Medical Professional Publications

Research Helps Demystify Sickle Cell Disease

(From the May 2014 Issue of PediatricsOnline)

Sickle cell disease is a severe, chronic genetic condition affecting the red blood cells that results in significant morbidity and shortened life expectancy. The condition affects millions of people worldwide. It is the most common inherited blood disorder in the United States, affecting as many as 100,000 Americans. The disease is most common among African Americans, with an incidence of 1 in 400, but it can affect individuals of any ethnicity.

Despite the prevalence of the disease, research is slow in accumulating. “Patients with sickle cell disease are usually willing to participate in research studies that have a potential to improve their health or the health of future patients,” says Susan Creary, MD, a hematologist at Nationwide Children’s Hospital and an expert in sickle cell disease, “but one of the biggest challenges in doing research in children with sickle cell disease is the paucity of research studies available to these patients.”

Research along the spectrum is needed, according to Dr. Creary, so that available treatments can be optimized and future treatments can be developed.

“Currently, stem cell transplantation is the only curative therapy available, but it is only available to a minority of patients due to the fact that most patients do not have adequately matched donors. In addition, few other disease-modifying therapies exist for children with sickle cell disease, and the existing therapies are not fully utilized,” she says. “Basic, translational and clinical research for sickle cell disease are all important so that when novel therapies are developed and tested in the laboratory setting they can be effectively applied in clinical practice.”

Here we provide a summary of the latest sickle cell disease research conducted by Nationwide Children’s clinicians and their collaborators at pediatric institutions around the country.


Therapy Research

Optimizing Curative Hematopoietic Stem Cell Transplantation
A 10 percent risk of mortality and up to a 23 percent chance of graft-versus-host disease in hematopoietic stem cell transplantation for severe sickle cell disease has, until now, been a major limiting factor in the willingness of eligible patients to undergo matched sibling donor transplants. But a new technique developed by clinician scientists at Nationwide Children’s has optimized the dosage of anti-thymocyte globulin (ATG), a serotherapy given to patients during the transplant to reduce the risk of graft rejection and mortality. In a series of 15 patients undergoing the transplant with intermediate doses of rabbit-ATG, there were no deaths and no cases of graft-versus-host disease greater than grade II.

The optimized process has raised survival to 100 percent and event-free survival to 93 percent, an unprecedented improvement in the safety and efficacy of hematopoietic stem cell transplantation for sickle cell disease patients. At a median follow-up of four years post-transplant, all patients remained asymptomatic, despite one patient’s rejection at two months post-surgery. Complications such as mucositis were common but responded well to therapy, with none of the 15 patients experiencing excessive acute toxicities. Although additional improvements to technique may help minimize toxicities, long-term effects and intraoperative complications, this study suggests that hematopoietic stem cell transplantation using optimized doses of rabbit-ATG may now be a better option for patients with severe sickle cell disease than in the past.

Related Citation
Soni S, Gross TG, Rangarajan H, Baker KS, Sturm M, Rhodes M. Outcomes of matched sibling donor hematopoietic stem cell transplantation for severe sickle cell disease with myeloablative conditioning and intermediate-dose of rabbit anti-thymocyte globulin. Pediatric Blood & Cancer. 2014 Apr 17. [Epub ahead of print.]

Improving Hydroxyurea Adherence with Electronic Observation
In another study, researchers examined a way to improve patient adherence to hydroxyurea (HU), the only FDA-approved sickle cell disease medication. When taken regularly, the long-term medication has been shown to improve symptoms in most patients, although it takes several months for the drug to begin working. Many children with sickle cell disease don’t receive the full benefit of HU, primarily because they don’t use the drug as prescribed. In fact, fewer than half of all patients achieve adherence of 80 percent or higher.

To determine whether a mobile version of direct observation of therapy could increase HU adherence, a pilot study followed 14 patients over six months, reminding them via text message to take their medication each day. Patients recorded themselves taking their HU so researchers could track how well they followed the treatment regimen. Patients received feedback and small monetary incentives from the research team to encourage high HU adherence rates.

