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Sickle cell disease

May 12, 2023

Sickle cell disease (SCD) is a group of blood disorders typically inherited.[2] The most common type is known as sickle cell anaemia.[2] It results in an abnormality in the oxygen-carrying protein haemoglobin found in red blood cells.[2] This leads to a rigid, sickle-like shape under certain circumstances.[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 a sickle cell crisis), anemia, swelling in the hands and feet, bacterial infections, and stroke.[1] Long-term pain may develop as people get older.[2] The average life expectancy in the developed world is 40 to 60 years.[2]

Sickle cell disease
Other namesSickle cell disorder
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 normal haemoglobin. 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.
SpecialtyHematology, medical genetics
SymptomsAttacks of pain, anemia, swelling in the hands and feet, bacterial infections, stroke[1]
ComplicationsChronic pain, stroke, aseptic bone necrosis, gallstones, leg ulcers, priapism, pulmonary hypertension, vision problems, kidney problems[2]
Usual onset5–6 months of age[1]
CausesGenetic, Homozygous mutation in the hemoglobin S gene. [3]
Diagnostic methodBlood test[4]
TreatmentVaccination, antibiotics, high fluid intake, folic acid supplementation, pain medication, blood transfusions[5][6]
PrognosisLife expectancy 40–60 years (developed world)[2]
Frequency4.4 million (2015)[7]
Deaths114,800 (2015)[8]

Sickle cell disease occurs when a person inherits two abnormal copies of the β-globin gene (HBB) that makes haemoglobin, one from each parent.[3] This gene occurs in chromosome 11.[9] Several subtypes exist, depending on the exact mutation 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 have sickle cell trait.[3] Such people are also referred to as carriers.[5] Diagnosis is by a blood test, and some countries test all babies at birth for the disease.[4] Diagnosis is also possible during pregnancy.[4]

The care of people with sickle cell disease may include infection prevention with vaccination and antibiotics, high fluid intake, folic acid supplementation, and pain medication.[5][6] Other measures may include blood transfusion and the medication hydroxycarbamide (hydroxyurea).[6] A small percentage of people can be cured by a transplant of bone marrow cells.[2]

As of 2015, about 4.4 million people have sickle cell disease, while an additional 43 million have sickle cell trait.[7][10] About 80% of sickle cell disease cases are believed to occur in Sub-Saharan Africa.[11] It also occurs to a lesser degree in parts of India, Southern Europe, West Asia, North Africa and among people of African origin (sub-Saharan) living in other parts of the world.[12] In 2015, it resulted in about 114,800 deaths.[8] The condition was first described in the medical literature by American physician James B. Herrick in 1910.[13][14] In 1949, its genetic transmission was determined by E. A. Beet and J. V. Neel.[14] In 1954, the protective effect against malaria of sickle cell trait was described.[14]

Signs and symptoms

 
Sickle cell anaemia
 
Sickle 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.[15] Sickle cell disease may lead to various acute and chronic complications, several of which have a high mortality rate.[16]

Sickle cell crisis

The terms "sickle cell crisis" or "sickling crisis" may be used to describe several independent acute conditions occurring in patients with SCD, which results in anaemia and crises that could be of many types, including the vaso-occlusive crisis, aplastic crisis, splenic sequestration crisis, haemolytic crisis, and others. Most episodes of sickle cell crises last between five and seven days.[17] "Although infection, dehydration, and acidosis (all of which favor sickling) can act as triggers, in most instances, no predisposing cause is identified."[18]

Vaso-occlusive crisis

The vaso-occlusive crisis is caused by sickle-shaped red blood cells that obstruct capillaries and restrict blood flow to an organ, resulting in ischaemia, pain, necrosis, and often organ damage. The frequency, severity, and duration of these crises vary considerably. Painful crises are treated with hydration, analgesics, and blood transfusion; pain management requires opioid drug administration at regular intervals until the crisis has settled. For milder crises, a subgroup of patients manages on nonsteroidal anti-inflammatory drugs such as diclofenac or naproxen. For more severe crises, most patients require inpatient management for intravenous opioids; patient-controlled analgesia devices are commonly used in this setting. Vaso-occlusive crisis involving organs such as the penis[19] or lungs are considered an emergency and treated with red blood cell transfusions. Incentive spirometry, a technique to encourage deep breathing to minimise the development of atelectasis, is recommended.[20]

Splenic sequestration crisis

The spleen is frequently affected in sickle cell disease, as the sickle-shaped red blood cells cause narrowing of blood vessels and reduced function in clearing the defective cells.[21] It is usually infarcted before the end of childhood in individuals with sickle cell anaemia. This spleen damage increases the risk of infection from encapsulated organisms;[22][23] preventive antibiotics and vaccinations are recommended for those lacking proper spleen function.

Splenic sequestration crises are acute, painful enlargements of the spleen, caused by intrasplenic trapping of red cells and resulting in a precipitous fall in haemoglobin levels with the potential for hypovolemic shock. Sequestration crises are considered an emergency. If not treated, patients may die within 1–2 hours due to circulatory failure. Management is supportive, sometimes with blood transfusion. These crises are transient; they continue for 3–4 hours and may last for one day.[24]

Acute chest syndrome

Acute chest syndrome is defined by at least two of these signs or symptoms: chest pain, fever, pulmonary infiltrate or focal abnormality, respiratory symptoms, or hypoxemia.[20] It is the second-most common complication 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.[25][26] Nevertheless, about 80% of people have vaso-occlusive crises during acute chest syndrome.[citation needed]

Aplastic crisis

Aplastic crises are instances of an acute worsening of the patient's baseline anaemia, producing pale appearance, fast heart rate, and fatigue. This crisis is normally triggered by parvovirus B19, which directly affects production of red blood cells by invading the red cell precursors and multiplying in and destroying them.[27] Parvovirus infection almost completely prevents red blood cell production for two to three days. 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 counts drop dramatically during the disease (causing reticulocytopenia), and the rapid turnover of red cells leads to the drop in haemoglobin. This crisis takes 4 to 7 days to disappear. Most patients can be managed supportively; some need a blood transfusion.[28]

Haemolytic crisis

Haemolytic crises are acute accelerated drops in haemoglobin level. The red blood cells break down at a faster rate. This is particularly common in people with coexistent G6PD deficiency.[29] Another influence of hemolytic crises in sickle cell disease is oxidative stress on the erythrocytes, leukocytes, and platelets. When there is not enough red blood cell production in the bone marrow, the oxygen that the body receives, processes, and transports is unbalanced with the body’s antioxidants. There is an imbalance in the oxygen reactive species in the cells, which leads to more production of red blood cells that are not properly oxygenated or formed. Oxidative stress may lead to anemia because of the imbalance of oxygen in the tissue.[30]

Management is supportive, sometimes with blood transfusions.[20]

Other

One of the earliest clinical manifestations is dactylitis, presenting as early as six months of age, and may occur in children with sickle cell trait.[31] The crisis can last up to a month.[32] Given that pneumonia and sickling in the lung can both produce symptoms of acute chest syndrome, the patient is treated for both conditions.[33] It can be triggered by painful crisis, respiratory infection, bone-marrow embolisation, or possibly by atelectasis, opiate administration, or surgery.[34] Hematopoietic ulcers may also occur.[35]

Complications

Sickle cell anaemia can lead to various complications, including:

Genetics

 
Sickle cell disease is inherited in an autosomal recessive pattern.
 
Distribution of the sickle cell trait, shown in pink and purple
 
Historical distribution of malaria (no longer endemic in Europe), shown in green
 
Modern distribution of malaria
 
Base-pair substitution that causes sickle cell anemia

Normally, humans have haemoglobin A, which consists of two alpha and two beta chains, haemoglobin A2, which consists of two alpha and two delta chains, and haemoglobin F (HbF), consisting of two alpha and two gamma chains in their bodies. Of these three types, haemoglobin F dominates until about 6 weeks of age. Afterwards, haemoglobin A dominates throughout life.[53] In people diagnosed with sickle cell disease, at least one of the β-globin subunits in haemoglobin A is replaced with what is known as haemoglobin S. In sickle cell anaemia, a common form of sickle cell disease, haemoglobin S replaces both β-globin subunits in the haemoglobin.[15]

Sickle cell disease has an autosomal recessive pattern of inheritance from parents.[54] The types of haemoglobin a person makes in the red blood cells depend on what haemoglobin genes are inherited from her or his parents. If one parent has sickle cell anaemia and the other has sickle cell trait, then the child has a 50% chance of having sickle cell disease and a 50% chance of having sickle cell trait. When both parents have sickle cell trait, a child has a 25% chance of sickle cell disease; 25% do not carry any sickle cell alleles, and 50% have the heterozygous condition.[55]

Sickle cell gene mutation probably arose spontaneously in different geographic areas, as suggested by restriction endonuclease analysis. These variants are known as Cameroon, Senegal, Benin, Bantu, and Saudi-Asian. Their clinical importance is because some are associated with higher HbF levels, e.g., Senegal and Saudi-Asian variants, and tend to have milder disease.[56]

The gene defect is a single nucleotide mutation (see single-nucleotide polymorphism – SNP) (GAG codon changing to GTG) of the β-globin gene, which results in glutamate (E/Glu) being substituted by valine (V/Val) at position 6 (E6V substitution).[57][note 1] Haemoglobin S with this mutation is referred to as HbS, as opposed to the normal adult HbA. This is normally a benign mutation, causing no apparent effects on the secondary, tertiary, or quaternary structures of haemoglobin in conditions of normal oxygen concentration. However, under low oxygen concentration, HbS polymerizes and forms fibrous precipitates because the deoxy form of haemoglobin exposes a hydrophobic patch on the protein between the E and F helices (Phe 85, Leu 88).[58]

In people heterozygous for HbS (carriers of sickling haemoglobin), the polymerisation problems are minor because the normal allele can produce half of the haemoglobin. In people homozygous for HbS, the presence of long-chain polymers of HbS distort the shape of the red blood cell from a smooth, doughnut-like shape to ragged and full of spikes, making it fragile and susceptible to breaking within capillaries. Carriers have symptoms only if they are deprived of oxygen (for example, while climbing a mountain) or while severely dehydrated.[citation needed]

 
HBB gene (responsible for sickle cell anaemia) is located on the short (p) arm of chromosome 11 at position 15.5.

