Dec 19 2014

Benefits Persist in T Cell Therapy for Children with Relapsed Leukemia

leukemiaAcute lymphoblastic leukemia (ALL) is the most common childhood cancer and the most common childhood leukemia. Some patients with ALL have a highly aggressive form of the disease, one that causes either the cancer to recur or is resistant from the start to standard treatment.

An innovative cell therapy for this stubborn form of ALL continues to show highly promising results in children treated in a pilot clinical trial. Study leader Stephan A. Grupp, MD, PhD, a pediatric oncologist at The Children’s Hospital of Philadelphia and a professor of Pediatrics at the Perelman School of Medicine of the University of Pennsylvania, described outcomes and follow-up results of this study for pediatric patients with ALL in a press program on Dec. 6 at the annual meeting of the American Society of Hematology (ASH) in San Francisco.

Dr. Grupp, first author Shannon Maude, MD, PhD, a pediatric oncologist at CHOP and assistant professor of Pediatrics at UPenn, and colleagues reported that of the 39 children treated, 36 (92 percent) had complete responses one month after treatment. Of those 36 patients, 25 (69 percent) remained in remission at a median follow-up of 6 months after treatment. There were 10 relapses among the 36 patients with complete responses; 5 of the relapsed patients died.

The treatment is a personalized cell therapy program that reprograms a patient’s immune system and offers the potential of long-term success. At the heart of the therapy are bioengineered “hunter” T cells called CTL019 cells.

A relatively new approach in cancer treatment, this type of immunotherapy modifies T cells, the workhorses of the body’s immune system, to attack B cells, other immune cells that become cancerous in specific leukemias such as ALL. The CTL019 cells function as cancer hunters, killing the leukemia cells that normally evade regular T cell surveillance.

Researchers first extract a patient’s own T cells. They then use bioengineering techniques to reprogram each patient’s T cells into chimeric antigen receptor cells—the CTL019 cells—custom-designed to bind to a protein called CD19 that exists only on the surface of B cells. After being returned to the patient’s body, the CTL019 cells proliferate and then eliminate B cells. Moreover, they persist in the circulation, helping to guard against the cancer’s recurrence.

As the CTL019 cells potently attack leukemia cells, they also stimulate an unwanted, toxic immune response called cytokine release syndrome in patients. The care team successfully counteracted these side effects with an immunomodulating drug that had never been used for that purpose before, an approach which now has been adopted widely by cell therapy groups. In addition, because the CTL019 therapy eliminates healthy B cells along with cancerous B cells, patients must receive infusions of immunoglobin to perform the immune function provided by normal B cells.

“As we continue to follow children in this study, we see exciting results for patients who have exhausted their other treatment options,” said Dr. Grupp, who is an ongoing collaborator with colleagues at Penn Medicine, led by Carl H. June, M.D., who offer this personalized cell therapy as a treatment for adult patients with other types of cancer.

The first child to undergo this therapy, 9-year-old Emily Whitehead, remains cancer-free since her T cell treatment in April 2012, and continues to enjoy normal childhood activities like going to school and playing with her dog, Lucy. Emily has appeared prominently in news stories since her doctors announced dramatic findings during the December 2012 ASH meeting.

“Our results show that these engineered ‘hunter’ cells greatly expand in patients, producing very high complete response rates that then persist in patients, potentially allowing for long-term disease control,” said Dr. Grupp. “Our next step is to conduct a Phase II, multi-site trial to assess safety and efficacy in multiple centers, which is now underway.”

This past July, the U.S. Food and Drug Administration designated the CTL019 approach as a Breakthrough Therapy, helping to expedite its progress into broader clinical trials.

In August 2012, Novartis acquired exclusive rights from Penn to CTL019. Several authors from Novartis are co-authors of the abstracts presented by Dr. Grupp and others at the ASH meeting.

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Dec 17 2014

Affordable Care Act Results in Patchwork of Coverage for Children

Affordable Care ActAn article published recently in Health Affairs is the first to investigate the Affordable Care Act’s (ACA) Essential Health Benefit (EHB) as it relates to children. The study — which was led by George Washington University’s Sara Rosenbaum, JD, and included contributions from CHOP PolicyLab experts Kathleen Noonan, JD, and David Rubin, MD, MSCE — found the EHB has resulted in a state-by-state patchwork of coverage for children and adolescents that has significant exclusions, particularly for children with developmental disabilities and other special needs.

