A rare and devastating pediatric skin condition – severe reactive infectious mucocutaneous eruption (RIME) – may now have an additional, previously undescribed trigger, according to a newly published case report.

Lead author Anna Yasmine Kirkorian, MD, chief of dermatology at Children’s National Hospital in Washington, said she wanted to get the word out in part because it seems like RIME is occurring more frequently. “I do feel like we’re seeing more cases and from a more diverse number of pathogens,” Dr. Kirkorian told this news organization.

There was a decrease in RIME during the early stages of the COVID-19 pandemic when people were isolating more, Dr. Kirkorian said. SARS-CoV-2 has been a trigger for some cases, but she did not find that remarkable, given that respiratory viruses are known RIME precursors. The question is why RIME is being triggered more frequently now that people have essentially gone back to their normal lives, she said.

Dr. Kirkorian and colleagues at Children’s National Hospital and George Washington University, Washington, wrote about a 5-year-old boy with norovirus-triggered RIME in a case report published in Pediatric Dermatology.

RIME – previously known as Mycoplasma pneumoniae–induced rash and mucositis (MIRM) – tends to arise after a viral infection, with upper respiratory viruses such as mycoplasma and Chlamydophila pneumoniae, influenza, and enterovirus among the common triggers. “We think this is actually your own immune system overreacting to a pathogen,” Dr. Kirkorian said in an interview, adding that the mechanism of RIME is still not understood.

While the norovirus discovery was a surprise, it shows that much is still unknown about this rare condition. “I don’t think we know what is usual and what is unusual,” Dr. Kirkorian said.

In this case, the boy swiftly declined, with progressive conjunctivitis, high fever, and rapidly developing mucositis. By the time the 5-year-old got to Children’s National Hospital, he had a spreading, painful rash, including tense vesicles and bullae involving more than 30% of his total body surface area, and areas of denuded skin on both cheeks and the back of his neck.

He had hemorrhagic mucositis of the lips, a large erosion at the urethral meatus, and hemorrhagic conjunctivitis of both eyes with thick yellow crusting on the eyelids.

The clinicians intubated the boy and admitted him to the intensive care unit. He was given a one-time injection of etanercept (25 mg) followed by 8 days of intravenous cyclosporine at a dose of 5 mg per kilogram, divided twice daily, which helped calm the mucositis and stopped the rash from progressing. There is not an accepted protocol or list of evidence-based therapeutics for RIME, Dr. Kirkorian noted.

The severe eye damage required amniotic membrane grafts. The patient was extubated after 9 days but remained in the hospital for a total of 26 days because he needed to receive nutritional support (the mucositis kept him from eating), and for pain control and weaning of sedation.

As the clinicians searched for a potential triggering virus, they came up empty. Results were negative for adenovirus, Epstein Barr virus, cytomegalovirus, herpes simplex, and varicella zoster. But they noted that the child’s household contacts had all been sick a week before with presumed viral gastroenteritis. They decided to run a stool screen and the polymerase chain reaction for norovirus was positive. The boy never had GI symptoms.

Dr. Kirkorian said in the interview that she has seen other RIME cases where a child did not have symptoms associated with the original virus but did have a sudden onset of mucositis.

Although the definition of RIME is evolving, it is defined in part by mucositis in at least two of three areas: the mouth, eyes, and genitals. “Once you have the inflammation of the mucous membranes you should be on alert to think about more serious conditions,” like RIME, said Dr. Kirkorian. “Why does it manifest with the mucositis? I don’t think we know that,” she added.

RIME recurrence has also been vexing for patients, families and clinicians. In May, at the annual Atlantic Dermatology Conference, held in Baltimore, Dr. Kirkorian also discussed an 11-year-old patient who had RIME after SARS-CoV-2 infection early in the pandemic, resulting in a 22-day hospitalization and placement of a peripherally inserted central catheter and a feeding tube. He improved with cyclosporine and was discharged on systemic tacrolimus.

He was fine for several years, until another COVID infection. He again responded to medication. But not long after, an undetermined viral infection triggered another episode of RIME.

Dr. Kirkorian said there is no way to predict recurrence – making a devastating condition all the more worrisome. “Knowing that it might come back and it’s totally haphazard as to what might make it come back – that is very stressful for families,” she said in the interview.

“Some of the most perplexing patients with RIME are those with recurrent disease,” wrote Warren R. Heymann, MD, professor of dermatology and pediatrics at Rowan University, Camden, N.J., wrote in an online column on RIME in the American Academy of Dermatology’s “Dermatology World Insights and Inquiries”.

“Recurrent RIME is of particular interest, given that we could potentially intervene and prevent additional disease,” wrote Camille Introcaso, MD, associate professor of medicine at Rowan University, in response to Dr. Heymann’s remarks. “Although multiple possible mechanisms for the clinical findings of RIME have been proposed, including molecular mimicry between infectious agent proteins and keratinocyte antigens, immune complex deposition, and combinations of medication and infection, the pathophysiology is unknown,” she added.

In the interview, Dr. Kirkorian said that she and colleagues in the Pediatric Dermatology Research Alliance (PeDRA) are trying to assemble more multicenter trials to assess the underlying pathology of RIME, effectiveness of various treatments, and to “find some predictive factors.” Given that RIME is an acute-onset emergency, it is not easy to conduct randomized controlled trials, she added.

Dr. Kirkorian, Dr. Heymann, and Dr. Introcaso report no relevant financial relationships.

A rare and devastating pediatric skin condition – severe reactive infectious mucocutaneous eruption (RIME) – may now have an additional, previously undescribed trigger, according to a newly published case report.

Lead author Anna Yasmine Kirkorian, MD, chief of dermatology at Children’s National Hospital in Washington, said she wanted to get the word out in part because it seems like RIME is occurring more frequently. “I do feel like we’re seeing more cases and from a more diverse number of pathogens,” Dr. Kirkorian told this news organization.

There was a decrease in RIME during the early stages of the COVID-19 pandemic when people were isolating more, Dr. Kirkorian said. SARS-CoV-2 has been a trigger for some cases, but she did not find that remarkable, given that respiratory viruses are known RIME precursors. The question is why RIME is being triggered more frequently now that people have essentially gone back to their normal lives, she said.

Dr. Kirkorian and colleagues at Children’s National Hospital and George Washington University, Washington, wrote about a 5-year-old boy with norovirus-triggered RIME in a case report published in Pediatric Dermatology.

RIME – previously known as Mycoplasma pneumoniae–induced rash and mucositis (MIRM) – tends to arise after a viral infection, with upper respiratory viruses such as mycoplasma and Chlamydophila pneumoniae, influenza, and enterovirus among the common triggers. “We think this is actually your own immune system overreacting to a pathogen,” Dr. Kirkorian said in an interview, adding that the mechanism of RIME is still not understood.

While the norovirus discovery was a surprise, it shows that much is still unknown about this rare condition. “I don’t think we know what is usual and what is unusual,” Dr. Kirkorian said.

In this case, the boy swiftly declined, with progressive conjunctivitis, high fever, and rapidly developing mucositis. By the time the 5-year-old got to Children’s National Hospital, he had a spreading, painful rash, including tense vesicles and bullae involving more than 30% of his total body surface area, and areas of denuded skin on both cheeks and the back of his neck.

He had hemorrhagic mucositis of the lips, a large erosion at the urethral meatus, and hemorrhagic conjunctivitis of both eyes with thick yellow crusting on the eyelids.

The clinicians intubated the boy and admitted him to the intensive care unit. He was given a one-time injection of etanercept (25 mg) followed by 8 days of intravenous cyclosporine at a dose of 5 mg per kilogram, divided twice daily, which helped calm the mucositis and stopped the rash from progressing. There is not an accepted protocol or list of evidence-based therapeutics for RIME, Dr. Kirkorian noted.

The severe eye damage required amniotic membrane grafts. The patient was extubated after 9 days but remained in the hospital for a total of 26 days because he needed to receive nutritional support (the mucositis kept him from eating), and for pain control and weaning of sedation.

As the clinicians searched for a potential triggering virus, they came up empty. Results were negative for adenovirus, Epstein Barr virus, cytomegalovirus, herpes simplex, and varicella zoster. But they noted that the child’s household contacts had all been sick a week before with presumed viral gastroenteritis. They decided to run a stool screen and the polymerase chain reaction for norovirus was positive. The boy never had GI symptoms.

Dr. Kirkorian said in the interview that she has seen other RIME cases where a child did not have symptoms associated with the original virus but did have a sudden onset of mucositis.

Although the definition of RIME is evolving, it is defined in part by mucositis in at least two of three areas: the mouth, eyes, and genitals. “Once you have the inflammation of the mucous membranes you should be on alert to think about more serious conditions,” like RIME, said Dr. Kirkorian. “Why does it manifest with the mucositis? I don’t think we know that,” she added.

RIME recurrence has also been vexing for patients, families and clinicians. In May, at the annual Atlantic Dermatology Conference, held in Baltimore, Dr. Kirkorian also discussed an 11-year-old patient who had RIME after SARS-CoV-2 infection early in the pandemic, resulting in a 22-day hospitalization and placement of a peripherally inserted central catheter and a feeding tube. He improved with cyclosporine and was discharged on systemic tacrolimus.

He was fine for several years, until another COVID infection. He again responded to medication. But not long after, an undetermined viral infection triggered another episode of RIME.

Dr. Kirkorian said there is no way to predict recurrence – making a devastating condition all the more worrisome. “Knowing that it might come back and it’s totally haphazard as to what might make it come back – that is very stressful for families,” she said in the interview.

“Some of the most perplexing patients with RIME are those with recurrent disease,” wrote Warren R. Heymann, MD, professor of dermatology and pediatrics at Rowan University, Camden, N.J., wrote in an online column on RIME in the American Academy of Dermatology’s “Dermatology World Insights and Inquiries”.

“Recurrent RIME is of particular interest, given that we could potentially intervene and prevent additional disease,” wrote Camille Introcaso, MD, associate professor of medicine at Rowan University, in response to Dr. Heymann’s remarks. “Although multiple possible mechanisms for the clinical findings of RIME have been proposed, including molecular mimicry between infectious agent proteins and keratinocyte antigens, immune complex deposition, and combinations of medication and infection, the pathophysiology is unknown,” she added.

In the interview, Dr. Kirkorian said that she and colleagues in the Pediatric Dermatology Research Alliance (PeDRA) are trying to assemble more multicenter trials to assess the underlying pathology of RIME, effectiveness of various treatments, and to “find some predictive factors.” Given that RIME is an acute-onset emergency, it is not easy to conduct randomized controlled trials, she added.

Dr. Kirkorian, Dr. Heymann, and Dr. Introcaso report no relevant financial relationships.

A rare and devastating pediatric skin condition – severe reactive infectious mucocutaneous eruption (RIME) – may now have an additional, previously undescribed trigger, according to a newly published case report.

Lead author Anna Yasmine Kirkorian, MD, chief of dermatology at Children’s National Hospital in Washington, said she wanted to get the word out in part because it seems like RIME is occurring more frequently. “I do feel like we’re seeing more cases and from a more diverse number of pathogens,” Dr. Kirkorian told this news organization.

There was a decrease in RIME during the early stages of the COVID-19 pandemic when people were isolating more, Dr. Kirkorian said. SARS-CoV-2 has been a trigger for some cases, but she did not find that remarkable, given that respiratory viruses are known RIME precursors. The question is why RIME is being triggered more frequently now that people have essentially gone back to their normal lives, she said.

Dr. Kirkorian and colleagues at Children’s National Hospital and George Washington University, Washington, wrote about a 5-year-old boy with norovirus-triggered RIME in a case report published in Pediatric Dermatology.

RIME – previously known as Mycoplasma pneumoniae–induced rash and mucositis (MIRM) – tends to arise after a viral infection, with upper respiratory viruses such as mycoplasma and Chlamydophila pneumoniae, influenza, and enterovirus among the common triggers. “We think this is actually your own immune system overreacting to a pathogen,” Dr. Kirkorian said in an interview, adding that the mechanism of RIME is still not understood.

While the norovirus discovery was a surprise, it shows that much is still unknown about this rare condition. “I don’t think we know what is usual and what is unusual,” Dr. Kirkorian said.

In this case, the boy swiftly declined, with progressive conjunctivitis, high fever, and rapidly developing mucositis. By the time the 5-year-old got to Children’s National Hospital, he had a spreading, painful rash, including tense vesicles and bullae involving more than 30% of his total body surface area, and areas of denuded skin on both cheeks and the back of his neck.

He had hemorrhagic mucositis of the lips, a large erosion at the urethral meatus, and hemorrhagic conjunctivitis of both eyes with thick yellow crusting on the eyelids.

The clinicians intubated the boy and admitted him to the intensive care unit. He was given a one-time injection of etanercept (25 mg) followed by 8 days of intravenous cyclosporine at a dose of 5 mg per kilogram, divided twice daily, which helped calm the mucositis and stopped the rash from progressing. There is not an accepted protocol or list of evidence-based therapeutics for RIME, Dr. Kirkorian noted.

The severe eye damage required amniotic membrane grafts. The patient was extubated after 9 days but remained in the hospital for a total of 26 days because he needed to receive nutritional support (the mucositis kept him from eating), and for pain control and weaning of sedation.

As the clinicians searched for a potential triggering virus, they came up empty. Results were negative for adenovirus, Epstein Barr virus, cytomegalovirus, herpes simplex, and varicella zoster. But they noted that the child’s household contacts had all been sick a week before with presumed viral gastroenteritis. They decided to run a stool screen and the polymerase chain reaction for norovirus was positive. The boy never had GI symptoms.

Dr. Kirkorian said in the interview that she has seen other RIME cases where a child did not have symptoms associated with the original virus but did have a sudden onset of mucositis.

