Thursday, March 16, 2023


New algorithms could improve pediatric tuberculosis diagnosis

Tuberculosis stands as one of the leading causes of death among young people across the world. Modeling studies suggest that in over 96% of the deadly cases involving children younger than 15 years old, the infected child did not receive treatment.

Two new evidence-based algorithms for diagnosing pediatric tuberculosis could help reverse this trend.

Yale School of Public Health scientists led the team that developed algorithm-based scoring systems that health care workers can use to inform their decisions when diagnosing the disease, which is often difficult to identify in under-resourced clinics. The Yale team, in collaboration with a global network of scientists, looked at data from more than 4,000 children with TB from across the world and, through statistical analysis, developed what they say are the most robust algorithms yet for pediatric tuberculosis.

As a result of the team's analysis, the World Health Organization now recommends the use of algorithms in its latest consolidated guidelines for treating the disease. The WHO is also encouraging the use of the Yale-led research team's algorithms.

"It's a lot of pressure for these health care workers to consider vague symptoms and make a diagnosis for TB, which might partly explain why we have gaps in treating TB in young children," said Kenneth Gunasekera, a Yale M.D.-Ph.D. student who was first author on the study. "Our work was motivated by this issue. We wanted to support health care workers operating in resource-limited settings to make treatment decisions for TB that are evidence-based."

The findings appear in The Lancet Child & Adolescent Health.

Algorithms are not new to pediatric tuberculosis. Other scientists have created similar algorithms to enhance disease diagnosis, but Gunasekera explained that those algorithms have largely relied on expert opinion, rather than a rigorous interpretation of data. Also, some of the algorithms that have been based on evidence were built using data from a relatively small sample size, which can limit their generalizability, Gunasekera said. Gunasekera's team combined data from 4,718 children from 13 studies and 12 countries, with the help of recommendations from a group of WHO-identified experts, in an effort to develop sturdier scoring systems.

The researchers built two algorithms depending on the ability of health care workers to obtain chest X-rays for their patients. In both algorithms, patients receive a set number of points for their presenting symptoms and other details, which workers then add up to receive the recommendation. If the score is above 10, on average, 85% of those children with TB will be diagnosed correctly. (Patients can also score above a 10 if they were known to be exposed to tuberculosis notwithstanding other symptoms.)

"Now we have a tool that is evidence-based and pragmatic in that it's easy for a health care worker to implement this score," Gunasekera said. The team hopes the new tool will result in more children receiving timely treatment for TB.

But, the researchers warn, there are some limitations to their scoring systems. Most importantly, the team could not formally test the algorithms before their paper published. However, studies will soon be underway to evaluate the algorithms' real-world ability to identify tuberculosis. And even though drawing from multiple studies can help improve statistical analysis and create more robust data sets, varying inclusion criteria, and study definitions could lead to slightly skewed data. Finally, since tuberculosis is already difficult to diagnose, some incorrect conclusions "might occur," the authors wrote in their study. More research into pediatric tuberculosis would undoubtedly help refine the new algorithms, as would additional data and better diagnostic tools.

Still, Gunasekera explained, the fact that the WHO conditionally recommended the use of algorithms in assisting with pediatric tuberculosis diagnosis and encouraged the Yale-led team's new algorithms for use in the field stands as a powerful encouragement for future research.

"I'm really looking forward to seeing the results of the prospective evaluation of these algorithms, when others are actually going to use them in a study setting to aid in treatment decision-making for children being investigated for TB," he said. "We built the algorithms based on evidence, but it will be exciting to see how well they will actually perform."

The research carries a personal resonance for Gunasekera, who is in the last year of his M.D.-Ph.D. program at Yale and hopes to work in pediatrics after graduation. The project emerged from valuable mentorship with leaders at YSPH and beyond, he said.

"Through this work, I got to work closely with some of the leaders in the pediatric TB field, and it was honestly such a delight to be working with so many of the people whose papers I had been reading," he said. "Now, the people whom I had idolized were people I was working with as colleagues. It was really an amazing opportunity and experience for me while trying to tackle this important problem in childhood TB and global public health."

