Respiratory syncytial virus (RSV) are currently rising across the globe along with Influenza and COVID-19 infections

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Research has shown that RSV infections can be dangerous for certain adults. Each year, it is estimated that between 60,000-120,000 older adults in the United States are hospitalized and 6,000-10,000 of them die due to RSV infection.

 Adults at highest risk for severe RSV infection include:

  • Older adults, especially those 65 years and older
  • Adults with chronic heart or lung disease
  • Adults with weakened immune systems

https://www.cdc.gov/rsv/high-risk/older-adults.html

Respiratory syncytial virus (RSV) also called human respiratory syncytial virus (hRSV) and human orthopneumovirus, is a common, contagious virus that causes infections of the respiratory tract. It is a negative-sense, single-stranded RNA virus. Its name is derived from the large cells known as syncytia that form when infected cells fuse.
 
Although RSV is the single most common cause of respiratory hospitalization in infants, and reinfection remains common in later life: it is an important pathogen in all age groups.
 
It has been found that infection rates are typically higher during the cold winter months, causing bronchiolitis in infants, common colds in adults, and more serious respiratory illnesses such as pneumonia in the elderly and immunocompromised.
https://thorax.bmj.com/content/74/10/986

Currently there is no vaccine against RSV, although many are under development.
 
Current treatment for severe illness is primarily supportive, including oxygen therapy and more advanced breathing support with CPAP or nasal high flow oxygen, as required. In cases of severe respiratory failure, intubation and mechanical ventilation may be required.
 
Ribavirin is the only antiviral medication currently licensed for the treatment of RSV in children and also in adults though its use remains controversial.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4345819/

RSV PROPHYLAXIS AND TREATMENT: LESSONS LEARNED FROM PAST EXPERIENCE
Potential antiviral strategies for infection and disease include the following: prophylaxis, during the RSV season (seasonal) or after potential exposure (postexposure) to prevent illness and possibly infection; preemptive or early therapy, given when virus has been detected in the upper respiratory tract to prevent progression to lower respiratory tract involvement; and treatment of LRTI, initiated when virus is detected in specimens obtained from lower respiratory tract samples in patients with LRTI. The following sections briefly review key findings with these strategies in at-risk target populations.

Infants and Children
Clearly, the most recognizable and clinically relevant treatment group is infants and young children with RSV bronchiolitis or LRTI. This population was the first for evaluation of therapeutic and prophylactic agents. The role of nonspecific interventions for the management of RSV LRTI was been summarized in a 2006 publication of the American Academy of Pediatrics [105] and will not be reviewed further here.

Seasonal prophylactic use of polyclonal RSV intravenous immunoglobulin (RespiGam) or human anti-F monoclonal antibodies (palivizumab, motavizumab) reduced the risk of RSV-associated acute LRTIs and hospitalizations in high-risk infants [106]. Palivizumab has become the accepted antibody product for prevention of RSV disease in at-risk children. It was licensed in 1988. Two Cochrane reports have summarized the use of palivizumab. The first assessed the data for disease prevention in infants. The data from 4 placebo-controlled trials demonstrated that active therapy decreased hospitalization (risk ratio, 0.49; 95% confidence interval, .37 to .64) compared with placebo [107]. Therapy was of greatest value in the premature and those at high risk (eg, congenital heart disease, chronic lung disease) Cost-effectiveness is greatest in this setting.

Currently, the American Academy of Pediatrics Red Book Committee recommends seasonal prophylaxis in the first year of life for infants of <29 weeks gestation. Prophylaxis is not recommended for healthy infants of >29 weeks gestation. In addition, those of <32 weeks gestation with chronic lung disease or heart disease or 32–35 weeks gestation with risk factors (daycare, siblings aged <1 year, smoke exposure in the home, congenital abnormalities of the airway) should be treated for 12 months. These recommendations will probably be further debated.

The second Cochrane Report analyzed the effect of palivizumab in children with cystic fibrosis ≤2 years of age. No meaningful differences in outcome were reported, albeit with small numbers [108].

A large prophylactic study comparing palivizumab with motavizumab in high-risk children showed that motavizumab was associated with a significant 50% reduction in the incidence of medically attended LRTI (MALRTI) compared with palivizumab, but also with a higher rate of adverse reactions [109].

Other studies compared the administration of palivizumab or motavizumab in infants hospitalized with established RSV LRTI and found inconsistent antiviral effect. Viral load was consistently reduced during these trials, as assessed by quantitative culture, [110], but this may have reflected ex vivo neutralization by the therapeutic antibody in the in vitro viral quantification, rather than reduced infection in the tissues of the patient [111]. A larger double-blind, randomized study of hospitalized infants treated with motavizumab or placebo demonstrated no antiviral effect, as measured by quantitative PCR [112], but the study was not powered to detect clinical benefit [111, 112].

Results of early studies of RSV prophylaxis with RSV intravenous immunoglobulin and palivizumab conducted in the United States [113], Canada, Europe [114, 115], and Japan [70] suggested that preventing RSV LRTI in high-risk infants also prevented subsequent recurrent wheezing up to 3 years of age. Similarly, a placebo-controlled trial in healthy preterm infants showed that palivizumab reduced the number of days of wheezing in the first year of life [116], even for wheezing not associated with an active RSV infection. If this association is indeed causal, as it seems, the development of an effective vaccine and perhaps a therapeutic(s) against RSV would have a major impact beyond the acute effects of RSV infection. Future studies of antiviral therapies should try to incorporate reduction in long-term wheezing as an outcome whenever feasible.

