Sickle cell disease affects every major organ and organ system in the body, causing severe morbidity and early mortality. The clinical management of acute and chronic complications of sickle cell disease is important for patients and clinicians. Questions remain as to what the most effective health care options are for treatment, testing and diagnosing these complications. Managing acute and chronic pain syndromes, including vaso-occlusive pain, priapism and avascular necrosis often present unique challenges for providers, especially emergency room providers. Promising new clinical evidence is available for prevention of some aspects of cerebrovascular disease. Clinical guidance is needed for role of Hematopoietic Stem Cell Transplantation; the best methods for diagnosing and testing cardiac, pulmonary and renal complications; and transfusion support. These issues apply to the 100,000 Americans with sickle cell disease spanning all ages.

The American Society of Hematology (ASH) has committed to the development of clinical practice guidelines on sickle cell disease in order to inform clinicians in addressing these clinical challenges. New evidence has emerged since the last comprehensive guidelines on SCD were published in the 2014 National Heart, Lung, and Blood Institutes (NHLBI) Evidence-Based Management of Sickle Cell Disease: Expert Panel Report, and NHLBI does not have plans to update these guidelines. ASH has allocated resources to address up to 50 questions, which have not yet been selected, similar to the preliminary questions listed below (some are listed in PICO format, others are not).

We anticipate that there will be more high-priority questions identified than we will have the resources to develop evidence reviews. Evidence reviews supported by EHC would allow for additional clinical questions to be addressed and increase the comprehensiveness of this effort.

Pain- Acute Pain

1. In children and adults with sickle cell disease that suffer from acute pain, are there adjuvant treatments (i.e., non-opioid drugs, complementary and alternative medicine, psychological interventions) that are effective at improving pain control and clinical outcomes in combination with opioids as compared to opioids alone?
2. In children and adults with sickle cell disease suffering from acute pain, does addition of a basal opioid infusion result in improved pain control as compared to no basal opioid?
3. In children and adults with sickle cell disease who are treated for acute pain in the emergency department or inpatient unit, does a follow-up outpatient appointment after discharge decrease the readmission rate as compared to no standardized follow-up?
4. In children and adults with sickle cell disease who seek treatment for acute pain, does the use of individualized emergency department comprehensive care plans improve the treatment of acute pain as compared to no care plans?
5. Does a comprehensive medical home for children and adults with sickle cell disease and/or a day hospital reduce emergency department visits and hospitalizations for pain?
6. In children and adults with sickle cell disease, are there other effective treatments to prevent acute pain that should be added to hydroxyurea as compared to the use of hydroxyurea alone?

Chronic Pain

1. In children and adults with sickle cell disease, what specific clinical criteria should be used to make the diagnosis of chronic pain?
2. In children and adults with sickle cell disease, are there valid measures to diagnose the presence of neuropathic pain?
3. In children and adults with sickle cell disease that suffer from chronic pain, are there adjuvant treatments (i.e., non-opioid drugs, complementary and alternative medicine, psychological interventions) that are effective at improving pain control and clinical outcomes in combination with opioids as compared to opioids alone?

Priapism

1. In males with sickle cell disease that suffer from acute priapism, are there medical, surgical and hematologic treatments (i.e., exchange transfusion, simple transfusion) that are shown to be effective therapy for this acute complication?
2. In males with sickle cell disease that suffer from recurrent priapism, are there hematologic (i.e., hydroxyurea, chronic transfusions), surgical or medical therapies that are effective at preventing recurrence compared to no intervention?

Avascular Necrosis

1. In children and adults with sickle cell disease suspected of having avascular necrosis, does initial screening with MRI offer significant diagnostic benefit compared to starting with x-ray alone?
2. In children and adults with sickle cell disease that have avascular necrosis, what should be the standardized approach to treatment including multimodal treatment with pain medicine, physical therapy, and orthopedic surgery?
3. In children and adults with sickle cell disease that have avascular necrosis, are there surgical treatment approaches that are effective as opposed to conservative management?

