Casting Light on a Rare Lung Disease
Nawaf and Fatemah Al-Shammari searched the world for a doctor who could help their daughter. By the time the search led them to Cincinnati Children’s, hope was running out for 3-year-old Nourah.
She was desperately ill from a mysterious lung disease.
At Cincinnati Children’s, the Al-Shammari family found a doctor with expertise in the complex treatment Nourah needs. And more, they found a research team with expertise in lung biology.
It’s a rare combination: outstanding patient care side-by-side with outstanding research; collaboration among the doctors who treat sick children and the researchers studying what underlies disease; basic science grounded in clinical challenges.
For Nourah, it’s a combination that made all the difference.
The best available treatment saved her life. Innovative research offers hope for a complete cure.
A Mysterious Lung Disease
Born in Kuwait in 2005, Nourah was an apparently healthy baby until she was 2½ years old. Then suddenly she became very sick with asthma and coughing. She grew lethargic. She turned blue.
What was making her so sick?
A lung specialist wanted to do a bronchoscopy exam, but Nourah was too sick to risk giving her anesthesia for the procedure.
Within a month Nourah was in the ICU, unconscious, on a respirator. While she was in the ICU, her doctors performed the bronchoscopy. The results were surprising: They didn’t find infection or inflammation, but sediments – evidence of a very rare lung disease.
Her parents and medical team began searching for help outside Kuwait.
“I sent her records to many hospitals,” her father recalls, “but no one would accept her case.”
Nourah’s doctor sought advice from pulmonary experts worldwide through an online discussion group on the internet. That’s how he found Robert Wood, MD, PhD, director of bronchoscopy at Cincinnati Children’s.
“I saw his inquiry and recommended whole lung lavage,” says Dr. Wood. “He asked if he could send his patient to me.”
‘Wood’s Lung Laundry’
Whole lung lavage (WLL) is a complicated procedure, used to treat pulmonary alveolar proteinosis (PAP). For decades the only thing known about this rare disease was that patients with PAP have too much surfactant in their lungs, making it difficult for them to get air in.
Surfactant, a fatty substance produced by the lungs, reduces surface tension and keeps the lung’s tiny air sacs (alveoli) open. Having either too little or too much surfactant is life-threatening.
Without it, air sacs in the lung collapse when we exhale and struggle to expand with a new breath. This is what happens in premature babies who are born before their lungs have developed the capacity to produce surfactant.
But if we have too much surfactant, as in PAP, it fills up space that should be filled with air.
There’s only one treatment for PAP: washing the lungs to get rid of excess surfactant. “Lung laundering,” as Dr. Wood calls it.
Not many hospitals have the ability to perform whole lung lavage on a child as young, tiny and fragile as Nourah.
Dr. Wood, one of the world’s experts, has 40 years of experience with the procedure in children. He agreed to see Nourah.
The US and Kuwaiti embassies worked together to get the family the necessary travel visas and arrange the 6,800-mile trip, accompanied by a doctor and nurse.
Dr. Wood performed Nourah’s first lavage treatment just three days after she arrived in Cincinnati in November 2008. He washed her lungs with many liters of saline to remove the surfactant sediment. Within three weeks, she was well enough to leave the hospital.
Though the treatment is effective, lavage is a temporary fix. Nourah’s lungs continue to become clogged with excess surfactant. As a result, her family has remained in Cincinnati since 2008. Dr. Wood washes her lungs every three to six weeks.
Cousin Bashayer Arrives
Nourah is alive today because of the expert care available at Cincinnati Children’s. But the story is far more complicated.
Back home in Kuwait, her cousin, Bashayer, also suffered from pulmonary alveolar proteinosis. Not long after Nourah arrived in Cincinnati, Bashayer’s family moved here, too.
Dr. Wood now was treating first cousins – just 3 and 4 years old – with PAP.
Very unusual.
For decades, PAP was believed to be an acquired disease, occasionally seen in children, but mostly in adults.
