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BRIGHAM’S ENDOCRINOLOGY CHIEF REFLECTS ON RECENT SUCCESSES

Source: Brigham and Women's Hospital
Date: 2/3/2021
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Brigham and Women’s Hospital’s Division of Endocrinology, Diabetes and Hypertension cares for patients with a wide range of hormonal and other related disorders, including diabetes, hypertension and thyroid disease. Division Chief Ursula B. Kaiser, MD, recently discussed some of her group’s accomplishments and how the COVID-19 pandemic has affected physicians and other health care providers in the division.

In addition to her leadership role at the Brigham, Dr. Kaiser serves on the National Institutes of Health (NIH)/National Institute of Child Health and Human Development Board of Scientific Counselors, as deputy editor-in-chief of The Journal of Clinical Endocrinology and Metabolism and as director of the Brigham Research Institute.

Facing the Challenges of COVID-19

Although endocrinology is not the specialty that most people think of first with regard to treating COVID-19, members of the division have helped care for those who were hospitalized.

“Many patients with severe cases of COVID-19 have underlying endocrine and metabolic disorders, and those can be profoundly exacerbated by the disease,” Dr. Kaiser explained. “Many critically ill patients with COVID-19 and underlying diabetes became profoundly hyperglycemic with severe insulin resistance, and we had to come up with completely new treatment protocols for them.”

Division members also helped lead the way in addressing the challenges of the pandemic to the broader endocrinology community. These included Marie E. McDonnell, MD, who co-authored several publications providing guidance for management of patients with diabetes mellitus and COVID-19. Brigham endocrine faculty and fellows also stepped in to help care for patients with COVID-19 when extra providers were needed.

Dr. Kaiser noted that the pandemic has substantially changed care delivery through an expanded use of telemedicine. “I was very proud of how quickly our endocrine faculty adapted,” she said. “Endocrinology is a field that’s well-suited to virtual care.”

She expects virtual care will continue to have an important role going forward because it offers many advantages to patients with chronic health conditions who need to be seen often. In addition to reducing the risk of exposure to the virus that causes COVID-19, telemedicine lessens the need for patients to take time off from work. This can translate to fewer missed or canceled appointments and hence improved, more regular and more frequent care.

Collaborative Programs to Address Obesity

Much progress has been made in supporting patients who struggle with weight management, weight control and obesity, Dr. Kaiser said. Within the Brigham’s Center for Weight Management and Wellness, division members work closely with Brigham bariatric surgeons, gastroenterologists and experts in other areas to provide comprehensive care for these patients.

“The Brigham has recognized that weight control is a major challenge for many people,” Dr. Kaiser said. “This is especially true for disadvantaged patients and underserved minority groups.” Many studies have shown higher rates of obesity in Black and Latinx populations compared with whites, she noted. One reason for this is socioeconomic status, which can impact access to fresh, healthy foods such as fruits and vegetables.

New efforts in weight management and wellness are being instituted not only at the main hospital, but also in critical satellite locations throughout the Boston area. “We’re going where there is the greatest need for these services, due to a higher number of people in these populations struggling with obesity,” Dr. Kaiser said.

A Focus on Interdisciplinary Initiatives

Dr. Kaiser, who recently received the Endocrine Society’s 2021 Sidney H. Ingbar Award for Distinguished Service and has been named president-elect of the society for 2021, highlighted several other interdisciplinary programs that she is excited about. These include new efforts in thyroid care, particularly for people with thyroid nodules and thyroid cancer.

Furthermore, division members are collaborating with colleagues in radiology and oncology to conduct laboratory research and to achieve new advances in diagnosis and clinical care. For example, thyroid specialists at the Brigham have been at the forefront of using gene-expression classifiers for preoperative risk assessment. They also have a multidisciplinary clinic, in which radiologists aid in preoperative diagnosis and surgeons aid in perioperative care and management.

Adrenal disorders is another area where the division continues to play a leading role. “Our Center for Adrenal Disorders brings in patients not only from around the United States, but international patients as well,” Dr. Kaiser said. This partnership among the Brigham, Boston Children’s Hospital and Dana-Farber Cancer Institute (DFCI) is focused on patient care along with basic and translational research.