Cerebrovascular Disease-

1. Prevalence of strokes and silent cerebral infarcts in adults with sickle cell disease.
2. Optimal red blood cell pheresis algorithm for secondary stroke prevention.
3. Cognitive and real life function in children and adults with SCD and silent cerebral infarcts and strokes.
4. Impact of strokes and silent cerebral infarcts on educational attainment and employment.
5. Optimal strategy for education and employment in children and adults with sickle cell disease and strokes and silent cerebral infarcts.
6. The impact of poverty in children and adults with sickle cell disease and strokes and silent cerebral infarcts education attainment and employment in.
7. Optimal management of acute strokes in children and adults with sickle cell disease.
8. The role of HSCT in secondary prevention of strokes and silent cerebral infarcts when compared to standard therapy.

Kidney and Cardiopulmonary-

1. In children and adults with sickle cell disease and either micro or macroalbuminuria, what is the benefit of angiotensin inhibition versus no therapy in preventing the progression of kidney disease or on reducing mortality?
2. In adults with sickle cell disease, what is the utility of screening for pulmonary vascular disease using echocardiography versus no screening in symptomatic and asymptomatic patients?
3. In children and adults with sickle cell disease and end stage renal disease, is there a survival benefit or quality of life benefit for those undergoing renal transplantation versus those remaining on dialysis?
4. In children and adults with sickle cell disease, at what threshold does the initiation of blood pressure medication decrease the risk of CNS events when compared to continued observation with lifestyle modification alone?
5. In children and adults with sickle cell disease, does the addition of cystatin C to microalbuminuria screening, compared to microalbuminuria screening alone, result in earlier detection of sickle glomerulonephropathy?
6. In children and adults with sickle cell disease, what is the impact of routine monitoring of pulmonary function versus no monitoring in asymptomatic patients on reducing morbidity and mortality?
7. In children and adults with sickle cell disease, does the addition of bronchoprovocation testing to pulmonary function testing, compared to pulmonary function testing alone, provide increased sensitivity for the diagnosis of lower airway hyperreactivity?
8. Compared to observation alone, do bosentan and sildenafil reduce mortality or improve quality of life in children and adults with sickle cell disease and confirmed pulmonary hypertension?
9. For adults with sickle cell disease, does routine screening by echocardiography for diastolic dysfunction in asymptomatic individuals versus no screening result in reduction of cardiovascular morbidity or overall mortality? 10. In children and adults with sickle cell disease, what is the role of combination therapy with hydroxyurea and erythropoietin, compared to erythropoietin alone, in lessening anemia in patients with chronic kidney disease?

Transfusions-

1. Should all patients with SCD be transfused with Rh and K matched RBCs to reduce the risk of alloimmunization, compared to matching for ABO/D only?

• Genotype specific (SS, SC, S-beta0, S-beta+)?
• Non-alloimmunized vs alloimmunized?
• Receiving chronic RBC transfusion vs intermittent RBC transfusions?

2. Should patients with SCD who have one or more alloantibodies be transfused with extended matched RBCs to include Rh, K, Duffy Kidd, and S antigens, compared to Rh and K matched only, or ABO/D matched only?
3. Should DNA-based assays be used to phenotype RBCs of patients with SCD and can this improve RBC matching and transfusion outcomes, compared to serologic phenotyping?
4. Should chronically transfused patients with SCD receive very fresh RBCs (stored 7 days or less), fresh (stored 14 days or 21 days or less), or RBCs with standard expirations (35 or 42 days depending on storage solution) to improve transfusion outcomes?
5. Does exchange transfusion for acute stroke in patients with SCD lead to better neurologic outcomes compared to simple transfusions?
6. Does exchange transfusion for acute chest syndrome in patients with SCD lead to better clinical outcomes compared to simple transfusions?
7. For patients with SCD, is chronic erythrocytapheresis a more effective RBC transfusion modality compared to chronic simple transfusion, assessed by adequate hemoglobin S suppression and ability to avoid or mitigate iron overload in patients with SCD?
8. Should patients with SCD who have had a severe delayed hemolytic transfusion reaction be treated with immunosuppression for future RBC transfusions? (versus no treatment)

