Houston, Texas, USA : A daily hydroxyurea pill may finally bring some relief for young children living with the painful and deadly blood disease sickle cell anemia (SCA) in resource-challenged sub-Saharan Africa, where the disease is prevalent and health care availability is suboptimal.
This is what a large multinational clinical trial called REACH discovered when it tested daily hydroxyurea treatment in 606 children between the ages of 1 and 10 years old. The children took a pill each day for six months, followed by increases in the daily dosages based on their health status and weight. Initial doses varied between 15-20 mg/kg a day.
The treatment improved their health by controlling SCA symptoms and, in an expected finding, giving them some protection from malaria that is also prevalent in the region, according to the study’s lead physicians at Cincinnati Children’s Hospital Medical Center and Centre Hospitalier Monkole in Kinshasa, in the Democratic Republic of the Congo.
Study results are published today online by The New England Journal of Medicine in conjunction with being presented at the American Society of Hematology’s annual meeting in San Diego.
The clinical trial determined that hydroxyurea therapy is feasible to use and safe for children in sub-Saharan Africa. Compared to pre-treatment levels, hydroxyurea use was linked to reduced rates of sickle cell pain by an average of 55 percent, infections by 38 percent, malaria by 51 percent, transfusions by 67 percent, and death by 70 percent.
“Hydroxyurea was safe and offered many benefits to these young patients, including improved anemia, fewer sickle cell pain events, less malaria, and better survival,” said Russell Ware, MD, PhD, the study’s senior investigator and a physician-scientist at the Cincinnati Children’s Cancer and Blood Diseases Institute.
Also leading the clinical trial was Leon Tshilolo, MD, PhD, at the Centre Hospitalier Monkole. Investigators named the study REACH, an acronym for Realizing Effectiveness Across Continents with Hydroxyurea. According to Tshilolo, the clinical trial lived up to its name.
“The study shows the importance of research partnerships between the US and Africa to improve clinical care,” he said. “Even in an African setting hydroxyurea is feasible to use, accepted by patients and families, well-tolerated, and safe for children with sickle cell anemia. Almost all of the children had clinical improvements, and the older patients were well enough to attend school.”
SCA’s Heavy Burden
Caused by a genetic mutation and most prevalent in people of African ancestry, SCA is a painful disease where blood cells turn sickle-shaped and become stuck in the vascular system where they block blood flow. This can damage vital organs and cause death. Hydroxyurea works by significantly increasing both hemoglobin and fetal hemoglobin in the blood, which helps reduce sickling, anemia and other impacts on patients.
Available therapies to treat SCA effectively are limited, although numerous studies in recent years–almost all in developed countries–show that hydroxyurea is a safe and effective drug for managing the disease and improving quality of life.
SCA affects more than 90,000 people in the United States and millions of people worldwide, with 75 percent of the disease’s burden in sub-Saharan Africa. Other nations with high incidence rates are India, nations in the Caribbean, Central America, and South America.
Because of the lack of detailed medical records, the best available estimates are that 50 to 90 percent of infants with SCA born in sub-Saharan Africa die before the age of 5, according to a 2017 paper published by Cincinnati Children’s researchers that included Ware. The paper also reported that efforts to help people in the region with SCA have been stagnant because most affected people lack access to basic diagnostics and clinical care.
Institutions like Cincinnati Children’s are working with ASH and the National Heart, Lung, and Blood Institute (part of NIH) to invest in research and clinical programs and address the global burden of SCA in limited-resource settings, especially sub-Saharan Africa.
The Phase 1-2 multi-center open-label REACH clinical trial treated children in four sub-Saharan countries: the Democratic Republic of Congo, Uganda, Kenya and Angola. Researchers plan to follow children in the study long-term to get additional data about growth and development and to look for any possible effects on organ function and fertility.
REACH is supported by funding from the National Heart, Lung, and Blood Institute (U01 HL133883, K23 HL128885), the Cincinnati Children’s Research Foundation, and Senior Research Fellowships from the Wellcome Trust (202800 and 091758).
Image: Russell Ware M.D., director of Hematology at the Cincinnati Children’s Hospital Medical Center, was senior investigator on a multi-national clinical trial focused on improving health outcomes for children in sub-Saharan African who have sickle cell anemia. He is pictured in front of his research laboratory at Cincinnati Children’s.
Image credit : Cincinnati Children’s Hospital Medical Center
A new Johns Hopkins study affirmed the challenges in managing the severe pain of sickle cell disease.
