Figure (A) shows normal red blood cells flowing freely through a blood vessel. The inset shows a cross-section of a normal red blood cell with normalhaemoglobin. Figure (B) shows abnormal, sickled red blood cells sticking at the branching point in a blood vessel. The inset image shows a cross-section of a sickle cell with long polymerized sickle haemoglobin (HbS) strands stretching and distorting the cell shape to look like a crescent moon.
34,000 p.a. (a contributory factor to a further 376,000 p.a.)[7]
Sickle cell disease (SCD), also simply calledsickle cell, is a group ofhemoglobin-relatedblood disorders that are typicallyinherited.[2] The most common type is known assickle cell anemia.[2] Sickle cell anemia results in an abnormality in the oxygen-carrying proteinhaemoglobin found inred blood cells.[2] This leads to the red blood cells adopting an abnormalsickle-like shape under certain circumstances; with this shape, they are unable to deform as they pass throughcapillaries, causing blockages.[2] Problems in sickle cell disease typically begin around 5 to 6 months of age.[1] A number of health problems may develop, such as attacks of pain (known as asickle cell crisis) in joints,anemia, swelling in the hands and feet,bacterial infections, dizziness[8] andstroke.[1] The probability of severe symptoms, including long-term pain, increases with age.[2] Without treatment, people with SCD rarely reach adulthood but with good healthcare, median life expectancy is between 58 and 66 years.[9][10] All of the major organs are affected by sickle cell disease. The liver, heart, kidneys, gallbladder, eyes, bones, and joints can be damaged from the abnormal functions of the sickle cells and their inability to effectively flow through the small blood vessels.[11]
Sickle cell disease occurs when a person inherits two abnormal copies of theβ-globin gene that makes haemoglobin, one from each parent.[3] Several subtypes exist, depending on the exactmutation in each haemoglobin gene.[2] An attack can be set off by temperature changes, stress,dehydration, and high altitude.[1] A person with a single abnormal copy does not usually have symptoms and is said to havesickle cell trait.[3] Such people are also referred to ascarriers.[5] Diagnosis is by ablood test, and some countries test all babies at birth for the disease.[4] Diagnosis is also possible during pregnancy.[4]
As of 2021[update], SCD is estimated to affect about 7.7 million people worldwide, directly causing an estimated 34,000 annual deaths and a contributory factor to a further 376,000 deaths.[7][15] About 80% of sickle cell disease cases are believed to occur inSub-Saharan Africa.[16] It also occurs to a lesser degree among people in parts ofIndia,Southern Europe,West Asia,North Africa and amongpeople of African origin (sub-Saharan) living in other parts of the world.[17] The condition was first described in the medical literature by American physicianJames B. Herrick in 1910.[18][19] In 1949, its genetic transmission was determined by E. A. Beet and J. V. Neel.[19] In 1954, it was established that carriers of the abnormal gene are protected to some degree againstmalaria.[19]
Dactylitis in the hands of an infantSickle cells in human blood - both normal red blood cells and sickle-shaped cells are present.Normal blood cells next to a sickle blood cell, coloured scanning electron microscope image
Signs of sickle cell disease usually begin in early childhood. The severity of symptoms can vary from person to person, as can the frequency of crisis events.[20][16] Sickle cell disease may lead to various acute and chroniccomplications, several of which have a high mortality rate.[21]
When SCD presents within the first year of life, the most common problem is an episode of pain and swelling in the child's hands and feet, known asdactylitis or "hand-foot syndrome."Pallor,jaundice, and fatigue can also be early signs due to anaemia resulting from sickle cell disease.[22]
In children older than 2 years, the most common initial presentation is a painful episode of a generalized or variable nature, while a slightly less common presentation involves acute chest pain. Dactylitis is rare or almost never occurs in children over the age of 2.[22][1]
Also termed "sickle cell crisis" or "sickling crisis", thevaso-occlusive crisis (VOC) manifests principally as extreme pain, most often affecting the chest, back, legs and/or arms.[23] The underlying cause is sickle-shaped red blood cells that obstruct capillaries and restrict blood flow to an organ, resulting inischaemia,pain,necrosis, and often organ damage. The frequency, severity, and duration of these crises vary considerably. Milder crises can be managed withnonsteroidal anti-inflammatory drugs. For more severe crises, patients may require inpatient management for intravenousopioids. Vaso-occlusive crisis involving organs such as the penis or lungs are considered an emergency and treated with red blood cell transfusions.[24]
A VOC can be triggered by anything which causes blood vessels to constrict; this includes physical or mentalstress, cold, anddehydration.[25] "After HbS deoxygenates in the capillaries, it takes some time (seconds) for HbS polymerization and the subsequent flexible-to-rigid transformation. If the transit time of RBC through the microvasculature is longer than the polymerization time, sickled RBC will lodge in the microvasculature."[26]