Previous studies have compared the EHB standard more broadly to the Children’s Health Insurance Program (CHIP), but this analysis presents the detailed evidence regarding the types of exclusionary practices that limit the effectiveness of coverage for children insured through health plans sold in the individual and small group markets. CHIP “provides low-cost health coverage to children in families that earn too much money to qualify for Medicaid,” according to As of 2013, there were roughly eight million children enrolled in CHIP nationwide, with more than 200,000 in New Jersey and 250,000 in Pennsylvania.

“The Affordable Care Act offers great promise for kids, but we are concerned that its intended benefits are not fully realized for children,” said the study’s lead author, Aimee M. Grace, MD, MPH, a pediatrician and fellow at Children’s National Health System. “We sought to understand which pediatric services are covered, and which ones are excluded, by health insurance plans in the health insurance Marketplaces.”

“Pediatric services” is one of ten benefit classes required by the Affordable Care Act that must be covered in all health insurance plans sold in the individual and small-group health insurance Marketplaces.  However, other than oral health and vision care, neither the ACA nor the regulations for implementing it define “pediatric services”.

And while the Affordable Care Act gave the U.S. Department of Health and Human Services (HHS) Secretary the ability to define a pediatric benefit standard at the national level, HHS chose instead a state-by-state benchmark plan approach akin to CHIP, which affords greater discretion to both states and payers.

In the Health Affairs study, the researchers found that the state-by-state approach has led to great variation in coverage. For example, 25 states specifically cover treatments for congenital defects, and 24 specifically include coverage for both autism spectrum disorder (at least in part) and hearing aids. There is also great variation among states regarding exclusion of certain pediatric services. For example, 13 states specifically exclude services for children with learning disabilities, and 10 states exclude speech therapy for developmental delays, stuttering, or both.

Stitching the Patchwork

“This benefit patchwork means significant state-to-state variation in what will be covered for children with special needs,” said Rosenbaum.

The analysis suggests four potential steps:

  1. Pediatric treatment limits and exclusions, particularly exclusions based on mental retardation, mental disability, or other developmental conditions, should be barred.
  2. The concept of “medical necessity” should be incorporated into the defined pediatric benefit. Medical necessity should include not only the clinical utility and appropriateness of a covered service, but also whether the service is appropriate in the pediatric developmental health context.
  3. The essential health benefits standard for pediatric services should be revised to address covered services, particularly for children with special needs, and actuarial value (the percentage that the average person can expect the plan to cover).
  4. The use of CHIP plans as a benchmark plan for pediatric services should be permitted.

HHS made a commitment to review its “benchmark plan” approach for the 2016 plan year. At this time, HHS could define a pediatric benefit standard at the national level. Establishing a benefit standard has important implications for the eight million children who currently receive their health insurance coverage through CHIP, whose funding has not been extended beyond 2015.

If this funding were not extended, many of these children would enter the Marketplaces for their insurance coverage. For these children, as well as the children already covered by plans in the Marketplaces, the appropriateness of the essential health benefits standard for children is one of the most important issues in child health policy today.

“With Congressional debate expected about whether to extend funding for CHIP beyond fiscal year 2015, how well the pediatric services element of the essential health benefits standard addresses the needs of children will be an important factor to consider,” said PolicyLab’s Noonan.

To read more, see the study abstract.

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Dec 15 2014

Oral, Intravenous Antibiotics Equally Effective at Treating Bone Infection

osteomyelitisThe Children’s Hospital of Philadelphia’s Ron Keren, MD, MPH, was the first author of a study published today in JAMA Pediatrics that showed treating the bone infection osteomyelitis with oral antibiotics did not result in more treatment failures than treatment with intravenous antibiotics. As a result, the researchers suggest physicians reconsider using intravenous antibiotics to treat this condition because of that treatment method’s complications.

A serious infection of the bone, osteomyelitis affects approximately 1 in 5000 children per year. Osteomyelitis can require multi-week regimens of antibiotics, often given intravenously, and in some cases the condition can lead to surgery to remove dead bone tissue.

