June 17, 2022
On this week’s episode of Talking Pediatrics, Dr. Gabi Hester talks with Dr. Anu Kalaskar, medical director of Children’s Minnesota Infectious Disease department and Dr. Christina Koutsari, antimicrobial stewardship/infectious diseases pharmacist, to discuss the most recent updates in the treatment of COVID-19 in children.
Dr. Angela Kade Goepferd: Dr. Angela Kade Goepferd: This is Talking Pediatrics, a clinical podcast by Children’s Minnesota, home to the Kid Experts, where the complex is our every day. Each week, we bring you intriguing stories and relevant pediatric health care information, as we partner with you in the care of your patients. Our guests’ data, ideas, and practical tips will surprise, challenge and perhaps change how you care for kids.
Welcome to Talking Pediatrics. I’m your host, Dr. Angela Kade Goepferd. As the COVID-19 pandemic continues, and no, it’s not over yet, the pace of change with treatments and variants has been remarkable. On this episode of Guidelines With Gabi, Dr. Hester talks with two of our kid experts at Children’s Minnesota, about current primary therapeutic treatment options for COVID, and why they keep changing.
Speaker 2: Welcome to Guidelines With Gabi.
Dr. Gabi Hester: We are over two years into the COVID-19 pandemic. Over 1 million people have died from COVID-19 in the United States. Phrases like R naught, herd immunity and PPE have made their way to the family dinner table. Health care workers have rapidly learned about and integrated new medications and therapeutic strategies into their workflows. A typical benchmark in the clinical guidelines field is that guidelines should be updated at a minimum every three to five years to assure that they’re staying current. With COVID-19, you can change that to more like every three to five weeks. The pace of change has been incredible.
Medications that were effective for one variant, have different impacts against the next. New strategies and recommendations emerge. Keeping up with those changes and recommendations has been critical. I’m thrilled today to chat with two of our kid experts at Children’s Minnesota. Dr. Anu Kalaskar is the medical director of infectious disease and the medical liaison to the infection prevention team. Dr. Christina Koutsari is an infectious disease’s pharmacist, and the co-lead of our Antimicrobial Stewardship Committee.
The first question I really have for you both is what’s currently in our toolbox for treating COVID-19 in kids?
Dr. Anu Kalaskar: The therapeutics for the patient who’s hospitalized with moderate to severe illness really haven’t changed a lot, as therapies for outpatients have. So, really the mainstay of treatment there remains Remdesivir early on for treatment, and Dexamethasone for patients who are requiring a supplemental oxygen. Then in more severely ill patients, we also think about Tocilizumab and Baricitinib possibly, although in a pediatric population, those aren’t typically utilized as much. Then the data on Remdesivir is also not as robust, I would say, in terms of reduction in morbidity and mortality. So, really, the recommendation is, its use is probably more useful early on in illness rather than later on in illness. Then in terms of outpatient therapy, there are several different medications that are used to prevent progression to needing to be hospitalized, so to decrease hospitalization and risk of mortality.
Dr. Gabi Hester: Christina, I know that some of those medications that have been used, particularly in those milder outpatient cases, have really evolved and changed throughout the pandemic. First explain a little bit about why do they keep changing, and why are some recommended for a few months, and then stopped as far as recommendation? Tell me a little bit about that.
Dr. Christina Koutsari: During COVID-19, the COVID therapeutics have been a roller coaster. There have been new therapeutics that are being added into our toolbox and being removed. The question mostly relates to monoclonal antibody therapy. This is therapy that we use in patients that are mildly or moderately sick due to COVID-19, and we would like to give them monoclonal antibody therapy, which is literally passive immunity, in order to prevent them from transitioning to more severe COVID-19. So, with monoclonal antibodies that have very complicated names, and they all end with the mab, M-A-B, like Tocilizumab or Vedolizumab and things like that, they target the spike protein of the virus of the SARS-CoV-2.
What happens is that as the virus evolves, unfortunately, as the virus continues to circulate in people and different communities, it mutates, and the spike protein is where most of the mutations take place, which is exactly what the target side of these monoclonal antibodies are. So, every time that the virus mutates enough, these monoclonal antibodies are not effective anymore. So, we need to transition to another monoclonal antibody that retains activity against the specific SARS-CoV-2 variant, in the specific spike protein of the SARS-CoV-2 variant.
