current research on sickle cell anemia 2022

• Open access
• Published: 03 March 2022

Advances in the diagnosis and treatment of sickle cell disease

• A. M. Brandow 1 &
• R. I. Liem   ORCID: orcid.org/0000-0003-2057-3749 2  

Journal of Hematology & Oncology volume  15 , Article number:  20 ( 2022 ) Cite this article

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Sickle cell disease (SCD), which affects approximately 100,000 individuals in the USA and more than 3 million worldwide, is caused by mutations in the βb globin gene that result in sickle hemoglobin production. Sickle hemoglobin polymerization leads to red blood cell sickling, chronic hemolysis and vaso-occlusion. Acute and chronic pain as well as end-organ damage occur throughout the lifespan of individuals living with SCD resulting in significant disease morbidity and a median life expectancy of 43 years in the USA. In this review, we discuss advances in the diagnosis and management of four major complications: acute and chronic pain, cardiopulmonary disease, central nervous system disease and kidney disease. We also discuss advances in disease-modifying and curative therapeutic options for SCD. The recent availability of l -glutamine, crizanlizumab and voxelotor provides an alternative or supplement to hydroxyurea, which remains the mainstay for disease-modifying therapy. Five-year event-free and overall survival rates remain high for individuals with SCD undergoing allogeneic hematopoietic stem cell transplant using matched sibling donors. However, newer approaches to graft-versus-host (GVHD) prophylaxis and the incorporation of post-transplant cyclophosphamide have improved engraftment rates, reduced GVHD and have allowed for alternative donors for individuals without an HLA-matched sibling. Despite progress in the field, additional longitudinal studies, clinical trials as well as dissemination and implementation studies are needed to optimize outcomes in SCD.

Introduction

Sickle cell disease (SCD), a group of inherited hemoglobinopathies characterized by mutations that affect the β-globin chain of hemoglobin, affects approximately 100,000 people in the USA and more than 3 million people worldwide [ 1 , 2 ]. SCD is characterized by chronic hemolytic anemia, severe acute and chronic pain as well as end-organ damage that occurs across the lifespan. SCD is associated with premature mortality with a median age of death of 43 years (IQR 31.5–55 years) [ 3 ]. Treatment requires early diagnosis, prevention of complications and management of end-organ damage. In this review, we discuss recent advances in the diagnosis and management of four major complications in SCD: acute and chronic pain, cardiopulmonary disease, central nervous system disease and kidney disease. Updates in disease-modifying and curative therapies for SCD are also discussed.

Molecular basis and pathophysiology

Hemoglobin S (HbS) results from the replacement of glutamic acid by valine in the sixth position of the β-globin chain of hemoglobin (Fig.  1 ). Severe forms of SCD include hemoglobin SS due to homozygous inheritance of HbS and S/β 0 thalassemia due to co-inheritance of HbS with the β 0 thalassemia mutation. Other forms include co-inheritance of HbS with other β-globin gene mutations such as hemoglobin C, hemoglobin D-Los Angeles/Punjab or β + thalassemia. Hb S has reduced solubility and increased polymerization, which cause red blood cell sickling, hemolysis and vaso-occlusion (Table 1 ) that subsequently lead to pain episodes and end-organ damage such as cardiopulmonary, cerebrovascular and kidney disease (Table 2 ).

Genetic and molecular basis of sickle cell disease. SCD is caused by mutations in the β globin gene, located on the β globin locus found on the short arm of chromosome 11. The homozygous inheritance of Hb S or co-inheritance of Hb S with the β 0 thalassemia mutation results in the most common forms of severe SCD. Co-inheritance of Hb S with other variants such as Hb C, Hb D-Los Angeles/Punjab, Hb O-Arab or β + thalassemia also leads to clinically significant sickling syndromes (LCR, locus control region; HS, hypersensitivity site)

Acute and chronic pain

Severe intermittent acute pain is the most common SCD complication and accounts for over 70% of acute care visits for individuals with SCD [ 4 ]. Chronic daily pain increases with older age, occurring in 30–40% of adolescents and adults with SCD [ 5 , 6 ]. Acute pain is largely related to vaso-occlusion of sickled red blood cells with ischemia–reperfusion injury and tissue infarction and presents in one isolated anatomic location (e.g., arm, leg, back) or multiple locations. Chronic pain can be caused by sensitization of the central and/or peripheral nervous system and is often diffuse with neuropathic pain features [ 7 , 8 ]. A consensus definition for chronic pain includes “Reports of ongoing pain on most days over the past 6 months either in a single location or multiple locations” [ 9 ]. Disease complications such as avascular necrosis (hip, shoulder) and leg ulcers also cause chronic pain [ 9 ].

Diagnosis of acute and chronic pain

The gold standard for pain assessment and diagnosis is patient self-report. There are no reliable diagnostic tests to confirm the presence of acute or chronic pain in individuals with SCD except when there are identifiable causes like avascular necrosis on imaging or leg ulcers on exam. The effects of pain on individuals’ function are assessed using patient-reported outcome measures (PROs) that determine to what extent pain interferes with individuals’ daily function. Tools shown to be valid, reliable and responsive can be used in clinical practice to track patients’ pain-related function over time to determine additional treatment needs and to compare to population norms [ 10 ]. There are currently no plasma pain biomarkers that improve assessment and management of SCD acute or chronic pain.

Depression and anxiety as co-morbid conditions in SCD can contribute to increased pain, more pain-related distress/interference and poor coping [ 11 ]. The prevalence of depression and anxiety range from 26–33% and 6.5–36%, respectively, in adults with SCD [ 11 , 12 , 13 ]. Adults with SCD have an 11% higher prevalence of depression compared to Black American adults without SCD [ 14 ]. Depression and anxiety can be assessed using self-reported validated screening tools (e.g., Depression: Patient Health Questionnaire (PHQ-9) [ 15 ] for adults, Center for Epidemiologic Studies Depression Scale for Children (CES-DC) [ 16 ], PROMIS assessments for adults and children; Anxiety: Generalized Anxiety Disorder 7-item (GAD-7) scale for adults, State-Trait Anxiety Inventory for Children (STAIC) [ 17 ], PROMIS assessments for adults and children). Individuals who screen positive using these tools should be referred for evaluation by a psychologist/psychiatrist.

Management of acute and chronic pain

The goal of acute pain management is to provide sufficient analgesia to return patients to their usual function, which may mean complete resolution of pain for some or return to baseline chronic pain for others. The goal of chronic pain management is to optimize individuals’ function, which may not mean being pain free. When there is an identifiable cause of chronic pain, treatment of the underlying issue (e.g., joint replacement for avascular necrosis, leg ulcer treatment) is important. Opioids, oral for outpatient management and intravenous for inpatient management, are first line therapy for acute SCD pain. In the acute care setting, analgesics should be initiated within 30–60 min of triage [ 18 ]. Ketamine, a non-opioid analgesic, can be prescribed at sub-anesthetic (analgesic) intravenous doses (0.1–0.3 mg/kg per h, maximum 1 mg/kg per h) as adjuvant treatment for acute SCD pain refractory to opioids [ 18 , 19 ]. In an uncontrolled observational study of 85 patients with SCD receiving ketamine infusions for acute pain, ketamine was associated with a decrease in mean opioid consumption by oral morphine equivalents (3.1 vs. 2.2 mg/kg/day, p  < 0.001) and reductions in mean pain scores (0–10 scale) from baseline until discontinuation of the infusion (7.81 vs. 5.44, p  < 0.001) [ 20 ]. Nonsteroidal anti-inflammatory drugs (NSAIDs) are routinely used as adjuvant therapy for acute pain treatment [ 18 ]. In a RCT ( n  = 20) of hospitalized patients with acute pain, ketorolac was associated with lower total dose of meperidine required (1866.7 ± 12.4 vs. 2804.5 ± 795.1 mg, p  < 0.05) and shorter hospitalization (median 3.3 vs. 7.2 days, p  = 0.027) [ 21 ]. In a case series of children treated for 70 acute pain events in the ED, 53% of events resolved with ketorolac and hydration alone with reduction in 100 mm visual analog scale (VAS) pain score from 60 to 13 ( p  < 0.001) [ 22 ]. Patients at risk for NSAID toxicity (e.g., renal impairment, on anticoagulation) should be identified.

Despite paucity of data, chronic opioid therapy (COT) can be considered after assessing benefits versus harms [ 23 ] and the functional status of patients with SCD who have chronic pain. Harms of COT seen in patient populations other than SCD are dose dependent and include myocardial infarction, bone fracture, increased risk of motor vehicle collisions, sexual dysfunction and mortality [ 23 ]. There are few published studies investigating non-opioid analgesics for chronic SCD pain [ 24 , 25 , 26 ]. In a randomized trial of 39 participants, those who received Vitamin D experienced a range of 6–10 pain days over 24 weeks while those who received placebo experienced 10–16 pain days, which was not significantly different [ 26 ]. In a phase 1, uncontrolled trial of 18 participants taking trifluoperazine, an antipsychotic drug, 8 participants showed a 50% reduction in the VAS (10 cm horizontal line) pain score from baseline on at least 3 assessments over 24 h without severe sedation or supplemental opioid analgesics, 7 participants showed pain reduction on 1 assessment, and the remaining 3 participants showed no reduction [ 24 ]. Although published data are not available for serotonin and norepinephrine reuptake inhibitors (SNRIs), gabapentinoids and tricyclic antidepressants (TCAs) in individuals with SCD, evidence supports their use in fibromyalgia, a chronic pain condition similar to SCD chronic pain in mechanism. A Cochrane Review that included 10 RCTs ( n  = 6038) showed that the SNRIs milnacipran and duloxetine, compared to placebo, were associated with a reduction in pain [ 27 ]. A systematic review and meta-analysis of 9 studies ( n  = 520) showed the TCA amitriptyline improved pain intensity and function [ 28 ]. Finally, a meta-analysis of 5 RCTs ( n  = 1874) of the gabapentinoid pregabalin showed a reduction in pain intensity [ 29 ]. Collectively, the indirect evidence from fibromyalgia supports the conditional recommendation in current SCD practice guidelines to consider these 3 drug classes for chronic SCD pain treatment [ 18 ]. Standard formulary dosing recommendations should be followed and reported adverse effects considered.

Non-pharmacologic therapies (e.g., integrative, psychological-based therapies) are important components of SCD pain treatment. In a case–control study of 101 children with SCD and chronic pain referred for cognitive behavioral therapy (CBT) (57 CBT, 44 no CBT) [ 30 ], CBT was associated with more rapid decrease in pain hospitalizations (estimate − 0.63, p  < 0.05) and faster reduction in hospital days over time (estimate − 5.50, p  < 0.05). Among 18 children who received CBT and completed PROs pre- and 12 months posttreatment, improvements were seen in mean pain intensity (5.47 vs. 3.76, p  = 0.009; 0–10 numeric rating pain scale), functional disability (26.24 vs. 15.18, p  < 0.001; 0–60 score range) and pain coping (8.00 vs. 9.65, p  = 0.03; 3–15 score range) post treatment [ 30 ]. In 2 uncontrolled clinical trials, acupuncture was associated with a significant reduction in pain scores by 2.1 points (0–10 numeric pain scale) in 24 participants immediately after treatment [ 31 ] or a significant mean difference in pre-post pain scores of 0.9333 (0–10 numeric pain scale) ( p  < 0.000) after 33 acupuncture sessions [ 32 ].

Cardiopulmonary disease

Cardiopulmonary disease is associated with increased morbidity and mortality in individuals with SCD. Pulmonary hypertension (PH), most commonly pulmonary arterial hypertension (PAH), is present based on right-heart catheterization in up to 10% of adults with SCD [ 33 ]. Chronic intravascular hemolysis represents the biggest risk factor for development of PAH in SCD and leads to pulmonary arteriole vasoconstriction and smooth muscle proliferation. Based on pulmonary function testing (PFT), obstructive lung disease may be observed in 16% of children and 8% of adults with SCD, while restrictive lung disease may be seen in up to 28% of adults and only 7% of children with SCD [ 34 , 35 ]. Sleep-disordered breathing, which can manifest as obstructive sleep apnea or nocturnal hypoxemia, occurs in up to 42% of children and 46% of adults with SCD [ 36 , 37 ]. Cardiopulmonary disease, including PH or restrictive lung disease, presents with dyspnea with or without exertion, chest pain, hypoxemia or exercise intolerance that is unexplained or increased from baseline. Obstructive lung disease can also present with wheezing.

