Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry . All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact [email protected].

Grandma was sitting in her chair in the corner of the living room, and her eyes were wide, filled with fear and suspicion as she glanced between me, Mom, and Papa. “They are out to get me,” she said, slightly frantic. She glanced down at her right hand, fixated on a spot on the dorsum. Gingerly lifting her arm, she angled her hand toward my mom’s face. “You see that? They have been conducting experiments on me. I AM THE QUEEN,” she sobbed, “and you are planning together” she said, directing her attention to Papa and me. In that moment, Grandma was convinced Papa and I were conspiring to assassinate her. It hurt to see my grandmother look at me with genuine fear in her eyes. It was overwhelming to watch her deteriorate from the person I had been accustomed to for most of my life to the paranoid individual shaking in front of me.

This was the first time I had really observed my grandmother experiencing acute psychosis. My mom explained to me at a young age that my grandmother had an illness in her mind. I noticed that compared to other people in my life, my grandmother seemed to express less emotion and changed topics in conversations frequently, but by having an understanding provided by my mother, my brother and I didn’t think much of it; that was just Grandma. She would occasionally talk about her experiences with hearing voices or people on the television talking about her. For the most part, though, she was stable; she was able to carry out cleaning, cooking, and watching her favorite shows.

That was until she turned 65 and started on Medicare for insurance. The government required her to trial a less expensive medication and wanted her family practitioner to adjust the medications she had been on for years. This decision was made by people unfamiliar with my grandmother and her story. As a result, my family struggled alongside Grandma for over a month as she battled hallucinations and labile emotions. Living in rural Ohio, she had no access to a psychiatrist or other mental health professional during this period. The adjustments to her medications, changes in her insurance coverage, and lack of consistent psychiatric care led to a deterioration of her stability. This was the only time in my life that I saw Grandma at a place where she would have needed to be hospitalized if the symptoms lasted much longer. I spent evenings sitting with her in that dark and scary place, listening, sympathizing, and challenging her distortions of reality. This experience laid the foundation for my growing passion for providing care and advocating for people experiencing mental illness. I observed firsthand how the absence of consistent, compassionate, and informed care could lead to psychiatric hospitalization.

In the past, my grandfather hid my grandmother’s diagnosis from those around them. This approach prevented my uncle from disclosing the same information to my cousins. I observed how they would look at her with confusion and sometimes fear, which was rooted in a lack of understanding. This desire to hide Grandma’s schizophrenia stemmed from the marginalization society imposed upon her. There were sneers, comments regarding lack of religious faith, and expressions that she was not trying hard enough. My grandparents decided together to inform their church of my grandmother’s illness. The results were astounding. People looked at my grandmother not with confusion but with sympathy and would go out of their way to check on her. Knowledge is power, and awareness can break down stigma. Seeing the difference knowledge could have on a church community further solidified my desire to educate not only patients and their family members but also communities.

Access is another huge barrier my grandmother has faced. There is a lack of referring and awareness as well as large geographic disparities of psychiatrists around my hometown. My grandmother has also had struggles with being able to pay for services, medication, and therapy. This shows the desperate need for more mental health professionals who are competent and knowledgeable in how social determinants of health impact outcomes. These factors contributed to my decision to pursue a Master of Public Health degree. I aspire to use this background to prevent what happened to my Grandma from happening to other patients and to be an advocate for enhanced access to services, improving community mental health and awareness, and promoting continuity of care to increase treatment compliance. That is what my Grandma has fostered in me as a future psychiatrist.

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry . All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact [email protected].

Grandma was sitting in her chair in the corner of the living room, and her eyes were wide, filled with fear and suspicion as she glanced between me, Mom, and Papa. “They are out to get me,” she said, slightly frantic. She glanced down at her right hand, fixated on a spot on the dorsum. Gingerly lifting her arm, she angled her hand toward my mom’s face. “You see that? They have been conducting experiments on me. I AM THE QUEEN,” she sobbed, “and you are planning together” she said, directing her attention to Papa and me. In that moment, Grandma was convinced Papa and I were conspiring to assassinate her. It hurt to see my grandmother look at me with genuine fear in her eyes. It was overwhelming to watch her deteriorate from the person I had been accustomed to for most of my life to the paranoid individual shaking in front of me.

This was the first time I had really observed my grandmother experiencing acute psychosis. My mom explained to me at a young age that my grandmother had an illness in her mind. I noticed that compared to other people in my life, my grandmother seemed to express less emotion and changed topics in conversations frequently, but by having an understanding provided by my mother, my brother and I didn’t think much of it; that was just Grandma. She would occasionally talk about her experiences with hearing voices or people on the television talking about her. For the most part, though, she was stable; she was able to carry out cleaning, cooking, and watching her favorite shows.

That was until she turned 65 and started on Medicare for insurance. The government required her to trial a less expensive medication and wanted her family practitioner to adjust the medications she had been on for years. This decision was made by people unfamiliar with my grandmother and her story. As a result, my family struggled alongside Grandma for over a month as she battled hallucinations and labile emotions. Living in rural Ohio, she had no access to a psychiatrist or other mental health professional during this period. The adjustments to her medications, changes in her insurance coverage, and lack of consistent psychiatric care led to a deterioration of her stability. This was the only time in my life that I saw Grandma at a place where she would have needed to be hospitalized if the symptoms lasted much longer. I spent evenings sitting with her in that dark and scary place, listening, sympathizing, and challenging her distortions of reality. This experience laid the foundation for my growing passion for providing care and advocating for people experiencing mental illness. I observed firsthand how the absence of consistent, compassionate, and informed care could lead to psychiatric hospitalization.

In the past, my grandfather hid my grandmother’s diagnosis from those around them. This approach prevented my uncle from disclosing the same information to my cousins. I observed how they would look at her with confusion and sometimes fear, which was rooted in a lack of understanding. This desire to hide Grandma’s schizophrenia stemmed from the marginalization society imposed upon her. There were sneers, comments regarding lack of religious faith, and expressions that she was not trying hard enough. My grandparents decided together to inform their church of my grandmother’s illness. The results were astounding. People looked at my grandmother not with confusion but with sympathy and would go out of their way to check on her. Knowledge is power, and awareness can break down stigma. Seeing the difference knowledge could have on a church community further solidified my desire to educate not only patients and their family members but also communities.

Access is another huge barrier my grandmother has faced. There is a lack of referring and awareness as well as large geographic disparities of psychiatrists around my hometown. My grandmother has also had struggles with being able to pay for services, medication, and therapy. This shows the desperate need for more mental health professionals who are competent and knowledgeable in how social determinants of health impact outcomes. These factors contributed to my decision to pursue a Master of Public Health degree. I aspire to use this background to prevent what happened to my Grandma from happening to other patients and to be an advocate for enhanced access to services, improving community mental health and awareness, and promoting continuity of care to increase treatment compliance. That is what my Grandma has fostered in me as a future psychiatrist.

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry . All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact [email protected].

Grandma was sitting in her chair in the corner of the living room, and her eyes were wide, filled with fear and suspicion as she glanced between me, Mom, and Papa. “They are out to get me,” she said, slightly frantic. She glanced down at her right hand, fixated on a spot on the dorsum. Gingerly lifting her arm, she angled her hand toward my mom’s face. “You see that? They have been conducting experiments on me. I AM THE QUEEN,” she sobbed, “and you are planning together” she said, directing her attention to Papa and me. In that moment, Grandma was convinced Papa and I were conspiring to assassinate her. It hurt to see my grandmother look at me with genuine fear in her eyes. It was overwhelming to watch her deteriorate from the person I had been accustomed to for most of my life to the paranoid individual shaking in front of me.

This was the first time I had really observed my grandmother experiencing acute psychosis. My mom explained to me at a young age that my grandmother had an illness in her mind. I noticed that compared to other people in my life, my grandmother seemed to express less emotion and changed topics in conversations frequently, but by having an understanding provided by my mother, my brother and I didn’t think much of it; that was just Grandma. She would occasionally talk about her experiences with hearing voices or people on the television talking about her. For the most part, though, she was stable; she was able to carry out cleaning, cooking, and watching her favorite shows.

That was until she turned 65 and started on Medicare for insurance. The government required her to trial a less expensive medication and wanted her family practitioner to adjust the medications she had been on for years. This decision was made by people unfamiliar with my grandmother and her story. As a result, my family struggled alongside Grandma for over a month as she battled hallucinations and labile emotions. Living in rural Ohio, she had no access to a psychiatrist or other mental health professional during this period. The adjustments to her medications, changes in her insurance coverage, and lack of consistent psychiatric care led to a deterioration of her stability. This was the only time in my life that I saw Grandma at a place where she would have needed to be hospitalized if the symptoms lasted much longer. I spent evenings sitting with her in that dark and scary place, listening, sympathizing, and challenging her distortions of reality. This experience laid the foundation for my growing passion for providing care and advocating for people experiencing mental illness. I observed firsthand how the absence of consistent, compassionate, and informed care could lead to psychiatric hospitalization.

In the past, my grandfather hid my grandmother’s diagnosis from those around them. This approach prevented my uncle from disclosing the same information to my cousins. I observed how they would look at her with confusion and sometimes fear, which was rooted in a lack of understanding. This desire to hide Grandma’s schizophrenia stemmed from the marginalization society imposed upon her. There were sneers, comments regarding lack of religious faith, and expressions that she was not trying hard enough. My grandparents decided together to inform their church of my grandmother’s illness. The results were astounding. People looked at my grandmother not with confusion but with sympathy and would go out of their way to check on her. Knowledge is power, and awareness can break down stigma. Seeing the difference knowledge could have on a church community further solidified my desire to educate not only patients and their family members but also communities.

Access is another huge barrier my grandmother has faced. There is a lack of referring and awareness as well as large geographic disparities of psychiatrists around my hometown. My grandmother has also had struggles with being able to pay for services, medication, and therapy. This shows the desperate need for more mental health professionals who are competent and knowledgeable in how social determinants of health impact outcomes. These factors contributed to my decision to pursue a Master of Public Health degree. I aspire to use this background to prevent what happened to my Grandma from happening to other patients and to be an advocate for enhanced access to services, improving community mental health and awareness, and promoting continuity of care to increase treatment compliance. That is what my Grandma has fostered in me as a future psychiatrist.

Our December 2022 issue marks the conclusion of GIHN’s 15th Anniversary Series. We hope you have enjoyed these special articles intended to celebrate the success of AGA’s official newspaper since its launch in 2007, mirroring equally rapid advances in our field. Over the past year, GIHN’s esteemed Associate Editors and former Editors-in-Chief have helped us “look back” on how the fields of gastroenterology and hepatology have changed since the newspaper’s inception, including advances in our understanding of the microbiome, innovations in endoscopic practice, changes in the demographics of the GI workforce, and breakthroughs in the treatment of hepatitis C. Now, as we conclude our 15th-anniversary year, it is only fitting that we “look forward” and consider the type of innovative coverage that will grace GIHN’s pages in the future. To that end, we asked a distinguished group of AGA thought leaders, representing various backgrounds and practice settings, to share their perspectives on what are likely to be the biggest change(s) in the field of GI over the next 15 years. We hope you find their answers inspiring as you consider your own reflections on this question.

As we close out 2022, we also wish to extend a big “thank you” to all the individuals who have provided thoughtful commentary to our coverage, helping us to understand the implications of innovative research findings on clinical practice and how changes in health policy impact our practices and our patients. I would also like to acknowledge our hardworking AGA and Frontline Medical Communications editorial teams, without whom this publication would not be possible. We wish you all a restful holiday season with your family and friends and look forward to reconnecting in 2023 – stay tuned for the launch of an exciting new GIHN initiative as part of our January issue!

Megan A. Adams, MD, JD, MSc
Editor-in-Chief

Our December 2022 issue marks the conclusion of GIHN’s 15th Anniversary Series. We hope you have enjoyed these special articles intended to celebrate the success of AGA’s official newspaper since its launch in 2007, mirroring equally rapid advances in our field. Over the past year, GIHN’s esteemed Associate Editors and former Editors-in-Chief have helped us “look back” on how the fields of gastroenterology and hepatology have changed since the newspaper’s inception, including advances in our understanding of the microbiome, innovations in endoscopic practice, changes in the demographics of the GI workforce, and breakthroughs in the treatment of hepatitis C. Now, as we conclude our 15th-anniversary year, it is only fitting that we “look forward” and consider the type of innovative coverage that will grace GIHN’s pages in the future. To that end, we asked a distinguished group of AGA thought leaders, representing various backgrounds and practice settings, to share their perspectives on what are likely to be the biggest change(s) in the field of GI over the next 15 years. We hope you find their answers inspiring as you consider your own reflections on this question.

As we close out 2022, we also wish to extend a big “thank you” to all the individuals who have provided thoughtful commentary to our coverage, helping us to understand the implications of innovative research findings on clinical practice and how changes in health policy impact our practices and our patients. I would also like to acknowledge our hardworking AGA and Frontline Medical Communications editorial teams, without whom this publication would not be possible. We wish you all a restful holiday season with your family and friends and look forward to reconnecting in 2023 – stay tuned for the launch of an exciting new GIHN initiative as part of our January issue!

Megan A. Adams, MD, JD, MSc
Editor-in-Chief

Our December 2022 issue marks the conclusion of GIHN’s 15th Anniversary Series. We hope you have enjoyed these special articles intended to celebrate the success of AGA’s official newspaper since its launch in 2007, mirroring equally rapid advances in our field. Over the past year, GIHN’s esteemed Associate Editors and former Editors-in-Chief have helped us “look back” on how the fields of gastroenterology and hepatology have changed since the newspaper’s inception, including advances in our understanding of the microbiome, innovations in endoscopic practice, changes in the demographics of the GI workforce, and breakthroughs in the treatment of hepatitis C. Now, as we conclude our 15th-anniversary year, it is only fitting that we “look forward” and consider the type of innovative coverage that will grace GIHN’s pages in the future. To that end, we asked a distinguished group of AGA thought leaders, representing various backgrounds and practice settings, to share their perspectives on what are likely to be the biggest change(s) in the field of GI over the next 15 years. We hope you find their answers inspiring as you consider your own reflections on this question.

As we close out 2022, we also wish to extend a big “thank you” to all the individuals who have provided thoughtful commentary to our coverage, helping us to understand the implications of innovative research findings on clinical practice and how changes in health policy impact our practices and our patients. I would also like to acknowledge our hardworking AGA and Frontline Medical Communications editorial teams, without whom this publication would not be possible. We wish you all a restful holiday season with your family and friends and look forward to reconnecting in 2023 – stay tuned for the launch of an exciting new GIHN initiative as part of our January issue!

Megan A. Adams, MD, JD, MSc
Editor-in-Chief

“The right drug at the right time with the right dose for the right bug for the right duration.” That, said professor Kristina Crothers, MD, is the general guidance for optimizing antibiotic use (while awaiting an infectious disease consult). In her oral presentation at the annual meeting of the American College of Chest Physicians, “Choosing newer antibiotics for nosocomial pneumonia,” Dr. Crothers asked the question: “Beyond the guidelines: When should novel antimicrobials be used?”

Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are the most common nosocomial infections at 22%, and are the leading cause of death attributable to hospital-acquired infections. They increase mortality by 20%-50%, with an economic burden of about $40,000 per patient. The incidence of multidrug-resistant (MDR) organism infections varies widely by locality, but several factors increase the likelihood: prior broad-spectrum antibiotic exposure within the past 90 days; longer hospitalization; indwelling vascular devices; tracheostomy; and ventilator dependence. The Centers for Disease Control and Prevention lists as “Serious Threat” the HAP/VAP MDR organisms methicillin resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa (PSA) with difficult-to-treat-resistance, and beta-lactamase producing Enterobacterales (ESBL). In the category of “Urgent Threat” the CDC lists: carbapenamase-resistant Enterobacterales (CRE) (carbapenamase producing or non–carbapenemase producing), and carbapenem-resistant Acinetobacter (CRAB), according to Dr. Crothers who is at the University of Washington Veterans Affairs Puget Sound Health Care System, Seattle.

Newer antibiotics for HAP/VAP that are still beyond the guidelines include telavancin and tedizolid as gram-positive agents, and as gram-negative ones: ceftazidime-avibactam, ceftolozane-tazobactam, cefiderocol, imipenem-cilastatin-relebactam and meropenem-vaborbactam, she added.
 

Tedizolid, Dr. Crothers stated, is a novel oxazolidinone, and is an alternative to vancomycin and linezolid for gram-positive HAP/VAP. In the VITAL noninferiority study versus linezolid with 726 patients, it was noninferior to linezolid for 28-day all-cause mortality (28% vs. 26%), but did not achieve noninferiority for investigator-assessed clinical cure (56% vs. 64%).

Televancin, a semisynthetic derivative of vancomycin, in the ATTAIN studies vs. vancomycin had overall similar cure rates. It is FDA-approved for S. aureus HAP/VAP but not other bacterial causes. It should be reserved for those who cannot receive vancomycin or linezolid, with normal renal function, according to Dr. Crothers. Excluded from first-line treatment of gram-positive HAP/VAP are daptomycin, ceftaroline, ceftobiprole, and tigecycline.

Ceftazidime-avibactam, a third-generation cephalosporin-plus novel beta-lactamase inhibitor has wide activity (Klebsiella pneumoniae, Enterobacter cloacae, Escherichia coli, Serratia marcescens, Proteus mirabilis, PSA and Haemophilus influenzae. It is also active against some extended-spectrum beta-lactamases (ESBLs), ampC beta-lactamases (AmpCs), and K. pneumoniae carbapenemase (KPC)–producing Enterobacterales, but not with metallo-beta-lactamases). Ceftazidime-avibactam is also indicated for HAP/VAP, and has a toxicity profile including nausea, vomiting, and diarrhea.

In the REPROVE trial of ceftazidime-avibactam vs. meropenem for 7-14 days with 527 clinically evaluable patients (37% K. pneumoniae, 30% P. aeruginosa, and 33%-35% VAP), the clinical cure at 21-25 days post randomization was 69% vs. 73%, respectively, with similar adverse events.
 

Ceftolozane-tazobactam, a novel fifth-generation cephalosporin plus a beta-lactamase inhibitor has activity against PSA including extensively drug-resistant PSA, AmpC, and ESBL-E, but it has limited activity against Acinetobacter and Stenotrophomonas. It is indicated for HAP/VAP, has reduced efficacy with creatine clearance of 50 mL/min or less, increases transaminases and renal impairment, and causes diarrhea. In ASPECT-NP (n = 726) ceftolozane-tazobactam versus meropenem for 8-14 days (HAP/VAP), showed a 28 day-mortality of 24% vs. 25%, respectively, with test of cure at 54% vs. 53% at 7-14 days post therapy. Adverse events were similar between groups.

Imipenem-cilastatin-relebactam, a novel beta-lactamase inhibitor plus carbapenem, is indicated for HAP/VAP and has activity against ESBL, CRE: KPC-producing Enterobacterales, PSA including AmpC. It can cause seizures (requires caution with central nervous system disorders and renal impairment). It increases transaminases, anemia, diarrhea, and reduces potassium and sodium. In RESTORE-IMI 2 (n = 537 with HAP/VAP) it was noninferior for 28-day all-cause mortality vs. piperacillin and tazobactam (16% vs. 21%), with similar adverse events.

Cefiderocol, a siderophore cephalosporin, is indicated for HAP/VAP. It has a wide spectrum of activity: ESBL, CRE, CR PSA, Stenotrophomonas maltophilia, Acinetobacter baumanii, Streptococcus.) It increases transaminases, diarrhea, and atrial fibrillation, and it reduces potassium and magnesium. In APEKS-NP versus linezolid plus cefiderocol or extended meropenem infusion (HAP/VAP n = 292; gram-negative pneumonia = 251; 60% invasive mechanical ventilation) it was noninferior for 14-day all-cause mortality (12.4% vs. 11.6%) with similar adverse events. In CREDIBLE-CR vs. best available therapy for carbapenem-resistant gram-negative infections, clinical cure rates were similar (50% vs. 53% in 59 HAP/VAP patients at 7 days), but with more deaths in the cefiderocol arm. Adverse events were > 90% in both groups and 34% vs. 19% died, mostly with Acinetobacter.

Meropenem-vaborbactam, a novel beta-lactamase inhibitor plus carbapenem, is approved and indicated for HAP/VAP in Europe. It has activity against MDR, Enterobacterales including CRE. Its toxicities include headache, phlebitis/infusion-site reactions and diarrhea. In TANGO-2 versus best available treatment for carbapenem-resistant Enterobacteriaceae (CRE) (n = 77, 47 with confirmed CRE), clinical cure was increased and mortality decreased compared with best available therapy. Treatment- and renal-related adverse events were lower for meropenem-vaborbactam.