Thespleen is especially prone to damage in SCD due to its role as a blood filter. A splenic sequestration crisis, also known as a spleen crisis, is a medical emergency that occurs when sickled red blood cells block thespleen's filter mechanism, causing the spleen to swell and fill with blood. The accumulation of red blood cells in the spleen results in a sudden drop in circulating hemoglobin and potentially life-threatening anemia. Symptoms include pain on the left side, swollen spleen (which can be detected bypalpation), fatigue, dizziness, irritability, rapid heartbeat, or pale skin. It most commonly affects young children, the median age of first occurrence is 1.4 years. By the age of 5 years repeated instances of sequestration causescarring and eventualatrophy of the spleen.[27][28][29]
Treatment is supportive, with blood transfusion if hemoglobin levels fall too low. Full or partialsplenectomy may be necessary.[30] Long term consequences of a loss of spleen function are increased susceptibility tobacterial infections.[29]
Acute chest syndrome is caused by a VOC which affects the lungs, possibly triggered by infection or byemboli which have circulated from other organs. Symptoms include wheezing, chest pain, fever,pulmonary infiltrate (visible on x-ray), andhypoxemia. After sickling crisis (see above) it is the second-most common cause of hospitalization and it accounts for about 25% of deaths in patients with SCD. Most cases present with vaso-occlusive crises, and then develop acute chest syndrome.[31][32]
Aplastic crises are instances of an acute worsening of the patient's baseline anaemia, producingpale appearance,fast heart rate, and fatigue. This crisis is normally triggered byparvovirus B19, which directly affectsproduction of red blood cells by invading the red cell precursors and multiplying in and destroying them.[33] Parvovirus infection[34] almost completely prevents red blood cell production for two to three days (red cell aplasia). In normal individuals, this is of little consequence, but the shortened red cell life of SCD patients results in an abrupt, life-threatening situation.Reticulocyte count drops dramatically during the disease (causingreticulocytopenia), red cell production lapses, and the rapid destruction of existing red cells leads to acute and severe anemia. This crisis takes four to seven days to resolve. Most patients can be managed supportively; some need a blood transfusion.[35]
Sickle cell anaemia can lead to various complications including:[36]
Increased risk of severe bacterial infections is due to loss of functioning spleen tissue. These infections are typically caused bybacteria such asStreptococcus pneumoniae andHaemophilus influenzae. Dailypenicillin prophylaxis is the most commonly used treatment during childhood, with some haematologists continuing treatment indefinitely. Patients benefit from routine vaccination forS. pneumoniae.[37]
Stroke can result from blockage of blood vessels in the brain, causing numbness, confusion, or weakness which may be long lasting.Silent stroke causes no immediate symptoms, but is associated with damage to the brain. Silent stroke is probably five times as common as symptomatic stroke. About 10–15% of children with SCD have strokes, with silent strokes predominating in the younger patients.[36][38][39]
Leg ulcers are relatively common in SCD and can be disabling.[45]
In eyes, background retinopathy, proliferative retinopathy, vitreous haemorrhages, and retinal detachments can result in blindness.[46] Regular annual eye checks are recommended.
Chronic pain: Even in the absence of acute vaso-occlusive pain, many patients have unreported chronic pain.[47]
Pulmonary hypertension (increased pressure on thepulmonary artery) can lead to strain on theright ventricle and a risk ofheart failure; typical symptoms are shortness of breath, decreased exercise tolerance, and episodes ofsyncope.[48] 21% of children and 30% of adults have evidence of pulmonary hypertension when tested; this is associated with reduced walking distance and increased mortality.[49]
Hemoglobin is an oxygen-binding protein, found inerythrocytes, which transports oxygen from the lungs (or in the fetus, from the placenta) to the tissues. Each molecule of hemoglobin comprises 4 protein subunits, referred to asglobins.[53] Normally, humans have:-
hemoglobin F (Fetal hemoglobin, HbF), consisting of twoalpha (α-globin) and twogamma (γ-globin) chains. This dominates during development of the fetus and until about 6 weeks of age. Afterwards, haemoglobin A dominates throughout life.[54]
hemoglobin A, (Adult hemoglobin, HbA) which consists of two alpha and twobeta (β-globin) chains. This is the most common humanhemoglobin tetramer, accounting for over 97% of the totalred blood cell hemoglobin in normal adults.[55]
hemoglobin A2, (HbA2) is a second form of adult hemoglobin and is composed of two alpha and two delta (δ-globin) chains. This hemoglobin typically makes up 1-3% of hemoglobin in adults.[55]
β-globin is encoded by theHBB gene onhuman chromosome 11; mutations in this gene produce variants of the protein which are implicated withabnormal hemoglobins. The mutation which causes sickle cell disease results in an abnormal hemoglobin known as hemoglobin S (HbS), which replaces HbA in adults.[20] The human genome contains a pair of genes for β-globin; in people with sickle cell disease, both genes are affected and theerythropoietic cells in the bone marrow will only create HbS. In people with sickle celltrait, only one gene is abnormal; erythropoiesis generates a mixture of normal HbA and sickle HbS. The person has very few if any symptoms of sickle cell disease but carries the gene and can pass it on to their children.[56]
Autosomal recessive inheritance means acquiring two changed genes from each parent. If both parents are carriers for the autosomal recessive gene, there is a 25% chance of their child having and expressing the disorder. Other children will be unaffected, but may be carriers.