Diagnosis of cardiopulmonary disease

The confirmation of PH in patients with SCD requires right-heart catheterization. Recently, the mean pulmonary artery pressure threshold used to define PH in the general population was lowered from ≥ 25 to ≥ 20 mm Hg [ 38 ]. Elevated peak tricuspid regurgitant jet velocity (TRJV) ≥ 2.5 m/s on Doppler echocardiogram (ECHO) is associated with early mortality in adults with SCD and may suggest elevated pulmonary artery pressures, especially when other signs of PH (e.g., right-heart strain, septal flattening) or left ventricular diastolic dysfunction, which may contribute to PH, are present [ 39 ]. However, the positive predictive value (PPV) of peak TRJV alone for identifying PH in adults with SCD is only 25% [ 40 ]. Increasing the peak TRJV threshold to at least 2.9 m/s has been shown to increase the PPV to 64%. For a peak TRJV of 2.5–2.8 m/s, an increased N-terminal pro-brain natriuretic peptide (NT-proBNP) ≥ 164.5 pg/mL or a reduced 6-min walk distance (6MWD) < 333 m can also improve the PPV to 62% with a false negative rate of 7% [ 33 , 40 , 41 ].

PFT, which includes spirometry and measurement of lung volumes and diffusion capacity, is standard for diagnosing obstructive and restrictive lung disease in patients with SCD. Emerging modalities include impulse oscillometry, a non-invasive method using forced sound waves to detect changes in lower airway mechanics in individuals unable to perform spirometry [ 42 ], and airway provocation studies using cold air or methacholine to reveal latent airway hyperreactivity [ 43 ]. Formal in-lab, sleep study/polysomnography remains the gold standard to evaluate for sleep-disordered breathing, which may include nocturnal hypoxemia, apnea/hypopnea events and other causes of sleep disruption. Nocturnal hypoxemia may increase red blood cell sickling, cellular adhesion and endothelial dysfunction. In 47 children with SCD, mean overnight oxygen saturation was higher in those with grade 0 compared to grade 2 or 3 cerebral arteriopathy (97 ± 1.6 vs. 93.9 ± 3.7 vs. 93.5 ± 3.0%, p  < 0.01) on magnetic resonance angiography and lower overnight oxygen saturation was independently associated with mild, moderate or severe cerebral arteriopathy after adjusting for reticulocytosis (OR 0.50, 95% CI 0.26–0.96, p  < 0.05) [ 44 ].

Management of cardiopulmonary disease

Patients with SCD who have symptoms suggestive of cardiopulmonary disease, such as worsening dyspnea, hypoxemia or reduced exercise tolerance, should be evaluated with a diagnostic ECHO and PFT. The presence of snoring, witnessed apnea, respiratory pauses or hypoxemia during sleep, daytime somnolence or nocturnal enuresis in older children and adults is sufficient for a diagnostic sleep study.

Without treatment, the mortality rate in SCD patients with PH is high compared to those without (5-year, all-cause mortality rate of 32 vs. 16%, p  < 0.001) [ 33 ]. PAH-targeted therapies should be considered for SCD patients with PAH confirmed by right-heart catheterization. However, the only RCT ( n  = 6) in individuals with SCD and PAH confirmed by right-heart catheterization (bosentan versus placebo) was stopped early for poor accrual with no efficacy endpoints analyzed [ 45 ]. In SCD patients with elevated peak TRJV, a randomized controlled trial ( n  = 74) of sildenafil, a phosphodiesterase-5 inhibitor, was discontinued early due to increased pain events in the sildenafil versus placebo arm (35 vs. 14%, p  = 0.029) with no treatment benefit [ 46 ]. Despite absence of clinical trial data, patients with SCD and confirmed PH should be considered for hydroxyurea or monthly red blood cell transfusions given their disease-modifying benefits. In a retrospective analysis of 13 adults with SCD and PAH, 77% of patients starting at a New York Heart Association (NYHA) functional capacity class III or IV achieved class I/II after a median of 4 exchange transfusions with improvement in median pulmonary vascular resistance (3.7 vs. 2.8 Wood units, p  = 0.01) [ 47 ].

Approximately 28% of children with SCD have asthma, which is associated with increased pain episodes that may result from impaired oxygenation leading to sickling and vaso-occlusion as well as with acute chest syndrome and higher mortality [ 48 , 49 , 50 ]. First line therapies include standard beta-adrenergic bronchodilators and supplemental oxygen as needed. When corticosteroids are indicated, courses should be tapered over several days given the risk of rebound SCD pain from abrupt discontinuation. Inhaled corticosteroids such as fluticasone proprionate or beclomethasone diproprionate are reserved for patients with recurrent asthma exacerbations, but their anti-inflammatory effects and impact on preventing pain episodes in patients with SCD who do not have asthma is under investigation [ 51 ]. Finally, management of sleep-disordered breathing is tailored to findings on formal sleep study in consultation with a sleep/pulmonary specialist.

Central nervous system (CNS) complications

CNS complications, such as overt and silent cerebral infarcts, cause significant morbidity in individuals with SCD. Eleven percent of patients with HbSS disease by age 20 years and 24% by age 45 years will have had an overt stroke [ 52 ]. Silent cerebral infarcts occur in 39% by 18 years and in > 50% by 30 years [ 53 , 54 ]. Patients with either type of stroke are at increased risk of recurrent stroke [ 55 ]. Overt stroke involves large-arteries, including middle cerebral arteries and intracranial internal carotid arteries, while silent cerebral infarcts involve penetrating arteries. The pathophysiology of overt stroke includes vasculopathy, increased sickled red blood cell adherence, and hemolysis-induced endothelial activation and altered vasomotor tone [ 56 ]. Overt strokes present as weakness or paresis, dysarthria or aphasia, seizures, sensory deficits, headache or altered level of consciousness, while silent cerebral infarcts are associated with cognitive deficits, including lower IQ and impaired academic performance.

Diagnosis of CNS complications in SCD

Overt stroke is diagnosed by evidence of acute infarct on brain MRI diffusion-weighted imaging and focal deficit on neurologic exam. A silent cerebral infarct is defined by a brain “MRI signal abnormality at least 3 mm in one dimension and visible in 2 planes on fluid-attenuated inversion recovery (FLAIR) T2-weighted images” and no deficit on neurologic exam [ 57 ]. Since silent cerebral infarcts cannot be detected clinically, a screening baseline brain MRI is recommended in school-aged children with SCD [ 58 ]. Recent SCD clinical practice guidelines also suggest a screening brain MRI in adults with SCD to facilitate rehabilitation services, patient and family understanding of cognitive deficits and further needs assessment [ 58 ]. An MRA should be added to screening/diagnostic MRIs to evaluate for cerebral vasculopathy (e.g., moyamoya), which may increase risk for recurrent stroke or hemorrhage [ 59 ].

Annual screening for increased stroke risk by transcranial doppler (TCD) ultrasound is recommended by the American Society of Hematology for children 2–16 years old with HbSS or HbS/β° thalassemia [ 58 ]. Increased stroke risk on non-imaging TCD is indicated by abnormally elevated cerebral blood flow velocity, defined as ≥ 200 cm/s (time-averaged mean of the maximum velocity) on 2 occasions or a single velocity of > 220 cm/s in the distal internal carotid or proximal middle cerebral artery [ 60 ]. Many centers rely on imaging TCD, which results in velocities 10–15% lower than values obtained by non-imaging protocols and therefore, require adjustments to cut-offs for abnormal velocities. Data supporting stroke risk assessment using TCD are lacking for adults with SCD and standard recommendations do not exist.

Neurocognitive deficits occur in over 30% of children and adults with severe SCD [ 61 , 62 ]. These occur as a result of overt and/or silent cerebral infarcts but in some patients, the etiology is unknown. The Bright Futures Guidelines for Health Supervision of Infants, Children and Adolescents or the Cognitive Assessment Toolkit for adults are commonly used tools to screen for developmental delays or neurocognitive impairment [ 58 ]. Abnormal results should prompt referral for formal neuropsychological evaluation, which directs the need for brain imaging to evaluate for silent cerebral infarcts and facilitate educational/vocational accommodations.

Management of CNS complications

Monthly chronic red blood cell transfusions to suppress HbS < 30% are standard of care for primary stroke prevention in children with an abnormal TCD. In an RCT of 130 children, chronic transfusions, compared to no transfusions, were associated with a difference in stroke risk of 92% (1 vs. 10 strokes, p  < 0.001) [ 60 ]. However, children with abnormal TCD and no MRI/MRA evidence of cerebral vasculopathy can safely transition to hydroxyurea after 1 year of transfusions [ 63 ]. Lifelong transfusions to maintain HbS < 30% remain standard of care for secondary stroke prevention in individuals with overt stroke [ 64 ]. Chronic monthly red blood cell transfusions should also be considered for children with silent cerebral infarct [ 58 ]. In a randomized controlled trial ( n  = 196), monthly transfusions, compared to observation without hydroxyurea, reduced risk of overt stroke, new silent cerebral infarct or enlarging silent cerebral infarct in children with HbSS or HbS/β 0 thalassemia and an existing silent cerebral infarct (2 vs. 4.8 events, incidence rate ratio of 0.41, 95% CI 0.12–0.99, p  = 0.04) [ 57 ].

Acute stroke treatment requires transfusion therapy to increase cerebral oxygen delivery. Red blood cell exchange transfusion, defined as replacement of patients’ red blood cells with donor red blood cells, to rapidly reduce HbS to < 30% is the recommended treatment as simple transfusion alone is shown to have a fivefold greater relative risk (57 vs. 21% with recurrent stroke, RR = 5.0; 95% CI 1.3–18.6) of subsequent stroke compared to exchange transfusion [ 65 ]. However, a simple transfusion is often given urgently while preparing for exchange transfusion [ 58 ]. Tissue plasminogen activator (tPA) is not recommended for children with SCD who have an acute stroke since the pathophysiology of SCD stroke is less likely to be thromboembolic in origin and there is risk for harm. Since the benefits and risks of tPA in adults with SCD and overt stroke are not clear, its use depends on co-morbidities, risk factors and stroke protocols but should not delay or replace prompt transfusion therapy.

Data guiding treatment of SCD cerebral vasculopathy (e.g., moyamoya) are limited, and only nonrandomized, low-quality evidence exists for neurosurgical interventions (e.g., encephaloduroarteriosynangiosis) [ 66 ]. Consultation with a neurosurgeon to discuss surgical options in patients with moyamoya and history of stroke or transient ischemic attack should be considered [ 58 ].

Kidney disease

Glomerulopathy, characterized by hyperfiltration leading to albuminuria, is an early asymptomatic manifestation of SCD nephropathy and worsens with age. Hyperfiltration, defined by an absolute increase in glomerular filtration rate, may be seen in 43% of children with SCD [ 67 ]. Albuminuria, defined by the presence of urine albumin ≥ 30 mg/g over 24 h, has been observed in 32% of adults with SCD [ 68 ]. Glomerulopathy results from intravascular hemolysis and endothelial dysfunction in the renal cortex. Medullary hypoperfusion and ischemia also contribute to kidney disease in SCD, causing hematuria, urine concentrating defects and distal tubular dysfunction [ 69 ]. Approximately 20–40% of adults with SCD develop chronic kidney disease (CKD) and are at risk of developing end-stage renal disease (ESRD), with rapid declines in estimated glomerular filtration rate (eGFR) > 3 mL/min/1.73 m 2 associated with increased mortality (HR 2.4, 95% CI 1.31–4.42, p  = 0.005) [ 68 ].

Diagnosis of kidney disease in SCD

The diagnosis of sickle cell nephropathy is made by detecting abnormalities such as albuminuria, hematuria or CKD rather than by distinct diagnostic criteria in SCD, which have not been developed. Traditional markers of kidney function such as serum creatinine and eGFR should be interpreted with caution in individuals with SCD because renal hyperfiltration affects their accuracy by increasing both. Practical considerations preclude directly measuring GFR by urine or plasma clearance techniques, which achieves the most accurate results. The accuracy of eGFR, however, may be improved by equations that incorporate serum cystatin C [ 70 ].

Since microalbuminuria/proteinuria precedes CKD in SCD, annual screening for urine microalbumin/protein is recommended beginning at age 10 years [ 71 ]. When evaluating urine for microalbumin concentration, samples from first morning rather than random voids are preferable to exclude orthostatic proteinuria. Recent studies suggest HMOX1 and APOL1 gene variants may be associated with CKD in individuals with SCD [ 72 ]. Potential novel predictors of acute kidney injury in individuals with SCD include urine biomarkers kidney injury molecule 1 (KIM-1) [ 73 ], monocyte chemotactic protein 1 (MCP-1) [ 74 ] and neutrophil gelatinase-associated lipocalin (NGAL) [ 75 ]. Their contribution to chronic kidney disease and interaction with other causes of kidney injury in SCD (e.g., inflammation, hemolysis) are not clear.