Dr. Gabi Hester: How are we learning which medications will work for each variant? Are these tests that are being done mostly in a lab setting, where we’re looking at the exact molecular makeup of the spike protein, or are we looking at larger like case studies in actual humans?
Dr. Christina Koutsari: Unfortunately, most of the information that we have comes from in vitro data, most typically from a pseudo virus that has the specific mutations, and then we get to know whether the specific monoclonal antibodies continue to work or do not work anymore. In some cases we might have data, not from pseudo virus, but from real SARS-CoV-2 virus, and we have very limited data from tumor studies, in terms of the effectiveness of specific monoclonal antibodies. So, overall, I would say for the most part in vitro data, and for the most part pseudo virus data.
Dr. Gabi Hester: Anu, you mentioned earlier a little bit about Remdesivir, and my understanding is that’s an antiviral-type medication. Are there other antivirals that we have available for use in patients? Heard a little bit about Paxlovid. Can you tell us more about what that medication is?
Dr. Anu Kalaskar: Yeah. So, other than Remdesivir, there’s really two other antivirals that are considered to be effective for treatment against SARS-CoV-2. So, one is Paxlovid, as you mentioned, and then the other is Molnupiravir. So, of the two, Paxlovid, which is a combination antiviral with a nuclide analog medication called Nirmatrelvir, and combined with Ritonavir. But the nuclide analog portion affects the replication of the virus basically, then the Ritonavir acts as a boosting agent to keep the first antiviral in the system for longer, so that it can work longer to fight against the virus. Molnupiravir is a nuclide analog, and it’s not as effective as Paxlovid is, and especially in the pediatric population, is really not a medication that we use, because of concerns for bone and cartilage toxicity.
So, it’s not approved in less than 18 years of age, and should not be used in women of childbearing age, if there’s concern for pregnancy. Molnupiravir really is a third, fourth line agent, much after all the other available treatments. Paxlovid is really the first line treatment for mild to moderate COVID, mainly because of its ease of administration, its oral administration. The only difficulty with Paxlovid is that it does have a lot of drug-drug interactions. So, that is something that prescribers have to pay particular attention to, because of the multiple medications that it can interact with.
Dr. Gabi Hester: So, we’ve talked a lot about different options for pediatric patients who have COVID 19 or may develop it. Are these approved in kids? What are the studies? Where do we stand on trials for these?
Dr. Anu Kalaskar: So, in terms of what is approved in children, really the one medication, and this was a recent change, is that Remdesivir became fully-approved, and is no longer under EUA. That is for children as well, and Paxlovid is under EUA for patients over 12 and over 40 kilos. But the trials were really performed in patients over 18 years of age, with the data kind of extrapolated to include children over 12, as long as they meet weight criteria. That is mainly because once the weight criteria is met, the way that the body is able to handle the medication in terms of kidney and liver processing is considered to be similar if their weight is similar to that in an adult’s weight. There is a trial that has recently started evaluating Paxlovid in patients over six years of age, through 17 years of age. So, we’ll have more pediatric-specific data regarding that medication, hopefully, sometimes soon.
Dr. Gabi Hester: Christina, is Paxlovid something that we would consider using in all pediatric patients with mild illness? Walk me through a little bit, if I’m an outpatient pediatrician, seeing a kid in clinic, how do I determine if Paxlovid might be a good option for them?
Dr. Christina Koutsari: Yes. There are a lot of steps that clinicians have to make in order to determine if a patient is eligible for Paxlovid. Something that is very important for all of us to remember is that there are specific rules and criteria that the patients have to meet in order to be eligible for these agents. So, I know that with FDA-approved agents, we can use them off-label. This off-label use is not allowed for agents like Paxlovid, that is under an emergency use authorization or EUA.
Dr. Gabi Hester: Is there anything that we can look to for more specific criteria for our pediatric population?
Dr. Christina Koutsari: The very first question we should ask ourselves is the age. The patient has to be at least 12 years old, and the weight. The pediatric patient has to weigh at least 40 kilograms. I would like to clarify here that we are dealing with an adult patient, that is a patient who is at least to 18 years of age, the 40 kilogram weight requirement does not apply to adult patients. This is a common cause of confusion when we determine eligibility. So, pediatric patients, at least 12 years of age, and they have to wait at least 40 kilograms. The next question you should be asking is, does the patient have COVID-19 symptoms? The patient has to be symptomatic with mild or moderate illness. So, that might be cough or fever or headache, but they should not be too ill that they would require hospitalization or oxygen supplementation.