In 2012 Dr. Keren and colleagues received an award from the Patient-Centered Outcomes Research Institute to study treatment of serious bacterial infections with antibiotics. In collaboration with researchers from Pediatric Research in Inpatient Settings Network-affiliated institutions and the Children’s Hospital Association, Dr. Keren and colleagues have been comparing oral antibiotics to those delivered via a peripherally inserted central catheter, or PICC line.

PICC lines are preferred by many clinicians for long-term treatment of severe infections, but often require sedation for insertion, need regular maintenance, and can clot, break, or become dislodged.

Oral antibiotics, on the other hand, are much easier for patients to take and caregivers to manage. However, to achieve the same efficacy as IV medications oral antibiotics must have high “bioavailability” — that is, the amount of medicine absorbed into the blood through the digestive tract needs to be high.  By definition, all antibiotics administered through PICC lines have 100 percent bioavailability, but only some oral antibiotics have high bioavailability.

In the JAMA Pediatrics study, Dr. Keren and colleagues — including Samir S. Shah, MD, MSCE, from Cincinnati Children’s Hospital — coordinated a retrospective review of medical records of children who were hospitalized between January 1, 2009 and December 31, 2012 across 36 children’s hospitals. The patients were split into two groups, one that received antibiotics via a PICC line, and another group that received antibiotics orally.

The investigators found similar treatment failure rates across the PICC and oral groups, at 4 and 5 percent, respectively. Adverse drug reactions were similarly low, at less than 4 percent in both groups. But the research group found that of children who received PICC lines, 15 percent developed a PICC-related complication, such as a blood stream infection, clot, or dislodgement that required a visit to an emergency department, rehospitalization, or both.

“PICC complications such as blood clots and blood stream infections are quite serious. We can avoid such complications by using oral antibiotics,” said Dr. Shah, a hospitalist and infectious diseases specialist.

Overall, the researchers showed children prescribed oral antibiotics did not have higher rates of treatment failure than did their peers who received antibiotics via a PICC line.

“Once a bone infection improves after a few days of intravenous antibiotics, children can be transitioned to oral antibiotics and have excellent outcomes, without the hassles and potential complications of PICC therapy,” Dr. Keren said.

To read more about Dr. Keren et al.’s antibiotics project, see the Pediatric Research in Inpatient Settings Network page about it. For more information about this study, see JAMA Pediatrics.

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Dec 12 2014

Study Questions Bringing Lunch from Home


The National School Lunch Program has been adopted by more than 100,000 schools as of 2012.

To pack a lunch or not to pack a lunch: that is every parent’s question. A study recently published in JAMA Pediatrics may supply some answers to the age-old question of what to do about your children’s lunch.

Baylor College of Medicine’s Karen Weber Cullen, DrPH, RD, and the Houston Department of Health and Human Service’s Michelle Caruso, MPH, RD, examined the nutritional value of lunches brought from home versus school lunches that follow National School Lunch Program (NSLP) guidelines. They found, on average, that lunches brought from home often contained more sodium and fewer servings of vegetables, fruits, and whole grains than NLSP guidelines specify.

And in an editorial that accompanied Drs. Cullen and Weber’s study, The Children’s Hospital of Philadelphia’s Virginia A. Stallings, MD, says NSLP guidelines — which were passed by Congress in 2011, and emphasize vegetables, fruits, and a variety of healthful foods — have “the potential to fundamentally change the diet quality and food variety of school-aged children.”

A program of the U.S. Department of Agriculture (USDA), the National School Lunch Program has been adopted by more than 100,000 schools and as of 2012 provided “nutritionally balanced, low-cost or free lunches to more than 31 million children each day,” according to the USDA website. Its nutritional requirements include increased portions of grains, vegetables, and fruits, and age-appropriate calorie limits ensure children receive the proper amount of nutrition and don’t overeat.

A Professor of Pediatrics at The Children’s Hospital of Philadelphia and the University of Pennsylvania’s Perelman School of Medicine, Dr. Stallings is a leading clinical nutrition and growth specialist. In Dr. Stalling’s JAMA Pediatrics editorial, she points out that lunches brought from home are not addressed by federal guidelines and “the general assumption is that home-prepared lunch will be as healthful as school lunch and possibly better.” However, Drs. Cullen and Weber’s investigation shows that may not be the case.