Sickle cell disease has anautosomal recessive pattern of inheritance from parents.[57] Both copies of the affected gene must carry the same mutation (homozygous condition) for a person to be affected by an autosomal recessive disorder. An affected person usually has unaffected parents who each carry one mutated gene and one normal gene (heterozygous condition) and are referred to asgenetic carriers; they may not have any symptoms.[58] When both parents have the sickle cell trait, any given child has a 25% chance of sickle cell disease; a 25% chance of no sickle cell alleles, and a 50% chance of the heterozygous condition (see diagram).[59]
There are several differenthaplotypes of the sickle cell gene mutation, indicating that it probably arose spontaneously in different geographic areas. The variants are known as Cameroon, Senegal, Benin, Bantu, and Saudi-Asian.[60] These are clinically important because some are associated with higher HbF levels, e.g., Senegal and Saudi-Asian variants, and tend to have milder disease.[61]
Base-pair substitution that causes sickle cell anemia
The gene defect is asingle nucleotide mutation of the β-globin gene, which results inglutamate being substituted byvaline at position 6 of the β-globin chain.[62] Hemoglobin S with this mutation is referred to as HbS, as opposed to the normal adult HbA. Under conditions of normaloxygen concentration this causes no apparent effects on the structure of haemoglobin or its ability to transport oxygen around the body. However, the deoxy form of HbS has an exposed hydrophobic patch which causes HbS molecules to join to form long inflexible chains. Under conditions of lowoxygen concentration in the bloodstream, such as exercise, stress, altitude or dehydration, HbSpolymerization forms fibrous precipitates within the red blood cell.[63] In people homozygous for the sickle cell mutation, the presence of long-chain polymers of HbS distort the shape of the red blood cell from a smooth,doughnut-like shape to the sickle shape, making it fragile and susceptible to blocking or breaking withincapillaries.[62]
In peopleheterozygous for HbS (carriers of sickle cell disease), the polymerisation problems are minor because the normalallele can produce half of the haemoglobin. Sickle cell carriers have symptoms only if they are deprived of oxygen (for example, at altitude) or while severelydehydrated.[64]
Historical distribution of the sickle cell traitHistorical distribution ofmalaria (no longer endemic in Europe)Modern distribution of malaria
SCD is most prevalent in areas which have historically been associated withendemicmalaria. The sickle cell trait provides a carrier with a survival advantage againstmalaria fatality over people with normal hemoglobin in regions where malaria is endemic.[65][66]
Infection with the malaria parasite affectsasymptomaticcarriers of the abnormal hemoglobin gene differently from patients with full SCD. Carriers (heterozygous for the gene) who catch malaria are less likely to suffer from severe symptoms than people with normal hemogolobin. SCD patients (homozygous for the gene) are similarly less likely to become infected with malaria; however once infected they are more likely to develop severe and life-threatening anemia.[67][68]
The impact of sickle cell anemia on malaria immunity illustrates some evolutionary trade-offs that have occurred because of endemic malaria. Although the shorter life expectancy for those with the homozygous condition would tend to disfavour the trait's survival, the trait is preserved in malaria-prone regions because of thebenefits provided by the heterozygous form; an example of natural selection.[69]
Due to the adaptive advantage of the heterozygote, the disease is still prevalent, especially among people with recent ancestry in malaria-stricken areas, such asAfrica, theMediterranean,India, and theMiddle East.[70] Malaria was historically endemic to southern Europe, but it was declared eradicated in the mid-20th century, with the exception of rare sporadic cases.[71]
Themalaria parasite has a complex lifecycle and spends part of it in red blood cells. There are two mechanisms which protect sickle cell carriers from malaria. One is that the parasite is hindered from growing and reproducing in a carrier's red blood cells; another is that a carrier's red cells show signs of damage when infected, and are detected and destroyed as they pass through the spleen.[72][73]
Scanning electron micrograph showing a mixture of red blood cells, some with round normal morphology, some with mild sickling showing elongation and bending
Under conditions of low oxygen concentration, HBS polymerises to form long strands within the red blood cell (RBC). These strands distort the shape of the cell and after a few seconds cause it to adopt an abnormal, inflexible sickle-like shape. This process reverses when oxygen concentration is raised and the cells resume their normal biconcave disc shape. If sickling takes place in the venous system, after blood has passed through the capillaries, it has no effect on the organs and the RBCs can unsickle when they become oxygenated in the lungs. Repeated switching between sickle and normal shapes damages the membrane of the RBC so that it eventually becomes permanently sickled.[74][75][76]
Normal red blood cells are quite elastic and have a biconcave disc shape, which allows the cells to deform to pass through capillaries. In sickle cell disease, lowoxygen tension promotes red blood cell sickling and repeated episodes of sickling damage the cell membrane and decrease the cell's elasticity. These cells fail to return to normal shape when normal oxygen tension is restored. As a consequence, these rigid blood cells are unable to deform as they pass through narrow capillaries, leading to vessel occlusion andischaemia.[26]
Cells which have become sickled are detected as they pass through the spleen and are destroyed. In young children with SCD, the accumulation of sickled cells in the spleen can result in splenic sequestration crisis. In this, the spleen becomes engorged with blood, depriving the general circulation of blood cells and leading to severe anemia. The spleen initially becomes noticeably swollen but the lack of a healthy blood flow through the organ culminates in scarring of the spleen tissues and eventually death of the organ, generally before the age of 5 years.[75][27]
The actual anaemia of the illness is caused byhaemolysis, the destruction of the red cells, because of their shape. Although thebone marrow attempts to compensate by creating new red cells, it does not match the rate of destruction. Healthy red blood cells typically function for 90–120 days, but sickled cells only last 10–20 days.[77][75]
The rapid breakdown of RBC's in SCD results in the release of freeheme into the bloodstream exceeding the capacity of the body's protective mechanisms. Although heme is an essential component of hemoglobin, it is also a potent oxidative molecule. Free heme is also analarmin - a signal of tissue damage or infection, which triggers defensive responses in the body and increases the risk of inflammation and vaso-occlusive events.[78][79]
Checking for SCD begins during pregnancy, with a prenatal screening questionnaire which includes, among other things, a consideration of health issues in the child's parents and close relatives. During pregnancy, genetic testing can be done on either a blood sample from thefetus or a sample ofamniotic fluid. During the first trimester of pregnancy, chorionic villus sampling (CVS) is also a technique used for SCD prenatal diagnosis.[80] A routineheel prick test, in which a small sample of blood is collected a few days after birth, is used to check conclusively for SCD as well as other inherited conditions.[81]
A schematic of hemoglobin electrophoresis, showing the banding which is typical of various types of hemoglobin. Note that sickle cell disease (SCD) gives a single, bold band whereas sickle cell trait gives two slightly fainter bands.
