While the cause of newborn infections and postinfectious hydrocephalus in industrialized countries is often widely known and less common than other causes of hydrocephalus, the contagious agent for thousands of hydrocephalic Ugandan infants avoided researchers for years. They then analyzed 800 babies who had actually developed a severe infection– sepsis– from various areas of Uganda. Of the newborns that endured the sepsis infection, numerous established post-infectious hydrocephalus.
Currently, Schiff is focusing on revealing the locations within rural environments where this bacterium lurks through fieldwork, and to understand the cultural newborn care practices that may contribute to high infection rates with this bacterium. If we can nail down how it is getting into the babies, then we can develop public health policies that can avoid these infections”, Schiff said.
After 16 years of research study, a team led by Steven Schiff recognized the germs Paenibacillus thiaminolyticus as the culprit behind the widespread postinfectious hydrocephalus in Ugandan infants, a discovery that unlocks to targeted treatments and interventions. Leveraging genomic sequencing and collaborative efforts, the group is now concentrating on developing public health policies to prevent infections and checking out the potential of affordable sequencing systems to enhance client treatment globally.
In 2007, Yale pediatric neurosurgeon, Dr. Steven Schiff, visited his colleague Dr. Benjamin Warf at the CURE Childrens Hospital in Uganda. The scenes at the hospital stunned him: every day moms originated from all over the country carrying babies with enlarged heads, desperate for a treatment.
The mothers all informed a comparable story: their kids were born without problems, however within their very first few weeks, they contracted a severe infection. Their heads began to grow at a worrying rate over the subsequent weeks to months once they recuperated. Unbeknownst to these mothers, their babies were experiencing postinfectious hydrocephalus.
Hydrocephalus, or “water on the brain,” is a disastrous neurological condition brought on by an abnormal buildup of cerebrospinal fluid within the ventricles deep within the brain. This excess fluid causes the ventricles to broaden, putting harmful pressure on the brains tissues. It can be genetic or develop after an infection or hemorrhage in the brain.
There is no known remedy, and the need to relieve pressure on the brain forms the most common sign for neurosurgery in infancy worldwide. East Africa had ended up being a hotbed for pediatric hydrocephalus for mysteriously unidentified factors, with an estimated 4,000 new cases in Uganda alone each year.
Without simple access to innovative care, infants typically died, and even those who made it to the CURE Childrens Hospital in the early phases of the disease struggled to recover due to the fact that of the damage already developed by the infection. Schiff was struck by the magnitude of suffering that he saw. “As a doctor and researcher and as a father, I am struck by how much we dont learn about newborn infections in establishing nations. I am concerned that one reason is that the newborn infants who die there have no political voice,” he would later affirm in front of the Congressional Subcommittee on Africa, Global Heath, and Human Rights.
On June 14, 2023, after 16 years of persistent pursuit of answers, the group released a landmark paper in The Lancet Microbe detailing the outcomes of 3 linked research studies, conclusively recognizing the Paenibacillus thiaminolyticus bacteria as accountable for postinfectious hydrocephalus in Uganda.
” These results are the conclusion of years of cooperation and offer a clear path forward for evaluating the impact of targeted medical diagnosis and treatment of Paenibacillus infections,” says Sarah Morton, MD, PhD, assistant teacher of Assistant Professor of Pediatrics, at Harvard Medical School and co-lead author of the paper.
A New Frontier
While the cause of newborn infections and postinfectious hydrocephalus in industrialized countries is typically well-known and less common than other causes of hydrocephalus, the transmittable agent for thousands of hydrocephalic Ugandan infants eluded researchers for years. Whats more, it isnt easy to draw sufficient blood in babies to dependably examine for germs.
And although it was possible to utilize innovative gene sequencing techniques to identify bacteria that would not grow in culture, those innovations were both costly and not readily available in Uganda. This combination of obstacles made the concern of what was causing all these cases of postinfectious hydrocephalus in Ugandan children daunting. However Schiff was identified to tackle this secret, thinking that it was an understandable problem.
After 9 years of smaller-scale stopped working efforts, their huge break came when they received a number of NIH Directors awards to scale up their efforts.” The NIH Directors high-risk high-reward programs took a threat on us, and we never ever could have brought the teams together and cracked this mystery appropriately if they had actually not provided us this opportunity,” Schiff says.
By 2020, Schiffs team of put together private investigators at Columbia and Penn State Universities identified through genomic sequencing that an organism formerly thought to be safe in the cerebrospinal fluid, called Paenibacillus thiaminolyticus, was swimming in the brains of the Ugandan infants with hydrocephalus. This enabled them to discover that the organism was resistant to the first-line prescription antibiotics used to treat ill infants.
Over the next three years, the group set out to find where the germs was coming from and if it was undoubtedly the underlying cause of postinfectious hydrocephalus or if it was an infection appearing in the hydrocephalic infants weeks and months later on but not the reason for the hydrocephalus itself.
Considering that numerous newborn infections are sent from mothers, they ran a maternal trial of 100 laboring Ugandan ladies from various areas but did not find any evidence that Paenibacillus germs was brought by the mothers or being transferred to babies. They then examined 800 babies who had established a serious infection– sepsis– from different locations of Uganda. Here, they did find the Paenibacillus bacteria– in about 6 percent of cases. Of the babies that survived the sepsis infection, lots of established post-infectious hydrocephalus.
