What’s New in Research: June 2019
Behold the Bili-ruler: A novel low-cost device for screening neonatal hyperbilirubinemia
Study validates new, low-cost, non-invasive tool in screening newborn jaundice with high diagnostic accuracy
Neonatal hyperbilirubinemia, commonly known as newborn jaundice, is a condition that affects up to 80 percent of newborns in the first week of life. Severe hyperbilirubinemia (bilirubin levels >20mg/dL) affects an estimated 1 million infants around the world annually. If diagnosed early, severe hyperbilirubinemia is largely treatable with high-intensity phototherapy, resulting in recovery without long-term consequences. If left undiagnosed or untreated, severe hyperbilirubinemia may lead to irreversible brain damage or even death. These complications often arise in low-resource settings; in low- and middle-income countries (LMICs), one-third of infants with extreme hyperbilirubinemia die from a condition that is largely treatable.
But access to treatment itself may not be the primary challenge.
One significant barrier to managing hyperbilirubinemia in LMICs is the failure to recognize the severity of the condition before the onset of irreversible symptoms. A team from Brigham and Women’s Hospital recently reported the creation and validation of a novel tool, the Bili-ruler, designed for use by frontline health workers to screen for hyperbilirubinemia in low-resource settings. The findings are published in Pediatrics.
“In low-income settings, many people don’t have access to very basic diagnostics, medications and interventions that could prevent a large burden of neonatal morbidity and mortality,” said lead author Anne CC Lee, MD, MPH, a pediatrician, director of the Brigham Global Newborn Health Lab and principal investigator of the project. “Improving early recognition and care seeking for potentially serious newborn illness is a first step.”
The first low-cost screening tool for jaundice was the Gosset icterometer developed in the 1950s. This device comprised five shades of yellow and presented good correlation with serum bilirubin concentrations; however, it was developed using robbialac paint which led to a lack of color standardization and was never widely adopted. Currently, in high-income settings, there are trancutenous bilirubin instruments, but these cost over $7,000 and are not affordable in most low-income settings.
“Ultimately, if the baby is not diagnosed or is diagnosed too late, there is very little that can be done before the effects are permanent,” said co-author Lian Folger, a program coordinator at the Global Newborn Health Lab.
To address this barrier of illness recognition, the team designed the Bili-ruler to improve the identification of clinically severe hyperbilirubinemia in low-resource settings. As its name suggests, the Bili-ruler is a portable, handheld “ruler” to measure the degree of newborn jaundice, using six color strips arranged in a stepwise gradient of increasing yellow hue. The colors were developed using advanced digital color processing of images of infants with different levels of hyperbilirubinemia.
To assess for jaundice, the Bili-ruler is pressed against the infant’s skin, and the underlying skin tone is visualized through a circular window enclosed by a uniform color strip. This process is repeated for all six colors, and the user chooses the score which corresponds to the color that most closely matches the underlying skin tone. The team went through many iterations of the design of the device and collaborated with groups at MIT that specialize in visual design,
To validate the Bili-ruler across diverse populations, the research team recruited a total of 790 newborns from the Brigham and its partner institution, the Sylhet Osmani Medical College Hospital (SOMCH) in Sylhet, Bangladesh. Newborns were eligible for inclusion if they were <28 days old, generally healthy, and had not previously received phototherapy or exchange transfusion.
In the study, the Bili-ruler was used to assess for jaundice alongside clinical measures of transcutaneous bilirubin (TcB) and total serum bilirubin (TSB) levels. Bili-ruler measurements were obtained on the forehead, nose, abdomen, palms, or soles of feet, without previous knowledge of bilirubin levels. The scores were then compared with TcB and TSB.
The Bili-ruler had high diagnostic accuracy and validity, showing strongest positive correlations between measurements taken on the nose with bilirubin concentrations measured by both TcB and TSB. In addition, measurements on the nose had high validity, sensitivity and specificity for identifying hyperbilirubinemia of several different thresholds. Bili-ruler scores on the foot also had high sensitivity, but lower specificity in identifying serum bilirubin at very high thresholds.