Where SCD is suspected, a number of tests can be used. Often a simpler, cheaper test is applied first with a more complex test such as DNA analysis used to confirm a positive result.[82]
Two tests which are specific for SCD:
Ablood smear is a thin layer of blood smeared on a glass microscope slide and then stained in such a way as to allow the various blood cells to be examined microscopically. This technique can be used to visually detect sickled cells, however it does not detect sickle carriers.[82]
Asolubility test relies on the fact that HbS is less soluble than normal hemoglobin (HbA); it is highly reliable but does not distinguish between full SCD and carrier status.[83]
Tests which can be used for SCD as well as for other hemoglobinopathies:
Hemoglobin electrophoresis is a test that can detect different types of hemoglobin. Hemoglobin is extracted from the red cells, then introduced into a porous gel and subjected to an electrical field. This separates the normal and abnormal types of hemoglobin which can then be identified and quantified.[84]
Isoelectric focusing (IEF) is a technique that can be used to diagnose sickle cell disease and other hemoglobinopathies. The technique separates molecules based on theirisoelectric point, or thepH at which they have no net electrical charge. IEF uses an electric charge to separate and identify different types of hemoglobin, which become focused into sharp stationary bands. The technique can distinguish many types of abnormal hemoglobin.[85]
High-performance liquid chromatography (HPLC) is reliable, fully automated, and able to distinguish most types of sickle cell disease including heterozygous, The method separates and quantifies hemoglobin fractions by measuring their rate of flow through a column of absorbent material.[82]
Genetic counselling is the process by which people with a hereditary disorder are advised of the probability of transmitting it and the ways in which this may be prevented or ameliorated.[86]
People who are known carriers of the disease or at risk of having a child with sickle cell anemia may undergogenetic counseling.Genetic counselors work with families to discuss the benefits, limitations, and logistics of genetic testing options as well as the potential impact of testing and test results on the individual.[87] Counselling is best given before a child is conceived, and a number of possible courses could be suggested. These include adoption, the use ofeggs orsperm from a healthy donor, andin-vitro fertilisation (IVF) when combined withpre-implantation genetic diagnosis of the embryos.[88]
There are a number of precautions which can help reduce the risk of developing a sickling crisis. Lifestyle behaviours include maintaining good hydration and avoiding physical stress or exhaustion. Since sickling can be triggered by low oxygen levels, people with SCD should avoid high altitudes such as high mountains or flying in unpressurised aircraft.[89][90] People with SCD should avoid alcohol and smoking, as alcohol can cause dehydration and smoking can trigger acute chest syndrome. Stress can also trigger a sickle cell crisis, so relaxation techniques like breathing exercises can help.[90]
Pneumococcal infection is a leading cause of death among children with SCD;penicillin is recommended daily during the first 5 years of life in order to minimise the risk of infection.[91][92]
Dietary supplementation offolic acid is sometimes recommended, on the basis that it facilitates the creation of new red blood cells and may reduce anemia. ACochrane review of its use in 2016 found "the effect of supplementation on anaemia and any symptoms of anaemia remains unclear" due to a lack of medical evidence.[93][94]
People with SCD are recommended to receive all vaccinations which arerecommended by health authorities in order to avoid serious infection which might trigger a sickling crisis.[95][96]
Hydroxyurea was the first approved drug for the treatment of SCD, which has been shown to decrease the number and severity of attacks and possibly increase survival time.[97][98] This is achieved, in part, by reactivatingfetal haemoglobin production in place of the haemoglobin S that causes sickling.Hydroxyurea lowers the expression of adhesion molecules on endothelial and red blood cells, which lowers the chance of small vessel blockages. Additionally, it encourages the release ofnitric oxide, which enhances blood flow and inhibits the formation of clots.[99] Hydroxyurea had previously been used as achemotherapy agent, and some concern exists that long-term use may be harmful.[100][101] A Cochrane review in 2022 found a weak evidence base for its use in SCD.[102]
Voxelotor was received accelerated approval as a treatment for SCD in the United States in 2019, and was approved by theEuropean Medicines Agency (EMA) in 2021.[103] In trials, it had been shown to have disease-modifying potential by increasing hemoglobin levels and decreasinghemolysis indicators[104][105] However, following an increased risk of vaso-occlusive seizures and death observed in registries and clinical trials, the manufacturer,Pfizer, withdrew it from the market worldwide.[106][107]
A simpleblood transfusion can be used to treat SCD when hemoglobin levels drop too low, or to prepare for an operation or pregnancy. It can also be used to protect against long-term complications, or to reduce the risk of stroke. The simple, or top-uptransfusion is a procedure in which healthy blood cells from a donor are infused into the patient's bloodstream. This benefits by alleviating anemia and increasing oxygen levels in the tissues, reducing the risk of sickling and relieving sickling symptoms. A simple transfusion can be used to treat SCD when hemoglobin levels drop too low, or to prepare for an operation or pregnancy. It can also be used to protect against long-term complications, or to reduce the risk of stroke.[108][109]
