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sickle cell disease

At the Intersection of Sickle Cell Disease and Asthma

A child uses an inhaler. (Stock photo)

While many people know of sickle cell disease (SCD), it may be surprising to learn that there is a high prevalence of co-occurring asthma among children with SCD. Brandi Pernell, DNP, has been researching social determinants of health that impact young patients with a double diagnosis.

“While I was pursuing different strategies for improvements among the asthma population, I discovered a connection between environmental stress and asthma,” said Pernell, an assistant professor in hematology and oncology at Children’s of Alabama and the University of Alabama at Birmingham (UAB). “When you look at the general population in comparison to the sickle cell population, you’re going to see that more children with sickle cell have a diagnosis of asthma because these two conditions have some overlapping inflammatory physiological pathways. That in itself is going to increase the risk of having asthma along with sickle cell.”

Asthma affects oxygen levels, especially among those who are undiagnosed or who are diagnosed but whose disease isn’t fully managed, Pernell said. And low oxygen is a risk factor for red-cell sickling. Patients with both asthma and SCD experience higher rates of pain and acute stress as a result.

Pernell estimates that she provides clinical care for 80 to 90% of young patients in the area who have both SCD and asthma, as well as any patient hospitalized with acute chest syndrome, an acute lung complication. “I have an acute care follow-up clinic where I see anybody who has been hospitalized with acute chest syndrome within four weeks of discharge to make sure that they have focused sickle cell management and any asthma management that needs to take place to reduce the risk of it happening again,” she said.

Another major component of care, Pernell believes, is patient education. She works with community-based organizations and the Sickle Cell Disease Foundation to provide health education. She also gives patients and their families handouts with up-to-date information for disease management. “I try to employ a multimodal approach to education, but I think that the best method is still face-to-face interaction,” she said. “After all the clinical care is done, I take time to see if there are any questions from patients. I explain why I’m recommending this therapy or why this therapy is so important and how it works exactly in your body—because I think that improves adherence if you understand why you need it—or what can happen if you don’t take a medicine or how it could further impact your health in a negative way.”

Support for her patients is also multi-modal. Pernell relies on assistance from a social worker who can lock in community services as needed. She also works with the Children’s of Alabama school liaison to ensure patients have comprehensive support. “By school age, about 30% of children with sickle cell will have suffered a silent stroke, which can impact the child neurocognitively and lead to a decline in academic performance,” Pernell said. She and the liaison also make sure that each patient has a 504 plan in place for important classroom accommodations, such as being able to maintain hydration and avoid temperature extremes to avoid a sickle cell crisis.

The research Pernell has undertaken looks closely at social determinants of health and those factors within a patient’s control that can improve symptoms. “We are focusing on lifestyle interventions,” she said. “Are there dietary changes (that can reduce symptoms?) Are there different stress reduction tactics that can be taken or things prenatally that moms can do?”

These and other research questions are also guided by input from the patients themselves. Pernell believes that patients, as the ultimate end users of any research discoveries, must be invested in the research planning process and study design. “We need to make sure that the outcomes that we’re pursuing are the outcomes that the patients themselves care about.”

August 24, 2023 by childrensal

Bench-to-Bedside: Translational Focus Moves Sickle Cell Research into Clinic Faster

Jeffrey Lebensburger, D.O., is a pediatric hematologist at Children’s of Alabama and an associate professor in the Division of Hematology/Oncology in the Department of Pediatrics at the University of Alabama at Birmingham.

Basic research is conducted in labs and on animal models, and clinical research is conducted in humans. Traditionally, the two don’t mix, with the basic happening before the clinical. Translational research, a mix of the two, is designed to get new discoveries and treatments to patients faster. “Translational research is a vital component to making breakthroughs in clinical care,” said Jeffrey D. Lebensburger, D.O., who directs the pediatric hematology section of Children’s of Alabama’s Department of Hematology and Oncology.