So, once we have identified age, weight and symptoms, now we have to make sure that the patient has COVID-19, that the virus is SARS-CoV-2. So, the [inaudible 00:11:51] authorization requires a positive direct SARS-CoV-2 test, namely either home antigen test or a PCR test. [inaudible 00:12:01] antibody test would not mean the criteria. Once we have done this evaluation, then the next question should be asking to ourselves is, is this patient at high risk for progressing from mild to COVID-19 illness to severe illness? Because as we know, most patients, especially pediatric patients do really well with no treatment at all, with just supportive care. Then the emergency use authorization has criteria. They’re very broad.
For example, if a patient is obese, if the patient has a chronic lung disease, if a patient has a heart disease, if they have other abnormalities or congenital abnormality. So, it is very broad. What we have done in the State of Minnesota, which is really remarkable and extremely unique as far as I’m concerned, is that pediatric clinicians from Children’s Minnesota and Mayo Clinic, and the University of Minnesota worked collaboratively amongst ourselves, as well as with support from the Minnesota Department of Health, and we came up with suggested pediatric high-risk criteria. So, we used our expertise in whatever minimal literature was available, and we came up with suggested pediatric criteria. These criteria are posted on the Minnesota Department of Health website.
Dr. Gabi Hester: So, if we’re going to be giving Paxlovid to our pediatric patients, Anu tell me a little bit about what are the main side effects that we should be watching out for? I know drug-drug interactions was mentioned before, but are there other specific ones for Paxlovid that we should be counseling patients and families about?
Dr. Anu Kalaskar: If a patient is eligible, and doesn’t have any concerning drug- drug interactions, Paxlovid seems to be actually quite well- tolerated. Some of the main side effects that are seen are actually hypertension in a very small percentage, and diarrhea is another possibility. Muscle aches or body aches can also be seen. So, those are some of the kind of main side effects that are seen, but generally, it is a quite well-tolerated medication.
Dr. Gabi Hester: Now, I know I’ve been reading a little bit in the media about Paxlovid and rebound, and actually a friend experienced that. Tell me a little bit about what is this rebound issue? Why is it happening, and how does that play into how many we might be talking with our patients and families about Paxlovid as an option?
Dr. Anu Kalaskar: What has been identified actually in initially in trials and then in case reports, is that in a quite small percentage of patients, at least up until now, after resolution of symptoms, several days after completing the Paxlovid treatment course of five days, there can be a return of symptoms, and there can also be a positive test, positive antigen testing after having had negative antigen testing. It seems that the rebound symptoms are more mild, perhaps even then the initial illness, and there have not been any reports of more severe rebound illness or needing hospitalization or anything like that from the rebound phenomenon. I think at this point, it’s something that is really through case reports, so we kind of need more time to gather information about why it may be happening.
It doesn’t seem that it’s related to, for example, resistance developing in the virus, and a second course of Paxlovid is not recommended in that situation. Really, what’s recommended is close monitoring of the symptoms, and seeking healthcare evaluation if the symptoms do worsen, and then actually entering a second period of isolation, according to the CDC guidance. So, if there were to be rebound symptoms, the recommendation would be that the patient enters isolation for five days after return of the symptoms, in a community setting. Then wear a mask for 10 days after return of symptoms.
Dr. Gabi Hester: So, it sounds like really shifting therapeutics, particularly in outpatient settings. What do you guys see as coming down the pipeline? What’s next? Where are the studies being conducted as far as new treatment options, and maybe starting with those more mild types of cases?
Dr. Christina Koutsari: There are a number of agents that are under investigation. Some of them are agents that are already available in the market, and they’re being repurposed for COVID-19 treatment. There are also monoclonal antibodies that are being studied or other more traditional antiviral agents. However, to the best of my knowledge, there aren’t really any specific agents that are very close to being as effective as the agents that we currently have available. So, there’re either at the very early stage of clinical trials or the data are very conflicting, that don’t allow us to make a firm conclusion as to what else we might be using in the near future.