Management of kidney disease

Managing kidney complications in SCD should focus on mitigating risk factors for acute and chronic kidney injury such as medication toxicity, reduced kidney perfusion from hypotension and dehydration, and general disease progression, as well as early screening and treatment of microalbuminuria/proteinuria. Acute kidney injury, either an increase in serum creatinine ≥ 0.3 mg/dL or a 50% increase in serum creatinine from baseline, is associated with ketorolac use in children with SCD hospitalized for pain [ 76 ]. Increasing intravenous fluids to maintain urine output > 0.5 to 1 mL/kg/h and limiting NSAIDs and antibiotics associated with nephrotoxicity in this setting are important. Despite absence of controlled clinical trials, hydroxyurea may be associated with improvements in glomerular hyperfiltration and urine concentrating ability in children with SCD [ 77 , 78 ]. Hydroxyurea is also associated with a lower prevalence (34.7 vs. 55.4%, p  = 0.01) and likelihood of albuminuria (OR 0.28, 95% CI 0.11–0.75, p  = 0.01) in adults with SCD after adjusting for age, angiotensin-converting enzyme inhibitor (ACE-I)/angiotensin receptor blockade (ARB) use and major disease risk factors [ 79 ].

ACE-I or ARB therapy reduces microalbuminuria in patients with SCD. In a phase 2 trial of 36 children and adults, a ≥ 25% reduction in urine albumin-to-creatinine ratio was observed in 83% ( p  < 0.0001) and 58% ( p  < 0.0001) of patients with macroalbuminuria (> 300 mg/g creatinine) and microalbuminuria (30–300 mg/g creatinine), respectively, after 6 months of treatment with losartan at a dose of 0.7 mg/kg/day (max of 50 mg) in children and 50 mg daily in adults [ 80 ]. However, ACE-I or ARB therapy has not been shown to improve kidney function or prevent CKD. Hemodialysis is associated with a 1-year mortality rate of 26.3% after starting hemodialysis and an increase risk of death in SCD patients with ESRD compared to non-SCD patients with ESRD (44.6 vs. 34.5% deaths, mortality hazard ratio of 2.8, 95% CI 2.31–3.38) [ 81 ]. Renal transplant should be considered for individuals with SCD and ESRD because of recent improvements in renal graft survival and post-transplant mortality [ 82 ].

Disease-modifying therapies in SCD

Since publication of its landmark trial in 1995, hydroxyurea continues to represent a mainstay of disease-modifying therapy for SCD. Hydroxyurea induces fetal hemoglobin production through stress erythropoiesis, reduces inflammation, increases nitric oxide and decreases cell adhesion. The FDA approved hydroxyurea in 1998 for adults with SCD. Subsequently, hydroxyurea was FDA approved for children in 2017 to reduce the frequency pain events and need for blood transfusions in children ≥ 2 years of age [ 63 ]. The landscape of disease-modifying therapies, however, has improved with the recent FDA approval of 3 other treatments— l -glutamine and crizanlizumab for reducing acute complications (e.g., pain), and voxelotor for improving anemia (Table 3 ) [ 83 , 84 , 85 ]. Other therapies in current development focus on inducing fetal hemoglobin, reducing anti-sickling or cellular adhesion, or activating pyruvate kinase-R.

l -glutamine

Glutamine is required for the synthesis of glutathione, nicotinamide adenine dinucleotide and arginine. The essential amino acid protects red blood cells against oxidative damage, which forms the basis for its proposed utility in SCD. The exact mechanism of benefit in SCD, however, remains unclear. In a phase 3 RCT of 230 participants (hemoglobin SS or S/β 0 thalassemia), l -glutamine compared to placebo was associated with fewer pain events (median 3 vs. 4, p  = 0.005) and hospitalizations for pain (median 2 vs. 3, p  = 0.005) over the 48-week treatment period [ 84 ]. The percentage of patients who had at least 1 episode of acute chest syndrome, defined as presence of chest wall pain with fever and a new pulmonary infiltrate, was lower in the l -glutamine group (8.6 vs. 23.1%, p  = 0.003). There were no significant between-group differences in hemoglobin, hematocrit or reticulocyte count. Common side effects of l -glutamine include GI upset (constipation, nausea, vomiting and abdominal pain) and headaches.

Crizanlizumab

P-selectin expression, triggered by inflammation, promotes adhesion of neutrophils, activated platelets and sickle red blood cells to the endothelial surface and to each other, which promotes vaso-occlusion in SCD. Crizanlizumab, given as a monthly intravenous infusion, is a humanized monoclonal antibody that binds P-selectin and blocks the adhesion molecule’s interaction with its ligand, P-selectin glycoprotein ligand 1. FDA approval for crizanlizumab was based on a phase 2 RCT ( n  = 198, all genotypes), in which the median rate of pain events (primary endpoint) was lower (1.63 vs. 2.68, p  = 0.01) and time to first pain event (secondary endpoint) was longer (4.07 vs. 1.38 months, p  = 0.001) for patients on high-dose crizanlizumab (5 mg/kg/dose) compared to placebo treated for 52 weeks (14 doses total) [ 83 ]. In this trial, patients with SCD on chronic transfusion therapy were excluded, but those on stable hydroxyurea dosing were not. Adverse events were uncommon but included headache, back pain, nausea, arthralgia and pain in the extremity.

Polymerization of Hb S in the deoxygenated state represents the initial step in red blood cell sickling, which leads to reduced red blood cell deformability and increased hemolysis. Voxelotor is a first-in-class allosteric modifier of Hb S that increases oxygen affinity. The primary endpoint for the phase 3 RCT of voxelotor ( n  = 274, all genotypes) that led to FDA approval was an increase in hemoglobin of at least 1 g/dL after 24 weeks of treatment [ 85 ]. More participants receiving 1500 mg daily of oral voxelotor versus placebo had a hemoglobin response of at least 1 g/dL (51%, 95% CI 41–61 vs. 7%, 95% CI 1–12, p < 0.001). Approximately 2/3 of the participants in these trials were on hydroxyurea, with treatment benefits observed regardless of hydroxyurea status. Despite improvements associated with voxelotor in biomarkers of hemolysis (reticulocyte count, indirect bilirubin and lactate dehydrogenase), annualized incidence rate of vaso-occlusive crisis was not significantly different among treatment groups. Adverse events included headaches, GI symptoms, arthralgia, fatigue and rash.

Curative therapies in SCD

For individuals with SCD undergoing hematopoietic stem cell transplantation (HSCT) using HLA-matched sibling donors and either myeloablative or reduced-intensity conditioning regimens, the five-year event-free and overall survival is high at 91% and 93%, respectively [ 86 ]. Limited availability of HLA-matched sibling donors in this population requires alternative donors or the promise of autologous strategies such as gene-based therapies (i.e. gene addition, transfer or editing) (Table 4 ). Matched unrelated donors have not been used routinely due to increased risk of graft-versus-host disease (GVHD) as high as 19% (95% CI 12–28) in the first 100 days for acute GVHD and 29% (95% CI 21–38) over 3 years for chronic GVHD [ 87 ]. Haplo-identical HSCT, using biological parents or siblings as donors, that incorporate post-transplant cyclophosphamide demonstrates acceptable engraftment rates, transplant-related morbidity and overall mortality [ 88 ]. Regardless of allogeneic HSCT type, older age is associated with lower event-free (102/418 vs. 72/491 events, HR 1.74, 95% CI 1.24–2.45) and overall survival (54/418 vs. 22/491 events, HR 3.15, 95% CI 1.86–5.34) in patients ≥ 13 years old compared to < 12 years old undergoing HSCT [ 87 ].

Advancing research in SCD

Despite progress to date, additional high-quality, longitudinal data are needed to better understand the natural history of the disease and to inform optimal screening for SCD-related complications. In the era of multiple FDA-approved therapies with disease-modifying potential, clinical trials to evaluate additional indications and test them in combination with or compared to each other are needed. Dissemination and implementation studies are also needed to identify barriers and facilitators related to treatment in everyday life, which can be incorporated into decision aids and treatment algorithms for patients and their providers [ 89 ]. Lastly, continued efforts should acknowledge social determinants of health and other factors that affect access and disease-related outcomes such as the role of third-party payers, provider and patient education, health literacy and patient trust. Establishing evidence-derived quality of care metrics can also drive public policy changes required to ensure care optimization for this population.

Conclusions

SCD is associated with complications that include acute and chronic pain as well as end-organ damage such as cardiopulmonary, cerebrovascular and kidney disease that result in increased morbidity and mortality. Several well-designed clinical trials have resulted in key advances in management of SCD in the past decade. Data from these trials have led to FDA approval of 3 new drugs, l -glutamine, crizanlizumab and voxelotor, which prevent acute pain and improve chronic anemia. Moderate to high-quality data support recommendations for managing SCD cerebrovascular disease and early kidney disease. However, further research is needed to determine the best treatment for chronic pain and cardiopulmonary disease in SCD. Comparative effectiveness research, dissemination and implementation studies and a continued focus on social determinants of health are also essential.

Availability of data and materials

Not applicable.

Abbreviations

Six-minute walk distance

Angiotensin-converting enzyme inhibitor

Angiotensin receptor blockade

Cognitive behavioral therapy

Chronic kidney disease

Chronic opioid therapy

Echocardiogram

End stage renal disease

Fluid-attenuated inversion recovery

Glomerular filtration rate

Graft-versus-host disease

Hemoglobin S

Hematopoietic stem cell transplant

Nonsteroidal anti-inflammatory drugs

N-terminal pro-brain natriuretic peptide

New York Heart Association

Pulmonary arterial hypertension

Pulmonary function test

Pulmonary hypertension

Positive predictive value

Patient-reported outcomes

Randomized controlled trial

• Sickle cell disease

Serotonin and norepinephrine reuptake inhibitors

Tricyclic antidepressants

Transcranial Doppler

Tissue plasminogen activator

Tricuspid regurgitant jet velocity

Visual Analog Scale

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Brandow, A.M., Liem, R.I. Advances in the diagnosis and treatment of sickle cell disease. J Hematol Oncol 15 , 20 (2022). https://doi.org/10.1186/s13045-022-01237-z

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FDA approves cure for sickle cell disease, the first treatment to use gene-editing tool CRISPR

The Food and Drug Administration on Friday approved a powerful treatment for sickle cell disease , a devastating illness that affects more than 100,000 Americans, the majority of whom are Black.

The therapy, called Casgevy, from Vertex Pharmaceuticals and CRISPR Therapeutics, is the first medicine to be approved in the United States that uses the gene-editing tool CRISPR , which won its inventors the Nobel Prize in chemistry in 2020.

“I think this is a pivotal moment in the field,” said Dr. Alexis Thompson, chief of the division of hematology at Children’s Hospital of Philadelphia, who has previously consulted for Vertex. “It’s been really remarkable how quickly we went from the actual discovery of CRISPR, the awarding of a Nobel Prize, and now actually seeing it being an approved product.”

The approval marks the first of two potential breakthroughs for the inherited blood disorder. The FDA on Friday also approved a second treatment for sickle cell disease, called Lyfgenia, a gene therapy from drugmaker Bluebird Bio. Both treatments work by genetically modifying a patient’s own stem cells.

Until now, the only known cure for sickle cell disease was a bone marrow transplant from a donor, which carries the risk of rejection by the immune system, in addition to the difficult process of finding a matching donor.

Casgevy, which was approved for people ages 12 and older, removes the need for a donor. Using CRISPR, it edits the DNA found in a patient’s stem cells to remove the gene that causes the disease.

“The patient is their own donor,” Thompson said.

“It’s a game-changer,” said Dr. Asmaa Ferdjallah, a pediatric hematologist and bone marrow transplant physician at the Mayo Clinic in Rochester, Minnesota. “To really reimagine and re-discuss sickle cell disease as a curable disease and not as this painful and debilitating chronic disease is hope enough with this news.”

Still, the new therapy is extremely expensive — $2.2 million per patient, Vertex said. The pricing strategy, experts argue, may place it out of reach for many families. What’s more, that price doesn’t include the cost of care associated with the treatment, like a stay in the hospital or chemotherapy.

“We really have to make sure that it is accessible,” said Dr. Rabi Hanna, a pediatric hematologist-oncologist at the Cleveland Clinic who has previously served on the advisory board for Vertex. “This could be an equalizer for people with sickle cell because many patients cannot pursue career options” because of the illness.

“It’s something families have been aware of in the early research stage, and they’ve been very patiently waiting for years,” Ferdjallah said. “It’s been eagerly awaited by patients and families, but also by providers and physicians.”