Dr. Lebensburger and his research partner, University of Alabama at Birmingham assistant professor Malgorzata Kasztan, Ph.D., are using this approach to find better ways to prevent early kidney disease in children with sickle cell disease. Between 20 percent and 30 percent of children with the disease already demonstrate kidney injury before they hit their teens, and up to 70 percent will develop chronic kidney disease by the time they’re middle-aged. Many will require dialysis or transplantation, often beginning in their 20s. However, the most commonly used test for kidney problems rarely identifies early signs.

“While we may think that the kidneys are doing okay in childhood based on the tests, there may be severe damage that leads to this early dialysis, which is why we greatly need this bench-to-bedside approach to prevent progression early in adulthood,” Dr. Lebensburger said.

“We are particularly interested in looking at which patients are at risk for kidney disease and if there is a way to identify those patients early in the process, so they can get better care,” said Dr. Kasztan.

Tracking the progression from childhood through adulthood, however, would take too long and cost too much. Yet mice genetically engineered to have sickle cell disease fully mature in just a few months, making them a perfect model for exploring kidney disease progression.

Using these mice, coupled with a biobank of patient blood and urine samples and a sophisticated assay for kidney damage available only in the research setting, Drs. Lebensburger and Kasztan identified high levels of the protein endothelin-1 (ET), which binds to two receptors, ETA and ETB, as a key contributor to early kidney damage. Blocking the ETA receptors with an already-FDA-approved drug, however, protected the mouse kidneys.

“That allows us to bring back to the patient what we’re seeing in the mouse model and understand if it will continue into adulthood,” Dr. Kasztan said. “Then we could potentially intervene earlier.”

At the same time, biomarkers of early damage they find in the human blood and urine samples can be “mirrored” in the mouse model to confirm the results, she said. Then interventions that work in the animal model can be tested in patients.

This type of bidirectional work provides the foundation for clinical trials in humans, said Dr. Lebensburger. “That’s an example of this bench-to-bedside approach: It works in the mouse model of sickle cell, so we can lobby the FDA to start a clinical trial in humans.”

February 15, 2022 by childrensal

Inside Pediatrics, Pulmonology

Solving the Mystery of Lung Disease in Children with Sickle Cell Disease

Dr-Saadoon-Ammar-Pulmonology-Headhsot-Resized

Children’s of Alabama pulmonologist Ammar Alishlash, M.D.

If lung disease is the leading cause of death in children with sickle cell disease, then why aren’t pulmonologists more involved in their care earlier? That’s a question Children’s of Alabama pulmonologist Ammar Alishlash, M.D., wanted to answer. “I felt for us to take care of those patients, especially those with underlying lung disease, would serve them better clinically,” Dr. Alishlash said.

In the past, the leading cause of death in those with sickle cell disease was infections. But the use of prophylactic antibiotics changed that. Today, it’s acute chest syndrome (ACS), marked by shortness of breath, low oxygen levels and fever. Many patients progress to respiratory failure, and some die. Yet lung specialists are not usually involved in their care while in the hospital or after discharge. Instead, in most children’s hospitals they are managed solely by hematologists.

“The problem is, we don’t have any specific treatment targeted for acute chest syndrome,” said Dr. Alishlash. Instead, patients are managed with supportive therapy, including oxygen, fluids, antibiotics and sometimes invasive or non-invasive ventilation.

Now Dr. Alishlash is on a mission to change that dynamic. He’s launched a three-pronged research initiative: identifying risk factors for ACS to proactively recognize children with a higher risk, developing clinical pathways to prevent progression and mortality and researching novel therapies to treat the condition.

“I became interested in this condition because I feel that, as pulmonologists, we have experience with other lung diseases,” he said. “We can apply our knowledge from other lung diseases to the sickle cell population, which could open a lot of doors for diagnosis and new treatments.”