Wednesday, March 15, 2023

 More Young Kids Can Get Bivalent COVID Booster

More children under age 5 are now eligible for a COVID-19 booster,

Kids ages 6 months to 4 years who completed their primary vaccination with three doses of the monovalent Pfizer-BioNTech shot can now get a booster with the companies' bivalent COVID vaccine -- which targets the Omicron BA.4/5 subvariants -- as long as 2 months have passed, the agency said.

"Today's authorization provides parents and caregivers of children 6 months through 4 years of age who received the three-dose primary series with the monovalent [Pfizer shot] an opportunity to update their children's protection by receiving a booster dose with the [bivalent vaccine]," Peter Marks, MD, PhD, director of the FDA's Center for Biologics Evaluation and Research (CDER), said in a statement.

Since December 2022opens in a new tab or window, children in this age group who got their first two doses with the companies' monovalent shot could complete their three-dose primary series with the bivalent vaccine. (At the time, Moderna's bivalent vaccine was authorized as a booster dose as well, for kids ages 6 months to 5 years following a two-dose primary series.)

Children who have received Pfizer's bivalent vaccine as their third dose will not be eligible for a booster dose of a bivalent vaccine at this time "and are expected to have protection against the most serious COVID-19 outcomes," according to an agency press release.

The updated emergency use authorizationopens in a new tab or window to allow for the fourth dose comes after reviewing immune response data from 60 children in this age group who had three doses of the monovalent vaccine and a bivalent booster, FDA said.

One month after the bivalent booster, these kids "demonstrated an immune response to both the original SARS-CoV-2 virus strain and to Omicron BA.4/BA.5," the agency said in its release.

Evidence of safety of a bivalent booster dose in this age group comes from previous data, FDA said, including studies evaluating the safety of an original strain/BA.1 booster in adults age 55 and up; the monovalent primary series in kids 6 months and older; monovalent boosters in those age 5 and up; and postmarketing safety data with the monovalent and bivalent shots.

Additional safety data come from two clinical studies involving pediatric patients that showed no new safety concerns and no previously unrecognized side effects with a bivalent booster, the FDA said.

International Conference on Pediatrics, Perinatology and Child Health

14th Edition of Pediatrics | 24-26 April 2023 | London, United Kingdom (Hybrid)

Tuesday, March 14, 2023


Exploring how the immune system does battle in the intestines to keep bacteria in check

Researchers from Penn observed, for the first time, an intestinal pyogranuloma, formed in response to Yersinia infection. The organized grouping of cells includes monocytes (in green), neutrophils (in magenta), and Yersinia bacteria (in white), and depends on monocytes to form and to control infection.

Yersinia bacteria cause a variety of human and animal diseases, the most notorious being the plague, caused by Yersinia pestis. A relative, Yersinia pseudotuberculosis, causes gastrointestinal illness and is less deadly, but naturally infects both mice and humans, making it a useful model for studying its interactions with the immune system.

These two pathogens, as well as a third close cousin, Y. enterocolitica, which affects swine and can cause food-borne illness if people consume infected meat, have many traits in common, particularly their knack for interfering with the immune system's ability to respond to infection.

The plague pathogen is blood-borne and transmitted by infected fleas. Infection with the other two depends on ingestion. Yet the focus of much of the work in the field had been on interactions of Yersinia with lymphoid tissues, rather than the intestine. A new study of Y. pseudotuberculosis, led by a team from Penn's School of Veterinary Medicine and published in Nature Microbiology demonstrates that in response to infection, the host immune system forms small, walled-off lesions in the intestines called granulomas. It's the first time these organized collections of immune cells have been found in the intestines in response to Yersinia infections.

The team went on to show that monocytes, a type of immune cell, sustain these granulomas. Without them, the granulomas deteriorated, allowing the mice to be overtaken by Yersinia.

"Our data reveal a previously unappreciated site where Yersinia can colonize and the immune system is engaged," says Igor Brodsky, senior author on the work and a professor and chair of pathobiology at Penn Vet. "These granulomas form in order to control the bacterial infection in the intestines. And we show that if they don't form or fail to be maintained, the bacteria are able to overcome the control of the immune system and cause greater systemic infection."

The findings have implications for developing new therapies that leverage the host immune system, Brodsky says. A drug that harnessed the power of immune cells to not only keep Yersinia in check but to overcome its defenses, the researchers say, could potentially eliminate the pathogen altogether.

