Sickle Cell: A Disease of Healthcare Disparities
This publication was approved and written in close collaboration with Dr. Andrew Campbell.
We’ve had the opportunity to speak with Dr. Andrew Campbell, director of the Consortium for the Advancement of Sickle Cell Research (CASiRe), to discuss the recent publication of two important research papers, and to go into greater depth about the systemic barriers that prevent access to care for sickle cell patients across the globe.
Sickle cell is a monogenic disorder with an array of clinical symptoms, so patients experience extreme variability throughout the continuum of care wherever they may be in the world. However, this variability is not yet well understood despite the millions of patients living with sickle cell disease world-wide. While the inherited gene may be the same, the clinical expression -- or phenotype -- differs, and this may be due to environmental or genetic factors. In an effort to answer these questions, Dr. Campbell and CASiRE conducted a cross-sectional analysis of clinical data from the US, UK, Ghana, and Italy.
CASiRe’s research utilized the presence of leg ulcers as the focal phenotype. This is because vasculopathy is a hallmark of sickle cell disease, and there is no controversy in diagnosis with respect to leg ulcers. Patients who reported the presence of leg ulcers in the multinational clinical data were selected as the subset for further research. In this cohort, the CASiRe analysis found trends that revealed various disparities.
The first disparity observed is how these ulcers statistically occur most frequently in the geographic region of Sub-Saharan Africa, including Ghana. Dr. Campbell explains:
Now, why those patients were predominant in Ghana versus the other sites can be also results of other factors. Could be genetic, ... or just being in a warm tropical climate (higher humidity favors the persistence of skin lesions). It could be delays in healthcare, period. Because the cost of healthcare in Ghana is astronomically high as it relates to an individual.
The cost of healthcare can be a significant, world-wide systemic barrier to accessing treatment and may contribute to this measurable disparity in the increased prevalence of leg ulcers for Ghanaians. Furthermore, this cost barrier often coincides with social pressures to ignore anything that might interfere with work productivity and income generation.
Is [the disparity] because of something simple, like if you have an open wound, you just continue to work. You don't worry about covering it up because you have more important things to do, such as providing for your family or working instead of stopping a little bit and ... take care of that open wound.
Evidence confirms there are numerous detrimental effects of sickle cell stigma across the world. Dr. Campbell references the additional CASiRe findings:
When you have sickle cell, it is stigmatized in Ghana… can you contribute to society in the same way? Will you be left debilitated when you're an adult? Will you get hired? Will people treat you differently because you have sickle cell? It's just really economic stigmas, and stigmas that drive the disparities that we see there.
Another potential factor for the prevalence of leg ulcers is nutrition. Leg ulcers were observed in patients with lower hemoglobin levels (more anemic), and those with lower BMIs.
These disparities highlight the importance of epidemiology as the relationship between environmental -- including societal -- factors and genetic markers affect health outcomes.
CASiRe analysis also identified disparities in access to disease-modifying treatments. When observing geographic regions like the US and Europe, sickle cell patients have better access to drug therapies like hydroxyurea or other recent FDA-approved treatments:
So all these drugs are new therapy for sickle cell disease, more of it really available in the United States and Europe versus places such as Ghana. And I will say that Hydroxyurea is being more used in Ghana, which my colleagues there, they have now hundreds of patients on it, but it's more pediatric.
Likewise, patients in the US and Europe also receive treatment earlier, and this treatment may borrow from other disease areas. Dr. Campbell clarifies:
For example, leg ulcers in diabetes... [Physicians] will sometimes borrow their treatments for sickle cell patients. And outside of providing the standard wound care, we can get more sophisticated medications to treat it.
If you look at the 30 to 41-year-old patients [in Ghana], the age of onset started at 19 years of age. And what we found in the pediatric patients, they started as young as 7… So, they are already starting with this, which can be a disability in some patients, which could potentially influence their ability to work..., it could potentially affect their ability to finish schooling if it becomes an interference of the daily life activities, causing chronic pain, repeated visits to the hospitals.
So when I look at the duration of leg ulcers for a lot of the patients, it really provides insight to the disparities that are there.
Overall, the value of a multinational analysis can provide validation of existing theories. For example, when data from a single region indicates that a symptom appears to be more prevalent in one subset of patients, a multinational analysis can corroborate that finding across numerous geographic areas. Dr. Campbell describes this important distinction in the CASiRe approach:
You have a more harmonized data set allowing you to then look directly, country A, country B, country C. And then when you look at the outcomes and the outputs of the data, you can say, "Hey, this patient is having more leg ulcers than the other." … We were validating all of these analyses that were published. They were saying, "Yes, it appears that males are more common to have leg ulcers." So we've always kind of known this … but we had to say, we looked at this [multinational data] as much as possible and we were like, "Wow, it is very very skewed towards males."