Accolades for Division Members

Dr. Kaiser noted a number of honors and awards received in the past year by members of the Division of Endocrinology, Diabetes and Hypertension, including:

  • Erik K. Alexander, MD, was appointed as the inaugural Brigham Health vice president of education.
  • Mehmet Furkan Burak, MD, was the recipient of the 2020 Endocrine Society Early Investigator Award.
  • Ole-Peter R. Hamnvik, MBBCH, received the Gail Backus Endocrinology Faculty Clinical Teaching Award and the Ambulatory Lecturing Attending Award.
  • Sylvia Kehlenbrink Oh, MD, was named chair of the International Alliance for Diabetes Action and was the invited Plenary Speaker at the IDF Congress 2019.
  • Meryl Susan LeBoff, MD, was awarded the 2020 American Association of Clinical Endocrinologists: ACE Distinction in Endocrinology Award in recognition of advancing the understanding of endocrinology through research and education.

A number of research grants also were awarded to division faculty, including a Dubai Harvard Foundation for Medical Research Fellowship, an NIH Specialized Center of Research Excellence (SCORE) in Women’s Health grant and an NIH Building Interdisciplinary Research Careers in Women’s Health K12 award.

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NEUROENDOCRINE COLLABORATION FOCUSES ON CUSHING’S DISEASE

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Cushing’s disease, caused by a pituitary adenoma, is the most common type of endogenous excessive cortisol production and results in Cushing’s syndrome. This is a particularly challenging disease to diagnose and treat. Surgery to remove the pituitary tumors that drive the disease can bring it under control, but these tumors can’t always be completely removed. In addition, they frequently recur, even a decade or more after surgery.

Brigham and Women’s Hospital has a long history of expertise in Cushing’s, going back to neurosurgeon Harvey Cushing, who founded the Department of Neurosurgery in 1913 and after whom the disease and syndrome are named. Now a unique collaboration between the Brigham’s Division of Endocrinology, Diabetes and Hypertension and its Department of Neurosurgery is taking a deeper look at why these tumors are so often unmanageable.

Part of this research is focused on studying the genetic underpinnings of these tumors. One of the goals is to develop drugs for treating the disease. Investigators are also looking for better ways to diagnosis it and to prevent recurrence or detect it at an earlier stage.

“Cushing’s disease is one of the most difficult things that we as neurosurgeons face,” said Edward R. Laws, MD, director of the Brigham’s Pituitary and Neuroendocrine Center.

“Every day that a patient lives with excess cortisol, it is doing damage to their bodies and their lives. If we can’t succeed in bringing those cortisol levels down, we’re not doing our jobs.”

Searching for Targetable Genetic Drivers

The first challenge of Cushing’s disease is getting a correct diagnosis. “In addition to treating patients with Cushing’s disease, we also work with patients who have an excess of cortisol that’s not due to pituitary disorders,” said physician-scientist Ana Paula Abreu Metzger, MD, PhD, co-director of the Endocrine Genetics Clinic at the Division of Endocrinology, Diabetes and Hypertension. “We first have to find out what’s causing overproduction of cortisol, because the tumors secreting ACTH that cause Cushing’s disease can be very small and hard to detect.”

In the laboratory, Dr. Abreu Metzger is also studying a more aggressive type of tumor in the pituitary gland that does not secrete ACTH, called silent ACTH pituitary adenomas. “They come from the same lineage as the tumors causing Cushing’s disease but become clinically distinct,” she said. “We want to understand the genetic drivers of these tumors to develop a more personalized approach to treating them.”

Her expectation is that by learning more about the signaling pathways that drive these tumors, drugs can be developed to treat them, similar to the way targeted therapies for cancer increasingly are being employed. She’s performing whole-exome sequencing on both somatic and germline DNA to identify driver mutations as well as RNA sequencing to determine the effects that the genetic changes that are observed have on gene expression.

Searching for Accurate Biomarkers

Dr. Laws is also working with endocrinologist Le Min, MD, PhD, associate director of neuroendocrinology in the Division of Endocrinology, Diabetes and Hypertension, to study postoperative cortisol levels as a biomarker for predicting remission versus recurrence after surgery. Their research on this topic was recently published in The Journal of Clinical Endocrinology & Metabolism.

“Patients always ask us what the chance is that their disease will come back,” Dr. Min said. “Our goal is to identify a biomarker that can reliably predict long-term remission of postoperative Cushing disease.” He added that their research has found that postoperative day one morning cortisol level has significant correlation to the recurrence of Cushing’s disease. This measure is useful as guidance for clinicians performing patient follow-up after surgery, he said.

