Goal 2: Reduce Human Disease

A Chidren's Oncology Group (COG) for sickle cell disease (SCD)?

We have all witnessed the success of the National Cancer Institute (NCI) funded Children's Oncology Group - an organization that has made tremendous advancements in the care of children with cancer, very rare compared to sickle cell disease. COG has been able to not only create a database of the numerous studies, but has the unique ability to make "smaller" institutions feel important as is evident by patient enrollment. ...more »

Submitted by (@smajumdar)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

- A database of all ongoing studies related to sickle cell disease that will be easily accessible by all pediatric hematologists

- A unified system of enrolling patients from academic centers for all the different studies, no matter how big or small

- Studies can be grouped depending on condition - renal disease, pulmonary hypertension etc.

- Should allow greater involvement/recruitment for patients into phase 1 studies

Name of idea submitter and other team members who worked on this idea : Suvankar Majumdar MD

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28 up votes
5 down votes
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Goal 2: Reduce Human Disease

Innovations in Red Cell Transfusion in Sickle Cell Disease

Challenges that need to be overcome in blood transfusion, especially in SCD, include: a. Adopting molecular genotyping as the standard in blood transfusion therapy. b. Advancing new generation, anti-oxidant hemoglobin-based oxygen carriers (HBOCs) for use in emergencies such as trauma, stroke, acute hemolysis, and in transfusion in SCD and related disorders. In SCD, HBOCs have the capacity to not only serve as substitutes ...more »

Submitted by (@nhlbiforumadministrator1)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Transfusion of RBC is major adjunct in the management of trauma, acute and chronic illness. Issues in blood transfusion include availability of donors, RBC typing and crossmatching, cold storage of donor cells, and limited viability of stored RBC. Globally, in many situations where blood is critically needed, these systems are not available.

An increasing percentage of people with SCD require regular RBC transfusion to prevent stroke and other major complications. In addition, RBC transfusion is employed repeatedly in the management of serious acute complications of SCD. Transfusion of normal RBC to replace or supplement the patient’s defective RBC is the most effective intervention in the management of SCD.

 

Impacts:

• Molecular genotyping of RBC will reduce alloimmunization.

• Use of new generation HBOCs that do not require blood typing, crossmatching, refrigeration, and that do not transmit infection, would save lives in conditions of severe hemorrhage, stroke, possibly heart attack, especially where there is no immediate access to adequate medical facilities.

• In SCD, HBOCs could prevent pain or reduce its severity and duration, prevent stroke, reduce severity of acute chest syndrome, and other vasoocclusive complications. Finally, HBOCs have the potential to alter the pathogenesis of SCD.

Feasibility and challenges of addressing this CQ or CC :

The problems in managing chronic RBC transfusion in SCD remain the same as they have been for decades: all immunization, iron overload, and infection transmission. It is clear that traditional serological RBC phenotyping is unable to detect several variants of RBC antigens, especially those in the Rh system, in populations of African descent. This leads to erroneous phenotyping and the appearance of “auto antibodies” that are truly alloantibodies resulting from transfusion of mismatched blood. As a result, people with SCD are the most frequent users of the American Rare Donor Program.

Name of idea submitter and other team members who worked on this idea : Kwaku Ohene-Frempong, MD

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29 net votes
47 up votes
18 down votes
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Goal 2: Reduce Human Disease

Identification and validation of surrogate endpoints for long-term morbidity in Sickle Cell Disease

Research in sickle cell disease (SCD) has mostly focused on preventing or treating acute medical events, such as vaso-occlusive pain, acute chest syndrome, and, in pediatric patients, acute strokes. Chronic SCD complications such as chronic kidney disease or pulmonary hypertension, develop over decades, thus are poor choices for clinical trial endpoints. There is a great need to develop surrogate endpoints that predict ...more »

Submitted by (@hulbertm)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Longitudinal cohorts of SCD patients, spanning childhood and adulthood, with biobanking DNA, plasma, and serum, and standardized clinical and imaging assessments will allow identification predictors of negative clinical outcomes. An NHLBI-funded national SCD clinical registry with biobanking will be necessary to validate any surrogate endpoints.

