Clinical trials seek way to prevent RSV, a common infection in infants and toddlers

Host Amber Smith: Upstate Medical University in Syracuse, New York invites you to be The Informed Patient with the podcast that features experts from Central New York's only academic medical center. I'm your host, Amber Smith. Almost all children will become infected with respiratory syncytial virus, called RSV, by the age of two. Infections range from mild to more severe, and RSV is a common cause of hospitalization in children under the age of five. But there's so much more that doctors still want to learn about RSV, and today I'm talking with the principal investigator of a study underway at Upstate. Dr. Joe Domachowske is a professor of pediatrics and microbiology and immunology. And he's a true expert in RSV. Welcome back to The Informed Patient, Dr. Domachowske.

Joe Domachowske, MD: Thanks, Amber. It's good to be here.

Host Amber Smith: First, some clinical questions about RSV. How do you describe this virus?

Joe Domachowske, MD: RSV is a cold- and flu-like virus. It comes every winter. It's quite predictable, although we don't know when the season will start and when it will go away. It's here every year. There's only been one exception. These are the babies, mostly under two years of age, that start with a nasty cold to have a lot of junk coming out of their nose -- we call it coryza, or just a diffuse rhinorrhea. And then they start to wheeze. Not all of them do, but the ones that develop lower respiratory infection begin to wheeze, and that's not typical for a lower respiratory tract infection in an infant otherwise. So pneumonia doesn't typically cause wheezing, but RSV causes this entity that we refer to as bronchiolitis. And that's a wheezing illness of infants and young kids.

Host Amber Smith: So, are pediatricians able to predict which child is going to have just the cold symptoms and the mild case versus the one that will develop the wheezing?

Joe Domachowske, MD: That's the tricky part, because we know that most kids will have this infection, at least once by the time they're two years old. And once the infection starts with the upper respiratory complaints, the coughing and the runny nose, we don't know who's going to progress. We know the high risk groups to progress. Typically the most common child in the hospital during the winter time has no underlying risk factors. Other than being only a few months old.

Host Amber Smith: You said they'll catch it, typically, at least once. Does that mean that if a child has RSV once, that doesn't protect them from getting the virus again?

Joe Domachowske, MD: The first infection that we get, all of us, is usually the worst of the bunch. And then we get a little bit of immunity from that. So subsequent infections tend to be much milder, and we even get reinfected with this during our adult years. So, it is a fairly common cause of just a regular common cold in adults. And if we're around newborn babies, we have to be careful because if we have RSV, we can subject them and expose them to the infection when they get sick for the first time with RSV. That's when they get into trouble.

Host Amber Smith: Why does RSV seem to prefer infants and toddlers? I know you said adults can get it, but doesn't it prefer the younger children?

Joe Domachowske, MD: It does infect and cause more dramatic clinical symptoms and the very young and in the very old, but the very young are being infected for the first time. So they have no immunity to this whatsoever. Subsequent infections occur in the context of some preexisting exposure and immunity. So the immune system is able to sort of dampen things down a bit. So typically the most severe of all of the infections will be in that first year or two of life.

Host Amber Smith: So, how do parents know? They may recognize cold symptoms, but how do they know that it's turned the corner and it's more of a severe, the bronchiolitis type of thing? Is it, is the wheezing sort of the giveaway?

Joe Domachowske, MD: Yes. And in the subset of the young infants that go from the upper respiratory infection to develop the lower respiratory tract illness with the wheezing, the first sign is usually that they'll start to breathe faster. And sometimes with effort. So you can see the babies tugging a little bit while they're breathing. And that's a pretty important clinical sign that we watch for as pediatricians, but the parents can also notice. Well, that doesn't look right. The breathing pattern just seems a little bit odd. In the first four to six weeks of life, RSV can be associated with apnea or periodic breathing where the breathing sort of starts and stops.

Joe Domachowske, MD: And we often admit young infants, newborns, to the hospital with RSV because they sort of are forgetting to breathe, and we have to just watch them carefully until they're past that acute phase of the infection. So they're not having those periodic breathing spells anymore.

Host Amber Smith: If a child at home is treated appropriately or cared for appropriately when they first developed symptoms, will that prevent it from progressing?