The researchers found that this type of intervention was feasible and acceptable, with patients reporting that the electronic observation program was convenient and unobtrusive. By the end of the study, median observed HU adherence reached 93 percent, and 12 of the 14 participants achieved 80 percent or higher adherence rates. Researchers also noted a corresponding significant increase in patients’ mean corpuscular volume and hemoglobin F percentages, which are important laboratory markers. Although a larger study is necessary to confirm the program’s long-term potential impact on HU adherence and clinical outcomes, this pilot study suggests that this electronic strategy may be an effective way to improve pediatric treatment adherence and health.

“Clinical trials support hydroxyurea therapy for most patients with sickle cell disease. In clinical practice, however, most children with sickle cell disease are not prescribed hydroxyurea, or if they are, patients do not adhere to it at the levels achieved in clinical trials, and this impacts their health outcomes,” says Dr. Creary, lead author on the study. “Research that is aimed at improving hydroxyurea utilization can show us how to better utilize this efficacious therapy and novel therapies for patients with this disease in the future.”

Related Citation
Creary SE, Gladwin MT, Byrne M, Hildesheim M, Krishnamurti L. A pilot study of electronic directly observed therapy to improve hydroxyurea adherence in pediatric patients with sickle-cell disease. Pediatric Blood & Cancer. 2014 Jun;61(6):1068-73. [Epub 2014 Jan 16.]

Illness and Pain Research

Predicting Acute Chest Syndrome
In another study led by Dr. Creary, researchers conducted a retrospective review of nearly 200 cases of acute chest syndrome (ACS) among pediatric sickle cell disease patients. ACS is a vaso-occlusive event affecting the lungs of sickle cell disease patients that causes nearly one-fourth of all deaths among adults with the disease.

Findings suggest that, in up to one-third of ACS diagnoses, acute related illness occurs in the two weeks prior to diagnosis of ACS. Of those children presenting for acute care within two weeks of an ACS episode, nearly two-thirds had vaso-occlusive pain crisis, half had mild hypoxia, almost one-third had tachypnea, 39 percent had a history of asthma and 80 percent had a history of ACS.

These precipitating symptoms suggest that ACS may represent a culmination of disease after prolonged illness instead of an acute attack, Dr. Creary says. Children with sickle cell disease presenting for urgent or emergent care may exhibit signs of an impending ACS episode, especially when symptoms include pulmonary difficulties.

If future studies confirm the connection between initial symptoms and proximal ACS diagnosis, it may be possible to predict ACS development and act to prevent it. By preventing or limiting the risk of ACS, Dr. Creary adds, physicians could feasibly avoid morbidity, mortality and health care utilization for ACS among pediatric sickle cell disease patients.

Related Citation
Creary SE, Krishnamurti L. Prodromal illness before acute chest syndrome in pediatric patients with sickle cell disease. Journal of Pediatric Hematology/Oncology. 2014 Mar 13. [Epub ahead of print]

Understanding Abdominal Pain
Differential diagnosis of abdominal pain is difficult in all children but crucial to the wellbeing of children with sickle cell disease, who are at risk for particular complications because of their illness. Some of these abdominal problems, such as hepatic sequestration, can be deadly if not diagnosed accurately and quickly. A clinical review and case report of a 10-year-old female with hemoglobin SS disease illustrates the complexity of abdominal pain in this population. Over the course of only three years, she was diagnosed with and treated for gastritis, constipation, vaso-occlusive pain, symptomatic cholelithiasis, hyposthenuria, peptic ulceration of the duodenum with formation of a stricture, gastric outlet obstruction and pyloric outlet obstruction.

