DEFINITION AND EPIDEMIOLOGY
Sickle cell disease (SCD) is one of the most common inherited blood disorders worldwide caused by an abnormal hemoglobin (Hb) called HbS. SCD affects nearly 100 million people globally and 300 000 children are born every year with this condition (data from World Health Organization). The highest disease prevalence is in sub-Saharan Africa (SSA) followed by South Asia, the Middle East, and South America. Over recent years and due to migration, SCD has become a global disease.
This disease which represents a major public health burden is often underrecognized, sub-optimally treated, and associated with major medical and psychosocial complications that have a negative impact on the lives of those living with it.
CAUSES
SCD is caused by an abnormal hemoglobin (Hb) called HbS that results from a mutation in the beta-globin gene. A mutation is a mistake or changes in your DNA sequence. People with SCD inherit genes that contain instructions for forming abnormal hemoglobin. There are different types of sickle cell disease depending on which genes have been passed from the parents to the child. Affected patients may have either 2 sickle genes (HbSS) or one sickle and one thalassemia gene (Hb S/beta thalassemia) or one sickle and one abnormal hemoglobin gene (compound heterozygosity). As for people carrying only one sickle gene from one parent with a normal gene from the other parent, these are called sickle carriers or have the sickle cell trait. Sickle carriers usually have no complications except rarely after intensive exercise or if they get dehydrated.
In healthy individuals with normal hemoglobin, red blood cells are round, flexible, and can move freely through small blood vessels to perform their oxygen-carrying function. In people with SCD and due to the abnormal HbS, red blood cells lose their normal shape and become crescent (sickle) shaped, sticky, and non-flexible. These structurally abnormal red blood cells die prematurely (hemolysis) leading to chronic hemolytic anemia and block the small blood vessels leading to vaso-occlusion. As a result, there is decreased blood supply and oxygen delivery to all tissues. Both hemolysis and vaso-occlusion lead to pain, fatigue, and organ damage.
CLINICAL PRESENTATION
SCD is a multi-organ and blood vessel disease. Even though it is caused by a single abnormal gene, it is clinically heterogeneous and leads to a multitude of acute and chronic complications affecting almost every organ, often presenting in early childhood and typically spanning a lifetime. Some of the early symptoms of SCD are pale skin, yellow eyes, dark-colored urine, fatigue, excessive crying, painful swelling of the hands and feet (dactylitis), recurrent fever due to infections, and at times a distended abdomen due to a large spleen.
Persons with SCD experience severe and recurrent pain called vaso-occlusive crises or VOCs (the most distinguishing feature of the disease), acute chest syndrome due to blockage of small blood vessels within the lungs, worsening anemia, gallstones, recurrent infections, strokes, leg ulcers and many other complications affecting every organ. Some organs as the kidneys and the eyes are severely affected by the disease but usually in a silent way. Affected patients often need frequent health care utilization including multiple emergency department visits, hospitalizations, and at times intensive care unit admissions. They do have a poor quality of life and reduced survival.
DIAGNOSIS
Diagnosis of SCD is based on a typical clinical presentation, presence of chronic hemolytic anemia, identification of a high amount of HbS on hemoglobin determination assays, demonstration of sickle forms on the blood smear, and genetic studies showing the sickle mutation alone or with concomitant thalassemia or other abnormal Hb mutations.
TREATMENT
Because SCD is a complex multi-system disorder, its management requires a comprehensive, patient-centered, multidisciplinary approach with disease self-management at its core. Treatment of SCD is aimed at preventing and treating complications mostly pain crises and organ damage, improving quality of life, and prolonging survival. The development of several interventional measures such as newborn screening, penicillin prophylaxis, vaccinations, screening for complications such as stroke, and disease-modifying therapies along with patient and caregiver education has led to a substantial improvement in the survival of affected patients. Known SCD-modifying therapies are hydroxyurea (HU), transfusion and chelation therapy, and stem cell transplant (SCT).
All children with sickle cell disease need to be started on HU as of 9 months of age. HU has been shown in randomized clinical trials across all age groups to be safe and effective in reducing pain, disease complications, and hospitalizations as well as in improving anemia and reducing transfusion requirements.
Different from thalassemia, transfusions in SCD are indicated for selected patients only and mostly to prevent and treat strokes. With recurrent transfusion, the body accumulates excess iron which if left untreated will result in irreversible organ damage (in the liver, heart, and endocrine organs) and early death. Nowadays, there is a highly effective and safe treatment for preventing and treating iron excess. This treatment is called iron chelation.
The only curative therapy for SCD is a bone marrow transplant, also called a stem cell transplant or hematopoietic stem cell transplant. Bone marrow is a spongy tissue inside bones, where blood cells are made. In bone marrow transplant, bone marrow cells from a healthy donor are infused into a patient with SCD, and these infused cells which are hematopoietic stem cells, help the body produce new healthy red blood cells. Only a small number of people with SCD can however find a well-matched donor and can benefit from this procedure.
More recently and driven by an improved understanding of the biology of SCD, 3 novel drugs (Crizanlizumab, Voxelotor, and L-glutamine) have received FDA approval based on their proven safety and efficacy in reducing pain crises and or improving hemoglobin. Multiple trials on gene therapy have been initiated and are still ongoing. More long-term safety and efficacy data related to these novel drugs and to gene therapy is however needed. Despite all these advances in the therapy of SCD, an important priority remains and this is Identifying and using strategies to decrease the intense suffering and morbidity from SCD pain.
CLINICAL TRIALS
Over recent years and with a better understanding of the complex etiology of SCD and the many unmet needs facing people living with this disease, there has been an increased interest in initiating SCD clinical trials. In addition to the 3 FDA-approved novel drugs emerging from these trials, several other drugs are being currently studied as well. These novel drug therapies would not have been developed without the contribution and participation of people living with SCD from all regions of the globe. The same applies to potentially curative therapies such as gene therapy.
If you would like to know more about ongoing SCD clinical trials or would like to participate in any of these trials, you can visit: ClinicalTrials.gov
DISEASE OUTCOME AND SURVIVAL
Early diagnosis of SCD and introduction of preventive and disease-modifying therapies have been shown to significantly improve survival and quality of life in affected children in high-resource countries. The burden of mortality is increasingly shifting to adults, and the transition from pediatric to adult medical care appears to be a high-risk period for death.
With improvement in therapy, affected people are living longer. As patients get older, new chronic complications leading to life-long disabilities and sometimes early death are appearing. Such complications affect vital organs such as the eyes, heart, lungs, liver, kidneys, and others. The impact of the disease on mental, emotional, and psychosocial health as well as on the quality of life is becoming more obvious. Sadly, the majority of those affected with SCD reside in low-resource areas such as sub-Saharan Africa and are diagnosed late or die in early childhood even before diagnosis due to lack of basic medical care.
CHALLENGES
The main challenges facing the SCD community remain to ensuring equitable access to disease-modifying therapies, securing dedicated comprehensive SCD centers, attracting expert compassionate life- long health care providers, fostering SCD public education and awareness, and engaging stakeholders to shape a more effective system of care for all people living with this disease across the globe.