The allele responsible for sickle cell anaemia can be found on the short arm of chromosome 11, more specifically 11p15.5. A person who receives the defective gene from both father and mother develops the disease; a person who receives one defective and one healthy allele remains healthy, but can pass on the disease and is known as a carrier or heterozygote. Heterozygotes are still able to contract malaria, but their symptoms are generally less severe.[59]

Due to the adaptive advantage of the heterozygote, the disease is still prevalent, especially among people with recent ancestry in malaria-stricken areas, such as Africa, the Mediterranean, India, and the Middle East.[60] Malaria was historically endemic to southern Europe, but it was declared eradicated in the mid-20th century, with the exception of rare sporadic cases.[61]

The malaria parasite has a complex lifecycle and spends part of it in red blood cells. In a carrier, the presence of the malaria parasite causes the red blood cells with defective haemoglobin to rupture prematurely, making the Plasmodium parasite unable to reproduce. Further, the polymerization of Hb affects the ability of the parasite to digest Hb in the first place. Therefore, in areas where malaria is a problem, people's chances of survival actually increase if they carry sickle cell traits (selection for the heterozygote).[citation needed]

In the United States, with no endemic malaria, the prevalence of sickle cell anaemia among people of African ancestry is lower (about 0.25%) than among people in West Africa (about 4.0%) and is falling. Without endemic malaria, the sickle cell mutation is purely disadvantageous and tends to decline in the affected population by natural selection, and now artificially through prenatal genetic screening. However, the African American community descends from a significant admixture of several African and non-African ethnic groups and also represents the descendants of survivors of slavery and the slave trade. Thus, a degree of genetic dilution via crossbreeding with non-African people and high health-selective pressure through slavery (especially the slave trade and the frequently deadly Middle Passage) may be the most plausible explanations for the lower prevalence of sickle cell anaemia (and, possibly, other genetic diseases) among African Americans compared to West Africans. Another factor that limits the spread of sickle cell genes in North America is the relative absence of polygamy. In polygamous societies, affected males may father many children with multiple partners.[62]

Pathophysiology

 
Scanning electron micrograph showing a mixture of red blood cells, some with round normal morphology, some with mild sickling showing elongation and bending

The loss of red blood cell elasticity is central to the pathophysiology of sickle cell disease. Normal red blood cells are quite elastic and have a biconcave disc shape, which allows the cells to deform to pass through capillaries.[63] In sickle cell disease, low oxygen 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 and ischaemia.[citation needed]

The actual anaemia of the illness is caused by haemolysis, the destruction of the red cells, because of their shape. Although the bone marrow attempts to compensate by creating new red cells, it does not match the rate of destruction.[64] Healthy red blood cells typically function for 90–120 days, but sickled cells only last 10–20 days.[65]

Diagnosis

In HbS, the complete blood count reveals haemoglobin levels in the range of 6–8 g/dl with a high reticulocyte count (as the bone marrow compensates for the destruction of sickled cells by producing more red blood cells). In other forms of sickle cell disease, Hb levels tend to be higher. A blood film may show features of hyposplenism (target cells and Howell-Jolly bodies).[66]

Sickling of the red blood cells, on a blood film, can be induced by the addition of sodium metabisulfite. The presence of sickle haemoglobin can also be demonstrated with the "sickle solubility test" (also called "sickledex").[67] A mixture of haemoglobin S (HbS) in a reducing solution (such as sodium dithionite) gives a turbid appearance, whereas normal Hb gives a clear solution.[68]

Abnormal haemoglobin forms can be detected on haemoglobin electrophoresis, a form of gel electrophoresis on which the various types of haemoglobin move at varying speeds. Sickle cell haemoglobin (HgbS) and haemoglobin C with sickling (HgbSC)—the two most common forms—can be identified from there. The diagnosis can be confirmed with high-performance liquid chromatography. Genetic testing is rarely performed, as other investigations are highly specific for HbS and HbC.[69]

An acute sickle cell crisis is often precipitated by infection. Therefore, a urinalysis to detect an occult urinary tract infection, and chest X-ray to look for occult pneumonia should be routinely performed.[70]

People who are known carriers of the disease or at risk of having a child with sickle cell anemia may undergo genetic 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.[71][72] During pregnancy, genetic testing can be done on either a blood sample from the fetus or a sample of amniotic fluid. During the first trimester of pregnancy, chorionic villus sampling (CVS) is also a technique used for SCD prenatal diagnosis.[73] Since taking a blood sample from a fetus has greater risks, the latter test is usually used. Neonatal screening sometimes referred to as newborn screening, provides not only a method of early detection for individuals with sickle cell disease but also allows for the identification of the groups of people who carry the sickle cell trait.[74] Genetic counselors can help individuals of colour and their families tackle the racial and ethnic disparities that exist in healthcare.[75]

In 2010, there was significant consideration and debate in the US surrounding comprehensive screening of athletes for SCD.[76][77][78][79] The American Society of Hematology concluded in a statement in 2012 that they do not support testing or disclosure of sickle cell trait status as a prerequisite for participation in athletic activities due to lack of scientific evidence, inconsistency with good medical practice, and inconsistency with public health ethics. They recommended universal interventions to reduce exertion-related injuries and deaths effective for all athletes irrespective of their sickle cell status.[80]

Management

Further information: Pain management in children

Treatment involves a number of measures. While it has been historically recommended that people with sickle cell disease avoid exercise, regular exercise may benefit people.[81] Dehydration should be avoided.[82] A diet high in calcium is recommended[83] but the effectiveness of vitamin D supplementation remains uncertain.[84] L-glutamine use was supported by the FDA starting at the age of five, as it decreases complications.[85]

Folic acid and penicillin

From birth to five years of age, penicillin daily, due to the immature immune system that makes them more prone to early childhood illnesses, is recommended.[86] Dietary supplementation of folic acid had been previously recommended by the WHO.[5] A 2016 Cochrane review of its use found "the effect of supplementation on anaemia and any symptoms of anaemia remains unclear" due to a lack of medical evidence.[87]

Malaria prevention

 
Possible advantage of being heterozygous for sickle cell anemia disease (A) vs. normal blood cell response (B) when infected with malaria

The protective effect of sickle cell trait does not apply to people with sickle cell disease; in fact, they are more vulnerable to malaria, since the most common cause of painful crises in malarial countries is infection with malaria. People with sickle cell disease living in malarial countries should receive lifelong medication for prevention.[88]

Vaso-occlusive crisis

Most people with sickle cell disease have intensely painful episodes called vaso-occlusive crises. However, the frequency, severity, and duration of these crises vary tremendously. Painful crises are treated symptomatically with pain medications; pain management requires opioid drug administration at regular intervals until the crisis has settled. For milder crises, a subgroup of patients manages on NSAIDs (such as diclofenac or naproxen). For more severe crises, most patients require inpatient management for intravenous opioids.[89]

Extra fluids, administered either orally or intravenously, are a routine part of treatment of vaso-occlusive crises but the evidence about the most effective route, amount and type of fluid replacement remains uncertain.[90]

Crizanlizumab, a monoclonal antibody target towards p-selectin was approved in 2019 in the United States to reduce the frequency of vaso-occlusive crisis in those 16 years and older.[91]

Stroke prevention

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.[92] In 2002 the National Institute of Health (NIH) issued a statement recommending that children with sickle cell get the Transcranial Doppler ultrasound screen annually, and in 2014 a panel of experts convened by the NIH issued guidelines reiterating the same recommendation. One review of medical records, by hematologist Dr. Julie Kanter at the University of Alabama at Birmingham, showed that on average only 48.4 percent of children with sickle cell get the recommended ultrasound test.[93]

A 1994 NIH study showed that children at risk for strokes who received blood transfusions had an annual stroke rate of less than 1 percent, whereas those children who did not receive blood transfusions had a 10 percent stroke rate per year. (Also see 1998 study in the New England Journal of Medicine.[92]) In addition to ultrasounds and blood transfusions, the inexpensive generic drug hydroxyurea can reduce the risk of irreversible organ and brain damage. Guidelines from NIH published in 2014 state that all children and adolescents should take hydroxyurea, as should adults with serious complications or three or more pain crises in a year.[94]

Acute chest syndrome

Management is similar to vaso-occlusive crisis, with the addition of antibiotics (usually a quinolone or macrolide, since cell wall-deficient ["atypical"] bacteria are thought to contribute to the syndrome),[95] oxygen supplementation for hypoxia, and close observation. In the absence of high quality evidence regarding the effectiveness of antibiotics for acute chest syndrome in people with sickle cell disease, there is no standard antibiotic treatment as of 2019.[96] It is recommended that people with suspected acute chest syndrome should be admitted to the hospital with worsening A-a gradient an indication for ICU admission.[20]

Should the pulmonary infiltrate worsen or the oxygen requirements increase, simple blood transfusion or exchange transfusion is indicated. The latter involves the exchange of a significant portion of the person's red cell mass for normal red cells, which decreases the level of haemoglobin S in the patient's blood. However, there is currently uncertain evidence about the possible benefits or harms of blood transfusion for acute chest syndrome in people with sickle cell disease.[97]

Hydroxyurea

Hydroxyurea, also known as hydroxycarbamide, probably reduces the frequency of painful episodes and the risk of life-threatening illness or death but there is currently insufficient evidence regarding the risk of adverse effects.[98] Hydroxyurea and phlebotomy combined may be more effective than transfusion and chelation combined in terms of pain, life-threatening illness and risk of death.[98]