Although the definition of RIME is evolving, it is defined in part by mucositis in at least two of three areas: the mouth, eyes, and genitals. “Once you have the inflammation of the mucous membranes you should be on alert to think about more serious conditions,” like RIME, said Dr. Kirkorian. “Why does it manifest with the mucositis? I don’t think we know that,” she added.

RIME recurrence has also been vexing for patients, families and clinicians. In May, at the annual Atlantic Dermatology Conference, held in Baltimore, Dr. Kirkorian also discussed an 11-year-old patient who had RIME after SARS-CoV-2 infection early in the pandemic, resulting in a 22-day hospitalization and placement of a peripherally inserted central catheter and a feeding tube. He improved with cyclosporine and was discharged on systemic tacrolimus.

He was fine for several years, until another COVID infection. He again responded to medication. But not long after, an undetermined viral infection triggered another episode of RIME.

Dr. Kirkorian said there is no way to predict recurrence – making a devastating condition all the more worrisome. “Knowing that it might come back and it’s totally haphazard as to what might make it come back – that is very stressful for families,” she said in the interview.

“Some of the most perplexing patients with RIME are those with recurrent disease,” wrote Warren R. Heymann, MD, professor of dermatology and pediatrics at Rowan University, Camden, N.J., wrote in an online column on RIME in the American Academy of Dermatology’s “Dermatology World Insights and Inquiries”.

“Recurrent RIME is of particular interest, given that we could potentially intervene and prevent additional disease,” wrote Camille Introcaso, MD, associate professor of medicine at Rowan University, in response to Dr. Heymann’s remarks. “Although multiple possible mechanisms for the clinical findings of RIME have been proposed, including molecular mimicry between infectious agent proteins and keratinocyte antigens, immune complex deposition, and combinations of medication and infection, the pathophysiology is unknown,” she added.

In the interview, Dr. Kirkorian said that she and colleagues in the Pediatric Dermatology Research Alliance (PeDRA) are trying to assemble more multicenter trials to assess the underlying pathology of RIME, effectiveness of various treatments, and to “find some predictive factors.” Given that RIME is an acute-onset emergency, it is not easy to conduct randomized controlled trials, she added.

Dr. Kirkorian, Dr. Heymann, and Dr. Introcaso report no relevant financial relationships.

TOPLINE:

Researchers found that, prior to resection, performing a minimally invasive staging procedure on newly diagnosed patients with pancreatic cancer helped identify metastatic disease and cancer stage, and prompted a change in management in about one in five patients.

METHODOLOGY:

• The study included 1,004 patients who underwent staging laparoscopy at the Mayo Clinic, Rochester, Minn., from January 2017 to December 2021. 
• Patients’ median age was 66 years; 48% of the cohort were female. 
• Tumor location was proximal in 644 patients (64%) and distal in 360 patients (36%); median tumor size was 29 mm. 
• Upfront resectable disease was present in 351 patients (35%), and borderline resectable or locally advanced anatomy was present in 653 (65%).

TAKEAWAY:

• Overall, 180 patients had a positive staging laparoscopy because of gross metastatic disease (n = 140) and/or positive peritoneal cytology (n = 96); patients who underwent neoadjuvant chemotherapy before staging laparoscopy had lower rates of positive laparoscopy (14% vs. 22%; P = .002).
• When the analysis was restricted to chemo-naive patients who had concurrent peritoneal lavage performed, 95 of 419 patients (23%) had positive laparoscopy. 
• Among 721 patients who had a staged procedure with peritoneal washings, 151 (21%) had confirmed metastatic disease; cytology was positive in 96 (13%).
• Among patients with positive staging laparoscopy, median overall survival was 11 months in those with gross metastatic disease and 13 months in those with positive peritoneal cytology only (P = .40).

IN PRACTICE:

“Staging laparoscopy should be considered in the majority of patients prior to resection and/or initiation of neoadjuvant therapy, specifically in patients with high-risk features such as indeterminate extrapancreatic lesions on imaging, young age, large tumor size, distal tumor location, or elevated serum tumor markers,” the authors concluded. 

SOURCE:

The study, led by Hallbera Gudmundsdottir, MD, of the Mayo Clinic was published in the  Journal of the American College of Surgeons  in June. 

LIMITATIONS:

Staging laparoscopy may have been performed in higher-risk patients in earlier years of the study. The Mayo Clinic is a high-volume pancreatic surgery center that sees high-risk patients with advances lesions. This study population may not be generalizable to the those at other centers.

DISCLOSURES:

The authors did not disclose any financial interests.

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

TOPLINE:

Researchers found that, prior to resection, performing a minimally invasive staging procedure on newly diagnosed patients with pancreatic cancer helped identify metastatic disease and cancer stage, and prompted a change in management in about one in five patients.

METHODOLOGY:

• The study included 1,004 patients who underwent staging laparoscopy at the Mayo Clinic, Rochester, Minn., from January 2017 to December 2021. 
• Patients’ median age was 66 years; 48% of the cohort were female. 
• Tumor location was proximal in 644 patients (64%) and distal in 360 patients (36%); median tumor size was 29 mm. 
• Upfront resectable disease was present in 351 patients (35%), and borderline resectable or locally advanced anatomy was present in 653 (65%).

TAKEAWAY:

• Overall, 180 patients had a positive staging laparoscopy because of gross metastatic disease (n = 140) and/or positive peritoneal cytology (n = 96); patients who underwent neoadjuvant chemotherapy before staging laparoscopy had lower rates of positive laparoscopy (14% vs. 22%; P = .002).
• When the analysis was restricted to chemo-naive patients who had concurrent peritoneal lavage performed, 95 of 419 patients (23%) had positive laparoscopy. 
• Among 721 patients who had a staged procedure with peritoneal washings, 151 (21%) had confirmed metastatic disease; cytology was positive in 96 (13%).
• Among patients with positive staging laparoscopy, median overall survival was 11 months in those with gross metastatic disease and 13 months in those with positive peritoneal cytology only (P = .40).

IN PRACTICE:

“Staging laparoscopy should be considered in the majority of patients prior to resection and/or initiation of neoadjuvant therapy, specifically in patients with high-risk features such as indeterminate extrapancreatic lesions on imaging, young age, large tumor size, distal tumor location, or elevated serum tumor markers,” the authors concluded. 

SOURCE:

The study, led by Hallbera Gudmundsdottir, MD, of the Mayo Clinic was published in the  Journal of the American College of Surgeons  in June. 

LIMITATIONS:

Staging laparoscopy may have been performed in higher-risk patients in earlier years of the study. The Mayo Clinic is a high-volume pancreatic surgery center that sees high-risk patients with advances lesions. This study population may not be generalizable to the those at other centers.

DISCLOSURES:

The authors did not disclose any financial interests.

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

TOPLINE:

Researchers found that, prior to resection, performing a minimally invasive staging procedure on newly diagnosed patients with pancreatic cancer helped identify metastatic disease and cancer stage, and prompted a change in management in about one in five patients.

METHODOLOGY:

• The study included 1,004 patients who underwent staging laparoscopy at the Mayo Clinic, Rochester, Minn., from January 2017 to December 2021. 
• Patients’ median age was 66 years; 48% of the cohort were female. 
• Tumor location was proximal in 644 patients (64%) and distal in 360 patients (36%); median tumor size was 29 mm. 
• Upfront resectable disease was present in 351 patients (35%), and borderline resectable or locally advanced anatomy was present in 653 (65%).

TAKEAWAY:

• Overall, 180 patients had a positive staging laparoscopy because of gross metastatic disease (n = 140) and/or positive peritoneal cytology (n = 96); patients who underwent neoadjuvant chemotherapy before staging laparoscopy had lower rates of positive laparoscopy (14% vs. 22%; P = .002).
• When the analysis was restricted to chemo-naive patients who had concurrent peritoneal lavage performed, 95 of 419 patients (23%) had positive laparoscopy. 
• Among 721 patients who had a staged procedure with peritoneal washings, 151 (21%) had confirmed metastatic disease; cytology was positive in 96 (13%).
• Among patients with positive staging laparoscopy, median overall survival was 11 months in those with gross metastatic disease and 13 months in those with positive peritoneal cytology only (P = .40).

IN PRACTICE:

“Staging laparoscopy should be considered in the majority of patients prior to resection and/or initiation of neoadjuvant therapy, specifically in patients with high-risk features such as indeterminate extrapancreatic lesions on imaging, young age, large tumor size, distal tumor location, or elevated serum tumor markers,” the authors concluded. 

SOURCE:

The study, led by Hallbera Gudmundsdottir, MD, of the Mayo Clinic was published in the  Journal of the American College of Surgeons  in June. 

LIMITATIONS:

Staging laparoscopy may have been performed in higher-risk patients in earlier years of the study. The Mayo Clinic is a high-volume pancreatic surgery center that sees high-risk patients with advances lesions. This study population may not be generalizable to the those at other centers.

DISCLOSURES:

The authors did not disclose any financial interests.

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

The risks of common postpartum mental health (PMH) problems may soon be more predictable, thanks to a new comprehensive index for identifying mothers’ 1-year risk at time of delivery.

Developed by Canadian researchers, the easily implementable PMH CAREPLAN index “creates a framework for clinically actionable risk stratification that could assist patients and providers in determining an individual’s level of risk for common postpartum mental health disorders and direct them to appropriate intervention,” wrote a group led by Simone N. Vigod, MD, MSc, head of the department of psychiatry at Women’s College Hospital, Toronto, in the British Journal of Psychiatry.

courtesy Women's College Hospital

After giving birth, women are especially vulnerable to major depression, anxiety, PTSD, and obsessive-compulsive disorder, which have a general postpartum prevalence of 7%-20%.

Common PMH disorders are to be distinguished from the more rare but severe PMH disorders such as postpartum psychosis and bipolar disorder, the researchers stressed.

“We know there are interventions that can prevent these disorders, but these seem to work best in people who are at high risk for developing the illnesses, “ Dr. Vigod said. “So, we wanted to be able to determine the level of risk that a person might actually experience them.”

In an ideal world, she continued, physicians might be able to say to a patient: “You have a 50% chance of developing postpartum depression and anxiety, so it may be worth investing your time and resources in a course of preventive psychotherapy.” Or: “You have a 90% chance of developing these disorders, so it might be worth going back on your medications even though you are breastfeeding.” Or: “You have only a 1% chance of developing them, so probably it’s not worthwhile to go back on your medication prophylactically.”

A need for a new assessment tool, akin to the Framingham Risk Score for 10-year cardiovascular events and the FRAX scoring system for 10-year fracture risk, was evident since previous indices based largely on patient self-reporting have had moderate predictive capacity, and have not been adopted in clinical practice, Dr. Vigod and associates noted.
 

Split-cohort design

Using population-based health administrative data and hospital birth records from Ontario during 2012-2015, Dr. Vigod’s group created and internally validated a predictive model for common PMH disorders in a cohort of 152,362 mothers. They then converted it to a risk index after validation in an additional cohort of 75,772 mothers. The women had delivered live infants during 2012-2014.

A common PMH disorder occurred in 13,608 mothers, while 214,526 were unaffected.

Independently associated PMH variables were many: prenatal care provider, mental health diagnosis history and medications during pregnancy, psychiatric hospital admissions or ED visits, conception type and complications, and apprehension of newborn by child services. Other factors were region of maternal origin, extremes of gestational age at birth, primary maternal language, lactation intention, maternal age, and number of prenatal visits.

Based on a broad span of scores from 0 to 39, 1-year common PMH disorder risk ranged from 1.5% to 40.5%, with an overall 1-year prevalence of 6%, consistent with previous studies. That included 11,262 (5%) mothers with an anxiety or related disorder, 3,392 (1.5%) with a depressive episode, and 1,046 (0.5%) with both. The best trade-off of sensitivity/specificity for risk appeared to be at a screening threshold score of 17 or above.
 

Risk drivers

PMH-affected mothers were slightly younger than unaffected women (mean age, 29.9 years vs. 30.6 years), more likely to be primiparous (45.2% vs. 42%), and less likely to be recent immigrants (16.7% vs. 27.2%).

They were also more likely to have previously experienced postpartum depression (4.4% vs. 1.4%), any depression (15.3% vs. 4.4%), and any anxiety disorder (13.8% vs. 4.3%).

As to lifestyle, smoking was more common in women with PMH (15.0% vs. 10.2%), as were the use of nonprescribed substances (3% vs. 1.4%) and intimate partner violence in pregnancy (2.7% vs. 1.5%).

In addition, the affected group experienced more pregnancy complications than their unaffected peers (16% vs. 13.9%), preterm birth (8.2% vs. 6.8%), and Apgar scores below 7 at 1 or 5 minutes (10.5% vs. 7.6%).

Low income did not appear to have an impact since just over 20% in either group fell into the lowest neighborhood income quintile.

courtesy Northwestern Medicine

Commenting on the index but not involved in developing it, LaTasha D. Nelson, MD, an associate professor or medicine and a maternal-fetal medicine specialist at Northwestern Medicine in Chicago, doubted the Canadian model would work as well in the more fragmented U.S. health care system, compared with Canada’s universal model with its large provincial health databases.

She also found the large number of variables and broad score range potentially problematic, especially if the risk threshold is set at less than half the maximum score at 17, at which some low-risk mothers might get screening and perhaps intervention. “Are we going to use up the resources we have for those who might not need help, or are we going to treat someone who really needs it?” she asked.

Another concern is the postpartum timing of assessment. At Dr. Nelson’s center, mothers are checked for mental health at two points during pregnancy and those with higher scores are triaged for further care.

Dr. Nelson was also puzzled by the score-lowering impact of prenatal care given by a nurse practitioner and “other” provider : –5 and –2, respectively, versus +3 for a midwife and +1 for a family doctor. “This may capture more relaxed, easy-going multiparous mothers who felt comfortable turning to an NP,” she said.