Focusing on one Houston school district, from October to December 2011, Drs. Cullen and Weber’s team observed 242 elementary students and 95 intermediate students brought their lunch from home. They found, compared to NLSP guidelines, lunches from home “contained a significantly greater amount of sodium,” fewer vegetables, and less liquid milk. In addition, about “90 percent of lunches from home contained desserts, snack chips, and sweetened beverages, which are not permitted in reimbursable school meals,” the researchers note.

For her part, Dr. Stallings says future studies “are needed to encourage families who choose to provide lunch from home to prepare meals that are similar to the NLSP diet patterns and the health promotion goals. Little contemporary information is available about families and students who choose not to participate in the school lunch and may result in less healthful lunch alternatives or skipping lunch.”

To learn more about healthy eating and nutrition for children, see Children’s Hospital’s page on school-aged child nutrition.

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Dec 10 2014

Prevention Bundle Reduces Hospital-acquired Infection in Pediatrics

infectionClinicians and researchers at The Children’s Hospital of Philadelphia are always striving to improve care, which is partly why the institution continues to rank as the No. 1 pediatric hospital in the country. So, when they determined in 2010 that the rate of catheter-associated urinary tract infections (CAUTIs) at CHOP was significantly higher than the national average, they got to work to develop a bundle of strategies aimed at improving care.

Eighty percent of urinary tract infections are associated with an indwelling urinary catheter, which is a tube inserted into the bladder through the urethra to drain urine, according to the Institute for Healthcare Improvement. Symptoms of a urinary tract infection are burning or pain in the lower abdomen, fever, burning during urination, or an increase in the frequency of urination.

Because they are so common and costly, CAUTIs have received national attention as a high-priority, preventable hospital-acquired condition. Yet, most of the research on CAUTI epidemiology and evidence-based prevention guidelines focused on adults, until an observational study was published in the September issue of Pediatrics by the multidisciplinary “Prevent CAUTI” team at CHOP that established a plan to reduce the infection in a pediatric setting.

“We had a huge ‘aha moment’ when we compared ourselves to data in the literature and we had more than two times the CAUTI rate for comparable institutions,” said Katherine Finn Davis, PhD, RN, CPNP, a nurse researcher for CHOP’s Center for Pediatric Nursing Research and Evidence-Based Practice. “That was unacceptable, of course, and we decided that we must do something immediately.”

In July 2010, the team initiated a bundle that focused on placing indwelling urinary catheters only when indicated, using sterile techniques at all points of care, and reviewing catheter necessity daily. A crucial part of the intervention was institution-wide training on proper urinary catheter insertion technique and maintenance practices.

Using an online tutorial and simulation training, four leaders of the quality improvement project who Dr. Davis described as “passionate about CAUTI prevention”  – Ann Colebaugh, RN, MSN, CPN; Benjamin Eithun, RN, MSN, CRNP; Natalie Plachter, CRNP; and Allison Thompson, MSN, RD, RN, CCRN, CRNP — trained 200 physicians, advanced practice providers, registered nurses, and radiology technicians in hospital areas with the highest rates of urinary catheter placement and utilization. Once the trainees mastered the insertion checklist, they became qualified observers who were responsible for promoting ongoing education by ensuring that other clinicians on their units completed the online tutorial and then followed the evidence-based practices.

Next, the Prevent CAUTI team rolled out the educational module to other hospital areas that had patients with urinary catheters, including the general medical and surgical units. In all, about 1,500 clinicians over a three-month period received training on the CAUTI prevention bundle.

“It was an incredible example of multidisciplinary work,” Dr. Davis said. “People from different aspects of the clinical world drew on their strengths and worked together toward a common goal to get our rate down.”

The Prevent CAUTI team also conducted a retrospective, observational analysis that compared CHOP’s hospital-wide CAUTI rates before and after implementation of the quality improvement project. Using data from July 2009 to June 2012, they found that the multifaceted intervention was associated with a 50 percent reduction in the hospital’s monthly CAUTI rate.