Results initially seemed consistent between infants of varying skin tones — an important consideration for use in multi-ethnic populations. However, since the largest populations validated in the study were south Asian and white, the researchers hope to expand validating the Bili-ruler in other ethnicities — namely Hispanic and black populations.
Currently, the team is working to partner with organizations in Ghana and Peru to expand the application and validity of the device. In Peru, the researchers are working with Little Sparrow Technologies, INMED, and Bilimetrix to implement a low-cost, package to guide both diagnostic evaluation and clinical management of jaundice.
Lee and Folger speak passionately about the significance and global health impact of their work.
“The hope is that this tool will improve the early recognition and more accurate diagnosis of severe jaundice in settings that traditionally do have not had access to care. Two of my own children had severe hyperbilirubinemia and required phototherapy. They likely would not have had the same healthy outcome if they were born at home and without postnatal care in rural Bangladesh. We hope that the Biliruler will improve access to treatment for hyperbilirubinemia and improve health outcomes for babies born in low-resource settings,” said Lee. “Every baby, no matter where they are born, deserves the equal opportunity for a healthy start in life.”
This work was funded by the U.S. Agency for International Development’s Saving Lives at Birth Program.
Paper cited: Lee, A.C. et al. “A Novel Icterometer for Hyperbilirubinemia Screening in Low Resource Settings,” Pediatrics, DOI: 10.1542/peds.2018-2039
Just a Phage? How Bacteria’s Predators Can Shape the Gut Microbiome
Study finds that bacteriophages can have a cascade of effects on the microbiome and change metabolite levels, with implications for therapeutic use
The gut microbiome is a complex, interconnected ecosystem of species. And, like any ecosystem, some organisms are predators and some are prey. A new study led by investigators at Brigham and Women’s Hospital and the Wyss Institute investigates the impact of bacteriophage, viruses that infect and kill bacteria. They find that phage can have a profound impact on the dynamics of the gut microbiome, not only affecting certain species directly but also having a cascading effect on others. Phage may also be impacting their human host by modulating metabolites, including chemical substances found in the brain. The team, which includes first author Bryan Hsu, PhD, and co-corresponding senior author Pamela Silver, PhD, at the Wyss Institute, and Lynn Bry, MD, PhD, at the Brigham and director of the Massachusetts Host-Microbiome Center, has published its results in Cell Host & Microbe.
“One of the major interests in my lab is understanding the changes in the dynamics of the gut microbiome. Bacteriophage are a huge component of the microbiome but haven’t been studied much yet,” said co-corresponding senior author Georg Gerber, MD, PhD, MPH, co-director of the Massachusetts Host-Microbiome Center and chief of the Division of Computational Pathology in the Department of Pathology at the Brigham. “Some people are exploring phage therapy, using phage to kill off microbes, but phage are also found naturally in the gut, co-existing with the rest of the ecosystem. We wanted to find out what they are doing in there.”
To address this question, the team colonized the guts of mice with a defined set of human bacterial species and then added phages, tracking the growth of each microbe. Using high-throughput sequencing and computational analyses, the team found that the phage caused attritions of the species they preyed upon as expected, but with a rippling effect on the rest of the ecosystem including blooms of non-targeted species.
In addition to looking at the effects on microbes, the team also looked for effects on the metabolome — chemical substances that can come from both the host and the bacteria present. They found that when they modulated the microbiome with phage, they could see targeted changes in the metabolome, including changes in neurotransmitter levels and bile acids.
“This finding fascinates me for followup and raises significant questions: Could we use phage to modulate these activities? Could this be an intervention for conditions, such as depression, where you’d want to change neurotransmitter levels?” said Gerber. “Even if they aren’t used as a direct therapeutic, our study suggests that phage may be a good tool for understanding the potential effects of other therapeutics that alter the microbiome.”
Gerber and colleagues are especially interested in looking at the intersection of phage and malnutrition in the developing world, given the profound effects on the metabolome and microbiome that malnutrition can have.