It was the first approved drug for the treatment of sickle cell anaemia, and was shown to decrease the number and severity of attacks in 1995[99] and shown to possibly increase survival time in a study in 2003.[100] This is achieved, in part, by reactivating fetal haemoglobin production in place of the haemoglobin S that causes sickle cell anaemia. Hydroxyurea had previously been used as a chemotherapy agent, and some concern exists that long-term use may be harmful, but this risk is either absent or very small and the benefits likely outweigh the risks.[16][101]

Voxelotor was approved in the United States in 2019 to increase hemoglobin in people with SS disease.[102]

Blood transfusion

Blood transfusions are often used in the management of sickle cell disease in acute cases and to prevent complications by decreasing the number of red blood cells (RBCs) that can sickle by adding normal red blood cells.[103] In children, preventive RBC transfusion 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.[104][105]

Bone marrow transplant

Bone marrow transplants have proven effective in children; they are the only known cure for SCD.[106] However, bone marrow transplants are difficult to obtain because of the specific HLA typing necessary. Ideally, a close relative (allogeneic) would donate the bone marrow necessary for transplantation. Some gene therapies are under development that would alter the patient's own bone marrow stem cells ex vivo, which can then be transplanted back into the patient after chemotherapy eliminates the original unmodified cells.[107]

Avascular necrosis

When treating avascular necrosis of the bone in people with sickle cell disease, the aim of treatment is to reduce or stop the pain and maintain joint mobility.[40] Current treatment options include resting the joint, physical therapy, pain-relief medicine, joint-replacement surgery, or bone grafting.[40] High quality, randomized, controlled trials are needed to assess the most effective treatment option and determine if a combination of physical therapy and surgery is more effective than physical therapy alone.[40]

Psychological therapies

Psychological therapies such as patient education, cognitive therapy, behavioural therapy, and psychodynamic psychotherapy, that aim to complement current medical treatments, require further research to determine their effectiveness.[21]

Prognosis

About 90% of people survive to age 20, and close to 50% survive beyond age 50.[108] In 2001, according to one study performed in Jamaica, the estimated mean survival for people was 53 years for men and 58 years for women with homozygous SCD.[109] The specific life expectancy in much of the developing world is unknown.[110] In 1975 about 7.3% of people with SCD died before their 23rd birthday; while in 1989 2.6% of people with SCD died by the age of 20.[111]: 348 

Epidemiology

The highest frequency of sickle cell disease is found in tropical regions, particularly sub-Saharan Africa, tribal regions of India, and the Middle East.[112] 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 as haemophilia and cystic fibrosis.[113] In 2015, it resulted in about 114,800 deaths.[8]

Sickle cell disease occurs more commonly among people whose ancestors lived in tropical and subtropical sub-Saharan regions where malaria is or was common. Where malaria is common, carrying a single sickle cell allele (trait) confers a heterozygote advantage; humans with one of the two alleles of sickle cell disease show less severe symptoms when infected with malaria.[114]

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.[115]

Africa

Three-quarters of sickle cell cases occur in Africa. A recent WHO report estimated that around 2% of newborns in Nigeria 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.[116] Studies in Africa show a significant decrease in infant mortality rate, ages 2–16 months, because of the sickle cell trait. This happened in areas of predominant malarial cases.[117]

Uganda has the fifth-highest sickle cell disease burden in Africa.[118] 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%.[119]

Country Population(2020) Subregion % of Prevalence Prevalence Incidence
Angola 32,866,272 Middle Africa 0.09375 3,081,213 14,869
Cameroon 26,545,863 Middle Africa 0.117 3,105,866 11,826
DR Congo 89,561,403 Middle Africa 0.1163333333 10,418,977 65,536
Ghana 31,072,940 Western Africa 0.09375 2,913,088 9,588
Guinea 13,132,795 Western Africa 0.139375 1,830,383 8,907
Niger 24,206,644 Western Africa 0.07025 1,700,517 8,756
Nigeria 206,139,589 Western Africa 0.1286666667 26,523,294 150,000
Tanzania 59,734,218 Eastern Africa 0.0545 3,255,515 19,585
Uganda 45,741,007 Eastern Africa 0.07025 3,213,306 17,936
Zambia 18,383,955 Eastern Africa 0.082 1,507,484 9,958
Algeria 43,851,044 Northern Africa 0.029 1,271,680 6,624
Benin 12,123,200 Western Africa 0.1286666667 1,559,852 8,125
Botswana 2,351,627 Southern Africa 0.029 68,197 355
Burkina Faso 20,903,273 Western Africa 0.07025 1,468,455 7,649
Burundi 11,890,784 Eastern Africa 0.023 273,488 1,425
Cabo Verde 555,987 Western Africa 0.023 12,788 67
Central African Republic 4,829,767 Middle Africa 0.082 396,041 2,063
Chad 16,425,864 Middle Africa 0.0585 960,913 5,005
Comoros 869,601 Eastern Africa 0.023 20,001 104
Congo 5,518,087 Middle Africa 0.1615 891,171 4,642
Côte d'Ivoire 26,378,274 Western Africa 0.07025 1,853,074 9,652
Djibouti 988,000 Eastern Africa 0.023 22,724 118
Egypt 102,334,404 Northern Africa 0.029 2,967,698 15,458
Equatorial Guinea 1,402,985 Middle Africa 0.181 253,940 1,323
Eritrea 3,546,421 Eastern Africa 0.023 81,568 425
Eswatini 1,160,164 Southern Africa 0.023 26,684 139
Ethiopia 114,963,588 Eastern Africa 0.029 3,333,944 17,366
Gabon 2,225,734 Middle Africa 0.181 402,858 2,098
Gambia 2,416,668 Western Africa 0.082 198,167 1,032
Guinea-Bissau 1,968,001 Western Africa 0.035 68,880 359
Kenya 53,771,296 Eastern Africa 0.04675 2,513,808 13,094
Lesotho 2,142,249 Southern Africa 0.023 49,272 257
Liberia 5,057,681 Western Africa 0.07025 355,302 1,851
Libya 6,871,292 Northern Africa 0.029 199,267 1,038
Madagascar 27,691,018 Eastern Africa 0.04675 1,294,555 6,743
Malawi 19,129,952 Eastern Africa 0.035 669,548 3,488
Mali 20,250,833 Western Africa 0.082 1,660,568 8,650
Mauritania 4,649,658 Western Africa 0.04675 217,372 1,132
Mauritius 1,271,768 Eastern Africa 0.023 29,251 152
Morocco 36,910,560 Northern Africa 0.029 1,070,406 5,576
Mozambique 31,255,435 Eastern Africa 0.035 1,093,940 5,698
Namibia 2,540,905 Southern Africa 0.03883333333 98,672 514
Rwanda 12,952,218 Eastern Africa 0.035 453,328 2,361
São Tomé and Príncipe 219,159 Middle Africa 0.181 39,668 207
Senegal 16,743,927 Western Africa 0.07025 1,176,261 6,127
Seychelles 98,347 Eastern Africa 0.023 2,262 12
Sierra Leone 7,976,983 Western Africa 0.1615 1,288,283 6,711
Somalia 15,893,222 Eastern Africa 0.029 460,903 2,401
South Africa 59,308,690 Southern Africa 0.029 1,719,952 8,959
South Sudan 11,193,725 Eastern Africa 0.04675 523,307 2,726
Sudan 43,849,260 Northern Africa 0.03883333333 1,702,813 8,870
Togo 8,278,724 Western Africa 0.09375 776,130 4,043
Tunisia 11,818,619 Northern Africa 0.023 271,828 1,416
Zimbabwe 14,862,924 Eastern Africa 0.035 520,202 2,710
Total 1,338,826,604 Africa 91,868,664 495,726

United States

The number of people with the disease in the United States is about 100,000 (one in 3,300), mostly affecting Americans of sub-Saharan African descent.[120] 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.[121] The life expectancy for men with SCD is approximately 42 years of age while women live approximately six years longer.[122] An additional 2 million are carriers of the sickle cell trait.[123] 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.[124] 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.[125] Sickle cell anemia is the most common genetic disorder among African Americans. Approximately 8% are carriers and 1 in 375 are born with the disease.[126] Patient advocates for sickle cell disease have complained that it gets less government and private research funding than similar rare diseases such as cystic fibrosis, with researcher Elliott Vichinsky saying this shows racial discrimination or the role of wealth in health care advocacy.[127]

France

 
Percentage of newborns screened for sickle cell disease within Metropolitan France from 2006 to 2018

As a result of population growth in African-Caribbean regions of overseas France and immigration from North and sub-Saharan Africa to mainland France, sickle cell disease has become a major health problem in France.[128] SCD has become the most common genetic disease in the country, with an overall birth prevalence of one in 2,415 in metropolitan France, ahead of phenylketonuria (one in 10,862), congenital hypothyroidism (one in 3,132), congenital adrenal hyperplasia (one in 19,008) and cystic fibrosis (one in 5,014) for the same reference period.[citation needed]

 
Percentage of newborns screened regionally and overall for sickle cell disease in Metropolitan 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, and Turkey), the Arabic peninsula, the French overseas islands, and the Indian subcontinent).[129]

United Kingdom

In the United Kingdom, between 12,000 and 15,000 people are thought to have sickle cell disease [130] 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.[131] 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.[132] 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.[133] Donors who are found to be carriers are then 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.[134]

West Asia

In Saudi 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.[135] In 2005, Saudi Arabia introduced a mandatory premarital test including HB electrophoresis, which aimed to decrease the incidence of SCD and thalassemia.[136]

In Bahrain, 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.[137] 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 free premarital counseling. These programs were accompanied by public education campaigns.[138]

India and Nepal

Sickle cell disease is common in some ethnic groups of central India,[139] where the prevalence has ranged from 9.4 to 22.2% in endemic areas of Madhya Pradesh, Rajasthan, and Chhattisgarh.[140] It is also endemic among Tharu people of Nepal and India; however, they have a sevenfold lower rate of malaria despite living in a malaria infested zone.[141]