A novel battlefield

Y. pestis, Y. pseudotuberculosis, and Y. enterocolitica share a keen ability to evade immune detection.

"In all three Yersinia infections, a hallmark is that they colonize lymphoid tissues and are able to escape immune control and replicate, cause disease, and spread," Brodsky says.

Earlier studies had shown that Yersinia prompted the formation of granulomas in the lymph nodes and spleen but had never observed them in the intestines until Daniel Sorobetea, a research fellow in Brodsky's group, took a closer look at the intestines of mice infected with Y. pseudotuberculosis.

"Because it's an orally acquired pathogen, we were interested in how the bacteria behaved in the intestines," Brodsky says. "Daniel made this initial observation that following Yersinia pseudotuberculosis infection, there were macroscopically visible lesions all along the length of the gut that had never been described before."

The research team, including Sorobetea and later Rina Matsuda, a doctoral student in the lab, saw that these same lesions were present when mice were infected with Y. enterocolitica, forming within five days after an infection.

A biopsy of the intestinal tissues confirmed that the lesions were a type of granuloma, known as a pyogranuloma, composed of a variety of immune cells, including monocytes and neutrophils, another type of white blood cell that is part of the body's front line in fighting bacteria and viruses.

Granulomas form in other diseases that involve chronic infection, including tuberculosis, for which Y. pseudotuberculosis is named. Somewhat paradoxically, these granulomas—while key in controlling infection by walling off the infectious agent—also sustain a population of the pathogen within those walls.

The team wanted to understand how these granulomas were both formed and maintained, working with mice lacking monocytes as well as animals treated with an antibody that depletes monocytes. In the animals lacking monocytes "these granulomas, with their distinct architecture, wouldn't form," Brodsky says.

Instead, a more disorganized and necrotic abscess developed, neutrophils failed to be activated, and the mice were less able to control the invading bacteria. These animals experienced higher levels of bacteria in their intestines and succumbed to their infections.

Groundwork for the future

The researchers believe the monocytes are responsible for recruiting neutrophils to the site of infection and thus launching the formation of the granuloma, helping to control the bacteria. This leading role for monocytes may exist beyond the intestines, the researchers believe.

"We hypothesize that it's a general role for the monocytes in other tissues as well," Brodsky says.

But the discoveries also point to the intestines as a key site of engagement between the immune system and Yersinia.

"Previous to this study, we knew of Peyer's patches to be the primary site where the body interacts with the outside environment through the mucosal tissue of the intestines," says Brodsky. Peyer's patches are small areas of lymphoid tissue present in the intestines that serve to regulate the microbiome and fend off infection.

In future work, Brodsky and colleagues hope to continue to piece together the mechanism by which monocytes and neutrophils contain the bacteria, an effort they're pursing in collaboration with Sunny Shin's lab in the Perelman School of Medicine's microbiology department.

A deeper understanding of the molecular pathways that regulate this immune response could one day offer inroads into host-directed immune therapies, by which a drug could tip the scales in favor of the host immune system, unleashing its might to fully eradicate the bacteria rather than simply corralling them in granulomas.

"These therapies have caused an explosion of excitement in the cancer field," Brodsky says, "the idea of reinvigorating the immune system. Conceptually we can also think about how to coax the immune system to be reinvigorated to attack pathogens in these settings of chronic infection as well.


Prompt treatment for functional neurological disorder in children found to be highly effective

Visual representation of the autonomic nervous system.

Treatment is scarce for functional neurological disorder (FND), which requires a multidisciplinary approach. A special report published in the March/April issue of Harvard Review of Psychiatry (HRP) aims to show clinicians and institutions around the world what is needed to establish effective community treatment programs for FND, as well as hospital inpatient and outpatient interventions, in their own health care settings.

Functional neurological disorder, formerly called conversion disorder, involves the biological embedding of lived experience in the body and brain. This is the process whereby stress, the social environment, or early experience affects the body's biological systems. The embedding culminates in stress-system activation or dysregulation and aberrant changes in neural network function.

Patients with FND have neurologic symptoms such as limb weakness, tremors, gait difficulties, seizures, or cognitive problems that are not explained by traditional neurological disorders.