“That reduction was impressive,” Dr. Davis said. “After analysis, we also determined that the children getting catheters were still the right kids — everyone had an indication. The usage rate of catheters did not decrease during that time period, but we were using them appropriately.”

In addition to understanding better which children are at risk for CAUTIs, Dr. Davis said the study is important because it is one of the first to provide information to healthcare institutions on how to prevent CAUTIs from a pediatric perspective. Other pediatric institutions can assess their CAUTI rates and then use CHOP’s tools, such as taking the insertion checklist to the bedside, to implement similar CAUTI prevention bundles.

In an effort to sustain CHOP’s success and reduce the rate of CAUTIs even further, the Prevent CAUTI team conducts bedside reviews to reinforce standardized care and performs “just in time” training if they identify a lapse that puts the patient at risk. They also continue to identify groups throughout the hospital that benefit from CAUTI prevention training, such as hospital staff who handle the urinary reservoir bag during patient transport. They should check the position of the collection bag and ensure that it is always below the level of the patient’s bladder, Dr. Davis said.

“We want to get our CAUTI rate to zero,” Dr. Davis said. “We’re not there yet, but for any infection that is preventable, we want to get there.”

Other members of the CHOP Prevent CAUTI team who contributed to the Pediatrics paper include Sarah B. Klieger, MPH; Dennis J. Meredith, DVM, CIC, of CHOP’s Department of Infection Prevention and Control; and Julia Shaklee Sammons, MD, MSCE, and Susan E. Coffin, MD, MPH, both of CHOP’s Division of Infectious Diseases and Department of Pediatrics at the Perelman School of Medicine of the University of Pennsylvania.

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Dec 08 2014

Obese Teens With OSAS Show Impaired Neurobehavioral Functioning


Some patients with obesity who were struggling to follow their treatment recommendations also reported having difficulties in school.

Navigating the tumultuous teenage years can be exhausting, and new research shows that they can be particularly challenging for overweight adolescents with obstructive sleep apnea syndrome (OSAS), a sleep disorder that affects an estimated 2 percent of youths. Obesity and OSAS often exist simultaneously, and both conditions have been associated with neurobehavioral changes such as problems with regulating emotions, school performance, attention, and alertness.

As child obesity rates have tripled among school-aged children and adolescents over the past 30 years, it appears that teens are on the fast track for increasing their risk of developing OSAS. It is a trend that Melissa Xanthopoulos, PhD, sees firsthand as a child and adolescent psychologist at The Children’s Hospital of Philadelphia and as an investigator for its Sleep Center and Healthy Weight Program.

At the clinical level, Dr. Xanthopoulos and colleagues observed a pattern among some young patients with obesity who were struggling to follow their treatment recommendations and also reporting difficulties in school. The research team wondered if an interaction between obesity and sleep could somehow be impeding their success.

“It is an important research question because during this critical period of adolescence, the brain’s frontal lobe, which is in charge of executive functioning, is making a lot of changes,” Dr. Xanthopoulos said. “Executive functioning involves higher order cognitive processing such as planning, monitoring, and initiating tasks.”

If a teen’s brain is busy reorganizing during this sensitive time, what happens when it is repeatedly disrupted by the many pauses in breathing during sleep — called apneas and hypopneas —  and ensuing abrupt dips in blood oxygen saturation that are the hallmarks of nightly episodes of OSAS?

Research performed with adults who have OSAS suggests that they experience cognitive changes, Dr. Xanthopoulos said, but she found that the obesity and sleep research literature involving teens was lacking in this area. In order to build evidence for the adolescent period, the study team looked at three groups of teens ages 12 to 16 years old: obese teens with OSAS, obese teens without OSAS, and lean teens without OSAS. The investigators hypothesized that obese teens with OSAS would exhibit more neurobehavioral functioning deficits.

They analyzed self-reports from the teens and their parents that focused on several dimensions of neurobehavioral abnormalities that have been associated with sleep disorders including executive function, attention, sleepiness, and behavior and mood. The results showed that executive function, in particular, was impacted in this age group of participants who had obesity and OSAS.

The study team also used sophisticated statistical methods to examine how participants’ BMI z-scores, which is a measure of relative weight adjusted for a child’s age and sex, related to their obstructive apnea hypopnea index (AHI), which is an average that represents the combined number of apneas and hypopneas that occur per hour of sleep. Their analysis revealed that the AHI level had a significant influence on the relationship between BMI-z scores and executive functioning, attention, and behavior.