Today, because of Nourah, Bashayer and a handful of other young patients, researchers at Cincinnati Children’s have identified a previously unknown hereditary type of PAP (hPAP).
Working rapidly, a research team led by Bruce Trapnell, MD, developed a test to diagnose hPAP and is conducting laboratory studies of an innovative genetic therapy that, in preliminary tests, cures it.
Nourah and Bashayer will be in the first group of patients offered the new therapy when it is approved for testing in humans.
Decades of Discovery
Scientists at Cincinnati Children’s have been at the leading edge of research on surfactant-related diseases since the 1980s, when a team led by neonatologist Jeffrey Whitsett, MD, did groundbreaking work on respiratory distress syndrome in premature infants.
The lungs of premature babies are not able to produce enough surfactant. Respiratory distress due to insufficient surfactant is a killer in these tiny babies.
Dr. Whitsett made an important breakthrough in the fight to save preemies. He identified and cloned two proteins essential to human surfactant. His research made it possible to produce a genetically engineered surfactant treatment for preemies. Surfactant replacement therapy is now routinely used in newborn ICUs – saving thousands of babies every year.
Dr. Whitsett and his research team have continued to focus intensively on lung biology and surfactant-related diseases. In fact, their research in the 1990s helped explain the basic biology of PAP.
The Basics of PAP
The work began when scientists at MIT turned to Dr. Whitsett for help. They were trying to understand the role of a newly identified protein, GM-CSF (granulocyte macrophage colony-stimulating factor). The protein appeared to promote the growth of macrophages. It was important to understand GM-CSF’s role, because macrophages in our white blood cells are a key part of the immune system.
Described as garbage collectors, macrophages travel through the body, looking for trash, such as worn out cells or toxins or bacteria. When they find something that shouldn’t be there, they surround it and digest it.
To learn more about the role of GM-CSF in this process, the scientists created a model in mice by knocking out the gene that makes the GM-CSF protein. They expected to find that the mice would not be able to make macrophages.
That’s not what happened. The mice did produce macrophages, but oddly enough, the mice had a lot of surfactant in their lungs. Why?
The researchers needed an expert in lung disease and surfactant. They turned to Dr. Whitsett, who recognized the mice had PAP.
Researchers at Cincinnati Children’s have been studying PAP ever since.
“When this work began, no one knew how PAP developed,” says Dr. Trapnell. “In fact, there was a lot of misunderstanding.” People thought PAP was the result of the body producing too much surfactant. Piece by piece, a different picture emerged from laboratory research at Cincinnati Children’s.
It turns out that PAP is not due to overproduction of surfactant but under-clearance of old, used surfactant.
Research showed that GM-CSF is needed for macrophages to mature. If the cells don’t mature, they can’t do their job. In the lung, a key job is to get rid of used surfactant. If they don’t do this, the surfactant accumulates as sediment. Over time, the lungs fill up.
As this insight became clear, a research team in Japan discovered that patients with PAP had an antibody against GM-CSF. By the early 2000s, the Japan and Cincinnati teams were working together.
Meticulous work at Cincinnati Children’s proved that the antibody was not merely present, but was actually causing the disease.
This finding defined PAP as an autoimmune disorder – a condition in which the body mistakenly attacks its own normal functioning.
One output of the research was a diagnostic test for autoimmune PAP, making a bridge from the basic science lab to clinically relevant information. Today Cincinnati Children’s is one of just four centers worldwide that performs diagnostic testing for autoimmune PAP.
After a decade of work, we thought we had a pretty clear picture of the basic biology of PAP. Until we started seeing patients like Nourah and Bashayer.
Because it turned out, they don’t have the antibody.
Hereditary PAP
In 2007, Dr. Wood saw a 6-year-old girl from North Carolina who appeared to have PAP. But when Dr. Trapnell ran the diagnostic test on a blood sample, she did not have the antibody. When he measured her GM-CSF level, it was elevated.
This was something new.