The authors’ key recommendations for evaluation of abdominal pain in this patient population include:

  • Physical exam is crucial and should focus on any peritoneal indications of acute surgical needs, enlarged spleen or liver or the presence of a mass.
  • Careful and complete history is essential. Record eating habits such as pica, hydration, dairy sensitivity, fiber content of diet and timing of pain relative to eating; make thorough inquiries into bowel habits, bathroom hygiene, blood or urine changes, vomiting and diarrhea; inquire about medication use, including dose and frequency; document location, severity and frequency of pain.
  • Simple lab tests can help identify urinary tract infection, H. pylori bacterial infection, decreased hemoglobin and platelets, hyperbilirubinemia, renal infarct and other indications of specific acute abdominal problems.
  • Additional tests that aid in differential diagnosis include abdominal ultrasound, contrast radiography and endoscopy.
  • Key conditions to consider for children with sickle cell disease include splenic sequestration, hepatic sequestration, bezoar (a mass of foreign material collected in the stomach, often the result of pica), cholelithiasis, renal infarction, pyelonephritis or urinary tract infection, peptic ulcer disease and duodenal ulcer, constipation and vaso-occlusive pain.

Related Citation
Rhodes MM, Bates DG, Andrews T, Adkins L, Thornton J, Denham JM. Abdominal pain in children with sickle cell disease. Journal of Clinical Gastroenterology. 2014 Feb;48(2):99-105.

Health Maintenance and Quality of Life Research

Oral Health and Sickle Cell
Little is currently known about the dental health and oral health-related quality of life of children with sickle cell disease. Much of the existing research on the topic suggests children with the disease have poorer perceived health but equal or better frequency of cavities (caries), although the literature is contradictory regarding number of caries and self-rated health scores by age group, gender or disease type.

In an adolescent medicine clinic at Nationwide Children’s, a team of researchers led by Homa Amini, DDS, MPH, MS, section chief of Dentistry at the hospital, attempted to resolve this question by surveying 54 sickle cell disease patients and 52 controls regarding their dental health and their oral health-related quality of life using the Child Oral Health Impact Profile.

The findings, published in Pediatric Dentistry, bode well for young children with sickle cell disease. Adolescents with the condition had similar oral health-related quality of life to their healthy peers. In addition, they had similar rates of dental caries. In general, girls had higher self-reported health than boys, and older children had more caries than younger children. Despite the impact sickle cell disease can have on craniofacial bones, oral soft tissues and mucous membranes, this research indicates little difference in real and perceived oral health indicators between healthy adolescents and those with sickle cell disease.

Related Citation
Ralstrom E, da Fonseca MA, Rhodes M, Amini H. The Impact of Sickle Cell Disease on Oral Health-related Quality of Life. Pediatric Dentistry. 2014;36(1):24-8.

Executive Function and Patients’ Social Skills
Research is conflicting regarding the social skills and peer relationship quality among children with sickle cell disease, although many studies indicate these children experience some difficulties. To examine potential predictors of social functioning with the hope of improving future research on social skills in these children, a team of investigators from across the country examined the link between parent- and child-reported social skills and executive function on a range of validated tests for 20 pediatric patients with sickle cell disease.

Preliminary findings suggest that executive function deficits (measured by performance tests and parent report) were correlated with lower social skills. The study did not compare patients to control children but did find that social skills and executive function results were in average ranges for many of the 20 participants. However, the study did not include patients with a history of stroke or neurological complications — which affect approximately 30 percent of the sickle cell disease population — a factor that, in future studies, might increase the percentage of patients with below-average executive function and social skills.

The authors recommend comprehensive neuropsychological evaluations of patients with sickle cell disease, including an in-depth assessment of executive function, to help identify patients at risk for social skills problems that could improve with treatment of underlying difficulties with executive function.

Related Citation
Hensler M, Wolfe K, Lebensburger J, Nieman J, Barnes M, Nolan W, King A, Madan-Swain A. Social skills and executive function among youth with sickle cell disease: A preliminary investigation. Journal of Pediatric Psychology. 2014 Jan 14. [Epub ahead of print]

myChildren’s mobile app

iPhone and Android.

Download Today! »

Nationwide Children's Hospital
700 Children's Drive Columbus, Ohio 43205 614.722.2000