It may indeed reflect that the risk level of a person who sees those providers is overall lower, Dr. Vigod agreed. “This is one reason why we would want to see replication of these results in other jurisdictions and by other ways of diagnosis before putting it out into clinical practice.”

As to the score-lowering effect of not speaking English as the primary tongue, Dr. Nelson wondered, “is that because we’re taking better care of mothers who speak the main language and missing those who speak other languages? Are they not getting the same level of interrogation?”

It may be that individuals in these groups were less likely to access mental health care, Dr. Vigod agreed, or it might reflect the so-called healthy immigrant effect or culturally different levels of postpartum support. “It might mean that there are more people who benefit from community-level protective factors in these groups. We know that social support is an important protective factor.”

Despite her reservations about the index, Dr. Nelson said that increasing attention to the pre- and postnatal mental health of mothers is an important part of maternal care. “This is an issue that needs to be recognized.”

The next step, Dr. Vigod said, is to determine whether the index holds up in other populations. “Then, we would want to test it out to see if recommending interventions based on a certain level of risk improves outcomes. At what percentage risk would starting an antidepressant medication result in a reduced risk for postpartum depression or anxiety – 90%, 80%, 70%, or less?”

The study received funding from the Canadian Institutes of Health Research. Data were analyzed by ICES, an independent nonprofit research organization that holds population-based data. Dr. Vigod reported royalties from UpToDate for materials related to depression and pregnancy. Dr. Nelson disclosed no relevant competing interests.

The risks of common postpartum mental health (PMH) problems may soon be more predictable, thanks to a new comprehensive index for identifying mothers’ 1-year risk at time of delivery.

Developed by Canadian researchers, the easily implementable PMH CAREPLAN index “creates a framework for clinically actionable risk stratification that could assist patients and providers in determining an individual’s level of risk for common postpartum mental health disorders and direct them to appropriate intervention,” wrote a group led by Simone N. Vigod, MD, MSc, head of the department of psychiatry at Women’s College Hospital, Toronto, in the British Journal of Psychiatry.

courtesy Women's College Hospital

After giving birth, women are especially vulnerable to major depression, anxiety, PTSD, and obsessive-compulsive disorder, which have a general postpartum prevalence of 7%-20%.

Common PMH disorders are to be distinguished from the more rare but severe PMH disorders such as postpartum psychosis and bipolar disorder, the researchers stressed.

“We know there are interventions that can prevent these disorders, but these seem to work best in people who are at high risk for developing the illnesses, “ Dr. Vigod said. “So, we wanted to be able to determine the level of risk that a person might actually experience them.”

In an ideal world, she continued, physicians might be able to say to a patient: “You have a 50% chance of developing postpartum depression and anxiety, so it may be worth investing your time and resources in a course of preventive psychotherapy.” Or: “You have a 90% chance of developing these disorders, so it might be worth going back on your medications even though you are breastfeeding.” Or: “You have only a 1% chance of developing them, so probably it’s not worthwhile to go back on your medication prophylactically.”

A need for a new assessment tool, akin to the Framingham Risk Score for 10-year cardiovascular events and the FRAX scoring system for 10-year fracture risk, was evident since previous indices based largely on patient self-reporting have had moderate predictive capacity, and have not been adopted in clinical practice, Dr. Vigod and associates noted.
 

Split-cohort design

Using population-based health administrative data and hospital birth records from Ontario during 2012-2015, Dr. Vigod’s group created and internally validated a predictive model for common PMH disorders in a cohort of 152,362 mothers. They then converted it to a risk index after validation in an additional cohort of 75,772 mothers. The women had delivered live infants during 2012-2014.

A common PMH disorder occurred in 13,608 mothers, while 214,526 were unaffected.

Independently associated PMH variables were many: prenatal care provider, mental health diagnosis history and medications during pregnancy, psychiatric hospital admissions or ED visits, conception type and complications, and apprehension of newborn by child services. Other factors were region of maternal origin, extremes of gestational age at birth, primary maternal language, lactation intention, maternal age, and number of prenatal visits.

Based on a broad span of scores from 0 to 39, 1-year common PMH disorder risk ranged from 1.5% to 40.5%, with an overall 1-year prevalence of 6%, consistent with previous studies. That included 11,262 (5%) mothers with an anxiety or related disorder, 3,392 (1.5%) with a depressive episode, and 1,046 (0.5%) with both. The best trade-off of sensitivity/specificity for risk appeared to be at a screening threshold score of 17 or above.
 

Risk drivers

PMH-affected mothers were slightly younger than unaffected women (mean age, 29.9 years vs. 30.6 years), more likely to be primiparous (45.2% vs. 42%), and less likely to be recent immigrants (16.7% vs. 27.2%).

They were also more likely to have previously experienced postpartum depression (4.4% vs. 1.4%), any depression (15.3% vs. 4.4%), and any anxiety disorder (13.8% vs. 4.3%).

As to lifestyle, smoking was more common in women with PMH (15.0% vs. 10.2%), as were the use of nonprescribed substances (3% vs. 1.4%) and intimate partner violence in pregnancy (2.7% vs. 1.5%).

In addition, the affected group experienced more pregnancy complications than their unaffected peers (16% vs. 13.9%), preterm birth (8.2% vs. 6.8%), and Apgar scores below 7 at 1 or 5 minutes (10.5% vs. 7.6%).

Low income did not appear to have an impact since just over 20% in either group fell into the lowest neighborhood income quintile.

courtesy Northwestern Medicine

Commenting on the index but not involved in developing it, LaTasha D. Nelson, MD, an associate professor or medicine and a maternal-fetal medicine specialist at Northwestern Medicine in Chicago, doubted the Canadian model would work as well in the more fragmented U.S. health care system, compared with Canada’s universal model with its large provincial health databases.

She also found the large number of variables and broad score range potentially problematic, especially if the risk threshold is set at less than half the maximum score at 17, at which some low-risk mothers might get screening and perhaps intervention. “Are we going to use up the resources we have for those who might not need help, or are we going to treat someone who really needs it?” she asked.

Another concern is the postpartum timing of assessment. At Dr. Nelson’s center, mothers are checked for mental health at two points during pregnancy and those with higher scores are triaged for further care.

Dr. Nelson was also puzzled by the score-lowering impact of prenatal care given by a nurse practitioner and “other” provider : –5 and –2, respectively, versus +3 for a midwife and +1 for a family doctor. “This may capture more relaxed, easy-going multiparous mothers who felt comfortable turning to an NP,” she said.

It may indeed reflect that the risk level of a person who sees those providers is overall lower, Dr. Vigod agreed. “This is one reason why we would want to see replication of these results in other jurisdictions and by other ways of diagnosis before putting it out into clinical practice.”

As to the score-lowering effect of not speaking English as the primary tongue, Dr. Nelson wondered, “is that because we’re taking better care of mothers who speak the main language and missing those who speak other languages? Are they not getting the same level of interrogation?”

It may be that individuals in these groups were less likely to access mental health care, Dr. Vigod agreed, or it might reflect the so-called healthy immigrant effect or culturally different levels of postpartum support. “It might mean that there are more people who benefit from community-level protective factors in these groups. We know that social support is an important protective factor.”

Despite her reservations about the index, Dr. Nelson said that increasing attention to the pre- and postnatal mental health of mothers is an important part of maternal care. “This is an issue that needs to be recognized.”

The next step, Dr. Vigod said, is to determine whether the index holds up in other populations. “Then, we would want to test it out to see if recommending interventions based on a certain level of risk improves outcomes. At what percentage risk would starting an antidepressant medication result in a reduced risk for postpartum depression or anxiety – 90%, 80%, 70%, or less?”

The study received funding from the Canadian Institutes of Health Research. Data were analyzed by ICES, an independent nonprofit research organization that holds population-based data. Dr. Vigod reported royalties from UpToDate for materials related to depression and pregnancy. Dr. Nelson disclosed no relevant competing interests.

The risks of common postpartum mental health (PMH) problems may soon be more predictable, thanks to a new comprehensive index for identifying mothers’ 1-year risk at time of delivery.

Developed by Canadian researchers, the easily implementable PMH CAREPLAN index “creates a framework for clinically actionable risk stratification that could assist patients and providers in determining an individual’s level of risk for common postpartum mental health disorders and direct them to appropriate intervention,” wrote a group led by Simone N. Vigod, MD, MSc, head of the department of psychiatry at Women’s College Hospital, Toronto, in the British Journal of Psychiatry.

courtesy Women's College Hospital

After giving birth, women are especially vulnerable to major depression, anxiety, PTSD, and obsessive-compulsive disorder, which have a general postpartum prevalence of 7%-20%.

Common PMH disorders are to be distinguished from the more rare but severe PMH disorders such as postpartum psychosis and bipolar disorder, the researchers stressed.

“We know there are interventions that can prevent these disorders, but these seem to work best in people who are at high risk for developing the illnesses, “ Dr. Vigod said. “So, we wanted to be able to determine the level of risk that a person might actually experience them.”

In an ideal world, she continued, physicians might be able to say to a patient: “You have a 50% chance of developing postpartum depression and anxiety, so it may be worth investing your time and resources in a course of preventive psychotherapy.” Or: “You have a 90% chance of developing these disorders, so it might be worth going back on your medications even though you are breastfeeding.” Or: “You have only a 1% chance of developing them, so probably it’s not worthwhile to go back on your medication prophylactically.”

A need for a new assessment tool, akin to the Framingham Risk Score for 10-year cardiovascular events and the FRAX scoring system for 10-year fracture risk, was evident since previous indices based largely on patient self-reporting have had moderate predictive capacity, and have not been adopted in clinical practice, Dr. Vigod and associates noted.
 

Split-cohort design

Using population-based health administrative data and hospital birth records from Ontario during 2012-2015, Dr. Vigod’s group created and internally validated a predictive model for common PMH disorders in a cohort of 152,362 mothers. They then converted it to a risk index after validation in an additional cohort of 75,772 mothers. The women had delivered live infants during 2012-2014.

A common PMH disorder occurred in 13,608 mothers, while 214,526 were unaffected.

Independently associated PMH variables were many: prenatal care provider, mental health diagnosis history and medications during pregnancy, psychiatric hospital admissions or ED visits, conception type and complications, and apprehension of newborn by child services. Other factors were region of maternal origin, extremes of gestational age at birth, primary maternal language, lactation intention, maternal age, and number of prenatal visits.

Based on a broad span of scores from 0 to 39, 1-year common PMH disorder risk ranged from 1.5% to 40.5%, with an overall 1-year prevalence of 6%, consistent with previous studies. That included 11,262 (5%) mothers with an anxiety or related disorder, 3,392 (1.5%) with a depressive episode, and 1,046 (0.5%) with both. The best trade-off of sensitivity/specificity for risk appeared to be at a screening threshold score of 17 or above.
 

Risk drivers

PMH-affected mothers were slightly younger than unaffected women (mean age, 29.9 years vs. 30.6 years), more likely to be primiparous (45.2% vs. 42%), and less likely to be recent immigrants (16.7% vs. 27.2%).

They were also more likely to have previously experienced postpartum depression (4.4% vs. 1.4%), any depression (15.3% vs. 4.4%), and any anxiety disorder (13.8% vs. 4.3%).

As to lifestyle, smoking was more common in women with PMH (15.0% vs. 10.2%), as were the use of nonprescribed substances (3% vs. 1.4%) and intimate partner violence in pregnancy (2.7% vs. 1.5%).

In addition, the affected group experienced more pregnancy complications than their unaffected peers (16% vs. 13.9%), preterm birth (8.2% vs. 6.8%), and Apgar scores below 7 at 1 or 5 minutes (10.5% vs. 7.6%).

Low income did not appear to have an impact since just over 20% in either group fell into the lowest neighborhood income quintile.

courtesy Northwestern Medicine

Commenting on the index but not involved in developing it, LaTasha D. Nelson, MD, an associate professor or medicine and a maternal-fetal medicine specialist at Northwestern Medicine in Chicago, doubted the Canadian model would work as well in the more fragmented U.S. health care system, compared with Canada’s universal model with its large provincial health databases.

She also found the large number of variables and broad score range potentially problematic, especially if the risk threshold is set at less than half the maximum score at 17, at which some low-risk mothers might get screening and perhaps intervention. “Are we going to use up the resources we have for those who might not need help, or are we going to treat someone who really needs it?” she asked.

Another concern is the postpartum timing of assessment. At Dr. Nelson’s center, mothers are checked for mental health at two points during pregnancy and those with higher scores are triaged for further care.

Dr. Nelson was also puzzled by the score-lowering impact of prenatal care given by a nurse practitioner and “other” provider : –5 and –2, respectively, versus +3 for a midwife and +1 for a family doctor. “This may capture more relaxed, easy-going multiparous mothers who felt comfortable turning to an NP,” she said.

It may indeed reflect that the risk level of a person who sees those providers is overall lower, Dr. Vigod agreed. “This is one reason why we would want to see replication of these results in other jurisdictions and by other ways of diagnosis before putting it out into clinical practice.”

As to the score-lowering effect of not speaking English as the primary tongue, Dr. Nelson wondered, “is that because we’re taking better care of mothers who speak the main language and missing those who speak other languages? Are they not getting the same level of interrogation?”

It may be that individuals in these groups were less likely to access mental health care, Dr. Vigod agreed, or it might reflect the so-called healthy immigrant effect or culturally different levels of postpartum support. “It might mean that there are more people who benefit from community-level protective factors in these groups. We know that social support is an important protective factor.”

Despite her reservations about the index, Dr. Nelson said that increasing attention to the pre- and postnatal mental health of mothers is an important part of maternal care. “This is an issue that needs to be recognized.”

The next step, Dr. Vigod said, is to determine whether the index holds up in other populations. “Then, we would want to test it out to see if recommending interventions based on a certain level of risk improves outcomes. At what percentage risk would starting an antidepressant medication result in a reduced risk for postpartum depression or anxiety – 90%, 80%, 70%, or less?”

