both upper and lower respiratory tract infections, the latter of which can exacerbate underlying lung disease, including chronic obstructive pulmonary disease and asthma.

Respiratory Syncytial Virus and Comorbid Conditions

Infection with RSV appears to be associated with the accelerated development of coronary artery disease and congestive heart failure. The association between RSV infection and cardiovascular disease is similar to that of other infectious causes of pulmonary infections, where the underlying pathophysiology is thought to be a combination of right ventricular strain and inflammation-associated plaque destabilization. RSV has been found within the myocardium, where it may contribute to direct tissue injury. Moreover, in those with preexisting coronary artery disease, the physiologic stress of infection due to fever and hypoxemia can cause demand ischemia.[28] 

As seen in other causes of respiratory tract infections in older adults, RSV infection can lead to acute cognitive and functional decline, with a prolonged impact on activities of daily living. The pathogenic mechanism behind this is not yet well understood, but it appears to share many similarities with other post-viral fatigue conditions.[29] Not surprisingly, functional impairment due to RSV infection in older adults occurs more frequently in those with underlying cardiopulmonary disease.[30] Similar immunosenescence associated with advanced age can predispose individuals to more severe illnesses through diminished T-cell responses.[31]

RSV lower respiratory tract infection can be exacerbated by coinfection with bacterial pneumonia, particularly involving Streptococcus pneumoniae.[4] The pathophysiology underlying this association is not fully established and likely includes inflammatory loss of respiratory tract epithelium and localized immune dysfunction. A recent study's results suggest that RSV enhances susceptibility to bacterial infection by attenuating the antibacterial protective immunity of alveolar macrophages.[32] 

History and Physical

As RSV can manifest both upper and lower respiratory tract symptoms, recognizing these presentations is important. In the case of upper respiratory tract infection (URTI), symptoms range from mild to moderate and are indistinguishable from those of other viral URTIs. Acute onset of cough, fever, fatigue, nasal congestion, rhinorrhea, and pharyngitis are prominent symptoms. Patients often do not seek medical attention at this undifferentiated stage, and in the absence of specific testing, the etiology remains unclear. In most cases occurring in healthy adults, the infection is self-limited and symptoms last for several days before full recovery. Fatigue and a lingering cough lasting several weeks are common sequelae.

Infection can progress to involve the lower respiratory tract, resulting in a presentation similar to viral pneumonia. Nasal congestion, productive cough, wheezing, and dyspnea are commonly associated symptoms, occurring in anywhere from 70% to 93% of cases.[33] Severe infection can progress to respiratory failure. Persons with underlying chronic obstructive pulmonary disease or asthma are at risk of developing exacerbations. Cardiovascular complications, including ischemia, infarcts, arrhythmias, congestive heart failure, and strokes, are potential complications, particularly in older adults and immunocompromised individuals.[22]

Evaluation

A discussion of evaluation must consider that most people with mild to moderate RSV infection neither require nor seek medical attention. The diagnostic evaluation will depend on the severity of illness, setting (eg, outpatient clinic, emergency department, or hospital), and resources.

Laboratory Evaluation

Within the last 5 years, nasopharyngeal swab specimens analyzed by nucleic acid amplification tests (NAATs) have been widely accepted as providing highly sensitive, specific, and rapid detection of various respiratory tract pathogens, including RSV.[34] These detection methods should be applied to patients presenting with severe illness, those at risk for developing severe disease, and for public health and surveillance purposes. Lower respiratory tract specimens from immunocompromised patients with severe disease, eg, through bronchoalveolar washings, may increase the sensitivity of diagnostic tests.[35] 

Due to costs, NAATs are not widely available in resource-limited parts of the world. Antigen tests of various types are less expensive and more readily available, but are less sensitive than NAAT.[12] Serology tests, including immunofluorescence, are prone to reader subjectivity and are not clinically useful in establishing a diagnosis with less sensitivity than NAAT.[36] Culture methods that look for the hallmark cytopathic effects of RSV are labor-intensive, time-consuming, and impractical.[37]

Imaging Evaluation

Chest x-rays are often routinely obtained in patients experiencing moderate to severe symptoms and those likely to be admitted to the hospital. However, no pathognomonic findings have been identified that help distinguish RSV as the cause of symptoms.