As many as a fifth of children and adolescents seen in pediatric neurology clinics are found to have FND. An estimated 63% to 95% of these patients can fully recover if they receive prompt diagnosis and proper treatment.

A treatment gap exists worldwide for pediatric patients with FND

Unfortunately, many children with FND do not receive the care they need. Kasia Kozlowska, MD, Ph.D., a child and adolescent psychiatrist at The Children's Hospital at Westmead in Sydney, Australia, and colleagues explain the scarcity of treatment is global, in part "the result of long-standing stigma and ingrained belief that patients with FND do not suffer from a real ('organic') disorder and that they therefore do not require, or even deserve, treatment."

In a Perspectives article in HRP, Dr. Kozlowska and her colleagues describe the elements of a biopsychosocial mind–body program intervention they designed that has been successful for managing FND in children and adolescents.

A seven-component treatment program

Over almost 30 years, the Mind–Body Program for children with FND at The Children's Hospital at Westmead has delivered inpatient care to hundreds of patients with FND. In collaboration with community-based clinicians, the program's staff has also designed individualized treatment for hundreds of outpatients.

The authors say that although care is personalized, their interventions for FND always have seven elements: prompt medical/neurological assessment and diagnosis by a physician; triaging the referral for a holistic (biopsychosocial) assessment; a holistic, biopsychosocial assessment of the child and family; co-constructing a formulation with the child and family to identify factors that contribute to and maintain the child's symptoms; assembling a personalized treatment plan; implementing the plan; and building resilience and preventing relapse.

The article describes each of these elements in detail.

Most health care professionals working in pediatrics can easily add an FND-informed skill set to their current clinical practice, Dr. Kozlowska's group notes:Pediatricians and pediatric neurologists already have the skills necessary to diagnose FND: they simply need to learn to recognize the rule-in signs for FND and to practice communicating an FND diagnosis.
Physical therapists can shift their approach from a "musculoskeletal framework that focuses attention on the problem area" to a framework in which the patient's attention is drawn away from the symptoms, with particular focus on building a therapeutic relationship, using play, and applying interventions in ways that address the problem indirectly.
Mental health clinicians already know how to conduct a biopsychosocial assessment and provide individual and family interventions; they just need to understand "the somatic narrative," the bottom-up approach to emotion regulation, and strategies for managing focus of attention.

Dr. Kozlowska and colleagues emphasize that FND is a positive diagnosis (rather than a diagnosis of exclusion) that should be made by a pediatrician, neurologist, neuropsychiatrist, family doctor, or other physician. "[C]linical interactions during the assessment process are, in themselves, a potentially valuable therapeutic intervention."

Saturday, March 11, 2023


Meta-analysis shows association between autism in children and cardiometabolic diseases

A study conducted by the Centers for Disease Control and Prevention (CDC) from 2009 to 2017 determined that approximately 1 in 44 children ages 3-17 are diagnosed with some form of autism spectrum disorder (ASD). Research also has established that children with ASD have an increased risk of obesity, and obesity has been linked to increased risks for cardiometabolic disorders such as diabetes and dyslipidemia (high level of cholesterol or fat in the blood).

However, the question of whether or not there is an association between autism, cardiometabolic disorders and obesity remains largely unanswered.

To help provide an insight into the possible ASD-cardiometabolic diseases link, Chanaka N. Kahathuduwa, M.D., Ph.D., and a collaborative team from Texas Tech University Health Sciences Center (TTUHSC) and Texas Tech University (TTU) conducted a systematic review and meta-analysis using the PubMed, Scopus, Web of Science, ProQuest, Embase and Ovid databases.

Their study, "Association Between Autism Spectrum Disorders and Cardiometabolic Diseases: A Systematic Review and Meta-analysis," was published in January by JAMA Pediatrics.

For Kahathuduwa, the seeds for the study were planted shortly after he received his Ph.D. in nutritional sciences with a focus on the neuroscience of obesity. Working as a research assistant professor under Mastergeorge, a nationally renowned ASD expert, he was invited by Naima Moustaid-Moussa, Ph.D., director of TTU's Obesity Research Cluster (now the Obesity Research Institute),to present a seminar discussing the neuroscience of obesity and autism.