Drs. Laws, Min and Abreu Metzger also are studying corticotroph hyperplasia, which has the same symptoms as Cushing’s disease caused by pituitary tumors, despite the fact that no pituitary tumor can be detected. Because this condition is much more difficult to manage surgically, it underscores the importance of developing better medical treatments that can target the overproduction of ACTH or related products.

The symptoms of Cushing’s disease, including weight gain, diabetes and high blood pressure, can wreak havoc on a patient’s health. But according to Dr. Laws, some of the most devastating effects on patients are the psychological ones, including depression and anxiety.

“Patients usually know when their disease has recurred even before tumors show up on scans, because they remember what it feels like,” he noted. “It’s heartbreaking for them when they don’t stay in remission, and we want to do everything we can to be able to help.”

At the end of the day, the aim of studying why these tumors are often so difficult to cure is what drives this exceptional research program forward.

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A CASE STUDY: TAVR IN PATIENT WITH CONGENITAL HEART DEFECT

Source: Brigham and Women's Hospital
Date: 11/24/2020
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Over the past decade, transcatheter aortic valve replacement (TAVR) has evolved from a high-risk procedure to one that has become a standard of care. Each year, thousands of patients undergo this minimally invasive procedure.

Recently, however, a multidisciplinary team of specialists at Brigham and Women’s Hospital planned and performed a TAVR procedure that was anything but standard: The 78-year-old patient had a congenitally corrected transposition of the great arteries (cc-TGA), a rare condition.

In 2008, the patient’s cardiologist in Maine referred them to the Brigham for replacement of the tricuspid valve. The valve, which was on the left side of the heart rather than the right due to their cc-TGA, was no longer able to withstand the pressure of essentially functioning as a mitral valve. When the patient was referred to the Brigham again in 2020, the ventricle that supplied blood for systemic circulation was found to be weak. Further studies revealed the aortic valve had developed severe calcification and become severely stenotic, resulting in pressure overload in the ventricle.

“The patient was not felt to be a good surgical candidate by the doctors in Maine because of the prior operation, the complexities of the congenital condition and the patient’s age,” said cardiovascular medicine specialist Pinak Bipin Shah, MD, director of the Interventional Cardiovascular Disease Training Program and director of the Cardiac Catheterization Laboratory at the Brigham. “The patient was sent to us to determine if we could safely perform TAVR.”

Congenital Heart Defect Heightens Risk of Complications

Upon arrival at the Brigham, the patient underwent an extensive evaluation in conjunction with several medical teams: cardiac imaging, interventional cardiology, cardiac surgery, adult congenital heart disease and advanced heart disease. “We put our heads together to figure out what diagnostic testing was needed and to come up with a plan for the patient’s survival,” Dr. Shah said.

The patient’s congenital defect meant that undergoing TAVR was especially high-risk. “The anatomy of the heart was rather atypical,” said Tsuyoshi Kaneko, MD, a surgical director of the Structural Heart Disease Program and a cardiac surgeon who specializes in endovascular approaches. “The aortic valve was more toward the left side of the heart. But with the expertise of our Structural Heart Disease Program as well as the anesthesiology team, we were able to do the procedure safely.”

The patient’s heart failure likely was due to the combination of the cc-TGA and the stenotic aortic valve. In people with cc-TGA, the right ventricle must maintain systemic pressure for the whole body, not just the pressure needed to pump blood to the lungs.

“Over time, that right ventricle wears out. It doesn’t have the motor to sustain the blood supply to the whole body,” Dr. Kaneko said. “The patient’s heart did well with this condition for 78 years, but once the ventricle began to fail, they deteriorated significantly over a relatively short period of time.”

Collaboration Leads to Successful TAVR Procedure

During the TAVR procedure, which was done in the Brigham’s catheterization laboratory, the patient was sedated but did not receive general anesthesia. The complex anatomy that switched the ventricle and the great arteries made the procedure complicated. However, thanks to extensive imaging and preprocedural planning, a balloon-expandable TAVR prosthesis was deployed safely. The team also placed an embolic protection device in from the patient’s right arm, as they were worried about stroke risk due to the high levels of calcium in the blood vessels.