The study received funding from the Canadian Institutes of Health Research. Data were analyzed by ICES, an independent nonprofit research organization that holds population-based data. Dr. Vigod reported royalties from UpToDate for materials related to depression and pregnancy. Dr. Nelson disclosed no relevant competing interests.

Dysphagia is one of the most common side effects of radiation for head and neck cancer and can be so bad that patients require a permanent gastrostomy tube for feeding.

A team of British investigators are now reporting a new strategy to help lessen this problem.

In the trial, the approach – dubbed dysphagia-optimized intensity-modulated radiotherapy (DO-IMRT) – reduced incidental radiation to the pharyngeal constrictor muscles responsible for swallowing during IMRT for pharyngeal cancer. Patients randomized to DO-IMRT reported significant improvements in swallowing at 1 year, compared with those receiving standard IMRT, at no cost to oncologic outcomes.

Overall, the findings show “DO-IMRT improves patient-reported swallowing function, compared with standard IMRT,” said investigators led by Christopher Nutting, MD, PhD, a head and neck cancer specialist at the Royal Marsden Hospital, London. “DO-IMRT should be considered a new standard of care.”

The team reported the results of their phase 3 trial in The Lancet Oncology.

Swallowing issues affect most patients with head and neck cancer after radiation therapy but strategies to mitigate this long-term adverse effect remain limited.

Dr. Nutting and colleagues wanted to assess whether a novel approach to radiation therapy could reduce the swallowing problems patients often encounter.

In the trial, 112 subjects with T1-4, N0-3, M0 oropharyngeal (90%) or hypopharyngeal cancer (10%) were randomized to standard IMRT or DO-IMRT. Patients received care at 22 radiation therapy centers in Ireland and the UK from 2016 to 2018.

Patients got radiation in 30 fractions over 6 weeks; most also had chemotherapy. The standard IMRT group received 65 Gy to their primary and nodal tumors and 54 Gy to other pharyngeal and nodal areas. In the DO-IMRT group, radiation doses to pharyngeal constrictor muscles lying outside of the tumor target area were limited to 50 Gy.

At 1 year, 56 patients randomized to DO-IMRT scored, on average, 7.2 points higher than the 56 patients randomized to standard IMRT – 77.7 points vs. 70.6 (P = .037) – on the 100-point MD Anderson Dysphagia Inventory (MDADI). MDADI is a validated scale for tracking radiation-induced dysphagia, with higher scores indicating better swallowing function.

The difference grew to 9.8 points when adjusted for chemotherapy use and tumor location and stage.

DO-IMRT patients were also more likely to report eating their normal diet and dining in public. Speech and language therapists who, like patients, were blinded to treatment allocation, reported better outcomes among patients receiving DO-IMRT as well.

At just over 3 years, oncologic outcomes were essentially equivalent in both groups. Two local recurrences occurred in both arms; distant metastatic recurrences occurred in three patients in the DO-IMRT group and two in the standard IMRT group.

The most common grade 3-4 late adverse events were hearing impairment (16% with DO-IMRT vs. 13% with standard IMRT), dry mouth (5% vs. 15%), and dysphagia (5% vs. 15%).

Taken together, the findings indicate that reducing doses to the pharyngeal constrictor muscle translates to “a meaningful benefit for patients” in terms of improved swallowing function, the investigators said.

In an accompanying editorial, Sandra Nuyts, MD, PhD, noted, however, that the trial failed to meet the predefined threshold for clinical significance, a 10-point difference in MDADI scores.

Still, “several other patient-reported and physician-reported secondary endpoints favored DO-IMRT,” explained Dr. Nuyts, a radiation oncologist at the Leuven Cancer Institute, Belgium. Considered alongside positive reports from smaller, nonrandomized studies, “there is now compelling evidence that the risk of dysphagia after head and neck radiotherapy can be reduced with this technology, without increasing the risk of local recurrences.”

The study team and Dr. Nuyts both called for further refinement of the technique, particularly figuring out what specific sections of the constrictor muscles need to be spared to optimize outcomes.

For now, there is a limit on “how much organ sparing can be achieved with the current DO-IMRT technique” because “use of even narrower margins” around the tumor runs the risk of not treating it adequately, investigators said.

The study was funded by Cancer Research UK. Dr. Nutting reports stock options in Advanced Oncotherapy. Another investigator reports institutional grants from Varian, AstraZeneca, Roche, and other companies. Dr. Nuyts reports no relevant financial relationships.

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

Dysphagia is one of the most common side effects of radiation for head and neck cancer and can be so bad that patients require a permanent gastrostomy tube for feeding.

A team of British investigators are now reporting a new strategy to help lessen this problem.

In the trial, the approach – dubbed dysphagia-optimized intensity-modulated radiotherapy (DO-IMRT) – reduced incidental radiation to the pharyngeal constrictor muscles responsible for swallowing during IMRT for pharyngeal cancer. Patients randomized to DO-IMRT reported significant improvements in swallowing at 1 year, compared with those receiving standard IMRT, at no cost to oncologic outcomes.

Overall, the findings show “DO-IMRT improves patient-reported swallowing function, compared with standard IMRT,” said investigators led by Christopher Nutting, MD, PhD, a head and neck cancer specialist at the Royal Marsden Hospital, London. “DO-IMRT should be considered a new standard of care.”

The team reported the results of their phase 3 trial in The Lancet Oncology.

Swallowing issues affect most patients with head and neck cancer after radiation therapy but strategies to mitigate this long-term adverse effect remain limited.

Dr. Nutting and colleagues wanted to assess whether a novel approach to radiation therapy could reduce the swallowing problems patients often encounter.

In the trial, 112 subjects with T1-4, N0-3, M0 oropharyngeal (90%) or hypopharyngeal cancer (10%) were randomized to standard IMRT or DO-IMRT. Patients received care at 22 radiation therapy centers in Ireland and the UK from 2016 to 2018.

Patients got radiation in 30 fractions over 6 weeks; most also had chemotherapy. The standard IMRT group received 65 Gy to their primary and nodal tumors and 54 Gy to other pharyngeal and nodal areas. In the DO-IMRT group, radiation doses to pharyngeal constrictor muscles lying outside of the tumor target area were limited to 50 Gy.

At 1 year, 56 patients randomized to DO-IMRT scored, on average, 7.2 points higher than the 56 patients randomized to standard IMRT – 77.7 points vs. 70.6 (P = .037) – on the 100-point MD Anderson Dysphagia Inventory (MDADI). MDADI is a validated scale for tracking radiation-induced dysphagia, with higher scores indicating better swallowing function.

The difference grew to 9.8 points when adjusted for chemotherapy use and tumor location and stage.

DO-IMRT patients were also more likely to report eating their normal diet and dining in public. Speech and language therapists who, like patients, were blinded to treatment allocation, reported better outcomes among patients receiving DO-IMRT as well.

At just over 3 years, oncologic outcomes were essentially equivalent in both groups. Two local recurrences occurred in both arms; distant metastatic recurrences occurred in three patients in the DO-IMRT group and two in the standard IMRT group.

The most common grade 3-4 late adverse events were hearing impairment (16% with DO-IMRT vs. 13% with standard IMRT), dry mouth (5% vs. 15%), and dysphagia (5% vs. 15%).

Taken together, the findings indicate that reducing doses to the pharyngeal constrictor muscle translates to “a meaningful benefit for patients” in terms of improved swallowing function, the investigators said.

In an accompanying editorial, Sandra Nuyts, MD, PhD, noted, however, that the trial failed to meet the predefined threshold for clinical significance, a 10-point difference in MDADI scores.

Still, “several other patient-reported and physician-reported secondary endpoints favored DO-IMRT,” explained Dr. Nuyts, a radiation oncologist at the Leuven Cancer Institute, Belgium. Considered alongside positive reports from smaller, nonrandomized studies, “there is now compelling evidence that the risk of dysphagia after head and neck radiotherapy can be reduced with this technology, without increasing the risk of local recurrences.”

The study team and Dr. Nuyts both called for further refinement of the technique, particularly figuring out what specific sections of the constrictor muscles need to be spared to optimize outcomes.

For now, there is a limit on “how much organ sparing can be achieved with the current DO-IMRT technique” because “use of even narrower margins” around the tumor runs the risk of not treating it adequately, investigators said.

The study was funded by Cancer Research UK. Dr. Nutting reports stock options in Advanced Oncotherapy. Another investigator reports institutional grants from Varian, AstraZeneca, Roche, and other companies. Dr. Nuyts reports no relevant financial relationships.

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

Dysphagia is one of the most common side effects of radiation for head and neck cancer and can be so bad that patients require a permanent gastrostomy tube for feeding.

A team of British investigators are now reporting a new strategy to help lessen this problem.

In the trial, the approach – dubbed dysphagia-optimized intensity-modulated radiotherapy (DO-IMRT) – reduced incidental radiation to the pharyngeal constrictor muscles responsible for swallowing during IMRT for pharyngeal cancer. Patients randomized to DO-IMRT reported significant improvements in swallowing at 1 year, compared with those receiving standard IMRT, at no cost to oncologic outcomes.

Overall, the findings show “DO-IMRT improves patient-reported swallowing function, compared with standard IMRT,” said investigators led by Christopher Nutting, MD, PhD, a head and neck cancer specialist at the Royal Marsden Hospital, London. “DO-IMRT should be considered a new standard of care.”

The team reported the results of their phase 3 trial in The Lancet Oncology.

Swallowing issues affect most patients with head and neck cancer after radiation therapy but strategies to mitigate this long-term adverse effect remain limited.

Dr. Nutting and colleagues wanted to assess whether a novel approach to radiation therapy could reduce the swallowing problems patients often encounter.

In the trial, 112 subjects with T1-4, N0-3, M0 oropharyngeal (90%) or hypopharyngeal cancer (10%) were randomized to standard IMRT or DO-IMRT. Patients received care at 22 radiation therapy centers in Ireland and the UK from 2016 to 2018.

Patients got radiation in 30 fractions over 6 weeks; most also had chemotherapy. The standard IMRT group received 65 Gy to their primary and nodal tumors and 54 Gy to other pharyngeal and nodal areas. In the DO-IMRT group, radiation doses to pharyngeal constrictor muscles lying outside of the tumor target area were limited to 50 Gy.

At 1 year, 56 patients randomized to DO-IMRT scored, on average, 7.2 points higher than the 56 patients randomized to standard IMRT – 77.7 points vs. 70.6 (P = .037) – on the 100-point MD Anderson Dysphagia Inventory (MDADI). MDADI is a validated scale for tracking radiation-induced dysphagia, with higher scores indicating better swallowing function.

The difference grew to 9.8 points when adjusted for chemotherapy use and tumor location and stage.

DO-IMRT patients were also more likely to report eating their normal diet and dining in public. Speech and language therapists who, like patients, were blinded to treatment allocation, reported better outcomes among patients receiving DO-IMRT as well.

At just over 3 years, oncologic outcomes were essentially equivalent in both groups. Two local recurrences occurred in both arms; distant metastatic recurrences occurred in three patients in the DO-IMRT group and two in the standard IMRT group.

The most common grade 3-4 late adverse events were hearing impairment (16% with DO-IMRT vs. 13% with standard IMRT), dry mouth (5% vs. 15%), and dysphagia (5% vs. 15%).

Taken together, the findings indicate that reducing doses to the pharyngeal constrictor muscle translates to “a meaningful benefit for patients” in terms of improved swallowing function, the investigators said.

In an accompanying editorial, Sandra Nuyts, MD, PhD, noted, however, that the trial failed to meet the predefined threshold for clinical significance, a 10-point difference in MDADI scores.

Still, “several other patient-reported and physician-reported secondary endpoints favored DO-IMRT,” explained Dr. Nuyts, a radiation oncologist at the Leuven Cancer Institute, Belgium. Considered alongside positive reports from smaller, nonrandomized studies, “there is now compelling evidence that the risk of dysphagia after head and neck radiotherapy can be reduced with this technology, without increasing the risk of local recurrences.”

The study team and Dr. Nuyts both called for further refinement of the technique, particularly figuring out what specific sections of the constrictor muscles need to be spared to optimize outcomes.

For now, there is a limit on “how much organ sparing can be achieved with the current DO-IMRT technique” because “use of even narrower margins” around the tumor runs the risk of not treating it adequately, investigators said.

The study was funded by Cancer Research UK. Dr. Nutting reports stock options in Advanced Oncotherapy. Another investigator reports institutional grants from Varian, AstraZeneca, Roche, and other companies. Dr. Nuyts reports no relevant financial relationships.

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

Experience with long COVID has shone a spotlight on persistent Lyme disease and other often debilitating chronic illnesses that follow known or suspected infections – and on the urgent need for a common and well-funded research agenda, education of physicians, growth of multidisciplinary clinics, and financially supported clinical care.

“We critically need to understand the epidemiology and pathogenesis of chronic symptoms, and identify more effective ways to manage, treat, and potentially cure these illnesses,” Lyle Petersen, MD, MPH, director of the division of vector-borne diseases at the Centers for Disease Control and Prevention, said at the start of a 2-day National Academies of Science, Engineering, and Medicine (NASEM) workshop, “Toward a Common Research Agenda in Infection-Associated Chronic Illnesses.”

Thinking about infection-associated chronic illnesses as an entity – one predicated on commonalities in chronic symptoms and in leading hypotheses for causes – represents a paradigm shift that researchers and patient advocates said can avoid research redundancies and is essential to address what the NASEM calls an overlooked, growing public health problem.

An estimated 2 million people in the United States are living with what’s called posttreatment Lyme disease (PTLD) – a subset of patients with persistent or chronic Lyme disease – and an estimated 1.7-3.3 million people in the United States have diagnoses of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). More than 700,000 people are living with multiple sclerosis. And as of January 2023, 11% of people in the United States reported having long COVID symptoms; the incidence of long COVID is currently estimated at 10%-30% of nonhospitalized cases of COVID-19.

