Michael Smith, MD (Host): This is Pediatrics in Practice, a CME podcast. I'm Dr. Mike. And with me is Dr. Shabnam Arsiwala, a pediatric hematologist-oncologist and Medical Director of the Sickle Cell Disease Program at Children's Mercy in Kansas City. Today, we are discussing pediatric sickle cell disease, an overview and treatment. Dr. Arsiwala, welcome to the show. It's great to have you.

Shabnam Arsiwala, MD: Thank you, Dr. Smith. It's my pleasure to be on this show, and I'm so excited to share all about sickle cell disease today.

Host: Can you start by giving us a brief overview of sickle cell disease in kids, what pediatricians should know about its pathophysiology and, say, some early signs?

Shabnam Arsiwala, MD: Certainly, sickle cell disease is a very well known and the most common genetic disorder of red blood cells, meaning the hemoglobin in the red blood cells is affected and it is called hemoglobin S. That results in the round blood cells to become very rigid and sickle-shaped. And these sickle-shaped red blood cells can block small blood vessels causing vaso-occlusion. They are very rigid. They breakdown very easily. They cause hemolysis and anemia and, over time, can lead to multiple organ damage.

Host: In children, what are some of the first-- like, is it the anemia that keeps happening? Is it more of a pain-type syndrome that makes you think this may be sickle cell? How does it present early?

Shabnam Arsiwala, MD: Absolutely. So, sickle cell disease can present as early as six months of age. Usually, in little babies, it presents like swelling of hands and feet, known as dactylitis. Sometimes, it can also present like splenic enlargement, abdominal distension, because of pooling of blood in the spleen called a splenic sequestration. This can be very life-threatening and it's an emergency, and kids need to be seen quickly in the ER. Because the spleen is affected due to sickle cell disease, it can increase the risk of infection, namely pneumococcal infections and meningococcal infections that can be life-threatening as well. So, it is very important to identify early signs of sickle cell disease in children, like hand and feet swelling, any fever, any abdominal distension, and refer them to appropriate care.

Host: Does it run in families?

Shabnam Arsiwala, MD: Absolutely. As I mentioned earlier, it is a genetic disorder. So, it's passed on from parents to their child. Both mom and dad are usually carrier of sickle cell disease known as sickle cell trait. They may not show any symptoms. Actually, they do not. Individuals of sickle cell trait do not show any symptoms, but they can pass on this trait to their child. So, it is an autosomal recessive disorder. So, the child receives two abnormal genes, one from each parent, to manifest the disease.

Host: So, how often do the parents know that they're carriers of this mutated gene?

Shabnam Arsiwala, MD: So, there is a very simple test called hemoglobin electrophoresis that parents can do to identify if they have sickle cell trait or not. Usually, there is one in four chance with every pregnancy for parents to pass on the disease through their child.

Host: When it comes to race or ethnicity, who's more at risk for having sickle cell disease?

Shabnam Arsiwala, MD: Yes. Sickle cell disease is a global disease. It's most common in people with black ancestry. However, it is also seen in people from Middle East, Mediterranean region, Asia, Brazil, and other countries in South America.

Host: Let's talk a little bit about best practices for routine care for children with sickle cell disease. What are some of the best practices you'd like to share with the audience?

Shabnam Arsiwala, MD: Yeah. So since the advent of the newborn screening a couple of decades ago, we are able to identify babies with sickle cell disease as early as two weeks of age. That gives us a headstart in managing them more proactively, like putting babies with hemoglobin SS and hemoglobin Sβ0 on penicillin prophylaxis. It is recommended guidelines that these babies with hemoglobin SS, hemoglobin Sβ0 be on penicillin prophylaxis by at least two months of age. As the child grows, there are several screenings that we do in a clinic. For example, we screen for risk of stroke by doing transcranial doppler, which is a Doppler ultrasound of the brain starting at age two. We refer them to our ophthalmology colleagues for screening for sickle cell retinopathy as early as seven years of ageWe look at the kidney function by measuring how much albumin they can spill in their urine, as early as two to three years of age when they're potty trained and things like that. We also check their heart function, because sickle cell disease can cause pulmonary hypertension by doing an echocardiography as early as 10 to 11 years of age.

At each visit when they come to see specialist in the sickle cell clinic, we have certain screening criteria that we utilize to identify complications early on and then manage them appropriately by sending them to various subspecialties.

Host: With such a comprehensive approach that starts early in life, how has this impacted overall outcomes and prognosis for kids with sickle cell?

Shabnam Arsiwala, MD: Early interventions and preventative measures have certainly improved the overall survival and prognosis of children with sickle cell disease earlier on. Children used to die in their early teens. But with the advent of these preventative measures, we have seen the lifespan and the survival increase by 20 to 40 years. So, they're surviving into adulthood, even up to 60, 70 years, although average lifespan of a black individual with sickle cell disease is still 20 years shorter than an average lifespan of a white individual. But we have made a lot of progress in improving overall prognosis and life.

Host: You've touched on some of this already, but I'd like to go back to it. What are some of the most common complications they face? You've mentioned stroke, you've talked about the spleen again, can you just run through that again? Like, what are the common medical complications that a specialist like you is really watching out for?

Shabnam Arsiwala, MD: Yeah, the most common complication, or as we say, hallmark of sickle cell disorder is pain crises. As I mentioned earlier, because the sickle shape cells are very rigid, they can block small blood vessels causing vaso-occlusion, and that results in pain and pain crises. That's the most common reason why individuals with sickle cell disease frequent the ER.

The other life-threatening complication of sickle cell disease is acute chest syndrome, where a child may present with fever, chest pain, difficulty breathing, cough. So, it might look like the child has pneumonia, but actually it could be a complication of sickle cell disease called acute chest syndrome. It is the number one cause of mortality of individuals with sickle cell disease.

Host: Let's talk about hydroxyurea. That's a cornerstone medical treatment for sickle cell disease. Can you explain its role and how early should it be introduced in pediatric care?

Shabnam Arsiwala, MD: Yes, exactly. Hydroxyurea is a cornerstone of sickle cell disease. So, it is a drug that modifies the course of sickle cell disease. So, it is not a curative option. However, it is very essential, because the way it acts is by increasing fetal hemoglobin. This over time improves anemia, decreases complications of sickle cell disease by making the red blood cells less sticky. So, that minimizes the blockage of small blood vessels and over time improves the course of sickle cell disease and improves complications. Hydroxyurea is approved by FDA to be started as early as nine months of age in babies with hemoglobin SS and hemoglobin Sβ0. It is a fairly well-tolerated drug, very rare side effects, and it's used once daily.

Host: Just real quick, you mentioned the hemoglobin SS again, that would be a child with full-blown sickle cell. But a child could also have just one mutation from a parent, but the other one is normal. How does that work out in how patients may present themselves? Is it only the hemoglobin SS that you see, or do you see some of those with just one recessive gene?

Shabnam Arsiwala, MD: Absolutely. So, I mentioned earlier, sickle cell disease is an autosomal recessive disorder. So, hemoglobin SS is a homozygous type of sickle cell disease, because the child will receive two abnormal genes, two abnormal genes that manifest hemoglobin S. So, that's why it is hemoglobin SS disease. If a child receives one hemoglobin S from one parent and a normal or no abnormal gene from the other parent, it'll be sickle cell trait. So, that is a benign condition, it's not a disease. It's a carrier status.

The other types of sickle cell disease that we see in our clinic is hemoglobin Sβ0, which is a compound heterozygous type of sickle cell disorder where the child receives one abnormal hemoglobin S gene from one parent and beta thalassemia trait from the other parent.

There are other several combinations like hemoglobin S from one parent and hemoglobin C from the other parent. That type of disease is called a hemoglobin SC disease. So, there are several combinations. And these combinations with hemoglobin S and other abnormal hemoglobin is called compound heterozygous. Hemoglobin SS disease is called sickle cell anemia, whereas the rest of hemoglobinopathies containing hemoglobin S is called sickle cell disease. So, that distinguishes hemoglobin SS from other forms of hemoglobin S, other forms of sickle cell disease.

Hemoglobin SS is the most severe form of sickle cell disease, resulting in all the complications we talked about earlier. So, it's the most severe phenotype followed by hemoglobin Sβ0, hemoglobin SC, hemoglobin SB+, and so on.

Host: Gotcha. Okay. That was very helpful. Thank you for that. You described a very comprehensive approach to treatment with these children. I want to talk about sickle cell patients in underserved communities. Are they getting that same type of care? And do they have the same prognosis and outcomes as children may be in better served communities?

Shabnam Arsiwala, MD: As we all know, there are several barriers in underserved communities like access to specialist, long distance to travel to sickle cell centers, insurance issues, health literacy gap, systemic inequalities, these all definitely affect the overall care and prognosis of individuals with sickle cell disease.

Obviously, the outcomes are not as optimal as we see in individuals who come to larger centers like in a bigger city, like our area in Kansas City. However, we do have several patients that travel long distances to come to our clinic. We try to help them with setting up telemedicine appointments so they don't have to travel as often, but still receive optimal care. We collaborate with their school, provide education to them, to the school nurse, collaborative meeting with school to help them understand how to manage, kind of give them tips of managing some symptoms of sickle cell disease in school children and so on. I think having a community health worker, a patient navigator, is also an useful resource to close this gap and improve barriers to care.

Host: Understood. That's fantastic. Again, very comprehensive on both the social side and the treatment side. So looking ahead, what are you most excited about in terms of innovations, new treatments associated with sickle cell disease?

Shabnam Arsiwala, MD: The most exciting piece of sickle cell care is the recent approval of gene therapy by FDA. Recently into 2024, FDA approved two gene therapies, Lyfgenia and Casgevy, which is deemed as transformative care for individuals with sickle cell disease.

These two work very differently from each other. Like in the case of Lyfgenia, the hemopoietic stem cells are modified in a way that they are able to produce a different type of adult hemoglobin. As a result, this replaces the hemoglobin S or the sickled hemoglobin, with the goal to minimize complications and ultimately cure the disease.

Casgevy is another type of gene therapy where they use CRISPR-Cas9 gene editing technology and reactivate hemoglobin F. That improves anemia and improves complications of sickle cell disease. Patients and families are also very excited for this type of transformative care. And here at Children's Mercy, we are awaiting, we have got approval for Casgevy and we are really excited to get started on this journey with our patients.

Host: That sounds really exciting, and I'm looking forward to following this in the future and see how it really impacts patients with sickle cell. Dr. Arsiwala, that was fantastic information. Thank you so much for coming on the show today.

Shabnam Arsiwala, MD: Yeah, absolutely. It's been my pleasure discussing all this with you.

Host: For more information, you can go to cmkc.link/cmepodcast. If you enjoyed this podcast, please share it on your social channels and check out the entire podcast library for topics of interest to you. This is Pediatrics in Practice, a CME podcast. I'm Dr. Mike. Thanks for listening.