So far, Dr. Alishlash has instituted a clinical pathway to standardize the care children with ACS receive after admission. The pathway has been in place for about 18 months, and the results are encouraging, with a nearly 50 percent reduction in length of stay. In addition, all patients have survived. Previously, one out of every 100 children would die. “That’s pretty significant, especially when you’re talking about children, who are typically between 2 and 4 years of age when they are most likely to develop ACS,” he said.

Dr. Alishlash has also made progress in identifying risk factors for ACS in children with sickle cell disease. One is nocturnal hypoxemia, when oxygen levels drop at night. This seems to induce the sickling and is associated with increased risk of ACS.¹ He also found a correlation between the neighborhood where patients live and ACS, due to, he thinks, air quality, socioeconomic factors and greater stress.²

On the laboratory side, Dr. Alishlash and his team are using a sickle cell mouse model to test potential treatments as well as identify triggers. One interesting finding is that chlorine can cause sickling, leading to the release of heme from red blood cells, which is toxic to the lung endothelium and subsequent development of ACS. A medication called hemopexin, however, scavenges the free heme. When given to mice exposed to chlorine who developed ACS, hemopexin reduced the death rate from 80 percent to 20 percent.³

At the same time, Dr. Alishlash has started a twice-monthly clinic for sickle cell patients with underlying lung disease. The clinic is very busy, he said. “And patients’ outcomes are improving, which is very encouraging.”

¹ Nourani AR, Rahman AKMF, Pernell B, et al. Nocturnal hypoxemia measured by polysomnogram is associated with acute chest syndrome in pediatric sickle cell disease. J Clin Sleep Med. 2021;17(2):219–226.

² Alishlash, AS, Rutland, SB, Friedman, AJ, et al. Acute chest syndrome in pediatric sickle cell disease: Associations with racial composition and neighborhood deprivation. Pediatr Blood Cancer. 2021; 68:e28877

³ Alishlash AS, Sapkota M, Ahmad I, et al. Chlorine inhalation induces acute chest syndrome in humanized sickle cell mouse model and ameliorated by postexposure hemopexin. Redox Biol. 2021;44:102009. doi:10.1016/j.redox.2021.102009

August 27, 2021 by childrensal

Hematology and Oncology, Inside Pediatrics

Asthma, Sickle Cell Disease and Trauma – Connecting the Dots

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Brandi M. Pernell, DNP, assistant professor of Pediatric Hematology and Oncology

Take a child with sickle cell disease who is already at a significantly higher risk for asthma, pain and acute chest syndrome—the leading cause of death in these children—and mix in adverse childhood experiences (ACEs) such as violence, racism, abuse, parental death or divorce. The result: sicker children who, due to toxic stress exposures, are more likely to experience poorer health outcomes.

That’s what Brandi M. Pernell, DNP, an assistant professor of pediatric hematology and oncology who works at the Children’s of Alabama dedicated pediatric sickle cell clinic, found in her research.

“The literature shows that those who experience ACEs early in life have a higher risk of chronic conditions like asthma, cardiovascular disease, and obesity”—even cancer, Dr. Pernell said. But until her work, there was limited documentation in the sickle cell literature about ACEs. What is known is that acute stress is a common trigger for pain episodes in children with sickle cell disease. Pernell is now connecting the dots to show that ACEs increase asthma risk in these children which, in turn, leads to an increased risk for pain and acute chest syndrome.

Her findings highlight the need to screen children with sickle cell disease, particularly adolescents, for ACEs and, if found, implement protective factors and buffering mechanisms to address the physiologic sequelae from these toxic exposures.

She’s already begun that process, teaming with the local chapter of the Sickle Cell Foundation to promote social and emotional competence and resilience among affected adolescents. That community-based approach is important, she said. “I believe we need to meet families and patients where they are,” she said. And the Foundation has a different relationship with patients and families than the clinic staff. “We address the medical side, but ACEs are things happening in the home and neighborhood,” said Dr. Pernell.