Name of idea submitter and other team members who worked on this idea : Monica Hulbert

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13 net votes
16 up votes
3 down votes
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Goal 2: Reduce Human Disease

Impact of Hydroxyurea on Organ Function

Does hydroxyurea preserve organ function in patients with sickle cell disease?

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Hydroxyurea is the only disease-modifying medication for sickle cell disease, and has been shown to be effective in reducing complications such as pain crisis and acute chest syndrome in some patients. Evidence suggests that hydroxyurea is underused, and, understandably, efforts are underway to encourage more people to take advantage of this treatment. Determining that it preserves organ function or reduces organ damage could encourage greater use or, if not, encourage the development of other medications that can.

Feasibility and challenges of addressing this CQ or CC :

Given the greater understanding of sickle cell disease and improvements in life expectancy, it should be feasible to design a study that will supply sufficient data to answer this question.

Name of idea submitter and other team members who worked on this idea : The Sickle Cell Association of New Jersey

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7 net votes
7 up votes
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Goal 2: Reduce Human Disease

Pulmonary Complications of Sickle Cell Disease

Do SCD patients with hemodynamics consistent with pulmonary arterial hypertension (PAH) respond to medications designed to treat PAH?

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

What is known about this topic:

1) Case series have demonstrated potential therapeutic benefits for endothelin receptor antagonists, phosphodiesterase 5 inhibitors and prostacyclins in PH of SCD patients

2) Three attempted randomized placebo controlled trials of these agents in SCD patients have not gone to completion and, as a result, were under-powered to demonstrate efficacy.

3) Sildenafil produced an increase in hospitalization for pain crises in this population.

4) Anecdotally, select SCD patients with PAH have hemodynamic and clinical benefits from PAH medications.

5) Approximately ½ of PH in SCD patients have some degree of pulmonary venous hypertension and these medications may not be helpful here.

Feasibility and challenges of addressing this CQ or CC :

Areas of controversy:

1) Only one of the three randomized controlled trials required a PAH diagnosis prior to randomization, so the actual question hasn’t been properly addressed.

2) SCD patients with PAH are different than idiopathic PAH patients in terms of their underlying disease, so possibly the treatment response is different.

3) What are the right clinical trial endpoints for this population?

4) What is the role of SCD specific therapy (hydroxyurea, transfusions) in treating PAH of SCD?

5) How can investigators design a clinical trial which allows for enough patient accrual to achieve its endpoints?

6) What novel therapies can be developed to treat this population?

7) What unrecognized medication toxicities are SCD patients at increased risk for?

Name of idea submitter and other team members who worked on this idea : ATS Member

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3 net votes
3 up votes
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Goal 2: Reduce Human Disease

Pulmonary Complications of Sickle Cell Disease - Contribution of Airways Disease

What is the contribution of airways disease to acute and chronic pulmonary distress?

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

What is known about this topic:

 

1) Pulmonary function testing is abnormal in 80-90% of kids and 90% of adults with SCD.

 

2) SCD kids with asthma have a higher frequency of ACS and those with a history of ACS have a higher prevalence of asthma.

 

3) An elevated TRV in SCD kids and adolescents may not predict mortality but does predict reduced exercise capacity at 22 months which may be irrespective of pulmonary hypertension

 

4) Dyspnea is extremely common in adults with SCD; 50% of HbSS and 40% of HbSC adults report at least mild dyspnea on exertion. The mechanisms responsible for this are unknown.

 

5) Bronchodilators are often used to treat patients with ACS, yet their benefit is unclear.

 

6) Systemic steroids will increase the rate of rebound pain if used during a vasoocclusive crisis.

 

7) Asthma in SCD is frequently under-treated because of fears associated with systemic and even inhaled corticosteroid use.

Feasibility and challenges of addressing this CQ or CC :

Areas of Controversy:

1) Is there an inter-relationship between airway and vascular disease in SCD?

 

2) Are systemic corticosteroids safe in SCD? Are they indicated in treatment of ACS? Are they indicated for treatment of asthma exacerbations?