In closing, Dr. Crothers cited advice from the paper by Tamma et al. (“Rethinking how Antibiotics are Prescribed” JAMA. 2018) about the need to review findings after therapy has been initiated to confirm the pneumonia diagnosis: Novel agents should be kept in reserve in the absence of MDR risk factors for MRSA and gram-negative bacilli; therapy should be deescalated after 48-72 hours if MDR organisms are not detected; and therapy should be directed to the specific organism detected. Most HAP and VAP in adults can be treated for 7 days, she added.

“Know indications for new therapeutic agents approved for nosocomial pneumonia,” she concluded.

Dr. Crothers reported having no disclosures.

“The right drug at the right time with the right dose for the right bug for the right duration.” That, said professor Kristina Crothers, MD, is the general guidance for optimizing antibiotic use (while awaiting an infectious disease consult). In her oral presentation at the annual meeting of the American College of Chest Physicians, “Choosing newer antibiotics for nosocomial pneumonia,” Dr. Crothers asked the question: “Beyond the guidelines: When should novel antimicrobials be used?”

Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are the most common nosocomial infections at 22%, and are the leading cause of death attributable to hospital-acquired infections. They increase mortality by 20%-50%, with an economic burden of about $40,000 per patient. The incidence of multidrug-resistant (MDR) organism infections varies widely by locality, but several factors increase the likelihood: prior broad-spectrum antibiotic exposure within the past 90 days; longer hospitalization; indwelling vascular devices; tracheostomy; and ventilator dependence. The Centers for Disease Control and Prevention lists as “Serious Threat” the HAP/VAP MDR organisms methicillin resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa (PSA) with difficult-to-treat-resistance, and beta-lactamase producing Enterobacterales (ESBL). In the category of “Urgent Threat” the CDC lists: carbapenamase-resistant Enterobacterales (CRE) (carbapenamase producing or non–carbapenemase producing), and carbapenem-resistant Acinetobacter (CRAB), according to Dr. Crothers who is at the University of Washington Veterans Affairs Puget Sound Health Care System, Seattle.

Newer antibiotics for HAP/VAP that are still beyond the guidelines include telavancin and tedizolid as gram-positive agents, and as gram-negative ones: ceftazidime-avibactam, ceftolozane-tazobactam, cefiderocol, imipenem-cilastatin-relebactam and meropenem-vaborbactam, she added.
 

Tedizolid, Dr. Crothers stated, is a novel oxazolidinone, and is an alternative to vancomycin and linezolid for gram-positive HAP/VAP. In the VITAL noninferiority study versus linezolid with 726 patients, it was noninferior to linezolid for 28-day all-cause mortality (28% vs. 26%), but did not achieve noninferiority for investigator-assessed clinical cure (56% vs. 64%).

Televancin, a semisynthetic derivative of vancomycin, in the ATTAIN studies vs. vancomycin had overall similar cure rates. It is FDA-approved for S. aureus HAP/VAP but not other bacterial causes. It should be reserved for those who cannot receive vancomycin or linezolid, with normal renal function, according to Dr. Crothers. Excluded from first-line treatment of gram-positive HAP/VAP are daptomycin, ceftaroline, ceftobiprole, and tigecycline.

Ceftazidime-avibactam, a third-generation cephalosporin-plus novel beta-lactamase inhibitor has wide activity (Klebsiella pneumoniae, Enterobacter cloacae, Escherichia coli, Serratia marcescens, Proteus mirabilis, PSA and Haemophilus influenzae. It is also active against some extended-spectrum beta-lactamases (ESBLs), ampC beta-lactamases (AmpCs), and K. pneumoniae carbapenemase (KPC)–producing Enterobacterales, but not with metallo-beta-lactamases). Ceftazidime-avibactam is also indicated for HAP/VAP, and has a toxicity profile including nausea, vomiting, and diarrhea.

In the REPROVE trial of ceftazidime-avibactam vs. meropenem for 7-14 days with 527 clinically evaluable patients (37% K. pneumoniae, 30% P. aeruginosa, and 33%-35% VAP), the clinical cure at 21-25 days post randomization was 69% vs. 73%, respectively, with similar adverse events.
 

Ceftolozane-tazobactam, a novel fifth-generation cephalosporin plus a beta-lactamase inhibitor has activity against PSA including extensively drug-resistant PSA, AmpC, and ESBL-E, but it has limited activity against Acinetobacter and Stenotrophomonas. It is indicated for HAP/VAP, has reduced efficacy with creatine clearance of 50 mL/min or less, increases transaminases and renal impairment, and causes diarrhea. In ASPECT-NP (n = 726) ceftolozane-tazobactam versus meropenem for 8-14 days (HAP/VAP), showed a 28 day-mortality of 24% vs. 25%, respectively, with test of cure at 54% vs. 53% at 7-14 days post therapy. Adverse events were similar between groups.

Imipenem-cilastatin-relebactam, a novel beta-lactamase inhibitor plus carbapenem, is indicated for HAP/VAP and has activity against ESBL, CRE: KPC-producing Enterobacterales, PSA including AmpC. It can cause seizures (requires caution with central nervous system disorders and renal impairment). It increases transaminases, anemia, diarrhea, and reduces potassium and sodium. In RESTORE-IMI 2 (n = 537 with HAP/VAP) it was noninferior for 28-day all-cause mortality vs. piperacillin and tazobactam (16% vs. 21%), with similar adverse events.

Cefiderocol, a siderophore cephalosporin, is indicated for HAP/VAP. It has a wide spectrum of activity: ESBL, CRE, CR PSA, Stenotrophomonas maltophilia, Acinetobacter baumanii, Streptococcus.) It increases transaminases, diarrhea, and atrial fibrillation, and it reduces potassium and magnesium. In APEKS-NP versus linezolid plus cefiderocol or extended meropenem infusion (HAP/VAP n = 292; gram-negative pneumonia = 251; 60% invasive mechanical ventilation) it was noninferior for 14-day all-cause mortality (12.4% vs. 11.6%) with similar adverse events. In CREDIBLE-CR vs. best available therapy for carbapenem-resistant gram-negative infections, clinical cure rates were similar (50% vs. 53% in 59 HAP/VAP patients at 7 days), but with more deaths in the cefiderocol arm. Adverse events were > 90% in both groups and 34% vs. 19% died, mostly with Acinetobacter.

Meropenem-vaborbactam, a novel beta-lactamase inhibitor plus carbapenem, is approved and indicated for HAP/VAP in Europe. It has activity against MDR, Enterobacterales including CRE. Its toxicities include headache, phlebitis/infusion-site reactions and diarrhea. In TANGO-2 versus best available treatment for carbapenem-resistant Enterobacteriaceae (CRE) (n = 77, 47 with confirmed CRE), clinical cure was increased and mortality decreased compared with best available therapy. Treatment- and renal-related adverse events were lower for meropenem-vaborbactam.

In closing, Dr. Crothers cited advice from the paper by Tamma et al. (“Rethinking how Antibiotics are Prescribed” JAMA. 2018) about the need to review findings after therapy has been initiated to confirm the pneumonia diagnosis: Novel agents should be kept in reserve in the absence of MDR risk factors for MRSA and gram-negative bacilli; therapy should be deescalated after 48-72 hours if MDR organisms are not detected; and therapy should be directed to the specific organism detected. Most HAP and VAP in adults can be treated for 7 days, she added.

“Know indications for new therapeutic agents approved for nosocomial pneumonia,” she concluded.

Dr. Crothers reported having no disclosures.

“The right drug at the right time with the right dose for the right bug for the right duration.” That, said professor Kristina Crothers, MD, is the general guidance for optimizing antibiotic use (while awaiting an infectious disease consult). In her oral presentation at the annual meeting of the American College of Chest Physicians, “Choosing newer antibiotics for nosocomial pneumonia,” Dr. Crothers asked the question: “Beyond the guidelines: When should novel antimicrobials be used?”

Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are the most common nosocomial infections at 22%, and are the leading cause of death attributable to hospital-acquired infections. They increase mortality by 20%-50%, with an economic burden of about $40,000 per patient. The incidence of multidrug-resistant (MDR) organism infections varies widely by locality, but several factors increase the likelihood: prior broad-spectrum antibiotic exposure within the past 90 days; longer hospitalization; indwelling vascular devices; tracheostomy; and ventilator dependence. The Centers for Disease Control and Prevention lists as “Serious Threat” the HAP/VAP MDR organisms methicillin resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa (PSA) with difficult-to-treat-resistance, and beta-lactamase producing Enterobacterales (ESBL). In the category of “Urgent Threat” the CDC lists: carbapenamase-resistant Enterobacterales (CRE) (carbapenamase producing or non–carbapenemase producing), and carbapenem-resistant Acinetobacter (CRAB), according to Dr. Crothers who is at the University of Washington Veterans Affairs Puget Sound Health Care System, Seattle.

Newer antibiotics for HAP/VAP that are still beyond the guidelines include telavancin and tedizolid as gram-positive agents, and as gram-negative ones: ceftazidime-avibactam, ceftolozane-tazobactam, cefiderocol, imipenem-cilastatin-relebactam and meropenem-vaborbactam, she added.
 

Tedizolid, Dr. Crothers stated, is a novel oxazolidinone, and is an alternative to vancomycin and linezolid for gram-positive HAP/VAP. In the VITAL noninferiority study versus linezolid with 726 patients, it was noninferior to linezolid for 28-day all-cause mortality (28% vs. 26%), but did not achieve noninferiority for investigator-assessed clinical cure (56% vs. 64%).

Televancin, a semisynthetic derivative of vancomycin, in the ATTAIN studies vs. vancomycin had overall similar cure rates. It is FDA-approved for S. aureus HAP/VAP but not other bacterial causes. It should be reserved for those who cannot receive vancomycin or linezolid, with normal renal function, according to Dr. Crothers. Excluded from first-line treatment of gram-positive HAP/VAP are daptomycin, ceftaroline, ceftobiprole, and tigecycline.

Ceftazidime-avibactam, a third-generation cephalosporin-plus novel beta-lactamase inhibitor has wide activity (Klebsiella pneumoniae, Enterobacter cloacae, Escherichia coli, Serratia marcescens, Proteus mirabilis, PSA and Haemophilus influenzae. It is also active against some extended-spectrum beta-lactamases (ESBLs), ampC beta-lactamases (AmpCs), and K. pneumoniae carbapenemase (KPC)–producing Enterobacterales, but not with metallo-beta-lactamases). Ceftazidime-avibactam is also indicated for HAP/VAP, and has a toxicity profile including nausea, vomiting, and diarrhea.

In the REPROVE trial of ceftazidime-avibactam vs. meropenem for 7-14 days with 527 clinically evaluable patients (37% K. pneumoniae, 30% P. aeruginosa, and 33%-35% VAP), the clinical cure at 21-25 days post randomization was 69% vs. 73%, respectively, with similar adverse events.
 

Ceftolozane-tazobactam, a novel fifth-generation cephalosporin plus a beta-lactamase inhibitor has activity against PSA including extensively drug-resistant PSA, AmpC, and ESBL-E, but it has limited activity against Acinetobacter and Stenotrophomonas. It is indicated for HAP/VAP, has reduced efficacy with creatine clearance of 50 mL/min or less, increases transaminases and renal impairment, and causes diarrhea. In ASPECT-NP (n = 726) ceftolozane-tazobactam versus meropenem for 8-14 days (HAP/VAP), showed a 28 day-mortality of 24% vs. 25%, respectively, with test of cure at 54% vs. 53% at 7-14 days post therapy. Adverse events were similar between groups.

Imipenem-cilastatin-relebactam, a novel beta-lactamase inhibitor plus carbapenem, is indicated for HAP/VAP and has activity against ESBL, CRE: KPC-producing Enterobacterales, PSA including AmpC. It can cause seizures (requires caution with central nervous system disorders and renal impairment). It increases transaminases, anemia, diarrhea, and reduces potassium and sodium. In RESTORE-IMI 2 (n = 537 with HAP/VAP) it was noninferior for 28-day all-cause mortality vs. piperacillin and tazobactam (16% vs. 21%), with similar adverse events.

Cefiderocol, a siderophore cephalosporin, is indicated for HAP/VAP. It has a wide spectrum of activity: ESBL, CRE, CR PSA, Stenotrophomonas maltophilia, Acinetobacter baumanii, Streptococcus.) It increases transaminases, diarrhea, and atrial fibrillation, and it reduces potassium and magnesium. In APEKS-NP versus linezolid plus cefiderocol or extended meropenem infusion (HAP/VAP n = 292; gram-negative pneumonia = 251; 60% invasive mechanical ventilation) it was noninferior for 14-day all-cause mortality (12.4% vs. 11.6%) with similar adverse events. In CREDIBLE-CR vs. best available therapy for carbapenem-resistant gram-negative infections, clinical cure rates were similar (50% vs. 53% in 59 HAP/VAP patients at 7 days), but with more deaths in the cefiderocol arm. Adverse events were > 90% in both groups and 34% vs. 19% died, mostly with Acinetobacter.

Meropenem-vaborbactam, a novel beta-lactamase inhibitor plus carbapenem, is approved and indicated for HAP/VAP in Europe. It has activity against MDR, Enterobacterales including CRE. Its toxicities include headache, phlebitis/infusion-site reactions and diarrhea. In TANGO-2 versus best available treatment for carbapenem-resistant Enterobacteriaceae (CRE) (n = 77, 47 with confirmed CRE), clinical cure was increased and mortality decreased compared with best available therapy. Treatment- and renal-related adverse events were lower for meropenem-vaborbactam.

In closing, Dr. Crothers cited advice from the paper by Tamma et al. (“Rethinking how Antibiotics are Prescribed” JAMA. 2018) about the need to review findings after therapy has been initiated to confirm the pneumonia diagnosis: Novel agents should be kept in reserve in the absence of MDR risk factors for MRSA and gram-negative bacilli; therapy should be deescalated after 48-72 hours if MDR organisms are not detected; and therapy should be directed to the specific organism detected. Most HAP and VAP in adults can be treated for 7 days, she added.

“Know indications for new therapeutic agents approved for nosocomial pneumonia,” she concluded.

Dr. Crothers reported having no disclosures.

Medicare expanded coverage of colorectal cancer (CRC) testing through the 2023 physician payment rule while also finalizing certain mandated budget cuts. AGA and its sister societies praised the federal plan to increase access to screening but are among the groups now calling on Congress to prevent pay decreases.

The 2023 Medicare Physician Fee Schedule (MPFS) lowers the minimum age for CRC screening to 45 from 50 years, in keeping with the recommendation from the U.S. Preventive Services Task Force. The physician payment rule, which was unveiled on November 1, also ends the copay for colonoscopies that follow a positive stool-based colon cancer test. However, it is important to note that colonoscopies that involve polyp removal are still subject to Medicare coinsurance requirements, although the financial responsibility eventually diminishes to zero by 2030: From 2023 to 2026, patient responsibility is 15% of the cost; from 2027 to 2029 it falls to 10%; and by 2030 it will be covered 100% by Medicare.

These changes come after a year of intense advocacy led by AGA, including multiple meetings with senior officials at the Centers for Medicare and Medicaid Services and legislative pressure by members across the country. In the 2023 MPFS proposed rule, CMS attributed its decision to expand Medicare benefits to colonoscopy following a positive stool test to involvement from AGA, saying, “We consulted with and reviewed recommendations from a number of professional societies in developing this proposal, including supportive letters and communications with representatives from American Gastroenterological Association, American Cancer Society, and Fight Colorectal Cancer.”

“This is a win for all patients and should elevate our nation’s screening rates while lowering the overall cancer burden, saving lives. Importantly, the changes will lessen colorectal cancer disparities, eliminating a financial burden for many patients,” says AGA President John Carethers, MD, AGAF, who met with CMS earlier this year to advocate for the coverage of colonoscopy following a positive noninvasive colorectal cancer screening test.

David Lieberman, MD, AGAF, who met with CMS officials multiple times, offered, “Cost-sharing is a well-recognized barrier to screening and has resulted in disparities. Patients can now engage in a CRC screening program and be confident that they will not face unexpected cost-sharing for colonoscopy after a positive noninvasive screening test.”
 

‘Déjà vu all over again’

CMS uses its annual updates of the Physician Fee Schedule to make myriad policy decisions, with the 2023 version of the rule running close to 3,000 pages. AGA’s summary of the 2023 MPFS final rule highlights changes that impact gastroenterologists.

But the most controversial provisions in the rule involve federal mandates meant to control spending that CMS has no control over. These include a reduction in one of the variables used in determining payment, known as the conversion factor. This will fall by $1.55 from the current level of $34.61 to $33.06 in 2023.

There’s widespread agreement that Congress needs to reconsider its approach to setting Medicare payment for clinicians.

Between 2003 and April 2014, Congress passed 17 laws overriding the cuts to physician pay that were required under the old sustainable growth rate (SGR) formula.

The Medicare Access and CHIP Reauthorization Act of 2015 was supposed to end the annual battles over reimbursement cuts resulting from the SGR formula by changing the way physician payment is updated each year.

However, physicians face a 4.42% Medicare payment cut under the new payment system, as reflected in 2023 payment rule.

Two physicians serving in Congress, Rep. Ami Bera, MD (D-CA), and Rep. Larry Bucshon, MD (R-IN), have introduced legislation that would block next year’s cuts.

The current fight to stave off 2023 cuts seems like “déjà vu all over again,” said Kathleen Teixeira, AGA’s vice president of government affairs, in an interview with this news organization. Congress needs to shift away from the “Band-Aid approach” and concentrate on longer-term issues with physician payment, she said.

Rep. Bera and Rep. Buchson in September issued a letter seeking feedback on ways to “stabilize the Medicare payment system” without dramatically increasing the cost to taxpayers.

Louis Wilson, MD, chair of the American College of Gastroenterology’s legislative and public policy council, told this news organization that Congress needs to revisit Medicare’s physician payment system, especially in terms of addressing inflation.

Lawmakers’ attempts to restrain growth in Medicare physician payments have had the unintended consequence of fueling the acquisition of practices by hospitals, said Dr. Wilson, the managing partner of a physician-owned single-specialty private practice in Wichita Falls, Tex. Once doctors are employed by hospitals, Medicare often pays higher rates for their services than it would pay to physicians for providing the same care in a private practice.

Indeed, the Federal Trade Commission has said the U.S. physician workplace is “undergoing a dramatic restructuring,” with traditional solo practices and small single-specialty group practices rapidly being replaced by large multispecialty physician group practices, or practices that are owned or employed by hospital systems. The FTC is in the midst of a major series of studies on the effects of this consolidation.

“There’s been so much market distortion, so much limitation in innovation by failing to adequately pay in the Physician Fee Schedule, that the consequence is the widespread consolidation,” said Dr. Wilson. “That’s recognized on both sides of the aisle as being essentially expensive and inefficient and not in patients’ best interest.”

Medicare expanded coverage of colorectal cancer (CRC) testing through the 2023 physician payment rule while also finalizing certain mandated budget cuts. AGA and its sister societies praised the federal plan to increase access to screening but are among the groups now calling on Congress to prevent pay decreases.

The 2023 Medicare Physician Fee Schedule (MPFS) lowers the minimum age for CRC screening to 45 from 50 years, in keeping with the recommendation from the U.S. Preventive Services Task Force. The physician payment rule, which was unveiled on November 1, also ends the copay for colonoscopies that follow a positive stool-based colon cancer test. However, it is important to note that colonoscopies that involve polyp removal are still subject to Medicare coinsurance requirements, although the financial responsibility eventually diminishes to zero by 2030: From 2023 to 2026, patient responsibility is 15% of the cost; from 2027 to 2029 it falls to 10%; and by 2030 it will be covered 100% by Medicare.

These changes come after a year of intense advocacy led by AGA, including multiple meetings with senior officials at the Centers for Medicare and Medicaid Services and legislative pressure by members across the country. In the 2023 MPFS proposed rule, CMS attributed its decision to expand Medicare benefits to colonoscopy following a positive stool test to involvement from AGA, saying, “We consulted with and reviewed recommendations from a number of professional societies in developing this proposal, including supportive letters and communications with representatives from American Gastroenterological Association, American Cancer Society, and Fight Colorectal Cancer.”