Anexchange transfusion is a procedure in which blood is removed from the body, then processed to extract sickled cells, which are replaced by healthy red blood cells from a donor. The treated blood, including white cells and plasma, is then returned to the patient. Exchange transfusions are likely to be needed in an emergency, in severe cases of SCD, or to support a mother during pregnancy.[110]
Transcranial Doppler ultrasound (TCD) can detect children with sickle cell that have a high risk for stroke. The ultrasound test detects blood vessels partially obstructed by sickle cells by measuring the rate of blood into the brain, as blood flow velocity is inversely related to arterial diameter, and consequently, high blood-flow velocity is correlated with narrowing of the arteries.[111]
In children, preventive RBCtransfusion therapy has been shown to reduce the risk of first stroke or silent stroke when transcranial Doppler ultrasonography shows abnormal cerebral blood flow.[6] In those who have sustained a prior stroke event, it also reduces the risk of recurrent stroke and additional silent strokes.[112][113]
Most people with sickle cell disease have intensely painful episodes called vaso-occlusive crises (VOC). However, the frequency, severity, and duration of these crises vary tremendously. In a VOC, the circulation ofblood vessels is obstructed by sickledred blood cells, causingischemic injuries to the tissues, inflammation and pain. Recurrent episodes may cause irreversible organ damage.[114][115]
The most common and obvious symptom of a VOC is pain, which may be felt anywhere in the body but most commonly in the limbs and back. The degree of pain varies from mild to severe.[114] Home treatment options include bedrest and hydration, and pain control using over-the-counter medication such asparacetamol oribuprofen.[116] More severe cases may require prescriptionopioids such ascodeine ormorphine for pain control.[117]
In 2019,crizanlizumab, a monoclonal antibody targetingP-selectin, was approved in the United States to reduce the frequency of vaso-occlusive crisis in those 16 years and older.[118] It had also been approved in the UK and Europe, but in both cases authorisation was subsequently withdrawn because of poor evidence of its effectiveness.[119][120]
Acute chest syndrome is caused by vaso-occlusion occurring in the lungs. As with a VOC, treatment includes pain control and hydration. Antibiotics are required because there is a severe risk of pulmonary infection, and oxygen supplementation forhypoxia.Blood transfusion may also be required, orexchange transfusion in severe cases.[121]
Hematopoietic stem cells (HSC) are cells in the bone marrow that can develop into all types of blood cells, including red blood cells, white blood cells, and platelets.[123] There are two possible ways to treat SCD and some other hemoglobinopathies by targeting HSCs. Since 1991, a small number of patients have received bone marrow transplants from healthy matched donors, although this procedure has a high level of risk.[124] More recently, it has become possible to useCRISPR gene editing technology to modify the patient's own HSCs in a way that reduces or eliminates the production of sickle hemoglobin HbS and replaces it with a non-sickling form of hemoglobin.[125]
All stem cell treatments must involvemyeloablation of the patients' bone marrow in order to remove HSCs containing the faulty gene. This requires high doses ofchemotherapy agents with side effects such as sickness and tiredness. A long hospital stay is necessary after infusion of the replacement HSCs while the cells take up residence in the bone marrow and start to make red blood cells with the stable form of haemoglobin.[126][127]
Gene therapy was first trialled in 2014 on a single patient,[128] and followed by clinical trials in which a number of patients were successfully treated.[129] In 2023, bothexagamglogene autotemcel (Casgevy) andlovotibeglogene autotemcel (Lyfgenia) were approved for the treatment of sickle cell disease.[12][130][14] Kendric Cromer in October 2024 became the first commercial case in the USA to receive gene therapy and was discharged fromChildren's National Hospital.[131] The one-off gene-editing therapy, Casgevy, also known as Exa-cel, is to be offered to patients on theNational Health Service (NHS) in England as from 2025.[132]
Both Casgevy and Lyfgenia work by first harvesting the patient's HSCs, then using CRISPR gene editing to modify their DNA in the laboratory. In parallel with this, the person with sickle cell disease's bone marrow is put through a myeloablation procedure to destroy the remaining HSCs. The treated cells are then infused back into the patient where they colonise the bone marrow and eventually resume production of blood cells. Casgevy works by editing the BCL11A gene, which normally inhibits the production of hemoglobin F (fetal hemoglobin) in adults. The edit has the effect of increasing production of HbF, which is not prone to sickling.[133] Lyfgenia introduces a new gene for T87Q-globin which coexists with the sickling beta-globin but reduces the incidence of sickling.[134]
Hematopoietic stem cell transplantation (HSCT) involves replacing the dysfunctional stem cells from a person with sickle cell disease with healthy cells from a well-matched donor.[135][124] Finding a well matched donor is essential to the process' success. Different types of donors may be suitable and includeumbilical cord blood,human leukocyte antigen (HLA) matched relatives, or HLA matched donors that are not related to the person being treated.[135] Risks associated with HSCT can includegraft-versus host disease, failure of the graft, and other toxicity related to the transplant.[135]