Dr. Xanthopoulos and her co-investigators want to spread the word about this study’s outcomes with their colleagues and raise patients’ awareness about the potential risks of OSAS and obesity. When a teen with obesity is exhibiting attention problems, difficulty in school, and signs of depression, she encourages healthcare providers to ask, “Does this patient snore?” and then to consider recommending a sleep study.

The next step, Dr. Xanthopoulos said, is figuring out which treatment method these patients need in order to be healthy physically, mentally, and emotionally. Typically, the treatment for adults and teens with OSAS is continuous positive airway pressure (CPAP), which delivers a steady stream of pressurized air through a mask that patients wear during sleep to keep their airways open and restore normal oxygen levels.

“CPAP is not something a teenager usually wants to hear about, but it might help them feel better and be better able to engage in weight loss behaviors such as making healthy choices and increasing physical activity,” Dr. Xanthopoulos said. “If you treat obesity, oftentimes sleep apnea is reduced or goes away. But, losing weight is very hard, especially for a teenager who is super sleepy and potentially has these neurobehavioral deficits.”

Dr. Xanthopoulos suggested that more research is needed to determine if OSAS treatment could potentially reverse neurobehavioral concerns for teens with obesity and OSAS, and also to see if the therapy could help them engage in weight loss interventions more effectively.

The study appeared ahead of print for the journal SLEEP. It is a sub-study of a larger research project led by Sleep Center Director Carole L. Marcus, MBBCh, that is focused on the pathophysiology of childhood OSAS and is funded by the National Heart, Lung, and Blood Institute. The sub-study also involved Paul R. Gallagher, MA, of the Clinical and Translational Research Center coordinated by CHOP and the Perelman School of Medicine at the University of Pennsylvania; Robert I. Berkowitz, MD, a CHOP psychiatrist who is director of the Weight and Eating Disorders Research Program and also an associate professor of psychiatry at UPenn; Jerilynn Radcliffe, PhD, a CHOP psychologist and professor of clinical psychology at UPenn; and Ruth Bradford, research coordinator for CHOP’s Sleep Center.

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Dec 05 2014

CHOP, ARUP Laboratories Form HLA Genotyping Partnership

HLA GenotypingThe Children’s Hospital of Philadelphia and the Salt Lake City, Ut.-based ARUP Laboratories recently announced an agreement to provide human leukocyte antigen (HLA) testing using next-generation sequencing (NGS) methods to ARUP customers.

In February, researchers from Children’s Hospital’s Division of Genomic Diagnostics announced that they had developed a unique laboratory test to characterize the genes that encode HLA molecules. HLAs are complex, highly variable proteins on cell surfaces that are essential to immune function, and their genes are the most complex gene family known in the entire human genome, which proved a challenge for prior testing methods.

The new test may improve transplantation, and provides an advanced tool for research in immunological diseases, infectious diseases, and pharmacogenomics. With its announcement, CHOP became the first hospital in the world to offer HLA genotyping.

HLA genotyping “addresses a 60-year old problem,” said Children’s Hospital’s Dimitri S. Monos, PhD, director of CHOP’s Immunogenetics Laboratory. “Since the discovery of HLAs in the early 1950s, it has been a challenge to accurately and thoroughly characterize HLA gene sequences. We have now used NGS tools to significantly advance HLA genotyping. This is the first technology that gives results free of any current or future ambiguities.”

“Our agreement with CHOP enables ARUP to offer this innovative test to our clients to help aid decisions in bone marrow transplantation. We are very pleased to include this testing as part of our comprehensive menu of services,” said Jerry Hussong, MD, ARUP’s chief medical officer and director of laboratories.

Based in Salt Lake City, Utah, ARUP Laboratories is a nonprofit enterprise of the University of Utah’s Department of Pathology, and “offers in excess of 3,000 tests and test combinations, ranging from routine screening tests to highly esoteric molecular and genetic assays,” according to its website.

“We are pleased to be able to provide this test to ARUP Laboratories’ customers. It allows us to provide greater access to our tests,” said Robert W. Doms, MD, PhD, CHOP’s pathologist-in-chief.