A very limited number of cases of people with cc-TGA undergoing TAVR have been reported, and the Brigham team believes this patient is the oldest. “We had a total of five teams involved,” Dr. Kaneko said. “Although the procedure carried high risk, we were confident that by leveraging the expertise of all the teams involved, the benefits for this patient would greatly outweigh the risks.”

A postoperative echocardiogram revealed the gradient across the valve was much better than what the patient had had before. The patient required dobutamine for the first few days due to their poor ventricular function but was discharged four days after the procedure. At the time of discharge to Maine, the patient reported tremendous symptomatic relief, was eating and sleeping well and no longer felt short of breath with exertion. Fatigue also improved dramatically.

“The fact that we treated a patient who would have had no treatment option a decade ago shows the vast treatment possibilities offered by our team,” Dr. Kaneko concluded.

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BRIGHAM LEADS THE WAY IN BRAIN CIRCUIT THERAPEUTICS

Source: Brigham and Women's Hospital
Date: 11/24/2020
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Brigham and Women’s Hospital recently opened its innovative Center for Brain Circuit Therapeutics. A joint clinical, research and education initiative, the new center brings together experts from neurology, psychiatry, neurosurgery and neuroradiology to develop innovative treatment methods for brain disorders that don’t respond to medication.

“This center was created to leverage what’s been a long-term initiative on the part of the Brigham: to develop unique approaches for taking care of brain diseases,” said Michael D. Fox, MD, PhD, director of the center. He is also the Raymond D. Adams Distinguished Chair in Neurology and the Kaye Family Director of Psychiatric Brain Stimulation.

A world-renowned investigator in brain imaging and brain stimulation, Dr. Fox recently joined the Brigham from Beth Israel Deaconess Medical Center. He has published many studies on the identification of human brain circuits that underlie neuropsychiatric symptoms.

The Center for Brain Circuit Therapeutics will provide treatments including deep-brain stimulation (DBS), focused ultrasound (FUS) and transcranial magnetic stimulation (TMS). Through its clinical trials program, the center will also seek to expand the applications for these therapies and study new treatment approaches. Translational research will be aimed at learning more about brain circuitry and lesion network mapping, among other investigations, to advance understanding of how the brain is wired and how that wiring could be targeted to treat different brain diseases.

In addition, the center will focus on training the next generation of leaders in neurology, psychiatry, neurosurgery and neuroradiology so that they can provide these therapies to patients.

Combining Circuit-Focused Treatments With Medication

Brain circuit-focused treatments work in a completely different way than medication. Rather than targeting chemical changes in the brain, they target specific anatomical brain regions or brain networks that are malfunctioning. The Brigham is a leader in many of these approaches, including MRI-guided FUS, which can noninvasively treat tissues deep in the brain. Furthermore, thanks to its advanced MRI technologies, the Brigham offers asleep DBS within an MRI scanner in addition to traditional awake DBS.

“Medication is still the first approach for almost all neurologic and psychiatric symptoms, but these symptoms can become refractory over time, or may not respond at all,” Dr. Fox said. “Patients who don’t respond to medication are ideal for referral to this center.”

Dr. Fox estimated that only one in five Parkinson’s patients who could benefit from DBS currently are referred for this therapy, even though studies show many of these patients do better after receiving it. He said that part of the problem may be a lack of understanding among other medical professionals about how much these therapies can improve outcomes.

“When someone comes to us for treatment, we work as a team with the neurologist or psychiatrist who referred them,” Dr. Fox explained. “The treatments we offer are not a replacement for medical therapy, and communication between our team and the patient’s other doctors is very important for successful treatment.”

Making TMS Treatments More Precise

Shan H. Siddiqi, MD, a neuropsychiatrist and director of psychiatric neuromodulation research for the center, is leading much of the research on TMS. He is currently leading a clinical trial looking at whether the treatment can be modulated to more specifically treat depression versus anxiety based on which circuit in the brain is being targeted with the magnetic stimulation.

“In the past, TMS has been aimed based on scalp landmarks,” he said. “We now know that imaging can help to determine whether we can more precisely target this therapy to choose the right target for the right patient.”

Dr. Siddiqi noted that besides providing better treatment for patients who don’t respond to medication, TMS may also be preferred in some cases because it has milder side effects. But he pointed out that insurance usually does not cover TMS unless patients have tried antidepressant medications.

