RSV vs. COVID-19: Why Infants Secure Sicker with RSV and Implications for Treatment

Young infants hospitalized with respiratory syncytial virus (RSV) often experience more severe illness compared to those infected with SARS-CoV-2, the virus that causes COVID-19. Fresh research from St. Jude Children’s Research Hospital and The Jackson Laboratory (JAX) published in Science Translational Medicine reveals that these two common respiratory viruses trigger distinct immune responses in infants, potentially explaining the differences in clinical outcomes and informing treatment strategies.¹

Differing Immune Responses at a Single-Cell Level

During the COVID-19 pandemic, clinicians observed that infants hospitalized with RSV frequently exhibited more severe symptoms than those with SARS-CoV-2, despite both being respiratory RNA viruses. To investigate this disparity, researchers compared the immune responses of infants hospitalized with either virus to those of healthy infants, analyzing data at a single-cell level. Measurements of proteins, genes, and epigenetic signatures in blood samples revealed key differences in immune cell activity and signaling.¹

“We showed, for the first time, that two similar respiratory viruses, RSV and SARS-CoV-2, cause very different types of immune dysregulation in young infants,” said Octavio Ramilo, MD, chair of the St. Jude Department of Infectious Diseases and co-corresponding author of the study. “The host response differs depending on the infecting virus at the chemical, cellular and even epigenetic level.”¹

RSV Linked to Low Inflammation and Poorly Coordinated Immune Response

The study found that severe RSV infection in infants was associated with unexpectedly low levels of systemic inflammation and a less effective early immune response, particularly from natural killer (NK) cells. This contrasts sharply with the hyperinflammatory immune response observed in infants infected with SARS-CoV-2.¹

“Most strikingly, we saw infants with RSV had significantly fewer numbers of natural killer cells, compared to those with SARS-CoV-2 infections,” said Asunción Mejías, MD, PhD, MsCS, of St. Jude Department of Infectious Diseases and co-first author. “In those patients, these cells also made less interferon-gamma, a key molecule to defend against viruses, which was strongly correlated with disease severity.”¹

Researchers also noted that RSV appeared to reprogram parts of the infant immune system at the epigenetic level—modifying molecular switches that control gene expression.¹ This suggests that RSV may have long-term effects on immune development.

SARS-CoV-2 Triggers Hyperinflammation

In contrast to RSV, SARS-CoV-2 infection generally caused significant immune dysregulation across multiple cell types, with a notable increase in pro-inflammatory molecules like TNF alpha and NF-κB activity.¹ This hyperinflammatory response may explain why anti-inflammatory treatments, such as steroids, can be beneficial for some patients with severe COVID-19.

Implications for Treatment: Avoiding Steroids for RSV

The findings have direct clinical implications, particularly regarding the employ of steroids in infants with RSV. Researchers emphasize that, unlike COVID-19, steroids should not be routinely administered to infants with RSV, as RSV is already immunosuppressive, and adding steroids could further impair the natural killer cell response.¹

The Importance of Understanding Infant Immunity

RSV remains a leading cause of infant hospitalizations and the second leading cause of infant mortality worldwide.¹ This study underscores the critical necessitate to understand the unique aspects of the infant immune system and how it responds to different pathogens.

“Globally, five million children die before the age of 5, half occurring in the first months of life due to infection, before vaccines are given,” said Ramilo. “With the tools we have developed, we have shown that we can start to uncover what’s happening in that early immunological window to begin improving those odds.”¹

Further Research and the IDEAL Study

Scientists at St. Jude are continuing to study the developing immune system in early life to better protect infants from serious infections. The IDEAL (Immune Development in Early Life) study is investigating how infections like flu, COVID-19, and RSV during the first year of life impact immune development.⁴

Understanding these early immune responses is crucial for developing effective prevention strategies and improving outcomes for infants worldwide.²

References

1. St. Jude Children’s Research Hospital. “Differing immune responses in infants may explain increased severity of RSV over SARS-CoV-2.” News Release. February 25, 2026. https://www.stjude.org/media-resources/news-releases/2026-medicine-science-news/differing-immune-responses-in-infants-may-explain-increased-severity-of-rsv-over-sars-cov-2.html
2. St. Jude Research. “The unique defenses of the infant immune system.” February 24, 2026. https://www.stjude.org/research/progress/2026/the-unique-defenses-of-the-infant-immune-system.html
3. Science.org. “A systems immunology approach reveals divergent immune profiles…” https://www.science.org/doi/abs/10.1126/scitranslmed.aea7097?af=R
4. St. Jude Children’s Research Hospital. “IDEAL: Immune Development in Early Life.” https://www.stjude.org/care-treatment/clinical-trials/ideal-immune-development.html