Rare Genetic Disease (NLRC-4): Olivia’s Story

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Olivia was diagnosed with a rare genetic disease as a baby. Two medicines, then in trial phase for other conditions, saved her life.

Two-year-old Olivia loves to dance and to play with her baby dolls. She also loves to join her older brother in games — playing with Legos (him building, she destroying) and joining in battles with his Star Wars figures.

Meeting her today, you would never know that Olivia has a rare genetic disease, one that threatened her life and kept her hospitalized for weeks as a baby.

An unexpected illness

Olivia smiling outside Olivia was a healthy baby at first. Her mother, Jill, remembers, “sleepless nights, nursing on demand, dirty diapers and my heart stretching with more love every day.” Then at 7 weeks old, Olivia came down with a fever. Her temperature was high enough that she needed to be taken to the emergency room. There, she was diagnosed with a viral respiratory illness and sent home with instructions on her care.

Back at home, the fever continued for several days, so the family’s pediatrician suggested she be taken back to the hospital. This time, Olivia was admitted, and spent a week undergoing more thorough examinations. The signs continued to point to a viral infection: fever, enlarged spleen and decreased appetite. With her temperature gradually coming down, she appeared to be on the mend and was discharged.

But the trend toward improvement didn’t last. “We were home for three days, and she was not doing well,” Jill remembers. “I knew something was wrong.”

Jill, a nurse, and her husband Gus, a university administrator, knew of Children’s Hospital of Philadelphia (CHOP) and had read stories of the great work being done there. So when their pediatrician advised them to take Olivia back to the hospital, that’s where Jill headed from the family’s home in Roxborough, Philadelphia.  “I drove her myself,” Jill says, “carefully but definitely over the speed limit down Interstate 76 — with my wonderful mother-in-law praying to our lady of the highway in the back seat.”

Care at CHOP

The pediatrician had called ahead with details of Olivia’s symptoms, and the Emergency Department staff at CHOP was ready and waiting when they arrived. “They took her right back into the resuscitation room,” Jill remembers. “Within what felt like 2 seconds, 40 people were in the room. Exactly the reason why I wanted her at CHOP. This was the place where she could get the help she needed.”

That was on April 13, 2014, and would be the start of a four-month stay at CHOP for Olivia. Her condition worsened, with fevers, vomiting, diarrhea and severe ulcers in her gastrointestinal tract. Unable to eat, she was losing weight at an alarming rate. She was examined by specialists in different fields, and tested for a wide range of possible conditions. Some of those possibilities were terrifying to Jill and Gus, but watching their daughter get sicker and sicker with no diagnosis was the worst trauma of all.

At one point, Jill recalls turning to Gus and saying, “I’m really scared something bad is going to happen.” On the drive home from the hospital, she remembers, “I couldn’t think straight, I couldn’t breathe. For the first time, I imagined losing my daughter.”

Two things stand out for Jill in helping her get through that dark time. First is the support she received from Olivia’s nurses. “As a nurse myself, I don’t think I ever truly appreciated how important it can be to patients to take time with them and to just be there. Olivia’s nurses were unbelievable. They took amazing care of my daughter. But they also took amazing care of Gus and me.”

The second is a walk she took one night over the bridge that connects the Main Building to the Wood Building at CHOP. Down the long hallway, photos of several patients alongside their stories are mounted on the wall. “I’d never ventured there before. I saw the posters on the wall, and I stopped and read them all. Each and every one of them told a story of a child that CHOP had ‘figured out.’”

when i got to the end, i stood there, alone, at 1 a.m., and for the first time in weeks i felt hope. i thought, 'they are going to figure it out. they are going to save my baby, and olivia is going to be in this hallway one day.

A few days later, her weight still dropping, Olivia was transferred to the Pediatric Intensive Care Unit (PICU). One of the doctors who saw her there was Edward Behrens, MD, Chief of the Division of Rheumatology.

Finally, a diagnosis

In researching Olivia’s case, Dr. Behrens found a recent article about a father and his baby son who had symptoms similar to Olivia’s. The diagnosis in that case was an auto-inflammatory disease, caused by a genetic mutation of the NLRC-4 protein. The mutation triggered an over-production of two proteins (interleukens): IL-1 and IL-18, resulting in fevers and inflammation, often of the gastrointestinal tract. In fact, the disease is similar to a form of inflammatory bowel disease.

The Immunology team confirmed that Olivia had the genetic mutation. Dr. Judith Kelsen, Director of the Very Early-Onset Inflammatory Bowel Disease Program, worked with Dr. Behrens. They initiated tests that showed off-scale levels of the two inflammatory proteins.

Olivia finally had a diagnosis. But that didn’t solve her problems. This was a rare condition with no history of treatment. The team decided that they would have to attempt to block the inflammatory proteins. They explained the discoveries as they were made to Jill and Gus, along with suggestions for treatment focusing on controlling the levels of IL-1 and IL-18.

A breakthrough treatment

The first attempt at treatment with steroids provided some relief to Olivia, but resulted in unpleasant side effects.

The next step was to try a medication that had recently been approved for adults with inflammatory bowel disease. The team worked to obtain special authorization for this non-approved use of the medication in a baby, and given Olivia’s critical need, that authorization was granted. She began to show some improvement, but not enough. This medication reduced the levels of IL-1, but not IL-18. No drug was available in the United States that affected IL-18.

In researching Olivia’s condition, Dr. Behrens had been in contact with Scott Canna, MD, head of the Autoinflammatory Pathogenesis Unit at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), part of the National Institutes of Health (NIH). Dr Canna had worked under Dr. Behrens as a fellow at CHOP. In his role at NIAMS, Dr. Canna kept track of new discoveries in autoinflammatory conditions and drug trials for their treatment. He directed the team to a new drug that was in a phase 2 trial in Europe as a treatment for adult Still’s disease. It appeared to affect the production of IL-18.

Dr. Behrens contacted the drug’s manufacturer in Switzerland and appealed to the FDA for approval for compassionate use with Olivia. His request was approved and the medication was shipped to CHOP by air express.

“Gus and I watched the overnight shipment of the medication online like hawks,” says Jill. As soon as it arrived, Olivia was given her first dose. She showed improvement almost immediately. Her fever disappeared and her digestion problems became much less severe. “After receiving just two doses of the medication, Dr. Behrens came to us with great news. Olivia’s IL-18 level was zero.”

This was precision medicine at work. This collaborative medical team at CHOP worked together to diagnose an extremely rare genetic condition and found a combination of two drugs that targeted the specific abnormal protein production that was making Olivia so sick. The little girl was on her way to recovery.

Olivia’s journey to recovery

Olivia smiling It took a few more weeks at CHOP before Olivia regained the weight she had lost and her doctors were confident that the medication dosages were correct. She was discharged in August, and has been at home ever since.

A CHOP home care nurse visits Olivia once a month to give an injection of one of her two medications. She takes the other medications by mouth every other day. Aside from her treatment with those two medications, Olivia is a perfectly normal 2-year-old. She’s in the middle of the curve on the height and weight chart for her age. And her brother puts up with her “help” when he builds Lego constructions.

“The medical team at CHOP never stopped trying,” says Jill. “They never gave up. I testify to CHOP’s brilliance to anyone who will listen.”

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