“This is a win for all patients and should elevate our nation’s screening rates while lowering the overall cancer burden, saving lives. Importantly, the changes will lessen colorectal cancer disparities, eliminating a financial burden for many patients,” says AGA President John Carethers, MD, AGAF, who met with CMS earlier this year to advocate for the coverage of colonoscopy following a positive noninvasive colorectal cancer screening test.

David Lieberman, MD, AGAF, who met with CMS officials multiple times, offered, “Cost-sharing is a well-recognized barrier to screening and has resulted in disparities. Patients can now engage in a CRC screening program and be confident that they will not face unexpected cost-sharing for colonoscopy after a positive noninvasive screening test.”
 

‘Déjà vu all over again’

CMS uses its annual updates of the Physician Fee Schedule to make myriad policy decisions, with the 2023 version of the rule running close to 3,000 pages. AGA’s summary of the 2023 MPFS final rule highlights changes that impact gastroenterologists.

But the most controversial provisions in the rule involve federal mandates meant to control spending that CMS has no control over. These include a reduction in one of the variables used in determining payment, known as the conversion factor. This will fall by $1.55 from the current level of $34.61 to $33.06 in 2023.

There’s widespread agreement that Congress needs to reconsider its approach to setting Medicare payment for clinicians.

Between 2003 and April 2014, Congress passed 17 laws overriding the cuts to physician pay that were required under the old sustainable growth rate (SGR) formula.

The Medicare Access and CHIP Reauthorization Act of 2015 was supposed to end the annual battles over reimbursement cuts resulting from the SGR formula by changing the way physician payment is updated each year.

However, physicians face a 4.42% Medicare payment cut under the new payment system, as reflected in 2023 payment rule.

Two physicians serving in Congress, Rep. Ami Bera, MD (D-CA), and Rep. Larry Bucshon, MD (R-IN), have introduced legislation that would block next year’s cuts.

The current fight to stave off 2023 cuts seems like “déjà vu all over again,” said Kathleen Teixeira, AGA’s vice president of government affairs, in an interview with this news organization. Congress needs to shift away from the “Band-Aid approach” and concentrate on longer-term issues with physician payment, she said.

Rep. Bera and Rep. Buchson in September issued a letter seeking feedback on ways to “stabilize the Medicare payment system” without dramatically increasing the cost to taxpayers.

Louis Wilson, MD, chair of the American College of Gastroenterology’s legislative and public policy council, told this news organization that Congress needs to revisit Medicare’s physician payment system, especially in terms of addressing inflation.

Lawmakers’ attempts to restrain growth in Medicare physician payments have had the unintended consequence of fueling the acquisition of practices by hospitals, said Dr. Wilson, the managing partner of a physician-owned single-specialty private practice in Wichita Falls, Tex. Once doctors are employed by hospitals, Medicare often pays higher rates for their services than it would pay to physicians for providing the same care in a private practice.

Indeed, the Federal Trade Commission has said the U.S. physician workplace is “undergoing a dramatic restructuring,” with traditional solo practices and small single-specialty group practices rapidly being replaced by large multispecialty physician group practices, or practices that are owned or employed by hospital systems. The FTC is in the midst of a major series of studies on the effects of this consolidation.

“There’s been so much market distortion, so much limitation in innovation by failing to adequately pay in the Physician Fee Schedule, that the consequence is the widespread consolidation,” said Dr. Wilson. “That’s recognized on both sides of the aisle as being essentially expensive and inefficient and not in patients’ best interest.”

Medicare expanded coverage of colorectal cancer (CRC) testing through the 2023 physician payment rule while also finalizing certain mandated budget cuts. AGA and its sister societies praised the federal plan to increase access to screening but are among the groups now calling on Congress to prevent pay decreases.

The 2023 Medicare Physician Fee Schedule (MPFS) lowers the minimum age for CRC screening to 45 from 50 years, in keeping with the recommendation from the U.S. Preventive Services Task Force. The physician payment rule, which was unveiled on November 1, also ends the copay for colonoscopies that follow a positive stool-based colon cancer test. However, it is important to note that colonoscopies that involve polyp removal are still subject to Medicare coinsurance requirements, although the financial responsibility eventually diminishes to zero by 2030: From 2023 to 2026, patient responsibility is 15% of the cost; from 2027 to 2029 it falls to 10%; and by 2030 it will be covered 100% by Medicare.

These changes come after a year of intense advocacy led by AGA, including multiple meetings with senior officials at the Centers for Medicare and Medicaid Services and legislative pressure by members across the country. In the 2023 MPFS proposed rule, CMS attributed its decision to expand Medicare benefits to colonoscopy following a positive stool test to involvement from AGA, saying, “We consulted with and reviewed recommendations from a number of professional societies in developing this proposal, including supportive letters and communications with representatives from American Gastroenterological Association, American Cancer Society, and Fight Colorectal Cancer.”

“This is a win for all patients and should elevate our nation’s screening rates while lowering the overall cancer burden, saving lives. Importantly, the changes will lessen colorectal cancer disparities, eliminating a financial burden for many patients,” says AGA President John Carethers, MD, AGAF, who met with CMS earlier this year to advocate for the coverage of colonoscopy following a positive noninvasive colorectal cancer screening test.

David Lieberman, MD, AGAF, who met with CMS officials multiple times, offered, “Cost-sharing is a well-recognized barrier to screening and has resulted in disparities. Patients can now engage in a CRC screening program and be confident that they will not face unexpected cost-sharing for colonoscopy after a positive noninvasive screening test.”
 

‘Déjà vu all over again’

CMS uses its annual updates of the Physician Fee Schedule to make myriad policy decisions, with the 2023 version of the rule running close to 3,000 pages. AGA’s summary of the 2023 MPFS final rule highlights changes that impact gastroenterologists.

But the most controversial provisions in the rule involve federal mandates meant to control spending that CMS has no control over. These include a reduction in one of the variables used in determining payment, known as the conversion factor. This will fall by $1.55 from the current level of $34.61 to $33.06 in 2023.

There’s widespread agreement that Congress needs to reconsider its approach to setting Medicare payment for clinicians.

Between 2003 and April 2014, Congress passed 17 laws overriding the cuts to physician pay that were required under the old sustainable growth rate (SGR) formula.

The Medicare Access and CHIP Reauthorization Act of 2015 was supposed to end the annual battles over reimbursement cuts resulting from the SGR formula by changing the way physician payment is updated each year.

However, physicians face a 4.42% Medicare payment cut under the new payment system, as reflected in 2023 payment rule.

Two physicians serving in Congress, Rep. Ami Bera, MD (D-CA), and Rep. Larry Bucshon, MD (R-IN), have introduced legislation that would block next year’s cuts.

The current fight to stave off 2023 cuts seems like “déjà vu all over again,” said Kathleen Teixeira, AGA’s vice president of government affairs, in an interview with this news organization. Congress needs to shift away from the “Band-Aid approach” and concentrate on longer-term issues with physician payment, she said.

Rep. Bera and Rep. Buchson in September issued a letter seeking feedback on ways to “stabilize the Medicare payment system” without dramatically increasing the cost to taxpayers.

Louis Wilson, MD, chair of the American College of Gastroenterology’s legislative and public policy council, told this news organization that Congress needs to revisit Medicare’s physician payment system, especially in terms of addressing inflation.

Lawmakers’ attempts to restrain growth in Medicare physician payments have had the unintended consequence of fueling the acquisition of practices by hospitals, said Dr. Wilson, the managing partner of a physician-owned single-specialty private practice in Wichita Falls, Tex. Once doctors are employed by hospitals, Medicare often pays higher rates for their services than it would pay to physicians for providing the same care in a private practice.

Indeed, the Federal Trade Commission has said the U.S. physician workplace is “undergoing a dramatic restructuring,” with traditional solo practices and small single-specialty group practices rapidly being replaced by large multispecialty physician group practices, or practices that are owned or employed by hospital systems. The FTC is in the midst of a major series of studies on the effects of this consolidation.

“There’s been so much market distortion, so much limitation in innovation by failing to adequately pay in the Physician Fee Schedule, that the consequence is the widespread consolidation,” said Dr. Wilson. “That’s recognized on both sides of the aisle as being essentially expensive and inefficient and not in patients’ best interest.”

A single dose of oral acoziborole resulted in a greater than 95% cure or probable cure rate for human African trypanosomiasis (HAT), also known as sleeping sickness, according to results from a clinical trial testing a one-dose experimental drug.

The drug has “the potential to revolutionize treatment” for the disease, which remains endemic in sub-Saharan Africa, said Antoine Tarral, MD, head of the human African trypanosomiasis clinical program at the Drugs for Neglected Diseases initiative, based in Geneva, and senior author of the study, in a press release.

“It’s fantastic news, because it’s the first time that with one single administration you can treat the disease,” he told this news organization. “It’s the first drug we can use without hospitalization. ... All the previous medications needed hospitalization, and therefore we could not treat the population early before they started expressing symptoms.”

The World Health Organization “has been working for decades for such a possibility to implement a new strategy for this disease,” Dr. Tarral said.

Current (2019) WHO guidelines recommend oral fexinidazole as first-line treatment for any stage of the disease. The 10-day course often requires hospitalization and skilled staff. Previous recommendations required disease-staging with cerebrospinal fluid (CSF) sampling and 7 days of intramuscular pentamidine for early-stage disease or nifurtimox-eflornithine combination therapy (NECT) with hospitalization for late-stage disease.

By contrast, acoziborole, which was codeveloped by the DND initiative and Sanofi, “is administered in a single dose and is effective across every stage of the disease, thereby eliminating the many barriers currently in place for people most vulnerable to the diseases, such as invasive treatments and long travel distances to a hospital or clinic, and opening the door to screen-and-treat approaches at the village level,” Dr. Tarral said in the statement.

“Today, and in the future, we will have less and less support to do this long and costly diagnostic process and treatment in the hospital,” he said in an interview. “This development means we can go for a simple test and a simple treatment, which means we can meet the WHO 2030 goal for ending transmission of this disease.”

Results from the multicenter, prospective, open-label, single-arm, noncomparative, phase 2/3 study were published in The Lancet.
 

Pragmatic study design

Sleeping sickness is caused by Trypanosoma brucei gambiense (gambiense HAT). It is transmitted by the tsetse fly and mostly fatal when left untreated.

The study enrolled 208 adults and adolescents (167 with late-stage, and 41 with early-stage or intermediate-stage disease) from 10 hospitals in the Democratic Republic of the Congo and Guinea. All patients were treated with acoziborole 960 mg – an unusual study design.

“Due to the substantial decline in incidence, enrolling patients with gambiense HAT into clinical trials is challenging,” the authors wrote. “Following advice from the European Medicines Agency, this study was designed as an open-label, single-arm trial with no comparator or control group.”

After 18 months of follow-up, treatment success, defined as absence of trypanosomes and less than 20 white blood cells per mcL of CSF, occurred in 159 (95.2%) of the late-stage patients, and 100% of the early- and intermediate-stage patients, “which was similar to the estimated historical results for NECT,” the authors noted.

Serious treatment-emergent adverse events were reported in 21 (10%) of patients, “but none of these events were considered drug-related,” they added.

The DND initiative and the WHO are currently nearing completion of a much larger, double-blind, placebo-controlled trial of acoziborole to “increase the safety database,” Dr. Tarral explained.

“Purists will say that acoziborole has not been evaluated according to current standards, because the study was not a randomized trial, there was no control group, and the number of participants was small,” said Jacques Pépin, MD, from the University of Sherbrooke (Que.), in a linked commentary.

“But these were difficult challenges to overcome, considering the drastic reduction in the number of patients with HAT and dispersion over a vast territory, particularly in the Democratic Republic of the Congo. For these reasons, the authors took a pragmatic approach instead,” he wrote.
 

A potential new tool for eradication of sleeping sickness

“This is really an exciting development, which will be useful in the drive for eradication/interruption of transmission of this disease,” Dr. Pépin told this news organization.

Dr. Pépin treated around 1,000 trypanosomiasis patients during an outbreak in Zaire in the early 1980s. Because the asymptomatic incubation period for the disease can be several months or even years, “the core strategy for controlling the disease is active screening,” he said in an interview.

“You try to convince the whole population of endemic villages to show up on a given day, and then you have a mobile team of nurses who examine everybody, trying to find those with early trypanosomiasis. This includes physical examination for lymph nodes in the neck, but also a blood test whose results are available within minutes,” he said.

“Until now, these persons with a positive serology would undergo additional and labor-intensive examinations of blood to try to find trypanosomes and prove that they have the disease. So far those with a positive serology and negative parasitological assays (‘serological suspects’) were left untreated, because the treatments were toxic and cumbersome, and because a substantial but unknown proportion of these ‘suspects’ just have a false positive of their serological test, without having the disease,” Dr. Pépin said.

“Now with acoziborole, which seems to have little serious toxicity ... and can be given as a single-dose oral med, it might be reasonable to treat the ‘serological suspects,’ ” he said.

“Take it one step further, it might be possible to do the serological test only and treat all individuals with a positive serology without bothering to do parasitological assays. This is what they call ‘test-and-treat’ strategy. It would make sense, provided that we are sure that the drug is very well tolerated.”

Dr. Pépin added that he is “just slightly worried” about three patients described in the paper who had psychiatric adverse events 3 months after treatment. “If that happens to patients who indeed have trypanosomiasis, that’s a reasonable price to pay considering the toxicity of other drugs,” he said. “If that happens to serological suspects, many of whom don’t have any disease, this becomes a preoccupation.”

But Dr. Tarral said, “We have no indication that the drug can provoke psychiatric symptoms. In fact, the psychiatric symptoms did not emerge – they re-emerged after 3 months due to some patients’ refusal to be followed up.”

“We included patients in very advanced stages of the disease, and these symptoms are considered disease sequelae,” Dr. Tarral said. “The majority of patients who have such psychiatric symptoms need follow-up after treatment. If not, they can relapse very early. There were a lot of patients who had such symptoms and the investigators proposed they should be followed by a psychiatrist and some of them refused. And due to that only three of our patients had this relapse, and they were cured after psychiatric support.”

The study was funded through the DND initiative and was supported by grants from the Bill & Melinda Gates Foundation; UK Aid; the Federal Ministry of Education and Research through Kreditanstalt für Wiederaufbau, Germany; the Swiss Agency for Development and Cooperation; Médecins Sans Frontières; the Dutch Ministry of Foreign Affairs; the Norwegian Agency for Development Cooperation; the Stavros Niarchos Foundation; the Spanish Agency for International Development Cooperation; and the Banco Bilbao Vizcaya Argentaria Foundation.

A number of study investigators, including Dr. Tarral, report employment at the DND initiative. Other investigators report fees from the DND initiative for the statistical report, consulting fees from CEMAG, D&A Pharma, Inventiva, and OT4B Pharma. The Swiss Tropical and Public Health Institute acted as a service provider for the DND initiative by monitoring the study sites. Dr. Pépin declared no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A single dose of oral acoziborole resulted in a greater than 95% cure or probable cure rate for human African trypanosomiasis (HAT), also known as sleeping sickness, according to results from a clinical trial testing a one-dose experimental drug.

The drug has “the potential to revolutionize treatment” for the disease, which remains endemic in sub-Saharan Africa, said Antoine Tarral, MD, head of the human African trypanosomiasis clinical program at the Drugs for Neglected Diseases initiative, based in Geneva, and senior author of the study, in a press release.

“It’s fantastic news, because it’s the first time that with one single administration you can treat the disease,” he told this news organization. “It’s the first drug we can use without hospitalization. ... All the previous medications needed hospitalization, and therefore we could not treat the population early before they started expressing symptoms.”

The World Health Organization “has been working for decades for such a possibility to implement a new strategy for this disease,” Dr. Tarral said.

Current (2019) WHO guidelines recommend oral fexinidazole as first-line treatment for any stage of the disease. The 10-day course often requires hospitalization and skilled staff. Previous recommendations required disease-staging with cerebrospinal fluid (CSF) sampling and 7 days of intramuscular pentamidine for early-stage disease or nifurtimox-eflornithine combination therapy (NECT) with hospitalization for late-stage disease.

By contrast, acoziborole, which was codeveloped by the DND initiative and Sanofi, “is administered in a single dose and is effective across every stage of the disease, thereby eliminating the many barriers currently in place for people most vulnerable to the diseases, such as invasive treatments and long travel distances to a hospital or clinic, and opening the door to screen-and-treat approaches at the village level,” Dr. Tarral said in the statement.

“Today, and in the future, we will have less and less support to do this long and costly diagnostic process and treatment in the hospital,” he said in an interview. “This development means we can go for a simple test and a simple treatment, which means we can meet the WHO 2030 goal for ending transmission of this disease.”

Results from the multicenter, prospective, open-label, single-arm, noncomparative, phase 2/3 study were published in The Lancet.
 

Pragmatic study design

Sleeping sickness is caused by Trypanosoma brucei gambiense (gambiense HAT). It is transmitted by the tsetse fly and mostly fatal when left untreated.

The study enrolled 208 adults and adolescents (167 with late-stage, and 41 with early-stage or intermediate-stage disease) from 10 hospitals in the Democratic Republic of the Congo and Guinea. All patients were treated with acoziborole 960 mg – an unusual study design.

“Due to the substantial decline in incidence, enrolling patients with gambiense HAT into clinical trials is challenging,” the authors wrote. “Following advice from the European Medicines Agency, this study was designed as an open-label, single-arm trial with no comparator or control group.”

After 18 months of follow-up, treatment success, defined as absence of trypanosomes and less than 20 white blood cells per mcL of CSF, occurred in 159 (95.2%) of the late-stage patients, and 100% of the early- and intermediate-stage patients, “which was similar to the estimated historical results for NECT,” the authors noted.

Serious treatment-emergent adverse events were reported in 21 (10%) of patients, “but none of these events were considered drug-related,” they added.

The DND initiative and the WHO are currently nearing completion of a much larger, double-blind, placebo-controlled trial of acoziborole to “increase the safety database,” Dr. Tarral explained.

“Purists will say that acoziborole has not been evaluated according to current standards, because the study was not a randomized trial, there was no control group, and the number of participants was small,” said Jacques Pépin, MD, from the University of Sherbrooke (Que.), in a linked commentary.

“But these were difficult challenges to overcome, considering the drastic reduction in the number of patients with HAT and dispersion over a vast territory, particularly in the Democratic Republic of the Congo. For these reasons, the authors took a pragmatic approach instead,” he wrote.
 

A potential new tool for eradication of sleeping sickness

“This is really an exciting development, which will be useful in the drive for eradication/interruption of transmission of this disease,” Dr. Pépin told this news organization.

Dr. Pépin treated around 1,000 trypanosomiasis patients during an outbreak in Zaire in the early 1980s. Because the asymptomatic incubation period for the disease can be several months or even years, “the core strategy for controlling the disease is active screening,” he said in an interview.

“You try to convince the whole population of endemic villages to show up on a given day, and then you have a mobile team of nurses who examine everybody, trying to find those with early trypanosomiasis. This includes physical examination for lymph nodes in the neck, but also a blood test whose results are available within minutes,” he said.

“Until now, these persons with a positive serology would undergo additional and labor-intensive examinations of blood to try to find trypanosomes and prove that they have the disease. So far those with a positive serology and negative parasitological assays (‘serological suspects’) were left untreated, because the treatments were toxic and cumbersome, and because a substantial but unknown proportion of these ‘suspects’ just have a false positive of their serological test, without having the disease,” Dr. Pépin said.

“Now with acoziborole, which seems to have little serious toxicity ... and can be given as a single-dose oral med, it might be reasonable to treat the ‘serological suspects,’ ” he said.

“Take it one step further, it might be possible to do the serological test only and treat all individuals with a positive serology without bothering to do parasitological assays. This is what they call ‘test-and-treat’ strategy. It would make sense, provided that we are sure that the drug is very well tolerated.”

Dr. Pépin added that he is “just slightly worried” about three patients described in the paper who had psychiatric adverse events 3 months after treatment. “If that happens to patients who indeed have trypanosomiasis, that’s a reasonable price to pay considering the toxicity of other drugs,” he said. “If that happens to serological suspects, many of whom don’t have any disease, this becomes a preoccupation.”

But Dr. Tarral said, “We have no indication that the drug can provoke psychiatric symptoms. In fact, the psychiatric symptoms did not emerge – they re-emerged after 3 months due to some patients’ refusal to be followed up.”

