Literature Review Dr. Shaukat Hussain Senior Registrar Paediatric Department Holy Family Hospital, Rawalpindi

SICKLE CELL DISEASE

History and Background The first description of sickle cell disease was by a Chicago physician, James B. Herrick, who noted in 1910 that a patient of his from the West Indies had an anemia characterized by unusual red cells that were "sickle shaped.". In 1927, Hahn and Gillespie observed that sickling of the red cells was related to low oxygen. In 1940, Sherman (a student at Johns Hopkins Medical School) noted a birefingence of deoxygenated red cells, suggesting that low oxygen altered the structure of the hemoglobin in the molecule.

Epidemiology The highest frequency of sickle cell disease is found in tropical regions, particularly sub-Saharan Africa, India and the Middle-East. USA Sickle cell anemia is the most common inherited blood disorder in the united states. Approximately 100,000 people have SCD. SCD occurs in about 1 of every 16,300 Hispanic - American births. Africa Three quarters of sickle-cell cases occur in Africa. WHO report 2% of newborns affected by sickle cell anemia United Kingdom In United Kingdom, more than 200 babies are born annually with SCD. Middle East About 6,000 children are born annually with SCD, at least 50% of these in Saudi Arabia. India The incidence rate is 0.5% in endemic areas.

Physiology

Pathology Autosomal recessive disorder characterized by substitution of the amino acid valine in one of the B chains at place of glutamic acid due to single base pair change thymine for adenine at 6th codon of beta globin gene.

Pathophysiology Hb S deoxygenated polymerization of Hb S molecules rigid strand of hemoglobin Molecule sickling of RBCs.

TYPES Sickle cell Anemia (HbSS) Sickle cell Disease HbS/b-0 thalassemia HbS/b+ thalassemia HbSC disease Hbs/HbD HbS/HbE syndrome Sickle cell Trait (HbAS)

Clinical Features of Sickle Cell Anemia Painful episodes Fever and bacteremia Pneumococcal disease Dactylitis Splenic sequestration Acute Chest syndrome Priapism Stroke Splenic infarction Gallstones Leg ulcers Osteonecrosis Renal abnormalities Osteopenia Nutritional deficiencies Pulmonary hypertension Retinopathy

Fever and Bacteremia Fever in a child with Sickle cell anemia is a medical emergency requiring immediate medical evaluation and delivery of antibiotics because of high risk of fatality with infection Encapsulated organisms like streptococcus pneumoniae and haemophilus influenzae are more common. Salmonella and staphylococcus aureus infections.

Symptoms Sickled RBCs Anemia Vascular Occlusions

Chronic hemolytic anemia Symptoms Sickle cell anemia Chronic hemolytic anemia Sickle cell crises

Chronic hemolytic anemia Jaundice. Gall stones. Hepato-splenomegaly (due to extramedullary hematopoiesis).

Splenic sequestration Sickle cell crises Vaso-Occulusive crises Splenic sequestration crisis Aplastic crisis Hemolytic crisis

Vaso-occulusive crisis Cold weather Hypoxia Infection Dehydration Acidosis Alcohol intoxication Emotional Stress

Vaso-Occulusive Crises Stroke Acute Chest syndrome Acute Abdominal pain Priapism Dactylitis Brain infarcts Infection, fat, embolism, pulmonary thombsis Splenic infarct Veno-occulusion resulting in blood trapping in erectile tissues Bone infarcts

Stroke Overt stroke 11% Silent stroke 20%

Acute chest syndrome It is a clinical syndrome characterized by Fever Chest pain. Cough Dyspnea. New radiodensity leison on chest radiograph

Acute pain Crisis Cardinal clinical feature of sickle cell anemia is pain Abdominal pain Due to splenic infarct. Pain can occurs in any part of the body but most often in chest abdomen and extremities.

Priapism Types Refractory Stuttering Painful sustained unwanted erection lasting for longer than 30 minutes. Due to veno-occlusion resulting in blood trapping in erectile Priapism tissue. Types Refractory Stuttering

Dactylitis Painful swollen fingers or toes due to bone infarction. It take place in 50% of patient with sickle cell anemia by their 2nd year. Dactylitis (Hand foot syndrome|) is often the first manifestation of pain in children with sickle cell anemia.

Dactylitis

Splenic sequestration crisis 30% of children. Life threatening complication. Can occur as early as 5th week of age. Due to sudden pooling of large amounts of blood into the spleen.

Splenic sequestration crisis Engorgement of spleen Painful spleen Enlarging spleen Hypovolemia Decreased in Hb>2gm/dl from baseline Reticulocytosis Thrombocytopenia may also be present.

Aplastic crisis Acute reticulocytopenia triggered by papovirus B19 infection.

Hemolytic crisis Acute accelerated drop in hemoglobin level. Occur in patients with co-existent G6PD deficiency.

Other Clinical Manifestations Pulmonary complications Sickle cell nephropathy Avascular necrosis Delayed onset of puberty Leg ulcers Sickle cell retinopathy Cognitive and psychological

Skin ulcer Pneumonia Avascular necrosis

Investigations Diagnostic: Complete Blood count with peripheral film and reticulocytes ESR Hb Electrophoresis Polymerase Chain Reaction (PCR)

Investigations Complications Chest X-ray X-Ray skull X-Ray Long bones X-Ray Hands and feet

Investigations Electrolytes, RFTs, Urine R/E Serum Ferritin levels Echocardiography MRI, Liver biopsy Ultrasound abdomen Ultrasound KUB Transcranial Doppler MRI Brain

Management Supportive Family Education Counseling Oxygen supply Hydration Pain relieving medications Acetaminophen NSAIDS Opioids (Oral, I/V)

Management Antibiotics (Oral or I/V) Folic Acid Blood transfusions RCC transfusion Exchange transfusion Erythrocytapheresis

Management Preventive Hydroxyurea became the first (and only) drug proven to prevent complications of sickle cell disease in the Multicenter Study of Hydroxyurea in Sickle Cell Anemia which was completed in 1995. A myelosuppressive agent. Decrease the rate of painful episodes, Acute chest syndrome and blood transfusion rates by 50%. Dose 15 to 20mg/kg daily Side effects Bone marrow suppression.

Management Curative Bone marrow transplant In 1984, bone marrow transplantion in a child with sickle cell disease produced the first reported cure of the disease.

Management Prophylaxis Oral Antibiotics Vaccine prophylaxis

Management Surgical Gallstones Splenectomy Hand foot ulcers Priapism

Family Screening All family members should be screened immediately to avoid untoward complications of the disease.

Prognosis Several factors predict the long term survival Type of Disorder Severity of the disease Frequency of complications Compliance with preventive regimens The life expectancy has increased over the past 30 years, many individual can now live in to their mid 40s and beyond.

Recent Advances Drugs targeting cell Adhesion Drugs targeting inflammatory pathways Anti coagulant and anti platelets agents Gene therapy