Approach

A holistic approach to treatment is recommended, with emphasis on patient education and guidance on home management, as well as on immediate clinical needs.[36]

Bone marrow transplantation is the only curative treatment, but it is infrequently used owing to lack of suitable bone marrow donors, cost, and risks (10% mortality in children).

Treatment goals

In young children, the main treatment goal is to improve survival by reducing the threat from infections. This can be achieved through:[35][37] [ Cochrane Clinical Answers logo ]

  • Early diagnosis

  • Pneumococcal immunisation

  • Antibiotic prophylaxis with penicillin in children under 5 years of age

  • Nutritional counselling

  • Prompt treatment when infections do occur.

In patients who survive early childhood and have chronic disease, the main treatment goals are symptom control and management of disease complications. This can be achieved through:[35][38][39][40][41][42]

  • Pain management (chronic and acute)

  • Pharmacological amelioration of disease severity

  • Consideration for bone marrow transplantation

  • Blood transfusion

  • Prophylaxis and prompt treatment of infections

  • Prevention and management of acute complications (e.g., acute chest syndrome, vaso-occlusive episodes)

  • Prevention of stroke

  • Prevention and treatment of chronic organ damage (kidney, renal, pulmonary)

  • Genetic counselling

  • Health and nutritional education of patient and/or parents

  • Counselling of patient and/or parents to avoid triggers (e.g., dehydration, cold and high altitudes, and strenuous exercise).

Prophylactic treatment

Hydroxycarbamide

  • Hydroxycarbamide can be considered in patients aged ≥2 years with sickle cell anaemia. In the short term, hydroxycarbamide has been shown to decrease the frequency of pain episodes, reduce transfusion requirements, and decrease the risk of acute chest syndrome.[43][44][45][46][47][48][49][50][51] It has also been shown to prevent life-threatening neurological events in patients at risk of stroke, and reduce the frequency of dactylitis in infants.[49][51]

  • The most common complication of hydroxycarbamide is neutropenia.[48][52][53] In one study, treatment with hydroxycarbamide for 12 months had no adverse effect on height, weight gain, or pubertal development in infants and older children.[48]

  • The long-term safety and efficacy of hydroxycarbamide is unclear due to the lack of good-quality evidence.[51]​ Long-term observational follow-up studies of adult patients have reported reduced mortality after long-term exposure to hydroxycarbamide, and no increased incidence of malignancy.[54][55][56]

  • High-quality evidence to support the use of hydroxycarbamide in variant haemoglobin SC (HbSC) sickle cell disease is lacking.

L-glutamine

  • L-glutamine can be considered in patients aged ≥5 years who are intolerant to hydroxycarbamide or who continue to have painful events while on hydroxycarbamide.[57] Its mechanism of action in sickle cell anaemia is unclear, but it is thought to decrease susceptibility of sickle erythrocytes to oxidative damage by raising the redox potential within these cells.

  • In one randomised placebo-controlled trial involving 230 patients aged between 5-58 years with HbSS or HbSB0 thalassaemia genotypes, and a history of two or more crises during the previous year, treatment with L-glutamine resulted in fewer sickle cell crises and fewer hospitalisations.[58]

  • L-glutamine should be avoided in patients with renal or hepatic impairment due to concerns about increased mortality when used in critically ill patients with multi-organ failure.[59]

  • There are no data available regarding the use of L-glutamine:

    • in patients with variant sickle cell disease

    • with crizanlizumab.

  • L-glutamine is licensed for the reduction of acute complications of sickle cell disease in the US, but availability may vary elsewhere. The European Medicines Agency (EMA) refused a marketing authorisation because the application failed to demonstrate that the drug was effective at reducing the number of sickle cell disease crises or hospital visits.