“We included patients in very advanced stages of the disease, and these symptoms are considered disease sequelae,” Dr. Tarral said. “The majority of patients who have such psychiatric symptoms need follow-up after treatment. If not, they can relapse very early. There were a lot of patients who had such symptoms and the investigators proposed they should be followed by a psychiatrist and some of them refused. And due to that only three of our patients had this relapse, and they were cured after psychiatric support.”

The study was funded through the DND initiative and was supported by grants from the Bill & Melinda Gates Foundation; UK Aid; the Federal Ministry of Education and Research through Kreditanstalt für Wiederaufbau, Germany; the Swiss Agency for Development and Cooperation; Médecins Sans Frontières; the Dutch Ministry of Foreign Affairs; the Norwegian Agency for Development Cooperation; the Stavros Niarchos Foundation; the Spanish Agency for International Development Cooperation; and the Banco Bilbao Vizcaya Argentaria Foundation.

A number of study investigators, including Dr. Tarral, report employment at the DND initiative. Other investigators report fees from the DND initiative for the statistical report, consulting fees from CEMAG, D&A Pharma, Inventiva, and OT4B Pharma. The Swiss Tropical and Public Health Institute acted as a service provider for the DND initiative by monitoring the study sites. Dr. Pépin declared no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A single dose of oral acoziborole resulted in a greater than 95% cure or probable cure rate for human African trypanosomiasis (HAT), also known as sleeping sickness, according to results from a clinical trial testing a one-dose experimental drug.

The drug has “the potential to revolutionize treatment” for the disease, which remains endemic in sub-Saharan Africa, said Antoine Tarral, MD, head of the human African trypanosomiasis clinical program at the Drugs for Neglected Diseases initiative, based in Geneva, and senior author of the study, in a press release.

“It’s fantastic news, because it’s the first time that with one single administration you can treat the disease,” he told this news organization. “It’s the first drug we can use without hospitalization. ... All the previous medications needed hospitalization, and therefore we could not treat the population early before they started expressing symptoms.”

The World Health Organization “has been working for decades for such a possibility to implement a new strategy for this disease,” Dr. Tarral said.

Current (2019) WHO guidelines recommend oral fexinidazole as first-line treatment for any stage of the disease. The 10-day course often requires hospitalization and skilled staff. Previous recommendations required disease-staging with cerebrospinal fluid (CSF) sampling and 7 days of intramuscular pentamidine for early-stage disease or nifurtimox-eflornithine combination therapy (NECT) with hospitalization for late-stage disease.

By contrast, acoziborole, which was codeveloped by the DND initiative and Sanofi, “is administered in a single dose and is effective across every stage of the disease, thereby eliminating the many barriers currently in place for people most vulnerable to the diseases, such as invasive treatments and long travel distances to a hospital or clinic, and opening the door to screen-and-treat approaches at the village level,” Dr. Tarral said in the statement.

“Today, and in the future, we will have less and less support to do this long and costly diagnostic process and treatment in the hospital,” he said in an interview. “This development means we can go for a simple test and a simple treatment, which means we can meet the WHO 2030 goal for ending transmission of this disease.”

Results from the multicenter, prospective, open-label, single-arm, noncomparative, phase 2/3 study were published in The Lancet.
 

Pragmatic study design

Sleeping sickness is caused by Trypanosoma brucei gambiense (gambiense HAT). It is transmitted by the tsetse fly and mostly fatal when left untreated.

The study enrolled 208 adults and adolescents (167 with late-stage, and 41 with early-stage or intermediate-stage disease) from 10 hospitals in the Democratic Republic of the Congo and Guinea. All patients were treated with acoziborole 960 mg – an unusual study design.

“Due to the substantial decline in incidence, enrolling patients with gambiense HAT into clinical trials is challenging,” the authors wrote. “Following advice from the European Medicines Agency, this study was designed as an open-label, single-arm trial with no comparator or control group.”

After 18 months of follow-up, treatment success, defined as absence of trypanosomes and less than 20 white blood cells per mcL of CSF, occurred in 159 (95.2%) of the late-stage patients, and 100% of the early- and intermediate-stage patients, “which was similar to the estimated historical results for NECT,” the authors noted.

Serious treatment-emergent adverse events were reported in 21 (10%) of patients, “but none of these events were considered drug-related,” they added.

The DND initiative and the WHO are currently nearing completion of a much larger, double-blind, placebo-controlled trial of acoziborole to “increase the safety database,” Dr. Tarral explained.

“Purists will say that acoziborole has not been evaluated according to current standards, because the study was not a randomized trial, there was no control group, and the number of participants was small,” said Jacques Pépin, MD, from the University of Sherbrooke (Que.), in a linked commentary.

“But these were difficult challenges to overcome, considering the drastic reduction in the number of patients with HAT and dispersion over a vast territory, particularly in the Democratic Republic of the Congo. For these reasons, the authors took a pragmatic approach instead,” he wrote.
 

A potential new tool for eradication of sleeping sickness

“This is really an exciting development, which will be useful in the drive for eradication/interruption of transmission of this disease,” Dr. Pépin told this news organization.

Dr. Pépin treated around 1,000 trypanosomiasis patients during an outbreak in Zaire in the early 1980s. Because the asymptomatic incubation period for the disease can be several months or even years, “the core strategy for controlling the disease is active screening,” he said in an interview.

“You try to convince the whole population of endemic villages to show up on a given day, and then you have a mobile team of nurses who examine everybody, trying to find those with early trypanosomiasis. This includes physical examination for lymph nodes in the neck, but also a blood test whose results are available within minutes,” he said.

“Until now, these persons with a positive serology would undergo additional and labor-intensive examinations of blood to try to find trypanosomes and prove that they have the disease. So far those with a positive serology and negative parasitological assays (‘serological suspects’) were left untreated, because the treatments were toxic and cumbersome, and because a substantial but unknown proportion of these ‘suspects’ just have a false positive of their serological test, without having the disease,” Dr. Pépin said.

“Now with acoziborole, which seems to have little serious toxicity ... and can be given as a single-dose oral med, it might be reasonable to treat the ‘serological suspects,’ ” he said.

“Take it one step further, it might be possible to do the serological test only and treat all individuals with a positive serology without bothering to do parasitological assays. This is what they call ‘test-and-treat’ strategy. It would make sense, provided that we are sure that the drug is very well tolerated.”

Dr. Pépin added that he is “just slightly worried” about three patients described in the paper who had psychiatric adverse events 3 months after treatment. “If that happens to patients who indeed have trypanosomiasis, that’s a reasonable price to pay considering the toxicity of other drugs,” he said. “If that happens to serological suspects, many of whom don’t have any disease, this becomes a preoccupation.”

But Dr. Tarral said, “We have no indication that the drug can provoke psychiatric symptoms. In fact, the psychiatric symptoms did not emerge – they re-emerged after 3 months due to some patients’ refusal to be followed up.”

“We included patients in very advanced stages of the disease, and these symptoms are considered disease sequelae,” Dr. Tarral said. “The majority of patients who have such psychiatric symptoms need follow-up after treatment. If not, they can relapse very early. There were a lot of patients who had such symptoms and the investigators proposed they should be followed by a psychiatrist and some of them refused. And due to that only three of our patients had this relapse, and they were cured after psychiatric support.”

The study was funded through the DND initiative and was supported by grants from the Bill & Melinda Gates Foundation; UK Aid; the Federal Ministry of Education and Research through Kreditanstalt für Wiederaufbau, Germany; the Swiss Agency for Development and Cooperation; Médecins Sans Frontières; the Dutch Ministry of Foreign Affairs; the Norwegian Agency for Development Cooperation; the Stavros Niarchos Foundation; the Spanish Agency for International Development Cooperation; and the Banco Bilbao Vizcaya Argentaria Foundation.

A number of study investigators, including Dr. Tarral, report employment at the DND initiative. Other investigators report fees from the DND initiative for the statistical report, consulting fees from CEMAG, D&A Pharma, Inventiva, and OT4B Pharma. The Swiss Tropical and Public Health Institute acted as a service provider for the DND initiative by monitoring the study sites. Dr. Pépin declared no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A striking characteristic of COVID-19 is that the severity of clinical outcomes is remarkably variable. Establishing a prognosis for individuals infected with COVID-19 remains a challenge.

Since the start of the COVID-19 pandemic, the heterogeneity of individuals who progress toward severe disease or death, along with the fact that individuals directly exposed to the virus do not necessarily become sick, supports the hypothesis that genetic risk or protective factors are at play.

In an interview with this news organization, Mayana Zatz, PhD, head professor of genetics and coordinator of the Human Genome and Stem Cell Study Center at the University of São Paulo, explained: “The first case that caught my eye was the case of my neighbors, a couple. He presented COVID-19 symptoms, but his wife, who took care of him, had absolutely no symptoms. I thought that it was strange, but we received 3,000 emails from people saying, ‘This happened to me, too.’”

Reports in the media about seven pairs of monozygotic (MZ) twins who died from COVID-19 within days of one another in Brazil also stood out, said the researcher.

Twin studies are important for investigating the contribution of genetics vs. that of the environment in the susceptibility or resistance to infectious diseases, as well as their pathology. Dr. Zatz’s team analyzed the case of a 31-year-old Brazilian MZ twin brother pair who presented simultaneously with severe COVID-19 and the need for oxygen support, despite their age and good health conditions. Curiously, they were admitted and intubated on the same day, but neither of the twins knew about the other’s situation; they found out only when they were extubated.

The study was carried out at the USP with the collaboration of the State University of São Paulo. The authors mapped the genetic profile (by sequencing the genome responsible for coding proteins, or whole-exome sequencing) and the immune cell profile to evaluate innate and adaptive immunity.

The MZ twin brothers shared the same two rare genetic mutations, which may be associated with their increased risk of developing severe COVID-19. However, since these variants were not studied at the protein or functional level, their pathogenicity has yet to be determined. The twins also had [human leukocyte antigen (HLA)] alleles associated with severe COVID-19, which are important candidates for the mechanisms of innate and adaptive immunity and susceptibility to COVID-19 infection and manifestation.

But one particular oddity stood out to the researchers: One of the brothers required longer hospitalization, and only he reported symptoms of long COVID.

In the authors’ eyes, even though the patients shared genetic mutations potentially associated with the risk of developing severe COVID-19, the differences in clinical progression emphasize that, beyond genetic risk factors, continuous exposure to pathogens over a lifetime and other environmental factors mean that each individual’s immune response is unique, even in twins.

“There is no doubt that genetics contribute to the severity of COVID-19, and environmental factors sometimes give us the opportunity to study the disease, too. Such [is the case with] MZ twins who have genetic similarities, even with changes that take place over a lifetime,” José Eduardo Krieger, MD, PhD, professor of molecular medicine at the University of São Paulo Medical School (FMUSP), told this news organization. “Examining MZ twins is a strategy that may help, but, with n = 2, luck really needs to be on your side to get straight to the problem. You need to combine [these findings] with other studies to solve this conundrum,” said Dr. Krieger, who did not take part in the research.
 

Large cohorts

Genomic and computer resources allow for the study of large sets of data from thousands of individuals. In each of those sets of data, the signal offered by thousands of markers distributed throughout the genome can be studied. This is the possibility offered by various genomic studies of large cohorts of patients with different clinical manifestations.

“Researchers examine thousands of genetic variants throughout the genome from a large sample of individuals and have the chance, for example, to identify genetic variants that are more prevalent in patients who have presented with severe disease than in those who presented with milder disease,” said Dr. Krieger. “These associations highlight a chromosome region in which one or more genes explain, at least in part, the differences observed.”

Genomewide association studies have identified some genetic variants that indicate severity of COVID-19, with potential impact on the virus entering the cell, the immune response, or the development of cytokine storms.

One of these studies, COVID-19 Host Genetics Initiative (COVID-19 HGI), is an international, open-science collaboration for sharing scientific methods and resources with research groups across the world, with the goal of robustly mapping the host genetic determinants of SARS-CoV-2 infection and the severity of the resulting COVID-19 disease. At the start of 2021, the COVID-19 HGI combined genetic data from 49,562 cases and 2 million controls from 46 studies in 19 countries. A total of 853 samples from the BRACOVID study were included in the meta-analysis. The endeavor enabled the identification of 13 genomewide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19.

The BRACOVID study, in which Dr. Krieger participates, aims to identify host genetic factors that determine the severity of COVID-19. It is currently the largest project of its kind in Latin America. An article provides the analysis of the first 5,233 participants in the BRACOVID study, who were recruited in São Paulo. Of these participants, 3,533 had been infected with COVID-19 and hospitalized at either the Heart Institute or the Central Institute of the FMUSP General Hospital. The remaining 1,700 made up the control group, which included health care professionals and members of the general population. The controls were recruited through serology assays or PCR tests for SARS-CoV-2.

The researchers discovered a region of chromosome 1 that could play a role in modulating immune response and that could lead to an increase in the likelihood of hospitalization across a wide range of COVID-19 risk factors. This region of chromosome 1 was observed only in Brazilians with a strong European ancestry; however, this finding had not been mentioned in previous studies, suggesting that it could harbor a risk allele specific to the Brazilian population.

The study also confirmed most, but not all, of the regions recorded in the literature, which may be significant in identifying factors determining severity that are specific to a given population.

Including information from the BRACOVID study, other studies have enhanced the knowledge on affected organs. Combined data from 14,000 patients from nine countries evaluated a region of a single chromosome and found that carriers of a certain allele had a higher probability of experiencing various COVID-19 complications, such as severe respiratory failure, venous thromboembolism, and liver damage. The risk was even higher for individuals aged 60 years and over.
 

Discordant couples

Smaller sample sizes of underrepresented populations also provide relevant data for genomic studies. Dr. Zatz’s team carried out genomic studies on smaller groups, comparing serodiscordant couples (where one was infected and symptomatic while the partner remained asymptomatic and seronegative despite sharing the same bedroom during the infection). Their research found genetic variants related to immune response that were associated with susceptibility to infection and progression to severe COVID-19. 

The team also went on to study a group of patients older than 90 years who recovered from COVID-19 with mild symptoms or who remained asymptomatic following a positive test for SARS-CoV-2. They compared these patients with a sample of elderly patients from the same city (São Paulo), sampled before the current pandemic. The researchers identified a genetic variant related to mucin production. “In individuals with mild COVID-19, the degradation of these mucins would be more efficient,” said Dr. Zatz. It is possible for this variant to interfere not only with the production of mucus, but also in its composition, as there is an exchange of amino acids in the protein.

“We continued the study by comparing the extremes, i.e., those in their 90s with mild COVID-19 and younger patients with severe COVID-19, including several who died,” said Dr. Zatz.
 

More personalized medicine

The specialists agreed that a genetic test to predict COVID-19 severity is still a long way away. The genetic component is too little understood to enable the evaluation of individual risk. It has been possible to identify several important areas but, as Dr. Krieger pointed out, a variant identified in a certain chromosome interval may not be just one gene. There may be various candidate genes, or there may be a regulatory sequence for a distant gene. Furthermore, there are regions with genes that make sense as moderators of COVID-19 severity, because they regulate an inflammatory or immunologic reaction, but evidence is still lacking.

Reaching the molecular mechanism would, in future, allow a medicine to be chosen for a given patient, as already happens with other diseases. It also could enable the discovery of new medicines following as-yet-unexplored lines of research. Dr. Zatz also considers the possibility of genetic therapy.

Even with the knowledge of human genetics, one part of the equation is missing: viral genetics. “Many of the individuals who were resistant to the Delta variant were later affected by Omicron,” she pointed out.
 

Significance of Brazil

“We have an infinite amount of genomic data worldwide, but the vast majority originates from White Americans of European origin,” said Dr. Krieger. Moreover, genomic associations of COVID-19 severity discovered in the Chinese population were not significant in the European population. Besides underscoring the importance of collaborating with international studies, this situation supports scientists’ interest in carrying out genetic studies within Brazil, he added.

“In the genomic study of the Brazilian population, we found 2 million variants that were not present in the European populations,” said Dr. Zatz.

Dr. Krieger mentioned a technical advantage that Brazil has. “Having been colonized by different ethnic groups and mixed many generations ago, Brazil has a population with a unique genetic structure; the recombinations are different. When preparing the samples, the regions break differently.” This factor could help to separate, in a candidate region, the gene that is significant from those that might not be.

In general, severe COVID-19 would be a complex phenomenon involving several genes and interactions with environmental factors. The Brazilian studies tried to find a factor that was unique to Brazil, but the significance of the differences remained unclear. “We found some signs that were specific to our population,” concluded Dr. Krieger. “But the reason that more people in Brazil died as a result of COVID-19 was not genetic,” he added.

Dr. Zatz and Dr. Krieger reported no conflicts of interest. This article was translated from the Medscape Portuguese edition.

A version of this article first appeared on Medscape.com.

A striking characteristic of COVID-19 is that the severity of clinical outcomes is remarkably variable. Establishing a prognosis for individuals infected with COVID-19 remains a challenge.

Since the start of the COVID-19 pandemic, the heterogeneity of individuals who progress toward severe disease or death, along with the fact that individuals directly exposed to the virus do not necessarily become sick, supports the hypothesis that genetic risk or protective factors are at play.

In an interview with this news organization, Mayana Zatz, PhD, head professor of genetics and coordinator of the Human Genome and Stem Cell Study Center at the University of São Paulo, explained: “The first case that caught my eye was the case of my neighbors, a couple. He presented COVID-19 symptoms, but his wife, who took care of him, had absolutely no symptoms. I thought that it was strange, but we received 3,000 emails from people saying, ‘This happened to me, too.’”

Reports in the media about seven pairs of monozygotic (MZ) twins who died from COVID-19 within days of one another in Brazil also stood out, said the researcher.

Twin studies are important for investigating the contribution of genetics vs. that of the environment in the susceptibility or resistance to infectious diseases, as well as their pathology. Dr. Zatz’s team analyzed the case of a 31-year-old Brazilian MZ twin brother pair who presented simultaneously with severe COVID-19 and the need for oxygen support, despite their age and good health conditions. Curiously, they were admitted and intubated on the same day, but neither of the twins knew about the other’s situation; they found out only when they were extubated.

The study was carried out at the USP with the collaboration of the State University of São Paulo. The authors mapped the genetic profile (by sequencing the genome responsible for coding proteins, or whole-exome sequencing) and the immune cell profile to evaluate innate and adaptive immunity.

The MZ twin brothers shared the same two rare genetic mutations, which may be associated with their increased risk of developing severe COVID-19. However, since these variants were not studied at the protein or functional level, their pathogenicity has yet to be determined. The twins also had [human leukocyte antigen (HLA)] alleles associated with severe COVID-19, which are important candidates for the mechanisms of innate and adaptive immunity and susceptibility to COVID-19 infection and manifestation.

But one particular oddity stood out to the researchers: One of the brothers required longer hospitalization, and only he reported symptoms of long COVID.

In the authors’ eyes, even though the patients shared genetic mutations potentially associated with the risk of developing severe COVID-19, the differences in clinical progression emphasize that, beyond genetic risk factors, continuous exposure to pathogens over a lifetime and other environmental factors mean that each individual’s immune response is unique, even in twins.

“There is no doubt that genetics contribute to the severity of COVID-19, and environmental factors sometimes give us the opportunity to study the disease, too. Such [is the case with] MZ twins who have genetic similarities, even with changes that take place over a lifetime,” José Eduardo Krieger, MD, PhD, professor of molecular medicine at the University of São Paulo Medical School (FMUSP), told this news organization. “Examining MZ twins is a strategy that may help, but, with n = 2, luck really needs to be on your side to get straight to the problem. You need to combine [these findings] with other studies to solve this conundrum,” said Dr. Krieger, who did not take part in the research.
 

Large cohorts

Genomic and computer resources allow for the study of large sets of data from thousands of individuals. In each of those sets of data, the signal offered by thousands of markers distributed throughout the genome can be studied. This is the possibility offered by various genomic studies of large cohorts of patients with different clinical manifestations.

“Researchers examine thousands of genetic variants throughout the genome from a large sample of individuals and have the chance, for example, to identify genetic variants that are more prevalent in patients who have presented with severe disease than in those who presented with milder disease,” said Dr. Krieger. “These associations highlight a chromosome region in which one or more genes explain, at least in part, the differences observed.”

Genomewide association studies have identified some genetic variants that indicate severity of COVID-19, with potential impact on the virus entering the cell, the immune response, or the development of cytokine storms.

One of these studies, COVID-19 Host Genetics Initiative (COVID-19 HGI), is an international, open-science collaboration for sharing scientific methods and resources with research groups across the world, with the goal of robustly mapping the host genetic determinants of SARS-CoV-2 infection and the severity of the resulting COVID-19 disease. At the start of 2021, the COVID-19 HGI combined genetic data from 49,562 cases and 2 million controls from 46 studies in 19 countries. A total of 853 samples from the BRACOVID study were included in the meta-analysis. The endeavor enabled the identification of 13 genomewide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19.

