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CF Research Cooperative Expands Patients’ Options

A mother helps her son use a nebulizer. (Stock photo)

In the last few decades, scientific collaboration has played a vital role in improving quality of life and extending life expectancy for patients with cystic fibrosis (CF). Now, the members of a new cooperative hope that sharing their research and expertise will lead to more progress. The Southeast Cystic Fibrosis Research Cooperative connects specialists from about two dozen high-volume centers across the Southeast region, including Children’s of Alabama. Members have been meeting for the last year with the goal of advancing a sea change in available CF treatments.

Launched by the Cystic Fibrosis Foundation, the research cooperative blends a social component with the work of effectively treating CF, for which breakthrough therapies targeting gene defects have transformed care in just the last several years. Members of the cooperative—who, in many cases, have attended the same medical conferences over the years—have held virtual meetings in recent months but hope to gather in person as more join the group.

“Our region is big, and our patients are spread out—all the way from eastern Texas to the tip of Florida,” Children’s of Alabama pulmonologist and sleep medicine specialist Christopher “Miles” Fowler, M.D., said. “Every big center is working on different research and has different strengths to offer, so I think we’re all bringing something different to the table.”

About 600 CF patients are receiving treatment at any given time from the combined adult and pediatric program at Children’s and the University of Alabama at Birmingham (UAB). “There are more than 30,000 patients with CF in the United States, and the Southeast represents a big percentage of those patients,” Fowler said.

Accordingly, each CF center in the Southeast is tackling diverse aspects of CF, from groundbreaking gene therapy studies to clinical trials assessing new infection-fighting protocols or ways to optimize nutrition or exercise. UAB will soon be enrolling patients for gene therapy trials, but other centers in the region will be analyzing both similar and different gene therapy endpoints.

“There are going to be different options: The drugs will be different, and the risks will be different,” Fowler explained. “There’s a need to disseminate information about the trials being offered and educate providers about the risks and benefits of the drugs we’re still learning about. That’s been part of our focus.”

Ultimately, CF patients here and elsewhere should greatly benefit from the research cooperative’s efforts, Fowler said. The collaboration makes it easy for patients to learn about trial options and for centers to refer patients to other studies.

“There’s so much going on with cystic fibrosis that I think it’s impossible for any one center to do all of this,” he said. “We all have different resources and expertise that allow us to do the studies we do, so one way the regional cooperative helps is by making more types of studies available to patients in our region.”


Interventional Pulmonology Now More Common for Kids

New technology is enabling Children’s of Alabama pulmonologists to offer more interventional procedures.

In his career as a pediatric pulmonologist at Children’s of Alabama, Ryne Simpson, M.D., has typically cared for children with conditions such as cystic fibrosis, prematurity and asthma. But as more children born with premature lungs survive and require tracheostomies and ventilators at home, “the flavor of the field has changed a bit,” Simpson said, “and interventional pulmonology is becoming more prevalent in pediatrics.” That’s why earlier this year Children’s began using new technology to offer more interventional procedures to its patients.

Interventional pulmonology is a subspecialty of pulmonary medicine dealing with minimally invasive, advanced bronchoscopic procedures, an example being removal of foreign bodies or other non-native material. Previously, that required surgery or a referral to an otolaryngologist, but both strategies have limitations. “Pulmonologists receive specific training in pediatric lung disease, which a surgeon or ENT physician may not always have,” Simpson said. With specialized equipment, “it can be a better situation for the patient.”

Historically, that equipment has been better suited for use in adults, and adult pulmonologists perform many more interventional procedures than pediatric pulmonologists. Thanks to the development of smaller tools and equipment, Children’s of Alabama can now offer certain interventional procedures to its patients.

One example is flexible bronchoscopic cryotherapy, something previously offered only in the adult setting. Children’s began using it in February 2023. It involves performing a bronchoscopy, then using a special probe to freeze a foreign body, piece of tissue or blood clot and pull it out for examination. “Previously, it could take hours because we often wouldn’t get the whole thing at once,” Simpson said. “Now we’re able to complete these procedures in significantly less time, which has been pretty amazing for the patients.”

Children’s also is working closely with the adult interventional pulmonology program at the University of Alabama at Birmingham (UAB), which has even more sophisticated equipment—such as robotic bronchoscopy—that in some cases is small enough to be used in the pediatric setting.

“It’s been a nice marriage between adult pulmonology at UAB and pediatric pulmonology at Children’s,” Simpson said. The pediatric department has been able to borrow certain equipment or, if needed, send children to UAB pulmonologists for help. “Sort of like: ‘You have the equipment, we have the knowledge, we can work together to get something done that previously we would have never been able to do,’” he said.


New Protocol Dramatically Improves Outcomes for Children with Acute Chest Syndrome

An initiative led by Dr. Ammar Saadoon Alishlash is helping children with acute chest syndrome.

Acute chest syndrome (ACS) is a respiratory disease that starts suddenly, progresses rapidly and is the leading cause of death in children with sickle cell disease in the U.S. and other countries. However, in the last three years, since Children’s of Alabama instituted a standardized ACS protocol, there have been no ACS-related deaths among the hospital’s patients included in the protocol.

