Why RSV Makes Babies Sicker Than COVID—And Why Steroids Could Make It Worse

Researchers have discovered that respiratory syncytial virus (RSV) and SARS-CoV-2 (the virus causing COVID-19) trigger completely different immune responses in infants, which explains why RSV infections are often far more severe despite both being respiratory viruses. A groundbreaking study from St. Jude Children's Research Hospital and The Jackson Laboratory found that RSV actually suppresses the infant immune system at a molecular level, while COVID-19 causes the opposite problem—an overactive inflammatory response. This discovery is changing how doctors treat these infections and could save lives.

Why Do Infants Get Sicker With RSV Than COVID-19?

During the COVID-19 pandemic, physicians noticed something puzzling: babies admitted to hospitals with RSV infection often became much sicker than those hospitalized with SARS-CoV-2, even though both viruses attack the respiratory system in similar ways. To understand why, researchers compared the immune responses of 19 infants hospitalized with RSV, 30 infants hospitalized with SARS-CoV-2, and 17 healthy age-matched infants—most around 2 months old. Using advanced single-cell analysis, they examined proteins, genes, and epigenetic signatures (molecular switches that control how genes turn on and off) in the infants' blood.

The findings were striking. Infants with RSV had significantly fewer natural killer cells—specialized immune cells that fight viruses—compared to those with COVID-19. These natural killer cells also produced less interferon-gamma, a key molecule that defends against viral infections. This shortage was strongly linked to disease severity. "What surprised us most was that the antiviral responses looked similar at first glance, but when we examined how immune genes were regulated, we saw striking differences," explained Dr. Duygu Ucar, Professor at The Jackson Laboratory. "RSV appears to reprogram parts of the infant immune system at the epigenetic level; which are molecular switches that control how genes are turned on or off".

How RSV and COVID-19 Create Opposite Immune Problems

The study revealed that RSV and COVID-19 create fundamentally different immune dysregulation patterns in infants:

• RSV Response: Causes unexpectedly low levels of systemic inflammation, poorly coordinated early immune response, reduced natural killer cell activity, lower interferon-gamma expression, and decreased activity of key inflammatory signals (IL-1B, NF-κB) that normally help fight infection
• COVID-19 Response: Triggers significant immune dysregulation across multiple cell types with a significant increase in pro-inflammatory molecules such as TNF alpha and elevated NF-κB activity, creating a hyperinflammatory state
• Clinical Implication: These opposite immune patterns explain why anti-inflammatory treatments like steroids help some severe COVID-19 patients but have not helped RSV patients and may even cause harm

"One very practical implication of our work is that we should not routinely give steroids to infants with RSV," said Dr. Asunción Mejías, co-first author at St. Jude. "RSV is already immunosuppressive; giving steroids that also suppress immunity may further impair the natural killer cell response combating the virus".

What This Means for Treatment and Prevention

This research provides critical guidance for how doctors should approach RSV infections differently from COVID-19. Because RSV suppresses the immune system rather than overstimulating it, the standard treatment approach used for severe COVID-19 cases—anti-inflammatory steroids—could actually backfire. Instead of reducing inflammation, steroids would further weaken an already compromised immune response, potentially making RSV infections worse.

The findings also highlight why RSV remains such a serious threat to infants worldwide. RSV is the primary cause of infant hospitalizations and the number two cause of infant mortality globally. Understanding these immune differences opens the door to developing targeted treatments that work with the infant immune system rather than against it. "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," noted Dr. Octavio Ramilo, chair of the Department of Infectious Diseases at St. Jude. "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".

Steps to Protect Your Infant From RSV

• Know the Symptoms: Watch for cough, congestion, wheezing, difficulty breathing, and fever in infants under 2 months old, and seek medical care promptly if symptoms develop
• Avoid Steroid Treatment: Discuss with your pediatrician that steroids are not recommended for RSV infections in infants, based on current medical evidence
• Ask About RSV Prevention: Talk to your doctor about RSV protection options available for high-risk infants, as new preventive strategies continue to emerge
• Practice Infection Control: Wash hands frequently, avoid exposing infants to people with respiratory symptoms, and maintain good hygiene during RSV season (typically fall and winter)

This research represents a major shift in how scientists understand infant immunity and could reshape treatment protocols for RSV and other respiratory infections in young children. By recognizing that RSV and COVID-19 require fundamentally different treatment approaches, doctors can now provide more targeted, effective care that works with each infant's unique immune response rather than against it.