“We hope that our work will provide a framework to guide future investigations to elucidate the interplay between phage, the microbiota, and host health and disease,” said Gerber.
Funding for this work was provided by the Bill & Melinda Gates Foundation through the Grand Challenges Explorations Initiative (OPP1150555), the Defense Advanced Research Program Agency (DARPA BRICS HR0011-15-C-0094), the National Institutes of Health (T32 HL007627) and a Rosenbloom postdoctoral fellowship. Gerber is a shareholder and member of the Strategic Advisory Board of Kaleido Biosciences, and shareholder and member of the Scientific Advisory Board of Consortia Therapeutics. Another co-author is a shareholder and Chair of the Scientific Advisory Board for Consortia Therapeutics, and shareholder and member of the Strategic Advisory Board for Inspirata, Inc.
Paper cited: Hsu, B et al. “Dynamic modulation of the gut microbiota and metabolome by bacteriophages in a mouse model” Cell Host & Microbe DOI: 10.1016/j.chom.2019.05.001
Among Older Women, 10,000 Steps Per Day Not Needed for Lower Mortality
Older women who took 4,400 steps per day had lower mortality than those taking 2,700; risk of death continued to decrease with more steps up to 7,500 steps per day before levelling off
In the world of step goals and activity trackers, the number 10,000 can sound like a magic one. Many wearable devices that track the number of steps a person takes each day come pre-programmed with a daily goal of 10,000 steps. But while a large body of evidence shows that physical activity is good for a person’s health and longevity, few studies have examined how many steps a day are associated with good health, particularly long-term health outcomes. A new study led by investigators from Brigham and Women’s Hospital sought to address this knowledge gap by examining outcomes over an average of more than four years for older women in the Women’s Health Study who had measured their steps for a full week. The team reports that, among older women, taking as few as 4,400 steps per day was significantly associated with lower risk of death compared to taking 2,700 steps per day. Risk of death continued to decrease with more steps taken but leveled off at around 7,500 steps per day — less than the 10,000 steps default goal in many wearables. The team’s results are presented today at the American College of Sports Medicine Annual Meeting and published simultaneously in JAMA Internal Medicine.
“Taking 10,000 steps a day can sound daunting. But we find that even a modest increase in steps taken is tied to significantly lower mortality in older women,” said I-Min Lee, MBBS, ScD, an epidemiologist in the Division of Preventive Medicine. “Our study adds to a growing understanding of the importance of physical activity for health, clarifies the number of steps related to lower mortality and amplifies the message: Step more — even a little more is helpful.”
According to previous studies, the average number of steps taken by people in the U.S. is between 4,000 and 5,000 per day. The origin of the 10,000-step goal is unclear but may trace back to 1965, when a Japanese company began marketing a pedometer called Manpo-kei, which translates to “10,000 steps meter” in Japanese.
To conduct their study, Lee and colleagues included participants from the Women’s Health Study, a randomized trial originally conducted to evaluate risk of cardiovascular disease and cancer among women taking low-dose aspirin and vitamin E. When the original trial ended, participants were invited to participate in a long-term observational study. For the present study of steps and health, almost 18,000 women were asked to wear an ActiGraph GT3X+ accelerometer device — a research grade wearable — on their hips for seven consecutive days during all waking hours. The team analyzed 16,741 of the women who were compliant with wearing the device; their average age was 72.
Participants were followed for an average of more than four years, during which time 504 women died. Participants in the bottom 25 percent of steps walked (average of 2,700 steps per day) were at greatest risk of death, with 275 women dying. Those who walked modestly more (average of 4,400 per day) were at 41 percent lower risk of death. Risk of death continued to decrease with more steps walked, up to 7,500 steps per day, after which risk leveled off. The team also found that for women who walked the same number of steps per day, the intensity — how fast or slow they walked — was not associated with risk of death.