The large amounts of data generated by research into brain circuits, including pinpointing specific areas to make treatment more personalized, require computational approaches. “The purpose of the Center for Brain Circuit Therapeutics more broadly is to break down all this research and data to find better real-world treatment targets that we can influence with these various approaches,” Dr. Siddiqi said.

“This initiative involves people from many different areas across the Brigham, including some of the best neurosurgeons, psychiatrists and other experts anywhere in the country,” Dr. Fox concluded. “It is the strength of this collection of individuals that makes this program so exciting.”

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EXAMINING IMPACT OF RACE IN STAGING CHRONIC KIDNEY DISEASE

Source: Brigham and Women's Hospital
Date: 11/12/2020
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An equation used for over a decade to estimate kidney function and stage chronic kidney disease (CKD) can underestimate kidney function and lead to gaps in care delivery in African-American patients, according to research led by investigators at Brigham and Women’s Hospital.

The researchers say the “race multiplier factor,” which is used as part of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) equations to estimate kidney function, can contribute to health disparities in African Americans with CKD. This is particularly important because African-American patients with CKD are known to have worse clinical outcomes with respect to hypertension control, timely nephrology referral, dialysis fistula or graft placement, adequate dialysis treatment and transplantation access.

“The race multiplier is something that all of us were taught to use during medical school and residency training,” said Mallika L. Mendu, MD, MBA, a Brigham nephrologist and senior author of the study, published in October in the Journal of General Internal Medicine (JGIM). “I was surprised to learn how many patients are impacted by the use of the race multiplier and its potential implications on care delivery, particularly referral to kidney transplantation.”

Changing the Math Results in Reclassification of CKD

The calculation in question uses serum creatinine levels to obtain the estimated glomerular filtration rate (eGFR). To account for differences among individuals, the equation includes factors for age, sex, weight and race to improve statistical precision.

Earlier research suggested African Americans had higher measured glomerular filtration rate with the same creatinine levels, leading to the adjustment. But there was no clear biological explanation for why it would be different, Dr. Mendu said.

The new JGIM study led by Dr. Mendu analyzed data and electronic health records from 56,845 patients who were in the Partners HealthCare system’s CKD registry as of June 2019; 2,225 of them self-identified as African American. The researchers recalculated eGFR for these patients, removing the race multiplier of 1.159, and classified the severity of the patients’ disease based on the revised eGFR numbers.

They found the race multiplier essentially designated African-American patients as being healthier than people of other races who had the same clinical findings. Overall, one in three African-American patients was reclassified to a more severe stage of disease when the multiplier was removed. One-quarter of them were moved from Stage 3 to Stage 4.

Differences in staging of patients with more advanced disease ultimately could affect whether they were considered for transplant surgery, the researchers said. Notably, 64 African-American patients were reclassified to an eGFR less than or equal to 20 (a common threshold for kidney transplant referral), but none had a referral. This indicated to Dr. Mendu and the co-authors that there were real, potential adverse consequences to using the race multiplier that could exacerbate disparities.

A Focus on Reducing Health Disparities

Leaders at the Brigham stopped using the race multiplier in June based on preliminary findings from the JGIM study. The team’s research has caught the attention of policymakers, and other hospital systems have said they will refrain from using the race multiplier as well.

Dr. Mendu said the findings from this study may help advance the use of cystatin C as a marker for CKD instead of creatinine. She considers cystatin C to be another acceptable measure of eGFR, as this test does not use a race adjustment factor. The Brigham has always been a leading institution when it comes to CKD treatment, she noted, adding that changing the way patients with CKD are staged and ensuring health equity are other key areas in which the institution can play a pivotal role.

“There are so many complicated issues related to race in medicine and health disparities, something that the COVID-19 pandemic has made very clear,” Dr. Mendu concluded. “But this is one problem we think is quite solvable.”

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FOCUS ON FAMILY MEMBERS POINTS TO NEW CLUES ABOUT IPF

Source: Brigham and Women's Hospital
Date: 11/16/2020
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Idiopathic pulmonary fibrosis (IPF) is more common than once thought. According to the American Lung Association, over 130,000 people are affected in the United States and about 50,000 new cases are diagnosed each year.

