September 2016

Going with the Flow: How Lymphatics is Emerging as Medicine’s Newest Specialty

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At first blush, the newest emerging field in medicine might sound very old: Lymphatics. Medicine has put so little emphasis on lymph, a protein-filled fluid that flows through vessels throughout most of the body, that the term can sound as archaic as doctors treating the four humors by purging blood, phlegm, or black bile. But new discoveries at The Children’s Hospital of Philadelphia and University of Pennsylvania are showing that the lymphatic system plays an understudied role in many diseases, providing new ideas for minimally invasive treatments and offering insights into other fields from neonatology to immunology.

“We have opened a small door to enormous opportunities to discover new diseases and explanations for known diseases,” said Maxim Itkin, MD, an interventional radiologist at the Hospital of the University of Pennsylvania (HUP) and director of the CHOP/HUP  Center for Lymphatic Imaging and Interventions Program, who is also an associate professor of Radiology at the Perelman School of Medicine. “And we’re already working on that.”

A team at CHOP and Penn led by Dr. Itkin and Yoav Dori, MD, PhD, a pediatric cardiologist and director of Pediatric Lymphatic Imaging and Interventions and Lymphatic Research at CHOP, caught the world’s attention this year with the publication of their results treating 18 patients with the devastating condition plastic bronchitis, in which the lungs suffuse with fluid that hardens into rubbery casts. Fifteen of the 17 patients who underwent their new intervention procedure had a significant improvement in symptoms nearly a year later, they reported in the journal Circulation. Previously, the only intervention that offered some patients long-term relief from plastic bronchitis was a heart transplant.

Drs. Itkin and Dori were the first to confirm the role of the lymphatic system in the mechanism of this disease. And their success is likely just the first of many to emerge from the team’s lymphatics discoveries.

How the Lymphatics Revolution Began

It is only an accident of history that the lymphatic system was largely ignored in modern medicine until now. The main obstacle was a lack of effective clinical imaging.

“Imaging drives many fields,” Dr. Itkin said. “The more you can see, the better you can treat.”

And the drive for better imaging in lymphatics emerged from the first treatments for the lymphatic system. Twenty years ago, one of the fathers of interventional radiology, Constantin Cope, MD, conceptualized the idea of accessing the lymphatic system through the abdomen to treat traumatic cases of a condition involving leakage of lymph into the chest, called chylothorax. This idea initially sounded like science fiction to other experts in the field, but, slowly, the concept emerged as the main treatment approach.  As Dr. Cope neared retirement, Dr. Itkin came to Penn to learn these techniques. He ultimately continued the tradition and refined the eight-hour surgical procedure into a 40-minute one.

Existing lymphatic imaging techniques at the time involved injecting imaging dye through a patient’s foot, and they were both difficult and time-consuming, while producing low-resolution imaging of the flow of lymph through the body. The small size of the vessels and the system’s unpredictable anatomy made it too hard to see contrast in the lymphatic system.

In 2012, Dr. Itkin began to make progress on a new method, the intranodal lymphangiogram. In this method, he injected dye into the lymph node in a patient’s groin, making it possible to see the lymphatic anatomy almost immediately. This technically simple replacement of a traditional lymphangiogram technique made lymphatic interventions easier to perform and more widely accepted by other physicians. But this method still lacked the level of detail of cross sectional imaging methods such as magnetic resonance imaging (MRI) and computerized tomography.

Everything changed again when, after a recreational basketball game, Dr. Itkin got into conversation with Dr. Dori, who is also an assistant professor of Pediatrics at the Perelman School of Medicine. Until that day, the pair had never worked together, and Dr. Dori had never given much thought to the lymphatic system. But Dr. Itkin had given a lot of thought to pediatric cardiology, trying for some time to find collaborators at CHOP to explore the possible role of lymphatic flows in complications of congenital heart disease.

Together, Dr. Dori and Dr. Itkin conceptualized the idea of MRI lymphangiography.  This technique utilizes the same approach as the intranodal lymphangiogram but delivers a magnetic resonance contrast agent.

“Suddenly we discover the whole world of lymphatic abnormalities,” Dr. Itkin said. “Nobody had ever done that before. We can actually light up almost the whole lymphatic system and see abnormalities there.”

How the Lymphatic System Works, Goes Awry, and Gets Fixed

The lymphatic system is a set of vessels throughout the body that collects fluids from soft tissues and organs, especially the liver and intestine. It carries those fluids to the thoracic duct, the largest lymphatic vessel, the one that was sealed off in Dr. Cope’s pioneering intervention.  From the thoracic duct, the fluid is transported back into the veins.

The first time they tried their new imaging technique on a patient with plastic bronchitis, it was immediately clear to Drs. Itkin and Dori that some lymph from the thoracic duct was leaking into the lungs — and they have since found a similar flow pattern in patients with other conditions. Dr. Itkin hypothesizes that such lymphatic leaks into the lungs are a normal variant that some people are born with, and that typically does not cause major medical problems.

But it predisposes some people to plastic bronchitis. Although plastic bronchitis can occur at any age and without any specific triggering event, doctors see it most commonly in children who have undergone a Fontan operation for congenital heart disease. The researchers suggest that this occurs because, in children who have congenital heart failure on the right side, soft tissues are congested, and the amount of fluid that the lymphatic system would normally absorb and carry away exceeds the system’s capacity. Far too much excess lymph flow can then accumulate in the lungs in patients prone to these flow leakages.

The ability to image the lymphatic system revolutionized the potential for treatments in the way imaging innovations transformed treatments in many of the body’s other systems 50 years ago. The advent of MRIs, arteriography, CAT scans, and other imaging technologies suddenly made physical abnormalities visible to physicians. Many of those abnormalities could then be treated with easy-to-explain interventions — embolizing to close off passages that should not be open, inserting stents to open those that should not be closed.

Now Drs. Dori and Itkin are treating plastic bronchitis with a minimally invasive procedure that is similarly simple to explain: While imaging the abnormal flows in a patient, they selectively embolize lymphatic passageways to stop the fluid from leaking into the lungs.

“Predictability is almost 100 percent,” Dr. Itkin said. “It’s a simple plumbing problem.”

An Exciting Future for Lymphatics and a Search for ‘Lymphomaniacs’

To expand their impact beyond plastic bronchitis, Drs. Itkin and Dori are now seeking out so-called “lymphomaniacs” from other clinical specialties at CHOP who can identify conditions that could have an unknown involvement of the lymphatic system. They are collaborating with neonatology and pulmonary divisions at CHOP to image and understand newborns with swollen limbs and children with unexplained lung diseases for possible underlying lymphatic involvement.

Often, this imaging teaches them more about how lymphatic flows are involved. Sometimes they are even able to intervene.

Their efforts have been designated as a CHOP Frontier Program, which has given the team the opportunity to further refine their imaging techniques for different areas of the body, and to establish a comprehensive research program focused on lymphatics with a prospective clinical study and a basic science research lab.

The lymph itself is opening up new possibilities for study in immunology as well.

“We now have the first-time opportunity to sample the lymphatic system from live human beings and analyze it,” Dr. Itkin said. “We are working closely with the Penn Institute for Immunology, of which CHOP is a member, with multiple studies planned and already going on to understand the immune function of the lymphatic system better than ever before. This has enormous implications in areas such as HIV and cancer immune therapy.”

For now, this intensive study and treatment innovation in lymphatics is unique to CHOP and Penn, found nowhere else in the world.

“This is kind of a new organ system,” Dr. Dori said. “It’s extraordinarily rare in medicine to fall on something like this, an organ system that has been ignored because people couldn’t see it.”

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