These illnesses “have come under one umbrella,” said Avindra Nath, MD, clinical director of the National Institute of Neurologic Disorders and Stroke (NINDS), Bethesda, Md.

Dr. Nath

Persistent infection, viral reactivation

RNA viral infections can lead to persistent inflammation and dysregulated immunity, with or without viral persistence over time, Timothy J. Henrich, MD, MMSc, associate professor of medicine at the University of California, San Francisco, said in a keynote address.

Research on Ebola survivors has documented long-lasting inflammation and severe immune dysfunction 2 years after infection, for instance. And it’s well known that HIV-1 leads to aberrant immune responses, inflammation, and organ damage despite antiretroviral therapy, said Dr. Henrich, who leads a laboratory/research group that studies approaches to HIV-1 cure and PET-based imaging approaches to characterize viral reservoirs and immune sequelae.

Viral persistence, which can be difficult to measure, has also been documented in Ebola survivors. And in patients living with HIV-1, HIV-1 RNA and protein expression have been shown to persist, again despite antiretroviral therapy. The UCSF Long-Term Immunological Impact of Novel Coronavirus (LIINC) study, for which Dr. Henrich is the principal investigator, found spike RNA in colorectal tissue more than 22 months post COVID, and other research documented viral protein in gut tissue for up to 6 months, he said.

“I think we’re appreciating now, in at least the scientific and treatment community, that there’s a potential for ‘acute’ infections to exhibit some degree of persistence leading to clinical morbidity,” said Dr. Henrich, one of several speakers to describe reports of pathogen persistence. Regarding long COVID, its “etiology is likely heterogeneous,” he said, but persistence of SARS-CoV-2 “may lay behind” other described mechanisms, from clotting/microvascular dysfunction to inflammation and tissue damage to immune dysregulation.

Reactivation of existing latent viral infections in the setting of new acute microbial illness may also play an etiologic role in chronic illnesses, Dr. Henrich said. Epstein-Barr virus (EBV) reactivation has been shown in some studies, including their UCSF COVID-19 cohort, to be associated with long COVID.

“Physicians have been trained to be skeptical about the role [of latent viral infections],” Michael Peluso, MD, an infectious disease physician and assistant professor at UCSF, said during a talk on viral reactivation. This skepticism needs to be “reexamined and overcome,” he said.

Herpesviruses have frequently been associated with ME/CFS, he noted. And evidence of a strong association between EBV and multiple sclerosis came recently from a prospective study of 10 million military recruits that found a 32-fold increased risk of MS after EBV infection but no increase after infection with other viruses, Dr. Peluso and Dr. Henrich both noted.
 

Research needs, treatment trials

Research needs are vast: The need to learn more about the mechanisms of pathogen persistence and immune evasion, for instance, and the need for more biomarker studies, more imaging studies and tissue analyses, more study of microbiome composition and activity, and continued development and application of metagenomic next-generation sequencing.

Workshop participants also spoke of the need to better understand the molecular mimicry that can occur between pathogen-produced proteins and self-antigens, for instance, and the effects of inflammation and infection-related immune changes on neuronal and microglial function in the brain.

“We should perform similar forms of analysis [across] patients with different infection-associated chronic conditions,” said Amy Proal, PhD, president of the PolyBio Research Foundation, which funds research on infection-associated chronic infections. And within individual conditions and well-characterized study groups “we should perform many different forms of analysis … so we can define endotypes and get more solid biomarkers so that industry [will have more confidence] to run clinical trials.”

In the meantime, patients need fast-moving treatment trials for long COVID, long Lyme, and other infection-associated chronic illnesses, speakers emphasized. “We all agree that treatment trials are overdue,” said the NINDS’ Dr. Nath. “We can’t afford to wait for another decade until we understand all the mechanisms, but rather we can do clinical trials based on what we understand now and study the pathophysiology in the context of the clinical trials.”

Just as was done with HIV, said Steven G. Deeks, MD, professor of medicine at UCSF, researchers must “practice experimental medicine” and select pathways and mechanisms of interest, interrupt those pathways in a controlled manner, and assess impact. “Much of this can be done by repurposing existing drugs,” he said, like antivirals for persistent viral infection, EBV-directed therapies for EBV reactivation, anti-inflammatory drugs for inflammation, B–cell-directed therapies for autoantibodies, and antiplatelet drugs for microvascular disease.

When done correctly, he said, such “probe” studies can deepen mechanistic understandings, lead to biomarkers, and provide proof-of-concept that “will encourage massive investment in developing new therapies” for long COVID and other infection-associated chronic illnesses.

Trials of treatments for long COVID “are starting, so I’m optimistic,” said Dr. Deeks, an expert on HIV pathogenesis and treatment and a principal investigator of the Researching COVID to Enhance Recovery (RECOVER) study. Among the trials: A study of intravenous immunoglobulin (IVIG) for neurologic long COVID; a study of an anti-SARS-CoV-2 monoclonal antibody that can deplete tissue/cellular reservoirs of viral particles (replicating or not); and a study evaluating baricitinib (Olumiant), a Janus kinase inhibitor, for neurocognitive impairment and cardiopulmonary symptoms of long COVID.

Alessio Fasano, MD, professor of pediatrics at Harvard Medical School and professor of nutrition at the Harvard T.H. Chan School of Public Health, Boston, described at the workshop how he began investigating the use of larazotide acetate – an inhibitor of the protein zonulin, which increases intestinal permeability – in children with COVID-19 Multisystem Inflammatory Syndrome (MIS-C) after learning that SARS-CoV-2 viral particles persist in the gastrointestinal tract, causing dysbiosis and zonulin upregulation.

In an ongoing phase 2, double-blind, placebo-controlled trial, the agent thus far has expedited the resolution of gastrointestinal symptoms and clearance of spike protein from the circulation, he said. A phase 2 trial of the agent for pediatric patients with long COVID and SARS-CoV-2 antigenemia is underway. “What if we were to stop [chains of events] by stopping the passage of elements from the virus into circulation?’ he said.

In the realm of Lyme disease, a recently launched Clinical Trials Network for Lyme and Other Tick-Borne Diseases has awarded pilot study grants to evaluate treatments aimed at a variety of possible disease mechanisms that, notably, are similar to those of other chronic illnesses: persistence of infection or remnants of infection, immune dysregulation and autoimmune reactions, neural dysfunction, and gut microbiome changes. (Microclots and mitochondrial dysfunction have not been as well studied in Lyme.)

Current and upcoming studies include evaluations of transcutaneous auricular vagus nerve stimulation for those with persistent Lyme fatigue, transcranial direct current stimulation with cognitive retraining for Lyme brain fog, and tetracycline for PTLD, said Brian Fallon, MD, MPH, professor of clinical psychiatry at Columbia University, New York, who directs the Lyme & Tick-Borne Diseases Research Center and the coordinating center of the new network.

Columbia University Irving Medical Center

Calls for a new NIH center and patient involvement

Patients and patient advocacy organizations have played a vital role in research thus far: They’ve documented post-COVID symptoms that academic researchers said they would not otherwise have known of. Leaders of the Patient-Led Research Collaborative have coauthored published reviews with leading long COVID experts. And patients with tick-borne illnesses have enrolled in the MyLymeData patient registry run by LymeDisease.org, which has documented patient-experienced efficacy of alternative treatments and described antibiotic responders and nonresponders.

At the workshop, they shared findings alongside academic experts, and researchers called for their continued involvement. “Patient engagement at every step of the research process is critical,” Dr. Nath said.

“We need to ensure that research is reflective of lived experiences … and [that we’re] accelerating clinical trials of therapeutics that are of priority to the patient community,” said Lisa McCorkell, cofounder of the long COVID-focused Patient-Led Research Collaborative.

Ms. McCorkell also called for the creation of an office for infection-associated chronic illnesses in the NIH director’s office. Others voiced their support. “I think it’s a great idea to have an NIH center for infection-associated chronic illnesses,” said Dr. Fallon. “I think it would have a profound impact.”

The other great need, of course, is funding. “We have ideas, we have drugs that can be repurposed, we have a highly informed and engaged community that will enroll in and be retained in studies, and we have outcomes we can measure,” Dr. Deeks said. “What we’re missing is industry engagement and funding. We need massive engagement from the NIH.”
 

Real-world treatment needs

In the meantime, patients are seeking treatment, and “clinicians need to have uncertainty tolerance” and try multiple treatments simultaneously, said David Putrino, PT, PhD, director of rehabilitation innovation for the Mount Sinai Health System and professor of rehabilitation and human performance at the Icahn School of Medicine at Mount Sinai, New York. He oversees a multidisciplinary hybrid clinical care research center that has seen over 1,500 patients with long COVID and is beginning to see patients with other infection-associated chronic illnesses.

Claudia Paul

It’s a model that should be replicated to help fill the “enormous unmet clinical need” of patients with infection-associated chronic illness, said Peter Rowe, MD, professor of pediatrics at the Johns Hopkins School of Medicine and an expert on ME/CFS. And “as we request [more research funding], we will also need [financial] support for clinical care,” he emphasized, to provide equitable access for patients and to attract treating physicians.

Moreover, said Linda Geng, MD, PhD, the culture of stigma needs to change. Right now, patients with long COVID often feel dismissed not only by friends, families, and coworkers, but by clinicians who find it find it hard “to grasp that this is real and a biological condition.”

And it’s not just conditions such as long COVID that are stigmatized, but treatments as well, she said. For instance, some clinicians view low-dose naltrexone, a treatment increasingly being used for inflammation, with suspicion because it is used for opioid use disorder and alcohol use disorder – or because the “low-dose” label summons mistrust of homeopathy. “Even with therapies, there are preconceived notions and biases,” said Dr. Geng, cofounder and codirector of the Stanford (Calif.) Long COVID program.

“What almost killed me,” said Meghan O’Rourke, who has ongoing effects from long-undiagnosed tick-borne illness, “was the invisibility of the illness.” Ms. O’Rourke teaches at Yale University and is the author of “The Invisible Kingdom: Reimagining Chronic Illness.”

Teaching young physicians about these illnesses would help, she and others said. During a question and answer session, Dr. Putrino shared that the Icahn School of Medicine has recently committed to “create a complex chronic illness medical curriculum” that will impact medical education from the first year of medical school through residencies. Dr. Putrino said his team is also working on materials to help other clinics develop care models similar to those at his Mount Sinai clinic.

The NASEM workshop did not collect or require disclosures of its participants.

Experience with long COVID has shone a spotlight on persistent Lyme disease and other often debilitating chronic illnesses that follow known or suspected infections – and on the urgent need for a common and well-funded research agenda, education of physicians, growth of multidisciplinary clinics, and financially supported clinical care.

“We critically need to understand the epidemiology and pathogenesis of chronic symptoms, and identify more effective ways to manage, treat, and potentially cure these illnesses,” Lyle Petersen, MD, MPH, director of the division of vector-borne diseases at the Centers for Disease Control and Prevention, said at the start of a 2-day National Academies of Science, Engineering, and Medicine (NASEM) workshop, “Toward a Common Research Agenda in Infection-Associated Chronic Illnesses.”

Thinking about infection-associated chronic illnesses as an entity – one predicated on commonalities in chronic symptoms and in leading hypotheses for causes – represents a paradigm shift that researchers and patient advocates said can avoid research redundancies and is essential to address what the NASEM calls an overlooked, growing public health problem.

An estimated 2 million people in the United States are living with what’s called posttreatment Lyme disease (PTLD) – a subset of patients with persistent or chronic Lyme disease – and an estimated 1.7-3.3 million people in the United States have diagnoses of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). More than 700,000 people are living with multiple sclerosis. And as of January 2023, 11% of people in the United States reported having long COVID symptoms; the incidence of long COVID is currently estimated at 10%-30% of nonhospitalized cases of COVID-19.

These illnesses “have come under one umbrella,” said Avindra Nath, MD, clinical director of the National Institute of Neurologic Disorders and Stroke (NINDS), Bethesda, Md.

Dr. Nath

Persistent infection, viral reactivation

RNA viral infections can lead to persistent inflammation and dysregulated immunity, with or without viral persistence over time, Timothy J. Henrich, MD, MMSc, associate professor of medicine at the University of California, San Francisco, said in a keynote address.

Research on Ebola survivors has documented long-lasting inflammation and severe immune dysfunction 2 years after infection, for instance. And it’s well known that HIV-1 leads to aberrant immune responses, inflammation, and organ damage despite antiretroviral therapy, said Dr. Henrich, who leads a laboratory/research group that studies approaches to HIV-1 cure and PET-based imaging approaches to characterize viral reservoirs and immune sequelae.

Viral persistence, which can be difficult to measure, has also been documented in Ebola survivors. And in patients living with HIV-1, HIV-1 RNA and protein expression have been shown to persist, again despite antiretroviral therapy. The UCSF Long-Term Immunological Impact of Novel Coronavirus (LIINC) study, for which Dr. Henrich is the principal investigator, found spike RNA in colorectal tissue more than 22 months post COVID, and other research documented viral protein in gut tissue for up to 6 months, he said.

“I think we’re appreciating now, in at least the scientific and treatment community, that there’s a potential for ‘acute’ infections to exhibit some degree of persistence leading to clinical morbidity,” said Dr. Henrich, one of several speakers to describe reports of pathogen persistence. Regarding long COVID, its “etiology is likely heterogeneous,” he said, but persistence of SARS-CoV-2 “may lay behind” other described mechanisms, from clotting/microvascular dysfunction to inflammation and tissue damage to immune dysregulation.

Reactivation of existing latent viral infections in the setting of new acute microbial illness may also play an etiologic role in chronic illnesses, Dr. Henrich said. Epstein-Barr virus (EBV) reactivation has been shown in some studies, including their UCSF COVID-19 cohort, to be associated with long COVID.