To read more about genetic testing and research at The Children’s Hospital of Philadelphia, see the Division of Genetic Testing’s list of lab tests.

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Dec 03 2014

Optimal Antibiotic Use Wanes Without Clinician Feedback


Offering pediatricians education, auditing their prescription patterns, and providing feedback can encourage them to choose the most appropriate antibiotics.

Clinicians must select antibiotics carefully, in order to maintain their effectiveness and limit antimicrobial resistance. Judicious use of antibiotics has important health benefits for children especially because they are prescribed so frequently, usually for outpatient acute respiratory tract infections.

A previously reported study of an antimicrobial stewardship program conducted by researchers at The Children’s Hospital of Philadelphia found that offering pediatricians education, auditing their prescription patterns, and providing feedback can encourage them to choose the most appropriate antibiotics. Jeffrey S. Gerber, MD, PhD, a CHOP infectious diseases specialist, gave an update to this study at the IDWeek 2014 meeting held in Philadelphia Oct. 8-12. He reported that reductions in prescribing rates for broad-spectrum antibiotics faltered when the researchers stopped providing antibiotic prescribing audit and feedback to clinicians in the intervention group.

“These data suggest that audit and feedback was a vital element of this intervention and that antimicrobial stewardship requires continued, active efforts to sustain initial improvements in prescribing,” Dr. Gerber and colleagues wrote in a research letter to the Journal of the American Medical Association that was released early to coincide with IDWeek.

In the cluster randomized trial, nine community-based pediatric primary care practices received the combined intervention of education plus prescribing audit and feedback, and nine practices received no intervention. Among the intervention practices, broad-spectrum antibiotic prescribing decreased from 26.8 percent to 14.3 percent, or nearly half, compared to a decrease from 28.4 percent to 22.6 percent in the control group.

At the end of the intervention, the researchers discontinued antibiotic prescribing audit and feedback to clinicians, but the study team extended their observation period for 18 months. Their latest data showed that prescribing of broad-spectrum antibiotics increased over time and reverted to above-baseline levels: 27.9 percent in the intervention group and 30.2 percent in controls.

“Our findings suggest that extending antimicrobial stewardship to the ambulatory setting can be effective but should include continued feedback to clinicians,” the authors concluded in the JAMA letter.

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Dec 01 2014

Medical Emergency Teams Improve Safety, Provide Cost Savings


Research has demonstrated that medical emergency teams are effective in preventing clinical deterioration.

Hospital administrators are always looking for ways to improve the equation of how to advance quality of care at a lower cost. A cost-benefit analysis performed by a research team at The Children’s Hospital of Philadelphia describes one winning combination that can improve safety of hospitalized children, while at the same time achieving financial savings.

Finding ways to better identify and respond to children who are getting sicker out on the pediatric wards has been a research focus of Christopher P. Bonafide, MD, MSCE, of the Division of General Pediatrics at the Children’s Hospital of Philadelphia, so he is a big METs fan — but we are not talking about baseball.

METs are medical emergency teams that involve critical care experts who are designated to be deployed to a unit when a patient is starting to show signs of clinical deterioration (CD), in order to head off cardiac arrests and other serious events that could require a transfer to the intensive care unit and life-sustaining interventions.

“Prior to implementation of medical emergency teams, you would call a Code Blue,” Dr. Bonafide said. “That’s when you’ve already missed all the warning signs, and the patient essentially is starting to die in front of you.”

Research has demonstrated that METs are effective in preventing CD events, but until Dr. Bonafide and his colleagues published a recent paper in Pediatrics, no studies had evaluated their financial benefits. First, the research team identified the cost of CDs, and then they analyzed various MET compositions and staffing models, in order to determine the annual reduction in CD events needed to offset MET costs.

“When you’re taking people who are doing critical care and moving them out onto the units to respond to patients, questions can come up: Is that the best use of their time? Is that providing a high value service?” Dr. Bonafide said.  “It’s nice to see that some of what we’re already doing and know improves patient safety, we also can justify financially.”