Crizanlizumab

  • Crizanlizumab is a monoclonal antibody that targets the P-selectin adhesion molecule on endothelial cells and platelets. It is approved by the Food and Drug Administration (FDA) for the reduction of frequency of vaso-occlusive crises in patients aged ≥16 years, but availability may vary elsewhere. The EMA has revoked its marketing authorisation based on preliminary results of a phase 3 trial (the STAND study) showing a lack of benefit compared with placebo in annualised rates of vaso-occlusive crises leading to a healthcare visit in the first year of treatment. Further assessment of the phase 3 trial data is ongoing.[60]

  • In one randomised phase 2 trial of patients with sickle cell disease (any genotype, with a history of at least two sickle cell-related pain crises in the preceding 12 months, some of whom were taking concomitant hydroxycarbamide), crizanlizumab significantly lowered the rate of sickle cell-related pain crises, and increased median time to first and second crises, compared with placebo.[61]​ Sub-group analysis found a significant decrease in the number of vaso-occlusive crises in both HbSS and non-HbSS disease (approximately 30% of patients were non-HbSS genotype).[61]​ A post-hoc analysis reported similar results across different groups, including those with a high number of previous vaso-occlusive crises, receiving concomitant hydroxycarbamide, and/or with the HbSS genotype.[62]

  • Common adverse effects of crizanlizumab therapy include arthralgia, diarrhoea, pruritus, vomiting, and chest pain.[61]​​

  • Crizanlizumab is typically used in addition to hydroxycarbamide in patients with HbSS or HbSB0 thalassaemia sickle cell disease. It may be used as monotherapy in patients who cannot tolerate hydroxycarbamide, or who have variant sickle cell disease (HbSC or HbSB+ thalassaemia).

  • There are no data regarding the use of crizanlizumab concomitantly with L-glutamine.

  • Several ongoing clinical trials are trying to establish the role of crizanlizumab in paediatric patients with sickle cell disease.[63]

Blood transfusion

  • A common prophylactic treatment, repeated simple transfusion is used to maintain HbS below 30%.[31]

  • Perioperative transfusion is often needed to prevent postoperative sickle cell complications in patients with sickle cell anaemia (HbSS) undergoing any form of surgery. One randomised controlled trial found that transfusion regimens designed to keep haemoglobin at 100 g/L (10 g/dL) were as effective as, and possibly safer than, exchange transfusions in these situations.[64] One Cochrane systematic review concluded that there is insufficient evidence from randomised controlled trials to determine whether conservative pre-operative blood transfusion is as effective as aggressive blood transfusion, owing to the risk of bias in the available trials.[65]

  • Patients with HbSC disease undergoing major surgery often require exchange transfusions prior to surgery, due to baseline haemoglobin levels that are already >100 g/L (10 g/dL) and the need to avoid hyperviscosity in the blood.

  • One multi-centre study that randomised adults and children with sickle cell anaemia (SS or Sb0 thalassaemia) to receive transfusion or no transfusion prior to undergoing medium-risk surgery was closed early due to significantly more complications in the no-transfusion arm, although all-cause mortality was not different between the two groups.[66]

  • In one randomised trial in children with sickle cell anaemia, researchers found a 90% reduction in risk of first stroke with chronic transfusion compared with standard supportive care.[67] Further research showed that higher rates of stroke followed discontinuation of transfusions.[68]

  • Selection of red cells for transfusion is an important consideration. Guidelines currently recommend ABO D CcEe K-matched red blood cells, even in the absence of alloantibodies, to reduce the risk of alloimmunisation.[69][70][71] In patients with sickle cell disease who have developed clinically significant alloantibodies, selection of red blood cells antigen negative to the alloantibody is recommended.[69][71] If possible, selection of more extended phenotype-matched red blood cells will likely reduce the risk of further alloimmunisation in these patients.[69] Observational studies provide some evidence that extended serological red blood cell antigen matching decreases the prevalence of alloimmunisation; further prospective randomised controlled trials are needed to determine the most effective ways of reducing alloimmunisation through serological and genotypical matching.[72]

Blood transfusion in pregnancy

  • Routine prophylactic transfusion is not generally recommended during pregnancy, but it may be considered for women:[70][73]

    • with previous or current medical, obstetric, or fetal problems related to sickle cell disease

    • previously on hydroxycarbamide due to severe disease

    • with additional features of high-risk pregnancy, or multiple pregnancy.

  • Pregnancy outcomes are worse in pregnant women with sickle cell disease than in those without.[74] One meta-analysis evaluating transfusion in pregnant women with sickle cell disease found that transfusion was associated with a reduction in maternal mortality, vaso-occlusive pain episodes, pulmonary complications, pulmonary embolism, pyelonephritis, perinatal mortality, neonatal death, and preterm birth.[75] The meta-analysis was limited by the small number of eligible studies, but suggests that prophylactic transfusion should be considered in high-risk pregnant women with sickle cell disease.