 

3) Are inhaled corticosteroids useful in treating or preventing ACS?

 

4) What are the mechanisms responsible for the decline in exercise capacity observed as SCD patients go from late adolescence to early adulthood?

 

5) Will more aggressive treatment of asthma prevent this decline?

 

6) What role does nocturnal hypoxemia and OSA play in disease modulation of SCD?

 

7) What are the mechanisms of the restrictive physiology observed by PFTs primarily in adults?

Name of idea submitter and other team members who worked on this idea : ATS Member

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3 net votes
3 up votes
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Goal 2: Reduce Human Disease

Risk factors and treatment options for pulmonary hypertension in Sickle Cell Disease

What are the risk factors and treatment options for pulmonary hypertension related to diastolic dysfunction in Sickle Cell Disease (SCD)?

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

What is known about this topic:

 

1) Pulmonary venous hypertension (PVH) related primarily to left ventricular diastolic dysfunction accounts for at least 50% of cases of PH in SCD patients.

 

2) PVH is an independent risk factor for mortality

 

3) Etiology of diastolic dysfunction in this population is unknown as well as the contribution of relative systemic hypertension

 

4) No specific therapies exist for this condition although traditional diastolic dysfunction CHF are at times eomployed. No standard of care exists.

Feasibility and challenges of addressing this CQ or CC :

Areas of Controversy:

 

1) What role, if any, does iron chelation play in disease prevention?

 

2) What role does treatment of systemic hypertension play in prevention and treatment?

 

3) Is obstructive sleep apnea a risk factor for diastolic dysfunction in this population?

 

4) Is there increased risk of VTE in this population?

 

5) Are SCD specific therapies (hydroxyurea, transfusions) beneficial in improving outcomes?

 

6) What is the best means of diagnosing PVH of SCD? Are there ways non-invasively to predict PAH vs PVH in this population?

 

7) Is cardiac MRI superior to echocardiography in evaluating diastolic function in this patient population?

Name of idea submitter and other team members who worked on this idea : ATS Member

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4 net votes
4 up votes
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Goal 3: Advance Translational Research

Allogeneic transplantation as a safe and universally available therapeutic strategy for treating non-malignant blood diseases

Can new advances in allogeneic blood or marrow transplantation (BMT) make the procedure a safe and universally available therapeutic strategy for treating non-malignant blood and immune disorders such as sickle cell anemia, thalassemia, aplastic anemia, and severe combined immune deficiency?

Submitted by (@rjjones)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

The ability of allogeneic blood or marrow transplantation (BMT) to cure diverse non-malignant diseases is well-documented. However, widespread use in diseases such as sickle cell anemia that cause substantial morbidity and shorten life but are not immediately life-threatening, has been limited by transplant-related toxicity and mortality especially in the majority of these patients who lack HLA-matched donors. Several new therapeutic approaches now exist that are promising strategies, separately or in combination, for addressing issues of donor availability, graft rejection, organ toxicity and acute and chronic graft-versus-host disease more effectively. Evaluation and refinement of these therapeutic strategies in both preclinical and Phase I-III clinical trials now offers a real possibility that allogeneic BMT could be applied early in the course of these diseases, allowing normal growth, development, quality of life and lifespan. If successful, allogeneic BMT offers a major advantage over gene therapy approaches even if such approaches become possible in the future; i.e., allogeneic BMT can be done with low-dose, non-toxic conditioning while gene therapy requires high-dose myeloablative therapy which not only can be toxic/fatal to these patients who often have end-organ dysfunction but also universally induces infertility, a major concern of patient groups who usually survive beyond child-bearing years.