Study affirms challenges in managing severe pain of sickle cell disease
In a study tracking the severe crisis pain of sickle cell disease and its management in 73 adults over a period of a year, Johns Hopkins researchers found that even among those on high doses of daily at-home opioids, a persistent subset was more likely to seek emergency hospital care for crisis pain and was less likely to have the pain controlled by intensive treatment.
The researchers say their findings, described in the September issue of the American Journal of Hematology, underscore the persistent difficulties, poor patient outcomes and high costs associated with assessing and addressing the 10 to 20 percent of patients with sickle cell who are the sickest and have the most pain.
“Although progress has been made in managing the pain crises of many with sickle cell, there remains a group of sicker patients who seek hospital care with greater than typical frequency and whose pain is not being treated effectively,” says C. Patrick Carroll, M.D., director of psychiatric services for the Johns Hopkins Sickle Cell Center for Adults and assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. “We want to focus our efforts on figuring out how to deliver high value care to our sickest patients.”
Sickle cell disease is the most common inherited blood disorder diagnosed in the United States, affecting an estimated 100,000 people, most of them African-Americans. In addition, about one in 13 Americans of African descent carry one copy of the gene that causes sickle cell disease, and have “sickle cell trait.” People who inherit two copies have sickle cell anemia, the disorder’s most common form. The disorder is marked by the characteristic “sickled” or crescent-shape red blood cells that can get stuck in small blood vessels feeding bones, creating recurrent bouts of crippling pain that require opioids and sometimes urgent hospitalization. Beyond the disabling toll on patients, the disease accounts for a significant amount of health care costs—an estimated $500 million per year. About 10-20 percent of people with sickle cell account for more than 50 percent of the costs, Carroll says, reflecting the reality of patients with sickle cell whose pain episodes are more frequent and more intense than usual.
“The most clinically interesting finding but also the most puzzling was the extent to which higher opioid doses—both at home and during acute visits—were tied to poorer outcomes and more complications,” says Carroll. “There is the conundrum that despite more aggressive treatment, a subset of people didn’t get as much benefit.”
He says growing tolerance to opioids may be one explanation, along with emergency room physicians who don’t know a patient’s history to quickly provide adequate pain medicines when pain crises occur, which may require higher opioid doses than are safe for a typical patient. Care is fragmented, Carroll says, and because there are no objective measures of pain, some physicians are reluctant to prescribe higher doses of opioids.
In their study that documented the source of higher-than-typical infusion center visits, the researchers looked at data from 73 patients seen at the Johns Hopkins Sickle Cell Center for Adults. Patients were an average age of 34, and 62 percent were women. Participants all underwent assessment on a standard Pain Anxiety Symptoms Scale, and researchers collected information on patients’ socioeconomic status, insurance coverage and education level. The researchers relied on medical records to document admission to the Sickle Cell Infusion Center, where patients get treated for crisis pain. Opioid doses were converted to a standard measurement of “morphine equivalents” so drug quantity could be easily compared among participants.
With those data, the researchers classified 23 people as “typical” users of the infusion center (less than five visits over a year). Another 23 people were considered “high” users of the infusion center (five visits or more). The remaining 27 people had no visits in a calendar year.
Typical users of the infusion center were on an average of about 26 morphine equivalents of opioids daily at home, compared to high-users who were on about 66 morphine equivalents of opioid medication daily.
Although the typical users had on average the same initial crisis pain rating as the high-users (8.5 versus 8.4 on a scale of 10), the typical users of infusion center care reported an average reduction of 3.8 pain points after treatment with opioids intravenously, putting their pain level around 5, compared to the high-users of infusion center care who only reported a drop of an average of 1.6 pain points, putting them at around 7 for reported pain after treatment. Pain improvement was twice as great for typical infusion center users, yet they received less than half the opioid dosage (~26 milligrams) during the emergency visits than those high users of the infusion center (~66 milligrams).
Because it’s a challenge to manage pain effectively without prescribing potentially unsafe amounts of opioids, what’s clear, Carroll says, is the need to develop more nonopioid pain relievers that don’t increase risks of tolerance and overdose.
One of the biggest drivers of cost and ineffective treatment of people with sickle cell, he says, is that in many cases the health care team dealing with people in an emergency setting during crisis isn’t the same providers who help the patient manage day-to-day care. “This typically means that emergency care providers don’t reliably know medication dosages and treatment plans in place for that person,” Carroll says.