How Casgevy works

In patients with sickle cell disease, red blood cells, which are usually disk-shaped, take on a crescent or sickle shape. This change can cause cells to clump together, leading to clots and blockages in the blood vessels, starving tissues of oxygen. Patients can experience excruciating pain, breathing problems and stroke .

Casgevy works by editing the DNA in a patient’s stem cells — which are responsible for making the body’s blood cells — so that they no longer produce sickle-shaped cells.

While technically a one-time treatment, a number of steps that span months are required before the patient actually gets the modified stem cells. It begins with a series of blood transfusions over three to four months, after which the stem cells are extracted from the patient’s bone marrow and sent off to a lab where they are edited, Hanna said.

Before they can be reinfused into the patient, however, doctors need to make sure no flawed stem cells remain in the body. To do so, chemotherapy is used to destroy the patient’s bone marrow. 

Only then can the edited stem cells be reinfused into the patient, followed by another month or two in the hospital to allow the cells to grow and the patient to recover.

Hanna said he’s always “cautious” when telling families and patients about the one-time treatment because they may have unrealistic expectations.

“There are multiple phases of this journey,” he said.

The clinical trial included 46 people in the U.S. and abroad, 30 of whom had at least 18 months of follow-up care after the treatment. Of those, the treatment has been successful in 29.

LaRae Morning, 29, of Phoenix, was among the trial patients whose treatment was successful.

Her doctors did not expect her to live past the age of 11. Her mother lost several jobs when Morning was a child and a teenager because of her frequent hospital visits.

In April 2021, Morning joined the clinical trial at Sarah Cannon Research Institute and HCA Healthcare’s The Children’s Hospital at TriStar Centennial in Nashville, Tennessee, a decision she initially regretted. Living in Phoenix, she had to fly to Nashville once a month for treatment. It included several blood transfusions, which lasted eight hours each, and taking a medication, called plerixafor, which she recalled causing her intense stomachaches. When she started chemotherapy, her hair began to fall out and her skin changed color, resembling the appearance of a chemical burn. She also experienced nausea.

It took about six to seven months for her to feel back to normal following the CRISPR treatment. Now, she said, she’s feeling the benefits, going out to coffee shops, spending time with her friends and finishing her first semester of law school in Washington, D.C.

“Now that I’m here, I’m so happy that I did it,” she said of the trial. “I’m just like a regular person. I wake up and do a 5K. I lift weights. If I wanted to swim, I can swim. I’m still trying to know how far I can stretch it, like what are all the things I can do.”

That’s been the experience for several other patients in the trial as well, according to Dr. Monica Bhatia, chief of pediatric stem cell transplantation at NewYork-Presbyterian/Columbia University Irving Medical Center. Bhatia is a principal investigator at one of the clinical trial sites in New York City.

Following the treatment, most patients were going back to school, going to the gym or resuming other activities — “things that a lot of people take for granted,” she said — after about three to four months.

“They’re really able to live life without restrictions,” Bhatia said.

Dr. Haydar Frangoul, medical director of pediatric hematology-oncology for the Sarah Cannon Research Institute, said he is hopeful the therapy will provide relief to more patients.

“I think this is a huge moment for patients with sickle cell disease,” said Frangoul, who was the lead investigator on the clinical trial and treated Morning.

Long-term questions 

Although Casgevy has been shown to be effective, experts still don’t know about potential long-term effects, since the trial is only set to run for two years.

During a meeting in October, an FDA advisory committee discussed the risk of “off-target” effects , which refers to when the gene-editing tool makes cuts to other stretches of DNA other than the intended target and how the FDA should consider those risks moving forward.

It’s unclear what effects an off-target edit would have on a patient, but the fear is that it could result in unintended health consequences down the road, Thompson said. “To date, there do not appear to be measurable consequences.”

The FDA did, however, add a boxed warning — the strongest safety warning label— to Bluebird Bio’s Lyfgenia, noting that in rare cases the treatment can cause certain blood cancers.

Dr. Nicole Verdun, director of the Office of Therapeutic Products in the FDA's Center for Biologics Evaluation and Research, said Lyfgenia was given the warning after two patients who got the therapy in a clinical trial died from a form of leukemia.

It's unclear whether the gene therapy itself or another part of the treatment process, such as the chemotherapy, caused the cancer, but Verdun said the agency thought the deaths "rose to the level of a black-box warning." No cases were seen in the Vertex clinical trial, she said.

Bhatia is following the patients for 15 years as part of a post-approval study for Casgevy and will be monitoring for signs of long-term effects.

“Long-term follow-up is still going to be so crucial,” she said.

Christopher Vega, 31, from Allentown, Pennsylvania, said the possibility of long-term effects aren’t a concern for him; he is happy to be living a life free of chronic pain.

He joined the clinical trial at the Children’s Hospital of Philadelphia in late 2020. He had suffered from chronic fatigue since he was a young child and would end up in the hospital every year with a pain crisis.

“When I was younger, my mom used to always tell me things happen for a reason. And I had so much trouble believing that, because I always thought, ‘Why me?’” he said.

While the treatment process was not always easy — Vega temporarily lost his hair, felt weak and nauseous and developed skin rashes — he said it was worth it.

“I am a whole different person,” said Vega, who is now attending the Los Angeles Film School online for visual effects while taking care of his 5-year-old daughter.

“Sometimes I would get small moments of anxiety that I would have a crisis,” he said. “And after going years now, I’m slowly coming to terms with, I’m OK, and I know I’m going to be here, present.”

Berkeley Lovelace Jr. is a health and medical reporter for NBC News. He covers the Food and Drug Administration, with a special focus on Covid vaccines, prescription drug pricing and health care. He previously covered the biotech and pharmaceutical industry with CNBC.

Marina Kopf is an associate producer with the NBC News Health and Medical Unit.

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NIH statement on new FDA-approved gene therapies for sickle cell disease

Today, the U.S. Food and Drug Administration (FDA) approved two gene therapies for the treatment of sickle cell disease in patients 12 years and older. About  100,000 Americans and millions of people  around the world have  sickle cell disease , a hereditary disease common among those whose ancestors come from sub-Saharan Africa, Mediterranean countries, India and the Middle East.

The U.S. National Institutes of Health (NIH) has long invested in basic genetics and genomics research, clinical trials, as well as translational medicine and social science studies, to advance our understanding of this widespread illness to help develop effective therapies.

For example:

• NIH investments in genome sequencing technology have led to the  costs of whole genome sequencing being over a million-fold less expensive  than a couple of decades ago. Affordable sequencing technology is critical to the diagnosis of sickle cell disease.  
• NIH researchers successfully edited the  disease-causing mutation in blood-forming cells  taken directly from people with sickle-cell disease. One of the new sickle cell treatments uses the CRISPR gene-editing system, a first for humans in the U.S.  
• NIH funds the  Cure Sickle Cell Initiative  to help speed the development of cures for sickle cell disease, which takes advantage of the latest genetic discoveries and technological advances to move the most promising genetic-based curative therapies safely into clinical trials.  
• NIH is working closely with the Centers for Medicare and Medicaid Services (CMS) to identify and reduce barriers to uptake and to support readiness of patients and clinicians for these therapies once available.  
• NIH leads  The Democratizing Education for Sickle Cell Disease Gene Therapy Project , a collaborative effort that aims to help patients and their support networks navigate emerging developments in gene therapies for sickle cell disease.

"NIH celebrates this enormous milestone in treatment for sickle cell disease, the first human genetic disease that was understood at the protein and DNA levels. Researchers have worked hard to find a long-term, durable therapy for sickle cell disease. Research has enabled the use of gene therapy to make genetic changes in the bone marrow of sickle cell patients, leading to normal red blood cell levels. None of this would be possible without federal investments in basic science research."

—Eric Green, M.D., Ph.D., Director of the National Human Genome Research Institute

"We have made some exciting research advances over the years and are ready to collect on our scientific investments in sickle cell research. However, we must remember that these advances need to go hand-in-hand with scalable innovations that will ensure equitable access to life-altering care and that we must continue to engage in additional research endeavors that will minimize or eliminate potential risks that might be associated with these therapies."

—Gary H. Gibbons, M.D., Director of the National Heart, Lung, and Blood Institute

“The sickle cell disease community has historically been underserved and underacknowledged when it comes to rare genetic conditions, so it is heartening to see sickle cell disease at the forefront of gene therapy. It is critical that people with sickle cell disease who are considering gene therapy fully understand the treatment so they can make an informed decision on whether it is appropriate for them. Patients need accessible, understandable and actionable educational materials to help them make such decisions, as well as support from practitioners and the healthcare system to consider these therapies.”

—Vence L. Bonham, Jr., J.D., Acting Deputy Director of the National Human Genome Research Institute

Additional Resources

For more information, visit:

• Sickle cell disease gene therapy education project
• Talking Glossary of Genomic and Genetic Terms: Sickle Cell Disease
• Sickle Cell Disease Treatment  (NHLBI)
• Sickle Cell Disease: Research, Programs, and Progress  (NHLBI)

About the National Heart, Lung, and Blood Institute (NHLBI):  NHLBI is the global leader in conducting and supporting research in heart, lung, and blood diseases and sleep disorders that advances scientific knowledge, improves public health, and saves lives. For more information, visit  www.nhlbi.nih.gov .

About the National Institutes of Health (NIH):  NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit  www.nih.gov .

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Sickle cell disease articles from across Nature Portfolio

Sickle cell disease is an autosomal recessive blood disorder that can lead to anaemia. It is caused by a mutation in the haemoglobin gene, which leads to deformation of red blood cells. Deformed red blood cells can obstruct small vessels and they are prone to destruction.

Latest Research and Reviews

Non-viral DNA delivery and TALEN editing correct the sickle cell mutation in hematopoietic stem cells

Sickle cell disease is a blood disorder that originates from a single point mutation in the HBB gene that codes for hemoglobin. Here, Moiani et al. developed an efficient TALEN-mediated HBB correction process that is compatible with gene therapy applications.

• Arianna Moiani
• Julien Valton

Brain network hypersensitivity underlies pain crises in sickle cell disease

• Minkyung Kim

Risk factors for acute chest syndrome among children with sickle cell anemia hospitalized for vaso-occlusive crises

• Faisal A. Alghamdi
• Fawaz Al-Kasim
• Rehab Alluqmani

Development of pathophysiologically relevant models of sickle cell disease and β-thalassemia for therapeutic studies

Sickle cell disease (SCD) and β-thalassemia (BT) are globally prevalent inherited blood disorders but, despite extensive research, no ex vivo system exists for SCD and BT. Here, the authors generate pathophysiologically relevant erythroid progenitor models of SCD and BT.

• Pragya Gupta
• Sangam Giri Goswami
• Sivaprakash Ramalingam

The value-based price of transformative gene therapy for sickle cell disease: a modeling analysis

• George Morgan
• Gregory F. Guzauskas

Evaluating sheep hemoglobins with MD simulations as an animal model for sickle cell disease

• Caroline E. Kuczynski
• Christopher D. Porada
• Graça Almeida-Porada

News and Comment

Autologous globin-edited HSCs ameliorate sickle cell disease

Gene correction for sickle cell disease hits its prime

Prime editing can efficiently rewrite the genetic mutation causing sickle cell disease, in haematopoietic stem cells from patients.

• Sébastien Levesque
• Daniel E. Bauer

Health-related quality of life in sickle cell disease

• Julie A. Panepinto
• Gregory J. Kato
• Wally R. Smith

Comparing health-related quality of life in chronic diseases: the importance of analyzing references

• Christine Maynié-François
• Stéphane Burtey

Omega-3 fatty acids are a potential therapy for patients with sickle cell disease

• Adrian Rabinowicz
• Kebreab Ghebremeskel

Sickle cell solutions in sight

New targets, new drug modalities and new business strategies are drawing long-awaited attention to sickle cell disease.

• Katie Kingwell

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Sickle Cell Disease : A Review

• 1 Division of General Pediatrics, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts
• 2 Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine and Texas Children’s Hospital, Houston
• 3 School of Medicine, Division of Hematology and Oncology, University of California Davis, Sacramento
• Comment & Response A Review of Sickle Cell Disease—Reply Patricia L. Kavanagh, MD; Titilope Fasipe, MD, PhD; Ted Wun, MD JAMA
• Comment & Response A Review of Sickle Cell Disease Nikolaos Vlachadis, MD, DMD, MPH, MSc, DSc; Nikolaos Vrachnis, MD, PhD JAMA
• JAMA Clinical Guidelines Synopsis Diagnosis and Management of Priapism Richard J. Fantus, MD; Robert E. Brannigan, MD; Andrew M. Davis, MD, MPH JAMA

Importance   Sickle cell disease (SCD) is an inherited disorder of hemoglobin, characterized by formation of long chains of hemoglobin when deoxygenated within capillary beds, resulting in sickle-shaped red blood cells, progressive multiorgan damage, and increased mortality. An estimated 300 000 infants are born annually worldwide with SCD. Most individuals with SCD live in sub-Saharan Africa, India, the Mediterranean, and Middle East; approximately 100 000 individuals with SCD live in the US.

