Overview
Respiratory syncytial virus (RSV)
RSV is the most prevalent cause of lower respiratory tract infection (LRTI) worldwide in teens and young children, in addition to immuno-compromised and elderly individuals. RSV is a single-stranded ribonucleic acid (RNA) virus that expresses 11 proteins. (G) and (F) transmembrane glycoproteins are responsible for attachment to the cell surface and cell entry through fusion to the cell membrane respectively.
The virus is transmitted primarily through direct contact and its incubation period is about 2-8 days, begins initially with an upper respiratory tract infection which is followed by a secondary development of lower respiratory tract infection due to intracellular transmission or aspiration, the common symptoms include low fever, runny nose, headache, dry cough, sneezing, sore throat, and breathing difficulty.1,2
Is there any effective treatment
RSV infection is usually a self-limiting disorder in healthy individuals. Thus, supportive therapy is the cornerstone of treatment which aims to reduce the duration and severity of the disease, avoid the risk of transmission, and relieve symptoms, in addition to the preventive measurements and vaccinations that play an essential role in disease management.
The treatment choices that have been studied involve palivizumab, ribavirin, RSV-immune globulin (RSV-IVIG), and motavizumab.2 However, to date, no approved or effective treatment has been used against RSV as a cure, the clinical outcomes of the ongoing studies demonstrate hopes for the approval of an effective therapy to cure RSV in the future.1
RSV therapeutics and vaccines
Specific respiratory syncytial virus therapy
- Ribavirin
Ribavirin is a broad-spectrum antiviral medication that acts by inhibiting the replication of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) viruses. There are three formulations of Ribavirin which are oral, aerosolised, and intravenous (IV).
A study was done previously that involved 12 randomised trials in cases that were RSV positive to compare between the group who received ribavirin and that with placebo. Four trials showed no significant difference in terms of mortality, illness severity, improvement in oxygenation, and length of hospitalisation.2
Aerosolised ribavirin should be applied in a room that maintains optimal airflow with six air exchanges per hour, at least, to reduce or avoid accidental inhalation by others in the patient’s room. The aerosolised formulation cannot be administered without using an inhalation device which is specialised for the aerosolised ribavirin like the small-particle aerosol generator model-2 (SPAG-2). Prior to removing any tent or hood, the SPAG-2 should be turned off for a few minutes.
Another randomised control trial (RCT) study was conducted among cases with bone marrow transplants, who tested positive for RSV. Eligible cases were administered a total of 2 g of aerosolized ribavirin at a concentration of 60 mg/ml over 2 hrs 3 times daily for 10 days combined with supportive care or supportive case alone. The study showed that ribavirin treatment was linked with a decrease in the viral amount (viral load) and pneumonia.
The recorded side effects of ribavirin are chest pain, conjunctivitis, skin rash, and shortness of breath. Additionally, headaches and vomiting can be found among family members and healthcare providers despite applying a suitable way of delivery. Ribavirin exhibits teratogenic effects which were demonstrated through examination in animals at a dose of 1 mg/kg but not less than 0.3 mg/kg (0.05mg/kg in humans). Aerosolised ribavirin exposure is a concern despite not observing any teratogenic effects in the offspring of exposed healthcare teams.
The oral ribavirin was studied in positive RSV cases who received lung transplants. In the beginning, these cases were given a loading dose of IV ribavirin followed by oral ribavirin for an average duration of 11 days. Post-lung transplant, oral ribavirin was shown to be of better efficiency with respect to that of IV formulation. Moreover, a meta-analysis and a systematic review study demonstrated an improvement in mortality rate in patients with haematological disorders who received ribavirin. Thus, oral ribavirin showed reasonable viral clearance and was a cost-effective safe treatment compared to the IV formulation.
Overall, ribavirin is not currently recommended due to the potential side effects and high cost. However, by referring to its advantageous outcomes in immunocompromised patients, it remains a consideration in this group. Interestingly, other antiviral agents are under investigation in randomised control trials such as AK0529 (ziresovir) and RV521 which act by using fusion or inhibition of replication mechanisms.
- Palivizumab
Palivizumab was approved in 1998, it showed high efficacy as a prophylactic agent in preventing severe RSV infection in high-risk groups. Palivizumab is a recombinant humanised monoclonal immunoglobulin which acts by binding to the fusion RSV protein. As it is given to be an effective prophylactic agent, scientists wanted to study its possible efficacy in treating acute RSV infections as well.
Therefore, a double-blinded RCT was conducted on healthy individuals with RSV bronchiolitis, they were administered randomly palivizumab or placebo. However, the outcomes did not show significant differences in terms of hospitalisation, stay duration, hospital readmission, or intensive care unit admission. Similarly, another RCT study did not demonstrate a significant change in the clinical outcomes between the group that received a placebo and that with palivizumab.
- Motavizumab
Motavizumab is a humanised anti-RSV monoclonal antibody, it's a derivative of palivizumab. A multicenter randomised control trial was carried out to evaluate motavizumab's therapeutic effect in RSV-positive cases. However, the studies showed no significant difference regarding hospital stay durations illness severity, and future wheezing episodes.