Treatment / Management

Treatment

No antiviral medications are indicated for the treatment of RSV-URTI in adults, and few antiviral treatment options for RSV-lower respiratory tract infections (RSV-LRTIs) exist.[38] Analgesics, antipyretics, and bronchodilators may provide symptomatic relief. Please see StatPearls' companion resource, "Upper Respiratory Tract Infection with a Focus on the Common Cold", for further information. Patients experiencing RSV-LRTI require supportive care that includes supplemental oxygen, intravenous hydration, antipyretics, analgesics, and bronchodilators. Antiviral therapy, in the form of ribavirin, is often used to treat patients who are severely immunocompromised with RSV infection, particularly those who have received hematopoietic stem cell transplants (HSCTs) or lung transplants.[39][40][41][42] 

Ribavirin, a guanosine analogue, acts by inhibiting viral replication by inhibiting inosine monophosphate dehydrogenase, which results in reduced guanosine triphosphate levels necessary for viral RNA synthesis. The effectiveness of ribavirin in this setting has not been definitively established, as few observational and randomized controlled trials have been performed.[43][44] Ribavirin can be administered in intravenous (IV), aerosolized, or oral formulations. The IV formulation is not readily available. The aerosolized formulation is cumbersome to administer; it can cause bronchospasm, rash, and headache, and is an exposure risk to medical staff.[45] Ribavirin can cause a dose-dependent hemolytic anemia and leucopenia, which warrants close monitoring of blood counts.

Ribavirin alone, or in combination with IV immunoglobulin (IVIG) and the monoclonal antibody palivizumab, has been administered to severely immunocompromised individuals with RSV upper and LRTIs. Benefits to this therapeutic approach have been reported in adult HSCT and lung transplant recipients.[43] A combination of ribavirin and corticosteroids has also demonstrated benefits in observational studies of RSV-infected lung transplant recipients.[46] The efficacy of this approach to therapy has not been established in controlled trials. Currently, no guidelines on the administration of ribavirin to older adults with severe RSV pneumonia have been established, and no definitive recommendation can be made at this time. The decision to administer ribavirin to the adult population should be made on an individual basis.

Respiratory Syncytial Virus Vaccines

Since 2023, major developments in the field of RSV immunizations have the potential to provide enormous benefit to adults at risk of severe infection. Recent vaccine platforms have successfully targeted the pre-F fusion protein on the viral envelope.[38][47][48] Currently, 3 RSV vaccines have been approved for administration to adults, with 2 of the vaccines (Arexvy, Galaxo Smith Kline, and Abrysvo, Pfizer) using protein subunits, and one (mResvia, Moderna) using messenger RNA platforms, respectively. In addition, Abrysvo is currently approved for pregnant women between 32 and 36 weeks of gestation to prevent severe RSV in newborns in the US, Canada, Europe, Japan, Singapore, and Australia.

The vaccines appear safe and provide approximately 75% to 84% efficacy over a 2-year follow-up period in people older than 60, and approximately 69% to 82% over 180 days after birth for pregnant women.[49][50][51] As of July 2024, the US Centers for Disease Control (CDC) and the Advisory Committee on Immunization Practices (ACIP) recommend that all adults aged 75 years and older, and adults aged 60 to 74 years who are at increased risk for severe RSV disease, should receive a single dose of RSV vaccine.[52] Similar recommendations are seen in guidelines worldwide. 

Current Vaccine Investigations

In the Phase 3 vaccine trials of the protein subunit vaccines, inflammatory neurologic events were identified as potential safety concerns; however, these were low in number, and the vaccine's benefits were deemed to outweigh the potential risks.[53] Important postauthorization pharmacovigilance studies to assess immunogenicity and adverse events are ongoing.[47][54] 

Several further RSV vaccines and treatments, including monoclonal antibodies, are in various stages of development.[38][48] The recent RSV vaccine landscape has generated several current knowledge gaps and important questions. The following represents a small sample of questions regarding RSV vaccinations being considered:

• How durable is vaccine efficacy?
• How frequently will vaccines need to be administered?
• Will the vaccines provide a protective effect if administered to people 80 years and older?
• Should the vaccine be recommended for adults younger than 60 with chronic cardiopulmonary disease, and if so, what specific diseases?
• Should the vaccine be administered to younger adults who are anticipating transplantation or other forms of immunosuppression?
• Should the vaccines be recommended to parents residing in a home with an immunosuppressed child?
• What, if any, effects occur when RSV vaccines are coadministered with influenza, SARS-CoV-2, pneumococcal, or zoster vaccines?
• In those cases where immunization is offered to those who do not meet current CDC–ACIP recommendations, who will bear the cost of vaccination?

