Adul with Hydrocephalus. Credit: CURE
After 16 years of research, a Yale pediatric neurosurgeon has conclusively identified the bacteria that is causing widespread newborn deaths and disease in Uganda. Previously considered harmless, Steven Schiff, MD, and team have identified Paenibacillus thiaminolyticus as the cause of postinfectious hydrocephalus.
The mysterious infection
Hydrocephalus, or “water on the brain,” is a neurological condition caused by an abnormal buildup of cerebrospinal fluid in the ventricles deep within the brain. This excess fluid causes the ventricles to expand, putting harmful pressure on the brain's tissues.
Over the years, East Africa has become a hotbed for pediatric hydrocephalus, with an estimated 4,000 new cases in Uganda alone annually. Mothers from all over the country tell a similar story: their infant was born healthy but developed a severe infection within the first weeks of life. After recovery, the infant’s head began to rapidly enlarge over weeks to months. The babies developed “postinfectious hydrocephalus,” and without easy access to advanced care, many infants die. Even those who do make it to an advanced hospital struggle to recover due to the damage already caused by the infection.
Until recently, the root of this postinfectious hydrocephalus in Uganda was unknown. The offending bacteria didn’t grow with traditional culture methods, which made it impossible to identify and characterize. Whereas researchers in the U.S. would then turn to genome sequencing to identify the pathogen, the expensive technology is not readily available in Uganda. Additionally, the limited resources of the country made it challenging for scientists to keep samples deep-frozen for later analysis off-site.
Ultimately, the poor infrastructure of the country turned the cases of postinfectious hydrocephalus into more of a mystery than it needed to be.
Identification
On June 14, after 16 years of persistent research, Schiff and colleagues published a landmark paper in The Lancet Microbe detailing the results of three linked studies, conclusively identifying the Paenibacillus thiaminolyticus bacteria as responsible for postinfectious hydrocephalus in Uganda.
But it wasn’t an easy road. Schiff and his team worked on small-scale identification efforts for 9 years—and each one failed. They didn’t get their big break until they were granted an NIH Director's Pioneer Award in 2015 and an NIH Director’s Transformative Research Award in 2018.
The $12 million in research monies allowed the team to scale up their efforts, and by 2020, they discovered P.thiaminolyticus in the brains of Ugandan infants with hydrocephalus through the use of genomic sequencing.
Still, the researchers needed to confirm if the bacteria were indeed the underlying cause of postinfectious hydrocephalus, or just a secondary infection.
Examining 800 newborns diagnosed with sepsis, the scientists found P.thiaminolyticus bacteria in about 6% of cases. Of the newborns that survived the sepsis infection, many developed post-infectious hydrocephalus. In fact, of 400 cases of infant hydrocephalus, 44% of postinfectious cases had PCR confirmation of P.thiaminolyticus infection. The bacteria were still present when the infants returned for treatment weeks and months later.
Eventually working out a way to grow some strains of P.thiaminolyticus using blood culture bottles for cerebrospinal fluid, the team quickly discovered that the pathogen is resistant to the first line antibiotics used to treat neonatal sepsis. They also discovered that the strains in Uganda contain a highly lethal virulent toxin, one that has an affinity for wet places.
Prevention and treatment
With the pathogen identified, Schiff and his team have turned their efforts to prevention.
“After all we have learned, the last thing we want to be doing is trying to treat infants after they’ve been infected with these highly virulent bacteria,” said Schiff. “If we can nail down how it is getting into the infants, then we can develop public health policies that can prevent these infections.”
To that end, the researchers are using geolocation and daily satellite rainfall measurements to better predict whether a newborn patient was likely infected with P.thiaminolyticus bacteria based upon when and where they were infected. The team is also working with local Ugandan hospitals to develop robust treatment protocols.
With one mystery solved, Schiff and colleagues are studying similar infections in Vietnam, Kenya and the U.S. with the idea of developing inexpensive sequencing systems at points of care to confirm infectious agents and tailor patient treatment.
“This is why doctors do research,” said Schiff. “If we’re really lucky, we can go from treating one person at a time to treating large numbers of people. I’m thrilled that after all these years working on this, we found a new disease process and grateful to the doctors, scientists and the patients’ families who have worked so hard together to enable us to get to this point.”