Respiratory syncytial virus

RSV was discovered in 1956 when researchers isolated a virus from a population of chimpanzees with respiratory illness. They named the virus chimpanzee coryza agent (CCA). In 1957, this same virus was identified by Robert M. Chanock in children with respiratory illness. Studies of human antibodies in infants and children revealed that the infection was common in early life. The virus was later renamed human orthopneumovirus, or human respiratory syncytial virus (hRSV). Several other pneumoviruses show great similarity to hRSV. Bovine RSV (bRSV) shares approximately 80% of its genome with hRSV. It also shares hRSV's predilection for the young, causing more severe disease in calves less than six months old. Because bRSV-infected calves have almost identical symptoms to hRSV-infected children, they have proven to be an important animal model in RSV research. ==Signs and symptoms==

RSV infection can present with a wide variety of signs and symptoms that range from mild upper respiratory tract infections (URTI) to severe and potentially life-threatening lower respiratory tract infections (LRTI) requiring hospitalization and mechanical ventilation. While RSV can cause respiratory tract infections in people of all ages and is among common childhood infections, its presentation often varies between age groups and immune status. Childhood RSV infections are fairly self-limited with typical upper respiratory tract signs and symptoms, such as nasal congestion, runny nose, cough, and low-grade fever. Approximately 15–50% of children will go on to develop more serious lower respiratory tracts infections, such as bronchiolitis, viral pneumonia, or croup. Infants are at the highest risk of disease progression. While several viruses can cause bronchiolitis, RSV is responsible for about 70% of cases. Adults Reinfection with RSV remains common throughout life. Reinfection in adulthood often produces only mild to moderate symptoms indistinguishable from the common cold or sinus infection. Symptom severity seems closely related to the extent of immune suppression. Those who have undergone hematopoietic stem cell transplant (HSCT), intensive chemotherapy, and lung transplant are particularly susceptible. Bone marrow transplant patients appear to be at the highest risk, especially before marrow engraftment. In this group, RSV infection carries a nearly 80% risk of both pneumonia and death. Elderly RSV or respiratory syncytial virus affects many populations differently. The most at-risk populations for RSV complications are older adults and those with underlying medical conditions or immunocompromised individuals. Between 60,000-160,000 older adults in the United States are hospitalized annually with RSV. Between 6,000 and 10,000 older adults die from RSV infection each year. Additionally RSV can "... lead to worsening of serious conditions such as, Asthma, Chronic obstructive pulmonary disease (COPD) – a chronic disease of the lungs that makes it hard to breathe, and even Congestive heart failure – when the heart can't pump enough blood and oxygen through the body." Expedient and proper medical care is important for older adults as waiting or receiving a misdiagnosis can be associated with an increased risk of complications. As of August 2023, adults aged 60 years and older qualify for vaccination against RSV in Canada and the United States. Complications ==Risk factors==

Risk factors for the development of severe lower respiratory tract infection with RSV vary by population. == Virology ==

Taxonomy RSV is a negative-sense, single-stranded RNA virus. It belongs to the genus Orthopneumovirus, family Pneumoviridae, order Mononegavirales. Structure and proteins of RSV RSV is a medium-sized (~150 nm) enveloped virus. While many particles are spherical, filamentous species have also been identified. There are 11 proteins, described further in the table below. G protein Surface protein G (glycoprotein) is primarily responsible for viral attachment to host cells. This protein is highly variable between strains. G protein exists in both membrane-bound and secreted forms. The membrane-found form is responsible for attachment by binding to glycosaminoglycans (GAGs), such as heparan sulfate, on the surface of host cells. The secreted form acts as a decoy, interacting with antigen-presenting cells to inhibit antibody-mediated neutralization. G protein also contains a CX3C fractalkine-like motif that binds to the CX3C chemokine receptor 1 (CX3CR1) on the surface of ciliated bronchial host cells. This binding may alter cellular chemotaxis and reduce the migration of immune cells into the lungs of infected individuals. G protein also alters host immune response by inhibiting signaling from several toll-like receptors, including TLR4. F protein Surface protein F (fusion protein) is responsible for the fusion of viral and host cell membranes, as well as syncytium formation between viral particles. Its sequence is highly conserved between strains. While viral attachment appears to involve both F and G proteins, F fusion occurs independently of G. F protein exists in multiple conformational forms. In the prefusion state (PreF), the protein exists in a trimeric form and contains the major antigenic site Ø. Ø serves as a primary target of neutralizing antibodies in the body. After binding to its target on the host cell surface (its exact ligand remains unclear), PreF undergoes a conformational change during which Ø is lost. This change enables the protein to insert itself into the host cell membrane and leads to fusion of the viral and host cell membranes. A final conformational shift results in a more stable and elongated form of the protein (postfusion, PostF). Opposite of the RSV G protein, the RSV F protein also binds to and activates toll-like receptor 4 (TLR4), initiating the innate immune response and signal transduction. Replication cycle Following the fusion of the viral and host cell membranes, the viral nucleocapsid (containing the viral genome) and the associated viral polymerase are delivered into the host cell cytoplasm. Transcription and translation both occur within the cytoplasm. RNA-dependent RNA polymerase transcribes the genome into 10 segments of messenger RNA (mRNA) which is translated into structural proteins by host cell machinery. During replication of the negative-sense viral genome, RNA-dependent RNA polymerase synthesizes a positive-sense complement called the antigenome. This complementary strand is used as a template to construct genomic negative-sense RNA, which is packaged into nucleocapsids and transported to the plasma membrane for assembly and particle budding. ==Mechanism==