"When I searched the literature to prepare my presentation, I realized that the evidence on the association between obesity and autism was quite ambiguous," Kahathuduwa recalled. "A solid meta-analysis was needed to address this gap."

That initial meta-analysis led Kahathuduwa to investigate further. He explored how neuroimaging may provide insight into relationships between ASD and obesity, the association between ASD and patients who are underweight and the just-published study on autism and cardiometabolic risks. The studies accelerated after Dhanasekara, who focused on obesity and metabolic health to earn her Ph.D. in nutritional sciences, joined the collaboration.

In their latest meta-analysis, Kahathuduwa, Dhanasekara and their collaborators evaluated 34 studies that included 276,173 participants who were diagnosed with ASD and 7,733,306 who were not. The results indicated that ASD was associated with greater risks of developing diabetes overall, including both type 1 and type 2 diabetes.

The meta-analysis also determined that autism is associated with increased risks of dyslipidemia and heart disease, though there was no significant increased risk of hypertension and stroke associated with autism. However, meta-regression analyses revealed that children with autism were at a greater associated risk of developing diabetes and hypertension when compared with adults.

Kahathuduwa said the overall results demonstrate the associated increased risk of cardiometabolic diseases in ASD patients, which should prompt clinicians to more closely monitor these patients for potential contributors, including signs of cardiometabolic disease and their complications.

"We have established the associations between autism and obesity, as well as autism and cardiometabolic disease, including diabetes and dyslipidemia," Kahathuduwa said. "We don't have data to support a conclusion that autism is causing these metabolic derangements, but since we know that a child with autism is more likely to develop these metabolic complications and derangements down the road, I believe physicians should evaluate children with autism more vigilantly and maybe start screening them earlier than the usual."

Kahathuduwa also believes the study shows that physicians should think twice before prescribing medications such as olanzapine that are well known to have metabolic adverse effects to children with autism.

"Our findings should also be an eye opener for patients with autism and parents of kids with autism to simply be mindful about the higher risk of developing obesity and metabolic complications," Kahathuduwa added. "Then they can talk with their physicians about strategies to prevent obesity and metabolic disease."

Kahathuduwa said the next logical step for the collaborative team would be to generate evidence that either supports or rejects causality with regard to the observed associations.

"We have done some work with the ABIDE (Autism Brain Imaging Data Exchange) dataset regarding how neuroimaging shows the correlation between autism and obesity, but there is more work to be done," Kahathuduwa said. "None of these studies would have been possible without the help of the wonderful mentors, collaborators and students at both TTUHSC and TTU who contributed in numerous ways, and who will continue their important efforts to move these studies forward."

Friday, March 10, 2023


New stem cell model for research into a life-threatening malformation of the newborn lung

Congenital diaphragmatic hernia (CDH) is a common condition, affecting one in every 2,500 births. Up to 30% of affected babies die from it. The main problem is underdeveloped lungs. The condition also involves a hole in the diaphragm, which pediatric surgeons surgically correct in the first week of life. Until now, there has been little medical knowledge about how CDH develops or about what exactly goes wrong during embryonic development.

Dr. Richard Wagner, a pediatric surgeon and scientist at Leipzig University Hospital, teamed up with researchers from Massachusetts General Hospital in Boston to establish a new patient-specific cell model at Harvard Medical School. Using their model, the researchers investigated possible ways of treating this condition. The work is published in the American Journal of Respiratory and Critical Care Medicine.

Babies with CDH are placed on a ventilator immediately after birth. "We were able to isolate stem cells from the fluid that is sucked out of the children's lungs and otherwise disposed of, and grow them in the laboratory," explains Dr. Wagner, first author of the study.

While working as a postdoctoral researcher in the U.S., the doctor from Leipzig examined the stem cells in the laboratory together with the American researchers, designing cell models of the airways of the tiny patients. This gave them access for the first time to "living" human lung tissue from patients with CDH. They then compared the stem cells from healthy and underdeveloped lungs.

When the researchers looked at the molecular properties of the stem cells, they found that they had been altered due to inflammation. However, drug therapy in the cell model was able to restore functionality. "We also tested this process in animal models and showed that the treatment contributed to better lung development there, too. With the same drug therapy, we were therefore able to achieve positive effects both in human cells in the Petri dish and in the living organism in the established animal model," explains Dr. Wagner.