Feasibility and challenges of addressing this CQ or CC :

There are now single institution and registry (CIBMTR) data showing that related haploidentical allogeneic BMT using post-transplantation cyclophosphamide (PTCy) produces results similar to those seen with HLA-matched sibling donors. Accordingly, every patient in need of allogeneic BMT now can safely undergo the procedure, including those ethnic groups (such as African-Americans and Hispanics) who are unlikely to find a donor in unrelated registries. Combining PTCy with other approaches for preventing graft-versus-host disease (GVHD) can even eliminate GVHD and transplant-related mortality. Although recurrence of malignant diseases remains an issue, especially as GVHD is eliminated, relapse is not a concern for non-malignant diseases after successful allogeneic engraftment. Moreover, the average cost of allogeneic BMT, about $150K, is a cost-savings over the long-term management of many of these diseases. The NHLBI-funded BMT Clinical Trials Network (CTN) has developed the infrastructure to rapidly and efficiently carry out large multi-institutional BMT trials. Over the last 15 year, thousands of patients have been entered on BMT CTN trials. Of note, African-Americans and Hispanics remarkably represent 30% of the accruals on one such trial, CTN1101, studying unrelated umbilical cord and related haploidentical allogeneic BMT. However, funding for the infrastructure for continuing this work remains problematic, since BMT trials generally lack corporate funding.

Name of idea submitter and other team members who worked on this idea : Rick Jones

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164 net votes
214 up votes
50 down votes
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Goal 2: Reduce Human Disease

Family centered interventions in sickle cell

Sickle cell is a genetic disease with lifelong health consequences for affected individuals and their families. Interventions for individuals with sickle cell must be patient and family-centered.

Submitted by (@coretta.jenerette)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Name of idea submitter and other team members who worked on this idea : International Association of Sickle Cell Nurses and Physician Assistants, Inc.

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18 net votes
20 up votes
2 down votes
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Goal 4: Develop Workforce and Resources

Community education on phenotypic expressions of sickle cell disease

How effective are current community education techniques on the various phenotypic expressions of SCD?

Submitted by (@sicklecellwarrior)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

If parents knew what to expect with precision they could be proactive in care

Name of idea submitter and other team members who worked on this idea : Sickle Cell Warriors, Inc. community members

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17 net votes
27 up votes
10 down votes
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Goal 3: Advance Translational Research

Financial and psycosocial impact of transition in sickle cell disease

What are the financial and social implications for individuals living with SCD from adolescence transitioning into adult care? What impact does this transition have on the caregiver and family as a whole?

Submitted by (@sicklecellwarrior)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

It is very difficult for many living with SCD to maintain employment (many people have to rely on disability benefits to survive) finish school, even maintain relationships. Greater understanding of the financial and social impact would enable advocacy and direct patient service organizations to better prepare the transitioning population, reducing the financial strain on the individual and the growing medical debt incurred by hospitals and government social service programs.

Name of idea submitter and other team members who worked on this idea : Sickle Cell Warriors, Inc. community members

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30 net votes
38 up votes
8 down votes
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Goal 3: Advance Translational Research

Improving Community-Based Care for Sickle Cell Disease

Sickle cell treatment centers are located throughout the United States, primarily in urban areas, and play an invaluable role. However, there is a critical need to identify and educate primary care providers who can provide routine and preventive care, but will also know when to consult with/refer to hematologists and other appropriate providers when necessary.

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

For the first time, comprehensive guidelines addressing the management of sickle cell disease were issued in 2014 by the NHLBI. (Previous guidelines were not comprehensive.) The 2014 guidelines, which address issues such as health maintenance and the treatment of acute and chronic complications, are based on a systematic review of available evidence; consensus of an expert panel; and published, vetted guidelines by other organizations when evidence was unavailable or insufficient. These guidelines can provide a solid overview of the knowledge essential for the care of people with sickle cell disease.

 

Identifying primary care providers who can provide routine and preventive care but at the same time are knowledgeable about sickle cell disease, should be a more efficient, less costly method of provide important health services to people with sickle cell disease and should ultimately improve the health and well being of this population, particularly for people who do not live near a sickle cell center.

Feasibility and challenges of addressing this CQ or CC :

Addressing this question is very feasible. However, for a variety of reasons, including misconceptions about patients with the condition, it may be challenging to recruit large numbers of primary care providers.

Name of idea submitter and other team members who worked on this idea : The Sickle Cell Association of New Jersey

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0 down votes
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