Observations   SCD is diagnosed through newborn screening programs, where available, or when patients present with unexplained severe atraumatic pain or normocytic anemia. In SCD, sickling and hemolysis of red blood cells result in vaso-occlusion with associated ischemia. SCD is characterized by repeated episodes of severe acute pain and acute chest syndrome, and by other complications including stroke, chronic pain, nephropathy, retinopathy, avascular necrosis, priapism, and leg ulcers. In the US, nearly all children with SCD survive to adulthood, but average life expectancy remains 20 years less than the general population, with higher mortality as individuals transition from pediatric to adult-focused health care systems. Until 2017, hydroxyurea, which increases fetal hemoglobin and reduces red blood cell sickling, was the only disease-modifying therapy available for SCD and remains first-line therapy for most individuals with SCD. Three additional therapies, L-glutamine, crizanlizumab, and voxelotor, have been approved as adjunctive or second-line agents. In clinical trials, L-glutamine reduced hospitalization rates by 33% and mean length of stay from 11 to 7 days compared with placebo. Crizanlizumab reduced pain crises from 2.98 to 1.63 per year compared with placebo. Voxelotor increased hemoglobin by at least 1 g/dL, significantly more than placebo (51% vs 7%). Hematopoietic stem cell transplant is the only curative therapy, but it is limited by donor availability, with best results seen in children with a matched sibling donor. While SCD is characterized by acute and chronic pain, patients are not more likely to develop addiction to pain medications than the general population.

Conclusions and Relevance   In the US, approximately 100 000 people have SCD, which is characterized by hemolytic anemia, acute and chronic pain, acute chest syndrome; increased incidence of stroke, nephropathy, and retinopathy; and a life span that is 20 years shorter than the general population. While hydroxyurea is first-line therapy for SCD, L-glutamine, crizanlizumab, and voxelotor have been approved in the US since 2017 as adjunctive or second-line treatments, and hematopoietic stem cell transplant with a matched sibling donor is now standard care for severe disease.

Read More About

Kavanagh PL , Fasipe TA , Wun T. Sickle Cell Disease : A Review . JAMA. 2022;328(1):57–68. doi:10.1001/jama.2022.10233

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• Small molecule shows promise in lab models for treating sickle cell

Novel molecule SR-18292 found to reduce disease severity in SCD mice

by Marisa Wexler, MS | August 6, 2024

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A novel small molecule called SR-18292, which acts to boost the production of fetal hemoglobin, was shown to reduce disease severity in a mouse model of sickle cell disease (SCD) and demonstrated benefits in other lab testing in a new study.

“We’ve uncovered a promising approach that can offer hope to patients with sickle cell disease who have not responded to traditional treatments,” Shuaiying Cui, PhD, a researcher at the Boston Medical Center (BMC) Center of Excellence in Sickle Cell Disease and the study’s senior author, said in a BMC press release .

Experiments in human blood cells showed the anti-sickling effects of SR-18292 combined with hydroxyurea , an established SCD treatment thought to also act on fetal hemoglobin, were more potent when compared with those of either therapy alone.

“Our research shows that combining a small molecule with hydroxyurea enhances the production of fetal hemoglobin through different mechanisms. This could provide a vital new treatment option for sickle cell disease patients who don’t respond well to hydroxyurea alone,” Cui said.

The study, “ PGC-1α agonism induces fetal hemoglobin and exerts antisickling effects in sickle cell disease ,” was published in the journal Science Advances .

1st SCD patient soon to be given therapy to restore fetal hemoglobin

Small molecule sr-18292 increased fetal hemoglobin in human blood cells.

Sickle cell disease is caused by mutations that lead to the production of an abnormal form of hemoglobin — the protein that red blood cells use to carry oxygen throughout the body. The abnormal hemoglobin tends to clump up inside red blood cells, deforming them into the sickle-like shape that gives the disease its name and ultimately drives its symptoms .

SCD specifically affects the adult version of hemoglobin. Fetal hemoglobin, or HbF for short, is an alternative version of this protein that’s made during early fetal development. Normally, the body stops making HbF and switches on the production of the adult version of hemoglobin shortly after birth.

In people with sickle cell, boosting HbF levels has been shown as a viable strategy for reducing red blood cell sickling and ultimately combatting the disease. However, treatment options targeting HbF are limited.

Previous research has shown that activating PGC-1 alpha, a protein that helps regulate the activity of various genes within cells, can increase HbF production in blood cells. Spurred on by that discovery, researchers at BMC tested the effects of SR-18292, a small molecule that activates PGC-1 alpha, in cell and animal models of SCD.

Initial experiments in human blood stem cells confirmed that SR-18292 treatment was able to increase HbF levels as expected.

Importantly, the researchers noted that the effect of SR-18292 combined with hydroxyurea was more potent at boosting HbF production than either therapy on its own.

Genetic analyses conducted in human blood stem cells also indicated that SR-18292 increased the activity of several genes that are known to boost HbF production. At the same time, the researchers also found that SR-18292 decreased the activity of genes that normally act to turn off HbF production, including BCL11A , which is the gene targeted by Casgevy (exagamglogene autotemcel) — a CRISPR/Cas9-based gene-editing therapy approved late last year for SCD.

Fewer infections in youth with sickle cell anemia on hydroxyurea

Scientists call sr-18292 a ‘promising’ potential scd treatment.

Following the cell experiments, the researchers tested the effects of this small molecule in a mouse model of SCD. In line with the cell experiments, results in mice showed that SR-18292 was able to boost HbF production.

SR-18292-treated mice also showed fewer signs of premature red blood cell destruction and organ damage compared with their untreated counterparts. The researchers also found evidence suggesting that SR-18292 increased the lifespan of red blood cells in SCD mice and reduced the number of sickled cells in treated animals.

“Induction of HbF by SR-18292 with improved [blood cell health] and reduced organ damage in SCD mice suggests that this small-molecule activator of PGC-1 [alpha] might be a new class of drugs that alone or in combination with other agents can enhance clinically useful increments of HbF,” the researchers wrote.

This breakthrough represents a significant step forward in BMC’s quest for more effective therapies to treat sickle cell disease for all patients.

The team noted that, in addition to suggesting that SR-18292 may be an effective sickle cell treatment, the results more broadly show “proof of principle for targeting PGC-1 [alpha] and its modulators to develop more effective HbF-boosting agents for SCD.”

Overall, the scientists concluded that “SR-18292, or agents in its class, could be a promising additional therapeutic for sickle cell disease.”

Cui said that the team hopes this treatment strategy may one day be used to help sickle cell patients worldwide manage their disease, especially those who don’t have access to cutting-edge, expensive treatments like gene therapies.

“This breakthrough represents a significant step forward in BMC’s quest for more effective therapies to treat sickle cell disease for all patients,” Cui said.

About the Author

Recent Posts

• Returning to work after an illness requires a considered approach
• Scientist earns Trailblazer Prize for work aiding Casgevy development
• FDA clears testing of potentially less toxic conditioning regimen for SCD
• Advancing representation of Black and sickle cell communities in media
• 1 step forward, 2 steps back — and trying to stay sane through it all
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Evolution of Extracranial Internal Carotid Artery Disease in Children With Sickle Cell Anemia

Affiliations.

• 1 Referral Center for Sickle Cell Disease, Department of Pediatric Imaging (S.V., C.O., I.C., S.B., A.K., A.N., H.O., A.T., A.S., N.B., M.E., M.A.), Robert-Debre Hospital, AP-HP, Nord, Paris University, France.
• 2 Department of Pediatrics (G.I.), Robert-Debre Hospital, AP-HP, Nord, Paris University, France.
• 3 Referral Center for Sickle Cell Disease, Department of Clinical Research, Intercommunal Creteil Hospital, France (F.B.).
• PMID: 35387492
• DOI: 10.1161/STROKEAHA.121.037980

Background: Cerebral arteriopathy in patients with sickle cell anemia mainly affects the intracranial anterior circulation. However, the extracranial internal carotid artery (eICA) can also be stenosed and responsible for ischemic lesions. In children with sickle cell anemia, we perform routine annual Doppler ultrasound assessment of the eICA and magnetic resonance imaging with 3-dimensional time-of-flight magnetic resonance angiography of the Willis circle and neck arteries in those with abnormal velocity. Our aim was to report the evolution of eICA stenoses from 2011 to the present as a function of therapy in a retrospective case-series study. We hypothesized that chronic transfusion (CTT) would be more effective than hydroxyurea and simple observation on the evolution of eICA stenosis.

Methods: Eligibility criteria were a history of eICA velocity ≥160 cm/s with a minimum Doppler and magnetic resonance imaging follow-up of 1 year. eICAs were graded for stenosis according to NASCET (The North American Symptomatic Carotid Endarterectomy Trial). Magnetic resonance imaging was investigated for ischemic lesions. Treatment with hydroxyurea and CTT were obtained from the chart review.

Results: Fifty-four patients were included. Eight patients had a stroke history. The median (range) follow-up was 4.7 years (1.1-9.2 years). On the first neck magnetic resonance angiography, stenosis was present in 48/54 (89%) patients. Kinking was found in 39/54 (72%) patients. On the last neck magnetic resonance angiography, the proportion of patients with eICA stenosis decreased to 39/54 (72%). ICA occlusion occurred in 5 patients despite CTT. Three patients had carotid webs without intracranial stenosis. The proportion of patients with improvement in stenosis score was 8% with no treatment intensification, 20% with hydroxyurea, and 48% with CTT ( P =0.016). The mean (SD) change per year in stenosis score was 0.40 (0.60) without intensification, 0.20 (0.53) with hydroxyurea, and -0.18 (0.55) with CTT ( P =0.006). Ischemic lesions were present initially in 46% of patients, and the incidence of progressive ischemic lesions was 2.5 events/100 patient-years. Cox regression analysis showed that the initial score for eICA stenosis was a significant predictive factor for the risk of new silent cerebral infarct events.

Conclusions: Our study reinforces the need to assess cervical arteries for better prevention of cerebral ischemia and encourage initiation of CTT in sickle cell anemia children with eICA stenosis.

Keywords: anemia, sickle cell; carotid arteries; magnetic resonance angiography; ultrasonography, Doppler.

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• J Hematol Oncol

Advances in the diagnosis and treatment of sickle cell disease

A. m. brandow.

1 Department of Pediatrics, Section of Pediatric Hematology/Oncology/Bone Marrow Transplantation, Medical College of Wisconsin, Milwaukee, WI USA

2 Division of Hematology, Oncology and Stem Cell Transplantation, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL USA

Associated Data

Not applicable.

Sickle cell disease (SCD), which affects approximately 100,000 individuals in the USA and more than 3 million worldwide, is caused by mutations in the βb globin gene that result in sickle hemoglobin production. Sickle hemoglobin polymerization leads to red blood cell sickling, chronic hemolysis and vaso-occlusion. Acute and chronic pain as well as end-organ damage occur throughout the lifespan of individuals living with SCD resulting in significant disease morbidity and a median life expectancy of 43 years in the USA. In this review, we discuss advances in the diagnosis and management of four major complications: acute and chronic pain, cardiopulmonary disease, central nervous system disease and kidney disease. We also discuss advances in disease-modifying and curative therapeutic options for SCD. The recent availability of l -glutamine, crizanlizumab and voxelotor provides an alternative or supplement to hydroxyurea, which remains the mainstay for disease-modifying therapy. Five-year event-free and overall survival rates remain high for individuals with SCD undergoing allogeneic hematopoietic stem cell transplant using matched sibling donors. However, newer approaches to graft-versus-host (GVHD) prophylaxis and the incorporation of post-transplant cyclophosphamide have improved engraftment rates, reduced GVHD and have allowed for alternative donors for individuals without an HLA-matched sibling. Despite progress in the field, additional longitudinal studies, clinical trials as well as dissemination and implementation studies are needed to optimize outcomes in SCD.

Introduction

Sickle cell disease (SCD), a group of inherited hemoglobinopathies characterized by mutations that affect the β-globin chain of hemoglobin, affects approximately 100,000 people in the USA and more than 3 million people worldwide [ 1 , 2 ]. SCD is characterized by chronic hemolytic anemia, severe acute and chronic pain as well as end-organ damage that occurs across the lifespan. SCD is associated with premature mortality with a median age of death of 43 years (IQR 31.5–55 years) [ 3 ]. Treatment requires early diagnosis, prevention of complications and management of end-organ damage. In this review, we discuss recent advances in the diagnosis and management of four major complications in SCD: acute and chronic pain, cardiopulmonary disease, central nervous system disease and kidney disease. Updates in disease-modifying and curative therapies for SCD are also discussed.

Molecular basis and pathophysiology

Hemoglobin S (HbS) results from the replacement of glutamic acid by valine in the sixth position of the β-globin chain of hemoglobin (Fig.  1 ). Severe forms of SCD include hemoglobin SS due to homozygous inheritance of HbS and S/β 0 thalassemia due to co-inheritance of HbS with the β 0 thalassemia mutation. Other forms include co-inheritance of HbS with other β-globin gene mutations such as hemoglobin C, hemoglobin D-Los Angeles/Punjab or β + thalassemia. Hb S has reduced solubility and increased polymerization, which cause red blood cell sickling, hemolysis and vaso-occlusion (Table ​ (Table1) 1 ) that subsequently lead to pain episodes and end-organ damage such as cardiopulmonary, cerebrovascular and kidney disease (Table ​ (Table2 2 ).

Genetic and molecular basis of sickle cell disease. SCD is caused by mutations in the β globin gene, located on the β globin locus found on the short arm of chromosome 11. The homozygous inheritance of Hb S or co-inheritance of Hb S with the β 0 thalassemia mutation results in the most common forms of severe SCD. Co-inheritance of Hb S with other variants such as Hb C, Hb D-Los Angeles/Punjab, Hb O-Arab or β + thalassemia also leads to clinically significant sickling syndromes (LCR, locus control region; HS, hypersensitivity site)

Sickle cell disease

Prevalence and pathophysiologic basis of major complications in SCD

Acute and chronic pain

Severe intermittent acute pain is the most common SCD complication and accounts for over 70% of acute care visits for individuals with SCD [ 4 ]. Chronic daily pain increases with older age, occurring in 30–40% of adolescents and adults with SCD [ 5 , 6 ]. Acute pain is largely related to vaso-occlusion of sickled red blood cells with ischemia–reperfusion injury and tissue infarction and presents in one isolated anatomic location (e.g., arm, leg, back) or multiple locations. Chronic pain can be caused by sensitization of the central and/or peripheral nervous system and is often diffuse with neuropathic pain features [ 7 , 8 ]. A consensus definition for chronic pain includes “Reports of ongoing pain on most days over the past 6 months either in a single location or multiple locations” [ 9 ]. Disease complications such as avascular necrosis (hip, shoulder) and leg ulcers also cause chronic pain [ 9 ].

Diagnosis of acute and chronic pain

The gold standard for pain assessment and diagnosis is patient self-report. There are no reliable diagnostic tests to confirm the presence of acute or chronic pain in individuals with SCD except when there are identifiable causes like avascular necrosis on imaging or leg ulcers on exam. The effects of pain on individuals’ function are assessed using patient-reported outcome measures (PROs) that determine to what extent pain interferes with individuals’ daily function. Tools shown to be valid, reliable and responsive can be used in clinical practice to track patients’ pain-related function over time to determine additional treatment needs and to compare to population norms [ 10 ]. There are currently no plasma pain biomarkers that improve assessment and management of SCD acute or chronic pain.

Depression and anxiety as co-morbid conditions in SCD can contribute to increased pain, more pain-related distress/interference and poor coping [ 11 ]. The prevalence of depression and anxiety range from 26–33% and 6.5–36%, respectively, in adults with SCD [ 11 – 13 ]. Adults with SCD have an 11% higher prevalence of depression compared to Black American adults without SCD [ 14 ]. Depression and anxiety can be assessed using self-reported validated screening tools (e.g., Depression: Patient Health Questionnaire (PHQ-9) [ 15 ] for adults, Center for Epidemiologic Studies Depression Scale for Children (CES-DC) [ 16 ], PROMIS assessments for adults and children; Anxiety: Generalized Anxiety Disorder 7-item (GAD-7) scale for adults, State-Trait Anxiety Inventory for Children (STAIC) [ 17 ], PROMIS assessments for adults and children). Individuals who screen positive using these tools should be referred for evaluation by a psychologist/psychiatrist.

Management of acute and chronic pain

The goal of acute pain management is to provide sufficient analgesia to return patients to their usual function, which may mean complete resolution of pain for some or return to baseline chronic pain for others. The goal of chronic pain management is to optimize individuals’ function, which may not mean being pain free. When there is an identifiable cause of chronic pain, treatment of the underlying issue (e.g., joint replacement for avascular necrosis, leg ulcer treatment) is important. Opioids, oral for outpatient management and intravenous for inpatient management, are first line therapy for acute SCD pain. In the acute care setting, analgesics should be initiated within 30–60 min of triage [ 18 ]. Ketamine, a non-opioid analgesic, can be prescribed at sub-anesthetic (analgesic) intravenous doses (0.1–0.3 mg/kg per h, maximum 1 mg/kg per h) as adjuvant treatment for acute SCD pain refractory to opioids [ 18 , 19 ]. In an uncontrolled observational study of 85 patients with SCD receiving ketamine infusions for acute pain, ketamine was associated with a decrease in mean opioid consumption by oral morphine equivalents (3.1 vs. 2.2 mg/kg/day, p  < 0.001) and reductions in mean pain scores (0–10 scale) from baseline until discontinuation of the infusion (7.81 vs. 5.44, p  < 0.001) [ 20 ]. Nonsteroidal anti-inflammatory drugs (NSAIDs) are routinely used as adjuvant therapy for acute pain treatment [ 18 ]. In a RCT ( n  = 20) of hospitalized patients with acute pain, ketorolac was associated with lower total dose of meperidine required (1866.7 ± 12.4 vs. 2804.5 ± 795.1 mg, p  < 0.05) and shorter hospitalization (median 3.3 vs. 7.2 days, p  = 0.027) [ 21 ]. In a case series of children treated for 70 acute pain events in the ED, 53% of events resolved with ketorolac and hydration alone with reduction in 100 mm visual analog scale (VAS) pain score from 60 to 13 ( p  < 0.001) [ 22 ]. Patients at risk for NSAID toxicity (e.g., renal impairment, on anticoagulation) should be identified.

Despite paucity of data, chronic opioid therapy (COT) can be considered after assessing benefits versus harms [ 23 ] and the functional status of patients with SCD who have chronic pain. Harms of COT seen in patient populations other than SCD are dose dependent and include myocardial infarction, bone fracture, increased risk of motor vehicle collisions, sexual dysfunction and mortality [ 23 ]. There are few published studies investigating non-opioid analgesics for chronic SCD pain [ 24 – 26 ]. In a randomized trial of 39 participants, those who received Vitamin D experienced a range of 6–10 pain days over 24 weeks while those who received placebo experienced 10–16 pain days, which was not significantly different [ 26 ]. In a phase 1, uncontrolled trial of 18 participants taking trifluoperazine, an antipsychotic drug, 8 participants showed a 50% reduction in the VAS (10 cm horizontal line) pain score from baseline on at least 3 assessments over 24 h without severe sedation or supplemental opioid analgesics, 7 participants showed pain reduction on 1 assessment, and the remaining 3 participants showed no reduction [ 24 ]. Although published data are not available for serotonin and norepinephrine reuptake inhibitors (SNRIs), gabapentinoids and tricyclic antidepressants (TCAs) in individuals with SCD, evidence supports their use in fibromyalgia, a chronic pain condition similar to SCD chronic pain in mechanism. A Cochrane Review that included 10 RCTs ( n  = 6038) showed that the SNRIs milnacipran and duloxetine, compared to placebo, were associated with a reduction in pain [ 27 ]. A systematic review and meta-analysis of 9 studies ( n  = 520) showed the TCA amitriptyline improved pain intensity and function [ 28 ]. Finally, a meta-analysis of 5 RCTs ( n  = 1874) of the gabapentinoid pregabalin showed a reduction in pain intensity [ 29 ]. Collectively, the indirect evidence from fibromyalgia supports the conditional recommendation in current SCD practice guidelines to consider these 3 drug classes for chronic SCD pain treatment [ 18 ]. Standard formulary dosing recommendations should be followed and reported adverse effects considered.

Non-pharmacologic therapies (e.g., integrative, psychological-based therapies) are important components of SCD pain treatment. In a case–control study of 101 children with SCD and chronic pain referred for cognitive behavioral therapy (CBT) (57 CBT, 44 no CBT) [ 30 ], CBT was associated with more rapid decrease in pain hospitalizations (estimate − 0.63, p  < 0.05) and faster reduction in hospital days over time (estimate − 5.50, p  < 0.05). Among 18 children who received CBT and completed PROs pre- and 12 months posttreatment, improvements were seen in mean pain intensity (5.47 vs. 3.76, p  = 0.009; 0–10 numeric rating pain scale), functional disability (26.24 vs. 15.18, p  < 0.001; 0–60 score range) and pain coping (8.00 vs. 9.65, p  = 0.03; 3–15 score range) post treatment [ 30 ]. In 2 uncontrolled clinical trials, acupuncture was associated with a significant reduction in pain scores by 2.1 points (0–10 numeric pain scale) in 24 participants immediately after treatment [ 31 ] or a significant mean difference in pre-post pain scores of 0.9333 (0–10 numeric pain scale) ( p  < 0.000) after 33 acupuncture sessions [ 32 ].

Cardiopulmonary disease

Cardiopulmonary disease is associated with increased morbidity and mortality in individuals with SCD. Pulmonary hypertension (PH), most commonly pulmonary arterial hypertension (PAH), is present based on right-heart catheterization in up to 10% of adults with SCD [ 33 ]. Chronic intravascular hemolysis represents the biggest risk factor for development of PAH in SCD and leads to pulmonary arteriole vasoconstriction and smooth muscle proliferation. Based on pulmonary function testing (PFT), obstructive lung disease may be observed in 16% of children and 8% of adults with SCD, while restrictive lung disease may be seen in up to 28% of adults and only 7% of children with SCD [ 34 , 35 ]. Sleep-disordered breathing, which can manifest as obstructive sleep apnea or nocturnal hypoxemia, occurs in up to 42% of children and 46% of adults with SCD [ 36 , 37 ]. Cardiopulmonary disease, including PH or restrictive lung disease, presents with dyspnea with or without exertion, chest pain, hypoxemia or exercise intolerance that is unexplained or increased from baseline. Obstructive lung disease can also present with wheezing.

Diagnosis of cardiopulmonary disease

The confirmation of PH in patients with SCD requires right-heart catheterization. Recently, the mean pulmonary artery pressure threshold used to define PH in the general population was lowered from ≥ 25 to ≥ 20 mm Hg [ 38 ]. Elevated peak tricuspid regurgitant jet velocity (TRJV) ≥ 2.5 m/s on Doppler echocardiogram (ECHO) is associated with early mortality in adults with SCD and may suggest elevated pulmonary artery pressures, especially when other signs of PH (e.g., right-heart strain, septal flattening) or left ventricular diastolic dysfunction, which may contribute to PH, are present [ 39 ]. However, the positive predictive value (PPV) of peak TRJV alone for identifying PH in adults with SCD is only 25% [ 40 ]. Increasing the peak TRJV threshold to at least 2.9 m/s has been shown to increase the PPV to 64%. For a peak TRJV of 2.5–2.8 m/s, an increased N-terminal pro-brain natriuretic peptide (NT-proBNP) ≥ 164.5 pg/mL or a reduced 6-min walk distance (6MWD) < 333 m can also improve the PPV to 62% with a false negative rate of 7% [ 33 , 40 , 41 ].

PFT, which includes spirometry and measurement of lung volumes and diffusion capacity, is standard for diagnosing obstructive and restrictive lung disease in patients with SCD. Emerging modalities include impulse oscillometry, a non-invasive method using forced sound waves to detect changes in lower airway mechanics in individuals unable to perform spirometry [ 42 ], and airway provocation studies using cold air or methacholine to reveal latent airway hyperreactivity [ 43 ]. Formal in-lab, sleep study/polysomnography remains the gold standard to evaluate for sleep-disordered breathing, which may include nocturnal hypoxemia, apnea/hypopnea events and other causes of sleep disruption. Nocturnal hypoxemia may increase red blood cell sickling, cellular adhesion and endothelial dysfunction. In 47 children with SCD, mean overnight oxygen saturation was higher in those with grade 0 compared to grade 2 or 3 cerebral arteriopathy (97 ± 1.6 vs. 93.9 ± 3.7 vs. 93.5 ± 3.0%, p  < 0.01) on magnetic resonance angiography and lower overnight oxygen saturation was independently associated with mild, moderate or severe cerebral arteriopathy after adjusting for reticulocytosis (OR 0.50, 95% CI 0.26–0.96, p  < 0.05) [ 44 ].

Management of cardiopulmonary disease

Patients with SCD who have symptoms suggestive of cardiopulmonary disease, such as worsening dyspnea, hypoxemia or reduced exercise tolerance, should be evaluated with a diagnostic ECHO and PFT. The presence of snoring, witnessed apnea, respiratory pauses or hypoxemia during sleep, daytime somnolence or nocturnal enuresis in older children and adults is sufficient for a diagnostic sleep study.

Without treatment, the mortality rate in SCD patients with PH is high compared to those without (5-year, all-cause mortality rate of 32 vs. 16%, p  < 0.001) [ 33 ]. PAH-targeted therapies should be considered for SCD patients with PAH confirmed by right-heart catheterization. However, the only RCT ( n  = 6) in individuals with SCD and PAH confirmed by right-heart catheterization (bosentan versus placebo) was stopped early for poor accrual with no efficacy endpoints analyzed [ 45 ]. In SCD patients with elevated peak TRJV, a randomized controlled trial ( n  = 74) of sildenafil, a phosphodiesterase-5 inhibitor, was discontinued early due to increased pain events in the sildenafil versus placebo arm (35 vs. 14%, p  = 0.029) with no treatment benefit [ 46 ]. Despite absence of clinical trial data, patients with SCD and confirmed PH should be considered for hydroxyurea or monthly red blood cell transfusions given their disease-modifying benefits. In a retrospective analysis of 13 adults with SCD and PAH, 77% of patients starting at a New York Heart Association (NYHA) functional capacity class III or IV achieved class I/II after a median of 4 exchange transfusions with improvement in median pulmonary vascular resistance (3.7 vs. 2.8 Wood units, p  = 0.01) [ 47 ].

Approximately 28% of children with SCD have asthma, which is associated with increased pain episodes that may result from impaired oxygenation leading to sickling and vaso-occlusion as well as with acute chest syndrome and higher mortality [ 48 – 50 ]. First line therapies include standard beta-adrenergic bronchodilators and supplemental oxygen as needed. When corticosteroids are indicated, courses should be tapered over several days given the risk of rebound SCD pain from abrupt discontinuation. Inhaled corticosteroids such as fluticasone proprionate or beclomethasone diproprionate are reserved for patients with recurrent asthma exacerbations, but their anti-inflammatory effects and impact on preventing pain episodes in patients with SCD who do not have asthma is under investigation [ 51 ]. Finally, management of sleep-disordered breathing is tailored to findings on formal sleep study in consultation with a sleep/pulmonary specialist.

Central nervous system (CNS) complications

CNS complications, such as overt and silent cerebral infarcts, cause significant morbidity in individuals with SCD. Eleven percent of patients with HbSS disease by age 20 years and 24% by age 45 years will have had an overt stroke [ 52 ]. Silent cerebral infarcts occur in 39% by 18 years and in > 50% by 30 years [ 53 , 54 ]. Patients with either type of stroke are at increased risk of recurrent stroke [ 55 ]. Overt stroke involves large-arteries, including middle cerebral arteries and intracranial internal carotid arteries, while silent cerebral infarcts involve penetrating arteries. The pathophysiology of overt stroke includes vasculopathy, increased sickled red blood cell adherence, and hemolysis-induced endothelial activation and altered vasomotor tone [ 56 ]. Overt strokes present as weakness or paresis, dysarthria or aphasia, seizures, sensory deficits, headache or altered level of consciousness, while silent cerebral infarcts are associated with cognitive deficits, including lower IQ and impaired academic performance.

Diagnosis of CNS complications in SCD

Overt stroke is diagnosed by evidence of acute infarct on brain MRI diffusion-weighted imaging and focal deficit on neurologic exam. A silent cerebral infarct is defined by a brain “MRI signal abnormality at least 3 mm in one dimension and visible in 2 planes on fluid-attenuated inversion recovery (FLAIR) T2-weighted images” and no deficit on neurologic exam [ 57 ]. Since silent cerebral infarcts cannot be detected clinically, a screening baseline brain MRI is recommended in school-aged children with SCD [ 58 ]. Recent SCD clinical practice guidelines also suggest a screening brain MRI in adults with SCD to facilitate rehabilitation services, patient and family understanding of cognitive deficits and further needs assessment [ 58 ]. An MRA should be added to screening/diagnostic MRIs to evaluate for cerebral vasculopathy (e.g., moyamoya), which may increase risk for recurrent stroke or hemorrhage [ 59 ].

Annual screening for increased stroke risk by transcranial doppler (TCD) ultrasound is recommended by the American Society of Hematology for children 2–16 years old with HbSS or HbS/β° thalassemia [ 58 ]. Increased stroke risk on non-imaging TCD is indicated by abnormally elevated cerebral blood flow velocity, defined as ≥ 200 cm/s (time-averaged mean of the maximum velocity) on 2 occasions or a single velocity of > 220 cm/s in the distal internal carotid or proximal middle cerebral artery [ 60 ]. Many centers rely on imaging TCD, which results in velocities 10–15% lower than values obtained by non-imaging protocols and therefore, require adjustments to cut-offs for abnormal velocities. Data supporting stroke risk assessment using TCD are lacking for adults with SCD and standard recommendations do not exist.

Neurocognitive deficits occur in over 30% of children and adults with severe SCD [ 61 , 62 ]. These occur as a result of overt and/or silent cerebral infarcts but in some patients, the etiology is unknown. The Bright Futures Guidelines for Health Supervision of Infants, Children and Adolescents or the Cognitive Assessment Toolkit for adults are commonly used tools to screen for developmental delays or neurocognitive impairment [ 58 ]. Abnormal results should prompt referral for formal neuropsychological evaluation, which directs the need for brain imaging to evaluate for silent cerebral infarcts and facilitate educational/vocational accommodations.

Management of CNS complications

Monthly chronic red blood cell transfusions to suppress HbS < 30% are standard of care for primary stroke prevention in children with an abnormal TCD. In an RCT of 130 children, chronic transfusions, compared to no transfusions, were associated with a difference in stroke risk of 92% (1 vs. 10 strokes, p  < 0.001) [ 60 ]. However, children with abnormal TCD and no MRI/MRA evidence of cerebral vasculopathy can safely transition to hydroxyurea after 1 year of transfusions [ 63 ]. Lifelong transfusions to maintain HbS < 30% remain standard of care for secondary stroke prevention in individuals with overt stroke [ 64 ]. Chronic monthly red blood cell transfusions should also be considered for children with silent cerebral infarct [ 58 ]. In a randomized controlled trial ( n  = 196), monthly transfusions, compared to observation without hydroxyurea, reduced risk of overt stroke, new silent cerebral infarct or enlarging silent cerebral infarct in children with HbSS or HbS/β 0 thalassemia and an existing silent cerebral infarct (2 vs. 4.8 events, incidence rate ratio of 0.41, 95% CI 0.12–0.99, p  = 0.04) [ 57 ].

Acute stroke treatment requires transfusion therapy to increase cerebral oxygen delivery. Red blood cell exchange transfusion, defined as replacement of patients’ red blood cells with donor red blood cells, to rapidly reduce HbS to < 30% is the recommended treatment as simple transfusion alone is shown to have a fivefold greater relative risk (57 vs. 21% with recurrent stroke, RR = 5.0; 95% CI 1.3–18.6) of subsequent stroke compared to exchange transfusion [ 65 ]. However, a simple transfusion is often given urgently while preparing for exchange transfusion [ 58 ]. Tissue plasminogen activator (tPA) is not recommended for children with SCD who have an acute stroke since the pathophysiology of SCD stroke is less likely to be thromboembolic in origin and there is risk for harm. Since the benefits and risks of tPA in adults with SCD and overt stroke are not clear, its use depends on co-morbidities, risk factors and stroke protocols but should not delay or replace prompt transfusion therapy.

Data guiding treatment of SCD cerebral vasculopathy (e.g., moyamoya) are limited, and only nonrandomized, low-quality evidence exists for neurosurgical interventions (e.g., encephaloduroarteriosynangiosis) [ 66 ]. Consultation with a neurosurgeon to discuss surgical options in patients with moyamoya and history of stroke or transient ischemic attack should be considered [ 58 ].

Kidney disease

Glomerulopathy, characterized by hyperfiltration leading to albuminuria, is an early asymptomatic manifestation of SCD nephropathy and worsens with age. Hyperfiltration, defined by an absolute increase in glomerular filtration rate, may be seen in 43% of children with SCD [ 67 ]. Albuminuria, defined by the presence of urine albumin ≥ 30 mg/g over 24 h, has been observed in 32% of adults with SCD [ 68 ]. Glomerulopathy results from intravascular hemolysis and endothelial dysfunction in the renal cortex. Medullary hypoperfusion and ischemia also contribute to kidney disease in SCD, causing hematuria, urine concentrating defects and distal tubular dysfunction [ 69 ]. Approximately 20–40% of adults with SCD develop chronic kidney disease (CKD) and are at risk of developing end-stage renal disease (ESRD), with rapid declines in estimated glomerular filtration rate (eGFR) > 3 mL/min/1.73 m 2 associated with increased mortality (HR 2.4, 95% CI 1.31–4.42, p  = 0.005) [ 68 ].

Diagnosis of kidney disease in SCD

The diagnosis of sickle cell nephropathy is made by detecting abnormalities such as albuminuria, hematuria or CKD rather than by distinct diagnostic criteria in SCD, which have not been developed. Traditional markers of kidney function such as serum creatinine and eGFR should be interpreted with caution in individuals with SCD because renal hyperfiltration affects their accuracy by increasing both. Practical considerations preclude directly measuring GFR by urine or plasma clearance techniques, which achieves the most accurate results. The accuracy of eGFR, however, may be improved by equations that incorporate serum cystatin C [ 70 ].

Since microalbuminuria/proteinuria precedes CKD in SCD, annual screening for urine microalbumin/protein is recommended beginning at age 10 years [ 71 ]. When evaluating urine for microalbumin concentration, samples from first morning rather than random voids are preferable to exclude orthostatic proteinuria. Recent studies suggest HMOX1 and APOL1 gene variants may be associated with CKD in individuals with SCD [ 72 ]. Potential novel predictors of acute kidney injury in individuals with SCD include urine biomarkers kidney injury molecule 1 (KIM-1) [ 73 ], monocyte chemotactic protein 1 (MCP-1) [ 74 ] and neutrophil gelatinase-associated lipocalin (NGAL) [ 75 ]. Their contribution to chronic kidney disease and interaction with other causes of kidney injury in SCD (e.g., inflammation, hemolysis) are not clear.

Management of kidney disease

Managing kidney complications in SCD should focus on mitigating risk factors for acute and chronic kidney injury such as medication toxicity, reduced kidney perfusion from hypotension and dehydration, and general disease progression, as well as early screening and treatment of microalbuminuria/proteinuria. Acute kidney injury, either an increase in serum creatinine ≥ 0.3 mg/dL or a 50% increase in serum creatinine from baseline, is associated with ketorolac use in children with SCD hospitalized for pain [ 76 ]. Increasing intravenous fluids to maintain urine output > 0.5 to 1 mL/kg/h and limiting NSAIDs and antibiotics associated with nephrotoxicity in this setting are important. Despite absence of controlled clinical trials, hydroxyurea may be associated with improvements in glomerular hyperfiltration and urine concentrating ability in children with SCD [ 77 , 78 ]. Hydroxyurea is also associated with a lower prevalence (34.7 vs. 55.4%, p  = 0.01) and likelihood of albuminuria (OR 0.28, 95% CI 0.11–0.75, p  = 0.01) in adults with SCD after adjusting for age, angiotensin-converting enzyme inhibitor (ACE-I)/angiotensin receptor blockade (ARB) use and major disease risk factors [ 79 ].

ACE-I or ARB therapy reduces microalbuminuria in patients with SCD. In a phase 2 trial of 36 children and adults, a ≥ 25% reduction in urine albumin-to-creatinine ratio was observed in 83% ( p  < 0.0001) and 58% ( p  < 0.0001) of patients with macroalbuminuria (> 300 mg/g creatinine) and microalbuminuria (30–300 mg/g creatinine), respectively, after 6 months of treatment with losartan at a dose of 0.7 mg/kg/day (max of 50 mg) in children and 50 mg daily in adults [ 80 ]. However, ACE-I or ARB therapy has not been shown to improve kidney function or prevent CKD. Hemodialysis is associated with a 1-year mortality rate of 26.3% after starting hemodialysis and an increase risk of death in SCD patients with ESRD compared to non-SCD patients with ESRD (44.6 vs. 34.5% deaths, mortality hazard ratio of 2.8, 95% CI 2.31–3.38) [ 81 ]. Renal transplant should be considered for individuals with SCD and ESRD because of recent improvements in renal graft survival and post-transplant mortality [ 82 ].

Disease-modifying therapies in SCD

Since publication of its landmark trial in 1995, hydroxyurea continues to represent a mainstay of disease-modifying therapy for SCD. Hydroxyurea induces fetal hemoglobin production through stress erythropoiesis, reduces inflammation, increases nitric oxide and decreases cell adhesion. The FDA approved hydroxyurea in 1998 for adults with SCD. Subsequently, hydroxyurea was FDA approved for children in 2017 to reduce the frequency pain events and need for blood transfusions in children ≥ 2 years of age [ 63 ]. The landscape of disease-modifying therapies, however, has improved with the recent FDA approval of 3 other treatments— l -glutamine and crizanlizumab for reducing acute complications (e.g., pain), and voxelotor for improving anemia (Table ​ (Table3) 3 ) [ 83 – 85 ]. Other therapies in current development focus on inducing fetal hemoglobin, reducing anti-sickling or cellular adhesion, or activating pyruvate kinase-R.

Major FDA-approved therapies for the treatment of SCD

l -glutamine

Glutamine is required for the synthesis of glutathione, nicotinamide adenine dinucleotide and arginine. The essential amino acid protects red blood cells against oxidative damage, which forms the basis for its proposed utility in SCD. The exact mechanism of benefit in SCD, however, remains unclear. In a phase 3 RCT of 230 participants (hemoglobin SS or S/β 0 thalassemia), l -glutamine compared to placebo was associated with fewer pain events (median 3 vs. 4, p  = 0.005) and hospitalizations for pain (median 2 vs. 3, p  = 0.005) over the 48-week treatment period [ 84 ]. The percentage of patients who had at least 1 episode of acute chest syndrome, defined as presence of chest wall pain with fever and a new pulmonary infiltrate, was lower in the l -glutamine group (8.6 vs. 23.1%, p  = 0.003). There were no significant between-group differences in hemoglobin, hematocrit or reticulocyte count. Common side effects of l -glutamine include GI upset (constipation, nausea, vomiting and abdominal pain) and headaches.

Crizanlizumab

P-selectin expression, triggered by inflammation, promotes adhesion of neutrophils, activated platelets and sickle red blood cells to the endothelial surface and to each other, which promotes vaso-occlusion in SCD. Crizanlizumab, given as a monthly intravenous infusion, is a humanized monoclonal antibody that binds P-selectin and blocks the adhesion molecule’s interaction with its ligand, P-selectin glycoprotein ligand 1. FDA approval for crizanlizumab was based on a phase 2 RCT ( n  = 198, all genotypes), in which the median rate of pain events (primary endpoint) was lower (1.63 vs. 2.68, p  = 0.01) and time to first pain event (secondary endpoint) was longer (4.07 vs. 1.38 months, p  = 0.001) for patients on high-dose crizanlizumab (5 mg/kg/dose) compared to placebo treated for 52 weeks (14 doses total) [ 83 ]. In this trial, patients with SCD on chronic transfusion therapy were excluded, but those on stable hydroxyurea dosing were not. Adverse events were uncommon but included headache, back pain, nausea, arthralgia and pain in the extremity.

Polymerization of Hb S in the deoxygenated state represents the initial step in red blood cell sickling, which leads to reduced red blood cell deformability and increased hemolysis. Voxelotor is a first-in-class allosteric modifier of Hb S that increases oxygen affinity. The primary endpoint for the phase 3 RCT of voxelotor ( n  = 274, all genotypes) that led to FDA approval was an increase in hemoglobin of at least 1 g/dL after 24 weeks of treatment [ 85 ]. More participants receiving 1500 mg daily of oral voxelotor versus placebo had a hemoglobin response of at least 1 g/dL (51%, 95% CI 41–61 vs. 7%, 95% CI 1–12, p < 0.001). Approximately 2/3 of the participants in these trials were on hydroxyurea, with treatment benefits observed regardless of hydroxyurea status. Despite improvements associated with voxelotor in biomarkers of hemolysis (reticulocyte count, indirect bilirubin and lactate dehydrogenase), annualized incidence rate of vaso-occlusive crisis was not significantly different among treatment groups. Adverse events included headaches, GI symptoms, arthralgia, fatigue and rash.

Curative therapies in SCD

For individuals with SCD undergoing hematopoietic stem cell transplantation (HSCT) using HLA-matched sibling donors and either myeloablative or reduced-intensity conditioning regimens, the five-year event-free and overall survival is high at 91% and 93%, respectively [ 86 ]. Limited availability of HLA-matched sibling donors in this population requires alternative donors or the promise of autologous strategies such as gene-based therapies (i.e. gene addition, transfer or editing) (Table ​ (Table4). 4 ). Matched unrelated donors have not been used routinely due to increased risk of graft-versus-host disease (GVHD) as high as 19% (95% CI 12–28) in the first 100 days for acute GVHD and 29% (95% CI 21–38) over 3 years for chronic GVHD [ 87 ]. Haplo-identical HSCT, using biological parents or siblings as donors, that incorporate post-transplant cyclophosphamide demonstrates acceptable engraftment rates, transplant-related morbidity and overall mortality [ 88 ]. Regardless of allogeneic HSCT type, older age is associated with lower event-free (102/418 vs. 72/491 events, HR 1.74, 95% CI 1.24–2.45) and overall survival (54/418 vs. 22/491 events, HR 3.15, 95% CI 1.86–5.34) in patients ≥ 13 years old compared to < 12 years old undergoing HSCT [ 87 ].

Therapies with curative intent

Advancing research in SCD

Despite progress to date, additional high-quality, longitudinal data are needed to better understand the natural history of the disease and to inform optimal screening for SCD-related complications. In the era of multiple FDA-approved therapies with disease-modifying potential, clinical trials to evaluate additional indications and test them in combination with or compared to each other are needed. Dissemination and implementation studies are also needed to identify barriers and facilitators related to treatment in everyday life, which can be incorporated into decision aids and treatment algorithms for patients and their providers [ 89 ]. Lastly, continued efforts should acknowledge social determinants of health and other factors that affect access and disease-related outcomes such as the role of third-party payers, provider and patient education, health literacy and patient trust. Establishing evidence-derived quality of care metrics can also drive public policy changes required to ensure care optimization for this population.

Conclusions

SCD is associated with complications that include acute and chronic pain as well as end-organ damage such as cardiopulmonary, cerebrovascular and kidney disease that result in increased morbidity and mortality. Several well-designed clinical trials have resulted in key advances in management of SCD in the past decade. Data from these trials have led to FDA approval of 3 new drugs, l -glutamine, crizanlizumab and voxelotor, which prevent acute pain and improve chronic anemia. Moderate to high-quality data support recommendations for managing SCD cerebrovascular disease and early kidney disease. However, further research is needed to determine the best treatment for chronic pain and cardiopulmonary disease in SCD. Comparative effectiveness research, dissemination and implementation studies and a continued focus on social determinants of health are also essential.

Acknowledgements

We would like to acknowledge Lana Mucalo, MD, for supporting data collection for this manuscript.

Abbreviations

Authors' contributions

AB and RL contributed equally to the writing and editing of this manuscript. All authors read and approved the final manuscript.

Availability of data and materials

Declarations.

The authors have no competing interests to declare.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

NIH Research Festival

September 23 – 25, 2024

Leveraging the Townes mice to study interactions between sickle cell disease and schistosome (human blood fluke worm) infection

• JPK Mukendi
• O Kamenyeva
• ZMN Quezado

Background: Sickle cell disease (SCD) is an inherited hematologic disease due to a single nucleotide mutation in the beta chain of human hemoglobin (Hb) that produces defective Hb called HbS. Hypoxic conditions make HbS polymerize, leading to red blood cells sickling and hemolyzing. Most disease cases are in sub-Saharan Africa, where schistosomiasis, a worm infection causing severe inflammation and anemia, is also endemic. However, possible interactions between SCD and schistosomiasis remain largely unknown. This study used the Townes mouse model of SCD to determine the interactions between SCD and schistosome infection. Methods: Townes mice were infected with Schistosoma mansoni for eight weeks. Hematologic parameters were analyzed before and after infection; histology of the liver and spleen and S. mansoni egg counts were performed. Liver microcirculation and tissue were also intravitally imaged. Results: S. mansoni infection increased granulocytes (neutrophils, p=0.0005; eosinophils, p<0.0001; basophils, p<0.0001) and monocyte (p<0.0001) counts in peripheral blood but did not worsen anemia in HbSS mice (RBC, p=0.3382; Hb, p=0.7000, Hct, p=0.4590). However, it significantly decreased hepatic hemosiderosis (p<0.0001) in HbSS mice. On the contrary, SCD did not affect peri-oval granuloma formation in the liver of infected mice but caused a slight reduction of S. mansoni egg burden. Conclusion: Townes mice are susceptible to S. mansoni infection and, therefore, constitute a good model for mechanistically characterizing the interactions between SCD and schistosomiasis. This study stands as a proof of concept for the use of Townes mice in the study of worm infections in SCD and warrants further investigations.

Scientific Focus Area : Microbiology and Infectious Diseases

This page was last updated on Tuesday, August 6, 2024

Targeted therapeutic management based on phytoconstituents for sickle cell anemia focusing on molecular mechanisms: Current trends and future perspectives

• August 2024
• Phytomedicine
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• Daffodil International University

• University of Swabi

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• Oluwole Taiwo

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• Sierra Leone 2024

Day 2: Visiting PHUs + Interviews

To begin our day, we traveled out to the Panlap PHU with our driver William. As we drove through the market of Makeni, people were walking everywhere. The stores of Makeni were bustling with activity as William weaved through traffic. Once we had passed the market, the activity slowly waned as we approached the PHU. With one final turn, we arrived at Panlap. Our team walked into the meeting room and explained to the head nurse that we were from Lehigh University and wished to interview a few staff members about sickle cell disease and their past experience. We rearranged the room to allow for better communication and, to our surprise, we were met with six nurses, all eager to participate. In talking with the PHU staff, the awareness and impact of sickle cell was made clear. 

The nurses emphasized some of the public’s practices, such as binding their limbs or applying heat using cooking stones. As we talked about the prevalence of sickle cell disease, its different nature than malaria, and how often PHU caregivers receive feedback from hospital referrals, we began to hand out copies of our new flipbooks. We hoped to receive constructive feedback from workers in the field to refine and improve upon our pilot version. Some recommendations they provided were the types of food available here in Makeni, to encourage not to smoke cigarettes, and advising not to drink iced water. Overall, they seemed to find our flipbook to have potential to be a strong presenting tool during outreach clinics. Although we requested the books not be used as they are only drafts and currently unapproved on the government level, we did choose to leave one copy behind for the nurses. In addition, we explained our lateral flow test project happening at home, showing the most recent pictures with lines and its ability to screen for sickle cell right in the clinic. With many “thank you”s, our team went outside to take one last picture with all of the nurses we had interviewed. 

After our visit to the Panlap PHU, we traveled to the Yoni PHU. At the clinic we were welcomed by a member of the clinic and were soon greeted by the head nurse. The head nurse was a useful contact for the team last year and brought the previous team to an outreach clinic in a rural community. At the outreach clinic the nurse had brought a flipbook on Malaria and presented it to the community. This inspired the team to create the flipbook on Sickle Cell Disease. In the interview, the nurse shared her knowledge of Sickle Cell Disease. She explained that her daughter has Sickle Cell Disease so she shared her own experience of the diagnosing and management processes. She shared that money was necessary for the diagnosis and management, making the option inaccessible for many people. To help manage it, she was given medicine for free, although much of it had expired so she stopped giving it to her daughter. She also provides her daughter with pain medication and ensures her daughter is eating plenty of leafy greens. 

The nurse said that the doctors and healthcare workers have an understanding of Sickle Cell Disease and that efforts should be focused on diagnosis and treatment. She also mentioned that although sickle cell disease affects much of the community, there is a lot of misinterpretation and lack of information about the disease within communities. In areas where there are members known to have sickle cell, the nurse encourages them to plant a garden composed of leafy greens for those with sickle cell to ensure they are eating nutrient rich food. 

We then turned our attention to our flipbook. The nurse gave us very helpful feedback on our current draft. Her suggestions included editing some of the pictures to show the leafy green leaves that are readily available in Sierra Leone as well as changing the expression and depiction of some of the characters to make the pictures more representative of the disease with easier interpretation. 

After the interview, we made our way back to the World Hope Office to continue planning, debrief the morning, and catch up on paperwork. 

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