Due to the observational nature of the study, the authors cannot definitively separate cause from correlation (that is, to differentiate between “do more steps lower mortality?” or “do women in better health step more?”). However, the team did take several measures to try to ensure that the association observed was more likely causal than not, such as excluding women with heart disease, cancer, diabetes and less than excellent or good self-rated health and excluding the first year of follow-up data. The findings also are supported by previous experiments showing physical activity causes beneficial changes in short-term markers of health e.g., blood pressure, insulin/glucose levels, lipid profile, inflammation, and more.
The Women’s Health Study included primarily older, white women, and further studies will be needed in younger and diverse populations to determine if the findings are applicable to other groups, especially those who may, on average, take more steps. Other outcomes — such as quality of life and risk of specific diseases — were not assessed, but will be addressed in future studies.
“Of course, no single study stands alone. But our work continues to make the case for the importance of physical activity,” said Lee. “Clearly, even a modest number of steps was related to lower mortality rate among these older women. We hope these findings provide encouragement for individuals for whom 10,000 steps a day may seem unattainable.”
Funding for this work was provided by the National Institutes of Health (CA154647, CA047988, CA182913, HL043851, HL080467, and HL099355). A co-author of the paper received personal and travel fees from ActiGraph outside of the submitted work and is a member of its Scientific Advisory Board; the device used in this study was selected in 2009, prior to his involvement in the study.
Paper cited: Lee IM et al. “Association of Step Volume and Intensity With All-Cause Mortality in Older Women” JAMA Internal Medicine doi:10.1001/jamainternmed.2019.0899
New Evidence: It’s Not Necessary to Fast Before Complete Cholesterol Test
Study compares nonfasting lipid levels and fasting lipid levels in the same individuals, finding similar association with cardiovascular events even among those on statins
A new study adds to the growing body of evidence that it is unnecessary for most patients to fast before having bloodwork done to measure lipid levels to determine risk of future cardiovascular events. Since the 1970s, studies have suggested that fasting and nonfasting before a complete cholesterol test, otherwise known as lipid level testing, may make little difference in assessing who is at risk for a future heart attack, stroke or other cardiovascular event. But most of these studies were conducted by comparing groups of people at a population level rather than in the same individuals. This left a lingering question about how well nonfasting lipid levels can predict future events for patients. A large study led by investigators at Brigham and Women’s Hospital, Harvard Medical School, and Imperial College provides robust evidence that nonfasting lipid levels were similar to fasting lipid levels in the same individuals, predicting cardiovascular risk just as well. The results are published in JAMA Internal Medicine.
“We hope this study will be the final nail in the coffin, providing strong evidence that, within the same person, fasting or not before a lipid level test doesn’t matter for predicting cardiovascular risk,” said corresponding author Samia Mora, MD, MHS, a cardiovascular medicine specialist and director of the Center for Lipid Metabolomics in the Divisions of Preventive and Cardiovascular Medicine at the Brigham and an associate professor at Harvard Medical School. “This should reassure health care providers and patients that it doesn’t make a difference if you fast or don’t fast if the goal is to predict your cardiovascular risk.”
To conduct their study, Mora and colleagues conducted a post hoc prospective follow-up study of participants from the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA), a randomized clinical trial. Fasting and nonfasting lipid levels for more than 8,000 participants were measured four weeks apart with no intervention in between. Patients were followed for a median of 3.3 years for major coronary events (heart attacks, fatal coronary heart disease) and atherosclerotic cardiovascular disease (heart attacks, stroke, and related deaths).
The team found that risk associations of nonfasting lipid levels with coronary events were similar to those for fasting lipid levels measured four weeks later. When patients were not fasting, they had modestly higher triglyceride levels but similar cholesterol levels compared to when they were fasting.
“We spend most of our lives in a nonfasting state. And for some patients, especially those who are elderly or have diabetes, it can be risky to fast before lipid testing,” said Mora. “Health care providers held back because of concerns of variability within individuals, but the data here is so convincing. It should allow people to feel more comfortable with nonfasting lipid testing for cardiovascular risk assessment, including when taking a statin.”