Transmission RSV is highly contagious and can cause outbreaks from both community and hospital transmission. RSV can spread when an infected person coughs or sneezes, releasing contaminated droplets into the air. Transmission usually occurs when these droplets come into contact with another person's eyes, nose, or mouth. As with all respiratory pathogens once presumed to transmit via respiratory droplets, it is highly likely to be carried by the aerosols generated during routine breathing, talking, and even singing. RSV can also live for up to 25 minutes on contaminated skin (i.e. hands) and several hours on other surfaces like countertops and doorknobs. An estimated of "36% of individuals" can be reinfected with RSV "at least once, during the winter season." The mild symptoms tend to be restricting upper airways. However, younger individuals are extremely vulnerable to developing "severe symptoms," which typically involve the lower airways. Since infants have smaller airways than children do, "they might be obstructed by inflammation, edema, and mucus." This can contribute to developing a "more severe lower respiratory tract illness." As mentioned, RSV reinfection is frequent among all ages and the type of host response to reinfection can determine "which children will develop persistent wheezing and possibly asthma." It is possible that the age you are infected with RSV can be a vital factor in "determining the phenotype of airway response to subsequent RSV infection." Immune escape Genetic variations in viral epitopes and adjacent regions affect protein folding, post-transcriptional modifications, and antigenic processing, influencing B and T cell immunity during viral infections. This alteration in conformation can lead to immune evasion, potentially impacting disease severity, outbreaks, and reinfections. Notably, the variability observed in the G gene, followed by the SH and F genes, suggests a correlation between structural differences in proteins and their immunogenicity. Specifically, the irregular curl and low bond energy of the G protein make it prone to conformational changes, affecting its immunogenicity and potentially modulating the immune response. Different genotypes of RSV exhibit variations in the structural conformation of key proteins such as G, SH, and F, impacting immune responses. The emergence of novel genotypes like ON1 and BA9 is associated with distinct structural differences, particularly in the G protein, which may contribute to immune evasion. Evidence suggests that RSV glycoprotein G plays a crucial role in immune modulation during infection, affecting cytokine expression and the antiviral response. In addition, positive selection pressure drives the dominance of certain genotypes over others, potentially driven by mutations within specific regions of the G gene. The F protein is a major target for neutralizing antibodies, but its variability enables viral evasion from neutralization, affecting the efficacy of antibodies like Palivizumab. Cross-reactions between RSV subtypes and genotypes are observed, but immune responses are subtype- or genotype-specific, indicating the impact of gene mutations, particularly in the G protein, on immune evasion. Additionally, differences in cytokine expression and immune cell responses highlight the complexity of immune interactions during RSV infection. Genomic variations in RSV, particularly in proteins like G and F, influence immune responses and contribute to immune evasion. This multifaceted immunomodulatory arsenal likely contributes to RSV's ability to cause mild respiratory symptoms in most cases, yet it poses a severe threat to vulnerable populations such as infants and the elderly, potentially leading to life-threatening lung disease characterized by immune dysregulation. RSV has evolved numerous strategies to evade the host's antiviral response, with over half of its proteins exerting immunomodulatory effects. ==Diagnosis==