Joe Domachowske, MD: We don't have any good prevention for that. And we can't predict which of these babies will progress from a cold to a lower respiratory infection itself. So really, it's watching them very carefully and knowing what to watch for: if the breathing rate starts to increase, or they look uncomfortable, if their nose is completely clogged. You know, young infants are obligate nose breathers, so they can't breathe and eat at the same time if their nose is completely congested. So we have to watch all of those things. And often, the reason for hospitalization may not be related to a need for oxygen for the respiratory infection. It may be because they become dehydrated because they just can't eat. They're breathing too fast.

Host Amber Smith: This is Upstate's The Informed Patient podcast. I'm your host, Amber Smith talking with Dr. Joe Domachowske. He's a professor of pediatrics and of microbiology and immunology at Upstate. And one of the projects he's involved with is a study on respiratory syncytial virus, or RSV.

Host Amber Smith: So tell us about your RSV clinical trials that you have underway. Is it true that you're following 3,000 children from several different countries in different parts of the world?

Joe Domachowske, MD: The combined trials that we have been working on, do include over 3,000 babies, yes, in over eight countries, both in the northern and southern hemisphere. So it is a lot of activity and, trying to figure out a safe and effective way to prevent this infection has been impossible for the last 50 years. The virus was discovered more than 50 years ago, and we have not been able to develop a vaccine for this particular infection. So the most promising movement in that direction has just been in the last few years. The type of studies that we're working on now are monoclonal antibody studies, where the babies are given these monoclonal antibody injections. And then they're followed over the course of the cold and flu season to see which ones become infected. Because of the way the studies are designed, some of the babies actually get the antibody itself and others get a placebo, or a salt water injection. So we've been able to show how well this antibody works in a number of different circumstances in the highest risk babies. And we've just started to enroll term newborns, in these trials as well, because it looks like this stuff is really working. Finally, we have a strategy that's going to change the landscape of RSV infection for pediatricians and for families, hopefully across the world, but certainly across the US.

Host Amber Smith: The way you described, it sounds like a vaccine, but it's not a vaccine is it?

Joe Domachowske, MD: Well, it's an immunization and, broadly speaking, immunizations are divided into two major categories. We have active immunization, typically referred to as vaccines, where we give doses in combination over time and eventually are able to boost doses or boost immunity so that there's, long-term protection. The other type of immunization is called passive immunity. That's where we just give the antibody itself because we can't figure out how to administer a vaccine by itself that can cause that same degree of protection. So this monoclonal antibody actually provides much higher level of protection than even a natural RSV infection.

Host Amber Smith: Wow. So would it protect the baby during toddlerhood and childhood, or would it protect them for life? Or maybe you don't know yet?

Joe Domachowske, MD: Well, the passive definition of immunization means that eventually the antibody is going to wear off. It's a protein, and it doesn't induce any active memory type immunity. So because we're doing it in a passive way, eventually it will wear off. And there's a tried and true concept with this because the very highest risk babies have received a similar type of antibody, for more than a decade and a half. And we know that it works very well, but the downside is they need monthly injections. The change for this new strategy was to make the antibody more potent at neutralizing virus, but also to have a much longer half-life. So some very fine biochemical tricks were used to take this antibody instead of a half-life of 19 days, it has a half-life of more than 100 days. So a single dose at the beginning of RSV season can offer protection for five months or longer. And that's most important during the first year of life, because that's when most of the more severe illness happens.

Host Amber Smith: So are you still recruiting new participants?

Joe Domachowske, MD: We are until the end of January. And then we're closing to new enrollment because we want to make sure these babies are enrolled during a time when RSV is present in the community so we can look at how well the antibody is protecting them.

Host Amber Smith: So for those who are participating, what is involved?

Joe Domachowske, MD: They come in for the screening visit to make sure they meet all of the criteria that are proposed in the protocol itself. And if so, we basically take a blood sample to look at their antibody levels at baseline. And they get the product, the investigational monoclonal antibody, at the same visit. They will be randomized of course, to get placebo, but none of us will know who gets placebo and who gets the antibody itself. It's a three to one ratio. So for every three children that get the antibody, only one will get placebo. So chances are pretty good that they'll get the real thing.

Host Amber Smith: And then, if over the winter months the baby becomes sick, does the parent call you, or do you get involved with them in any way after that?

Joe Domachowske, MD: Yep, we follow them for a full year, and we do passive surveillance where we ask them to call anytime the baby develops any kind of respiratory signs or symptoms. And we also do active surveillance where we reach out and touch base with the families at very specific times, over the course of the year. We also bring them in two other times for blood work, to check their antibody levels, to watch how the neutralizing antibody that they got at the beginning decays over time. So the pharmacokinetics, if you will, of how well their antibody will last in their system.