“Physicians have been trained to be skeptical about the role [of latent viral infections],” Michael Peluso, MD, an infectious disease physician and assistant professor at UCSF, said during a talk on viral reactivation. This skepticism needs to be “reexamined and overcome,” he said.

Herpesviruses have frequently been associated with ME/CFS, he noted. And evidence of a strong association between EBV and multiple sclerosis came recently from a prospective study of 10 million military recruits that found a 32-fold increased risk of MS after EBV infection but no increase after infection with other viruses, Dr. Peluso and Dr. Henrich both noted.
 

Research needs, treatment trials

Research needs are vast: The need to learn more about the mechanisms of pathogen persistence and immune evasion, for instance, and the need for more biomarker studies, more imaging studies and tissue analyses, more study of microbiome composition and activity, and continued development and application of metagenomic next-generation sequencing.

Workshop participants also spoke of the need to better understand the molecular mimicry that can occur between pathogen-produced proteins and self-antigens, for instance, and the effects of inflammation and infection-related immune changes on neuronal and microglial function in the brain.

“We should perform similar forms of analysis [across] patients with different infection-associated chronic conditions,” said Amy Proal, PhD, president of the PolyBio Research Foundation, which funds research on infection-associated chronic infections. And within individual conditions and well-characterized study groups “we should perform many different forms of analysis … so we can define endotypes and get more solid biomarkers so that industry [will have more confidence] to run clinical trials.”

In the meantime, patients need fast-moving treatment trials for long COVID, long Lyme, and other infection-associated chronic illnesses, speakers emphasized. “We all agree that treatment trials are overdue,” said the NINDS’ Dr. Nath. “We can’t afford to wait for another decade until we understand all the mechanisms, but rather we can do clinical trials based on what we understand now and study the pathophysiology in the context of the clinical trials.”

Just as was done with HIV, said Steven G. Deeks, MD, professor of medicine at UCSF, researchers must “practice experimental medicine” and select pathways and mechanisms of interest, interrupt those pathways in a controlled manner, and assess impact. “Much of this can be done by repurposing existing drugs,” he said, like antivirals for persistent viral infection, EBV-directed therapies for EBV reactivation, anti-inflammatory drugs for inflammation, B–cell-directed therapies for autoantibodies, and antiplatelet drugs for microvascular disease.

When done correctly, he said, such “probe” studies can deepen mechanistic understandings, lead to biomarkers, and provide proof-of-concept that “will encourage massive investment in developing new therapies” for long COVID and other infection-associated chronic illnesses.

Trials of treatments for long COVID “are starting, so I’m optimistic,” said Dr. Deeks, an expert on HIV pathogenesis and treatment and a principal investigator of the Researching COVID to Enhance Recovery (RECOVER) study. Among the trials: A study of intravenous immunoglobulin (IVIG) for neurologic long COVID; a study of an anti-SARS-CoV-2 monoclonal antibody that can deplete tissue/cellular reservoirs of viral particles (replicating or not); and a study evaluating baricitinib (Olumiant), a Janus kinase inhibitor, for neurocognitive impairment and cardiopulmonary symptoms of long COVID.

Alessio Fasano, MD, professor of pediatrics at Harvard Medical School and professor of nutrition at the Harvard T.H. Chan School of Public Health, Boston, described at the workshop how he began investigating the use of larazotide acetate – an inhibitor of the protein zonulin, which increases intestinal permeability – in children with COVID-19 Multisystem Inflammatory Syndrome (MIS-C) after learning that SARS-CoV-2 viral particles persist in the gastrointestinal tract, causing dysbiosis and zonulin upregulation.

In an ongoing phase 2, double-blind, placebo-controlled trial, the agent thus far has expedited the resolution of gastrointestinal symptoms and clearance of spike protein from the circulation, he said. A phase 2 trial of the agent for pediatric patients with long COVID and SARS-CoV-2 antigenemia is underway. “What if we were to stop [chains of events] by stopping the passage of elements from the virus into circulation?’ he said.

In the realm of Lyme disease, a recently launched Clinical Trials Network for Lyme and Other Tick-Borne Diseases has awarded pilot study grants to evaluate treatments aimed at a variety of possible disease mechanisms that, notably, are similar to those of other chronic illnesses: persistence of infection or remnants of infection, immune dysregulation and autoimmune reactions, neural dysfunction, and gut microbiome changes. (Microclots and mitochondrial dysfunction have not been as well studied in Lyme.)

Current and upcoming studies include evaluations of transcutaneous auricular vagus nerve stimulation for those with persistent Lyme fatigue, transcranial direct current stimulation with cognitive retraining for Lyme brain fog, and tetracycline for PTLD, said Brian Fallon, MD, MPH, professor of clinical psychiatry at Columbia University, New York, who directs the Lyme & Tick-Borne Diseases Research Center and the coordinating center of the new network.

Columbia University Irving Medical Center

Calls for a new NIH center and patient involvement

Patients and patient advocacy organizations have played a vital role in research thus far: They’ve documented post-COVID symptoms that academic researchers said they would not otherwise have known of. Leaders of the Patient-Led Research Collaborative have coauthored published reviews with leading long COVID experts. And patients with tick-borne illnesses have enrolled in the MyLymeData patient registry run by LymeDisease.org, which has documented patient-experienced efficacy of alternative treatments and described antibiotic responders and nonresponders.

At the workshop, they shared findings alongside academic experts, and researchers called for their continued involvement. “Patient engagement at every step of the research process is critical,” Dr. Nath said.

“We need to ensure that research is reflective of lived experiences … and [that we’re] accelerating clinical trials of therapeutics that are of priority to the patient community,” said Lisa McCorkell, cofounder of the long COVID-focused Patient-Led Research Collaborative.

Ms. McCorkell also called for the creation of an office for infection-associated chronic illnesses in the NIH director’s office. Others voiced their support. “I think it’s a great idea to have an NIH center for infection-associated chronic illnesses,” said Dr. Fallon. “I think it would have a profound impact.”

The other great need, of course, is funding. “We have ideas, we have drugs that can be repurposed, we have a highly informed and engaged community that will enroll in and be retained in studies, and we have outcomes we can measure,” Dr. Deeks said. “What we’re missing is industry engagement and funding. We need massive engagement from the NIH.”
 

Real-world treatment needs

In the meantime, patients are seeking treatment, and “clinicians need to have uncertainty tolerance” and try multiple treatments simultaneously, said David Putrino, PT, PhD, director of rehabilitation innovation for the Mount Sinai Health System and professor of rehabilitation and human performance at the Icahn School of Medicine at Mount Sinai, New York. He oversees a multidisciplinary hybrid clinical care research center that has seen over 1,500 patients with long COVID and is beginning to see patients with other infection-associated chronic illnesses.

Claudia Paul

It’s a model that should be replicated to help fill the “enormous unmet clinical need” of patients with infection-associated chronic illness, said Peter Rowe, MD, professor of pediatrics at the Johns Hopkins School of Medicine and an expert on ME/CFS. And “as we request [more research funding], we will also need [financial] support for clinical care,” he emphasized, to provide equitable access for patients and to attract treating physicians.

Moreover, said Linda Geng, MD, PhD, the culture of stigma needs to change. Right now, patients with long COVID often feel dismissed not only by friends, families, and coworkers, but by clinicians who find it find it hard “to grasp that this is real and a biological condition.”

And it’s not just conditions such as long COVID that are stigmatized, but treatments as well, she said. For instance, some clinicians view low-dose naltrexone, a treatment increasingly being used for inflammation, with suspicion because it is used for opioid use disorder and alcohol use disorder – or because the “low-dose” label summons mistrust of homeopathy. “Even with therapies, there are preconceived notions and biases,” said Dr. Geng, cofounder and codirector of the Stanford (Calif.) Long COVID program.

“What almost killed me,” said Meghan O’Rourke, who has ongoing effects from long-undiagnosed tick-borne illness, “was the invisibility of the illness.” Ms. O’Rourke teaches at Yale University and is the author of “The Invisible Kingdom: Reimagining Chronic Illness.”

Teaching young physicians about these illnesses would help, she and others said. During a question and answer session, Dr. Putrino shared that the Icahn School of Medicine has recently committed to “create a complex chronic illness medical curriculum” that will impact medical education from the first year of medical school through residencies. Dr. Putrino said his team is also working on materials to help other clinics develop care models similar to those at his Mount Sinai clinic.

The NASEM workshop did not collect or require disclosures of its participants.

Experience with long COVID has shone a spotlight on persistent Lyme disease and other often debilitating chronic illnesses that follow known or suspected infections – and on the urgent need for a common and well-funded research agenda, education of physicians, growth of multidisciplinary clinics, and financially supported clinical care.

“We critically need to understand the epidemiology and pathogenesis of chronic symptoms, and identify more effective ways to manage, treat, and potentially cure these illnesses,” Lyle Petersen, MD, MPH, director of the division of vector-borne diseases at the Centers for Disease Control and Prevention, said at the start of a 2-day National Academies of Science, Engineering, and Medicine (NASEM) workshop, “Toward a Common Research Agenda in Infection-Associated Chronic Illnesses.”

Thinking about infection-associated chronic illnesses as an entity – one predicated on commonalities in chronic symptoms and in leading hypotheses for causes – represents a paradigm shift that researchers and patient advocates said can avoid research redundancies and is essential to address what the NASEM calls an overlooked, growing public health problem.

An estimated 2 million people in the United States are living with what’s called posttreatment Lyme disease (PTLD) – a subset of patients with persistent or chronic Lyme disease – and an estimated 1.7-3.3 million people in the United States have diagnoses of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). More than 700,000 people are living with multiple sclerosis. And as of January 2023, 11% of people in the United States reported having long COVID symptoms; the incidence of long COVID is currently estimated at 10%-30% of nonhospitalized cases of COVID-19.

These illnesses “have come under one umbrella,” said Avindra Nath, MD, clinical director of the National Institute of Neurologic Disorders and Stroke (NINDS), Bethesda, Md.

Dr. Nath

Persistent infection, viral reactivation

RNA viral infections can lead to persistent inflammation and dysregulated immunity, with or without viral persistence over time, Timothy J. Henrich, MD, MMSc, associate professor of medicine at the University of California, San Francisco, said in a keynote address.

Research on Ebola survivors has documented long-lasting inflammation and severe immune dysfunction 2 years after infection, for instance. And it’s well known that HIV-1 leads to aberrant immune responses, inflammation, and organ damage despite antiretroviral therapy, said Dr. Henrich, who leads a laboratory/research group that studies approaches to HIV-1 cure and PET-based imaging approaches to characterize viral reservoirs and immune sequelae.

Viral persistence, which can be difficult to measure, has also been documented in Ebola survivors. And in patients living with HIV-1, HIV-1 RNA and protein expression have been shown to persist, again despite antiretroviral therapy. The UCSF Long-Term Immunological Impact of Novel Coronavirus (LIINC) study, for which Dr. Henrich is the principal investigator, found spike RNA in colorectal tissue more than 22 months post COVID, and other research documented viral protein in gut tissue for up to 6 months, he said.

“I think we’re appreciating now, in at least the scientific and treatment community, that there’s a potential for ‘acute’ infections to exhibit some degree of persistence leading to clinical morbidity,” said Dr. Henrich, one of several speakers to describe reports of pathogen persistence. Regarding long COVID, its “etiology is likely heterogeneous,” he said, but persistence of SARS-CoV-2 “may lay behind” other described mechanisms, from clotting/microvascular dysfunction to inflammation and tissue damage to immune dysregulation.

Reactivation of existing latent viral infections in the setting of new acute microbial illness may also play an etiologic role in chronic illnesses, Dr. Henrich said. Epstein-Barr virus (EBV) reactivation has been shown in some studies, including their UCSF COVID-19 cohort, to be associated with long COVID.

“Physicians have been trained to be skeptical about the role [of latent viral infections],” Michael Peluso, MD, an infectious disease physician and assistant professor at UCSF, said during a talk on viral reactivation. This skepticism needs to be “reexamined and overcome,” he said.

Herpesviruses have frequently been associated with ME/CFS, he noted. And evidence of a strong association between EBV and multiple sclerosis came recently from a prospective study of 10 million military recruits that found a 32-fold increased risk of MS after EBV infection but no increase after infection with other viruses, Dr. Peluso and Dr. Henrich both noted.
 

Research needs, treatment trials

Research needs are vast: The need to learn more about the mechanisms of pathogen persistence and immune evasion, for instance, and the need for more biomarker studies, more imaging studies and tissue analyses, more study of microbiome composition and activity, and continued development and application of metagenomic next-generation sequencing.

Workshop participants also spoke of the need to better understand the molecular mimicry that can occur between pathogen-produced proteins and self-antigens, for instance, and the effects of inflammation and infection-related immune changes on neuronal and microglial function in the brain.

“We should perform similar forms of analysis [across] patients with different infection-associated chronic conditions,” said Amy Proal, PhD, president of the PolyBio Research Foundation, which funds research on infection-associated chronic infections. And within individual conditions and well-characterized study groups “we should perform many different forms of analysis … so we can define endotypes and get more solid biomarkers so that industry [will have more confidence] to run clinical trials.”

In the meantime, patients need fast-moving treatment trials for long COVID, long Lyme, and other infection-associated chronic illnesses, speakers emphasized. “We all agree that treatment trials are overdue,” said the NINDS’ Dr. Nath. “We can’t afford to wait for another decade until we understand all the mechanisms, but rather we can do clinical trials based on what we understand now and study the pathophysiology in the context of the clinical trials.”

Just as was done with HIV, said Steven G. Deeks, MD, professor of medicine at UCSF, researchers must “practice experimental medicine” and select pathways and mechanisms of interest, interrupt those pathways in a controlled manner, and assess impact. “Much of this can be done by repurposing existing drugs,” he said, like antivirals for persistent viral infection, EBV-directed therapies for EBV reactivation, anti-inflammatory drugs for inflammation, B–cell-directed therapies for autoantibodies, and antiplatelet drugs for microvascular disease.