The HbS gene can be found in every ethnic group.[139] The highest frequency of sickle cell disease is found in tropical regions, particularly sub-Saharan Africa, tribal regions of India, and the Middle East.[140] About 80% of sickle cell disease cases are believed to occur inSub-Saharan Africa.[16] Migration of substantial populations from these high-prevalence areas to low-prevalence countries in Europe has dramatically increased in recent decades and in some European countries, sickle cell disease has now overtaken more familiar genetic conditions such ashaemophilia andcystic fibrosis.[141] In 2015, it resulted in about 114,800 deaths.[142]
Sickle cell disease occurs more commonly among people whose ancestors lived intropical andsubtropical sub-Saharan regions where malaria is or was common. Where malaria is common, carrying a single sickle cellallele (trait) confers aheterozygote advantage; humans with one of the two alleles of sickle cell disease show less severe symptoms when infected with malaria.[143]
This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.[20]
Three-quarters of sickle cell cases occur in Africa. AWHO report dated 2006 estimated that around 2% of newborns inNigeria were affected by sickle cell anaemia, giving a total of 150,000 affected children born every year in Nigeria alone. The carrier frequency ranges between 10 and 40% across equatorial Africa, decreasing to 1–2% on the North African coast and <1% in South Africa.[144]
Uganda has the fifth-highest sickle cell disease burden in Africa.[145] One study indicates that 20 000 babies per year are born with sickle cell disease with the sickle cell trait at 13.3% and with disease 0.7%.[146]
The number of people with the disease in theUnited States is about 100,000 (one in 3,300), mostly affecting Americans of sub-Saharan African descent.[147] In the United States, about one out of 365 African-American children and one in every 16,300 Hispanic-American children have sickle cell anaemia.[148] The life expectancy for men with SCD is approximately 42 years of age while women live approximately six years longer.[149] An additional 2million are carriers of the sickle cell trait.[150] Most infants with SCD born in the United States are identified by routine neonatal screening. As of 2016 all 50 states include screening for sickle cell disease as part of their newborn screen.[151] The newborn's blood is sampled through a heel-prick and is sent to a lab for testing. The baby must have been eating for a minimum of 24 hours before the heel-prick test can be done. Some states also require a second blood test to be done when the baby is two weeks old to ensure the results.[152]
Sickle cell anemia is the most common genetic disorder among African Americans. Approximately 8% arecarriers and 1 in 375 are born with the disease.[153] Patient advocates for sickle cell disease have complained that it gets less government and private research funding than similar rare diseases such ascystic fibrosis, with researcherElliott Vichinsky saying this shows racial discrimination or the role of wealth in health care advocacy.[154] Overall, without considering race, approximately 1.5% of infants born in the United States are carriers of at least one copy of the mutant (disease-causing) gene.[155]
Percentage of newborns screened for sickle cell disease within mainland France from 2006 to 2018
As a result of population growth in African-Caribbean regions ofoverseas France and immigration fromNorth and sub-Saharan Africa to mainland France, sickle cell disease has become a major health problem in France.[156] SCD has become the most common genetic disease in the country, with an overall birth prevalence of one in 2,415 inmainland France, ahead ofphenylketonuria (one in 10,862), congenitalhypothyroidism (one in 3,132), congenitaladrenal hyperplasia (one in 19,008) andcystic fibrosis (one in 5,014) for the same reference period.[157]
Percentage of newborns screened regionally and overall for sickle cell disease in mainland France in 2018
Since 2000, neonatal screening of SCD has been performed at the national level for all newborns defined as being "at-risk" for SCD based on ethnic origin (defined as those born to parents originating from sub-Saharan Africa, North Africa, the Mediterranean area (South Italy,Greece, andTurkey), the Arabic peninsula, the French overseas islands, and the Indian subcontinent).[158]
In the United Kingdom, between 12,000 and 15,000 people are thought to have sickle cell disease[159] with an estimated 250,000 carriers of the condition in England alone. As the number of carriers is only estimated, all newborn babies in the UK receive a routine blood test to screen for the condition.[160] Due to many adults in high-risk groups not knowing if they are carriers, pregnant women and both partners in a couple are offered screening so they can get counselling if they have the sickle cell trait.[161] In addition, blood donors from those in high-risk groups are also screened to confirm whether they are carriers and whether their blood filters properly.[162] Donors who are found to be carriers are informed and their blood, while often used for those of the same ethnic group, is not used for those with sickle cell disease who require a blood transfusion.[163]
InSaudi Arabia, about 4.2% of the population carry the sickle cell trait and 0.26% have sickle cell disease. The highest prevalence is in the Eastern province, where approximately 17% of the population carry the gene and 1.2% have sickle cell disease.[164]In 2005, Saudi Arabia introduced a mandatory premarital test including HB electrophoresis, which aimed to decrease the incidence of SCD andthalassemia.[165]
InBahrain, a study published in 1998 that covered about 56,000 people in hospitals in Bahrain found that 2% of newborns have sickle cell disease, 18% of the surveyed people have the sickle cell trait, and 24% were carriers of the gene mutation causing the disease.[166] The country began screening of all pregnant women in 1992, and newborns started being tested if the mother was a carrier. In 2004, a law was passed requiring couples planning to marry to undergo freepremarital counseling. These programs were accompanied by public education campaigns.[167]
Sickle cell disease is common in some ethnic groups of central India,[168] where the prevalence has ranged from 9.4 to 22.2% in endemic areas ofMadhya Pradesh,Rajasthan, andChhattisgarh.[169] It is also endemic amongTharu people of Nepal and India; however, they have a sevenfold lower rate of malaria despite living in a malaria infested zone.[170]
The first modern report of sickle cell disease may have been in 1846, where the autopsy of an executed runaway slave was discussed; the key finding was the absence of the spleen.[172][173] Reportedly, African slaves in the United States exhibited resistance to malaria, but were prone to leg ulcers.[173] The abnormal characteristics of the red blood cells, which later lent their name to the condition, was first described byErnest E. Irons (1877–1959), intern to Chicago cardiologist and professor of medicineJames B. Herrick (1861–1954), in 1910. Irons saw "peculiar elongated and sickle-shaped" cells in the blood of a man named Walter Clement Noel, a 20-year-old first-year dental student fromGrenada. Noel had been admitted to the Chicago Presbyterian Hospital in December 1904 with anaemia.[18][174] Noel was readmitted several times over the next three years for "muscular rheumatism" and "bilious attacks" but completed his studies and returned to the capital of Grenada (St. George's) to practicedentistry. He died ofpneumonia in 1916 and is buried in the Catholic cemetery atSauteurs in the north of Grenada.[18][19] Shortly after the report by Herrick, another case appeared in theVirginia Medical Semi-Monthly with the same title, "Peculiar Elongated and Sickle-Shaped Red Blood Corpuscles in a Case of Severe Anemia."[175] This article is based on a patient admitted to theUniversity of Virginia Hospital on 15 November 1910.[176] In the later description byVerne Mason in 1922, the name "sickle cell anemia" is first used.[19][177] Childhood problems related to sickle cells disease were not reported until the 1930s, despite the fact that this cannot have been uncommon in African-American populations.[173]
Memphis physicianLemuel Diggs, a prolific researcher into sickle cell disease, first introduced the distinction between sickle cell disease and trait in 1933, although until 1949, the genetic characteristics had not been elucidated byJames V. Neel and E.A. Beet.[19] 1949 was the year whenLinus Pauling described the unusual chemical behaviour of haemoglobin S, and attributed this to an abnormality in the molecule itself.[19][178] The molecular change in HbS was described in 1956 byVernon Ingram.[179] The late 1940s and early 1950s saw further understanding in the link between malaria and sickle cell disease. In 1954, the introduction ofhaemoglobin electrophoresis allowed the discovery of particular subtypes, such as HbSC disease.[19]
Large-scale natural history studies and further intervention studies were introduced in the 1970s and 1980s, leading to widespread use of prophylaxis against pneumococcal infections amongst other interventions.Bill Cosby's Emmy-winning 1972 TV movie,To All My Friends on Shore, depicted the story of the parents of a child with sickle cell disease.[180] The 1990s had the development of hydroxycarbamide, and reports of cure through bone marrow transplantation appeared in 2007.[19]
Some old texts refer to it as drepanocytosis.[181]
Sickle cell disease is frequently contested as a disability.[182] Effective 15 September 2017, the U.S.Social Security Administration issued a Policy Interpretation Ruling providing background information on sickle cell disease and a description of howSocial Security evaluates the disease during its adjudication process for disability claims.[183][184]
In the US, there arestigmas surrounding SCD that discourage people with SCD from receiving necessary care. These stigmas mainly affect people of African American and Latin American ancestries, according to the National Heart, Lung, and Blood Institute.[2] People with SCD experience the impact of stigmas of the disease on multiple aspects of life including social and psychological well-being. Studies have shown that those with SCD frequently feel as though they must keep their diagnosis a secret to avoid discrimination in the workplace and also among peers in relationships.[185] In the 1960s, the US government supported initiatives for workplacescreening for genetic diseases in an attempt to be protective towards people with SCD. By having this screening, it was intended that employees would not be placed in environments that could potentially be harmful and trigger SCD.[186]
Uganda has the 5th highest sickle cell disease (SCD) burden in the world.[187] InUganda,social stigma exists for those with sickle cell disease because of the lack of general knowledge of the disease. The general gap in knowledge surrounding sickle cell disease is noted among adolescents and young adults due to the culturally sanctioned secrecy about the disease.[187] While most people have heard generally about the disease, a large portion of the population is relatively misinformed about how SCD is diagnosed or inherited. Those who are informed about the disease learned about it from family or friends and not fromhealth professionals. Failure to provide the public with information about sickle cell disease results in a population with a poor understanding of the causes of the disease, symptoms, and prevention techniques.[145] The differences, physically and socially, that arise in those with sickle cell disease, such as jaundice, stunted physical growth, and delayed sexual maturity, can also lead them to become targets of bullying, rejection, and stigma.[187]