Host Amber Smith: Now, since you've looked at this disease in babies and other countries, I wonder, are there similarities or differences between how RSV presents in different countries or how it'streated?

Joe Domachowske, MD: The clinical presentation is very similar. And since we don't really have any treatment, other than trying to keep the nose as clear as possible and bringing them into the hospital to support their hydration or give them extra oxygen, or even more invasive type of respiratory support, it really depends on the hospital system and the resources that are available in that country. Of course we have optimal healthcare in the U S for young infants, and we can maximize the support that we can offer them. But in underdeveloped countries, often babies will just suffer at home, and if they can't work their way through the infection, many of them will die. So the main difference between what happens in the developed world and the underdeveloped world is that access to healthcare, that high-end of healthcare, a subset of those kids will die. So infant mortality is still quite high from RSV infection, if we're talking about areas of the world that aren't like the United States.

Host Amber Smith: Has the COVID pandemic had an impact on RSV in any way?

Joe Domachowske, MD: It sure did. When we first shut things down in March of 2020, we were in the middle of one of these studies, and we were at the end of our usual typical RSV season. We were getting two or three families calling us because the kids had respiratory symptoms from whatever cold and flu virus happened to be going around. And so we were doing surveillance and taking nasal swabs on all of those kids, every time they called us. Well, about a week after we shut everything down, those phone calls stopped completely. We didn't hear anything at all. Nothing. We were kind of surprised because we expect RSV to kind of linger through April and even maybe into the first part of May, typically in Upstate New York.

Joe Domachowske, MD: We said, okay, well, you know, all the masking and social distancing must be influencing this to some degree. We'll just wait for RSP to come back that Halloween or Thanksgiving time in the fall. And it did not. It just disappeared. And we didn't have an RSV season that subsequent year at all until the following summer. It wasn't until July we started seeing cases, and we never see RSV disease in infants in the summer in Central New York. We just don't see it. So to have outbreaks, it wasn't an epidemic, but to see outbreaks in clusters of infection in July and August was extremely unusual. And I really think it has a lot to do with a relaxation of the distancing and the masking that people were doing, which was really protecting the babies from RSV and many other respiratory viral infections, including influenza.

Host Amber Smith: That's very curious. So it was just like a normal outbreak, except that it happened in July?

Joe Domachowske, MD: It started in this past July, and it has continued. So normally the RSV season that we suffer and deal with every year, we do not look forward to this as pediatricians. We know it's coming, and we just dread it. But we knew it was coming, eventually, and when it appeared early, we thought, well, maybe it'll fizzle out in five or six months. Nope. It has not. We continued to see them even now into January and, at this point, it's expected that we will continue to see cases of babies hospitalized with RSV infection even into March and April, because it's behaving now more like it used to in a typical season. It just started very early.

Host Amber Smith: Well, I'm sure you would not want parents to panic, but what do they need to know if their pediatrician diagnoses their child with RSV?

Joe Domachowske, MD: Just watch carefully for signs and symptoms of inability to feed effectively, depending on the baby's age, if they're nursing, or if they're taking a bottle. You want to make sure that they're not struggling to feed because they're trying to breathe instead, right? So if that starts to happen, we would bring those babies into the hospital, and we support them the best we can. We keep their nose and their upper respiratory tract as clear as we can using suctioning techniques and, a saltwater syringe with a bulb syringe to clean out their nose.

Joe Domachowske, MD: But there really isn't anything else that we can offer them as an outpatient because nothing works. Things have been tried, and they just do not change the natural course of this infection. When we bring them in the hospital, that's also true, but we have IVs. We can put IVs into babies, and hydrate them up. We can have a nurse at the bedside keeping their nose as clean and as clear as possible and supplemental oxygen or more invasive types of respiratory support, as needed. So when those events start to be considered, that's when we bring the babies in, and the younger, they are, the more inclined we are to hospitalize them.

Host Amber Smith: Well, good luck with the clinical trials, and I really appreciate you making time for this interview.

Joe Domachowske, MD: My pleasure. Thanks for getting the word out.

Host Amber Smith: My guest has been Dr. Joe Domachowske, a professor of pediatrics and of microbiology and immunology at Upstate and the principal investigator of a clinical trial on RSV. The Informed Patient is a podcast covering health, science and medicine brought to you by Upstate Medical University in Syracuse, New York. Find our archive of previous episodes at upstate.edu/informed. I'm your host Amber Smith, thanking you for listening.