“IPF has a mortality rate that’s worse than that of most cancers, yet it gets far less attention,” said Gary “Matt” Hunninghake, MD, director of the Interstitial Lung Disease Program at Brigham and Women’s Hospital. “Because of that, our group has been trying to find ways to detect this disease at its early stages, which we think could eventually lead to better outcomes for those at risk.”

IPF often does not cause symptoms until it’s at an advanced stage. So, to learn more about what early disease looks like and how it behaves, researchers took advantage of a distinct feature of the disease: About 30 to 40 percent of cases have a strong hereditary component. This is different from other common lung diseases such as emphysema and chronic obstructive pulmonary disease, which are overwhelmingly caused by smoking and other environmental factors.

Looking to Relatives for Clues

In May 2020, Dr. Hunninghake had a study published in the American Journal of Respiratory and Critical Care Medicine looking at family members of people with IPF. The researchers surveyed 105 first-degree relatives of patients with IPF. The family members were screened with questionnaires, pulmonary function tests, chest CTs, blood sampling for immunophenotyping, telomere length assessment and genetic testing.

The researchers found that 31 percent (33 individuals) had evidence of chest CT abnormalities, which may be a precursor to the more serious IPF. Their findings suggested that undiagnosed interstitial lung disease may be present in greater than one in six older first-degree relatives of IPF patients.

“These findings suggest that it would be rational to screen for IPF in close relatives,” Dr. Hunninghake said. “It also provides an opportunity for us to learn more about the earlier stages of IPF, if we can identify and follow these family members.”

A Focus on Preventive Care for IPF

According to Dr. Hunninghake, the ultimate goal of this research is to create better diagnostic methods and to eventually develop interventions for treating the disease early. “The paradigm is similar to the approach that’s been used over the years with cardiovascular disease,” he said. In the past, most people who had heart attacks experienced poor outcomes. Now, a significant component of cardiovascular disease care and research is focused on preventive cardiology.

“We think that same preventive model could be applied to IPF in the future,” he noted. “We can identify those who are at highest risk of having bad outcomes so that we can intervene.”

According to Dr. Hunninghake, studies published in 2014 demonstrating that pirfenidone and nintedanib showed some efficacy in treating IPF marked a turning point for treating the disease. “These drugs don’t provide a cure, but they do slow down the progression of the IPF by targeting fibrotic pathways,” he said.

Dr. Hunninghake and his colleagues, whose previous research was funded by the National Heart, Lung, and Blood Institute, have applied for additional funding to continue studying IPF in families. “We hope that one day we can identify interventions—not only pharmaceuticals, but lifestyle interventions—that might benefit people with this disease,” he concluded.

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UNCOVERING RISKS FOR SEVERE AKI IN COVID-19 PATIENTS

Source: Brigham and Women's Hospital
Date: 11/12/2020
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Infection with SARS-CoV-2 can affect any organ system in the body, and acute kidney injury (AKI) is common in people with more severe cases of COVID-19. Researchers at Brigham and Women’s Hospital recently led a study that looked at critically ill patients with COVID-19 and identified both patient- and hospital-level risk factors for development of AKI treated with dialysis.

“Our study is different from others that preceded it because we specifically focused on what we thought was the most clinically meaningful form of AKI — kidney injury that’s severe enough to require dialysis,” said Shruti Gupta, MD, MPH, a Brigham nephrologist and first author of the study published in October in the Journal of the American Society of Nephrology.

The investigators used data from 3,099 critically ill patients with COVID-19 admitted to intensive care units (ICUs) at 67 hospitals, primarily in March and April. The analysis was part of Study of the Treatment of Outcomes in Patients with COVID-19 (STOP-COVID), a multicenter initiative that includes geographically diverse hospitals across the United States.

Analysis revealed that slightly more than one in five (637 patients) required dialysis within 14 days of ICU admission, and more than half of those who required dialysis (350 patients) died within 28 days. Of the 216 patients with AKI treated with dialysis who survived to hospital discharge, more than one in three (73 patients) still required dialysis at the time of discharge. In addition, 39 patients were still dependent on dialysis 60 days after their ICU admission, illustrating the long-lasting effects that COVID-19 can have on the kidneys.

Preexisting Conditions Linked to AKI

The researchers identified several preexisting conditions in COVID-19 patients that were linked to a higher risk of developing severe AKI. These included high blood pressure, diabetes, male sex, non-White race and a higher body mass index. COVID-19-specific features linked to severe AKI were higher levels of D-dimer and greater severity of hypoxemia.

