Sickle-cell disease natural history, complications, and prognosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2] Shyam Patel [3]

Overview

The natural history of sickle cell disease is characterized by various vascular phenomenon that begin at variable ages, and these vascular complications include, but are not limited to, the extremities and the brain. The complications of sickle cell disease involve various tissues and organs, including the chest, bones, and GI tract. The prognosis of sickle cell disease is variable, with a median survival of age 50 years. Of note, the prognosis of patients with malaria who have sickle cell disease is better than patients without sickle cell, since there a protective advantage.

Natural History

The natural history of sickle cell disease involves manifestations that begin shortly after birth. Once gamma-globin chains (from fetal hemoglobin) are replaced by the defective beta-globin chains, patients can experience symptoms. This usually occurs at 8-10 weeks of life.[1]

By 2 months of life, infants can be affected by dactylitis (vaso-occlusive episodes in the hands and feet), or other complications. Dactylitis episodes typically resolve after 5-7 days with conservative measures. The reason is that bone marrow is present in the small extremity bones during the early weeks of life.

By 3 months of life, splenic sequestration can occur.[2] This is the age at which routine spleen size examination is important. If a person has 2 episodes of splenic sequestration, splenectomy should be considered. Symptoms include tachycardia, tachypnea, abdominal pain, and abdominal fullness, which are reflective of trapping of sickled red blood cells in splenic sinuses.[2]

By 6-12 months of life, death has been observed but can generally occur at any age after 1 year. One of the causes of death is acute chest syndrome. Other reasons for death in sickle cell anemia include sepsis and aplastic crises.[1] Splenic dysfunction can occur by the first year of life.[2]

By 24 months of life, stroke can occur from vaso-occlusive episodes in the brain.[1] Within 3 years of the first stroke, recurrent strokes are known to occur, which can pose significant morbidity.

By 5 years of age, dactylitis usually does not occur, since the bone marrow is no longer present in small bones of the extremities by age 5.

By late childhood, bone pain crises and avascular necrosis of the femoral head can occur. If sickled red blood cells become lodged in the penis, priapism can occur. Chronic leg ulceration is also a common problem in late adolescence.

By adult age, patients can develop subarachnoid hemorrhage, berry aneurysms, and direct intracerebral bleeding.

Complications

Sickle-cell anemia can lead to various complications, including:

  • Vaso-occlusive crisis (otherwise known as painful crisis): Most patients with sickle-cell disease have periodic intensely painful episodes called vaso-occlusive crises. The frequency, severity, and duration of these crises vary tremendously. Painful crises are treated with hydration and analgesics; pain management requires opioid administration at regular intervals until the crisis has settled. For milder crises a subgroup of patients manage on NSAIDs (such as diclofenac or naproxen). For more severe crises most patients require inpatient management for intravenous opioids; patient-controlled analgesia (PCA) devices are commonly used in this setting. Diphenhydramine is effective for the itching associated with the opioid use. Incentive spirometry, a technique to encourage deep breathing to minimise the development of atelectasis, is recommended.
  • Acute chest syndrome is a life-threatening condition characterised by chest pain, shortness of breath, fever, hypoxaemia and pulmonary infiltrates on chest X-ray. It can be triggered by pain crisis, respiratory infection, bone-marrow embolization, or possibly by atelectasis, such as can be caused by opiate administration, or surgery.
  • Overwhelming post-(auto)splenectomy infection is due to functional asplenia, 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 H. influenzae, S. pneumoniae and Neisseria meningitidis.
  • Stroke can result from a progressive vascular narrowing of blood vessels, preventing oxygen from reaching the brain. Cerebral infarction occurs in children with peak incidence at age 7, and cerebral hemorrhage in adults. The etiology is hyperplasia of the tunica intima and tunic media of cerebral microvasculature, which causes thrombosis.[3]
  • Cholelithiasis and cholecystitis (gallstones) may result from excessive bilirubin production and precipitation due to prolonged haemolysis.
  • Avascular necrosis (aseptic bone necrosis) of the hip may occur as a result of ischemia.
  • Decreased immune reactions due to hyposplenism (malfunctioning of the spleen)
  • Priapism and infarction of the penis.[4] There is some role of various agents to help prevent priapism. These include hydroxyurea, which increases fetal hemoglobin production, leuprolide, and sildenafil, which is a PD5 inhibitor that improves blood flow to the penis.[4]
  • Osteomyelitis (bacterial bone infection) - Salmonella is noted much more commonly than in the general population, although Staphylococcus is still the most common.
  • Opioid tolerance can occur as a normal, physiologic response to the therapeutic use of opiates. Addiction to opiates occurs no more commonly among individuals with sickle cell disease than among other individuals treated with opiates for other reasons.
  • Acute papillary necrosis in the kidneys.
  • Leg ulcers
  • Ocular manifestations such as orbital infarcts or central retinal artery occlusion can occur. In the eyes, there can be background retinopathy, proliferative retinopathy, vitreous hemorrhages and retinal detachments can occur. Regular annual eye checks are required.
  • During pregnancy, intrauterine growth retardation, spontaneous abortion and pre-eclampsia are the possibilities.
  • Pulmonary hypertension, which is defined as mean pulmonary arterial pressure > 25 mmHg on right heart catheterization.[3] Patients with sickle cell disease should be screened for pulmonary hypertension via transthoracic echocardiogram. The risk of development of pulmonary hypertension is associated with systemic hypertension in patients with sickle cell disease.[5]
  • Left-sided heart disease is caused by diastolic dysfunction induced the sickled rec blood cells.[3]
  • Neurocognitive impairment can occur in some patients and is not related to vaso-occlusion.[2] Imaging cannot detect or diagnose neurocognitive impairment. Depression is also common.[6]