When done correctly, he said, such “probe” studies can deepen mechanistic understandings, lead to biomarkers, and provide proof-of-concept that “will encourage massive investment in developing new therapies” for long COVID and other infection-associated chronic illnesses.

Trials of treatments for long COVID “are starting, so I’m optimistic,” said Dr. Deeks, an expert on HIV pathogenesis and treatment and a principal investigator of the Researching COVID to Enhance Recovery (RECOVER) study. Among the trials: A study of intravenous immunoglobulin (IVIG) for neurologic long COVID; a study of an anti-SARS-CoV-2 monoclonal antibody that can deplete tissue/cellular reservoirs of viral particles (replicating or not); and a study evaluating baricitinib (Olumiant), a Janus kinase inhibitor, for neurocognitive impairment and cardiopulmonary symptoms of long COVID.

Alessio Fasano, MD, professor of pediatrics at Harvard Medical School and professor of nutrition at the Harvard T.H. Chan School of Public Health, Boston, described at the workshop how he began investigating the use of larazotide acetate – an inhibitor of the protein zonulin, which increases intestinal permeability – in children with COVID-19 Multisystem Inflammatory Syndrome (MIS-C) after learning that SARS-CoV-2 viral particles persist in the gastrointestinal tract, causing dysbiosis and zonulin upregulation.

In an ongoing phase 2, double-blind, placebo-controlled trial, the agent thus far has expedited the resolution of gastrointestinal symptoms and clearance of spike protein from the circulation, he said. A phase 2 trial of the agent for pediatric patients with long COVID and SARS-CoV-2 antigenemia is underway. “What if we were to stop [chains of events] by stopping the passage of elements from the virus into circulation?’ he said.

In the realm of Lyme disease, a recently launched Clinical Trials Network for Lyme and Other Tick-Borne Diseases has awarded pilot study grants to evaluate treatments aimed at a variety of possible disease mechanisms that, notably, are similar to those of other chronic illnesses: persistence of infection or remnants of infection, immune dysregulation and autoimmune reactions, neural dysfunction, and gut microbiome changes. (Microclots and mitochondrial dysfunction have not been as well studied in Lyme.)

Current and upcoming studies include evaluations of transcutaneous auricular vagus nerve stimulation for those with persistent Lyme fatigue, transcranial direct current stimulation with cognitive retraining for Lyme brain fog, and tetracycline for PTLD, said Brian Fallon, MD, MPH, professor of clinical psychiatry at Columbia University, New York, who directs the Lyme & Tick-Borne Diseases Research Center and the coordinating center of the new network.

Columbia University Irving Medical Center

Calls for a new NIH center and patient involvement

Patients and patient advocacy organizations have played a vital role in research thus far: They’ve documented post-COVID symptoms that academic researchers said they would not otherwise have known of. Leaders of the Patient-Led Research Collaborative have coauthored published reviews with leading long COVID experts. And patients with tick-borne illnesses have enrolled in the MyLymeData patient registry run by LymeDisease.org, which has documented patient-experienced efficacy of alternative treatments and described antibiotic responders and nonresponders.

At the workshop, they shared findings alongside academic experts, and researchers called for their continued involvement. “Patient engagement at every step of the research process is critical,” Dr. Nath said.

“We need to ensure that research is reflective of lived experiences … and [that we’re] accelerating clinical trials of therapeutics that are of priority to the patient community,” said Lisa McCorkell, cofounder of the long COVID-focused Patient-Led Research Collaborative.

Ms. McCorkell also called for the creation of an office for infection-associated chronic illnesses in the NIH director’s office. Others voiced their support. “I think it’s a great idea to have an NIH center for infection-associated chronic illnesses,” said Dr. Fallon. “I think it would have a profound impact.”

The other great need, of course, is funding. “We have ideas, we have drugs that can be repurposed, we have a highly informed and engaged community that will enroll in and be retained in studies, and we have outcomes we can measure,” Dr. Deeks said. “What we’re missing is industry engagement and funding. We need massive engagement from the NIH.”
 

Real-world treatment needs

In the meantime, patients are seeking treatment, and “clinicians need to have uncertainty tolerance” and try multiple treatments simultaneously, said David Putrino, PT, PhD, director of rehabilitation innovation for the Mount Sinai Health System and professor of rehabilitation and human performance at the Icahn School of Medicine at Mount Sinai, New York. He oversees a multidisciplinary hybrid clinical care research center that has seen over 1,500 patients with long COVID and is beginning to see patients with other infection-associated chronic illnesses.

Claudia Paul

It’s a model that should be replicated to help fill the “enormous unmet clinical need” of patients with infection-associated chronic illness, said Peter Rowe, MD, professor of pediatrics at the Johns Hopkins School of Medicine and an expert on ME/CFS. And “as we request [more research funding], we will also need [financial] support for clinical care,” he emphasized, to provide equitable access for patients and to attract treating physicians.

Moreover, said Linda Geng, MD, PhD, the culture of stigma needs to change. Right now, patients with long COVID often feel dismissed not only by friends, families, and coworkers, but by clinicians who find it find it hard “to grasp that this is real and a biological condition.”

And it’s not just conditions such as long COVID that are stigmatized, but treatments as well, she said. For instance, some clinicians view low-dose naltrexone, a treatment increasingly being used for inflammation, with suspicion because it is used for opioid use disorder and alcohol use disorder – or because the “low-dose” label summons mistrust of homeopathy. “Even with therapies, there are preconceived notions and biases,” said Dr. Geng, cofounder and codirector of the Stanford (Calif.) Long COVID program.

“What almost killed me,” said Meghan O’Rourke, who has ongoing effects from long-undiagnosed tick-borne illness, “was the invisibility of the illness.” Ms. O’Rourke teaches at Yale University and is the author of “The Invisible Kingdom: Reimagining Chronic Illness.”

Teaching young physicians about these illnesses would help, she and others said. During a question and answer session, Dr. Putrino shared that the Icahn School of Medicine has recently committed to “create a complex chronic illness medical curriculum” that will impact medical education from the first year of medical school through residencies. Dr. Putrino said his team is also working on materials to help other clinics develop care models similar to those at his Mount Sinai clinic.

The NASEM workshop did not collect or require disclosures of its participants.

The key to reducing problem drinking may just be an app away.

A brief intervention with web- and app-based components helped risky drinkers substantially reduce their alcohol intake to a level that is considered not to be hazardous, researchers in Australia have found.

Participants in the randomized controlled trial tracked information about their alcohol consumption, including the quantity and frequency. The intervention then generated an impulsivity score and implications for their risk for alcohol-related disorders and diseases, hospitalization, and death. The findings were published in Alcohol: Clinical & Experimental Research.

Worldwide each year, alcohol consumption accounts for 5.3% of all deaths. In the United States, an estimated 29.5 million people older than 12 years had alcohol use disorder in 2021.

More than 60% of people with alcohol use problems never seek out in-person treatment. Many are deterred from doing so by fear of judgment, stigma, and embarrassment, especially those at the low end of the alcohol use severity spectrum, according to the Australian researchers. Such fear-based barriers, however, may be overcome through the anonymity of a smartphone app.

The researchers tested whether hazardous drinkers who receive personalized feedback about their alcohol consumption and level of self-control would reduce their problem drinking more than hazardous drinkers who received only personalized information about their alcohol consumption or no feedback at all would.

“I knew from my previous research that just putting in the information is not enough to change someone’s drinking: It seems that putting in the information and then having someone tell you, ‘You drank x number of drinks, and that level of drinking is high according to Australian or WHO [World Health Organization] standards’ seems to be the critical point,” said Antoinette Poulton, PhD, of the University of Melbourne, who developed the app and led the study.

The study was conducted among first-year psychology students at the University of Melbourne between 2020 and 2022.

Each of the 313 participants in the study (average age 21.7 years; 74% women) provided estimates of alcohol intake over 14 days. A subset of 178 individuals utilized Alcohol Capture, the validated smartphone app, which records alcohol intake in real-time and includes an online cognitive task assessing impulsivity.

Participants were categorized as “hazardous” or “nonharmful” drinkers according to guidelines from the World Health Organization and were divided into three groups. Members in the alcohol intake feedback (Alc) group were given personalized feedback about their alcohol consumption, including whether their drinking exceeded Australian and/or WHO guidelines. Others were assigned to the Alc plus cognitive feedback (AlcCog) group and received the same feedback plus details about their level of self-control and information about the links between poor self-control and vulnerability for transition to alcohol use disorder. The control group did not receive personalized feedback. After 8 weeks, alcohol intake was again recorded over 14 days.

Relative to hazardous drinkers in the control group, total alcohol consumption among risky drinkers in the Alc group fell by 32% (or 3.8 standard drinks per week) and by 35% (or 4.2 standard drinks per week) in the AlcCog group, according to the researchers. That difference was not statistically significant.

“Our brief electronic intervention had clear impact on the drinking behavior of hazardous drinkers,” the researchers reported. “In fact, following the intervention, hazardous drinkers did not differ from non-harmful ones on total alcohol intake, quantity of intake per drinking day, or frequency of six or more drinking occasions.”

Drinks per drinking day also decreased by 31% (or 1.6 standard drinks) and 32% (or 2.1 standard drinks) in the Alc and AlcCog groups, respectively, compared with the control group.

Alcohol use did not appear to change among nonharmful drinkers in any of the study groups.

“This is a nice study, because it shows that a simple, small intervention can really have a profound effect on hazardous drinking,” said Akhil Anand, MD, an addiction psychiatrist and Medical Director of the Alcohol and Drug Recovery Center at Cleveland Clinic. “It’s hard to say if this intervention would work on very severe cases, but I like it because it’s anonymous, it’s quick, it’s easily accessible, and it doesn’t take too much health care personnel power to apply it,” Dr. Anand added.

This research was supported by an Early Career Researcher grant from the University of Melbourne. Dr. Poulton and Dr. Anand reported no financial conflicts of interest.

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

The key to reducing problem drinking may just be an app away.

A brief intervention with web- and app-based components helped risky drinkers substantially reduce their alcohol intake to a level that is considered not to be hazardous, researchers in Australia have found.

Participants in the randomized controlled trial tracked information about their alcohol consumption, including the quantity and frequency. The intervention then generated an impulsivity score and implications for their risk for alcohol-related disorders and diseases, hospitalization, and death. The findings were published in Alcohol: Clinical & Experimental Research.

Worldwide each year, alcohol consumption accounts for 5.3% of all deaths. In the United States, an estimated 29.5 million people older than 12 years had alcohol use disorder in 2021.

More than 60% of people with alcohol use problems never seek out in-person treatment. Many are deterred from doing so by fear of judgment, stigma, and embarrassment, especially those at the low end of the alcohol use severity spectrum, according to the Australian researchers. Such fear-based barriers, however, may be overcome through the anonymity of a smartphone app.

The researchers tested whether hazardous drinkers who receive personalized feedback about their alcohol consumption and level of self-control would reduce their problem drinking more than hazardous drinkers who received only personalized information about their alcohol consumption or no feedback at all would.

“I knew from my previous research that just putting in the information is not enough to change someone’s drinking: It seems that putting in the information and then having someone tell you, ‘You drank x number of drinks, and that level of drinking is high according to Australian or WHO [World Health Organization] standards’ seems to be the critical point,” said Antoinette Poulton, PhD, of the University of Melbourne, who developed the app and led the study.

The study was conducted among first-year psychology students at the University of Melbourne between 2020 and 2022.

Each of the 313 participants in the study (average age 21.7 years; 74% women) provided estimates of alcohol intake over 14 days. A subset of 178 individuals utilized Alcohol Capture, the validated smartphone app, which records alcohol intake in real-time and includes an online cognitive task assessing impulsivity.

Participants were categorized as “hazardous” or “nonharmful” drinkers according to guidelines from the World Health Organization and were divided into three groups. Members in the alcohol intake feedback (Alc) group were given personalized feedback about their alcohol consumption, including whether their drinking exceeded Australian and/or WHO guidelines. Others were assigned to the Alc plus cognitive feedback (AlcCog) group and received the same feedback plus details about their level of self-control and information about the links between poor self-control and vulnerability for transition to alcohol use disorder. The control group did not receive personalized feedback. After 8 weeks, alcohol intake was again recorded over 14 days.

Relative to hazardous drinkers in the control group, total alcohol consumption among risky drinkers in the Alc group fell by 32% (or 3.8 standard drinks per week) and by 35% (or 4.2 standard drinks per week) in the AlcCog group, according to the researchers. That difference was not statistically significant.

“Our brief electronic intervention had clear impact on the drinking behavior of hazardous drinkers,” the researchers reported. “In fact, following the intervention, hazardous drinkers did not differ from non-harmful ones on total alcohol intake, quantity of intake per drinking day, or frequency of six or more drinking occasions.”

Drinks per drinking day also decreased by 31% (or 1.6 standard drinks) and 32% (or 2.1 standard drinks) in the Alc and AlcCog groups, respectively, compared with the control group.

Alcohol use did not appear to change among nonharmful drinkers in any of the study groups.

“This is a nice study, because it shows that a simple, small intervention can really have a profound effect on hazardous drinking,” said Akhil Anand, MD, an addiction psychiatrist and Medical Director of the Alcohol and Drug Recovery Center at Cleveland Clinic. “It’s hard to say if this intervention would work on very severe cases, but I like it because it’s anonymous, it’s quick, it’s easily accessible, and it doesn’t take too much health care personnel power to apply it,” Dr. Anand added.

This research was supported by an Early Career Researcher grant from the University of Melbourne. Dr. Poulton and Dr. Anand reported no financial conflicts of interest.

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

The key to reducing problem drinking may just be an app away.

A brief intervention with web- and app-based components helped risky drinkers substantially reduce their alcohol intake to a level that is considered not to be hazardous, researchers in Australia have found.