Mora and colleagues note some important limitations to the study. ASCOT-LLA involved European participants, and while they represent multiple European countries, the majority were white and male. The researchers expect that the findings will be relevant to more diverse populations but note that future research should assess potential ethnic and/or racial differences.
This study was supported by an investigator-initiated institutional research grant from Pfizer, the National, Heart, Lung and Blood Institutes of Health (K24HL136852, R01HL134811, and HL117861), National Institutes of Health (Senior Investigator Award), and a Biomedical Research Centre Award to Imperial College from the Healthcare National Health Service Trust. The ASCOT trial was financially supported by Pfizer. Mora and co-authors report receiving personal fees and grants from Pfizer, Amgen, and Quest Diagnostics, and Atherotech Diagnostics Lab.
Paper cited: Mora, S et al. “Association of Nonfasting vs Fasting Lipid Levels With Risk of Major Coronary Events in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm” JAMA Internal Medicine DOI: 0.1001/jamainternmed.2019.0392
Eliminating Extended Work Shifts Improves Sleep Duration for Senior Resident Physicians
Hours slept per week increased by 8 percent among pediatric resident physicians who worked a rapid cycling work roster
Getting a good night’s sleep is important for everyone — including physicians. In 2011, the Accreditation Council for Graduate Medical Education (ACGME) set a limit on first-year resident physician shifts of 16 or fewer continuous hours of work. This policy change was based primarily on the results of studies comparing outcomes for first-year residents who worked extended-duration work shifts (24 hours or more) to those who worked rapid-cycling work shifts.
But data for more senior resident physicians has been lacking. Currently, resident physicians are permitted to work extended-duration shifts of up to 28 hours after their first postgraduate year. A new study led by investigators from Brigham and Women’s Hospital is the first multi-center randomized clinical trial of senior resident physicians (postgraduate year two and higher) to compare the work hours and sleep obtained by those working extended shifts with those whose scheduled shift lengths were limited to no more than 16 consecutive hours. The team found that hours of sleep per week increased by 8 percent for pediatric resident physicians working under the modified schedule. The team’s results are presented today at the American Thoracic Meeting and simultaneously published in Sleep.
“Sleep deficiency impairs performance and patient safety, adversely affects the mental and physical health of resident physicians and increases their risk of occupational injury and motor vehicle crashes,” said senior author Charles Czeisler, PhD, MD, FRCP, chief of the Division of Sleep and Circadian Disorders at the Brigham, who presented the findings at the meeting. “This operational trial, conducted in six pediatric intensive care units across the country, showed that rosters eliminating scheduled extended-duration shifts reduced weekly work hours and improved sleep of resident physicians.”
The current study enrolled 302 resident physicians working in pediatric intensive care units at six U.S. academic medical centers. Sleep was measured using wrist-worn actigraphs, and work hours and sleep data were collected using electronic diaries. In the clustered-randomized crossover clinical trial, resident physicians were randomized to an Extended Duration Work Roster (EDWR), with extended-duration (24 hours or more) shifts, or a Rapidly Cycling Work Roster (RCWR), in which scheduled shift lengths were limited to 16 or fewer consecutive hours.
Resident physicians worked 10 percent fewer total hours per week during the RCWR compared to the EDWR and obtained significantly more sleep per week. Weekly sleep duration increased nearly four hours overall in the RCWR as compared to the EDWR.
The authors note that the RCWR schedule was implemented differently across the six hospitals and that more information is needed about optimal scheduling practices that ensure enough opportunity for residents to sleep.
“There is a compelling need for the design of schedules that enable sufficient sleep in settings that require safety-sensitive 24-hour operations,” said corresponding author Laura Barger, PhD, an associate physiologist in the Division of Sleep and Circadian Disorders. “These findings extend the evidence from our previous single-site study, provide data on more senior resident physicians, and indicate that eliminating extended-duration shifts may improve sleep duration for senior resident physicians.”
Funding for this work was provided by the National Heart, Lung, and Blood Institute (U01-HL-111478 and U01-HL-111691), National Institutes of Health (K24-HL-105664, R01-HL-128538, R01-HL-114088, R01-GM-105018, R21-HD-086392, P01-AG-009975 and NSBRI HFP-02802, HFP-0006, and HFP-04201) and the National Institute of Occupational Safety and Health (R01-OH-010300).