Prognosis

The prognosis of patients varies. There are plenty of patients who live into adulthood and survival with supportive measures. However, in the event of severe sickling and vaso-occlusive crises in vital organs, such as the brain, the prognosis can be dismal. Importantly, sickle cell heterozygosity has a protective advantage in infection with Plasmodium falciparum, one of the causative agents of malaria.[7]

The median survival of patients with sickle cell disease in the USA is 45-55 years.[1] With improvement in treatment modalities, the median survival is likely to improve. The prognosis of sickle cell disease is better in geographic areas where there is a lower burden of infections, such as malaria or other blood-born pathogens. For example, HbSS in the USA has a better prognosis than HbSS in Africa.

References

  1. 1.0 1.1 1.2 1.3 Serjeant GR (2013). "The natural history of sickle cell disease". Cold Spring Harb Perspect Med. 3 (10): a011783. doi:10.1101/cshperspect.a011783. PMC 3784812. PMID 23813607.
  2. 2.0 2.1 2.2 2.3 Ballas SK, Kesen MR, Goldberg MF, Lutty GA, Dampier C, Osunkwo I; et al. (2012). "Beyond the definitions of the phenotypic complications of sickle cell disease: an update on management". ScientificWorldJournal. 2012: 949535. doi:10.1100/2012/949535. PMC 3415156. PMID 22924029.
  3. 3.0 3.1 3.2 Kato GJ, Hebbel RP, Steinberg MH, Gladwin MT (2009). "Vasculopathy in sickle cell disease: Biology, pathophysiology, genetics, translational medicine, and new research directions". Am J Hematol. 84 (9): 618–25. doi:10.1002/ajh.21475. PMC 3209715. PMID 19610078.
  4. 4.0 4.1 Kato GJ (2012). "Priapism in sickle-cell disease: a hematologist's perspective". J Sex Med. 9 (1): 70–8. doi:10.1111/j.1743-6109.2011.02287.x. PMC 3253142. PMID 21554552.
  5. Gordeuk VR, Sachdev V, Taylor JG, Gladwin MT, Kato G, Castro OL (2008). "Relative systemic hypertension in patients with sickle cell disease is associated with risk of pulmonary hypertension and renal insufficiency". Am J Hematol. 83 (1): 15–8. doi:10.1002/ajh.21016. PMC 3398810. PMID 17696198.
  6. Hasan SP, Hashmi S, Alhassen M, Lawson W, Castro O (2003). "Depression in sickle cell disease". J Natl Med Assoc. 95 (7): 533–7. PMC 2594635. PMID 12911250.
  7. Colah RB, Mukherjee MB, Martin S, Ghosh K (2015). "Sickle cell disease in tribal populations in India". Indian J Med Res. 141 (5): 509–15. PMC 4510747. PMID 26139766.

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