There are additional disparities in regional sickle cell treatment options. Blood transfusions are a cornerstone of sickle cell care, and limited access to regular transfusions results in disparities in health outcomes. In some situations, a transfusion can mean the difference for patient survival. The COVID-19 pandemic has predictably affected both blood donations as well as transfusion therapy recommendations. Furthermore, sickle cell patients are also less inclined to seek emergency care for pain episodes due to risk of exposure. Dr. Campbell explains:
The COVID pandemic has significantly impacted the sickle cell care in general, and as it relates to the blood donations, it's doing the same thing. So a lot of sickle cell patients are afraid to come to the hospital and come to the Emergency Room, just because of COVID exposure at the healthcare facility that they will be going to. As it relates to blood transfusions, it is also having an impact on donors coming in to give blood.
When there is blood supply shortage, treating physicians must take different approaches to transfusion therapy recommendations. Dr. Campbell continues:
And [the pandemic] led us and many centers to start thinking about blood preservation strategies. And unfortunately, that affects patient care. So for example, you may want to transfuse the patient if they have a certain condition. … We still transfuse them, but we may delay in giving them blood.
Transfusions are a critical therapy in treating sickle cell disease because they are utilized in both preventive and acute treatment. Acute symptoms include virally induced drops in hemoglobin, or the very serious acute chest syndrome. This syndrome is the most common cause of death for sickle cell patients.
Dr. Campbell speaks on the role transfusions play in immediate sickle cell care:
The acute reasons are so many. So, if you have an acute chest syndrome, which is like pneumonia and sickle cell disease where the sickling can happen in the lungs affecting your body's ability to breathe and adequately take in enough oxygen, that can result in significant complications in the hospital. So you need to do blood transfusions to improve the oxygen delivery by giving fresh, non-sickle blood to the body.
Some patients get very, very anemic from a virus called parvovirus. We call that aplastic crisis, where it causes the hemoglobin to be dangerously low to like two or three. … And then there are other reasons like multi-organ failure. … It happens enough in adults where you have to give blood type support … to keep them alive.
There are also numerous preventive reasons for blood transfusion therapy in sickle cell patients that all center around ensuring the delivery of properly oxygenated blood to vital organs. It is important to recognize that sickle cell is a lifelong disease, and many of these serious reasons for transfusion are to prevent children and young adults from experiencing debilitating and permanent injuries.
Dr. Campbell goes into detail:
Some [sickle cell patients] may have what's called significant vasculopathy with narrowing of the vessels in the brain. So if they have elevated velocities and narrowing vessels in the brain, we keep them on blood transfusions because they're at significant risk of having a stroke. You have a stroke, there's a 50% chance of having another stroke. … We know that chronic blood transfusions can significantly decrease your chances of having a stroke, versus those who've had a stroke and are not on chronic blood transfusions.
Other complications include splenic sequestration, which about 20-25% of the blood volume can pool into the spleen of a young child with sickle cell disease. If that happens under the age of two we'll temporarily do blood transfusions so the sickle cells do not get trapped in the veins of the spleen causing the spleen to enlarge acutely. And then if that happens they can have significant anemia, and in some cases, heart failure, because you don't have enough volume pumping throughout the body.
There's some patients who need blood transfusions monthly up until the time they get a bone marrow transplant, or curative therapies. So that what we do is we put them on transfusions prior to the transplant, to minimize organ damage that they have going into transplant. So there's so many reasons we need blood transfusions.
However, preventive therapy relies on early screening first to identify whether the child is born with sickle cell trait or disease, and then to identify markers for the need for treatment. Sickle cell is the most common inherited blood disorder worldwide. Access to screening is another critical disparity in global sickle cell treatment. For example, the US has universal infant screening, but in countries with very high percentages of sickle cell gene carriers, there is woefully inadequate care. Dr. Campbell reveals the geographic disparities:
In 1987, [the National Institute of Health] recommended widespread newborn screening for sickle cell disease. … But it's not until mid-90s it reached all 50 states. … Any individual now, in the 2000s, should be able to find out their sickle cell status based on those newborn screens. I would say if you're less than 20 years of age, you should comfortably have the ability to get those results from the state. But we also caution that it's a screening study, so we recommend follow-up study to confirm sickle cell trait with your local provider.
So I know that places like Ghana got funded by the Novartis Corporation to provide newborn screening for the next one or two years, just countrywide. And that was significant because they'd only had targeted site screenings at certain hospitals. It wasn't widespread. They tried to get testing for most hospitals, but still was lacking. In Nigeria, the same way, … they're doing some newborn screening. But the problem is getting that information and putting it into a cohesive database so that it can be tracked by local health officials to say, "These kids, these babies have sickle cell disease. They need to be followed up with a sickle cell provider."
It's just not enough. In Nigeria, for example, there're 200,000 plus babies born with sickle cell disease [per year]. In the United States, we have 100,000 cases total. So one year in Nigeria, they birthed double the whole population of sickle cell patients in the United States. They have millions of cases, millions.
