Literature
From Pages to Practice
Published July 20, 2022
The ubiquitous respiratory syncytial virus (RSV) has historically affected millions of children worldwide. The viral infection is associated with the clinical syndrome of bronchiolitis, consisting of rhinorrhea, a fluctuating physical examination, and varying levels of respiratory distress. The rhinorrhea (also known as coryza) is such a prominent feature that RSV was originally named chimpanzee coryza virus. Microscopically, the fusion (F) protein of RSV leads to the merging of cell membranes and the formation of giant cells called syncytia (hence, “syncytial” virus). These syncytia are theorized to be prone to necrosis, leading to shedding of unviable cells into the airway, with subsequent bronchiolar plugging and respiratory distress.
The mainstay of treatment for RSV is supportive care, including suctioning of secretions related to the pathophysiology of bronchiolitis. Glucocorticoids and bronchodilatorshave not been shown to improve outcomes, and even initial enthusiasm for inhaled hypertonic saline has recently waned due to the emergence of contradictory data and guidelines recommending against its use.
Monthly prophylaxis with palivizumab, an injected monoclonal antibody against the F protein, is indicated during the first 1–2 years of life in high-risk infants, including those with prematurity, congenital heart disease, and chronic lung disease. RSV prophylaxis with nirsevimab, a similar monoclonal antibody that also binds the F protein, has been shown to be effective in healthy preterm infants, and notably reduces the number of injections to one per season. However, to date, no effective therapies are available to prevent bronchiolitis in average-risk infants.
To examine the efficacy of nirsevimab prophylaxis in a wider population of children, investigators in the MELODY trial randomized average-risk infants born at ≥35 weeks (80% were born at term) to receive a single injection of nirsevimab or placebo before the RSV season. Nirsevimab reduced the primary endpoint of medically attended RSV visits. Notably, hospitalization outcomes did not differ between groups, but the trial spanned the Covid-19 pandemic and resulted in low RSV infection rates in both groups. In analyses of data from the northern hemisphere before the Covid-19 pandemic spread, the number needed to treat to prevent one medically attended RSV visit was 12–14 infants.
Nirsevimab has been submitted for FDA approval, but pending a regulatory decision, clinicians can do little currently to change practice. However, if such a drug is approved and affordable, one can imagine the potential benefit given the prevalence of RSV disease in a regular respiratory season, especially salient now that masking requirements are subsiding. Perhaps we can look forward to a time when bronchiolitis will be a rare event, as witnessed during the winter of 2020 at the height of Covid-19 respiratory precautions.
The following NEJM Journal Watch summary provides more details of the study.
Marie Claire O'Dwyer, MB BCh BAO, MPH, reviewing Hammitt LL et al. N Engl J Med 2022 Mar 3
Lower respiratory tract infection caused by respiratory syncytial virus (RSV) infection is a leading cause of hospitalization among infants. Although RSV prophylaxis with palivizumab, given as a monthly injection, is recommended for certain high-risk preterm infants, no prophylaxis agent currently is approved for late-preterm or average-risk infants, despite the fact that most RSV-associated hospitalizations occur in these groups.
Nirsevimab (a monoclonal antibody against RSV that is not yet U.S. FDA-approved) previously was shown to be effective at limiting RSV-associated illness and hospitalization among preterm infants (NEJM JW Pediatr Adolesc Med Sep 2020 and N Engl J Med 2020; 383:415). In this new industry-funded multicenter trial, 1490 healthy infants (born at or after 35 weeks' gestation, entering their first RSV season, and younger than 12 months of age) were randomized to receive a single intramuscular injection of nirsevimab or placebo. Compared with placebo, nirsevimab significantly lowered the incidence of medically attended RSV-associated lower respiratory tract infection (5.0% vs. 1.2%) and RSV-associated hospitalizations (1.6% vs. 0.6%). Adverse event rates were similar in both groups.
Comment: For at-risk infants who do not meet current RSV prophylaxis criteria, nirsevimab represents a potentially practice-changing advance; it reportedly has more-potent anti-RSV activity than the currently available monoclonal antibody (palivizumab) and is administered as a single dose rather than monthly. However, whether monoclonal antibody prophylaxis will be broadly acceptable to parents of average-risk healthy infants remains uncertain.
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