For Dr. Pernell, the work is more than a scientific endeavor; it’s personal. She felt called to this research, she said, both as a Black woman (sickle cell primarily affects Black people) and as a healthcare provider, particularly given the events of 2020. “In the wake of COVID and the social and racial uprising prior to and throughout 2020, it just spoke to me,” she said. So when she joined the University of Alabama at Birmingham faculty in 2016, this is where she focused her research. “I can relate to my patients in a way that some others can’t,” she said. “I’ve experienced some of the same things they have.”

“If not me, then who?” she asked, quoting the late congressman and civil rights leader John Lewis. “If not now, then when?”

August 27, 2021 by childrensal

Hematology and Oncology

Pain Clinic Provides Safe Space for Sickle Cell Patients to Receive Treatment

Raven Myrick, CRNP, right, places a virtual reality headset on patient Olivia Parker in Children’s of Alabama’s Sickle Cell Pain Clinic.

Throbbing. Sharp. Pounding. Dull. Stabbing. Cutting. Gnawing.” That’s how patients describe the pain of sickle cell disease.[1]

While current guidelines call for patients to receive pain medications within an hour of arriving at a treatment center or emergency room (ER), that’s difficult to achieve in a busy emergency department (ED), said Jeffrey Lebensburger, D.O., MSPH, who directs the Cancer and Blood Disorders’ hematology section at Children’s of Alabama. This delay in pain relief allows the pain intensity to increase and may lead to a child requiring hospitalization. In addition, in this era of an opioid epidemic, more families report discrimination when they ask for opioids for pain and are accused of drug-seeking behavior.

That’s why Children’s started its own sickle cell pain clinic, Lebensburger said. It’s not just for patients in crisis. “About half our patients also experience daily, chronic pain,” he said.

Targeting Pain

The clinic has four main goals:

Provide care in a familiar setting
Reduce the number of hospitalizations
Get the patient’s pain under control more quickly
Provide non-medicine treatment strategies for pain

The clinic is run out of the regular pediatric hematology clinic with a dedicated nurse practitioner, Raven Myrick, CRNP. Patients can call a hotline or email the hematology team any time and get a same-day or next-day appointment. Eventually, the team would like to offer night hours.

“Our families appreciate being able to go to the clinic versus the ER,” Myrick said. “It’s a familiar, nonjudgmental atmosphere. It’s not our job to say if they are having pain or not. Our job is to make them feel comfortable and to show that we care.”

“It’s not a cure for their disease,” she said, “but the pain clinic gives them hope that someone is working to make them feel better.”

Virtual Reality as Treatment

The clinic uses Starlight Virtual Reality (VR) headsets, donated to Children’s of Alabama by the Starlight Children’s Foundation, to teach kids how to relax and breathe through the pain. Studies have found that VR can reduce pain sensation. When patients come to the clinic, they first spend at least 10 minutes with a VR deep breathing/visualization program. Then they can continue to use other programs as a distraction technique or even just watch movies. “Being able to watch Netflix in the virtual reality environment without cues from other people provides superior distraction to non-virtual reality distraction,” Lebensburger said. Then they go home with a list of relaxation apps to download on their phones.

Patients also receive pain kits to help with distraction, including items like squeezable balls and Silly Putty, as well as their own “tools,” such as action figures and trading cards that they can only play with during a pain crisis.

The clinic has seen more than 30 patients since it opened in Marchand had just three hospitalizations, which is “an amazing outcome for our patients,” Myrick said.

“We know our patients and are familiar with what works for them with use of our Individualized Pain Plans,” Myrick said.

Cancer Fighters

Get more information about the Cancer and Blood Disorders Program at Children’s of Alabama.

[1] Ballas SK, Gupta K, Adams-Graves P. Sickle cell pain: a critical reappraisal. Blood. 2012;120:3647-3656;

August 20, 2019 by childrensal