The BRACOVID study, in which Dr. Krieger participates, aims to identify host genetic factors that determine the severity of COVID-19. It is currently the largest project of its kind in Latin America. An article provides the analysis of the first 5,233 participants in the BRACOVID study, who were recruited in São Paulo. Of these participants, 3,533 had been infected with COVID-19 and hospitalized at either the Heart Institute or the Central Institute of the FMUSP General Hospital. The remaining 1,700 made up the control group, which included health care professionals and members of the general population. The controls were recruited through serology assays or PCR tests for SARS-CoV-2.

The researchers discovered a region of chromosome 1 that could play a role in modulating immune response and that could lead to an increase in the likelihood of hospitalization across a wide range of COVID-19 risk factors. This region of chromosome 1 was observed only in Brazilians with a strong European ancestry; however, this finding had not been mentioned in previous studies, suggesting that it could harbor a risk allele specific to the Brazilian population.

The study also confirmed most, but not all, of the regions recorded in the literature, which may be significant in identifying factors determining severity that are specific to a given population.

Including information from the BRACOVID study, other studies have enhanced the knowledge on affected organs. Combined data from 14,000 patients from nine countries evaluated a region of a single chromosome and found that carriers of a certain allele had a higher probability of experiencing various COVID-19 complications, such as severe respiratory failure, venous thromboembolism, and liver damage. The risk was even higher for individuals aged 60 years and over.
 

Discordant couples

Smaller sample sizes of underrepresented populations also provide relevant data for genomic studies. Dr. Zatz’s team carried out genomic studies on smaller groups, comparing serodiscordant couples (where one was infected and symptomatic while the partner remained asymptomatic and seronegative despite sharing the same bedroom during the infection). Their research found genetic variants related to immune response that were associated with susceptibility to infection and progression to severe COVID-19. 

The team also went on to study a group of patients older than 90 years who recovered from COVID-19 with mild symptoms or who remained asymptomatic following a positive test for SARS-CoV-2. They compared these patients with a sample of elderly patients from the same city (São Paulo), sampled before the current pandemic. The researchers identified a genetic variant related to mucin production. “In individuals with mild COVID-19, the degradation of these mucins would be more efficient,” said Dr. Zatz. It is possible for this variant to interfere not only with the production of mucus, but also in its composition, as there is an exchange of amino acids in the protein.

“We continued the study by comparing the extremes, i.e., those in their 90s with mild COVID-19 and younger patients with severe COVID-19, including several who died,” said Dr. Zatz.
 

More personalized medicine

The specialists agreed that a genetic test to predict COVID-19 severity is still a long way away. The genetic component is too little understood to enable the evaluation of individual risk. It has been possible to identify several important areas but, as Dr. Krieger pointed out, a variant identified in a certain chromosome interval may not be just one gene. There may be various candidate genes, or there may be a regulatory sequence for a distant gene. Furthermore, there are regions with genes that make sense as moderators of COVID-19 severity, because they regulate an inflammatory or immunologic reaction, but evidence is still lacking.

Reaching the molecular mechanism would, in future, allow a medicine to be chosen for a given patient, as already happens with other diseases. It also could enable the discovery of new medicines following as-yet-unexplored lines of research. Dr. Zatz also considers the possibility of genetic therapy.

Even with the knowledge of human genetics, one part of the equation is missing: viral genetics. “Many of the individuals who were resistant to the Delta variant were later affected by Omicron,” she pointed out.
 

Significance of Brazil

“We have an infinite amount of genomic data worldwide, but the vast majority originates from White Americans of European origin,” said Dr. Krieger. Moreover, genomic associations of COVID-19 severity discovered in the Chinese population were not significant in the European population. Besides underscoring the importance of collaborating with international studies, this situation supports scientists’ interest in carrying out genetic studies within Brazil, he added.

“In the genomic study of the Brazilian population, we found 2 million variants that were not present in the European populations,” said Dr. Zatz.

Dr. Krieger mentioned a technical advantage that Brazil has. “Having been colonized by different ethnic groups and mixed many generations ago, Brazil has a population with a unique genetic structure; the recombinations are different. When preparing the samples, the regions break differently.” This factor could help to separate, in a candidate region, the gene that is significant from those that might not be.

In general, severe COVID-19 would be a complex phenomenon involving several genes and interactions with environmental factors. The Brazilian studies tried to find a factor that was unique to Brazil, but the significance of the differences remained unclear. “We found some signs that were specific to our population,” concluded Dr. Krieger. “But the reason that more people in Brazil died as a result of COVID-19 was not genetic,” he added.

Dr. Zatz and Dr. Krieger reported no conflicts of interest. This article was translated from the Medscape Portuguese edition.

A version of this article first appeared on Medscape.com.

A striking characteristic of COVID-19 is that the severity of clinical outcomes is remarkably variable. Establishing a prognosis for individuals infected with COVID-19 remains a challenge.

Since the start of the COVID-19 pandemic, the heterogeneity of individuals who progress toward severe disease or death, along with the fact that individuals directly exposed to the virus do not necessarily become sick, supports the hypothesis that genetic risk or protective factors are at play.

In an interview with this news organization, Mayana Zatz, PhD, head professor of genetics and coordinator of the Human Genome and Stem Cell Study Center at the University of São Paulo, explained: “The first case that caught my eye was the case of my neighbors, a couple. He presented COVID-19 symptoms, but his wife, who took care of him, had absolutely no symptoms. I thought that it was strange, but we received 3,000 emails from people saying, ‘This happened to me, too.’”

Reports in the media about seven pairs of monozygotic (MZ) twins who died from COVID-19 within days of one another in Brazil also stood out, said the researcher.

Twin studies are important for investigating the contribution of genetics vs. that of the environment in the susceptibility or resistance to infectious diseases, as well as their pathology. Dr. Zatz’s team analyzed the case of a 31-year-old Brazilian MZ twin brother pair who presented simultaneously with severe COVID-19 and the need for oxygen support, despite their age and good health conditions. Curiously, they were admitted and intubated on the same day, but neither of the twins knew about the other’s situation; they found out only when they were extubated.

The study was carried out at the USP with the collaboration of the State University of São Paulo. The authors mapped the genetic profile (by sequencing the genome responsible for coding proteins, or whole-exome sequencing) and the immune cell profile to evaluate innate and adaptive immunity.

The MZ twin brothers shared the same two rare genetic mutations, which may be associated with their increased risk of developing severe COVID-19. However, since these variants were not studied at the protein or functional level, their pathogenicity has yet to be determined. The twins also had [human leukocyte antigen (HLA)] alleles associated with severe COVID-19, which are important candidates for the mechanisms of innate and adaptive immunity and susceptibility to COVID-19 infection and manifestation.

But one particular oddity stood out to the researchers: One of the brothers required longer hospitalization, and only he reported symptoms of long COVID.

In the authors’ eyes, even though the patients shared genetic mutations potentially associated with the risk of developing severe COVID-19, the differences in clinical progression emphasize that, beyond genetic risk factors, continuous exposure to pathogens over a lifetime and other environmental factors mean that each individual’s immune response is unique, even in twins.

“There is no doubt that genetics contribute to the severity of COVID-19, and environmental factors sometimes give us the opportunity to study the disease, too. Such [is the case with] MZ twins who have genetic similarities, even with changes that take place over a lifetime,” José Eduardo Krieger, MD, PhD, professor of molecular medicine at the University of São Paulo Medical School (FMUSP), told this news organization. “Examining MZ twins is a strategy that may help, but, with n = 2, luck really needs to be on your side to get straight to the problem. You need to combine [these findings] with other studies to solve this conundrum,” said Dr. Krieger, who did not take part in the research.
 

Large cohorts

Genomic and computer resources allow for the study of large sets of data from thousands of individuals. In each of those sets of data, the signal offered by thousands of markers distributed throughout the genome can be studied. This is the possibility offered by various genomic studies of large cohorts of patients with different clinical manifestations.

“Researchers examine thousands of genetic variants throughout the genome from a large sample of individuals and have the chance, for example, to identify genetic variants that are more prevalent in patients who have presented with severe disease than in those who presented with milder disease,” said Dr. Krieger. “These associations highlight a chromosome region in which one or more genes explain, at least in part, the differences observed.”

Genomewide association studies have identified some genetic variants that indicate severity of COVID-19, with potential impact on the virus entering the cell, the immune response, or the development of cytokine storms.

One of these studies, COVID-19 Host Genetics Initiative (COVID-19 HGI), is an international, open-science collaboration for sharing scientific methods and resources with research groups across the world, with the goal of robustly mapping the host genetic determinants of SARS-CoV-2 infection and the severity of the resulting COVID-19 disease. At the start of 2021, the COVID-19 HGI combined genetic data from 49,562 cases and 2 million controls from 46 studies in 19 countries. A total of 853 samples from the BRACOVID study were included in the meta-analysis. The endeavor enabled the identification of 13 genomewide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19.

The BRACOVID study, in which Dr. Krieger participates, aims to identify host genetic factors that determine the severity of COVID-19. It is currently the largest project of its kind in Latin America. An article provides the analysis of the first 5,233 participants in the BRACOVID study, who were recruited in São Paulo. Of these participants, 3,533 had been infected with COVID-19 and hospitalized at either the Heart Institute or the Central Institute of the FMUSP General Hospital. The remaining 1,700 made up the control group, which included health care professionals and members of the general population. The controls were recruited through serology assays or PCR tests for SARS-CoV-2.

The researchers discovered a region of chromosome 1 that could play a role in modulating immune response and that could lead to an increase in the likelihood of hospitalization across a wide range of COVID-19 risk factors. This region of chromosome 1 was observed only in Brazilians with a strong European ancestry; however, this finding had not been mentioned in previous studies, suggesting that it could harbor a risk allele specific to the Brazilian population.

The study also confirmed most, but not all, of the regions recorded in the literature, which may be significant in identifying factors determining severity that are specific to a given population.

Including information from the BRACOVID study, other studies have enhanced the knowledge on affected organs. Combined data from 14,000 patients from nine countries evaluated a region of a single chromosome and found that carriers of a certain allele had a higher probability of experiencing various COVID-19 complications, such as severe respiratory failure, venous thromboembolism, and liver damage. The risk was even higher for individuals aged 60 years and over.
 

Discordant couples

Smaller sample sizes of underrepresented populations also provide relevant data for genomic studies. Dr. Zatz’s team carried out genomic studies on smaller groups, comparing serodiscordant couples (where one was infected and symptomatic while the partner remained asymptomatic and seronegative despite sharing the same bedroom during the infection). Their research found genetic variants related to immune response that were associated with susceptibility to infection and progression to severe COVID-19. 

The team also went on to study a group of patients older than 90 years who recovered from COVID-19 with mild symptoms or who remained asymptomatic following a positive test for SARS-CoV-2. They compared these patients with a sample of elderly patients from the same city (São Paulo), sampled before the current pandemic. The researchers identified a genetic variant related to mucin production. “In individuals with mild COVID-19, the degradation of these mucins would be more efficient,” said Dr. Zatz. It is possible for this variant to interfere not only with the production of mucus, but also in its composition, as there is an exchange of amino acids in the protein.

“We continued the study by comparing the extremes, i.e., those in their 90s with mild COVID-19 and younger patients with severe COVID-19, including several who died,” said Dr. Zatz.
 

More personalized medicine

The specialists agreed that a genetic test to predict COVID-19 severity is still a long way away. The genetic component is too little understood to enable the evaluation of individual risk. It has been possible to identify several important areas but, as Dr. Krieger pointed out, a variant identified in a certain chromosome interval may not be just one gene. There may be various candidate genes, or there may be a regulatory sequence for a distant gene. Furthermore, there are regions with genes that make sense as moderators of COVID-19 severity, because they regulate an inflammatory or immunologic reaction, but evidence is still lacking.

Reaching the molecular mechanism would, in future, allow a medicine to be chosen for a given patient, as already happens with other diseases. It also could enable the discovery of new medicines following as-yet-unexplored lines of research. Dr. Zatz also considers the possibility of genetic therapy.

Even with the knowledge of human genetics, one part of the equation is missing: viral genetics. “Many of the individuals who were resistant to the Delta variant were later affected by Omicron,” she pointed out.
 

Significance of Brazil

“We have an infinite amount of genomic data worldwide, but the vast majority originates from White Americans of European origin,” said Dr. Krieger. Moreover, genomic associations of COVID-19 severity discovered in the Chinese population were not significant in the European population. Besides underscoring the importance of collaborating with international studies, this situation supports scientists’ interest in carrying out genetic studies within Brazil, he added.

“In the genomic study of the Brazilian population, we found 2 million variants that were not present in the European populations,” said Dr. Zatz.

Dr. Krieger mentioned a technical advantage that Brazil has. “Having been colonized by different ethnic groups and mixed many generations ago, Brazil has a population with a unique genetic structure; the recombinations are different. When preparing the samples, the regions break differently.” This factor could help to separate, in a candidate region, the gene that is significant from those that might not be.

In general, severe COVID-19 would be a complex phenomenon involving several genes and interactions with environmental factors. The Brazilian studies tried to find a factor that was unique to Brazil, but the significance of the differences remained unclear. “We found some signs that were specific to our population,” concluded Dr. Krieger. “But the reason that more people in Brazil died as a result of COVID-19 was not genetic,” he added.

Dr. Zatz and Dr. Krieger reported no conflicts of interest. This article was translated from the Medscape Portuguese edition.

A version of this article first appeared on Medscape.com.

By the time Mira Halker started high school, hardly a day passed that she wasn’t either getting a migraine attack or recovering from one. She missed volleyball team practice. She missed classes. She missed social events. And few people understood. After all, she looked healthy.

“A lot of times, people think I’m faking it,” said Mira, now 16, who lives in Phoenix. Friends called her flaky; her volleyball coaches questioned her dedication to the team. “I’m like, ‘I’m not trying to get out of this. This is not what this is about,’ ” she said.

Her mother, Rashmi B. Halker Singh, MD, is a neurologist at Mayo Clinic who happens to specialize in migraine. Even so, finding a solution was not easy. Neither ibuprofen nor triptans, nor various preventive measures such as a daily prescription for topiramate controlled the pain and associated symptoms. Mira was barely making it through her school day and had to quit volleyball. Then, in the spring of 10th grade, Mira told her mother that she couldn’t go to prom because the loud noises and lights could give her a migraine attack.

Mother and daughter decided it was time to get even more aggressive. “There are these key moments in life that you can’t get back,” Dr. Singh said. “Migraine steals so much from you.”
 

Diagnosis

One of the challenges Mira’s physicians faced was deciding which medications and other therapies to prescribe to a teenager. Drug companies have been releasing a steady stream of new treatments for migraine headaches, and researchers promise more are on the way soon. Here’s what works for children, what hasn’t yet been approved for use with minors, and how to diagnose migraines in the first place, from experts at some of the nation’s leading pediatric headache centers.

Migraine affects about 10% of children, according to the American Migraine Foundation. The headaches can strike children as early as age 3 or 4 years, said Robert Little, MD, a pediatric neurologist at Phoenix Children’s Hospital.

Before puberty, boys report more migraine attacks than girls, according to the American Academy of Pediatrics. But that reverses in adolescence: By age 17, as many as 8% of boys and 23% of girls have had migraine. To diagnose migraine, Juliana H. VanderPluym, MD, associate professor of neurology at Mayo Clinic in Phoenix, said she uses the criteria published in the latest edition of the International Classification of Headache Disorders (ICHD): A patient must have had at least five attacks in their life; and in children and adolescents, the attacks must last no less than 2 hours.

In addition, the headaches should exhibit at least two out of four features:

1. Occur more on one side of the head than the other (although Dr. VanderPluym said in children and adolescents headaches often are bilateral).

2. Be of moderate to severe intensity.

3. Have a pounding or throbbing quality.

4. Grow worse with activity or cause an avoidance of activity.

If the attacks meet those criteria, clinicians should check to see if they meet at least one out of the two following:

1. Are sensitive to light and sounds.

2. Are associated with nausea and/or vomiting.

A clinician should consider whether the headaches are not better accounted for by another diagnosis, according to the ICHD criteria. But, Dr. VanderPluym warned that does not necessarily mean running a slew of tests.

“In the absence of red flag features, it is more than likely going to be migraine headache,” she said. That’s especially true if a child has a family history of migraine, as the condition is often passed down from parent to child.

Ultimately, the diagnosis is fairly simple and can be made in a minute or less, said Jack Gladstein, MD, a pediatrician at the University of Maryland whose research focuses on the clinical care of children and adolescents with headache.

“Migraine is acute,” Dr. Gladstein said. “It’s really bad. And it’s recurrent.”
 

First line of treatment

Whatever a patient takes to treat a migraine, they should hit it early and hard, Dr. Gladstein said.

“The first thing you say, as a primary care physician, is treat your migraine at first twinge, whatever you use. Don’t wait, don’t wish it away,” he said. “The longer you wait, the less chance anything will work.”

The second piece of advice, Dr. Gladstein said, is that whatever drug a patient is taking, they should be on the highest feasible dose. “Work as fast as you can to treat them. You want the brain to reset as quickly as you can,” he said.

Patients should begin with over-the-counter pain relievers, Dr. Little said. If those prove insufficient, they can try a triptan. Rizatriptan is the only such agent that the Food and Drug Administration has approved for children aged 6-17 years. Other drugs in the class – sumatriptan/naproxen, almotriptan, and zolmitriptan – are approved for children 12 and older.

Another migraine therapy recently approved for children aged 12 and older is the use of neurostimulators. “It’s helpful to be aware of them,” Dr. VanderPluym said.

However, if neurostimulators and acute medications prove insufficient, clinicians should warn patients not to up their doses of triptans. Rebound headaches can occur if patients take triptans more than twice a week, or a maximum 10 days per month.

Another possibility is to add a preventive therapy. One mild, first option is nutraceuticals, like riboflavin (vitamin B₂) or magnesium, said Anisa F. Kelley, MD, a neurologist and associate director of the headache program at the Ann and Robert H. Lurie Children’s Hospital of Chicago.

“We don’t have definitive evidence, but they’re probably doing more benefit than they are harm,” Dr. Kelley said of these therapies. “In patients who have anywhere from 4 to 8 migraine days a month, where you’re in that in-between period where you don’t necessarily need a [prescription] prophylactic, I will often start with a nutraceutical,” Dr. Kelley said.

For those patients who don’t respond to nutraceuticals, or who need more support, clinicians can prescribe amitriptyline or topiramate. Dr. VanderPluym said.

A 2017 study found such prophylactics to be no more effective than placebo in pediatric migraine patients, but experts caution the results should not be considered definitive.

For one thing, the study enrolled a highly selective group of participants, with milder forms of migraine who may have improved anyway, Dr. VanderPluym said. All participants also received lifestyle counseling.

Every time participants came in for a follow-up, they were asked questions such as how much water were they drinking and how much sleep were they getting, Dr. Kelley noted. The takeaway, she said: “Pediatric and adolescent migraine [management] is very, very much reliant on lifestyle factors.”
 

Lifestyle triggers

Clinicians should counsel their migraine patients about lifestyle changes, experts said. Getting adequate sleep, staying hydrated, and managing stress can help reduce the intensity and frequency of attacks.

Migraine patients should also be mindful of their screen time, Dr. Kelley added.

“I’ve had lots and lots of patients who find excessive screen time will trigger or worsen migraine,” she said.

As for other potential triggers of attacks, the evidence is mixed.

“There’s clearly an association with disrupted sleep and migraine, and that has been very well established,” Dr. Little said. “And there is some modest amount of evidence that regular exercise can be helpful.” But for reported food triggers, he said, there have been very inconclusive results.

Commonly reported triggers include MSG, red wine, chocolate, and aged cheese. When Dr. Little’s patients keep headache diaries, tracking their meals alongside when they got migraine attacks, they often discover individualized triggers – strawberries, for instance, in one case, he said.

Scientists believe migraines result from the inappropriate activation of the trigeminal ganglion. “The question is, what causes it to get triggered? And how does it get triggered?” Dr. Gladstein said. “And that’s where there’s a lot of difference of opinion and no conclusive evidence.” Clinicians also should make sure that something else – usually depression, anxiety, insomnia, and dizziness – is not hindering effective migraine management. “If someone has terrible insomnia, until you treat the insomnia, the headaches aren’t going to get better,” he said.