The treatment was performed with the steroid dexamethasone. This drug is already used in clinical practice to induce lung maturity in the fetus when there is a risk of premature birth during pregnancy.

"What is most appealing is the fact that we already know that this drug is not harmful in pregnancy. If we were to collect more data in laboratory research, it would be possible to investigate later in clinical trials whether there are advantages to administering the drug during pregnancy in order to slow down the possible inflammation in the organism and help the lungs grow," says Dr. Wagner. He added that the aim in the future is to be able to intervene with a drug directly after the diagnosis of a diaphragmatic hernia, which happens at around the 20th week of pregnancy.

International Conference on Pediatrics, Perinatology and Child Health

Thursday, March 9, 2023


Whether born naturally or via cesarean section, babies receive essential microbes from their mothers, says study

This is an illustration of a mother and infant and the microbes that are transmitted from mother to infant. Credit: Mari-Lee Odendaal....

Do cesarean-born babies miss out on essential microbes? New evidence suggests that the answer may be "no." Researchers report on March 8 in the journal Cell Host & Microbe that mothers are able to transfer microbes to their babies via alternative, compensatory routes. While cesarean-born babies do receive less of their mother's gut microbiome during birth, they make up for this by drinking their mother's microbes in breastmilk

Most microbiome research has focused on the gut, but we also house beneficial microbial communities in other parts of our bodies, such as in our respiratory tracts and on our skin. This study helps clarify how babies, who are generally considered sterile before birth, get essential microbes for their various microbiomes.

"We wanted to have a better idea of how the infant microbiome develops in different parts of their bodies and how it's influenced by factors such as birth mode, antibiotic use, and lack of breastfeeding," says senior author Wouter de Steenhuijsen Piters, a physician and data scientist at the University Medical Center Utrecht in the Netherlands.

To understand how the microbiome develops during the first month of life, the team recruited and repeatedly sampled 120 Dutch mothers and soon-to-be-born babies. From the babies, they collected skin, nose, saliva, and gut microbiome samples two hours after they were born and when they were one day old, one week old, two weeks old, and one month old.

The team also collected six different types of microbiome samples from the mothers—skin, breastmilk, nose, throat, fecal, and vaginal—to determine which of these sources were "seeding" the babies' various microbiomes. Then, they analyzed these results in the context of several factors that are thought to impact microbiome transfer, including mode of delivery, antibiotic use, and breastfeeding.

"We saw that many niches of the mother are important for the transmission of microbes, and if some of these pathways are blocked for one reason or another—in this case, we saw that happening with the cesarean section—then these microbes can still reach the infant through other paths," says de Steenhuijsen Piters.

Regardless of birth route, the researchers found that approximately 58.5% of a baby's microbiome is derived from its mother. However, different maternal microbial communities contributed to different infant microbiomes. Cesarean-born babies received fewer microbes from their mother's vaginal and fecal microbiomes, but—seemingly in compensation—acquired more microbes from breastmilk.

"Microbiome transfer and development are so important that evolution has ensured that those microbes are transferred one or another way from mother to child," says first author Debby Bogaert, a physician scientist at the University of Edinburgh. "Breastfeeding becomes even more important for children born by cesarean section who do not receive gut and vaginal microbes from their mom."

"It's a smart system, and it makes sense from an evolutionary perspective that these types of pathways are redundant to ensure that the child can begin life with the appropriate 'starter kit,'" says de Steenhuijsen Piters.

Now, the team want to know more about non-maternal influences on infant microbiome development. "We could see that the maternal microbiome explains almost 60% of the infant's total microbiome, but there's still 40% that we don't know about," says de Steenhuijsen Piters. "It would be interesting to stratify that unknown fraction to see where all the microbes come from; whether fathers contribute, for example, or siblings, or the environment."

Ultimately, the researchers want to understand how microbiome development in infants relates to long-term health. "Next, we want to explore whether this early life process, influenced by mom, is affecting not only short-term infection risk in the first year of life but also longer-term health in terms of things like allergies and asthma," says Bogaert. "In the future, we might be able to utilize this knowledge to help prevent, diagnose, or treat health problems."

  New algorithms could improve pediatric tuberculosis diagnosis Tuberculosis stands as one of the leading causes of death among young people...