Caribbean Islands

In Jamaica, 10% of the population carry the sickle cell gene, making it the most prevalent genetic disorder in the country.[142]

History

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.[143][144] Reportedly, African slaves in the United States exhibited resistance to malaria, but were prone to leg ulcers.[144] The abnormal characteristics of the red blood cells, which later lent their name to the condition, was first described by Ernest E. Irons (1877–1959), intern to Chicago cardiologist and professor of medicine James 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 from Grenada. Noel had been admitted to the Chicago Presbyterian Hospital in December 1904 with anaemia.[13][145] 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 practice dentistry. He died of pneumonia in 1916 and is buried in the Catholic cemetery at Sauteurs in the north of Grenada.[13][14] Shortly after the report by Herrick, another case appeared in the Virginia Medical Semi-Monthly with the same title, "Peculiar Elongated and Sickle-Shaped Red Blood Corpuscles in a Case of Severe Anemia."[146] This article is based on a patient admitted to the University of Virginia Hospital on 15 November 1910.[147] In the later description by Verne Mason in 1922, the name "sickle cell anemia" is first used.[14][148] 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.[144]

Memphis physician Lemuel 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 by James V. Neel and E.A. Beet.[14] 1949 was the year when Linus Pauling described the unusual chemical behaviour of haemoglobin S, and attributed this to an abnormality in the molecule itself.[14][149] The molecular change in HbS was described in 1956 by Vernon Ingram.[150] The late 1940s and early 1950s saw further understanding in the link between malaria and sickle cell disease. In 1954, the introduction of haemoglobin electrophoresis allowed the discovery of particular subtypes, such as HbSC disease.[14]

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.[151] The 1990s had the development of hydroxycarbamide, and reports of cure through bone marrow transplantation appeared in 2007.[14]

Some old texts refer to it as drepanocytosis.[152]

Society and culture

United States

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 how Social Security evaluates the disease during its adjudication process for disability claims.[153][154]

In the U.S., there are stigmas 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.[155] 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.[156] In the 1960s, the US government supported initiatives for workplace screening 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.[157]

Uganda

Uganda has the 5th highest sickle cell disease (SCD) burden in the world.[158] In Uganda, 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.[158] 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 from health 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.[159] 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.[158]

Rate of sickle cell disease in Uganda

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.[160] Data shows that the trait frequency of sickle cell disease is 20% of the population in Uganda.[160] This means that 66 million people are at risk of having a child who has sickle cell disease.[160] It is also estimated that about 25,000 Ugandans are born each year with SCD and 80% of those people don't live past five years old.[160] SCD also contributes 25% to the child mortality rate in Uganda.[160] 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.[160] The Sickle Cell Clinic in Mulago is only one sickle cell disease clinic in the country and on average sees 200 patients a day.[160]

Misconceptions about sickle cell disease

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 from God or witchcraft.[161] Other misconceptions about SCD include the belief that it is caused by environmental factors but, in reality, SCD is a genetic disease.[162] 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.[163] In addition to this organization's efforts, there is a need for the inclusion of sickle cell disease education in preexisting community health education programs in order to reduce the stigmatization of sickle cell disease in Uganda.[159]

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.[164] 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.[164] 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[158] SCD-related stigma and social isolation in schools, especially, can make a life for young people living with sickle cell disease extremely difficult.[158] For school-aged children living with SCD, the stigma they face can lead to peer rejection.[158] 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.[158] This social isolation is also likely to negatively impact people with SCD's self-esteem and overall quality of life.[158]

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's diagnosis 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.[162] 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.[162] 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.[162] 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.[162]

Women living with SCD who become pregnant often face extreme discrimination and discouragement in Uganda. These women are frequently branded by their peers as irresponsible for having a baby while living with sickle cell disease or even engaging in sex while living with SCD.[citation needed] The criticism and judgement these women receive, not only from healthcare professionals but also from their families, often leaves them feeling alone, depressed, anxious, ashamed, and with very little social support.[citation needed] Most pregnant women with SCD also go on to be single mothers as it is common for them to be left by their male partners who claim they were unaware of their partner's SCD status.[citation needed] Not only does the abandonment experienced by these women cause emotional distress for them, but this low level of parental support can be linked to depressive symptoms and overall lower quality of life for the child once they are born.[165]

United Kingdom

In 2021 many patients were found to be afraid to visit hospitals so purchasing pain relief to treat themselves outside the NHS, such was the level of ignorance among staff. 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 prefer to work in bigger, teaching hospitals, leading to shortages of expertise elsewhere.[166] In 2021 the NHS initiated its first new treatment in 20 years for Sickle Cell. This involved the use of Crizanlizumab, a drug given via transfusion drips, which reduces the number of visits to A and E by sufferers. The treatment can be accessed, via consultants, at any of ten new hubs set up around the country.[167] In the same year, however, an All-Party Parliamentary Group produced a report on Sickle Cell and Thalassaemia entitled 'No-one is listening'.[168] Partly in response to this, on 19 June 2022, World Sickle Cell Day, the NHS 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 are 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.[169]

Research

Umbilical cord blood transplant

While umbilical cord blood transplant can potentially cure the condition, a suitable donor is available in only 10% of people.[170] About 7% of people also die as a result of the procedure and graft versus host disease may occur.[170]

Gene therapy

Diseases such as sickle cell disease for which a person's normal phenotype or cell function may be restored in cells that have the disease by a normal copy of the gene that is mutated, may be a good candidate for gene therapy treatment. The risks and benefits related to gene therapy for sickle cell disease are not known.[171]

In 2001, sickle cell disease reportedly had been successfully treated in mice using gene therapy.[172][173] The researchers used a viral vector to make the mice—which have essentially the same defect that causes human sickle cell disease—express production of fetal haemoglobin (HbF), which an individual normally ceases to produce shortly after birth. In humans, using hydroxyurea to stimulate the production of HbF has been known to temporarily alleviate sickle cell disease symptoms. The researchers demonstrated that this gene therapy method is a more permanent way to increase therapeutic HbF production.[174]

Phase 1 clinical trials of gene therapy for sickle cell disease in humans were started in 2014. The clinical trials will assess the safety of lentiviral vector-modified bone marrow for adults with severe sickle cell disease.[175][176] As of 2020, however, no randomized controlled trials have been reported.[171] A case report for the first person treated was published in March 2017, with a few more people being treated since then.[177][178]

Gene editing platforms like CRISPR/Cas9 have been used to correct the disease-causing mutation in hematopoietic stem cells taken from a person with the condition.[179] In July 2019 the gene-editing tool CRISPR was used to edit bone marrow cells from a person with SCD to boost fetal haemoglobin by inhibiting the BCL11A gene.[180][181] A number of researchers have considered the ethical implications of SCD being one of the first potential applications of CRISPR technology, given the historical abuses and neglect of the African American community by the medical field.[182]

In 2017 twelve clinical trials were focusing on gene therapy to treat sickle cell anemia. Of those 12 trials, four of them replaced the mutated HBB gene with a healthy one. Three trials used Mozobil, a medication used to treat types of cancer, to determine whether the increase of stem cells can be used for gene therapy. One trial focused on analyzing bone marrow samples from patients with sickle cell anemia. Another trial experimented with using umbilical cord blood from babies both with and without sickle cell anemia to develop gene therapy.[183]

Hematopoietic stem cell transplantation

There is no strong medical evidence to determine the risks and potential benefits related to treating people with sickle cell disease with hematopoietic stem cell transplantations.[184]

Notes

  1. ^ Historic numbering put this glutamic acid residue at position 6 due to skipping the methionine (M/Met) start codon in protein amino acid position numbering. Current nomenclature calls for counting the methionine as the first amino acid, resulting in the glutamic acid residue falling at position 7. Many references still refer to position 6 and both should likely be referenced for clarity.

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Further reading

  • Brown RT, ed. (2006). Comprehensive handbook of childhood cancer and sickle cell disease: a biopsychosocial approach. Oxford University Press. ISBN 978-0-19-516985-0.
  • Hill SA (2003). Managing Sickle Cell Disease in Low-Income Families. Temple University Press. ISBN 978-1-59213-195-2.
  • Serjeant GR, Serjeant BE (2001). Sickle Cell Disease. Oxford University Press. ISBN 978-0-19-263036-0.
  • Tapper M (1999). In the blood: sickle cell anemia and the politics of race. University of Pennsylvania Press. ISBN 978-0-8122-3471-8.

External links

 
Wikimedia Commons has media related to Sickle-cell disease.