As for Mira, her migraine attacks did not significantly improve, despite trying triptans, prophylactics, lifestyle changes, and shots to block nerve pain. When the headaches threatened Mira’s chance to go to her prom, her neurologist suggested trying something different. The physician persuaded the family’s insurance to cover a calcitonin gene-related peptide antagonist, an injectable monoclonal antibody treatment for migraine that the FDA has currently approved only for use in adults.

The difference for Mira has been extraordinary.

“I can do so much more than I was able to do,” said Mira, who attended the dance migraine free. “I feel liberated.”

It’s only migraine

One of the greatest challenges in diagnosing migraine can be reassuring the patient, the parents, even clinicians themselves that migraine really is the cause of all this pain and discomfort, experts said.

“A lot of migraine treatment actually comes down to migraine education,” Dr. VanderPluym said.

Patients and their parents often wonder how they can be sure that this pain is not resulting from something more dangerous than migraine, Dr. Little said. In these cases, he cites practice guidelines published by the American Academy of Neurology.

“The gist of those guidelines is that most pediatric patients do not need further workup,” he said. “But I think that there’s always a fear that you’re missing something because we don’t have a test that we can do” for migraine.

Some warning signs that further tests might be warranted, Dr. Kelley said, include:

• Headaches that wake a patient up in the middle of the night.
• Headaches that start first thing in the morning, especially those that include vomiting.
• A headache pattern that suddenly gets much worse.
• Certain symptoms that accompany the headache, such as tingling, numbness or double vision.

Although all of these signs can still stem from migraines – tingling or numbness, for instance, can be signs of migraine aura – running additional tests can rule out more serious concerns, she said.

By the time Mira Halker started high school, hardly a day passed that she wasn’t either getting a migraine attack or recovering from one. She missed volleyball team practice. She missed classes. She missed social events. And few people understood. After all, she looked healthy.

“A lot of times, people think I’m faking it,” said Mira, now 16, who lives in Phoenix. Friends called her flaky; her volleyball coaches questioned her dedication to the team. “I’m like, ‘I’m not trying to get out of this. This is not what this is about,’ ” she said.

Her mother, Rashmi B. Halker Singh, MD, is a neurologist at Mayo Clinic who happens to specialize in migraine. Even so, finding a solution was not easy. Neither ibuprofen nor triptans, nor various preventive measures such as a daily prescription for topiramate controlled the pain and associated symptoms. Mira was barely making it through her school day and had to quit volleyball. Then, in the spring of 10th grade, Mira told her mother that she couldn’t go to prom because the loud noises and lights could give her a migraine attack.

Mother and daughter decided it was time to get even more aggressive. “There are these key moments in life that you can’t get back,” Dr. Singh said. “Migraine steals so much from you.”
 

Diagnosis

One of the challenges Mira’s physicians faced was deciding which medications and other therapies to prescribe to a teenager. Drug companies have been releasing a steady stream of new treatments for migraine headaches, and researchers promise more are on the way soon. Here’s what works for children, what hasn’t yet been approved for use with minors, and how to diagnose migraines in the first place, from experts at some of the nation’s leading pediatric headache centers.

Migraine affects about 10% of children, according to the American Migraine Foundation. The headaches can strike children as early as age 3 or 4 years, said Robert Little, MD, a pediatric neurologist at Phoenix Children’s Hospital.

Before puberty, boys report more migraine attacks than girls, according to the American Academy of Pediatrics. But that reverses in adolescence: By age 17, as many as 8% of boys and 23% of girls have had migraine. To diagnose migraine, Juliana H. VanderPluym, MD, associate professor of neurology at Mayo Clinic in Phoenix, said she uses the criteria published in the latest edition of the International Classification of Headache Disorders (ICHD): A patient must have had at least five attacks in their life; and in children and adolescents, the attacks must last no less than 2 hours.

In addition, the headaches should exhibit at least two out of four features:

1. Occur more on one side of the head than the other (although Dr. VanderPluym said in children and adolescents headaches often are bilateral).

2. Be of moderate to severe intensity.

3. Have a pounding or throbbing quality.

4. Grow worse with activity or cause an avoidance of activity.

If the attacks meet those criteria, clinicians should check to see if they meet at least one out of the two following:

1. Are sensitive to light and sounds.

2. Are associated with nausea and/or vomiting.

A clinician should consider whether the headaches are not better accounted for by another diagnosis, according to the ICHD criteria. But, Dr. VanderPluym warned that does not necessarily mean running a slew of tests.

“In the absence of red flag features, it is more than likely going to be migraine headache,” she said. That’s especially true if a child has a family history of migraine, as the condition is often passed down from parent to child.

Ultimately, the diagnosis is fairly simple and can be made in a minute or less, said Jack Gladstein, MD, a pediatrician at the University of Maryland whose research focuses on the clinical care of children and adolescents with headache.

“Migraine is acute,” Dr. Gladstein said. “It’s really bad. And it’s recurrent.”
 

First line of treatment

Whatever a patient takes to treat a migraine, they should hit it early and hard, Dr. Gladstein said.

“The first thing you say, as a primary care physician, is treat your migraine at first twinge, whatever you use. Don’t wait, don’t wish it away,” he said. “The longer you wait, the less chance anything will work.”

The second piece of advice, Dr. Gladstein said, is that whatever drug a patient is taking, they should be on the highest feasible dose. “Work as fast as you can to treat them. You want the brain to reset as quickly as you can,” he said.

Patients should begin with over-the-counter pain relievers, Dr. Little said. If those prove insufficient, they can try a triptan. Rizatriptan is the only such agent that the Food and Drug Administration has approved for children aged 6-17 years. Other drugs in the class – sumatriptan/naproxen, almotriptan, and zolmitriptan – are approved for children 12 and older.

Another migraine therapy recently approved for children aged 12 and older is the use of neurostimulators. “It’s helpful to be aware of them,” Dr. VanderPluym said.

However, if neurostimulators and acute medications prove insufficient, clinicians should warn patients not to up their doses of triptans. Rebound headaches can occur if patients take triptans more than twice a week, or a maximum 10 days per month.

Another possibility is to add a preventive therapy. One mild, first option is nutraceuticals, like riboflavin (vitamin B₂) or magnesium, said Anisa F. Kelley, MD, a neurologist and associate director of the headache program at the Ann and Robert H. Lurie Children’s Hospital of Chicago.

“We don’t have definitive evidence, but they’re probably doing more benefit than they are harm,” Dr. Kelley said of these therapies. “In patients who have anywhere from 4 to 8 migraine days a month, where you’re in that in-between period where you don’t necessarily need a [prescription] prophylactic, I will often start with a nutraceutical,” Dr. Kelley said.

For those patients who don’t respond to nutraceuticals, or who need more support, clinicians can prescribe amitriptyline or topiramate. Dr. VanderPluym said.

A 2017 study found such prophylactics to be no more effective than placebo in pediatric migraine patients, but experts caution the results should not be considered definitive.

For one thing, the study enrolled a highly selective group of participants, with milder forms of migraine who may have improved anyway, Dr. VanderPluym said. All participants also received lifestyle counseling.

Every time participants came in for a follow-up, they were asked questions such as how much water were they drinking and how much sleep were they getting, Dr. Kelley noted. The takeaway, she said: “Pediatric and adolescent migraine [management] is very, very much reliant on lifestyle factors.”
 

Lifestyle triggers

Clinicians should counsel their migraine patients about lifestyle changes, experts said. Getting adequate sleep, staying hydrated, and managing stress can help reduce the intensity and frequency of attacks.

Migraine patients should also be mindful of their screen time, Dr. Kelley added.

“I’ve had lots and lots of patients who find excessive screen time will trigger or worsen migraine,” she said.

As for other potential triggers of attacks, the evidence is mixed.

“There’s clearly an association with disrupted sleep and migraine, and that has been very well established,” Dr. Little said. “And there is some modest amount of evidence that regular exercise can be helpful.” But for reported food triggers, he said, there have been very inconclusive results.

Commonly reported triggers include MSG, red wine, chocolate, and aged cheese. When Dr. Little’s patients keep headache diaries, tracking their meals alongside when they got migraine attacks, they often discover individualized triggers – strawberries, for instance, in one case, he said.

Scientists believe migraines result from the inappropriate activation of the trigeminal ganglion. “The question is, what causes it to get triggered? And how does it get triggered?” Dr. Gladstein said. “And that’s where there’s a lot of difference of opinion and no conclusive evidence.” Clinicians also should make sure that something else – usually depression, anxiety, insomnia, and dizziness – is not hindering effective migraine management. “If someone has terrible insomnia, until you treat the insomnia, the headaches aren’t going to get better,” he said.

As for Mira, her migraine attacks did not significantly improve, despite trying triptans, prophylactics, lifestyle changes, and shots to block nerve pain. When the headaches threatened Mira’s chance to go to her prom, her neurologist suggested trying something different. The physician persuaded the family’s insurance to cover a calcitonin gene-related peptide antagonist, an injectable monoclonal antibody treatment for migraine that the FDA has currently approved only for use in adults.

The difference for Mira has been extraordinary.

“I can do so much more than I was able to do,” said Mira, who attended the dance migraine free. “I feel liberated.”

It’s only migraine

One of the greatest challenges in diagnosing migraine can be reassuring the patient, the parents, even clinicians themselves that migraine really is the cause of all this pain and discomfort, experts said.

“A lot of migraine treatment actually comes down to migraine education,” Dr. VanderPluym said.

Patients and their parents often wonder how they can be sure that this pain is not resulting from something more dangerous than migraine, Dr. Little said. In these cases, he cites practice guidelines published by the American Academy of Neurology.

“The gist of those guidelines is that most pediatric patients do not need further workup,” he said. “But I think that there’s always a fear that you’re missing something because we don’t have a test that we can do” for migraine.

Some warning signs that further tests might be warranted, Dr. Kelley said, include:

• Headaches that wake a patient up in the middle of the night.
• Headaches that start first thing in the morning, especially those that include vomiting.
• A headache pattern that suddenly gets much worse.
• Certain symptoms that accompany the headache, such as tingling, numbness or double vision.

Although all of these signs can still stem from migraines – tingling or numbness, for instance, can be signs of migraine aura – running additional tests can rule out more serious concerns, she said.

By the time Mira Halker started high school, hardly a day passed that she wasn’t either getting a migraine attack or recovering from one. She missed volleyball team practice. She missed classes. She missed social events. And few people understood. After all, she looked healthy.

“A lot of times, people think I’m faking it,” said Mira, now 16, who lives in Phoenix. Friends called her flaky; her volleyball coaches questioned her dedication to the team. “I’m like, ‘I’m not trying to get out of this. This is not what this is about,’ ” she said.

Her mother, Rashmi B. Halker Singh, MD, is a neurologist at Mayo Clinic who happens to specialize in migraine. Even so, finding a solution was not easy. Neither ibuprofen nor triptans, nor various preventive measures such as a daily prescription for topiramate controlled the pain and associated symptoms. Mira was barely making it through her school day and had to quit volleyball. Then, in the spring of 10th grade, Mira told her mother that she couldn’t go to prom because the loud noises and lights could give her a migraine attack.

Mother and daughter decided it was time to get even more aggressive. “There are these key moments in life that you can’t get back,” Dr. Singh said. “Migraine steals so much from you.”
 

Diagnosis

One of the challenges Mira’s physicians faced was deciding which medications and other therapies to prescribe to a teenager. Drug companies have been releasing a steady stream of new treatments for migraine headaches, and researchers promise more are on the way soon. Here’s what works for children, what hasn’t yet been approved for use with minors, and how to diagnose migraines in the first place, from experts at some of the nation’s leading pediatric headache centers.

Migraine affects about 10% of children, according to the American Migraine Foundation. The headaches can strike children as early as age 3 or 4 years, said Robert Little, MD, a pediatric neurologist at Phoenix Children’s Hospital.

Before puberty, boys report more migraine attacks than girls, according to the American Academy of Pediatrics. But that reverses in adolescence: By age 17, as many as 8% of boys and 23% of girls have had migraine. To diagnose migraine, Juliana H. VanderPluym, MD, associate professor of neurology at Mayo Clinic in Phoenix, said she uses the criteria published in the latest edition of the International Classification of Headache Disorders (ICHD): A patient must have had at least five attacks in their life; and in children and adolescents, the attacks must last no less than 2 hours.

In addition, the headaches should exhibit at least two out of four features:

1. Occur more on one side of the head than the other (although Dr. VanderPluym said in children and adolescents headaches often are bilateral).

2. Be of moderate to severe intensity.

3. Have a pounding or throbbing quality.

4. Grow worse with activity or cause an avoidance of activity.

If the attacks meet those criteria, clinicians should check to see if they meet at least one out of the two following:

1. Are sensitive to light and sounds.

2. Are associated with nausea and/or vomiting.

A clinician should consider whether the headaches are not better accounted for by another diagnosis, according to the ICHD criteria. But, Dr. VanderPluym warned that does not necessarily mean running a slew of tests.

“In the absence of red flag features, it is more than likely going to be migraine headache,” she said. That’s especially true if a child has a family history of migraine, as the condition is often passed down from parent to child.

Ultimately, the diagnosis is fairly simple and can be made in a minute or less, said Jack Gladstein, MD, a pediatrician at the University of Maryland whose research focuses on the clinical care of children and adolescents with headache.

“Migraine is acute,” Dr. Gladstein said. “It’s really bad. And it’s recurrent.”
 

First line of treatment

Whatever a patient takes to treat a migraine, they should hit it early and hard, Dr. Gladstein said.

“The first thing you say, as a primary care physician, is treat your migraine at first twinge, whatever you use. Don’t wait, don’t wish it away,” he said. “The longer you wait, the less chance anything will work.”

The second piece of advice, Dr. Gladstein said, is that whatever drug a patient is taking, they should be on the highest feasible dose. “Work as fast as you can to treat them. You want the brain to reset as quickly as you can,” he said.

Patients should begin with over-the-counter pain relievers, Dr. Little said. If those prove insufficient, they can try a triptan. Rizatriptan is the only such agent that the Food and Drug Administration has approved for children aged 6-17 years. Other drugs in the class – sumatriptan/naproxen, almotriptan, and zolmitriptan – are approved for children 12 and older.

Another migraine therapy recently approved for children aged 12 and older is the use of neurostimulators. “It’s helpful to be aware of them,” Dr. VanderPluym said.

However, if neurostimulators and acute medications prove insufficient, clinicians should warn patients not to up their doses of triptans. Rebound headaches can occur if patients take triptans more than twice a week, or a maximum 10 days per month.

Another possibility is to add a preventive therapy. One mild, first option is nutraceuticals, like riboflavin (vitamin B₂) or magnesium, said Anisa F. Kelley, MD, a neurologist and associate director of the headache program at the Ann and Robert H. Lurie Children’s Hospital of Chicago.

“We don’t have definitive evidence, but they’re probably doing more benefit than they are harm,” Dr. Kelley said of these therapies. “In patients who have anywhere from 4 to 8 migraine days a month, where you’re in that in-between period where you don’t necessarily need a [prescription] prophylactic, I will often start with a nutraceutical,” Dr. Kelley said.

For those patients who don’t respond to nutraceuticals, or who need more support, clinicians can prescribe amitriptyline or topiramate. Dr. VanderPluym said.

A 2017 study found such prophylactics to be no more effective than placebo in pediatric migraine patients, but experts caution the results should not be considered definitive.

For one thing, the study enrolled a highly selective group of participants, with milder forms of migraine who may have improved anyway, Dr. VanderPluym said. All participants also received lifestyle counseling.

Every time participants came in for a follow-up, they were asked questions such as how much water were they drinking and how much sleep were they getting, Dr. Kelley noted. The takeaway, she said: “Pediatric and adolescent migraine [management] is very, very much reliant on lifestyle factors.”
 

Lifestyle triggers

Clinicians should counsel their migraine patients about lifestyle changes, experts said. Getting adequate sleep, staying hydrated, and managing stress can help reduce the intensity and frequency of attacks.

Migraine patients should also be mindful of their screen time, Dr. Kelley added.

“I’ve had lots and lots of patients who find excessive screen time will trigger or worsen migraine,” she said.

As for other potential triggers of attacks, the evidence is mixed.

“There’s clearly an association with disrupted sleep and migraine, and that has been very well established,” Dr. Little said. “And there is some modest amount of evidence that regular exercise can be helpful.” But for reported food triggers, he said, there have been very inconclusive results.

Commonly reported triggers include MSG, red wine, chocolate, and aged cheese. When Dr. Little’s patients keep headache diaries, tracking their meals alongside when they got migraine attacks, they often discover individualized triggers – strawberries, for instance, in one case, he said.

Scientists believe migraines result from the inappropriate activation of the trigeminal ganglion. “The question is, what causes it to get triggered? And how does it get triggered?” Dr. Gladstein said. “And that’s where there’s a lot of difference of opinion and no conclusive evidence.” Clinicians also should make sure that something else – usually depression, anxiety, insomnia, and dizziness – is not hindering effective migraine management. “If someone has terrible insomnia, until you treat the insomnia, the headaches aren’t going to get better,” he said.

As for Mira, her migraine attacks did not significantly improve, despite trying triptans, prophylactics, lifestyle changes, and shots to block nerve pain. When the headaches threatened Mira’s chance to go to her prom, her neurologist suggested trying something different. The physician persuaded the family’s insurance to cover a calcitonin gene-related peptide antagonist, an injectable monoclonal antibody treatment for migraine that the FDA has currently approved only for use in adults.

The difference for Mira has been extraordinary.

“I can do so much more than I was able to do,” said Mira, who attended the dance migraine free. “I feel liberated.”

It’s only migraine

One of the greatest challenges in diagnosing migraine can be reassuring the patient, the parents, even clinicians themselves that migraine really is the cause of all this pain and discomfort, experts said.

“A lot of migraine treatment actually comes down to migraine education,” Dr. VanderPluym said.

Patients and their parents often wonder how they can be sure that this pain is not resulting from something more dangerous than migraine, Dr. Little said. In these cases, he cites practice guidelines published by the American Academy of Neurology.

“The gist of those guidelines is that most pediatric patients do not need further workup,” he said. “But I think that there’s always a fear that you’re missing something because we don’t have a test that we can do” for migraine.

Some warning signs that further tests might be warranted, Dr. Kelley said, include:

• Headaches that wake a patient up in the middle of the night.
• Headaches that start first thing in the morning, especially those that include vomiting.
• A headache pattern that suddenly gets much worse.
• Certain symptoms that accompany the headache, such as tingling, numbness or double vision.

Although all of these signs can still stem from migraines – tingling or numbness, for instance, can be signs of migraine aura – running additional tests can rule out more serious concerns, she said.

CHICAGO – Higher weight and body mass index (BMI) in preadolescents are linked with poor brain health, new research suggests.

Poor brain health has been linked with obesity in adults, but little has been known about the link in children.

Lead author Simone Kaltenhauser, a postgraduate research fellow in radiology and biomedical imaging at the Yale School of Medicine, New Haven, Conn., presented her findings at the annual meeting of the Radiological Society of North America.

To represent the national sociodemographic makeup, the researchers used baseline information from the Adolescent Brain Cognitive Development (ABCD) study, which included 11,878 children aged 9 and 10 years from 21 centers across the United States.

This study included 5,169 children (51.9% girls). Children who had had traumatic brain injury, eating disorders, neurodevelopmental problems, and psychiatric diseases were excluded from the final analysis.

The researchers analyzed information from structural MRI and resting-state functional MRI, which allowed them to measure brain activity by detecting changes in blood flow.

“We analyzed the average fractional anisotropy (FA), mean (MD), axial (AD) and radial diffusivity (RD), and neurite density (ND) of 35 white matter (WM) tracts; cortical thickness and surface of 68 regions; and functional connectivity of 91 predefined network correlations,” the authors explained.

They adjusted for age, sex, race/ethnicity, handedness, and socioeconomic status. They used linear models to determine associations between weight and BMI z-scores and the imaging metrics.
 

Loss of white matter integrity

Among children with obesity, there was pervasive loss of white matter integrity and neurite density, cortical gray matter thinning, and decreased connectivity within and between networks that have been associated with impulse control and reward-based decision-making.

“These changes persisted in a similar pattern also 2 years later,” she said.

A member of the audience asked whether a reverse relationship might be at work – that poor brain health might drive obesity rather than the other way around.

Ms. Kaltenhauser agreed that other factors could be driving the link and acknowledged as a limitation that they did not have access to genetic information on the children.