Dr. Gabi Hester: Christina, you mentioned some of the importance of looking for drug-drug interactions, and I know, I’d have to hearken back in the depths of my brain to remember drug-drug interactions from medical school, and certainly don’t have knowledge for some of these new treatments. Are there any existing tools that providers might use to look up or check a list of the medications that the patients on, against some of these new therapeutics?
Dr. Christina Koutsari: There is a number of tools, but I would mention three of them. Two are from the FDA itself. The first is the FDA Fact Sheet for Paxlovid for Healthcare Providers. The second tool is the FDA Paxlovid Patient Eligibility Screening Checklist Tools for Prescribers. Again, these two are from FDA, and I would certainly recommend them. But the third one that I would like clinicians to be aware of is the University of Liverpool COVID-19 Drug Interaction Checker.
Dr. Gabi Hester: So, we’ve talked a little bit about medications that we can use after a kid is sick, right? So, whether it’s a mild, moderate illness or a child who’s in the hospital, is there anything that we can do after an exposure? Say we went to a graduation ceremony or prom or Grandma’s house and learned that people there have now contracted COVID. Is there anything we can do to prevent getting ill?
Dr. Anu Kalaskar: In terms of post exposure, really what we have for treatment options are kind of what we’ve discussed. The Paxlovid, Remdesivir as an outpatient. If you’ve been exposed, and don’t have any symptoms, then really there’s no specific therapeutic options other than supportive care. If you’ve been exposed, and you have mild illness or moderate illness, not requiring hospitalization, and you’re high risk for progressing to severe illness, then that’s when the treatment options of Paxlovid and the three-day Remdesivir come into play. There is a treatment option for preexposure prophylaxis, which is a medication, a monoclonal antibody called Evusheld, which is a brand name.
That is really for patients who are at high risk for progressing to severe illness, or may not mount a response to the vaccine as we would expect, because of an underlying immuno-compromising condition or the receipt of available vaccines is contraindicated, for example, for a known allergic reaction. But that medication really is for preexposure prophylaxis, and again, has the same kind of age and weight criteria as other monoclonal antibodies have. There’s, I guess, more specific immuno-compromising conditions that would be covered by that, including solid tumor and hematologic malignancies, being on specific immunosuppressive therapies, being a stem cell transplant recipient or CAR T-cell recipient. At least at our facility, that medication is really administered in the cancer and blood disorders clinic, and previously there were categories to be followed, given a sort of shortage of availability of medication, although more recently the medication has become more available.
Dr. Gabi Hester: Thank you so much to both of you for joining me today, and helping to walk me through all these different options. It’s such a dynamic field. I am sure I will be talking to you both again in a few months to learn more, and certainly appreciate your leadership in this area to keep all of us on our toes, and doing the right things for our patients and families. So, thank you both for coming today.
Dr. Anu Kalaskar: Thank you for having us, Dr. Hester.
Dr. Christina Koutsari: It was a pleasure.
Speaker 2: Take-home point.
Dr. Gabi Hester: Number one, treatment options for patients who are hospitalized for COVID-19 include Remdesivir, if given early in the course of illness, Dexamethasone, if needing supplemental oxygen, and in very severe cases, there are additional options such as Tocilizumab. Number two, first line options for patients who have mild to moderate illness with COVID 19 include either oral Paxlovid or IV Remdesivir. Number three, outpatient treatment options for COVID-19, really are reserved for children who are at high risk for progression to more severe illness, and must be used within the first few days of illness in order to have any benefit. Number four, we know that vaccines are our best tool in the toolkit, so encourage all of your patients to get vaccinated if they’re age-eligible, and we’re excited that the booster is now available for children five years of age and older. Number five, clinical guidelines for the management of COVID-19 are available on our website, www.childrensMN.org, on the health professionals page. They’re also available on Star Net.
Dr. Angela Kade Goepferd: Thank you for joining us for Talking Pediatrics. Come back each week for a new episode with our caregivers and experts in pediatric health. Our executive producer and showrunner is Ilze Vogel. Episodes are engineered, produced, and edited by Jake Beaver. Amy Juba is our marketing representative. For more information and additional episodes, visit us at childrensmn.org/talkingpediatrics, and to rate and review our show, please go to childrensmn.org/survey.