  • Women who experience SCD-related complications in their current pregnancy would benefit from transfusion.[70][73] Transfusion may be required with worsening anaemia.[73]

Voxelotor, a first-in-class oral haemoglobin S polymerisation inhibitor, was voluntarily withdrawn from the market in September 2024 due to safety concerns.[76][77]

Treatment of vaso-occlusive episodes

The goal of treatment for vaso-occlusive crises is to alleviate pain while minimising adverse effects.

  • Comprehensive pain assessment using age-appropriate pain scales, and patient input, informs analgesic choice.

  • Pain should be reassessed frequently (every 30 to 60 minutes in the emergency department) to optimise pain control.[78]

  • Paracetamol or non-steroidal anti-inflammatory drugs (NSAIDs) are used for mild pain, often with supportive measures, such as heating pads. Stronger opioids administered orally are used for moderate to severe pain. If the pain is severe, parenteral opioid therapy is often required. One randomised, placebo-controlled trial found no significant difference between oral controlled-release morphine and intravenous morphine in patients aged 5 to 17 years with respect to frequency of rescue analgesia, duration of pain, and frequency of adverse events.[79] High-quality evidence regarding pharmacological interventions for adults with painful vaso-occlusive crisis is lacking.[80][81]

  • Older children, adolescents, and adults may be allowed to self-administer analgesia via a patient-controlled analgesia device (PCA).[82] Note that intermittent administration of shorter-acting opioid analgesics may fail to control pain if the patient falls asleep. In these patients, particularly those that are not opioid naive, the use of long-acting oral opioids along with PCA/bolus dosing can assist with pain management.

  • Patients receiving long-term opioid analgesia who develop tolerance will likely require higher doses of opioids. Baseline opioid therapy and previous effective therapy should be taken into account.[78]

  • Many opioids cause pruritus, which should be managed with an oral antihistamine.

  • If pain remains uncontrolled with opioids, anaesthetic or pain specialist consult should be sought.

Patients with vaso-occlusive crisis require supportive care (e.g., oxygen for hypoxic patients) and management of precipitating factors (e.g., dehydration or infection).

  • Oxygen is given nasally at a rate of 2 L/minute to patients with moderate hypoxaemia (PaO₂ 70-80 mmHg or O₂ saturation 92% to 95%). Patients with more severe hypoxaemia will require a higher flow rate. Patients with chronic hypoxaemia whose admission PaO₂ is not lower than their usual level may also benefit from oxygen.

  • Fluid replacement corrects intravascular volume depletion; compensates for any ongoing volume losses caused by fever, hyposthenuria, vomiting, or diarrhoea; and compensates for increased urinary sodium losses during crises. Patients with chronic severe anaemia and those with pulmonary hypertension need careful monitoring during fluid replacement therapy due to the risk of congestive heart failure. If dehydration is mild, oral rehydration may be possible. Patients may require supplemental intravenous fluids if unable or unwilling to take oral fluids. If dehydration is severe, treatment with fluid boluses and strict measurement of intake and output followed by intravenous fluids at a rate of at least 1.5 times the maintenance rate is recommended. This rate will need to be adjusted if patients have a history of heart disease or pulmonary hypertension, and caution should be used in older patients who may have undiagnosed pulmonary/heart disease.

  • Antibiotics should be considered if there is evidence of infection. The appropriate antibiotics depend on whether community-acquired, hospital-acquired, or atypical pneumonia is suspected.

Blood transfusion (simple or exchange) is indicated for life-threatening vaso-occlusive events, symptomatic anaemia, acute organ dysfunction, high-risk procedures (including general anaesthesia), and in selected pregnancies.

Transfusion is not indicated in a patient who has asymptomatic anaemia with a vaso-occlusive crisis, as there is no evidence that transfusion decreases the length of a crisis in this setting.