Children’s admits as many as 100 children with ACS every year, and the new protocol has improved outcomes among these patients, decreasing the average number of inpatient days from seven to four (a 42% drop) and reducing ICU admissions and mortality.

“We did not expect such significant results,” pediatric pulmonologist Ammar Saadoon Alishlash, M.D., the leader of the initiative, said. When the initiative began, it was up to each child’s physician whether to follow the protocol or standard procedure because it wasn’t clear if the protocol would actually improve outcomes. “But now we’re pushing to have all patients diagnosed with acute chest syndrome be put on the protocol,” he said.

The protocol is based on the latest evidence on the management of ACS. It includes order sets for tests and medications that are embedded in the electronic medical record, which makes it possible for the patient to receive appropriate care in the emergency room rather than waiting until they’re admitted. It also provides three order sets depending on where the child is in the hospital: in the emergency department, the hematology floor or the ICU. “Each has a specific set of orders designed for that specific population to improve outcomes wherever they are in the hospital,” Alishlash said. The standardization also reduces variation in how physicians treat the patients, which is one reason for the improved outcomes, he said. The protocol involves initiating therapy early in the emergency department before the condition progresses. The main interventions include oxygen supplementation and respiratory support.

To further improve ACS outcomes, Alishlash, who leads the pediatric pulmonary sickle cell disease program at Children’s and the University of Alabama at Birmingham, is performing clinical and laboratory research on the condition. He received a National Institutes of Health grant to study the effects of environmental exposures on its development and to test novel therapies. He has also identified risk factors for ACS, including low oxygen levels during sleep and an association between where the child lives and the condition. “To prevent death in these small children is a great achievement,” he said. “Hopefully it will dramatically improve outcomes in our sickle cell patient community.”

Inside Pediatrics, Pulmonology

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


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

Inside Pediatrics, Pulmonology

Children’s of Alabama Muscular Dystrophy Care Center Offers Life-Saving Treatment for Rare, Fatal Disease


Brad Troxler, M.D., director of the Muscular Dystrophy Care Center (MDA) at Children’s of Alabama, chats with a patient. The MDA Care Center is the only MDA clinic in Alabama and one of only a few in the region.

The Muscular Dystrophy Care Center (MDA) at Children’s of Alabama sees about 280 patients a year with a wide variety of neuromuscular conditions. They require multidisciplinary care from neuromuscular specialists, neurologists, pulmonologists, genetic counselors and cardiologists, among others. They also need respiratory, physical and occupational therapies, nutritional counseling and social work support.

One of the most devastating conditions the clinic sees is spinal muscular atrophy (SMA), a rare autosomal recessive genetic disorder that is the leading cause genetic cause of death in infants. It is characterized by degeneration and loss of lower motor neurons, leading to muscle atrophy. Infants with the most serious form of the disease, Type 0, can be diagnosed prenatally and typically die before 6 months, while those with Type 1 begin showing symptoms around 6 months, require ventilation and typically die before age 2. Other types of SMA may not manifest until childhood or even adulthood and are less severe, although all of those affected experience some neuromuscular effects.

Until recently, SMA was primarily treated with supportive care. Today, however, there are two groundbreaking treatments and Children’s is the only MDA clinic in the state, and one of only few in the region, to offer both: nusinersen (Spinraza), approved for children and adults, which is administered in several doses the first year and annually after that; and onasemnogene abeparvovec-xioi (Zolgensma), a single-dose treatment approved for use in children with SMA Type 1 under age 2.

Both are gene therapies designed to address genetic mutations in the SMN1 and/or SMN2 genes, which make the protein required to control muscle movement. Both are also extremely expensive, with the first 10 years of treatment with Spinraza estimated at $4 million and a single dose of Zolgensma costing $2.1 million, making it the most expensive drug ever marketed.[1]

The cost could be worth it, though, given the benefits of the drugs. “Clinical trials showed huge improvement,” said Brad Troxler, M.D., who MDA Care Center director. Indeed, after four years, infants treated with Spinraza before they turned 6 weeks were still achieving and maintaining motor milestones such as walking and sitting without assistance, things SMA babies would not normally be able to do.[2]

Participants in the Zolgensma trials were demonstrating similar results, with all children who received the drug still alive at 2 years and none requiring ventilation.[3]

Don’t call the treatments cures, however, says Troxler. “‘Cure’ is a hard word to define,” he said. While improved, patients still don’t have normal neuromuscular function after receiving the drug, with some muscle weakness remaining and an increased risk of scoliosis and other issues related to the disease. “But if we give it early enough, they are able to walk and talk and eat so it’s pretty close to a cure,” he said.

The earlier the drugs are administered, the greater the benefit. “Time is neurons,” said Shelley Coskery, MSN, CRNP-AC, MDA Care Center coordinator. However, Alabama is one of the few states that doesn’t screen newborns for SMA, which could delay treatment until symptoms appear. “We’re working on it,” Coskery said. “We need to start treating these patients before they develop symptoms and then, hopefully, we will see fewer and fewer affected with the disease.”