May 12, 2023
sickle, cell, disease, group, blood, disorders, typically, inherited, most, common, type, known, sickle, cell, anaemia, results, abnormality, oxygen, carrying, protein, haemoglobin, found, blood, cells, this, leads, rigid, sickle, like, shape, under, certain, . Sickle cell disease SCD is a group of blood disorders typically inherited 2 The most common type is known as sickle cell anaemia 2 It results in an abnormality in the oxygen carrying protein haemoglobin found in red blood cells 2 This leads to a rigid sickle like shape under certain circumstances 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 a sickle cell crisis anemia swelling in the hands and feet bacterial infections and stroke 1 Long term pain may develop as people get older 2 The average life expectancy in the developed world is 40 to 60 years 2 Sickle cell diseaseOther namesSickle cell disorderFigure 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 normal haemoglobin 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 SpecialtyHematology medical geneticsSymptomsAttacks of pain anemia swelling in the hands and feet bacterial infections stroke 1 ComplicationsChronic pain stroke aseptic bone necrosis gallstones leg ulcers priapism pulmonary hypertension vision problems kidney problems 2 Usual onset5 6 months of age 1 CausesGenetic Homozygous mutation in the hemoglobin S gene 3 Diagnostic methodBlood test 4 TreatmentVaccination antibiotics high fluid intake folic acid supplementation pain medication blood transfusions 5 6 PrognosisLife expectancy 40 60 years developed world 2 Frequency4 4 million 2015 7 Deaths114 800 2015 8 Sickle cell disease occurs when a person inherits two abnormal copies of the b globin gene HBB that makes haemoglobin one from each parent 3 This gene occurs in chromosome 11 9 Several subtypes exist depending on the exact mutation 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 have sickle cell trait 3 Such people are also referred to as carriers 5 Diagnosis is by a blood test and some countries test all babies at birth for the disease 4 Diagnosis is also possible during pregnancy 4 The care of people with sickle cell disease may include infection prevention with vaccination and antibiotics high fluid intake folic acid supplementation and pain medication 5 6 Other measures may include blood transfusion and the medication hydroxycarbamide hydroxyurea 6 A small percentage of people can be cured by a transplant of bone marrow cells 2 As of 2015 update about 4 4 million people have sickle cell disease while an additional 43 million have sickle cell trait 7 10 About 80 of sickle cell disease cases are believed to occur in Sub Saharan Africa 11 It also occurs to a lesser degree in parts of India Southern Europe West Asia North Africa and among people of African origin sub Saharan living in other parts of the world 12 In 2015 it resulted in about 114 800 deaths 8 The condition was first described in the medical literature by American physician James B Herrick in 1910 13 14 In 1949 its genetic transmission was determined by E A Beet and J V Neel 14 In 1954 the protective effect against malaria of sickle cell trait was described 14 Contents 1 Signs and symptoms 1 1 Sickle cell crisis 1 2 Vaso occlusive crisis 1 3 Splenic sequestration crisis 1 4 Acute chest syndrome 1 5 Aplastic crisis 1 6 Haemolytic crisis 1 7 Other 1 8 Complications 2 Genetics 3 Pathophysiology 4 Diagnosis 5 Management 5 1 Folic acid and penicillin 5 2 Malaria prevention 5 3 Vaso occlusive crisis 5 4 Stroke prevention 5 5 Acute chest syndrome 5 6 Hydroxyurea 5 7 Blood transfusion 5 8 Bone marrow transplant 5 9 Avascular necrosis 5 10 Psychological therapies 6 Prognosis 7 Epidemiology 7 1 Africa 7 2 United States 7 3 France 7 4 United Kingdom 7 5 West Asia 7 6 India and Nepal 7 7 Caribbean Islands 8 History 9 Society and culture 9 1 United States 9 2 Uganda 9 2 1 Rate of sickle cell disease in Uganda 9 2 2 Misconceptions about sickle cell disease 9 2 3 Social isolation of people with sickle cell disease 9 3 United Kingdom 10 Research 10 1 Umbilical cord blood transplant 10 2 Gene therapy 10 3 Hematopoietic stem cell transplantation 11 Notes 12 References 13 Further reading 14 External linksSigns and symptoms Edit Sickle cell anaemia Sickle 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 15 Sickle cell disease may lead to various acute and chronic complications several of which have a high mortality rate 16 Sickle cell crisis Edit The terms sickle cell crisis or sickling crisis may be used to describe several independent acute conditions occurring in patients with SCD which results in anaemia and crises that could be of many types including the vaso occlusive crisis aplastic crisis splenic sequestration crisis haemolytic crisis and others Most episodes of sickle cell crises last between five and seven days 17 Although infection dehydration and acidosis all of which favor sickling can act as triggers in most instances no predisposing cause is identified 18 Vaso occlusive crisis Edit The vaso occlusive crisis is caused by sickle shaped red blood cells that obstruct capillaries and restrict blood flow to an organ resulting in ischaemia pain necrosis and often organ damage The frequency severity and duration of these crises vary considerably Painful crises are treated with hydration analgesics and blood transfusion pain management requires opioid drug administration at regular intervals until the crisis has settled For milder crises a subgroup of patients manages on nonsteroidal anti inflammatory drugs such as diclofenac or naproxen For more severe crises most patients require inpatient management for intravenous opioids patient controlled analgesia devices are commonly used in this setting Vaso occlusive crisis involving organs such as the penis 19 or lungs are considered an emergency and treated with red blood cell transfusions Incentive spirometry a technique to encourage deep breathing to minimise the development of atelectasis is recommended 20 Splenic sequestration crisis Edit The spleen is frequently affected in sickle cell disease as the sickle shaped red blood cells cause narrowing of blood vessels and reduced function in clearing the defective cells 21 It is usually infarcted before the end of childhood in individuals with sickle cell anaemia This spleen damage increases the risk of infection from encapsulated organisms 22 23 preventive antibiotics and vaccinations are recommended for those lacking proper spleen function Splenic sequestration crises are acute painful enlargements of the spleen caused by intrasplenic trapping of red cells and resulting in a precipitous fall in haemoglobin levels with the potential for hypovolemic shock Sequestration crises are considered an emergency If not treated patients may die within 1 2 hours due to circulatory failure Management is supportive sometimes with blood transfusion These crises are transient they continue for 3 4 hours and may last for one day 24 Acute chest syndrome Edit Acute chest syndrome is defined by at least two of these signs or symptoms chest pain fever pulmonary infiltrate or focal abnormality respiratory symptoms or hypoxemia 20 It is the second most common complication 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 25 26 Nevertheless about 80 of people have vaso occlusive crises during acute chest syndrome citation needed Aplastic crisis Edit Aplastic crises are instances of an acute worsening of the patient s baseline anaemia producing pale appearance fast heart rate and fatigue This crisis is normally triggered by parvovirus B19 which directly affects production of red blood cells by invading the red cell precursors and multiplying in and destroying them 27 Parvovirus infection almost completely prevents red blood cell production for two to three days 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 counts drop dramatically during the disease causing reticulocytopenia and the rapid turnover of red cells leads to the drop in haemoglobin This crisis takes 4 to 7 days to disappear Most patients can be managed supportively some need a blood transfusion 28 Haemolytic crisis Edit Haemolytic crises are acute accelerated drops in haemoglobin level The red blood cells break down at a faster rate This is particularly common in people with coexistent G6PD deficiency 29 Another influence of hemolytic crises in sickle cell disease is oxidative stress on the erythrocytes leukocytes and platelets When there is not enough red blood cell production in the bone marrow the oxygen that the body receives processes and transports is unbalanced with the body s antioxidants There is an imbalance in the oxygen reactive species in the cells which leads to more production of red blood cells that are not properly oxygenated or formed Oxidative stress may lead to anemia because of the imbalance of oxygen in the tissue 30 Management is supportive sometimes with blood transfusions 20 Other Edit One of the earliest clinical manifestations is dactylitis presenting as early as six months of age and may occur in children with sickle cell trait 31 The crisis can last up to a month 32 Given that pneumonia and sickling in the lung can both produce symptoms of acute chest syndrome the patient is treated for both conditions 33 It can be triggered by painful crisis respiratory infection bone marrow embolisation or possibly by atelectasis opiate administration or surgery 34 Hematopoietic ulcers may also occur 35 Complications Edit Sickle cell anaemia can lead to various complications including Increased risk of severe bacterial infections is due to loss of functioning spleen tissue and comparable to the risk of infections after having the spleen removed surgically These infections are typically caused by encapsulated organisms such as Streptococcus pneumoniae and Haemophilus influenzae Daily penicillin prophylaxis is the most commonly used treatment during childhood with some haematologists continuing treatment indefinitely Patients benefit today from routine vaccination for S pneumoniae 36 Stroke which can result from a progressive narrowing of blood vessels prevents oxygen from reaching the brain Cerebral infarction occurs in children and cerebral haemorrhage in adults citation needed 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 37 38 Cholelithiasis gallstones and cholecystitis may result from excessive bilirubin production and precipitation due to prolonged haemolysis 39 Avascular necrosis aseptic bone necrosis of the hip and other major joints may occur as a result of ischaemia 40 Decreased immune reactions due to hyposplenism malfunctioning of the spleen 41 Priapism and infarction of the penis 42 Osteomyelitis bacterial bone infection the most common cause of osteomyelitis in SCD is Salmonella especially the atypical serotypes Salmonella typhimurium Salmonella enteritidis Salmonella choleraesuis and Salmonella paratyphi B followed by Staphylococcus aureus and Gram negative enteric bacilli perhaps because intravascular sickling of the bowel leads to patchy ischaemic infarction 43 Acute papillary necrosis in the kidneys citation needed Leg ulcers 44 In eyes background retinopathy proliferative retinopathy vitreous haemorrhages and retinal detachments can result in blindness 45 Regular annual eye checks are recommended During pregnancy intrauterine growth restriction spontaneous abortion and pre eclampsia Chronic pain Even in the absence of acute vaso occlusive pain many patients have unreported chronic pain 46 Pulmonary hypertension increased pressure on the pulmonary artery can lead to strain on the right ventricle and a risk of heart failure typical symptoms are shortness of breath decreased exercise tolerance and episodes of syncope 47 21 of children and 30 of adults have evidence of pulmonary hypertension when tested this is associated with reduced walking distance and increased mortality 48 Cardiomyopathy and left ventricular diastolic dysfunction caused by fibrosis or scarring of cardiac tissues 49 50 This also contributes to pulmonary hypertension decreased exercise capacity and arrhythmias 51 Chronic kidney failure due to sickle cell nephropathy manifests itself with hypertension protein loss in the urine loss of red blood cells