Sickle-cell disease medical therapy

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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

Treatment of sickle cell disease is largely supportive and focuses on measures that prevent red blood cell sickling and improve oxygen delivery to tissues and organs. Such general measures include oxygen therapy, hydration with IV fluids, and exchange transfusions. Pain control is also an important component of therapy; patients with vaso-occlusive crises should receive analgesics when appropriate. Hydroxyurea can be used to increase fetal hemoglobin production. Bone marrow transplantation has been effective in some patients but is not a standard of care since the outcomes of transplant have not been consistent.

Medical Therapy

Febrile illness

Children with fever are screened for bacteremia i.e. complete blood count and blood culture should be obtained. Younger children (varies from center to center) are sometimes admitted for intravenous antibiotics while older children with reassuring white cell counts are sometimes managed at home with oral antibiotics. Children with previous bacteremic episodes should be admitted. Antibiotic should be targeted to the specific organism, if known.

Zn administration

Zinc is given as it stabilizes cell membrane by serving an anti-oxidant function. One theory about sickle cell pathogenesis involved oxidative stress, and deficiencies in antioxidant enzymes and cofactors are thought to contribute to the disease. Zinc serves as a cofactor for antioxidant enzymes, like superoxide dismutase and catalase. Other cofactors include like copper and iron have also been studied as treatment options.

Painful (vaso-occlusive) crises

Most people with sickle cell disease have intensely painful episodes called vaso-occlusive crises. The frequency, severity, and duration of these crises, however, vary tremendously. Painful crises are treated symptomatically with 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.

Prevention

Hydroxyurea reduced the mean number of painful crises per year from 8 to 5 (crises requiring hospitalization: 4 versus 2.5) according to a systematic review by the Cochrane Collaboration.

Crizanlizumab reduced crises from 3 to 1.6 according to a randomized controlled trial.

Acute chest crises

Management is similar to vaso-occlusive crises with the addition of antibiotics (usually a quinolone or macrolide, since wall-deficient ["atypical"] bacteria are thought to contribute to the syndrome), oxygen supplementation for hypoxia, and close observation. 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 patients red cell mass for normal red cells, which decreases the percent hemoglobin S in the patient's blood.

2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines

Recommendations for Evaluation of Acute Chest Pain in Patients With Sickle Cell Disease

Class I

1.In patients with sickle cell disease who report acute chest pain, emergency transfer by EMS to an acute care setting is recommended. (Level of Evidence: B-NR)

2.In patients with sickle cell disease who report acute chest pain, ACS should be excluded.(Level of Evidence: C-LD)

Hydroxyurea

The first approved drug for the causative treatment of sickle cell anemia, hydroxyurea, was shown to decrease the number and severity of attacks in a study in 1995 (Charache et al) and shown to possibly increase survival time in a study in 2003 (Steinberg et al) . This is achieved, in part, by reactivating fetal hemoglobin production in place of the hemoglobin S that causes sickle cell anemia. Fetal hemoglobin consists of two alpha chains and two gamma chains, which has higher affinity for oxygen compared to adult hemoglobin (HbA) which has two alpha chains and two beta chains. Hydroxyurea reduces end-organ dysfunction, including liver dysfunction, in patients with sickle cell disease. Hydroxyurea's clinical benefits can actually precede the induction of fetal hemoglobin, however. Hydroxyurea had previously been used as a chemotherapy agent, and there is some concern that long-term use may be harmful, but it is likely that the benefits outweigh the risks. The adverse effects of hydroxyurea must be monitored in patients undergoing treatment. These adverse effects include cytopenias (low hemoglobin, platelets, white blood cells), skin ulcers, open sores, and flu-like symptoms. Cytopenias, in turn, can cause fatigue, bleeding and bruising, and infection. The mechanism of this is due hydroxyurea-mediated inhibition of ribonucleotide reductase, which results in impaired cells proliferation.

Recommendations for use of hydroxyurea.

Recommendations for use of Hydroxyurea in Sickle cell Disease
Adults	Children
Occurrence of ≥ 3 moderate or severe pain episodes in 12 month duration. (Grade 1A)	Occurrence of ≥ 3 moderate or severe pain episodes in 12 month duration. (Grade 1B)
History of Acute Chest Syndrome or Symptomatic anemia. (Grade 1B)	History if Acute Chest Syndrome or Symptomatic anemia. (Grade 1B)

Bone marrow transplantation

Similar to other hematological conditions characterized by a defective or nonfunctional blood cell, bone marrow transplantation (or stem cell transplantation) is a treatment option for sickle cell disease. This is typically reserved for people who do not have adequate control of disease of symptoms with conventional medical measures. The patients who benefit most from stem cell transplant include young persons with significant symptoms. Ideally, a transplant is performed prior to age 17. Family members of a patient with sickle cell disease should undergo HLA typing in case there is a need for transplant. Stem cells from allogeneic donors can serve as the source of the normal hematopoietic cells, allowing for repopulation of the peripheral blood with functional red blood cells. In 1986, the myeloablative regimen of busulfan and cyclophosphamide was used in preparation of a transplant for a patient with sickle cell disease. Other potential conditioning regimens include anti-thymocyte globulin, cyclosporine, and/or total lymphoid irradiation. In order to bypass significant toxicity of the myeloablative regimens, reduced-intensity regimens can be used. However, there is currently no commonly accepted standard or protocol for bone marrow transplant for patients with sickle cell disease.

Gene therapy

Given that sickle cell disease is a disorder for which the pathophysiology involves a defective gene product, gene therapy has been explored as a treatment option. A therapeutic beta-globin gene encoded in a lentivirus can be transferred to a hematopoietic stem cell as ex vivo therapy. If the lentivirus is expressed highly within erythroid precursors, all derivatives of those precursors will contain the functional hemoglobin product. Such therapy helps decrease HbS production and thus sickling. In theory, a similar strategy can be used for beta-thalassemia.

Experimental agents

Inducers of fetal hemoglobin have been studied in sickle cell disease. The agent HQK-1001, which is sodium dimethylbuytrate, is an oral inducer of fetal hemoglobin. It has been shown to have favorable pharmacokinetic profile in phase I/II clinical trials. Further studies are needed to determine its efficacy. Omega-3 fatty acids have been studied in sickle cell disease. These have been shown to reduce vascular activation and inflammation. Supplementation with these fatty acids has been proposed to reduce the burden of disease, but the data is not robust.

Contraindicated medications

Sickle-cell disease is considered an absolute contraindication to the use of the following medications:

• Pegylated interferon alfa-2b