The data compiled on sickle cell disease in Uganda has not been updated since the early 1970s. The deficiency of data is due to a lack of government research funds, even though Ugandans die daily from SCD.[188] Data shows that the trait frequency of sickle cell disease is 20% of the population in Uganda.[188] This means that 66 million people are at risk of having a child who has sickle cell disease.[188] It is also estimated that about 25,000 Ugandans are born each year with SCD and 80% of those people do not live past five years old.[188] SCD also contributes 25% to the child mortality rate in Uganda.[188] The Bamba people of Uganda, located in the southwest of the country, carry 45% of the gene which is the highest trait frequency recorded in the world.[188] The Sickle Cell Clinic in Mulago is only one sickle cell disease clinic in the country and on average sees 200 patients a day.[188]
The stigma around the disease is particularly bad in regions of the country that are not as affected. For example, Eastern Ugandans tend to be more knowledgeable of the disease than Western Ugandans, who are more likely to believe that sickle cell disease resulted as a punishment fromGod orwitchcraft.[189] Other misconceptions about SCD include the belief that it is caused by environmental factors but, in reality, SCD is a genetic disease.[190] There have been efforts throughout Uganda to address the social misconceptions about the disease. In 2013, the Uganda Sickle Cell Rescue Foundation was established to spread awareness of sickle cell disease and combat the social stigma attached to the disease.[191] In addition to this organization's efforts, there is a need for the inclusion of sickle cell disease education in preexisting communityhealth education programs in order to reduce the stigmatization of sickle cell disease in Uganda.[145]
Social isolation of people with sickle cell disease
The deeply rooted stigma of SCD from society causes families to often hide their family members' sick status for fear of being labeled, cursed, or left out of social events.[192] Sometimes in Uganda, when it is confirmed that a family member has sickle cell disease, intimate relationships with all members of the family are avoided.[192] The stigmatization and social isolation people with sickle cell disease tend to experience is often the consequence of popular misconceptions that people with SCD should not socialize with those free from the disease. This mentality robs people with SCD of the right to freely participate in community activities like everyone else[187] SCD-related stigma and social isolation in schools, especially, can make a life for young people living with sickle cell disease extremely difficult.[187] For school-aged children living with SCD, the stigma they face can lead to peer rejection.[187] Peer rejection involves the exclusion from social groups or gatherings. It often leads the excluded individual to experience emotional distress and may result in their academic underperformance, avoidance of school, and occupational failure later in life.[187] This social isolation is also likely to negatively impact people with SCD'sself-esteem and overall quality of life.[187]
Mothers of children with sickle cell disease tend to receive disproportionate amounts of stigma from their peers and family members. These women will often be blamed for their child'sdiagnosis of SCD, especially if SCD is not present in earlier generations, due to the suspicion that the child's poor health may have been caused by the mother's failure to implement preventative health measures or promote a healthy environment for her child to thrive.[190] The reliance on theories related to environmental factors to place blame on the mother reflects many Ugandan's poor knowledge of how the disease is acquired as it is determined by genetics, not environment.[190] Mothers of children with sickle cell disease are also often left with very limited resources to safeguard their futures against the stigma of having SCD.[190] This lack of access to resources results from their subordinating roles within familial structures as well as the class disparities that hinder many mothers' ability to satisfy additional childcare costs and responsibilities.[190]
In 2021 many patients were found to be afraid to visit hospitals, so purchased pain relief to treat themselves outside the NHS. They were often waiting a long time for pain relief, and sometimes suspected of "drugs-seeking" behaviour. Delays to treatment, failure to inform the hospital haematology team and poor pain management had caused deaths. Specialist haematology staff preferred to work in bigger, teaching hospitals, leading to shortages of expertise elsewhere.[194] In 2021, the NHS initiated its first new treatment in 20 years for Sickle Cell. This involved the use ofCrizanlizumab, a drug given via transfusion drips, which reduces the number of visits toA&E by sufferers. The treatment can be accessed, via consultants, at any of ten new hubs set up around the country.[195] In the same year, however, an All-Party Parliamentary Group produced a report on Sickle Cell and Thalassaemia entitled 'No-one is listening'.[196] Partly in response to this, on 19 June 2022, World Sickle Cell Day, theNHS launched a campaign called "Can you tell it's sickle cell?". The campaign had twin aims. One was to increase awareness of the key signs and symptoms of the blood disorder so that people would be as alert to signs of a sickle cell crisis as they are to an imminent heart attack or stroke. The second aim was to set up a new training programme to help paramedics, Accident and Emergency staff, carers and the general public to care effectively for sufferers in crisis.[197]
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