“We obviously don’t have control over preexisting conditions,” Dr. Gupta said. “But there are ways we can optimize the treatment of hospitalized patients with COVID-19 so that they are likely to do better with regard to their renal function.”

These measures include careful management of patients on ventilators so that they don’t become hypotensive, according to Dr. Gupta. She added that AKI also can be minimized by avoiding major shifts in fluids that can put strain on the kidneys — for example, through more mindful use of infusions and diuretics.

Diverse Factors Influence AKI Incidence

The study also looked at hospital-level risk factors. The investigators found that the percentage of patients who developed AKI treated with dialysis varied widely, from 7.5 percent at the lowest-risk hospitals to 44.6 percent at the highest. Patients admitted to hospitals with greater regional density of COVID-19, which the investigators used as a surrogate for hospital strain, were less likely to be treated with dialysis.

“There might have been issues related to strain or availability of resources that prevented people from getting treated,” Dr. Gupta said. However, she cautioned that there were several other potential explanations that could account for this finding, including differences in patient populations and severity of illness that may not have been captured.

As nephrologists and other specialists continue to treat COVID-19 patients, they’re learning more about the underlying mechanisms of the disease. Some degree of kidney damage may be caused by tubular injury and possible direct viral invasion. In addition, there are issues likely related to inflammation and cytokine storm.

“We recently found in another study published in JAMA Internal Medicine that early use of the interleukin-6 inhibitor, tocilizumab, is associated with a 30 percent reduction in mortality among critically ill patients with COVID-19,” said David E. Leaf, MD, MMSc, a nephrologist at the Brigham and senior author on both studies. “It would be interesting to see if drugs such as tocilizumab may reduce rates of AKI in patients with COVID-19, perhaps due to lowering of the inflammatory burden.”

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RESEARCH EFFORTS FOCUS ON ASTHMA-COPD OVERLAP

Source: Brigham and Women's Hospital
Date: 11/9/2023
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Asthma and chronic obstructive pulmonary disease (COPD) each affect millions of people in the United States. So it’s not unexpected that a subset of patients would have both lung conditions. Yet surprisingly, little is known about the science of what’s called asthma-COPD overlap, or ACO. Experts at Brigham and Women’s Hospital are focused on changing that.

“From a clinical perspective, primary care doctors, respiratory specialists and emergency departments see these patients all the time. They know how to recognize when someone has both conditions,” said Craig P. Hersh, MD, MPH, a specialist in pulmonology and critical care medicine at The Lung Center at the Brigham. “But from a scientific perspective, much less is known.”

Based on observational studies, experts believe anywhere between 15 and 45 percent of people with COPD have a previous asthma diagnosis. One effort that promises to help researchers get a better handle on those numbers is COPDGene, a National Institutes of Health-sponsored, multicenter study in which Hersh is a site co-principal investigator at the Brigham. The study has enrolled 10,000 smokers with and without COPD to follow them longitudinally.

Seeking a Clearer ACO Diagnosis

The first step in studying these patients is learning to identify them. “Right now, we don’t have a clear way to do that,” Dr. Hersh said. “As part of the COPDGene study, we’re collecting data on CT scans, lung function and blood samples, which we think will help to find markers that are unique to the subset of patients with ACO.”

The lack of clear diagnostic markers has been a major impediment to clinical research. In fact, Hersh noted, a suspected diagnosis of ACO has traditionally been a disqualifier for clinical trials: Patients with an asthma diagnosis are excluded from COPD trials, and patients with a COPD diagnosis are excluded from asthma trials. Because people with a history of asthma were not excluded from COPDGene, the effort provides a unique opportunity.

Using what Dr. Hersh called a “fairly strict” definition, investigators have discovered that about 12 percent of people enrolled in the observational study have asthma-COPD overlap. “We’ve found that it’s more common in women, which we already knew,” he said. “But we’ve also found that it’s more common in African Americans. That frequency wasn’t known, and it’s an important new finding.”

COPDGene Study: A Move Toward Precision Medicine

As the name suggests, the COPDGene study is also seeking genetic variants that could be linked to a predisposition to COPD. “We know that both asthma and COPD have genetic or hereditary influences, so we’ve been studying that overlap as well,” Hersh said. “To do these kinds of studies, you need very large patient populations, so we’re not there yet. But we do have some suggestive findings already.”

