Newborn screening is the most important factor in the survival of the blister child over the past 40 years

UCSF pediatrics professor Jennifer Puck, MD, has spent decades pushing for universal newborn screening to detect severe combined immunodeficiency (SCID), a rare but deadly genetic disorder. Today, her grit has been affirmed by a Hand study directly showing that, by enabling early treatment, newborn screening has been the most significant factor in improving survival outcomes in children with SCID over the past 40 years.

Babies with SCID, or bubble baby disease, are born without a functioning immune system, so even a common cold can be life-threatening. Early identification of SCID is the key to treatment early in life, before the onset of infections.

Co-led by UCSF transplant specialist Christopher Dvorak, MD and colleagues from the National Institutes of Health Primary Immune Deficiency Treatment Consortium (PIDTC), the Hand study looked at more than 900 cases of babies diagnosed with SCID between 1982 and 2018. Researchers found that newborn SCID screening and the early treatment it made possible increased the five-year survival rate to 87 percent in the period from 2010 to 2018, when screening was increasingly used. In the subgroup of children who received newborn screenings, the five-year survival rate was 92.5%. This is the 73% survival rate before newborn SCID screening was invented or popularized (1982 to 2009).

It surprised us! said Puck, who directs the UCSF Jeffrey Modell Diagnostic Center for Primary Immunodeficiencies. For all of our advances in better antibiotics, better ways to do transplants, there really wasn’t any improvement in survival until newborn screening appeared. We knew that providing treatment early made a difference in survival; we just didn’t expect it to be the only factor explaining the difference.

That’s not to say transplants and new drugs aren’t important, Puck was quick to add that they improve other outcomes such as comorbidities and quality of life, and future studies will continue to examine them. Treatments that Puck, Dvorak and other UCSF colleagues have been working on, such as autologous gene therapy, for example, have shown remarkable success in helping children with the deadliest forms of the disease.

But when it comes to survival, timing is almost everything.

From the laboratory to the legislator

Puck herself conceived and developed the SCID newborn screening test in 2005 while working as a scientist at the National Human Genome Research Institute at the National Institutes of Health. The test works by detecting a lack of infection-fighting T cells in dried blood spots that have long been collected from the heels of newborns for various screenings.

After moving to California in 2006, Puck helped convince California lawmakers to require statewide screening, which they finally did in 2010, becoming the third state to do so.

I went to legislative hearings with families, Puck remembered. One mother described losing her first child to her SCID while she was pregnant with her second, and there was no dry eye in her room. Meanwhile, that second kid whose SCID was detected early ran around with his big blond locks, looking like a million dollars.

Sure enough, the committee unanimously approved the screening, Puck added. Why should a family endure the tragedy of losing a child with SCID before the second can be recognized and saved with early treatment? A population-level newborn screening test identifies SCID at birth.

She continued her advocacy, and eventually all 50 states adopted SCID screening as part of their standard newborn panel, with the last three doing so in 2018.

California has one-eighth of all babies born in the United States and a half-million babies born annually, so getting this state involved gave a big boost for other states to follow, Puck said.

Mort Cowan and Jennifer Puck visit an Artemis-SCID patient in the hospital who is being treated with his own genetically corrected stem cells
Pediatric immunologists Morton Cowan, MD, (left) and Jennifer Puck, MD, (right) visit 10-month-old patient Luciana Moscoso Pareja. Her family of four was flown by UCSF from Peru to be treated by Cowan and Puck in a procedure that used her own genetically engineered stem cells as a treatment for Artemis-SCID.Photo by Barbara Ries

Switching from an emergency to a plan of care

SCID is typically fatal within the first two years of life, unless the immune system is restored through stem cell transplantation, gene therapy, or enzyme therapy.

Before newborn screening was in place in California, SCID patients often arrived at UCSF Benioff Children’s Hospitals very ill, said Dvorak, who heads UCSF’s Pediatric Allergy, Immunology and Bone Marrow Transplantation Division.

SCID screening is the only test or process I can think of that has completely and utterly changed how we care for these patients from start to finish, Dvorak said. It went from being this huge emergency of like, we need to transplant this baby right now because they’re dying from a horrible infection to having a baby that looks great, has been properly isolated, hasn’t had an infection and the whose family has time to prepare for the transplant.

Jennifer hugs her young Artemis-SCID patient's mom, Gina Pareja Ponce de Leon, who smiles at the camera
Jennifer Puck, MD, (left) hugs the mother, Gina Pareja Ponce de Leon, of a 10-month-old patient with Artemis-SCID. Photo by Barbara Ries

Previous research has shown that being younger than 3.5 months at the time of bone marrow transplantation is the main treatment for SCID, and having no active infection improves five-year survival rates for children with SCID. Both of these factors are facilitated by newborn screening.

Push to expand screening worldwide

Puck and Dvorak hope for the new Hand The National Institutes of Health-funded study will convince countries outside the United States to adopt newborn screening for SCID as well. Some have resisted because of the money, the logistics and concerns about making parents anxious, they said.

Screening is not just a test, but a program that requires a lot of work and quality control to get tested, contact family, a plan for when the test is positive, Puck said. One objection is that false positives can really upset many parents.

However, the SCID test has the lowest false-positive and false-negative rates of any existing newborn screening test, he added.

With some other tests, a positive result will end up with only 1 percent of those children actually having the condition, Puck said. For the SCID test, nearly 50% of those with a positive test have at least low T cells. Even if they don’t have SCID, they should be seen by immunologists.

Research by UCSF fellow Lena Winestone, MD, assistant professor of pediatrics, suggests another impressive aspect of universal SCID newborn screening: It can eliminate racial disparities in treatment access and outcomes for children with the disorder.

The SCID newborn screening test is a leveler, Puck said. It’s about equity and providing screening and treatment so that all children, regardless of race or background, can have their healthiest and longest life.

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