Differential Diagnosis

The differential diagnosis of RSV infection is extensive and includes all pathogens capable of causing upper and LRTIs, including bacteria, other viruses, and fungal infections. During the winter months in temperate climates, the cocirculation of RSV, influenza, and SARS-CoV-2 makes it impossible to distinguish the cause of a “flu-like” illness based on clinical symptoms; therefore, multiplex test strategies should be employed to establish a diagnosis. This diagnostic conundrum likely also exists in tropical climates, where RSV and SARS-CoV-2 are endemic throughout the year.[55]

Prognosis

In healthy adults with RSV-URTIs, the prognosis is excellent as the illness is often self-limiting. Approximately 10% to 31% of hospitalized adults with RSV require intensive care, of which 3% to 17% require mechanical ventilation. Factors associated with the need for invasive ventilation include neutropenia, chronic heart failure, chronic respiratory failure, and coinfection with other pathogens.[56] 

Mortality rates in hospitalized adults range from approximately 4% to 7%.[18] Cumulative mortality at 1 year after diagnosis has been observed in one study to be up to 26%, attributed to deconditioning posthospitalization and the exacerbation of preexisting patient comorbidities.[57] Most of the mortality during hospitalization is attributed to patient factors, including immunosuppression and advanced age; they are also associated with the severity of illness, including respiratory failure, neutropenia, and the need for invasive ventilation. Examples of immunosuppression associated with mortality in RSV include patients who have received HSCT and solid organ transplants.[11][27] The results of these studies should be interpreted with caution, as viral testing was not always routinely performed on all hospitalized patients during observation periods. Moreover, studies on long-term outcomes and subgroup risk stratification are limited and not always conducted.

Complications

Complications of RSV-URTI include:

• The potential to extend to the lower respiratory tract
• Prolonged fatigue and cough during convalescence

Complications of RSV-LRTI may include:

• Prolonged hospitalization and deconditioning
• Respiratory failure with invasive ventilation dependency
• Exacerbation of chronic obstructive pulmonary disease
• Exacerbation of asthma
• Cardiovascular dysfunction, including ischemia, myocardial infarction, arrhythmias, exacerbations of congestive heart failure, and stroke
• Neurocognitive decline
• Postviral fatigue
• Mortality

Deterrence and Patient Education

A recent survey conducted in France highlights a significant lack of knowledge among healthcare professionals and the general population regarding the burden of RSV and its prevention in adults.[58] Recent US surveys identified similar knowledge gaps among adults who were at risk for severe RSV infection.[59][60] Assuming that this knowledge deficit exists throughout many parts of the industrialized and developing regions of the world is reasonable and is partly due to relatively recent advances in RSV detection and prevention.[23][61][62] 

The lack of awareness about RSV, concerns regarding vaccine safety, and misinformation about vaccines in general have contributed to relatively low vaccine uptake.[62][63][64] However, observational evidence is emerging that education and clinician discussions specific to vulnerable target groups, including pregnant women, can motivate and sustain RSV vaccine uptake, thereby decreasing healthcare costs.[60][65] Therefore, educating medical professionals and the public about RSV infection, diagnosis, and prevention requires substantial and sustained efforts in individual and public health to ensure effective vaccine uptake.

Pearls and Other Issues

Outbreaks of RSV can occur in hospital wards where infected patients may unknowingly transmit the virus to other vulnerable individuals.[66] As the symptoms of RSV can mimic other respiratory illnesses, clinicians may not always test for it, despite the availability of rapid results through the use of nucleic acid amplification tests. Therefore, having a low threshold for testing for RSV is important, as it may enable the isolation or cohorting of infected individuals to limit exposure to others.[67] The RSV vaccines can be administered at any time of the year, given their efficacy remains adequate over many months to years. The vaccines can be administered simultaneously with other vaccines, including those for diphtheria, pertussis, tetanus, influenza, and COVID-19.

Enhancing Healthcare Team Outcomes

The diagnosis tools and vaccination platforms for RSV infection have advanced knowledge about the significant prevalence, risks, and prevention strategies involving the adult population. However, many healthcare professionals are unfamiliar with this recent scientific and public health knowledge bank related to RSV in adults. There is a benefit to interprofessional education among medical, nursing, and allied health clinicians in the hospital setting, enabling them to recognize and care for patients with RSV. Appropriate staff protocols for the use of personal protective equipment are necessary to limit the transmission of RSV on the ward when caring for patients. Patients with RSV infection are also likely to be encountered in outpatient clinics, primary care settings, community health centers, and emergency rooms.

In the outpatient setting, efforts should be made to educate primary care clinicians, emergency department clinicians, infectious disease and pulmonary-critical care clinicians, nurse practitioners, and pharmacists about recent advances in RSV infection diagnosis, treatment, and prevention tools. Patient-centered care will require a well-informed team approach that may include infectious disease clinicians, pulmonologists, internists, rehabilitation clinicians, pharmacists, nurses, and other allied health staff who can engage in collegial and patient education regarding the risks of acquiring RSV infection and the importance of targeting vaccine strategies toward those at high risk. Efforts should additionally be undertaken to educate patient-facing healthcare professionals about recent advances in RSV infection diagnosis, treatment, and prevention tools. 

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Disclosure: Ellis Tobin declares no relevant financial relationships with ineligible companies.

Disclosure: Andrew Nguyen declares no relevant financial relationships with ineligible companies.