Yet regardless of this regional advantage in birth screening, the experience of sickle cell patients in America demonstrates there is more to be done. States are taking steps to acknowledge systemic racism as it contributes to health inequity, declaring it a public health crisis. Dr. Campbell describes how sickle cell patients seeking care during a pain crisis experience injustice:
This is a long history, not only in the US but also in Europe. We have international conferences, one's called ASCAT (Annual Sickle Cell and Thalassemia Conference), ran by Dr. Baba Inusa in London. And when we have these patient panels from Europe, they're almost a mirror of statements of patients from the US.
However, unfortunately, some [providers] continue to show signs of inequalities and injustices, and even overt racism in providing care for patients with sickle cell disease. … They're not hearing out patients. When they're saying they're in pain, they're not hearing them. It just falls on deaf ears.
Just like the COVID pandemic, you don't want to go to the healthcare center because you're concerned about exposure, some sickle cell patients have the same feelings about going to that local hospital. So now they have to drive an hour, two hours to a facility that will accept them as a patient and accept them as a human, regardless of race: "You're in pain, I'm going to treat you."
These types of injustices are systemic barriers that affect health outcomes for patients of color. There is an intersection between racism and health outcomes.
Sickle cell pain episodes can often be a precursor to serious complications. Depending on circumstances, there may not be an intervention possible; however, humane pain management is always possible. Since sickle cell patients cannot be clinically tested for the originating, “real” cause of their pain, some physicians believe instead that the patient must be an addict seeking prescription painkillers. Yet until 2016, the American opioid epidemic was an overwhelmingly white problem, affecting a 10:1 ratio of whites compared to Blacks. Dr. Campbell points out this emergent treatment disparity:
But in Europe and the US, there are systemic healthcare disparities as relates to pain that unfortunately continue and persist to this day. There are providers that are just not comfortable with sickle cell patients getting pain meds, most notably opioids. This drives the sickle cell providers to provide pain management plans, individualized plans, so that they get the appropriate pain management.
Most hospitals have sickle cell pathways that allow any Emergency Room staff to provide appropriate pain management in the Emergency Room, based on the agreed-on pathway between the hematologist or healthcare providers providing for sickle cell disease patients, and the pharmacist, and also the ER providers. When they all agree and you put that into place, that does somewhat mitigate the healthcare disparities that you do see.
The opioid crisis has contributed to [physician disbelief]. ... Even though it has affected the sickle cell community but only a very small percentage. So a lot of what's driving the disparity of opioids and other pain medicines is that the opioid crisis is teaching a lot of our young providers, medical students, residents and young faculty members not to prescribe them.
Regardless of pain mitigation disparities, chronic pain resulting from sickle cell is a constant reminder of how the disease affects the entire body. Tissue necrosis, central nervous system changes, and other factors, including the cumulative impact of pain itself, influence a patient’s lifelong experience with sickle cell. Further research is necessary to understand the relationship between sickle cell and other diseases. Dr. Campbell goes further:
Sickle cell patients can also get, we call it hematuria -- blood in the urine -- where they could get damage to the kidneys over time. ... You can get this damage in the kidneys, where there's lack of oxygen and blood supply. That causes little bits of injury. That causes blood to go into the urine. However, less than 1% of patients with sickle cell trait actually can get a form of cancer called renal medullary carcinoma.
Renal medullary carcinoma (RMC) is noteworthy because it specifically targets people living with sickle cell trait: essentially, Black people. Fifty percent of cases occur before the age of 28, and in otherwise healthy individuals. Because its risk factors are atypical for kidney cancer, RMC is often diagnosed at later stages when the cancer has metastasized. At this point, these young patients’ expected lifespan is measured in months.
Stories of the premature passing of young Black athletes in the prime of their lives are heartbreaking. Awareness of the disease is crucial, both for vulnerable populations living with sickle cell and for the treating physicians, in order to improve health outcomes through quicker diagnosis and treatment. Advocacy groups such as the RMC Alliance and RMC Support provide community support. Find more information about RMC from experts in our Kidney Cancer Hub.
Dr. Campbell offers parting advice to the next generation going into medicine.
Sickle cell is a disease of healthcare disparities, in terms of being under-researched, poorly understood, and the lack of appropriate therapies. So make a difference, go into public health to be part of the stakeholders who play a role in improving access to care for sickle cell disease patients.
Physicians can register to attend free sickle cell professional development seminars organized through the US Health and Human Services department. Make sure your family physician is aware of these resources. Learn more about the Sickle Cell Disease Training and Mentoring Program (STAMP).
Discover more about nutrition and eating well with sickle cell. Learn others’ experiences through testimonials and build a diet that supports you the best.
Support local blood drive efforts! Donations are needed more than ever these days. Find out more about participating in local blood drives for sickle cell disease.
Interested in learning more about sickle cell disparities? Find more expert interview programs with Dr. Andrew Campbell here. Access our extensive Sickle Cell Hub for additional experts and programs.
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