Becoming one of the first centers to offer SMA treatments, she said, “puts us at the forefront of the gene replacement movement.” Indeed, the center is also beginning clinical trials for genetic therapies for children with Duchenne, one of the most common neuromuscular diseases.

The ability to provide such effective treatments to children who otherwise would have died before age 2 “is very profound,” Troxler said. “You can see the difference it makes on individual families in a really powerful way. Conversations historically been about how ‘this is a terrible disease that will likely end in your child’s death.’” Now, Troxler said, the conversation has changed to, “‘Your child has a horrible disease, but we have some therapies that are going to change what this looks like.’ It’s completely different.”

“There is a lot of excitement throughout the SMA community,” Coskery said. “We are very grateful when the parents send emails of the child standing and achieving milestones we didn’t think they would.”

[1] Thomas K. his New Treatment Could Save the Lives of Babies. But It Costs $2.1 Million. The New York Times. May 24, 2019.

[2] Biogen Announces New Data Further Establishing SPINRAZA® (nusinersen) as a Foundation of Care in Spinal Muscular Atrophy for a Broad Range of Patients. Available at:

[3] New Data Shows Long-Term Benefits of Zolgensma in SMA Patients. Available at:

Inside Pediatrics, Pulmonology

Using Pharmacogenetics to Help Identify Patients with Cystic Fibrosis Most Likely to Respond to Targeted Therapies


Children’s of Alabama and the University of Alabama at Birmingham (UAB) are on a mission to determine how patients use Cystic Fibrosis Transmembrane Conductance Regulator modulators at the cellular level.

The discovery of the genetic mutation responsible for cystic fibrosis (CF) and the subsequent development of drugs that target this mutation, called Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators, together with improved supportive treatments, has revolutionized the management of the disease. Today, the median life expectancy of someone with CF has increased from age 10 in 1962 to 47, with many patients living into their 50s or 60s. With the newer drugs, many expect those with CF will be able to live a normal lifespan.

However, studies of the four currently available CFTR modulator therapies, three of which are combination drugs, find that between 20 and 25 percent of patients who should respond based on their disease’s genetic fingerprint don’t.1,2 Given that the drugs can cost up to $300,000 a year, it is important to find biomarkers to identify which drug will be most effective for which patient.3 Currently, the only option is a rectal biopsy followed by complicated testing or nasal brushing, neither of which are approved by the U.S. Food and Drug Administration, accepted by insurance or widely used.

Children’s of Alabama pulmonologist Jennifer S. Guimbellot, M.D., Ph.D., together with Steven M. Rowe M.D., who directs the Gregory Fleming James Cystic Fibrosis Research Center at the University of Alabama at Birmingham (UAB), and  Edward P. Acosta, Pharm.D.,  who directs UAB’s Division of Clinical Pharmacology, are on a mission to change that.  Their research focuses on how patients use CFTR modulators at the cellular level.

Until fairly recently, Guimbellot said,We didn’t have the tools to measure levels in the tissue.” Now they can use a simple, minimally invasive test Guimbellot helped develop. The assay measures concentrations of CFTR modulators in plasma and nasal epithelial cells, which, like epithelial cells in the lungs, are the drug’s site of action. Obtaining the cells is simple and inexpensive, requiring only a nasal brush, and can be done repeatedly to monitor drug levels.

After obtaining cells from patients, Guimbellot said, her team found that while plasma concentrations seem to correlate with the drug response, concentrations in tissue differ from those in plasma.

The question is why.

The answer may be related to pharmacogenomics, or the genetic variation in the way individuals metabolize drugs. Thanks to the epithelial tissue assays, she said, “our lab found that there may be substantial differences in the levels of modulators and also of metabolism proteins in people with CF.” Thus, once the drug is delivered to the cell, the effect may differ between patients. For instance, one person may be a fast metabolizer and clear the drug quickly; while the other may be a slow metabolizer and the drug accumulates in the tissue.

The protein known to metabolize CFTR modulators, CYP3A4, is primarily active in the liver. But in about 20 percent of people, it may also be produced in other tissues. While Guimbellot’s team has not found CYP3A4 in the epithelial cells from CF patients they’ve examined, they have found substantial levels of mRNA from the almost identical CYP3A7 protein and its cousin, CYP3A5. “So we hypothesize the CFTR modulator drugs are substantially metabolized by those proteins since it’s so similar to CYP3A4, and that this could affect how well patients respond to the drug.” They also found wide variation in the expression levels of both, which could contribute to the amount of available modulator at the target site.

“By understanding how genetic variation may influence the expression of these proteins and how that might affect the amount of drug available to do its job in the target tissue we can then relate the findings back to whether or not a patient can be expected to respond well to it or not,” she said.

Which is the next step in their research.

The team’s work is currently funded by the Cystic Fibrosis Foundation.

[1] National Institutes of Health. Cystic Fibrosis. 2019;

[2] Cystic Fibrosis News Today. Cystic Fibrosis Statistics. 2019; Accessed June 19, 2019.

[3] Starner CI. How much is too much? Prime Therapeutics. May 31, 2019. Available at: