Reference: N Engl J Med. 2023 Dec 28;389(26):2425
Practice Point: A single IM injection of nirsevimab in healthy infants entering their first RSV season may decrease the risk of hospitalization from lower respiratory tract infections.
EBM Pearl: Randomized controlled trials on newborns and pregnant people can be terrifying, but taking shortcuts (in the form of open-label studies) undercuts our certainty in the results.
RSV is a major cause of acute lower respiratory tract infection (LRTI) and hospitalization for young infants, and considering the lack of treatment other than supportive care, prevention of RSV is crucial. Fortunately, we now have two preventative measures against RSV in infants: maternal vaccination during pregnancy and long-lasting monoclonal antibody injections for infants. Nirsevimab is a monoclonal antibody that may offer protection for the entirety of an infant’s first RSV season, when they are most vulnerable. A recent study published in the NEJM suggests that a single dose of nirsevimab may prevent hospitalization and severe LRTI due to RSV in healthy term and late preterm infants.
Investigators enrolled 8,058 healthy infants ≤ 12 months old born at ≥ 29 weeks gestation entering their first RSV season during 2022-2023. The trial was conducted in France, Germany, and the United Kingdom. Infants were randomized to receive either one dose of nirsevimab IM or standard care (no intervention). Infants were followed remotely through electronic diaries completed by caregivers for 3 months. The primary and secondary outcomes were hospitalization for RSV LRTI and very severe RSV LRTI, defined as an oxygen saturation < 90% and a requirement for supplemental oxygen. Infants were excluded from the study if they were eligible for palivizumab (a monoclonal antibody approved for use in infants with risk factors for severe RSV) or if their birthing parent received RSV vaccination during pregnancy. The investigators, parents, legal representatives, and outcome assessors were all aware of group assignment.
Hospitalization for RSV LRTI occurred in 11 infants (0.3%) in the nirsevimab group and 60 infants (1.5%) in the standard care group (p < 0.001, NNT 84). Very severe RSV LRTI occurred in 5 infants (0.1%) in the nirsevimab group and 19 infants (0.5%) in the standard care group (p = 0.004, NNT 250). There were more treatment-related adverse events like fever and rash with nirsevimab (2.1%) and 1 infant had infantile spasms 23 days after nirsevimab injection. No deaths were reported.
Though the results initially seem promising, wishful thinking may be playing a role in the hope and excitement about this intervention, especially given the lack of treatment for RSV other than supportive care. The open-label design and lack of placebo control, especially in the setting of NNTs already in the hundreds, give us pause. Not blinding investigators, parents, and outcome assessors puts the results at risk for multiple forms of bias, most of which tend to overestimate the magnitude of benefit and thus favor the intervention. Caretakers who knew that their child received nirsevimab could alter behavior in terms of seeking healthcare (or not) or testing for RSV. Awareness by treating clinicians could have influenced decisions regarding hospital admission, as there may have been less of a need to be on the safe side and admit if they knew the infant had received nirsevimab.
Let’s put the potential bias aside for a moment and assume the NNT to prevent one case of severe RSV with nirsevimab is not higher than the 250 reported. That is less impressive than the NNT of ~70 demonstrated by the trial of the RSV vaccine in pregnant women, but it will be interesting to see what the combined effect could (will) be if we do both interventions. Deciding what we as a healthcare system and society are willing to pay or risk or do to “all” in order to save one infant life is one of the trickiest decisions we have to navigate. It should be noted that the CDC is already recommending nirsevimab for healthy infants < 8 months entering their first RSV season and through 19 months for those at risk of severe RSV infection, and many hospitals have already rolled out widespread implementation. All in all, we remain hopeful about this new treatment, but we also think it’s important to look at the big picture with eyes wide open.
For more information, see the topic Respiratory Syncytial Virus (RSV) Infection in Infants and Children in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Nicole Jensen, MD, Family Physician at WholeHealth Medical. Edited by Alan Ehrlich, MD, FAAFP, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Katharine DeGeorge, MD, MS, Senior Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia; Dan Randall, MD, MPH, FACP, Deputy Editor at DynaMed; Vincent Lemaitre, PhD, Medical Editor at DynaMed; Elham Razmpoosh, PhD, Postdoctoral Fellow at McMaster University; Hannah Ekeh, MA, Senior Associate Editor at DynaMed; and Jennifer Wallace, BA, Associate Editor at DynaMed.