Another focus of COPDGene is to look for particular antibodies in the blood, although specific markers for ACO have not been found yet.

“There have been a lot of promising new treatments with asthma biologic therapies over the last several years, and there’s a lot of interest in figuring out if these medications would be useful for patients with ACO,” Dr. Hersh said. “If we can learn to define ACO based on biomarkers found on CT scans or in the blood, we may be able to more accurately apply precision medicine, offer these biologics or develop potential new medications for this important group of patients.

Dr. Hersh added that even before specific clinical trials for ACO are launched, having better diagnostic guidelines will have an impact on clinical care. “We could start using these biomarkers in clinical practice right away,” he concluded.

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CLINIC SCREENS HIGH-RISK PATIENTS TO REDUCE INCIDENCE OF ANAL CANCER

Source: Brigham And Women's - On a Mission
Date: 5/30/2023
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Screening guidelines for cervical cancer have been recognized for decades. But for other cancers linked to human papillomavirus (HPV), including anal cancer, cancer screening guidelines are not well-developed.

Since 2020, a unique Brigham and Women’s Hospital clinic has offered high-resolution anoscopy (HRA) to screen for anal dysplasia in people at increased risk of anal cancer due to HPV infection, HIV status, and other factors. The clinic aims to reduce the incidence of anal cancer in high-risk populations.

“The value of treating anal dysplasia to prevent anal cancer for the highest-risk patient population has now been established and is still being studied for lower-risk groups,” says colorectal surgeon James Yoo, MD, one of the two founders of the HRA clinic. “The field is still evolving, and more data are needed to determine the best practices. But this is clearly an area where we can make an impact in cancer prevention, especially for patients at higher risk.”

“As an infectious disease doctor, I’m obviously interested in the different diseases and complications that affect HIV patients,” says Jennifer A. Johnson, MD, a clinician-educator and the clinic’s other co-founder. “We know that people with HIV are one of the highest-risk groups for the development of anal dysplasia and anal cancer, making this an important population to focus on.”

A Collaborative Approach to Patient Care

Results from the phase 3 Anal Cancer–HSIL Outcomes Research (ANCHOR) trial, published in The New England Journal of Medicine in June 2022, demonstrated for the first time that treatment for anal high-grade squamous intraepithelial lesions reduced the progression to anal cancer when compared with active monitoring. Drs. Yoo and Johnson note that this study’s findings help illustrate the value of the Brigham’s HRA clinic.

“HRA requires special equipment that’s not commonly available as well as special training to learn how to perform the procedure and to know what to look for,” Dr. Yoo says. “In terms of what our clinic can offer, it’s relatively special.”

In addition to Drs. Yoo and Johnson, colorectal surgeon Ronald Bleday, MD, also participates in the clinic.

The clinic’s collaborative approach produces significant benefits for patients. Follow-up care may consist of a range of actions depending on what is found during the HRA exam. These include annual anal Pap smears, HRA exams offered on an annual or semiannual basis, ablation of dysplastic lesions, and more extensive surgical procedures.

HRA Offered as Simple Office Procedure

When a patient is referred to the clinic, they can have their HRA exam performed on their first visit. This makes scheduling less burdensome.

“The HRA procedure is very similar to a cervical colposcopy,” Dr. Johnson notes. “It requires no anesthesia beyond sometimes a local anesthetic. It is minimally invasive, doesn’t require any specific preparation on the patient’s part, and doesn’t affect their activities for the rest of the day.”

Beyond those with HIV, patients taking immune-suppressing drugs to treat autoimmune diseases may also be at increased risk of developing lesions caused by HPV. The leaders of the HRA clinic provide consultations to physicians both inside and outside the Brigham to help them identify which patients may benefit from enrollment in the clinic’s programs. The clinic also provides opportunities to counsel patients on topics like HPV vaccination.

“These visits provide a good opportunity to make sure we’re paying attention to any concerns the patients have about minimizing their cancer risks,” Dr. Johnson says.

“We have a pipeline of patients who come to us because their providers are aware of the need to screen for anal dysplasia,” Dr. Yoo adds. “One of our continuing roles is to educate other doctors about which patients they should send to us for evaluation.”