Ribavirin was first marketed in 1980 for treatment of RSV in children, but many of the original proof of concept studies, showing reduction in RSV load and its association with reduced disease severity, are considered flawed [117–124]. First, at that time, the only method to quantify RSV was by quantitative culture. Because aerosolized ribavirin is delivered in high concentrations to the same respiratory secretions from which samples were obtained for quantification, the observed reduction in viral load may have been at least partially attributed to an in vitro effect in the secretions due to the presence of drug. Second, in some studies, the placebo was aerosolized water, which is potentially bronchoconstrictive [124].

Third, efficacy outcomes were generally based on reductions in clinical severity scores which were of arguable clinical relevance. Furthermore, no ribavirin-induced mutations in RSV have been observed, which some (including the Division of Antiviral Products of the Food and Drug Administration [FDA]), interpret as suggesting a lack of a selective antiviral effect. Inhaled ribavirin has additional problems, including the potential for mutagenicity, teratogenicity, and carcinogenicity in preclinical models and the associated exposure risk to healthcare workers. Because of these occupational exposure issues and unclear efficacy, its use has been restricted to only very high-risk populations, namely HSCT and lung transplant recipients, as noted below, and replacement with selective small molecules is desirable [125].

Immunocompromised Individuals of All Ages
Aerosolized ribavirin, with or without antibody treatment, has been commonly used in HSCT recipients, but no adequately powered randomized trials have been performed. One randomized controlled trial (RCT) compared preemptive aerosolized ribavirin to supportive care for RSV URTI in HSCT recipients but was discontinued after 5 years because of slow accrual, although trends toward reduced LRTI progression and nasal viral load reductions were observed in the ribavirin group [126]. Accrual problems in this trial were probably due to the complicated study design, which required masked clinical evaluations and the level of complexity caused by aerosolized ribavirin administration [126].

In retrospective cohort analyses, aerosolized ribavirin therapy reduced the risk of RSV LRTI by 83% and all-cause mortality by 57% in 280 HSCT recipients [45, 127]. Another recent study of 181 HSCT recipients with RSV URTI showed a trend toward less frequent progression to LRTI with aerosolized ribavirin [47].

In another uncontrolled and nonrandomized study, aerosolized ribavirin for the treatment of LRTI in 118 HSCT recipients was shown to be effective by multivariate analysis [42]. Systemic, namely oral, ribavirin showed trends toward moderate efficacy in uncontrolled observational studies, but the small sample size hampered statistical analysis.

These results are consistent with results from a 2011 pooled analysis [43]. However, the concentrations of ribavirin achievable in humans by oral administration fall significantly below the concentration required to inhibit RSV replication (highlighting a major reason why ribavirin for RSV infection was developed as an aerosol) [128]. Ribavirin is deployed in high-risk immunocompromised children, as based upon adult uncontrolled treatment studies, as noted above.

Whether the addition of immunoglobulin products to antiviral therapy confers a significant benefit remains controversial. One uncontrolled retrospective cohort study (N = 280) suggested a benefit of the combination of immunoglobulin and ribavirin, but the relative contribution of the immunoglobulin products could not be evaluated [45].

In another study of HSCT recipients with RSV LRTI (N = 118) immunoglobulin products were not associated with a survival benefit [42]. Controversy also persists about the use of the RSV-specific monoclonal antibody palivizumab. A phase I study of aerosolized ribavirin plus palivizumab had an overall survival rate of 83% [129], but a follow-up phase III study was discontinued because of an inability to accrue patients owing to a perceived benefit of the interventions.

Investigators conducting a retrospective uncontrolled single-center multivariate analysis (N = 84) concluded that the addition of palivizumab to aerosolized ribavirin did not improve outcomes in those with RSV-related LRTI compared with ribavirin alone [117]. In contrast, results of another study suggested that ribavirin, with or without an immune intervention, decreases progression to RSV-LRTI from 45% to 15% and death from 70% to 35% [127].

In RSV-infected lung transplant recipients, results of 2 double-blind, randomized, placebo-controlled trials suggest that early antiviral therapy can reduce the incidence of BOS compared with placebo. In the first RCT, involving 24 lung transplant recipients with RSV respiratory tract infection [130], inhaled Alnylam (ALN)-RSV01, a small interfering RNA targeting the N gene of RSV, lowered the incidence of new or progressive BOS at day 90 by 50% (P = .05).

A follow-up RCT involving 77 RSV-infected lung transplant recipients demonstrated >50% reduction in new or progressive BOS development at both 90 and 180 days (intention-to-treat analysis, P < .05) [131, 132]. Preliminary results suggest that the treatment effect may be enhanced if ALN-RSV01 is given within 5 days of symptom onset, as opposed to later, although there were no significant differences in viral parameters or symptom scores during the acute phase of illness.

Only limited data are available on the association of viral load with outcome in immunocompromised patients. To our knowledge, there are no data on viral load in nasal secretions and progression to LRTI in transplant recipients. In a retrospective study of 30 HSCT recipients with RSV LRTI, no association was found with survival [42, 132, 133].

The lack of association of viral load and outcome in these studies may have been due to small sample size and the retrospective nature of the study, which prevented appropriate adjustment for bronchioalveloar lavage dilution effects. There was a higher probability of RSV RNA detection in serum samples from patients with higher viral load in bronchioalveloar lavage, but the effect did not reach statistical significance [42].

RSV RNA detection in blood has been associated with increased mortality in a study of HSCT recipients with RSV lower respiratory tract disease, and peak serum viral load above the median further increased the mortality risk [42]. Whether RSV RNA detection in blood represents active viral replication remains to be investigated.

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