Paper cited: Barger, L et al. “Effects on Resident Work Hours, Sleep Duration and Work Experience in a Randomized Order Safety Trial Evaluating Resident-physician Schedules (ROSTERS)” Sleep
What Happens to Young Adults After a First Heart Attack?
Study finds that the vast majority of patients with familial hypercholesterolemia still had elevated cholesterol levels a year later, highlighting an opportunity for more aggressive treatment
Heart attacks among adults younger than 50 years of age are on the rise. In fact, the proportion of very young people has been increasing, rising by 2 percent each year for the last 10 years, according to a team of investigators a Brigham and Women’s Hospital who are focused on studying heart attacks among young adults. The research team is now investigating why, by evaluating both risk factors and outcomes for this population in order to help prevent heart attacks in the first place. In a paper published today in the Journal of the American College of Cardiology, the team reports on the prevalence of familial hypercholesterolemia (FH), a genetic disorder that results in high cholesterol, and outcomes for patients. Investigators have found that nearly one in 10 patients who suffer a first heart attack before age 50 had FH, and many continued having elevated cholesterol levels a year after their first heart attack. Many were not on a statin therapy before their first heart attack, highlighting opportunities for prevention and more aggressive treatment for those at risk.
“One of the challenges of familial hypercholesterolemia is that it is under-recognized and under-treated,” said corresponding author Ron Blankstein, MD, a preventative cardiology specialist and associate director of the Cardiovascular Imaging Program at the Brigham. “Only about half of the FH patients in our study were on a statin therapy before their first heart attack, and many were not treated aggressively following their event. Intervening to lower cholesterol could mean preventing not only subsequent heart attacks but first heart attacks, too.”
Blankstein and colleagues collected data on all patients at the Brigham and Massachusetts General Hospital who had suffered a heart attack before age 50 between 2000 and 2016. Using the Dutch Lipid Clinic (DLC) Network criteria, the team identified those patients with FH and used electronic medical records to determine cardiovascular risk factors as well as what medications the patients had been taking prior to their heart attack and what medications were prescribed at discharge.
Blankstein and colleagues found that nearly 1 in 10 young adults who had suffered a heart attack met the clinical definition for FH. Of those who had elevated LDL cholesterol (greater than or equal to 160 mg/dl), that proportion increased to 4 out of every 10. And among those who had both family history of premature coronary artery disease and high cholesterol, the proportion was 6 in 10. On average, FH patients had LDL cholesterol levels of 180 mg/dl at the time of their heart attack, and 43 percent were not on a statin therapy.
Following their first heart attack, only 49 percent of FH patients were prescribed a high-density statin therapy. One year after their heart attack, most had elevated cholesterol levels, with 43 percent having cholesterol levels greater than 100 mg/dl and 82 percent having cholesterol levels above 70 mg/dl.
Over 11 years of follow-up, 10 percent of FH patients died.
The team notes that the underutilization of high-intensity statin therapy after a first heart attack was not unique to FH patients, and that there are opportunities for more aggressive lipid-lowering therapy for young FH and non-FH patients alike.
“It’s important for both providers and patients to be aware of the real benefit associated with reducing cholesterol. It’s important to do so after a heart attack, but even before, if a patient has risk factors, there’s an important opportunity to avoid heart attacks through aggressive therapy,” said Blankstein. “However, there is also an enormous need to improve other risk factors. Our team is examining both modifiable risk factors, such as smoking, being overweight, or having an elevated blood pressure, as well as well as non-modifiable factors such as genetics. But in this study, we find clinically defined FH in only 1 in 10 young patients who have had a heart attack. “Other factors beyond FH seem to play a much larger role in explaining why individuals in our study cohort experienced a myocardial infarction at a young age.”