In 400 cases of hydrocephalus in infants, 44 percent of postinfectious cases had PCR verification of Paenibacillus infection. And when the team ran PCR tests on samples of those babies with sepsis who had actually established postinfectious hydrocephalus, the same bacteria was found causing the newborn infection and, following treatment, still present when they returned for treatment weeks and months later on with an enlarging head from hydrocephalus.
The resulting documents released in The Lancet Microbe and the journal Clinical Infectious Disease conclusively recognized the Paenibacillus infection not just as the disease-causing prevalent hydrocephalus in infants, but likewise newborn deaths.
” Our results recommend that Paenibacillus is an underrecognized cause of neonatal infection, which is necessary due to the fact that the antibiotics that are commonly utilized to treat neonatal sepsis often will not work for Paenibacillus infections,” states Jessica Ericson, MD, assistant teacher of pediatric and contagious diseases at Penn State, lead author of the paper published in the journal Clinical Infectious Disease.
” For the first time, we had the ability to explain the progression of infections during the neonatal duration to the development of infant post-infectious hydrocephalus enabling us to guide the vital diagnostics and interventions required to prevent the terrible brain damage associated with post-infectious hydrocephalus,” states Christine Hehnly, PhD, post-doctoral fellow and co-lead author of The Lancet Microbe paper.
From Discovery to Treatment
The team was now positive that the Paenibacillus bacteria is at the root of countless postinfectious hydrocephalus cases each year in Uganda. They likewise found that the pathogen has an affinity for damp places– the cases clustered around the swampy areas on the northern banks of Lake Victoria, the source of the Nile River, and the southern and northern banks of Lake Kyoga, where the Nile River flows in and out. Cases are likewise directly correlated with the rainy seasons, consistent with an environmental source of the Paenibacillus.
To navigate the restrictions that avoid medical professionals from utilizing gene sequencing and PCR for medical diagnosis in resource-limited settings, Schiff and partners are using geolocation and everyday satellite rainfall measurements to better predict whether a newborn patient was most likely contaminated with Paenibacillus bacteria depending upon when and where they had been infected. His team is working with regional Ugandan healthcare facilities to develop robust treatment protocols for these clients.
Presently, Schiff is concentrating on revealing the places within rural environments where this bacterium hides through fieldwork, and to comprehend the cultural newborn care practices that might add to high infection rates with this germs. “After all we have discovered, the last thing we wish to be doing is trying to treat babies after theyve been contaminated with these extremely virulent germs. If we can pin down how it is getting into the infants, then we can establish public health policies that can prevent these infections”, Schiff said.
Having split the response to one seemingly intractable problem, Schiff and his coworkers are already setting their technologies and sights on others. They are studying similar infections in Vietnam, Kenya, and the U.S. and looking at the possibility of developing affordable sequencing systems at points of care to verify infectious agents and tailor client treatment.
” This is why medical professionals research,” says Schiff. “If were actually fortunate, we can go from dealing with someone at a time to dealing with great deals of people. Im delighted that after all these years working on this, we found a new illness procedure and grateful to the medical professionals, researchers, and the patients households who have actually worked so difficult together to allow us to get to this point. Newborn babies at threat of dying are the universal currency binding together many individuals who have worked so difficult together on this problem.”
References: “Paenibacillus spp infection amongst babies with postinfectious hydrocephalus in Uganda: an observational case-control research study” by Sarah U Morton, Christine Hehnly, Kathy Burgoine, Paddy Ssentongo, Jessica E Ericson, M Senthil Kumar, Cornelia Hagmann, Claudio Fronterre, Jasmine Smith, Mercedeh Movassagh, Nicholas Streck, Lisa M Bebell, Joel Bazira, Elias Kumbakumba, Francis Bajunirwe, Ronald Mulondo, Edith Mbabazi-Kabachelor, Brian K Nsubuga, Davis Natukwatsa, Esther Nalule and Steven J Schiff, 19 June 2023, The Lancet Microbe.DOI: 10.1016/ S2666-5247( 23 )00106-4.
” Neonatal Paenibacilliosis: Paenibacillus Infection as a Novel Cause of Sepsis in Term Neonates With High Risk of Sequelae in Uganda” by Jessica E Ericson, Kathy Burgoine, Elias Kumbakumba, Moses Ochora, Christine Hehnly, Francis Bajunirwe, Joel Bazira, Claudio Fronterre, Cornelia Hagmann, Abhaya V Kulkarni, M Senthil Kumar, Joshua Magombe, Edith Mbabazi-Kabachelor, Sarah U Morton, Mercedeh Movassagh, John Mugamba, Ronald Mulondo, Davis Natukwatsa, Brian Nsubuga Kaaya, Peter Olupot-Olupot, Justin Onen, Kathryn Sheldon, Jasmine Smith, Paddy Ssentongo, Peter Ssenyonga, Benjamin Warf, Emmanuel Wegoye, Lijun Zhang, Julius Kiwanuka, Joseph N Paulson, James R Broach and Steven J Schiff, 5 June 2023, Clinical Infectious Diseases.DOI: 10.1093/ cid/ciad337.