in urine and worsened anaemia If it progresses to end stage kidney failure it carries a poor prognosis 52 Genetics Edit Sickle cell disease is inherited in an autosomal recessive pattern Distribution of the sickle cell trait shown in pink and purple Historical distribution of malaria no longer endemic in Europe shown in green Modern distribution of malaria Base pair substitution that causes sickle cell anemia Normally humans have haemoglobin A which consists of two alpha and two beta chains haemoglobin A2 which consists of two alpha and two delta chains and haemoglobin F HbF consisting of two alpha and two gamma chains in their bodies Of these three types haemoglobin F dominates until about 6 weeks of age Afterwards haemoglobin A dominates throughout life 53 In people diagnosed with sickle cell disease at least one of the b globin subunits in haemoglobin A is replaced with what is known as haemoglobin S In sickle cell anaemia a common form of sickle cell disease haemoglobin S replaces both b globin subunits in the haemoglobin 15 Sickle cell disease has an autosomal recessive pattern of inheritance from parents 54 The types of haemoglobin a person makes in the red blood cells depend on what haemoglobin genes are inherited from her or his parents If one parent has sickle cell anaemia and the other has sickle cell trait then the child has a 50 chance of having sickle cell disease and a 50 chance of having sickle cell trait When both parents have sickle cell trait a child has a 25 chance of sickle cell disease 25 do not carry any sickle cell alleles and 50 have the heterozygous condition 55 Sickle cell gene mutation probably arose spontaneously in different geographic areas as suggested by restriction endonuclease analysis These variants are known as Cameroon Senegal Benin Bantu and Saudi Asian Their clinical importance is because some are associated with higher HbF levels e g Senegal and Saudi Asian variants and tend to have milder disease 56 The gene defect is a single nucleotide mutation see single nucleotide polymorphism SNP GAG codon changing to GTG of the b globin gene which results in glutamate E Glu being substituted by valine V Val at position 6 E6V substitution 57 note 1 Haemoglobin S with this mutation is referred to as HbS as opposed to the normal adult HbA This is normally a benign mutation causing no apparent effects on the secondary tertiary or quaternary structures of haemoglobin in conditions of normal oxygen concentration However under low oxygen concentration HbS polymerizes and forms fibrous precipitates because the deoxy form of haemoglobin exposes a hydrophobic patch on the protein between the E and F helices Phe 85 Leu 88 58 In people heterozygous for HbS carriers of sickling haemoglobin the polymerisation problems are minor because the normal allele can produce half of the haemoglobin In people homozygous for HbS the presence of long chain polymers of HbS distort the shape of the red blood cell from a smooth doughnut like shape to ragged and full of spikes making it fragile and susceptible to breaking within capillaries Carriers have symptoms only if they are deprived of oxygen for example while climbing a mountain or while severely dehydrated citation needed HBB gene responsible for sickle cell anaemia is located on the short p arm of chromosome 11 at position 15 5 The allele responsible for sickle cell anaemia can be found on the short arm of chromosome 11 more specifically 11p15 5 A person who receives the defective gene from both father and mother develops the disease a person who receives one defective and one healthy allele remains healthy but can pass on the disease and is known as a carrier or heterozygote Heterozygotes are still able to contract malaria but their symptoms are generally less severe 59 Due to the adaptive advantage of the heterozygote the disease is still prevalent especially among people with recent ancestry in malaria stricken areas such as Africa the Mediterranean India and the Middle East 60 Malaria was historically endemic to southern Europe but it was declared eradicated in the mid 20th century with the exception of rare sporadic cases 61 The malaria parasite has a complex lifecycle and spends part of it in red blood cells In a carrier the presence of the malaria parasite causes the red blood cells with defective haemoglobin to rupture prematurely making the Plasmodium parasite unable to reproduce Further the polymerization of Hb affects the ability of the parasite to digest Hb in the first place Therefore in areas where malaria is a problem people s chances of survival actually increase if they carry sickle cell traits selection for the heterozygote citation needed In the United States with no endemic malaria the prevalence of sickle cell anaemia among people of African ancestry is lower about 0 25 than among people in West Africa about 4 0 and is falling Without endemic malaria the sickle cell mutation is purely disadvantageous and tends to decline in the affected population by natural selection and now artificially through prenatal genetic screening However the African American community descends from a significant admixture of several African and non African ethnic groups and also represents the descendants of survivors of slavery and the slave trade Thus a degree of genetic dilution via crossbreeding with non African people and high health selective pressure through slavery especially the slave trade and the frequently deadly Middle Passage may be the most plausible explanations for the lower prevalence of sickle cell anaemia and possibly other genetic diseases among African Americans compared to West Africans Another factor that limits the spread of sickle cell genes in North America is the relative absence of polygamy In polygamous societies affected males may father many children with multiple partners 62 Pathophysiology Edit Scanning electron micrograph showing a mixture of red blood cells some with round normal morphology some with mild sickling showing elongation and bending The loss of red blood cell elasticity is central to the pathophysiology of sickle cell disease Normal red blood cells are quite elastic and have a biconcave disc shape which allows the cells to deform to pass through capillaries 63 In sickle cell disease low oxygen 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 and ischaemia citation needed The actual anaemia of the illness is caused by haemolysis the destruction of the red cells because of their shape Although the bone marrow attempts to compensate by creating new red cells it does not match the rate of destruction 64 Healthy red blood cells typically function for 90 120 days but sickled cells only last 10 20 days 65 Diagnosis EditIn HbS the complete blood count reveals haemoglobin levels in the range of 6 8 g dl with a high reticulocyte count as the bone marrow compensates for the destruction of sickled cells by producing more red blood cells In other forms of sickle cell disease Hb levels tend to be higher A blood film may show features of hyposplenism target cells and Howell Jolly bodies 66 Sickling of the red blood cells on a blood film can be induced by the addition of sodium metabisulfite The presence of sickle haemoglobin can also be demonstrated with the sickle solubility test also called sickledex 67 A mixture of haemoglobin S HbS in a reducing solution such as sodium dithionite gives a turbid appearance whereas normal Hb gives a clear solution 68 Abnormal haemoglobin forms can be detected on haemoglobin electrophoresis a form of gel electrophoresis on which the various types of haemoglobin move at varying speeds Sickle cell haemoglobin HgbS and haemoglobin C with sickling HgbSC the two most common forms can be identified from there The diagnosis can be confirmed with high performance liquid chromatography Genetic testing is rarely performed as other investigations are highly specific for HbS and HbC 69 An acute sickle cell crisis is often precipitated by infection Therefore a urinalysis to detect an occult urinary tract infection and chest X ray to look for occult pneumonia should be routinely performed 70 People who are known carriers of the disease or at risk of having a child with sickle cell anemia may undergo genetic 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 71 72 During pregnancy genetic testing can be done on either a blood sample from the fetus or a sample of amniotic fluid During the first trimester of pregnancy chorionic villus sampling CVS is also a technique used for SCD prenatal diagnosis 73 Since taking a blood sample from a fetus has greater risks the latter test is usually used Neonatal screening sometimes referred to as newborn screening provides not only a method of early detection for individuals with sickle cell disease but also allows for the identification of the groups of people who carry the sickle cell trait 74 Genetic counselors can help individuals of colour and their families tackle the racial and ethnic disparities that exist in healthcare 75 In 2010 there was significant consideration and debate in the US surrounding comprehensive screening of athletes for SCD 76 77 78 79 The American Society of Hematology concluded in a statement in 2012 that they do not support testing or disclosure of sickle cell trait status as a prerequisite for participation in athletic activities due to lack of scientific evidence inconsistency with good medical practice and inconsistency with public health ethics They recommended universal interventions to reduce exertion related injuries and deaths effective for all athletes irrespective of their sickle cell status 80 Management EditFurther information Pain management in children Treatment involves a number of measures While it has been historically recommended that people with sickle cell disease avoid exercise regular exercise may benefit people 81 Dehydration should be avoided 82 A diet high in calcium is recommended 83 but the effectiveness of vitamin D supplementation remains uncertain 84 L glutamine use was supported by the FDA starting at the age of five as it decreases complications 85 Folic acid and penicillin Edit From birth to five years of age penicillin daily due to the immature immune system that makes them more prone to early childhood illnesses is recommended 86 Dietary supplementation of folic acid had been previously recommended by the WHO 5 A 2016 Cochrane review of its use found the effect of supplementation on anaemia and any symptoms of anaemia remains unclear due to a lack of medical evidence 87 Malaria prevention Edit Possible advantage of being heterozygous for sickle cell anemia disease A vs normal blood cell response B when infected with malaria The protective effect of sickle cell trait does not apply to people with sickle cell disease in fact they are more vulnerable to malaria since the most common cause of painful crises in malarial countries is infection with malaria People with sickle cell disease living in malarial countries should receive lifelong medication for prevention 88 Vaso occlusive crisis Edit Most people with sickle cell disease have intensely painful episodes called vaso occlusive crises However the frequency severity and duration of these crises vary tremendously Painful crises are treated symptomatically with pain medications pain management requires opioid drug administration at regular intervals until the crisis has settled For milder crises a subgroup of patients manages on NSAIDs such as diclofenac or naproxen For more severe crises most patients require inpatient management for intravenous opioids 89 Extra fluids administered either orally or intravenously are a routine part of treatment of vaso occlusive crises but the evidence about the most effective route amount and type of fluid replacement remains uncertain 90 Crizanlizumab a monoclonal antibody target towards p selectin was approved in 2019 in the United States to reduce the frequency of vaso occlusive crisis in those 16 years and older 91 Stroke prevention Edit 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 92 In 2002 the National Institute of Health NIH issued a statement recommending that children with sickle cell get the Transcranial Doppler ultrasound screen annually and in 