This work was funded in part by Amgen, Inc. via a grant to Brigham and Women’s Hospital. Authors of this work are supported by grants from the National Institutes of Health (5T32HL094301. T32HL007604.). Blankstein has served on the advisory board of Amgen, Inc.; and has received research support from Amgen, Astellas, and Sanofi. Co-authors of this work have been employed by, hold stock in, consulted for, and received grant support from Amgen, AstraZeneca, Merck, Pfizer and other pharmaceutical companies. For a complete listing of disclosures, please visit https://doi.org/10.1016/j.jacc.2019.02.059
Paper cited: Singh A, et al. “Familial Hypercholesterolemia Among Young Adults With Myocardial Infarction” JACC DOI: 10.1016/j.jacc.2019.02.059
What Are the Neurological Side Effects of CAR T-Cell Therapy?
Researchers report complex neural toxicities observed after CAR-T treatment for blood cancers
The recent advent of chimeric antigen receptor (CAR) T-cell therapy has revolutionized the clinical treatment of cancer. Under the umbrella of immunotherapy, CAR T-cell treatment trains and strengthens a patient’s own immune system to attack tumors. Early successes in clinical trials have led to approval of the treatment for recurrent blood cancers, including leukemia and lymphoma.
Despite the therapeutic successes of CAR T-cell therapy, the intervention carries the risk of severe side effects. These include neurotoxicity, which can result in headache, confusion, and delirium, among other neural changes. These debilitating effects remain poorly understood and characterized. A team at Brigham and Women’s Hospital recently cataloged the neurological symptoms of patients who had received CAR T-cell therapy to better understand its neurotoxic side effects. While neurological symptoms were prevalent — 77 percent of patients experienced at least one symptom — they were also temporary. The findings are published in Brain.
“The mechanism underlying CAR T-cell-associated neurotoxicity is unknown and symptoms can be very hard to predict,” said lead author Daniel Rubin, MD, PhD, of the Department of Neurology at the Brigham. “We conducted this study to better define the specific neurologic symptoms experienced by patients after CAR T-cell therapy.”
To define clinical symptoms of CAR-T-associated neurotoxicity, the team conducted an observational cohort study of 100 lymphoma patients admitted to the Dana-Farber/Brigham and Women’s Cancer Center for CAR T-cell therapy between 2015 and 2018. The team evaluated symptoms from the start of CAR T-cell therapy infusion through two months’ post-infusion. In addition, all diagnostic assessments, including laboratory tests and imaging scans, were reviewed.
“We shared a few clinical cases early in the therapies which were very severe and unusual from a neurological standpoint,” said senior author Henrikas Vaitkevicius, MD, of the Department of Neurology. “This sparked an interest to collaborate with oncology and T-cell therapy groups, and allowed us to evaluate the majority of patients prospectively rather than retrospectively.”
Their findings reveal the widespread prevalence of neurological symptoms after starting CAR-T therapy. The most prevalent symptom was encephalopathy, a type of brain disease that causes confusion, but additional symptoms such as headache, tremor, weakness and language dysfunction were also observed. Importantly, most of these effects were reversible, and symptoms almost always resolved over time.
In addition, the researchers observed a unique pattern of activity, or inactivity, in their study. The neurological deficits associated with therapy often originated from areas which appeared metabolically silent. This finding carries important implications for the clinical assessment of neurotoxicity and the use of imaging.
“Despite the common occurrence of neurologic symptoms, imaging studies such as MRI, which serve as a cornerstone of neurologic diagnosis, were almost always normal,” remarked Rubin. “In contrast, diagnostic studies that more directly evaluated neuronal functioning, like EEG and PET scan, could reliably detect and predict neurologic dysfunction.”
As a next step, investigators are building and validating a model for more accurate scoring and diagnosis of CAR T-associated neurotoxicity.
No funding was received towards this work. Co-authors report consulting for Kite, Novartis, Precision Biosciences, Humanigen, Pfizer, Bayer, and Celgene.
Paper cited: Rubin D et al. “Neurological toxicities associated with chimeric antigen receptor T-cell therapy” Brain DOI: 10.1093/brain/awz053