Over the years the research team had carefully maintained a database of patient information and blood samples. They reanalyzed the data and retrospectively found five other cases. Then Nourah and Bashayer arrived.
By now there were enough cases to begin to define the natural history of this new condition. Going further, Dr. Trapnell developed a test to diagnose it, and he created a mouse model to study it in the lab.
Molecular analysis identified a genetic defect in the macrophages. They can’t receive signals from GM-CSF. Since they don’t get the right message, they don’t clean up old surfactant.
The outcome is the same as in autoimmune PAP – too much surfactant in the lungs. But the disease pathway in hPAP is quite different.
Next Steps
In a stunning advance, the basic research quickly led to a new type of therapy: pulmonary macrophage transplantation.
In the lab, Dr. Trapnell’s team is able to correct the gene defect in mice macrophage cells and put the cells back into the lung.
“Because the GM-CSF levels are high, the macrophages we put into the lung proliferate,” he explains. “They go through the lung like Pac-Man, cleaning up surfactant.
As they do this, they also get rid of excess GM-CSF, so the whole system comes back into equilibrium. It works so well, with just one treatment.”
Cincinnati Children’s is uniquely positioned to move this research from the lab to patients.
“We have all the facilities here,” says Dr. Trapnell. “We’ll do the preclinical studies on safety and dosing. The Cincinnati Children’s Vector Lab will make the gene therapy vector and the Cell Manipulation Lab will prepare the cells for genetic therapy. We have all the necessary infrastructure.”
For Nourah and Bashayer, macrophage transplant offers the hope of a complete cure.
“We’re very happy that there’s a treatment,” says Fatemah Al-Shammari. “The girls can’t have lung lavage all their lives.”
“Despite more than 20 years of research, not one lung disease has been successfully treated by gene therapy,”
Dr. Trapnell points out. “This has the potential to be a major advance, the first successful lung gene therapy.”
Parents, physicians and researchers all feel a sense of urgency, yet know the work must move forward step by step. It may take two years or more before all the preclinical work is completed and Cincinnati Children’s receives approval to begin human testing through a clinical trial.
In the meantime, Nourah and Bashayer need regular lavage treatments. Is there a way they can have these treatments in Kuwait?
Dr. Wood has begun training Kuwaiti physicians to perform whole lung lavage in children as small as Nourah and Bashayer. As a first step, a Kuwaiti team visited Cincinnati Children’s in April to observe the procedure. A second trip for more training and hands-on experience is being planned, in preparation for the children to return to Kuwait.
“They deserve to be home,” Dr. Wood says.
Why Study Rare Disease?
PAP is a very rare disease – fortunately. One of the reasons to focus on rare diseases, Dr. Trapnell points out, is that they typically have a single cause that can be isolated and studied.
Autoimmune PAP is caused by an antibody that attacks only one protein in a single signaling pathway that macrophages require to function normally. Hereditary PAP is caused by a defect in another single component of the same signaling pathway.
“We know exactly where the target is,” says Dr. Trapnell. “By deepening our understanding of the basic biology, we can move toward therapy for these conditions, and we are likely to learn something more general about autoimmune and genetic diseases that can be applied to other, more common and complex conditions.”
The long-term investment in lung research at Cincinnati Children’s has had an enormous impact. It bridged the gap between understanding basic biology and advancing care to improve the health of children.
Basic science studies of surfactant led to a lifesaving treatment for respiratory distress syndrome in premature infants and to an ongoing interest in other surfactant-related diseases, including PAP.
Studying hPAP led to inventing a new procedure – pulmonary macrophage transplantation. “It’s not just a new treatment,” Dr. Trapnell says, “but a new class of treatment.” It opens the potential for new therapeutic approaches to other lung diseases.
The possibilities are speculative at this stage. But that’s a critical part of clinical science: linking clinical need, creative thinking and meticulous basic science to push the boundaries of knowledge, advance care and improve outcomes for patients.
Cincinnati Children’s is proud to be at the forefront of such cutting-edge translational research.