Transplantation-

1. In pediatric patients with SCD and a matched sibling donor, does myeloablative allogeneic bone marrow transplantation produce superior quality of life compared to routine supportive care in those who have not yet experienced complications of the disease?
2. In adult patients with SCD and an irreversible complication of the disease, does nonmyeloablative transplantation using a matched sibling donor provide superior quality of life compared to standard supportive care?
3. Is non-myeloablative conditioning aimed at fertility preservation in pediatric patients with SCD undergoing transplantation justified compared to the established experience with myeloablative conditioning producing high cure rates at the expense of fertility in most?
4. Is allogeneic transplantation with a matched sibling donor superior to chronic transfusions in pediatric patients with SCD at high risk for stroke?
5. Do the current indications for bone marrow transplantation developed by experts in SCD predict those who will benefit by the intervention compared to standard of care better than the diagnosis of SCD alone?
6. Is nonmyeloablative bone marrow transplantation cost-effective in adults with severe disease?
7. Is bone marrow transplantation superior to umbilical cord blood transplantation from a matched sibling donor in pediatric patients undergoing allogeneic transplantation?
8. When considering alternative donor sources for patients with SCD undergoing allogeneic transplantation, do haploidentical donors produce superior event free survival compared to matched unrelated donors?

Sickle cell disease is a group of disorders that affects hemoglobin. It is considered a rare disease, with approximately 100,000 cases in the United States. It is an inherited red blood cell disorder in which the person s hemoglobin is abnormally shaped, causing the cells to take on a crescent or sickled shape. Due to the abnormal shape of the cells, the cells have difficulty passing through small blood vessels, resulting in a number of devastating health effects for the patient. Among the most common health effects is severe pain crises also known as vaso-occlusive crisis.

SCD is expensive to treat. It attributes a multi-billion dollar annual cost to the United States healthcare system 8, largely because of emergency department and hospital admissions, especially for chronic pain.

For an average person with SCD reaching age 45, total lifetime health care costs were estimated to be nearly $1 million, with annual costs ranging from over $10,000 for children to over $30,000 for adults.1

SCD causes significant burden to patients. Many children with SCD do not receive the necessary services to prevent serious complications from the disease, and people with SCD in the emergency department for pain experienced longer delays to administration of the initial analgesic compared with control patients, despite higher arrival pain scores and triage acuity levels.2 Only one-third of children with SCD receive appropriate monitoring for stroke risk. Twenty five percent of children with SCD do not receive pneumococcal vaccination, which is recommended for all children younger than five years of age.3 Children not receiving these necessary services are at greater risk of dying or suffering from cognitive defects as a result of stroke and invasive pneumococcal infections. The lack of available specialized providers (e.g., hematologists) plays a significant role in an over-reliance on emergency departments care for some individuals with SCD, especially adults.4, 5

SCD is difficult to treat. Because it is a multi-organ disease, specialists across the spectrum of healthcare manage different aspects of SCD care. In a national survey, only 20.4 percent of family physicians reported that they felt comfortable treating people with SCD. Many physicians lack knowledge on how to effectively use existing treatments. Disease-modifying treatments, including hydroxyurea and transfusions, exist, but are underutilized. More than 75 percent of adults with SCD with frequent pain crises fail to get hydroxyurea, which is the recommended treatment.6. In a two year pediatric study, overall health care costs for children on hydroxyurea were $1.8 million, compared with $2.5 million for those who did not receive this treatment.7 Unfortunately, despite the National Heart, Lung, and Blood Institute s (NHLBI) recommendations, hydroxyurea is not regularly prescribed and adherence to the therapy is poor.

ASH has convened a multi-stakeholder coalition to improve outcomes for individuals with SCD. Its membership includes public health, research, and provider organizations, patient groups, faith-based organizations, federal agencies, industry representatives, and foundations. ASH has committed to the development and ongoing maintenance of clinical practice guidelines on sickle cell disease as part of a large-scale initiative. ASH is committed to employing a robust dissemination and implementation strategy to ensure that its clinical practice guidelines are broadly available to clinicians, including but not limited to ASH s hematologist membership. In addition to the publication of the guidelines in an academic journal, dissemination and implementation will include electronic and paper pocket guides; podcasts and webinars; clinician education targeting hematologists and other physicians and clinicians; patient versions of guidelines; and potentially clinical performance measures.

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