Another treatment option, which is RSV-IGIV, was investigated further as it showed promising effects in reducing RSV replication and preventing respiratory disorders in animal models. However, another double-blinded RCT including high-risk individuals demonstrated no significant clinical outcomes between those administered RSV-IGIV and those receiving a placebo. In 2003, RSV-IGIV was withdrawn from the market voluntarily due to its potential risks, such as blood product transmission, and alternative treatment options became available.
Non-specific RSV treatments
It is essential to understand the pathophysiology of RSV in order to observe the role of non-specific treatments in RSV bronchiolitis. RSV initially infects and replicates in the mucosa lining of the respiratory tract. The effects of the RSV virus are more severe in younger individuals, particularly at the level of the lower respiratory tract, unlike older patients, one of these potentially life-threatening complications includes bronchiolitis. Infants are more sensitive to RSV due to the small diameter of the airways and immature lung parameters.
RSV impairs the defence mechanism (mucociliary escalator) through the pathway of the airways, this process facilitates the elimination of foreign particles and pathogens. It consists of a lining of mucus with a tiny-hair-like structure known as cilia. This cilia act in a manner that moves the mucus along the respiratory tract towards the throat easing the elimination of pathogens and inhaled particles and preventing them from reaching the lungs.
Any impairment in this defence mechanism can lead to airway obstruction, elevated mucus production and viral impact on cilia. Therefore, non-specific therapeutics are used to target airway obstruction, such as bronchodilators, mucolytics, and anti-inflammatory agents.
| Product Name | Mode of administration/ Mechanism of Action | Recommendation |
| Deoxyribonuclease (hrDNase) | Mucous Therapies - Nebulised solution - Mucolytic product that cleaves extracellular DNA | - Not recommended. It can be considered which conventional therapy fails. |
| N-acetylcysteine | - Nebulised solution - Oral formulation is of poor bioavailability -Mucolytic compound - Acts by hydrolysing disulfide bonds of mucus proteins - Exhibits antioxidant properties | - Further investigations recommended as no sufficient details are available - Not recommended |
| 3% hypertonic saline | - Nebulised solution - Through osmotic gradient, it pulls water into mucus enhancing ciliary activity - Triggers cough - May decrease airway edema | - May reduce hospitalisation risk - No recommended for inpatient management - Further studies required regarding the reduction of admission episodes for infants |
| Salbutamol, Albuterol etc | Bronchodilators - Nebulised solutionβ-2 adrenergic receptor agonist - Acts by causing muscle relaxation and improving airways | Not recommended, but can be trialled and prescribed in certain cases where advantageous outcomes can be seen. |
| Epinephrine | - Nebulised solution - Some β-2 adrenergic effectsα-1 adrenergic receptor effects cause vasoconstrictionReduce airways edema | Not recommended Can be considered when it is highly expected to have severe reactive airways, such as asthma, but there is no enough evidence |
| Glucocorticoids (e.g. dexamethasone) | Therapies targeting inflammation Inhaled, nebulised or oral solution formulations Broad spectrum anti inflammatory properties | Therapies targeting inflammation Inhaled, nebulised or oral solution formulations Broad spectrum anti-inflammatory properties |
| Leukotriene inhibitors | - Oral solution - They inhibit leukotriene endogenous mediators of inflammation | Not recommended due to poor evidence |
| Chest physiotherapy | Manual Therapies Helps in clearance of secretions Expected to reduce ventilatory efforts in infants | Not recommended regularly Can be considered in the presence of certain complications like neuromuscular conditions |
Updates on vaccine development
Currently, there is no approved or licensed specific vaccine for RSV, but there is an urgent need for one, particularly in high-risk groups, pregnant women, and infants. Scientists are focusing on designing vaccines that trigger rapid immune reactions, ideally to be administered within the first month of birth.
This vaccine targets the F and G proteins of RSV acting by inducing the neutralising of antibodies for cross-protective responses. However, vaccine development is facing challenges in terms of inadequate research funding, ethical concerns, clinical trials limited by early phases, and patient immunocompromisation.1
Summary
RSV is the most prevalent cause of lower respiratory tract infection worldwide in teens and young children, in addition to immuno-compromised and elderly individuals.
Common symptoms include low fever, runny nose, headache, dry cough, sneezing, sore throat, and breathing difficulty.
Supportive therapy is the cornerstone of treatment which aims to reduce the duration and severity of the disease.
The treatment choices that have been studied involve palivizumab, ribavirin, RSV-immune globulin (RSV-IVIG), and motavizumab. However, to date, no approved or effective treatment to be used against RSV as a cure, the clinical outcomes of the ongoing studies demonstrate hopes for the approval of an effective therapy to cure RSV in the future.
Non-specific therapeutics are used to target airway obstruction, such as bronchodilators, mucolytics, and anti-inflammatory agents.
Currently, there is no approved or licensed specific vaccine for RSV due to certain challenges.
References
- Gatt, Dvir, et al. ‘Prevention and Treatment Strategies for Respiratory Syncytial Virus (RSV)’. Pathogens, vol. 12, no. 2, Jan. 2023, p. 154. PubMed Central, https://doi.org/10.3390/pathogens12020154.
- Malik, Shiza, et al. ‘Respiratory Syncytial Virus Infection: Treatments and Clinical Management’. Vaccines, vol. 11, no. 2, Feb. 2023, p. 491. PubMed Central, https://doi.org/10.3390/vaccines11020491.