2014 a panel of experts convened by the NIH issued guidelines reiterating the same recommendation One review of medical records by hematologist Dr Julie Kanter at the University of Alabama at Birmingham showed that on average only 48 4 percent of children with sickle cell get the recommended ultrasound test 93 A 1994 NIH study showed that children at risk for strokes who received blood transfusions had an annual stroke rate of less than 1 percent whereas those children who did not receive blood transfusions had a 10 percent stroke rate per year Also see 1998 study in the New England Journal of Medicine 92 In addition to ultrasounds and blood transfusions the inexpensive generic drug hydroxyurea can reduce the risk of irreversible organ and brain damage Guidelines from NIH published in 2014 state that all children and adolescents should take hydroxyurea as should adults with serious complications or three or more pain crises in a year 94 Acute chest syndrome Edit Management is similar to vaso occlusive crisis with the addition of antibiotics usually a quinolone or macrolide since cell wall deficient atypical bacteria are thought to contribute to the syndrome 95 oxygen supplementation for hypoxia and close observation In the absence of high quality evidence regarding the effectiveness of antibiotics for acute chest syndrome in people with sickle cell disease there is no standard antibiotic treatment as of 2019 96 It is recommended that people with suspected acute chest syndrome should be admitted to the hospital with worsening A a gradient an indication for ICU admission 20 Should the pulmonary infiltrate worsen or the oxygen requirements increase simple blood transfusion or exchange transfusion is indicated The latter involves the exchange of a significant portion of the person s red cell mass for normal red cells which decreases the level of haemoglobin S in the patient s blood However there is currently uncertain evidence about the possible benefits or harms of blood transfusion for acute chest syndrome in people with sickle cell disease 97 Hydroxyurea Edit Hydroxyurea also known as hydroxycarbamide probably reduces the frequency of painful episodes and the risk of life threatening illness or death but there is currently insufficient evidence regarding the risk of adverse effects 98 Hydroxyurea and phlebotomy combined may be more effective than transfusion and chelation combined in terms of pain life threatening illness and risk of death 98 It was the first approved drug for the treatment of sickle cell anaemia and was shown to decrease the number and severity of attacks in 1995 99 and shown to possibly increase survival time in a study in 2003 100 This is achieved in part by reactivating fetal haemoglobin production in place of the haemoglobin S that causes sickle cell anaemia Hydroxyurea had previously been used as a chemotherapy agent and some concern exists that long term use may be harmful but this risk is either absent or very small and the benefits likely outweigh the risks 16 101 Voxelotor was approved in the United States in 2019 to increase hemoglobin in people with SS disease 102 Blood transfusion Edit Blood transfusions are often used in the management of sickle cell disease in acute cases and to prevent complications by decreasing the number of red blood cells RBCs that can sickle by adding normal red blood cells 103 In children preventive RBC transfusion 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 104 105 Bone marrow transplant Edit Bone marrow transplants have proven effective in children they are the only known cure for SCD 106 However bone marrow transplants are difficult to obtain because of the specific HLA typing necessary Ideally a close relative allogeneic would donate the bone marrow necessary for transplantation Some gene therapies are under development that would alter the patient s own bone marrow stem cells ex vivo which can then be transplanted back into the patient after chemotherapy eliminates the original unmodified cells 107 Avascular necrosis Edit When treating avascular necrosis of the bone in people with sickle cell disease the aim of treatment is to reduce or stop the pain and maintain joint mobility 40 Current treatment options include resting the joint physical therapy pain relief medicine joint replacement surgery or bone grafting 40 High quality randomized controlled trials are needed to assess the most effective treatment option and determine if a combination of physical therapy and surgery is more effective than physical therapy alone 40 Psychological therapies Edit Psychological therapies such as patient education cognitive therapy behavioural therapy and psychodynamic psychotherapy that aim to complement current medical treatments require further research to determine their effectiveness 21 Prognosis EditAbout 90 of people survive to age 20 and close to 50 survive beyond age 50 108 In 2001 according to one study performed in Jamaica the estimated mean survival for people was 53 years for men and 58 years for women with homozygous SCD 109 The specific life expectancy in much of the developing world is unknown 110 In 1975 about 7 3 of people with SCD died before their 23rd birthday while in 1989 2 6 of people with SCD died by the age of 20 111 348 Epidemiology EditThe highest frequency of sickle cell disease is found in tropical regions particularly sub Saharan Africa tribal regions of India and the Middle East 112 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 as haemophilia and cystic fibrosis 113 In 2015 it resulted in about 114 800 deaths 8 Sickle cell disease occurs more commonly among people whose ancestors lived in tropical and subtropical sub Saharan regions where malaria is or was common Where malaria is common carrying a single sickle cell allele trait confers a heterozygote advantage humans with one of the two alleles of sickle cell disease show less severe symptoms when infected with malaria 114 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 115 Africa Edit Three quarters of sickle cell cases occur in Africa A recent WHO report estimated that around 2 of newborns in Nigeria 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 lt 1 in South Africa 116 Studies in Africa show a significant decrease in infant mortality rate ages 2 16 months because of the sickle cell trait This happened in areas of predominant malarial cases 117 Uganda has the fifth highest sickle cell disease burden in Africa 118 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 7 119 Country Population 2020 Subregion of Prevalence Prevalence IncidenceAngola 32 866 272 Middle Africa 0 09375 3 081 213 14 869Cameroon 26 545 863 Middle Africa 0 117 3 105 866 11 826DR Congo 89 561 403 Middle Africa 0 1163333333 10 418 977 65 536Ghana 31 072 940 Western Africa 0 09375 2 913 088 9 588Guinea 13 132 795 Western Africa 0 139375 1 830 383 8 907Niger 24 206 644 Western Africa 0 07025 1 700 517 8 756Nigeria 206 139 589 Western Africa 0 1286666667 26 523 294 150 000Tanzania 59 734 218 Eastern Africa 0 0545 3 255 515 19 585Uganda 45 741 007 Eastern Africa 0 07025 3 213 306 17 936Zambia 18 383 955 Eastern Africa 0 082 1 507 484 9 958Algeria 43 851 044 Northern Africa 0 029 1 271 680 6 624Benin 12 123 200 Western Africa 0 1286666667 1 559 852 8 125Botswana 2 351 627 Southern Africa 0 029 68 197 355Burkina Faso 20 903 273 Western Africa 0 07025 1 468 455 7 649Burundi 11 890 784 Eastern Africa 0 023 273 488 1 425Cabo Verde 555 987 Western Africa 0 023 12 788 67Central African Republic 4 829 767 Middle Africa 0 082 396 041 2 063Chad 16 425 864 Middle Africa 0 0585 960 913 5 005Comoros 869 601 Eastern Africa 0 023 20 001 104Congo 5 518 087 Middle Africa 0 1615 891 171 4 642Cote d Ivoire 26 378 274 Western Africa 0 07025 1 853 074 9 652Djibouti 988 000 Eastern Africa 0 023 22 724 118Egypt 102 334 404 Northern Africa 0 029 2 967 698 15 458Equatorial Guinea 1 402 985 Middle Africa 0 181 253 940 1 323Eritrea 3 546 421 Eastern Africa 0 023 81 568 425Eswatini 1 160 164 Southern Africa 0 023 26 684 139Ethiopia 114 963 588 Eastern Africa 0 029 3 333 944 17 366Gabon 2 225 734 Middle Africa 0 181 402 858 2 098Gambia 2 416 668 Western Africa 0 082 198 167 1 032Guinea Bissau 1 968 001 Western Africa 0 035 68 880 359Kenya 53 771 296 Eastern Africa 0 04675 2 513 808 13 094Lesotho 2 142 249 Southern Africa 0 023 49 272 257Liberia 5 057 681 Western Africa 0 07025 355 302 1 851Libya 6 871 292 Northern Africa 0 029 199 267 1 038Madagascar 27 691 018 Eastern Africa 0 04675 1 294 555 6 743Malawi 19 129 952 Eastern Africa 0 035 669 548 3 488Mali 20 250 833 Western Africa 0 082 1 660 568 8 650Mauritania 4 649 658 Western Africa 0 04675 217 372 1 132Mauritius 1 271 768 Eastern Africa 0 023 29 251 152Morocco 36 910 560 Northern Africa 0 029 1 070 406 5 576Mozambique 31 255 435 Eastern Africa 0 035 1 093 940 5 698Namibia 2 540 905 Southern Africa 0 03883333333 98 672 514Rwanda 12 952 218 Eastern Africa 0 035 453 328 2 361Sao Tome and Principe 219 159 Middle Africa 0 181 39 668 207Senegal 16 743 927 Western Africa 0 07025 1 176 261 6 127Seychelles 98 347 Eastern Africa 0 023 2 262 12Sierra Leone 7 976 983 Western Africa 0 1615 1 288 283 6 711Somalia 15 893 222 Eastern Africa 0 029 460 903 2 401South Africa 59 308 690 Southern Africa 0 029 1 719 952 8 959South Sudan 11 193 725 Eastern Africa 0 04675 523 307 2 726Sudan 43 849 260 Northern Africa 0 03883333333 1 702 813 8 870Togo 8 278 724 Western Africa 0 09375 776 130 4 043Tunisia 11 818 619 Northern Africa 0 023 271 828 1 416Zimbabwe 14 862 924 Eastern Africa 0 035 520 202 2 710Total 1 338 826 604 Africa 91 868 664 495 726United States Edit The number of people with the disease in the United States is about 100 000 one in 3 300 mostly affecting Americans of sub Saharan African descent 120 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 121 The life expectancy for men with SCD is approximately 42 years of age while women live approximately six years longer 122 An additional 2 million are carriers of the sickle cell trait 123 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 124 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 125 Sickle cell anemia is the most common genetic disorder among African Americans Approximately 8 are carriers and 1 in 375 are born with the disease 126 Patient advocates for sickle cell disease have complained that it gets less government and private research funding than similar rare diseases such as cystic fibrosis with researcher Elliott Vichinsky saying this shows racial discrimination or the role of wealth in health care advocacy 127 France Edit Percentage of newborns screened for sickle cell disease within Metropolitan France from 2006 to 2018 As a result of population growth in African Caribbean regions of overseas France and immigration from North and sub Saharan Africa to mainland France sickle cell disease has become a major health problem in France 128 SCD has become the most common genetic disease in the country with an overall birth prevalence of one in 2 415 in metropolitan France ahead of phenylketonuria one in 10 862 congenital hypothyroidism one in 3 132 congenital adrenal hyperplasia one in 19 008 and cystic fibrosis one in 5 014 for the same reference period citation needed Percentage of newborns screened regionally and overall for sickle cell disease in Metropolitan 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 and Turkey the Arabic peninsula the French overseas islands and the Indian subcontinent 129 United Kingdom Edit In the United Kingdom between 12 000 and 15 000 people are thought to have sickle cell disease 130 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 131 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 132 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 133 Donors who are found to be carriers are then 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 134 West Asia Edit In Saudi 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 135 In 2005 Saudi Arabia introduced a mandatory premarital test including HB electrophoresis which aimed to decrease the incidence of SCD and thalassemia 136 In Bahrain 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 137 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 free