In order to calculate the costs of CDs, the study team compared unplanned ICU transfers that did not require subsequent life-sustaining interventions to unplanned ICU transfers that required initiation of noninvasive or invasive mechanical ventilation and vasopressor infusion. They determined that a hospital can potentially save $100,000 every time a MET can quickly assess and stabilize a patient without the need for life-sustaining interventions.

Next, the researchers tackled some complicated math. Since there is no single way to stack a MET, they had to consider several configurations to estimate the costs of running those teams. They looked at 75th percentile salaries for a nurse, respiratory therapist, critical care fellow, and ICU attending as the folks who might make up the MET. They also took into consideration if those responders had any other concurrent responsibilities, or if they were part of a freestanding unit that is staffed 24-hours a day.

“Based on how you staff your MET, it varies a ton on what the team actually costs,” said Dr. Bonafide, who also is an assistant professor of pediatrics at the Perelman School of Medicine at the University of Pennsylvania. “The correlate to that is the number of critical deterioration events that you actually have to prevent. So if you have an inexpensive team model, you actually don’t have to prevent that many events in order for the team to pay for itself.”

The MET at Children’s Hospital consists of a critical care fellow, a respiratory therapist, and a nurse who have concurrent responsibilities, which is the most common MET configuration in the U.S. Based on that model, the investigators calculated that in order to recoup MET costs, the team has to prevent between three and four critical deterioration events for the entire year.

“That really is not a difficult thing to do,” Dr. Bonafide said. “We know that we can have a significant impact on these bad outcomes by implementing medical emergency teams, so the three to four number is very attainable.”

The financial benefits could add up significantly. In a hospital that has approximately 300 unplanned transfers from ward to ICU per year, a reduction of 15 CD events per year by implementing CHOP’s MET model could result in eliminating $1,496,595 in excess costs per year for a net savings of $1,145,897 annually, the researchers wrote in the Pediatrics paper.

A future research challenge will be to determine what percentage of CD events are preventable, Dr. Bonafide pointed out. Another question he would like to consider is how cost-effective are METs, which takes into account how the teams’ interventions could impact not only the costs of care but also quantify the years of lives saved and patients’ quality of life.

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Nov 26 2014

International Team Finds Blood Disorder Mutation

blood disorderAn international team of gene experts has identified a mutation that causes aplastic anemia, a serious blood disorder in which the bone marrow fails to produce normal amounts of blood cells. Studying a family in which three generations had blood disorders, the researchers discovered a defect in a gene that regulates telomeres, chromosomal structures with crucial roles in normal cell function.

“Identifying this causal defect may help suggest future molecular-based treatments that bypass the gene defect and restore blood cell production,” said the study’s co-leader, Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics at The Children’s Hospital of Philadelphia. Dr. Hakonarson and a number of other CHOP investigators collaborated with Australian scientists on the study, what was published in the journal Blood.

The research team studied an Australian family with aplastic anemia and other blood disorders, including leukemia. The investigators identified an inherited mutation on the ACD gene, which codes for the telomere-binding protein TPP1.Complex structures made of DNA and protein, telomeres are located on the end of chromosomes, where they protect the chromosomes’ stability. They are sometimes compared to shoelaces’ plastic tips.

Telomeres shorten after each cell division, and gradually lose their protective function. Aging cells, with their shortened telomeres, become progressively more vulnerable to DNA damage and cell death. Separately from the aging process, certain inherited and acquired disorders may shorten telomeres and injure rapidly dividing blood-forming cells produced in bone marrow. This leads to bone marrow failure, one example of which is aplastic anemia.

The Australian team investigated the function of the ACD gene. They determined that the mutation shortened telomeres and interrupted the ability of telomeres to attract the enzyme telomerase, which counteracts telomere shortening and thus protects cells. The researchers showed that the mutation in ACD alters the telomere-binding protein TPP1, disrupting the interactions between telomere and telomerase. Without access to telomerase to help maintain telomeres, blood cells lose their structural integrity and die, resulting in bone marrow failure and aplastic anemia.

“This improved understanding of the underlying molecular mechanisms may suggest new approaches to treating disorders such as aplastic anemia,” said Dr. Hakonarson. “For instance, investigators may identify other avenues for recruiting telomerase to telomeres to restore its protective function.”

To read more about the innovative work being done at the Center for Applied Genomics, see the Center’s website.

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