Information on the effects of overweight and obesity is critical, especially in the United States, where an estimated 1 in 5 children are obese.

Ms. Kaltenhauser said she hopes her study raises awareness of potential brain health consequences as well as the physical consequences of childhood obesity.

Senior author Sam Payabvash, MD, a neuroradiologist and assistant professor of radiology and biomedical imaging at the Yale School of Medicine, said in a press release that the study may help explain the findings from previous studies that show an association between higher BMI in children and poor cognitive functioning and academic performance.

“The longitudinal ABCD study gives us the opportunity to observe any changes that occur in children with higher weight and BMI z-scores,” Dr. Payabvash said. “We’ll need to watch over the next 6-10 years.”
 

Avenues for future research

Amit B. Desai, MD, a neuroradiologist with Mayo Clinic in Jacksonville, Fla., who was not part of the study, said that while the research demonstrates an association between brain structure and BMI and obesity, “there may be other lurking variables.”

“What’s happening at an earlier stage in life could be causing both,” he said.

He noted that he would like to see future studies involving children at even earlier ages, along with investigations of the role of genetics or socioeconomic factors.

Including older children would be interesting as well, he said.

“Myelination doesn’t complete until you’re in your late teens or early 20s, so there are structural changes happening in the brain much later on into adolescence and early adulthood,” Dr. Desai said.

It would be premature, he said, to conclude from these findings that if children have obesity, there must be something wrong with their brain.

He would like to see whether there are changes in this link if a child is obese early on and later has normal weight or if a child has normal weight early and then becomes obese.

“It’s definitely an eye-opening study, but [it] needs additional work to expand upon it,” he said.

Ms. Kaltenhauser and Dr. Desai report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

CHICAGO – Higher weight and body mass index (BMI) in preadolescents are linked with poor brain health, new research suggests.

Poor brain health has been linked with obesity in adults, but little has been known about the link in children.

Lead author Simone Kaltenhauser, a postgraduate research fellow in radiology and biomedical imaging at the Yale School of Medicine, New Haven, Conn., presented her findings at the annual meeting of the Radiological Society of North America.

To represent the national sociodemographic makeup, the researchers used baseline information from the Adolescent Brain Cognitive Development (ABCD) study, which included 11,878 children aged 9 and 10 years from 21 centers across the United States.

This study included 5,169 children (51.9% girls). Children who had had traumatic brain injury, eating disorders, neurodevelopmental problems, and psychiatric diseases were excluded from the final analysis.

The researchers analyzed information from structural MRI and resting-state functional MRI, which allowed them to measure brain activity by detecting changes in blood flow.

“We analyzed the average fractional anisotropy (FA), mean (MD), axial (AD) and radial diffusivity (RD), and neurite density (ND) of 35 white matter (WM) tracts; cortical thickness and surface of 68 regions; and functional connectivity of 91 predefined network correlations,” the authors explained.

They adjusted for age, sex, race/ethnicity, handedness, and socioeconomic status. They used linear models to determine associations between weight and BMI z-scores and the imaging metrics.
 

Loss of white matter integrity

Among children with obesity, there was pervasive loss of white matter integrity and neurite density, cortical gray matter thinning, and decreased connectivity within and between networks that have been associated with impulse control and reward-based decision-making.

“These changes persisted in a similar pattern also 2 years later,” she said.

A member of the audience asked whether a reverse relationship might be at work – that poor brain health might drive obesity rather than the other way around.

Ms. Kaltenhauser agreed that other factors could be driving the link and acknowledged as a limitation that they did not have access to genetic information on the children.

Information on the effects of overweight and obesity is critical, especially in the United States, where an estimated 1 in 5 children are obese.

Ms. Kaltenhauser said she hopes her study raises awareness of potential brain health consequences as well as the physical consequences of childhood obesity.

Senior author Sam Payabvash, MD, a neuroradiologist and assistant professor of radiology and biomedical imaging at the Yale School of Medicine, said in a press release that the study may help explain the findings from previous studies that show an association between higher BMI in children and poor cognitive functioning and academic performance.

“The longitudinal ABCD study gives us the opportunity to observe any changes that occur in children with higher weight and BMI z-scores,” Dr. Payabvash said. “We’ll need to watch over the next 6-10 years.”
 

Avenues for future research

Amit B. Desai, MD, a neuroradiologist with Mayo Clinic in Jacksonville, Fla., who was not part of the study, said that while the research demonstrates an association between brain structure and BMI and obesity, “there may be other lurking variables.”

“What’s happening at an earlier stage in life could be causing both,” he said.

He noted that he would like to see future studies involving children at even earlier ages, along with investigations of the role of genetics or socioeconomic factors.

Including older children would be interesting as well, he said.

“Myelination doesn’t complete until you’re in your late teens or early 20s, so there are structural changes happening in the brain much later on into adolescence and early adulthood,” Dr. Desai said.

It would be premature, he said, to conclude from these findings that if children have obesity, there must be something wrong with their brain.

He would like to see whether there are changes in this link if a child is obese early on and later has normal weight or if a child has normal weight early and then becomes obese.

“It’s definitely an eye-opening study, but [it] needs additional work to expand upon it,” he said.

Ms. Kaltenhauser and Dr. Desai report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

CHICAGO – Higher weight and body mass index (BMI) in preadolescents are linked with poor brain health, new research suggests.

Poor brain health has been linked with obesity in adults, but little has been known about the link in children.

Lead author Simone Kaltenhauser, a postgraduate research fellow in radiology and biomedical imaging at the Yale School of Medicine, New Haven, Conn., presented her findings at the annual meeting of the Radiological Society of North America.

To represent the national sociodemographic makeup, the researchers used baseline information from the Adolescent Brain Cognitive Development (ABCD) study, which included 11,878 children aged 9 and 10 years from 21 centers across the United States.

This study included 5,169 children (51.9% girls). Children who had had traumatic brain injury, eating disorders, neurodevelopmental problems, and psychiatric diseases were excluded from the final analysis.

The researchers analyzed information from structural MRI and resting-state functional MRI, which allowed them to measure brain activity by detecting changes in blood flow.

“We analyzed the average fractional anisotropy (FA), mean (MD), axial (AD) and radial diffusivity (RD), and neurite density (ND) of 35 white matter (WM) tracts; cortical thickness and surface of 68 regions; and functional connectivity of 91 predefined network correlations,” the authors explained.

They adjusted for age, sex, race/ethnicity, handedness, and socioeconomic status. They used linear models to determine associations between weight and BMI z-scores and the imaging metrics.
 

Loss of white matter integrity

Among children with obesity, there was pervasive loss of white matter integrity and neurite density, cortical gray matter thinning, and decreased connectivity within and between networks that have been associated with impulse control and reward-based decision-making.

“These changes persisted in a similar pattern also 2 years later,” she said.

A member of the audience asked whether a reverse relationship might be at work – that poor brain health might drive obesity rather than the other way around.

Ms. Kaltenhauser agreed that other factors could be driving the link and acknowledged as a limitation that they did not have access to genetic information on the children.

Information on the effects of overweight and obesity is critical, especially in the United States, where an estimated 1 in 5 children are obese.

Ms. Kaltenhauser said she hopes her study raises awareness of potential brain health consequences as well as the physical consequences of childhood obesity.

Senior author Sam Payabvash, MD, a neuroradiologist and assistant professor of radiology and biomedical imaging at the Yale School of Medicine, said in a press release that the study may help explain the findings from previous studies that show an association between higher BMI in children and poor cognitive functioning and academic performance.

“The longitudinal ABCD study gives us the opportunity to observe any changes that occur in children with higher weight and BMI z-scores,” Dr. Payabvash said. “We’ll need to watch over the next 6-10 years.”
 

Avenues for future research

Amit B. Desai, MD, a neuroradiologist with Mayo Clinic in Jacksonville, Fla., who was not part of the study, said that while the research demonstrates an association between brain structure and BMI and obesity, “there may be other lurking variables.”

“What’s happening at an earlier stage in life could be causing both,” he said.

He noted that he would like to see future studies involving children at even earlier ages, along with investigations of the role of genetics or socioeconomic factors.

Including older children would be interesting as well, he said.

“Myelination doesn’t complete until you’re in your late teens or early 20s, so there are structural changes happening in the brain much later on into adolescence and early adulthood,” Dr. Desai said.

It would be premature, he said, to conclude from these findings that if children have obesity, there must be something wrong with their brain.

He would like to see whether there are changes in this link if a child is obese early on and later has normal weight or if a child has normal weight early and then becomes obese.

“It’s definitely an eye-opening study, but [it] needs additional work to expand upon it,” he said.

Ms. Kaltenhauser and Dr. Desai report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A new collaborative position paper on radiation exposure during pregnancy states that pregnant women can safely work in an ionizing radiation environment if exposure to the fetus does not exceed certain dose thresholds.

The position paper aims to “avoid discouraging” women from pursuing careers in interventional cardiology/electrophysiology (IC/EP) and to “dismantle” a barrier that says, “activity under x-rays, without any weighting, is incompatible with continuation of pregnancy,” lead author Stéphane Manzo-Silberman, MD, of AP-HP, Sorbonne Université, Paris, told this news organization.

“The main point of the statement is to show that it is possible and safe to maintain activity under radiation during pregnancy, [given] the data we have on the risk for the fetus at exposed doses, the regulations, and feedback from practice,” she said. “The data we currently have allowed us to be largely reassuring.”

The research showed that adverse effects on a fetus generally occur when radiation exposure is greater than 100 mGy. Most countries that permit pregnant women to work in IC/EP require that the cumulative dose during the pregnancy be less than 1 mSv. An exception is the United States, which permits a cumulative dose of less than 5 mSv.

The position paper, a collaboration among the European Association of Percutaneous Cardiovascular Interventions, the European Heart Rhythm Association, the European Association of Cardiovascular Imaging, the European Society of Cardiology Regulatory Affairs Committee, and Women as One, was published online in EuroIntervention.

The position paper covers regulations in various countries; fetal radiation doses that have been associated with ill effects, including abortion, malformations, and intelligence quotient reductions; the spontaneous probability of having a newborn with a congenital malformation or childhood cancer; and proposals to improve practice.

Highlights include the following:
 

• European, North American, Japanese, and Australian regulations permit pregnant women to work if closely monitored with an abdominal dosimeter; some countries, such as Austria, Hungary, Portugal, and Romania, do not allow women to work in IC/EP during pregnancy or breastfeeding.
• The maximum fetal dose exposure during pregnancy is 1 mSv in Europe, Australia, and Israel; 2 mSv in Japan; and 5 mSv in the United States.
• Doses associated with fetal harm are 100 times higher than those allowed during an interventional cardiologist’s entire pregnancy.
• There is a negligible risk increase in the spontaneous probability of a newborn having a congenital malformation or childhood cancer when the occupational exposure range of the mother respects a country’s limits.
• No studies have shown an increased risk of noncancerous adverse effects from prenatal radiation exposure less than 50 mSv.

To improve practice, the position paper suggests the following:

• Fluoroscopy operators must be guided by the “as low as reasonably achievable” principle: Obtaining optimal images must be balanced with procedure safety.
• Scatter radiation emitted from the patient is the main source of radiation exposure to the operator and personnel; reducing radiation to the patient will reduce exposure for staff.
• The three fundamentals of radiation safety for an operator are (1) time, (2) distance, and (3) shielding and dosimeter monitoring. Time refers to the amount of time the operator spends using the x-ray system; distance means maximizing distance from the x-ray source; and shielding includes personal, tableside, or external protection, with each form having a degree of lead equivalence defining its radiation protective effect.
• Changes in medical school curricula and creating a friendlier workplace environment for families and pregnant interventionists are among the strategies that will promote gender equity in the profession.

“Institutional radiation protection programs should be established to increase knowledge about radiation exposure and improve specific safety requirements for everyone. This would ensure safe exposure for all physicians, [including] during pregnancy,” Dr. Manzo-Silberman concluded.

Furthermore, she said, “As has already been demonstrated in the business world, improving representation and gender equity and diversity is key to improving results and efficiency. In the field of health, this translates into better care for our patients and better working conditions for health care professionals.”

No commercial funding was disclosed. Dr. Manzo-Silberman has received consulting fees from Bayer, Organon, and Exeltis; lecture fees from Bayer, BMS, Exeltis, and Organon; and has served on the adjudication board for a study for Biotronik.

A version of this article first appeared on Medscape.com.

A new collaborative position paper on radiation exposure during pregnancy states that pregnant women can safely work in an ionizing radiation environment if exposure to the fetus does not exceed certain dose thresholds.

The position paper aims to “avoid discouraging” women from pursuing careers in interventional cardiology/electrophysiology (IC/EP) and to “dismantle” a barrier that says, “activity under x-rays, without any weighting, is incompatible with continuation of pregnancy,” lead author Stéphane Manzo-Silberman, MD, of AP-HP, Sorbonne Université, Paris, told this news organization.

“The main point of the statement is to show that it is possible and safe to maintain activity under radiation during pregnancy, [given] the data we have on the risk for the fetus at exposed doses, the regulations, and feedback from practice,” she said. “The data we currently have allowed us to be largely reassuring.”

The research showed that adverse effects on a fetus generally occur when radiation exposure is greater than 100 mGy. Most countries that permit pregnant women to work in IC/EP require that the cumulative dose during the pregnancy be less than 1 mSv. An exception is the United States, which permits a cumulative dose of less than 5 mSv.

The position paper, a collaboration among the European Association of Percutaneous Cardiovascular Interventions, the European Heart Rhythm Association, the European Association of Cardiovascular Imaging, the European Society of Cardiology Regulatory Affairs Committee, and Women as One, was published online in EuroIntervention.

The position paper covers regulations in various countries; fetal radiation doses that have been associated with ill effects, including abortion, malformations, and intelligence quotient reductions; the spontaneous probability of having a newborn with a congenital malformation or childhood cancer; and proposals to improve practice.

Highlights include the following:
 

• European, North American, Japanese, and Australian regulations permit pregnant women to work if closely monitored with an abdominal dosimeter; some countries, such as Austria, Hungary, Portugal, and Romania, do not allow women to work in IC/EP during pregnancy or breastfeeding.
• The maximum fetal dose exposure during pregnancy is 1 mSv in Europe, Australia, and Israel; 2 mSv in Japan; and 5 mSv in the United States.
• Doses associated with fetal harm are 100 times higher than those allowed during an interventional cardiologist’s entire pregnancy.
• There is a negligible risk increase in the spontaneous probability of a newborn having a congenital malformation or childhood cancer when the occupational exposure range of the mother respects a country’s limits.
• No studies have shown an increased risk of noncancerous adverse effects from prenatal radiation exposure less than 50 mSv.

To improve practice, the position paper suggests the following:

• Fluoroscopy operators must be guided by the “as low as reasonably achievable” principle: Obtaining optimal images must be balanced with procedure safety.
• Scatter radiation emitted from the patient is the main source of radiation exposure to the operator and personnel; reducing radiation to the patient will reduce exposure for staff.
• The three fundamentals of radiation safety for an operator are (1) time, (2) distance, and (3) shielding and dosimeter monitoring. Time refers to the amount of time the operator spends using the x-ray system; distance means maximizing distance from the x-ray source; and shielding includes personal, tableside, or external protection, with each form having a degree of lead equivalence defining its radiation protective effect.
• Changes in medical school curricula and creating a friendlier workplace environment for families and pregnant interventionists are among the strategies that will promote gender equity in the profession.

“Institutional radiation protection programs should be established to increase knowledge about radiation exposure and improve specific safety requirements for everyone. This would ensure safe exposure for all physicians, [including] during pregnancy,” Dr. Manzo-Silberman concluded.

Furthermore, she said, “As has already been demonstrated in the business world, improving representation and gender equity and diversity is key to improving results and efficiency. In the field of health, this translates into better care for our patients and better working conditions for health care professionals.”

No commercial funding was disclosed. Dr. Manzo-Silberman has received consulting fees from Bayer, Organon, and Exeltis; lecture fees from Bayer, BMS, Exeltis, and Organon; and has served on the adjudication board for a study for Biotronik.

A version of this article first appeared on Medscape.com.

A new collaborative position paper on radiation exposure during pregnancy states that pregnant women can safely work in an ionizing radiation environment if exposure to the fetus does not exceed certain dose thresholds.

The position paper aims to “avoid discouraging” women from pursuing careers in interventional cardiology/electrophysiology (IC/EP) and to “dismantle” a barrier that says, “activity under x-rays, without any weighting, is incompatible with continuation of pregnancy,” lead author Stéphane Manzo-Silberman, MD, of AP-HP, Sorbonne Université, Paris, told this news organization.

“The main point of the statement is to show that it is possible and safe to maintain activity under radiation during pregnancy, [given] the data we have on the risk for the fetus at exposed doses, the regulations, and feedback from practice,” she said. “The data we currently have allowed us to be largely reassuring.”

The research showed that adverse effects on a fetus generally occur when radiation exposure is greater than 100 mGy. Most countries that permit pregnant women to work in IC/EP require that the cumulative dose during the pregnancy be less than 1 mSv. An exception is the United States, which permits a cumulative dose of less than 5 mSv.

The position paper, a collaboration among the European Association of Percutaneous Cardiovascular Interventions, the European Heart Rhythm Association, the European Association of Cardiovascular Imaging, the European Society of Cardiology Regulatory Affairs Committee, and Women as One, was published online in EuroIntervention.

The position paper covers regulations in various countries; fetal radiation doses that have been associated with ill effects, including abortion, malformations, and intelligence quotient reductions; the spontaneous probability of having a newborn with a congenital malformation or childhood cancer; and proposals to improve practice.

Highlights include the following:
 

• European, North American, Japanese, and Australian regulations permit pregnant women to work if closely monitored with an abdominal dosimeter; some countries, such as Austria, Hungary, Portugal, and Romania, do not allow women to work in IC/EP during pregnancy or breastfeeding.
• The maximum fetal dose exposure during pregnancy is 1 mSv in Europe, Australia, and Israel; 2 mSv in Japan; and 5 mSv in the United States.
• Doses associated with fetal harm are 100 times higher than those allowed during an interventional cardiologist’s entire pregnancy.
• There is a negligible risk increase in the spontaneous probability of a newborn having a congenital malformation or childhood cancer when the occupational exposure range of the mother respects a country’s limits.
• No studies have shown an increased risk of noncancerous adverse effects from prenatal radiation exposure less than 50 mSv.

To improve practice, the position paper suggests the following:

• Fluoroscopy operators must be guided by the “as low as reasonably achievable” principle: Obtaining optimal images must be balanced with procedure safety.
• Scatter radiation emitted from the patient is the main source of radiation exposure to the operator and personnel; reducing radiation to the patient will reduce exposure for staff.
• The three fundamentals of radiation safety for an operator are (1) time, (2) distance, and (3) shielding and dosimeter monitoring. Time refers to the amount of time the operator spends using the x-ray system; distance means maximizing distance from the x-ray source; and shielding includes personal, tableside, or external protection, with each form having a degree of lead equivalence defining its radiation protective effect.
• Changes in medical school curricula and creating a friendlier workplace environment for families and pregnant interventionists are among the strategies that will promote gender equity in the profession.

“Institutional radiation protection programs should be established to increase knowledge about radiation exposure and improve specific safety requirements for everyone. This would ensure safe exposure for all physicians, [including] during pregnancy,” Dr. Manzo-Silberman concluded.

Furthermore, she said, “As has already been demonstrated in the business world, improving representation and gender equity and diversity is key to improving results and efficiency. In the field of health, this translates into better care for our patients and better working conditions for health care professionals.”

No commercial funding was disclosed. Dr. Manzo-Silberman has received consulting fees from Bayer, Organon, and Exeltis; lecture fees from Bayer, BMS, Exeltis, and Organon; and has served on the adjudication board for a study for Biotronik.

A version of this article first appeared on Medscape.com.

Many more people are at risk for early cardiovascular events because of raised lipoprotein(a) levels than from having familial hypercholesterolemia (FH), a new study suggests.

The Danish study set out to try and establish a level of Lp(a) that would be associated with a cardiovascular risk similar to that seen with FH. As there are many different definitions of FH, results showed a large range of Lp(a) values that corresponded to risk levels of the different FH definitions.

However, if considering one of the broadest FH definitions (from MEDPED – Make Early Diagnoses, Prevent Early Deaths), which is the one most commonly used in the United States, results showed that the level of cardiovascular risk in patients with this definition of FH is similar to that associated with Lp(a) levels of around 70 mg/dL (0.7 g/L).

