March 2020: They didn’t cough. They didn’t wheeze. But in NICUs worldwide, doctors grew uneasy: COVID-19 was hiding in newborns, its symptoms masquerading as harmless lethargy or poor feeding. The virus wasn’t milder in babies—it was different. Why were some babies born with COVID-19 infections? Why were infants, who don’t have fully developed lungs or immune systems, surviving COVID-19 unscathed? Yet, facing the unease were the researchers looking for answers.
One of these scientists is Dr. Chintan Gandhi, a pediatrician and researcher who specializes in lung diseases in newborns. His work focuses on why some babies get extremely sick from viruses like COVID-19, while others barely show symptoms. The answer, he believes, lies deep inside the lungs in tiny proteins that most people have never heard of.
Dr. Gandhi is a rare kind of scientist, one who works both in the hospital and the lab. Some weeks, he cares for sick newborns in the Neonatal Intensive Care Unit (NICU) at Penn State Health Children’s Hospital. Other weeks, he’s buried in the lab, trying to make sense of the patterns he and his colleagues find in their patients, and translating those results into real-world medicine. Dr. Gandhi’s journey began in India, where he earned his medical degree before moving to the U.S. for specialized training in pediatrics and neonatal medicine. Dr. Gandhi wasn’t satisfied with just treating sick babies; he wanted to understand how to prevent those illnesses in the first place.
That curiosity led him to Michigan State University, where he studied the renin-angiotensin system, which plays a key role in maintaining blood pressure and fluid balance, and which he believed played a critical role in lung diseases in neonates. He focused on a protein called ACE, which is produced by the lungs to increase blood pressure, and ACE2, its counterpart, which keeps it under control. It was believed that, because babies had low ACE2 levels, they were less able to protect themselves against acute respiratory disorders, making them more vulnerable to breathing problems. Scientists discovered ACE2 also acts like a "doorway" that SARS-CoV-2 (the virus that causes COVID-19) uses to infect cells. In addition, reports emerged showing that COVID-19 could be vertically transmitted from mother to baby during childbirth. So, right as the world started going into lockdown to fight COVID-19, Dr. Gandhi found himself on the frontlines of the fight - both in the hospital ward and the lab.
In the first months of the pandemic, Dr. Gandhi collected samples from patients ranging from 3 months to 80 years old. But his attention continuously fell back to the patients he’d been trained to specialize in– neonates, infants, and their mothers. The newborn immune system starts out incredibly fragile. Unlike adults, whose immune systems have built up defenses against countless diseases throughout their lives, neonates enter the world with immune systems that are still learning to function. This "naive" state makes them uniquely vulnerable to infections, including respiratory viruses like COVID-19. Dr. Gandhi and his colleagues noticed that mothers who were infected with COVID-19, but hadn’t yet developed immunity to the virus, passed on the disease to their babies during childbirth in a process called vertical transmission. To ensure the safety of the child, they developed a system to triage and manage laboring mothers with COVID-19. For example, in cases where either the mother or child was potentially infected, precautions to control droplet-borne transmission were added to PPE and sanitation methods. In addition, researchers helped establish consensus on conditions in which providing antenatal corticosteroids, drugs that help advance organ development in children at risk of premature birth, but also increase viral transmission in women sick with SARS or MERS, two similar diseases, was appropriate.
These new recommendations start even before childbirth. Immunoglobulin G (IgG) antibodies cross the placenta in the third trimester, offering the newborn passive immunity for the first few months of life. This process, known as vertical transmission of immunity, is why vaccinating pregnant women against diseases like RSV, influenza, and, as it turns out, COVID-19, is so critical. However, this protection is temporary. Maternal IgG antibodies gradually wane, typically disappearing by 6-12 months of age, leaving the infant vulnerable until they can generate their own immune responses through vaccination or natural infection. This disappearing immunity is why, although infants have less severe COVID-19 symptoms, reinfection can be particularly dangerous. New evidence also suggests that breastfeeding may help reintroduce maternal antibodies and keep children safe for longer. Throughout the pandemic, Dr. Gandhi further contributed to research on how to improve breastfeeding and vaccination acceptance for pregnant mothers, and which populations needed more vaccine education and support.
Two years into the pandemic, Dr. Gandhi began observing what epidemiologists had predicted: COVID-19 was evolving from a pandemic crisis into an endemic presence. As more and more people became immune to the disease, the virus mutated to become more contagious with less severe symptoms. He believes that the spread of the disease will shrink into smaller, but continuous waves, much like the flu.
Today, Dr. Gandhi is working with other researchers to predict the severity of COVID-19 in children before they’ve even been infected. A recent report, headed by Natalie Sicher, discovered that surfactant proteins play a huge role in how babies fight infections. These proteins, most abundant in the lungs, act like a lubricant, keeping the small air sacs open so humans can breathe. In addition, they help the body detect bacteria, viruses, and other pathogens. The team found that some babies have genetic differences in these surfactant proteins, which make them more likely to develop severe lung infections. High levels of a specific type of surfactant protein involved in the immune system, SP-A, were particularly strongly associated with severe COVID-19. According to Dr. Gandhi, it’s important to implement precautions against the disease in all aspects of pediatrics as medicine adapts to a world where COVID-19 may be a more regular presence.
Translating these findings into clinical practice might look like DNA tests at hospital admission to identify high-risk children. Pilot studies suggest that providing synthetic surfactants may stabilize patients' lungs.
The translational science led by researchers like Dr. Gandhi builds upon large networks and infrastructure that facilitate their work. Organizations helping manage and fund research, publishing platforms that help disseminate their work, and biological supply companies like Biomatik, which create the proteins and genes often used in many of these studies. Throughout their research looking for markers to predict severe COVID-19 in infants, Natalie Sicher and Dr. Gandhi used ELISA kits from Biomatik to help measure levels of different surfactant proteins. Kits like these use antibodies to detect different proteins and are a crucial part of many diagnostic models.
Going forward, Dr. Gandhi is looking to continue his work on translating findings about respiratory diseases, particularly Respiratory Syncytial Virus (RSV), a cold-like virus that is especially severe in infants. He is also on a mission to help disseminate much of the medicine that already exists to underserved communities. Currently, Dr. Gandhi says, “Most of the molecular research in pediatric immunology happens in young mice, whose immune systems share many features with those of young children. But the next frontier in this research lies in human lung organoids, three-dimensional, lab-grown structures that replicate the complexity of living tissues. By using different biomarkers and levels of differentiation, organ systems of any age, including the lungs, can be replicated in the lab. As COVID-19 becomes endemic, such tools will be vital for preparing the next generation against the disease to come.