Treatment of acute chest syndrome

The goal of treatment of acute chest syndrome is to prevent progression to acute respiratory failure. Treatment consists of oxygen therapy (for hypoxic patients), blood transfusions, and antibiotics. Optimal pain control and hydration, together with incentive spirometry, are also advised. If pain is reduced, the patient will not splint the chest during breathing and atelectasis will be less likely to develop. Incentive spirometry will further prevent atelectasis. Intensive care unit support can be life-saving in severe cases.

  • Transfusions are recommended because they decrease the proportion of sickle red cells. Although guidelines suggest that a transfusion is indicated if patients have a PaO₂ <70 mmHg on room air or, in chronic hypoxaemia, if there is more than a 10% drop in PaO₂ from their usual baseline, clinical judgement will form the basis of the decision.[35]

  • Transfusions are especially recommended in patients who have a history of cardiovascular disease, low platelet count, or have multi-lobar pneumonia, as these risks have been found to be associated with an increased risk of mechanical ventilation.[83]

  • While offering blood transfusions is widely accepted practice, evidence from randomised controlled trials is currently lacking.[84]

  • Intravenous broad-spectrum antibiotics are given because bacterial pneumonia cannot always be ruled out. In a large prospective cohort study the most common organisms identified were atypical, so both typical and atypical antibiotic coverage is required.[83] Observational data suggest that children treated with guideline-adherent antibiotic therapy have a lower rate of readmission to hospital in the next 30 days, for both acute chest syndrome and all causes.[85]

Stem cell transplantation

Haematopoietic stem cell transplantation (HSCT) is the only curative treatment for sickle cell disease, but is used infrequently owing to lack of suitable stem cell donors, cost, and risks.

Guidelines from the American Society of Hematology (ASH) make the following conditional recommendations on the use of HSCT in sickle cell anaemia:[86]

  • Matched related allogeneic transplantation is suggested in patients who have neurological injury (e.g., stroke or abnormal transcranial Doppler ultrasound), patients experiencing frequent pain, or patients who continue to have recurrent episodes of acute chest syndrome (ACS) despite standard of care.

  • Transplant from alternative donors in the context of a clinical trial is suggested for patients who lack a matched sibling donor; consideration should be given to risks related to transplant complications and potential benefits derived from transplantation.

  • Either total-body irradiation ≤400 cGy or chemotherapy-based conditioning regimens is suggested for allogeneic transplantation.

  • Myeloablative conditioning is suggested over reduced intensity conditioning (that contains melphalan/fludarabine) for children with an indication for allogeneic transplantation and a matched sibling donor.

  • Non-myeloablative conditioning is suggested over reduced intensity conditioning (that contains melphalan/fludarabine) for adults with an indication for allogeneic transplantation and a matched sibling donor.

  • Allogeneic transplantation is suggested at an earlier age rather than at an older age; impact of age on transplantation outcome may also be affected by the conditioning regimen employed.

  • Using human leukocyte antigen (HLA)-identical sibling cord blood when available (and associated with an adequate cord blood cell dose and good viability) is suggested over bone marrow.

The American Society of Hematology recommendations are based on limited evidence. Randomised clinical trials evaluating the use of bone marrow transplantation in sickle cell anaemia are lacking.[87] The decision to undergo transplantation should rely on informed discussions between patient and physician. 

More research is needed into long-term effects post transplant.[88]

Chronic daily pain

Many patients will develop chronic daily pain. In a study of 232 patients aged 16 years or older, pain was reported on 55% of 31,017 days analysed.[89] Crisis pain in which the patient did not utilise care in a hospital or ambulatory setting was reported on 12.7% of days; medical care for pain (either crisis or not) was reported on 3.5% of days. The remainder of the days included chronic pain treated at home.

Causes of chronic pain should be investigated and managed as needed. Recognising the prevalence of chronic daily pain in this patient population is important, and referral to a pain specialist should be considered.[89] Several studies have looked at psychological interventions to improve pain outcomes, but no definitive intervention has been identified.[90] [ Cochrane Clinical Answers logo ]

Peripheral venous cannulation animated demonstration
Peripheral venous cannulation animated demonstration

How to insert a peripheral venous cannula into the dorsum of the hand.

Other potentially treatable causes of pain include avascular necrosis and chronic leg ulcers.[92]

Use of this content is subject to our disclaimer