Laboratory diagnosis A variety of laboratory tests are available for the diagnosis of RSV infection. While the American Academy of Pediatrics (AAP) does not routinely recommend the use of lab testing to diagnose RSV bronchiolitis (for which the treatment is largely supportive), confirmation of RSV infection may be warranted in high-risk groups if the result will guide clinical decisions. Common identification techniques include antigen testing, molecular testing, and viral culture. • Direct fluorescence assay (DFA) allows for direct microscopic examination of virus-infected cells. The sensitivity of DFA testing depends on an adequate specimen. However, they tend to be more expensive and require more complex equipment than other testing methods, making them less practical in resource-limited areas. Molecular testing for RSV is not routinely recommended for all people with respiratory symptoms. However, it may be recommended for those at high risk of RSV complications, such as infants, older adults, and people with chronic medical conditions. RT-PCR has a sensitivity of 90-95% and a specificity of 98-99%, while LAMP has a sensitivity of 95-100% and a specificity of 99-100%. • Polymerase chain reaction (PCR) is a type of NAAT that allows a very small sample of genetic material to be rapidly amplified into millions of copies for study. PCR is more sensitive than either antigen testing or viral culture. Differential diagnosis The differential diagnosis for individuals presenting with signs and symptoms of upper and lower respiratory tract infection includes other viral infections (such as rhinovirus, metapneumovirus, and influenza) and primary bacterial pneumonia. In children, inhaled foreign bodies and congenital conditions such as cystic fibrosis or asthma are typically considered. ==Prevention==

Other than vaccination, the main prevention measure is to avoid close contact with infected individuals. Mresvia is an mRNA vaccine that was approved for medical use in the United States in May 2024. The primary pharmaceutical developers, GSK and Pfizer, obtained Food and Drug Administration (FDA) approval for RSV vaccines targeting adults aged 60 and above. GSK's Arexvy boasts 94% efficacy against severe and 83% against symptomatic RSV in this age group, while Pfizer's Abrysvo is 86% effective against severe symptoms and 67% against symptomatic disease in adults aged 60 and older. Background The virus's disease burden and the lack of disease-specific therapies spurs interest and research in vaccine development, which faced obstacles that blocked its progress. Among these were infant-specific factors, such as the immature infant immune system and the presence of maternal antibodies, which make infantile immunization difficult. RSV-IVIG has since been replaced with the use of a monoclonal antibody (MAb) that can be delivered through muscular injection. Palivizumab (Synagis) is a monoclonal antibody directed against the surface fusion (F) protein of the RSV virus. It was licensed in 1998 and is effective in providing temporary prophylaxis against both RSV A and B. It is given by monthly injections, which begin just before the RSV season and are usually continued for five months. Palivizumab has been shown to reduce both hospitalization rates and all-cause mortality in certain groups of high-risk children (such as those with chronic lung disease, congenital heart disease, and those born preterm). However, its cost limits its use in many parts of the world. More potent derivatives of this antibody have since been developed (including motavizumab) but were associated with considerable adverse events. The American Academy of Pediatrics (AAP 2014) recommends RSV prophylaxis with palivizumab during RSV season for: Nirsevimab requires only one dose that lasts the entire RSV season, unlike palivizumab, which has to be injected about once a month for up to four times to remain effective. and the United Kingdom in November 2022, and in Canada in April 2023. ==Treatment==

Supportive care Treatment for RSV infection is focused primarily on supportive care. This may include monitoring a patient's breathing or using suction to remove secretions from the upper airway. Supplemental oxygen may also be delivered through a nasal cannula or face mask in order to improve airflow. In severe cases of respiratory failure, intubation and mechanical ventilation may be required to support breathing. If signs of dehydration are present, fluids may also be given orally or through an IV. • Heliox, a mixture of oxygen with helium, may reduce respiratory distress within the first hour of treatment. It works by decreasing airway resistance and easing the work of breathing. However, it has not been shown to affect overall illness outcomes. • Chest physiotherapy including forced respiratory techniques for infants has not been found to reduce disease severity or yield any other improvement. Evidence supporting other physiotherapy approaches including instrumental physiotherapy and rhinopharyngeal retrograde technique (RRT) is very limited, The effects and any potential use needs further assessment in clinical trials. As such, treatment guidelines do not make recommendations for its use in children. In adults, ribavirin is used off-label and is generally reserved for the severely immunocompromised, such as those undergoing hematopoietic stem cell transplants. • Immunoglobins, both RSV-specific and non-specific, have historically been used for RSV-related illnesses. However, there is insufficient evidence to support the use of immunoglobins in children with RSV infection. Anti-inflammatories • Corticosteroids (systemic or inhaled) have not been found to decrease hospitalization length or disease severity in viral bronchiolitis. Their use may also prolong viral shedding, and thus is not commonly recommended. However, the use of oral corticosteroids remains common in adults with RSV-related exacerbation of underlying lung disease. Bronchodilators Bronchodilators, medications commonly used to treat asthma, are sometimes used to treat the wheezing associated with RSV infection. These medications (such as albuterol (sin. salbutamol)) are beta-agonists that relax the muscles of the airways to allow for improved airflow. However, bronchodilators have not been found to improve the clinical severity of infection or the rate of hospitalization among those with RSV infection. Given their limited benefit, plus their adverse event profile, they are not routinely recommended for use in RSV bronchiolitis. Antibiotics target bacterial pathogens, not viral pathogens such as RSV. However, antibiotics may be considered if there is clear evidence that a secondary bacterial infection has developed. Ear infections may also develop in a small number of infants with RSV bronchiolitis, in which case oral antibiotics may sometimes be used. Beyond vaccines, AstraZeneca and Sanofi introduced nirsevimab, a prophylactic monoclonal antibody with 75% efficacy against RSV cases in infants under one year. Europe approved nirsevimab in November 2022, and the FDA followed suit in July 2023. Merck's clesrovimab, a similar monoclonal antibody, is in late-stage trials. ==Epidemiology==