premarital counseling These programs were accompanied by public education campaigns 138 India and Nepal Edit Sickle cell disease is common in some ethnic groups of central India 139 where the prevalence has ranged from 9 4 to 22 2 in endemic areas of Madhya Pradesh Rajasthan and Chhattisgarh 140 It is also endemic among Tharu people of Nepal and India however they have a sevenfold lower rate of malaria despite living in a malaria infested zone 141 Caribbean Islands Edit In Jamaica 10 of the population carry the sickle cell gene making it the most prevalent genetic disorder in the country 142 History EditThe 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 143 144 Reportedly African slaves in the United States exhibited resistance to malaria but were prone to leg ulcers 144 The abnormal characteristics of the red blood cells which later lent their name to the condition was first described by Ernest E Irons 1877 1959 intern to Chicago cardiologist and professor of medicine James 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 from Grenada Noel had been admitted to the Chicago Presbyterian Hospital in December 1904 with anaemia 13 145 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 practice dentistry He died of pneumonia in 1916 and is buried in the Catholic cemetery at Sauteurs in the north of Grenada 13 14 Shortly after the report by Herrick another case appeared in the Virginia Medical Semi Monthly with the same title Peculiar Elongated and Sickle Shaped Red Blood Corpuscles in a Case of Severe Anemia 146 This article is based on a patient admitted to the University of Virginia Hospital on 15 November 1910 147 In the later description by Verne Mason in 1922 the name sickle cell anemia is first used 14 148 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 144 Memphis physician Lemuel 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 by James V Neel and E A Beet 14 1949 was the year when Linus Pauling described the unusual chemical behaviour of haemoglobin S and attributed this to an abnormality in the molecule itself 14 149 The molecular change in HbS was described in 1956 by Vernon Ingram 150 The late 1940s and early 1950s saw further understanding in the link between malaria and sickle cell disease In 1954 the introduction of haemoglobin electrophoresis allowed the discovery of particular subtypes such as HbSC disease 14 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 151 The 1990s had the development of hydroxycarbamide and reports of cure through bone marrow transplantation appeared in 2007 14 Some old texts refer to it as drepanocytosis 152 Society and culture EditUnited States Edit 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 how Social Security evaluates the disease during its adjudication process for disability claims 153 154 In the U S there are stigmas 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 155 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 156 In the 1960s the US government supported initiatives for workplace screening 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 157 Uganda Edit Uganda has the 5th highest sickle cell disease SCD burden in the world 158 In Uganda 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 158 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 from health 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 159 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 158 Rate of sickle cell disease in Uganda Edit 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 160 Data shows that the trait frequency of sickle cell disease is 20 of the population in Uganda 160 This means that 66 million people are at risk of having a child who has sickle cell disease 160 It is also estimated that about 25 000 Ugandans are born each year with SCD and 80 of those people don t live past five years old 160 SCD also contributes 25 to the child mortality rate in Uganda 160 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 160 The Sickle Cell Clinic in Mulago is only one sickle cell disease clinic in the country and on average sees 200 patients a day 160 Misconceptions about sickle cell disease Edit 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 from God or witchcraft 161 Other misconceptions about SCD include the belief that it is caused by environmental factors but in reality SCD is a genetic disease 162 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 163 In addition to this organization s efforts there is a need for the inclusion of sickle cell disease education in preexisting community health education programs in order to reduce the stigmatization of sickle cell disease in Uganda 159 Social isolation of people with sickle cell disease Edit 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 164 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 164 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 158 SCD related stigma and social isolation in schools especially can make a life for young people living with sickle cell disease extremely difficult 158 For school aged children living with SCD the stigma they face can lead to peer rejection 158 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 158 This social isolation is also likely to negatively impact people with SCD s self esteem and overall quality of life 158 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 s diagnosis 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 162 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 162 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 162 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 162 Women living with SCD who become pregnant often face extreme discrimination and discouragement in Uganda These women are frequently branded by their peers as irresponsible for having a baby while living with sickle cell disease or even engaging in sex while living with SCD citation needed The criticism and judgement these women receive not only from healthcare professionals but also from their families often leaves them feeling alone depressed anxious ashamed and with very little social support citation needed Most pregnant women with SCD also go on to be single mothers as it is common for them to be left by their male partners who claim they were unaware of their partner s SCD status citation needed Not only does the abandonment experienced by these women cause emotional distress for them but this low level of parental support can be linked to depressive symptoms and overall lower quality of life for the child once they are born 165 United Kingdom Edit In 2021 many patients were found to be afraid to visit hospitals so purchasing pain relief to treat themselves outside the NHS such was the level of ignorance among staff 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 prefer to work in bigger teaching hospitals leading to shortages of expertise elsewhere 166 In 2021 the NHS initiated its first new treatment in 20 years for Sickle Cell This involved the use of Crizanlizumab a drug given via transfusion drips which reduces the number of visits to A and E by sufferers The treatment can be accessed via consultants at any of ten new hubs set up around the country 167 In the same year however an All Party Parliamentary Group produced a report on Sickle Cell and Thalassaemia entitled No one is listening 168 Partly in response to this on 19 June 2022 World Sickle Cell Day the NHS 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 are 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 169 Research EditUmbilical cord blood transplant Edit While umbilical cord blood transplant can potentially cure the condition a suitable donor is available in only 10 of people 170 About 7 of people also die as a result of the procedure and graft versus host disease may occur 170 Gene therapy Edit Diseases such as sickle cell disease for which a person s normal phenotype or cell function may be restored in cells that have the disease by a normal copy of the gene that is mutated may be a good candidate for gene therapy treatment The risks and benefits related to gene therapy for sickle cell disease are not known 171 In 2001 sickle cell disease reportedly had been successfully treated in mice using gene therapy 172 173 The researchers used a viral vector to make the mice which have essentially the same defect that causes human sickle cell disease express production of fetal haemoglobin HbF which an individual normally ceases to produce shortly after birth In humans using hydroxyurea to stimulate the production of HbF has been known to temporarily alleviate sickle cell disease symptoms The researchers demonstrated that this gene therapy method is a more permanent way to increase therapeutic HbF production 174 Phase 1 clinical trials of gene therapy for sickle cell disease in humans were started in 2014 The clinical trials will assess the safety of lentiviral vector modified bone marrow for adults with severe sickle cell disease 175 176 As of 2020 however no randomized controlled trials have been reported 171 A case report for the first person treated was published in March 2017 with a few more people being treated since then 177 178 Gene editing platforms like CRISPR Cas9 have been used to correct the disease causing mutation in hematopoietic stem cells taken from a person with the condition 179 In July 2019 the gene editing tool CRISPR was used to edit bone marrow cells from a person with SCD to boost fetal haemoglobin by inhibiting the BCL11A gene 180 181 A number of researchers have considered the ethical implications of SCD being one of the first potential applications of CRISPR technology given the historical abuses and neglect of the African American community by the medical field 182 In 2017 twelve clinical trials were focusing on gene therapy to treat sickle cell anemia Of those 12 trials four of them replaced the mutated HBB gene with a healthy one Three trials used Mozobil a medication used to treat types of cancer to determine whether the increase of stem cells can be used for gene therapy One trial focused on analyzing bone marrow samples from patients with sickle cell anemia Another trial experimented with using umbilical cord blood from babies both with and without sickle cell anemia to develop gene therapy 183 Hematopoietic stem cell transplantation Edit There is no strong medical evidence to determine the risks and potential benefits related to treating people with sickle cell disease with hematopoietic stem cell transplantations 184 Notes Edit Historic numbering put this glutamic acid residue at position 6 due to skipping the methionine M Met start codon in protein 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NPR org Retrieved 31 July 2019 Zipkin Mark 6 December 2019 CRISPR s magnificent moment in the clinic Nature Biotechnology doi 10 1038 d41587 019 00035 2 Persaud A Desine S Blizinsky K Bonham VL August 2019 A CRISPR focus on attitudes and beliefs toward somatic genome editing from stakeholders within the sickle cell disease community Genetics in Medicine 21 8 1726 1734 doi 10 1038 s41436 018 0409 6 PMC 6606394 PMID 30581191 Walker M 15 January 2018 Gene Therapy Sickle Cell Disease News Retrieved 14 March 2020 Oringanje C Nemecek E Oniyangi O July 2020 Hematopoietic stem cell transplantation for people with sickle cell disease The Cochrane Database of Systematic Reviews 2020 7 CD007001 doi 10 1002 14651858 CD007001 pub5 PMC 7390490 PMID 32617981 Further reading EditBrown RT ed 2006 Comprehensive handbook of childhood cancer and sickle cell disease a biopsychosocial approach Oxford University Press ISBN 978 0 19 516985 0 Hill SA 2003 Managing Sickle Cell Disease in Low Income Families Temple University Press ISBN 978 1 59213 195 2 Serjeant GR Serjeant BE 2001 Sickle Cell Disease Oxford University Press ISBN 978 0 19 263036 0 Tapper M 1999 In the blood sickle cell anemia and the politics of race University of Pennsylvania Press ISBN 978 0 8122 3471 8 External links Edit Wikimedia Commons has media related to Sickle cell disease Sickle cell at Curlie Retrieved from https en wikipedia org w index php title Sickle cell disease amp oldid 1151212058, wikipedia, wiki, book, books, library,

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