Sickle Cell Disease (SCD) is a disease with few curative treatments that affects people globally. Both young and older patients who struggle with SCD must drastically change their daily routines to survive. With preventive and educational measures, SCD symptoms can be properly addressed. In light of World Sickle Cell Day, we spoke with Natalia Velez, Medical Director, about her insights on SCD, treatments, and ways the public can remain aware and educated.
Sickle Cell Disease (SCD) is a disease with few curative treatments that affects people globally. Learn about how we can stay informed in our latest Ask the Experts blog article. #WorldSickleCellDay
What Is your background in SCD?
I am a pediatric hematology oncologist, so I treat children with blood disorders and cancer. My interest in SCD started from the beginning of my fellowship training. I trained at Duke University Medical Center in North Carolina, and they housed a large population of patients with SCD. Two of my mentors were heavily involved with research development for SCD.
Much of my passion came from directly taking care of these patients for many years. They had a great influence on me. I could tell these patients needed love and care from healthcare providers like me who were truly interested in taking care of them.
One thing that drew my attention to the specialty is that, unfortunately, a lot of health care providers avoid taking care of patients with SCD, in part because of the stigmas surrounding the disease. I felt like they were orphans in the medical field, and they needed providers who could learn and properly take care of them.The kids were amazing. I loved how these kids drove their lives, despite knowing that they had a chronic illness. Their parents were equally as strong.
Can you tell us what SCD is?
It comes down to the basics of what hemoglobin is. In the body, we have red blood cells, white blood cells, and platelets. Each of those cells have different roles. The red blood cells are the cells that transport oxygen from the lungs to the tissues everywhere in the body. This is accomplished by the hemoglobin. The hemoglobin is the protein inside the red blood cells.
The hemoglobin has two components—the heme and the globin. Patients who have SCD have a gene mutation that affects the globin part of the hemoglobin. This genetic mutation causes the hemoglobin, under certain circumstances, to change its consistency from a sort of jelly-like substance to a glass-like consistency, which is called a polymer.
Normal red blood cells carry oxygen throughout the body, so they need to be able to squeeze and stretch. When they leave the heart, the blood vessels carrying red blood cells become smaller and smaller until they’re microscopic size, and then the red blood cells must go through the tiny blood vessels to deliver oxygen.
But when the red cells lose the ability to do this because their consistency changes, their shape changes from being donut-like to what we call the sickle cell shape, which is like a crescent moon. When a sickled red blood cell reaches the tiny blood vessels, they get stuck. When they get stuck, there is no oxygen going to the tissues.
This can cause what we call an ischemia or infraction, which causes acute complications like pain from having no oxygenation going to the tissues. Over time, tissues suffering lack of oxygenation can die, which means patients also suffer from chronic complications that affect critical organ functions. Many times, patients don’t recover or suffer irreversible damage. For example, patients can end up requiring dialysis when the kidneys stop working due to lack of adequate oxygen over a long period of time. Also, when the patient has a stroke due to acute or chronic lack of oxygen delivery, they are left significantly disabled from brain damage.
How does SCD affect people and their daily lives?
Just imagine you’re living with chronic pain. Some patients have pain or complications that happen intermittently, but when they happen, it significantly impacts their quality of life.
The older the patient is, the more complications they get from SCD. In general, patients don't see the results of organ damage until they get older and start displaying medical issues related to chronic damage of the organ affected. Take for example the brain, over time patients can have significant neurocognitive issues due to chronic lack oxygenation to the brain. This can present many problems with their normal day-to-day activities.
An acute pain crisis comes from the acute obstruction of the blood vessels and acute lack of oxygenation, that causes crippling pain. For many patients, there are pain-free periods where they can function normally, but during periods of crisis they are in excruciating pain and can’t function normally. Some patients live in constant chronic pain.
Pain crises are just the tip of the SCD iceberg. Every single organ is affected—for example, many kids with SCD don't grow normally. They have chronic anemia, so they lose their ability to grow and develop at normal speed. Their body is constantly making new red cells, but the hemoglobin levels are always low because they are constantly consuming red cells that are destroyed in the blood vessels due to the sickle hemoglobin. That anemia also causes multiple issues like fatigue.
Urology issues can also arise from SCD and affect a person’s quality of life. Young patients can lose their ability to concentrate their urine because of the chronic damage on the kidneys. They urinate all the time and this affects their ability to sleep, so they frequently wet their beds. This can be a huge cause of embarrassment and frustration, particularly when it comes to social interaction like attending school, going to friends’ houses or summer camps. Later on, these patients can develop renal failure, and may have to go into dialysis.
Kids can also have difficulty with daily tasks like concentrating on school, doing normal peer activities and participating in sports. They also have delayed puberty, so some teenage sickle cell patients look much younger. That affects their self-esteem because they don't look like their peers, which can lead to depression and anxiety. Many don't want to tell their peers that they have SCD because they are embarrassed to say they have a chronic illness.
This continues on into adulthood, where in addition to the physical ailments, mental health related issues play a heavy role. Patients can have multiple hospital admissions and complications. They can become isolated because of a lack of social supports, social stigmatization, low self-esteem and self-confidence.
What kind of impact has SCD had around the world?
SCD is particularly common among those whose ancestors came from sub-Saharan Africa, Spanish-speaking regions in the Western Hemisphere (South America, the Caribbean, and Central America), Saudi Arabia, India, and Mediterranean countries such as Turkey, Greece, and Italy.
As of 2010, about 10% of African Americans carry the sickled hemoglobin. In the United States, around 100,000 Americans have SCD. Around the world, about 300,000 people have SCD. It’s estimated that between 2010 to 2050,14 million babies will be born with SCD.
In developed countries like the United States, there’s newborn screening for SCD that detects the disease at birth. We can educate parents right away about the medical condition and start preventive measures to decrease early complications. For example, the spleen is one of the first organs affected. By age 2, a baby with SCD loses a normally functioning spleen.
In the early 80s, US scientists started looking for ways to prevent this. They learned that starting babies with SCD on penicillin within two months from birth would decrease the risk of dying from blood bacterial infections by about 90%. The clinical trial that led to this discovery was terminated early because it was obvious that patients who received penicillin were not dying from early bacterial infection in the blood. That became the standard of care, and newborn screening programs for SCD were then developed in the United States, with the goal of starting penicillin prophylaxis and education of parents in the first 2 months of life.
Unfortunately, none of this happens in Africa, which carries one of the greatest burdens for the disease. There is a gap in healthcare for SCD in the United States compared to other countries. Patients in Africa typically get diagnosed because they present with complications from SCD like pain crises or more serious complications like strokes. Many babies die because doctors don't even know they have the disease. There is inadequate data to support definite statements, but early life mortality from SCD among children born in Africa has been estimated somewhere between 50% and 90%. The World Health Organization states that “when health impact is measured by under-five mortality, sickle-cell anemia contributes the equivalent of 5% of under-five deaths on the African continent, more than 9% of such deaths in west Africa, and up to 16% of under-five deaths in individual west African countries.”
How are we helping to stop the progression of SCD?
SCD is a genetic mutation. The only way to change the disease is to replace the gene, but there are therapies that help control the disease and its symptoms. Prevention, education and supportive care measures like transfusions, penicillin and vaccines are the best methods available to manage and control SCD.
There are also some therapeutic modalities that were developed especially in the past few decades. One available medication, which has become standard of care for many patients with SCD, is called hydroxyurea. It increases Fetal Hemoglobin and is largely present in babies, but declines after birth. Fetal Hemoglobin decreases the risk of sickling in red blood cells and medical providers have used this medication for about 20 years.
Blood transfusions (of non-sickled hemoglobin) are used commonly in patients with SCD to help raise the hemoglobin. However, these blood transfusions are typically reserved for patients who have severe complications or patients with significant chronic organ damage. Patients with chronic organ damage requiring blood transfusions have to be put on a chronic transfusion regimen.
Chronic transfusion also affects the patient’s quality of life because blood only lasts for a couple of weeks. Patients who are on chronic transfusion are required to go to the hospital for transfusions every three to four weeks, sometimes indefinitely. There are areas in the world where their blood supply is not as clean as developed countries, so there’s a higher risk for infection. When you give repetitive blood transfusions to patients, they also develop other complications, such as high iron levels.
For many years, there wasn’t any clinical research targeting development of new medications for patients with SCD. Now, medications are under development that target the sickling complications. Three medications have been approved by the FDA in the past five years, two of them in 2019. But as of now, there is no approved gene therapy for patients.
The only curative therapy that is available is a bone marrow transplant. The problem with a bone marrow transplant is that the standard of care involves using a full sibling donor who is a full match and who doesn't have SCD. About 15-20% of African Americans have a sibling who is a full match. So, it's not a therapy that you can do for every patient. Also, a bone marrow transplant has long implications because it requires high doses of chemotherapy prior to getting the transplant. This causes serious side effects in the long run.
Advancements in research are promising, especially using unrelated stem cells, using less intense chemotherapy regimens and gene therapy. But we still have a long way to go.
What’s the best way to educate the public on SCD?
It’s important to increase awareness of SCD wherever possible, because many people still don't know much about it. The good news is that there are many educational sources available.
On social media, there are different focus groups. For example, there’s the Sickle Cell Disease Association of America, who works with the general public educating about SCD. Honestly, I think it’s important for those of us in the industry to go out there and bring stories to the general public from patients with SCD. You have real life examples from real people that shows how SCD affects their daily lives.
This disease is very stigmatized. Patients with SCD suffering a pain crisis require strong medications to relieve the symptoms or pain. These medication regimes often include opioids. Many people, including health care providers, stigmatize these patients in general as drug seekers. Many patients avoid getting medical care because of fear of being stigmatized or worse—when they see a health care provider who hasn’t been well-educated in this patient population, they don’t receive the care they need. I think that’s the first misconception that needs to be addressed.
Are the awareness campaigns and websites and pages you mentioned the best ways to help end stigma surrounding SCD? Are there other strategies we can use?
Yes, but I also think healthcare providers must be educated properly on SCD. One of the major limitations to SCD treatment is healthcare providers who are uneducated on the disease. Many sickle cell patients don't like to go to the hospital because when they go, they're treated like they’re just seeking drugs like opioids. Increasing awareness of the disease and what it’s like living with the disease is important, but it’s just as important to educate healthcare providers about what chronic pain involved with SCD is and how to treat it.
Unfortunately, the public still seems to think SCD happens only in black people, which is not true. As I mentioned, it happens in Latin America, Middle Eastern and Mediterranean areas, Africa, and of course the US. The US has 100,000 patients with SCD alone. I had some rare cases of Caucasian patients with SCD as well.
We need to let people know that SCD is a chronic illness with serious implications. It’s not just a disease of pain crisis that only happens in black people. Education of healthcare providers about pain control, chronic pain syndromes, and the psychological effects of chronic pain symptoms is critical.
Can you speak to the recent developments in research and gene therapy treatment for SCD? For instance, there are two clinical trials taking place in the US for SCD. Have you heard about any developments with those trials?
I know there are clinical trials ongoing on for stem cell transplants using unrelated donors and using less intense chemotherapy regimens. I also know about gene therapy, which is a little bit different. I’ll explain the differences.
For a patient to receive an unrelated or a matched sibling donor, chemotherapy is typically given to the patient prior to receiving the transplant. This eliminates the patient’s own stem cells, which normally live inside the bone marrow. It’s not like when you have, for example, a kidney transplant, where you take out the kidney and put in a new kidney. You cannot get rid of the inside of the patient’s bone marrow and put in new bone marrow. So, you have to use chemotherapy to clean out all of the bone marrow and open space for new stem cells. Then, you infuse stem cells that come from a donor.
Now, let’s move on to gene therapy using stem cells. This is done as an auto-transplant, giving the patient back their own stem cells after being genetically modified. Typically a patient is given a medication that has a growth factor, a protein that stimulates the bone marrow to make a lot of stem cells. The stem cells are then collected using a special mechanism. The cells are taken to a lab, where they undergo different types of genetic modification. For example, in a patient with SCD, the gene that controls the production of Fetal Hemoglobin can be modified so production of Fetal Hemoglobin increases. This procedure was reported by this group in Boston, where it was successfully completed in a teenager with SCD.
Earlier I mentioned how Fetal Hemoglobin, which can be found in babies, helps prevent sickling. Hydroxyurea enhances the production of Fetal Hemoglobin. Hydroxyurea is not perfect because some patients respond better than others.
Patients undergoing gene therapy still require a bit of immunosuppression because they’re going to be getting cells that have been genetically modified. You don’t want the body to reject those cells. But it’s not the same chemotherapy or the same immunosuppressive therapy that patients normally receive with a full bone marrow transplant.
There are three medications that have been approved in the past few years. One of them is an oral medication called L-glutamine that helps decreasing complications associated with sickling. Another medication, used as an injection that also decreases complications associated with sickling, is called Crinzalizumab . This medication and Voxelotor were just approved last year. Voxelotor prevents red cells to form polymers and sickling. In November of 2019, two new medications were approved by the FDA.
There will be an explosion of clinical trials soon. It feels like we’ve reached a new era of treatment for SCD patients and it’s about time because a lot of the studies and treatments that exist are decades old.
What does the future look like for SCD patients?
I think it’s brighter compared to what it was 20 years ago. When I started my fellowship, which was in 2004, we really only had hydroxyurea, transfusions, and penicillin. Now we have a lot of therapy studies underway. I think it’s much better and the disease is getting a lot of attention, but I still think that there is a huge gap in between developed countries and non-developed countries where there is a huge burden of the disease. I am concerned about how we're going to take these therapies to these patients who don't even know they’re born with SCD.
There is a discrepancy in how the future of SCD looks in countries like the United States, where patients know they have the disease. They have access to education and research about the disease. They start preventive therapy in early life, compared to countries in Africa where they don’t even know they have SCD. Those countries don’t even have the basic newborn screening and penicillin prophylaxis vaccines.
I think the global burden of disease is still going to be pretty significant. There needs to be better worldwide access to the normal standard of care that we've been doing in the US for 20 years.
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