Infants and children Worldwide, RSV is the leading cause of bronchiolitis and pneumonia in infants and children under the age of 5. The risk of serious infection is highest during the first 6 months of life. Of those infected with RSV, 2–3% will develop bronchiolitis, necessitating hospitalization. Each year, approximately 30 million acute respiratory illnesses and over 60,000 childhood deaths are caused by RSV worldwide. An estimated 87% of infants will have experienced an RSV infection by the age of 18 months, and nearly all children will have been infected by 3 years. In the United States, RSV is responsible for up to 20% of acute respiratory infection hospitalizations in children under the age of 5. However, the vast majority of RSV-related deaths occur in low-income countries that lack access to basic supportive care. Researchers analyzed over 14,000 SUID cases using CDC records and found that the rate per 100,000 live births increased by 10% between 2019 and 2021. The study revealed that the risk of SUID was highest from June to December 2021, coinciding with an off-season spike in RSV hospitalizations after the virus deviated from its typical winter pattern in 2020. Adults It is rare for healthy young adults to develop severe illness requiring hospitalization from RSV. However, it is now recognized as a significant cause of morbidity and mortality in certain adult populations, including the elderly and those with underlying heart or lung diseases. Its clinical impact among elderly adults is estimated to be similar to that of influenza. Each year, approximately 5–10% of nursing home residents will experience RSV infection, with significant rates of pneumonia and death. RSV is also responsible for 2–5% of adult community-acquired pneumonias. Immunocompromised In both adults and children, immunosuppression increases susceptibility to RSV infection. Children living with HIV are more likely to develop acute illness and are 3.5 times more likely to require hospitalization than children without HIV. Bone marrow transplant patients before marrow engraftment are at particularly high risk, with RSV accounting for nearly half of the viral infections in this population. This group has also demonstrated mortality rates of up to 80% among those with RSV pneumonia. While infection may occur within the community, hospital-acquired infection is thought to account for 30–50% of cases among immunocompromised individuals. Seasonality RSV seasonality varies around the world. In temperate climates, infection rates tend to be highest during the cold winter months. This is often attributed to increased indoor crowding and increased viral stability in lower temperatures. In tropical and arctic climates, however, the annual variation is less well-defined and seems to be more prevalent during the rainy season. Annual epidemics are generally caused by the presence of several different viral strains. Subtype A and B viruses will often circulate simultaneously within a specific geographic region, although group A viruses are more prevalent. == Research ==

A study investigated RSV-specific T cell responses in 55 infants hospitalized for RSV bronchiolitis and found that these responses were similar during both acute illness and recovery, and did not increase after subsequent RSV infections. SARS-CoV-2 infections, the virus responsible for COVID-19, may lead to a higher risk of infection with RSV. In November 2022, the RSV hospitalization rate for newborns was seven times the rate in 2018. This, combined with increasing influenza circulation, caused the US state of Oregon to declare a state of emergency. The findings of a 2024 cross-sectional study of 6,248 hospitalized adults with RSV infection suggest that acute cardiac events are common among hospitalized older adults with RSV infection, and are associated with severe clinical outcomes. Nearly a quarter of hospitalized people over 50 with RSV experienced an acute cardiac event (most frequently acute heart failure), including 1 in 12 adults (8.5%) without documented underlying cardiovascular disease. Patients who had acute cardiac events had nearly twice the risk of a severe outcome than patients who did not. ==Notes==