There is a great need, he adds, for sickle cell disease clinical centers that manage both day-to-day and 24/7 emergency care, such as those with the integrated approach used by the Johns Hopkins Sickle Cell Infusion Center that can help bridge the care gap and keep treatment consistent.
Sickle cell disease is most common in people with ancestry near the equator, such as African, Indian, Asian, Middle Eastern and Mediterranean, or places where malaria is common. Sickle cell disease can damage the internal organs and, on average, the life spans of people with the disease are 30 years shorter than in the general population.
Citation for John Hopkins study: C. Patrick Carroll et al. Predictors of acute care utilization and acute pain treatment outcomes in adults with sickle cell disease: The role of non-hematologic characteristics and baseline chronic opioid dose, American Journal of Hematology. DOI: 10.1002/ajh.25168
How sickled red blood cells stick to blood vessels
One of the most common complications of sickle-cell disease occurs when deformed red blood cells clump together, blocking tiny blood vessels and causing severe pain and swelling in the affected body parts.
A new study from MIT sheds light on how these events, known as vaso-occlusive pain crises, arise. The findings also represent a step toward being able to predict when such a crisis might occur.
“These painful crises are very much unpredictable. In a sense, we understand why they happen, but we don’t have a good way to predict them yet,” says Ming Dao, a principal research scientist in MIT’s Department of Materials Science and Engineering and one of the senior authors of the study.
The researchers found that these painful events are most likely to be produced by immature red blood cells, called reticulocytes, which are more prone to stick to blood vessel walls.
Subra Suresh, president of Singapore’s Nanyang Technological University, former dean of engineering at MIT, and the Vannevar Bush Professor Emeritus of Engineering, is also a senior author of the study, which appears in Proceedings of the National Academy of Sciences the week of Sept. 3. The paper’s lead authors are MIT postdoc Dimitrios Papageorgiou and former postdoc Sabia Abidi.
Simulating blood flow
Patients with sickle cell disease have a single mutation in the gene that encodes hemoglobin, the protein that allows red blood cells to carry oxygen. This produces misshapen red blood cells: Instead of the characteristic disc shape, cells become sickle-shaped, especially in low-oxygen conditions. Patients often suffer from anemia because the abnormal hemoglobin can’t carry as much oxygen, as well as from vaso-occlusive pain crises, which are usually treated with opioids or other drugs.
To probe how red blood cells interact with blood vessels to set off a vaso-occlusive crisis, the researchers built a specialized microfluidic system that mimics the post-capillary vessels, which carry deoxygenated blood away from the capillaries. These vessels, about 10-20 microns in diameter, are where vaso-occlusions are most likely to occur.
The microfluidic system is designed to allow the researchers to control the oxygen level. They found that when oxygen is very low, or under hypoxia, similar to what is seen in post-capillary vessels, sickle red cells are two to four times more likely to get stuck to the blood vessel walls than they are at normal oxygen levels.
When oxygen is low, hemoglobin inside the sickle cells forms stiff fibers that grow and push the cell membrane outward. These fibers also help the cells stick more firmly to the lining of the blood vessel.
“There has been little understanding of why, under hypoxia, there is much more adhesion,” Suresh says. “The experiments of this study provide some key insights into the processes and mechanisms responsible for increased adhesion.”
The researchers also found that in patients with sickle cell disease, immature red blood cells called reticulocytes are most likely to adhere to blood vessels. These young sickle red cells, just released from bone marrow, carry more cell membrane surface area than mature red blood cells, allowing them to create more adhesion sites.
“We observed the growth of sickle hemoglobin fibers stretching reticulocytes within minutes,” Papageorgiou says. “It looks like they’re trying to grab more of the surface and adhere more strongly.”
The researchers now hope to devise a more complete model of vaso-occlusion that combines their new findings on adhesion with previous work in which they measured how long it takes blood cells from sickle cell patients to stiffen, making them more likely to block blood flow in tiny blood vessels. Not all patients with sickle cell disease experience vaso-occlusion, and the frequency of attacks can vary widely between patients. The MIT researchers hope that their findings may help them to devise a way to predict these crises for individual patients.
“Blood cell adhesion is indeed a very complex process, and we had to develop new models based on such microfluidic experiments. These adhesion experiments and corresponding simulations for sickle red cells under hypoxia are quantitative and unique,” says George Karniadakis, a professor of applied mathematics at Brown University and a senior author of the study.
Citation for third study: Dimitrios P. Papageorgiou el al., “Simultaneous polymerization and adhesion under hypoxia in sickle cell disease,” PNAS. doi/10.1073/pnas.1807405115