“While FH is fairly unusual, occurring in less than 1% of the population, levels of Lp(a) of 70 mg/dL or above are much more common, occurring in around 10% of the White population,” Børge Nordestgaard, MD, Copenhagen University Hospital, said in an interview. Around 20% of the Black population have such high levels, while levels in Hispanics are in between.

“Our results suggest that there will be many more individuals at risk of premature MI or cardiovascular death because of raised Lp(a) levels than because of FH,” added Dr. Nordestgaard, the senior author of the current study.

Dr. Nordestgaard explained that FH is well established to be a serious condition. “We consider FH to be the genetic disease that causes the most cases of early heart disease and early death worldwide.”

“But we know now that raised levels of Lp(a), which is also genetically determined, can also lead to an increased risk of cardiovascular events relatively early in life, and when you look into the numbers, it seems like high levels of Lp(a) could be more common than FH. We wanted to try and find the levels of Lp(a) that corresponded to similar cardiovascular risk as FH.”

The Danish study was published  in the Journal of the American College of Cardiology.

The authors note that the 2019 joint European Society of Cardiology and European Atherosclerosis Society guidelines suggested that an Lp(a) level greater than 180 mg/dL (0.8 g/L) may confer a lifetime risk for heart disease equivalent to the risk associated with heterozygous FH, but they point out that this value was speculative and not based on a direct comparison of risk associated with the two conditions in the same population.

For their study, Dr. Nordestgaard and colleagues analyzed information from a large database of the Danish population, the Copenhagen General Population Study, including 69,644 individuals for whom data on FH and Lp(a) levels were available. As these conditions are genetically determined, and the study held records on individuals going back several decades, the researchers were able to analyze event rates over a median follow up time of 42 years. During this time, there were 4,166 cases of myocardial infarction and 11,464 cases of atherosclerotic cardiovascular disease (ASCVD).

Results showed that Lp(a) levels associated with MI risk equivalent to that of clinical FH ranged from 67 to 402 mg/dL depending on the definition used for FH. The Lp(a) level corresponding to the MI risk of genetically determined FH was 180 mg/dL.

In terms of risk of ASCVD events, the levels of Lp(a) corresponding to the risk associated with clinical FH ranged from 130 to 391 mg/dL, and the Lp(a) level corresponding to the ASCVD risk of genetically determined FH was 175 mg/dL.

“All these different definitions of FH may cause some confusion, but basically we are saying that if an individual is found to have an Lp(a) above 70 mg/dL, then they have a similar level of cardiovascular risk as that associated with the broadest definition of FH, and they should be taken as seriously as a patient diagnosed with FH,” Dr. Nordestgaard said.

He estimated that these individuals have approximately a doubling of cardiovascular risk, compared with the general population, and risk increases further with rising Lp(a) levels.

The researchers also found that if an individual has both FH and raised Lp(a) they are at very high risk, as these two conditions are independent of each other.

Although a specific treatment for lowering Lp(a) levels is not yet available, Dr. Nordestgaard stresses that it is still worth identifying individuals with raised Lp(a) as efforts can be made to address other cardiovascular risk factors.

“We know raised Lp(a) increases cardiovascular risk, but there are also many other factors that likewise increase this risk, and they are all additive. So, it is very important that individuals with raised Lp(a) levels address these other risk factors,” he said. “These include stopping smoking, being at healthy weight, exercising regularly, eating a heart-healthy diet, and aggressive treatment of raised LDL, hypertension, and diabetes. All these things will lower their overall risk of cardiovascular disease.”

And there is the promise of new drugs to lower Lp(a) on the horizon, with several such products now in clinical development.

Dr. Nordestgaard also points out that as Lp(a) is genetically determined, cascade screening of close relatives of the individual with raised Lp(a) should also take place to detect others who may be at risk.

Although a level of Lp(a) of around 70 mg/dL confers similar cardiovascular risk than some definitions of FH, Dr. Nordestgaard says lower levels than this should also be a signal for concern. 

“We usually say Lp(a) levels of 50 mg/dL are when we need to start to take this seriously. And it’s estimated that about 20% of the White population will have levels of 50 mg/dL or over and even more in the Black population,” he added. 
 

‘Screen for both conditions’

In an accompanying editorial, Pamela Morris, MD, Medical University of South Carolina, Charleston; Jagat Narula, MD, Icahn School of Medicine, New York; and Sotirios Tsimikas, MD, University of California, San Diego, say “the weight of evidence strongly supports that both genetic lipid disorders, elevated Lp(a) levels and FH, are causally associated with an increased risk of premature ASCVD and should be carefully considered in risk assessment and management for ASCVD risk reduction.”

Catherine Hackett/MDedge News

Dr. Morris told this news organization that the current study found a very large range of Lp(a) levels that conferred a similar cardiovascular risk to FH, because of the many different definitions of FH in use.

“But this should not take away the importance of screening for raised Lp(a) levels,” she stressed.  

“We know that increased Lp(a) levels signal a high risk of cardiovascular disease. A diagnosis of FH is also a high-risk condition,” she said. “Both are important, and we need to screen for both, but it is difficult to directly compare the two conditions because the different definitions of FH get in the way.”

Dr. Morris agrees with Dr. Nordestgaard that raised levels of Lp(a) may actually be more important for the population risk of cardiovascular disease than FH, as the prevalence of increased Lp(a) levels is higher.

“Because raised Lp(a) levels are more prevalent than confirmed FH, the risk to the population is greater,” she said.  

Dr. Morris points out that cardiovascular risk starts to increase at Lp(a) levels of 30 mg/dL (75 nmol/L).

The editorialists recommend that “in addition to performing a lipid panel periodically according to evidence-based guidelines, measurement of Lp(a) levels should also be performed at least once in an individual’s lifetime for ASCVD risk assessment.”

They conclude that “it is vital to continue to raise awareness among clinicians and patients of these high-risk genetic lipid disorders. Our understanding of both disorders is rapidly expanding, and promising novel therapeutics may offer hope for prevention of cardiovascular disease in patients with elevated Lp(a) levels in the future.”

This work was supported by Copenhagen University Hospital – Herlev Gentofte, Denmark, and the Danish Beckett-Foundation. The Copenhagen General Population Study is supported by the Copenhagen County Foundation and Copenhagen University Hospital – Herlev Gentofte. Dr. Nordestgaard has been a consultant and a speaker for AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Kowa, Denka, Amarin, Novartis, Novo Nordisk, Silence Therapeutics, Abbott, and Esperion.

A version of this article first appeared on Medscape.com.

Many more people are at risk for early cardiovascular events because of raised lipoprotein(a) levels than from having familial hypercholesterolemia (FH), a new study suggests.

The Danish study set out to try and establish a level of Lp(a) that would be associated with a cardiovascular risk similar to that seen with FH. As there are many different definitions of FH, results showed a large range of Lp(a) values that corresponded to risk levels of the different FH definitions.

However, if considering one of the broadest FH definitions (from MEDPED – Make Early Diagnoses, Prevent Early Deaths), which is the one most commonly used in the United States, results showed that the level of cardiovascular risk in patients with this definition of FH is similar to that associated with Lp(a) levels of around 70 mg/dL (0.7 g/L).

“While FH is fairly unusual, occurring in less than 1% of the population, levels of Lp(a) of 70 mg/dL or above are much more common, occurring in around 10% of the White population,” Børge Nordestgaard, MD, Copenhagen University Hospital, said in an interview. Around 20% of the Black population have such high levels, while levels in Hispanics are in between.

“Our results suggest that there will be many more individuals at risk of premature MI or cardiovascular death because of raised Lp(a) levels than because of FH,” added Dr. Nordestgaard, the senior author of the current study.

Dr. Nordestgaard explained that FH is well established to be a serious condition. “We consider FH to be the genetic disease that causes the most cases of early heart disease and early death worldwide.”

“But we know now that raised levels of Lp(a), which is also genetically determined, can also lead to an increased risk of cardiovascular events relatively early in life, and when you look into the numbers, it seems like high levels of Lp(a) could be more common than FH. We wanted to try and find the levels of Lp(a) that corresponded to similar cardiovascular risk as FH.”

The Danish study was published  in the Journal of the American College of Cardiology.

The authors note that the 2019 joint European Society of Cardiology and European Atherosclerosis Society guidelines suggested that an Lp(a) level greater than 180 mg/dL (0.8 g/L) may confer a lifetime risk for heart disease equivalent to the risk associated with heterozygous FH, but they point out that this value was speculative and not based on a direct comparison of risk associated with the two conditions in the same population.

For their study, Dr. Nordestgaard and colleagues analyzed information from a large database of the Danish population, the Copenhagen General Population Study, including 69,644 individuals for whom data on FH and Lp(a) levels were available. As these conditions are genetically determined, and the study held records on individuals going back several decades, the researchers were able to analyze event rates over a median follow up time of 42 years. During this time, there were 4,166 cases of myocardial infarction and 11,464 cases of atherosclerotic cardiovascular disease (ASCVD).

Results showed that Lp(a) levels associated with MI risk equivalent to that of clinical FH ranged from 67 to 402 mg/dL depending on the definition used for FH. The Lp(a) level corresponding to the MI risk of genetically determined FH was 180 mg/dL.

In terms of risk of ASCVD events, the levels of Lp(a) corresponding to the risk associated with clinical FH ranged from 130 to 391 mg/dL, and the Lp(a) level corresponding to the ASCVD risk of genetically determined FH was 175 mg/dL.

“All these different definitions of FH may cause some confusion, but basically we are saying that if an individual is found to have an Lp(a) above 70 mg/dL, then they have a similar level of cardiovascular risk as that associated with the broadest definition of FH, and they should be taken as seriously as a patient diagnosed with FH,” Dr. Nordestgaard said.

He estimated that these individuals have approximately a doubling of cardiovascular risk, compared with the general population, and risk increases further with rising Lp(a) levels.

The researchers also found that if an individual has both FH and raised Lp(a) they are at very high risk, as these two conditions are independent of each other.

Although a specific treatment for lowering Lp(a) levels is not yet available, Dr. Nordestgaard stresses that it is still worth identifying individuals with raised Lp(a) as efforts can be made to address other cardiovascular risk factors.

“We know raised Lp(a) increases cardiovascular risk, but there are also many other factors that likewise increase this risk, and they are all additive. So, it is very important that individuals with raised Lp(a) levels address these other risk factors,” he said. “These include stopping smoking, being at healthy weight, exercising regularly, eating a heart-healthy diet, and aggressive treatment of raised LDL, hypertension, and diabetes. All these things will lower their overall risk of cardiovascular disease.”

And there is the promise of new drugs to lower Lp(a) on the horizon, with several such products now in clinical development.

Dr. Nordestgaard also points out that as Lp(a) is genetically determined, cascade screening of close relatives of the individual with raised Lp(a) should also take place to detect others who may be at risk.

Although a level of Lp(a) of around 70 mg/dL confers similar cardiovascular risk than some definitions of FH, Dr. Nordestgaard says lower levels than this should also be a signal for concern. 

“We usually say Lp(a) levels of 50 mg/dL are when we need to start to take this seriously. And it’s estimated that about 20% of the White population will have levels of 50 mg/dL or over and even more in the Black population,” he added. 
 

‘Screen for both conditions’

In an accompanying editorial, Pamela Morris, MD, Medical University of South Carolina, Charleston; Jagat Narula, MD, Icahn School of Medicine, New York; and Sotirios Tsimikas, MD, University of California, San Diego, say “the weight of evidence strongly supports that both genetic lipid disorders, elevated Lp(a) levels and FH, are causally associated with an increased risk of premature ASCVD and should be carefully considered in risk assessment and management for ASCVD risk reduction.”

Catherine Hackett/MDedge News

Dr. Morris told this news organization that the current study found a very large range of Lp(a) levels that conferred a similar cardiovascular risk to FH, because of the many different definitions of FH in use.

“But this should not take away the importance of screening for raised Lp(a) levels,” she stressed.  

“We know that increased Lp(a) levels signal a high risk of cardiovascular disease. A diagnosis of FH is also a high-risk condition,” she said. “Both are important, and we need to screen for both, but it is difficult to directly compare the two conditions because the different definitions of FH get in the way.”

Dr. Morris agrees with Dr. Nordestgaard that raised levels of Lp(a) may actually be more important for the population risk of cardiovascular disease than FH, as the prevalence of increased Lp(a) levels is higher.

“Because raised Lp(a) levels are more prevalent than confirmed FH, the risk to the population is greater,” she said.  

Dr. Morris points out that cardiovascular risk starts to increase at Lp(a) levels of 30 mg/dL (75 nmol/L).

The editorialists recommend that “in addition to performing a lipid panel periodically according to evidence-based guidelines, measurement of Lp(a) levels should also be performed at least once in an individual’s lifetime for ASCVD risk assessment.”

They conclude that “it is vital to continue to raise awareness among clinicians and patients of these high-risk genetic lipid disorders. Our understanding of both disorders is rapidly expanding, and promising novel therapeutics may offer hope for prevention of cardiovascular disease in patients with elevated Lp(a) levels in the future.”

This work was supported by Copenhagen University Hospital – Herlev Gentofte, Denmark, and the Danish Beckett-Foundation. The Copenhagen General Population Study is supported by the Copenhagen County Foundation and Copenhagen University Hospital – Herlev Gentofte. Dr. Nordestgaard has been a consultant and a speaker for AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Kowa, Denka, Amarin, Novartis, Novo Nordisk, Silence Therapeutics, Abbott, and Esperion.

A version of this article first appeared on Medscape.com.

Many more people are at risk for early cardiovascular events because of raised lipoprotein(a) levels than from having familial hypercholesterolemia (FH), a new study suggests.

The Danish study set out to try and establish a level of Lp(a) that would be associated with a cardiovascular risk similar to that seen with FH. As there are many different definitions of FH, results showed a large range of Lp(a) values that corresponded to risk levels of the different FH definitions.

However, if considering one of the broadest FH definitions (from MEDPED – Make Early Diagnoses, Prevent Early Deaths), which is the one most commonly used in the United States, results showed that the level of cardiovascular risk in patients with this definition of FH is similar to that associated with Lp(a) levels of around 70 mg/dL (0.7 g/L).

“While FH is fairly unusual, occurring in less than 1% of the population, levels of Lp(a) of 70 mg/dL or above are much more common, occurring in around 10% of the White population,” Børge Nordestgaard, MD, Copenhagen University Hospital, said in an interview. Around 20% of the Black population have such high levels, while levels in Hispanics are in between.

“Our results suggest that there will be many more individuals at risk of premature MI or cardiovascular death because of raised Lp(a) levels than because of FH,” added Dr. Nordestgaard, the senior author of the current study.

Dr. Nordestgaard explained that FH is well established to be a serious condition. “We consider FH to be the genetic disease that causes the most cases of early heart disease and early death worldwide.”

“But we know now that raised levels of Lp(a), which is also genetically determined, can also lead to an increased risk of cardiovascular events relatively early in life, and when you look into the numbers, it seems like high levels of Lp(a) could be more common than FH. We wanted to try and find the levels of Lp(a) that corresponded to similar cardiovascular risk as FH.”

The Danish study was published  in the Journal of the American College of Cardiology.

The authors note that the 2019 joint European Society of Cardiology and European Atherosclerosis Society guidelines suggested that an Lp(a) level greater than 180 mg/dL (0.8 g/L) may confer a lifetime risk for heart disease equivalent to the risk associated with heterozygous FH, but they point out that this value was speculative and not based on a direct comparison of risk associated with the two conditions in the same population.

For their study, Dr. Nordestgaard and colleagues analyzed information from a large database of the Danish population, the Copenhagen General Population Study, including 69,644 individuals for whom data on FH and Lp(a) levels were available. As these conditions are genetically determined, and the study held records on individuals going back several decades, the researchers were able to analyze event rates over a median follow up time of 42 years. During this time, there were 4,166 cases of myocardial infarction and 11,464 cases of atherosclerotic cardiovascular disease (ASCVD).

Results showed that Lp(a) levels associated with MI risk equivalent to that of clinical FH ranged from 67 to 402 mg/dL depending on the definition used for FH. The Lp(a) level corresponding to the MI risk of genetically determined FH was 180 mg/dL.

In terms of risk of ASCVD events, the levels of Lp(a) corresponding to the risk associated with clinical FH ranged from 130 to 391 mg/dL, and the Lp(a) level corresponding to the ASCVD risk of genetically determined FH was 175 mg/dL.

“All these different definitions of FH may cause some confusion, but basically we are saying that if an individual is found to have an Lp(a) above 70 mg/dL, then they have a similar level of cardiovascular risk as that associated with the broadest definition of FH, and they should be taken as seriously as a patient diagnosed with FH,” Dr. Nordestgaard said.

He estimated that these individuals have approximately a doubling of cardiovascular risk, compared with the general population, and risk increases further with rising Lp(a) levels.

The researchers also found that if an individual has both FH and raised Lp(a) they are at very high risk, as these two conditions are independent of each other.

Although a specific treatment for lowering Lp(a) levels is not yet available, Dr. Nordestgaard stresses that it is still worth identifying individuals with raised Lp(a) as efforts can be made to address other cardiovascular risk factors.

“We know raised Lp(a) increases cardiovascular risk, but there are also many other factors that likewise increase this risk, and they are all additive. So, it is very important that individuals with raised Lp(a) levels address these other risk factors,” he said. “These include stopping smoking, being at healthy weight, exercising regularly, eating a heart-healthy diet, and aggressive treatment of raised LDL, hypertension, and diabetes. All these things will lower their overall risk of cardiovascular disease.”

And there is the promise of new drugs to lower Lp(a) on the horizon, with several such products now in clinical development.

Dr. Nordestgaard also points out that as Lp(a) is genetically determined, cascade screening of close relatives of the individual with raised Lp(a) should also take place to detect others who may be at risk.

Although a level of Lp(a) of around 70 mg/dL confers similar cardiovascular risk than some definitions of FH, Dr. Nordestgaard says lower levels than this should also be a signal for concern. 

“We usually say Lp(a) levels of 50 mg/dL are when we need to start to take this seriously. And it’s estimated that about 20% of the White population will have levels of 50 mg/dL or over and even more in the Black population,” he added. 
 

‘Screen for both conditions’

In an accompanying editorial, Pamela Morris, MD, Medical University of South Carolina, Charleston; Jagat Narula, MD, Icahn School of Medicine, New York; and Sotirios Tsimikas, MD, University of California, San Diego, say “the weight of evidence strongly supports that both genetic lipid disorders, elevated Lp(a) levels and FH, are causally associated with an increased risk of premature ASCVD and should be carefully considered in risk assessment and management for ASCVD risk reduction.”

Catherine Hackett/MDedge News

Dr. Morris told this news organization that the current study found a very large range of Lp(a) levels that conferred a similar cardiovascular risk to FH, because of the many different definitions of FH in use.

“But this should not take away the importance of screening for raised Lp(a) levels,” she stressed.  

“We know that increased Lp(a) levels signal a high risk of cardiovascular disease. A diagnosis of FH is also a high-risk condition,” she said. “Both are important, and we need to screen for both, but it is difficult to directly compare the two conditions because the different definitions of FH get in the way.”

Dr. Morris agrees with Dr. Nordestgaard that raised levels of Lp(a) may actually be more important for the population risk of cardiovascular disease than FH, as the prevalence of increased Lp(a) levels is higher.

“Because raised Lp(a) levels are more prevalent than confirmed FH, the risk to the population is greater,” she said.  

Dr. Morris points out that cardiovascular risk starts to increase at Lp(a) levels of 30 mg/dL (75 nmol/L).

The editorialists recommend that “in addition to performing a lipid panel periodically according to evidence-based guidelines, measurement of Lp(a) levels should also be performed at least once in an individual’s lifetime for ASCVD risk assessment.”

They conclude that “it is vital to continue to raise awareness among clinicians and patients of these high-risk genetic lipid disorders. Our understanding of both disorders is rapidly expanding, and promising novel therapeutics may offer hope for prevention of cardiovascular disease in patients with elevated Lp(a) levels in the future.”

This work was supported by Copenhagen University Hospital – Herlev Gentofte, Denmark, and the Danish Beckett-Foundation. The Copenhagen General Population Study is supported by the Copenhagen County Foundation and Copenhagen University Hospital – Herlev Gentofte. Dr. Nordestgaard has been a consultant and a speaker for AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Kowa, Denka, Amarin, Novartis, Novo Nordisk, Silence Therapeutics, Abbott, and Esperion.

A version of this article first appeared on Medscape.com.