Participants in the randomized controlled trial tracked information about their alcohol consumption, including the quantity and frequency. The intervention then generated an impulsivity score and implications for their risk for alcohol-related disorders and diseases, hospitalization, and death. The findings were published in Alcohol: Clinical & Experimental Research.

Worldwide each year, alcohol consumption accounts for 5.3% of all deaths. In the United States, an estimated 29.5 million people older than 12 years had alcohol use disorder in 2021.

More than 60% of people with alcohol use problems never seek out in-person treatment. Many are deterred from doing so by fear of judgment, stigma, and embarrassment, especially those at the low end of the alcohol use severity spectrum, according to the Australian researchers. Such fear-based barriers, however, may be overcome through the anonymity of a smartphone app.

The researchers tested whether hazardous drinkers who receive personalized feedback about their alcohol consumption and level of self-control would reduce their problem drinking more than hazardous drinkers who received only personalized information about their alcohol consumption or no feedback at all would.

“I knew from my previous research that just putting in the information is not enough to change someone’s drinking: It seems that putting in the information and then having someone tell you, ‘You drank x number of drinks, and that level of drinking is high according to Australian or WHO [World Health Organization] standards’ seems to be the critical point,” said Antoinette Poulton, PhD, of the University of Melbourne, who developed the app and led the study.

The study was conducted among first-year psychology students at the University of Melbourne between 2020 and 2022.

Each of the 313 participants in the study (average age 21.7 years; 74% women) provided estimates of alcohol intake over 14 days. A subset of 178 individuals utilized Alcohol Capture, the validated smartphone app, which records alcohol intake in real-time and includes an online cognitive task assessing impulsivity.

Participants were categorized as “hazardous” or “nonharmful” drinkers according to guidelines from the World Health Organization and were divided into three groups. Members in the alcohol intake feedback (Alc) group were given personalized feedback about their alcohol consumption, including whether their drinking exceeded Australian and/or WHO guidelines. Others were assigned to the Alc plus cognitive feedback (AlcCog) group and received the same feedback plus details about their level of self-control and information about the links between poor self-control and vulnerability for transition to alcohol use disorder. The control group did not receive personalized feedback. After 8 weeks, alcohol intake was again recorded over 14 days.

Relative to hazardous drinkers in the control group, total alcohol consumption among risky drinkers in the Alc group fell by 32% (or 3.8 standard drinks per week) and by 35% (or 4.2 standard drinks per week) in the AlcCog group, according to the researchers. That difference was not statistically significant.

“Our brief electronic intervention had clear impact on the drinking behavior of hazardous drinkers,” the researchers reported. “In fact, following the intervention, hazardous drinkers did not differ from non-harmful ones on total alcohol intake, quantity of intake per drinking day, or frequency of six or more drinking occasions.”

Drinks per drinking day also decreased by 31% (or 1.6 standard drinks) and 32% (or 2.1 standard drinks) in the Alc and AlcCog groups, respectively, compared with the control group.

Alcohol use did not appear to change among nonharmful drinkers in any of the study groups.

“This is a nice study, because it shows that a simple, small intervention can really have a profound effect on hazardous drinking,” said Akhil Anand, MD, an addiction psychiatrist and Medical Director of the Alcohol and Drug Recovery Center at Cleveland Clinic. “It’s hard to say if this intervention would work on very severe cases, but I like it because it’s anonymous, it’s quick, it’s easily accessible, and it doesn’t take too much health care personnel power to apply it,” Dr. Anand added.

This research was supported by an Early Career Researcher grant from the University of Melbourne. Dr. Poulton and Dr. Anand reported no financial conflicts of interest.

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

TOPLINE:

Among patients with type 1 diabetes, glycemic control may worsen in the 2 weeks after a heat wave, according to research published online May 17 in Science of The Total Environment.

METHODOLOGY:

Researchers in Spain analyzed data from 2,701 adults with type 1 diabetes who had been using intermittently scanned continuous glucose monitoring (CGM) devices during a 2022 heat wave (July 9-26) and 14 days after. Extreme heat claimed nearly 62,000 lives across Europe in the summer of 2022.

TAKEAWAY:

Time in range (between 70 mg/dL and 180 mg/dL of interstitial glucose) decreased by 4%, from 60.8% during the heat wave to 54.8% after (P < .001).

Patients who scanned their CGM results the most during the heat wave (more than 13 scans per day) scanned less often after the weather broke (1.8 fewer scans per day) and experienced the biggest drop in time in range (−5.4%).

More patients met all time-in-range recommendations during the heat wave (10.6% vs. 8.4%, P < .001).
 

IN PRACTICE:

“We hypothesized that people with diabetes, who are highly vulnerable, have more time for self-management as they spend more time indoors,” study author Jesús Moreno Fernández, MD, PhD, said in an interview. “During the COVID-19 pandemic, something similar was observed among people with diabetes.”

SOURCE:

Moreno Fernández, with the department of endocrinology and nutrition at Ciudad Real General University Hospital in Spain, is the study’s lead author.

LIMITATIONS:

The CGM data were anonymized, so researchers could not examine how individual patient factors like sex, education, or treatment type may have influenced outcomes. Temperatures remained higher than usual even after the heat wave. Worsening glycemic control could be interpreted as a lag effect of prolonged heat exposure, the researchers note.

DISCLOSURES:

The authors reported no conflicts of interest.

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

TOPLINE:

Among patients with type 1 diabetes, glycemic control may worsen in the 2 weeks after a heat wave, according to research published online May 17 in Science of The Total Environment.

METHODOLOGY:

Researchers in Spain analyzed data from 2,701 adults with type 1 diabetes who had been using intermittently scanned continuous glucose monitoring (CGM) devices during a 2022 heat wave (July 9-26) and 14 days after. Extreme heat claimed nearly 62,000 lives across Europe in the summer of 2022.

TAKEAWAY:

Time in range (between 70 mg/dL and 180 mg/dL of interstitial glucose) decreased by 4%, from 60.8% during the heat wave to 54.8% after (P < .001).

Patients who scanned their CGM results the most during the heat wave (more than 13 scans per day) scanned less often after the weather broke (1.8 fewer scans per day) and experienced the biggest drop in time in range (−5.4%).

More patients met all time-in-range recommendations during the heat wave (10.6% vs. 8.4%, P < .001).
 

IN PRACTICE:

“We hypothesized that people with diabetes, who are highly vulnerable, have more time for self-management as they spend more time indoors,” study author Jesús Moreno Fernández, MD, PhD, said in an interview. “During the COVID-19 pandemic, something similar was observed among people with diabetes.”

SOURCE:

Moreno Fernández, with the department of endocrinology and nutrition at Ciudad Real General University Hospital in Spain, is the study’s lead author.

LIMITATIONS:

The CGM data were anonymized, so researchers could not examine how individual patient factors like sex, education, or treatment type may have influenced outcomes. Temperatures remained higher than usual even after the heat wave. Worsening glycemic control could be interpreted as a lag effect of prolonged heat exposure, the researchers note.

DISCLOSURES:

The authors reported no conflicts of interest.

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

TOPLINE:

Among patients with type 1 diabetes, glycemic control may worsen in the 2 weeks after a heat wave, according to research published online May 17 in Science of The Total Environment.

METHODOLOGY:

Researchers in Spain analyzed data from 2,701 adults with type 1 diabetes who had been using intermittently scanned continuous glucose monitoring (CGM) devices during a 2022 heat wave (July 9-26) and 14 days after. Extreme heat claimed nearly 62,000 lives across Europe in the summer of 2022.

TAKEAWAY:

Time in range (between 70 mg/dL and 180 mg/dL of interstitial glucose) decreased by 4%, from 60.8% during the heat wave to 54.8% after (P < .001).

Patients who scanned their CGM results the most during the heat wave (more than 13 scans per day) scanned less often after the weather broke (1.8 fewer scans per day) and experienced the biggest drop in time in range (−5.4%).

More patients met all time-in-range recommendations during the heat wave (10.6% vs. 8.4%, P < .001).
 

IN PRACTICE:

“We hypothesized that people with diabetes, who are highly vulnerable, have more time for self-management as they spend more time indoors,” study author Jesús Moreno Fernández, MD, PhD, said in an interview. “During the COVID-19 pandemic, something similar was observed among people with diabetes.”

SOURCE:

Moreno Fernández, with the department of endocrinology and nutrition at Ciudad Real General University Hospital in Spain, is the study’s lead author.

LIMITATIONS:

The CGM data were anonymized, so researchers could not examine how individual patient factors like sex, education, or treatment type may have influenced outcomes. Temperatures remained higher than usual even after the heat wave. Worsening glycemic control could be interpreted as a lag effect of prolonged heat exposure, the researchers note.

DISCLOSURES:

The authors reported no conflicts of interest.

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

Regular consumption of fish and other foods rich in omega-3 fatty acids (FA) won’t raise an individual’s risk for developing atrial fibrillation (AFib), suggests a meta-analysis of population-based studies.

Lynda Banzi/MDedge News

The finding may alleviate recent concerns about higher-dose omega-3 FA supplement intake in clinical-trial patients at elevated cardiovascular (CV) risk, researchers say.

Indeed, across the 17 cohort studies in the meta-analysis, risk for incident AFib was unaffected by elevated circulating and adipose tissue levels of eicosapentaenoic acid (EPA) from dietary intake. Moreover, the risk appeared to drop significantly with such levels of docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), and EPA plus DHA.

The signals of AFib risk associated with high-dose omega-3 FA in supplements or prescription form in some clinical trials “may not necessarily be generalizable to lower-dose habitual dietary omega-3 intakes,” concludes the study’s report published in the Journal of the American College of Cardiology.

Other recent research suggests that any elevated AFib risk from omega-3 FA intake is dose-related and may be associated with omega-3 FA supplement or medication intake in high doses, such as 4 g/day.

“Coupled with the more consistent benefits of these fatty acids in the prevention of adverse coronary events, our study suggests that current dietary guidelines recommending fish/omega-3 fatty acid consumption should be maintained,” conclude the authors of the report, led by Frank Qian, MD, MPH, Harvard T.H. Chan School of Public Health and Beth Israel Deaconess Medical Center, Boston.

The current study is “important in showing that physiologic levels of omega-3s that would accumulate through diet don’t seem to increase the risk of arrhythmia,” preventive cardiologist Sean Heffron, MD, NYU Langone Health and Grossman School of Medicine, told this news organization.

“It also lends credence to the fact that the increased risk is specific to the high dose supplementation, because that’s the only instance in which we’ve seen increased atrial fibrillation in association with omega-3s,” said Dr. Heffron, who wasn’t involved in the meta-analysis.

An accompanying editorial agrees. “Based on present evidence, moderate dietary intake of fish and seafood is unlikely to achieve sufficiently high levels of omega-3-FAs in blood or tissue that would result in increased AFib risk as observed in clinical trials of fish oil supplements and high-dose prescriptions,” write Christie Ballantyne, MD, and Xiaoming Jia, MD, Baylor College of Medicine, Houston.

Therefore, they conclude, “fish should continue to be an important part of the menu of a heart-healthy diet.”

The meta-analysis comprised 54,799 participants from 21 countries worldwide in 17 prospective cohort studies that yielded data on incident AFib, in which there were 7,720 cases of the arrhythmia over a median follow-up of 13 years. It looked at associations between such cases and levels of omega-3 FA in blood and adipose tissue samples.

In multivariable analysis, EPA levels were not associated with incident AFib, with a hazard ratio of 1.00 (95% confidence interval, 0.95-1.05) per interquintile range, which the report describes as the difference between the 90th and 10th percentiles.

In contrast, levels of DPA, DHA, and EPA plus DHA were all associated with reduced AFib incidence at interquintile-range HRs of 0.89 (95% CI, 0.83-0.95) for DPA, 0.90 (95% CI, 0.85-0.96) for DHA and 0.93 (95% CI, 0.87-0.99) for EPA and DHA combined.

“We found little evidence that the associations significantly varied by age, sex, or global region, or across the various lipid compartments,” the report states. “Moreover, the relationship between omega-3 fatty acids and AFib did not significantly differ among individuals at higher CV risk.”

The authors observe that the prevalence of omega-3 FA supplement use in the cohorts was very low, suggesting that the omega-3 FA biomarker levels largely reflected habitual dietary intake.

Most of the meta-analysis population were free of CV disease or at relatively low CV risk, they write, and “it is conceivable that the effects of omega-3 fatty acids on atrial arrhythmias may differ in those with existing CV disease versus without.”

However, they note, in a prespecified subgroup analysis of participants mirroring the REDUCE-IT cohort of people with established CV disease or at elevated CV risk, no association with incident AFib was observed for EPA and inverse associations emerged for DPA, DHA, and EPA plus DHA.

In their editorial, Dr. Ballantyne and Dr. Jia say the meta-analysis “represents the largest epidemiological study assessing laboratory-measured omega-3 fatty acid concentrations and AFib risk in the general population.”

But significant heterogeneity across the studies and their populations is a major limitation of the analysis, they write, and made for differences in protocols, sample preparation, outcomes ascertainment, follow-up time, and other variables.

“Despite a rigorous approach to harmonize the data across cohorts and adjusting for multiple confounders,” note Dr. Ballantyne and Dr. Jia, “observational studies always have potential for residual confounders.”

The findings support fish consumption as heart-healthy, they write, but “clinicians should be aware of and discuss with patients the risks versus benefits when prescribing high-dose omega-3 FA therapies.”

The Fatty Acid Research Institute retrospectively provided a small honorarium to a subset of the analysts who participated in this study, but it had no role in its design, analysis, manuscript writing, or decision to submit for publication, the report states. Dr. Ballantyne received grant/research support through his institution from Akcea, Amgen, Arrowhead, Esperion, Ionis, Merck, Novartis, and Regeneron, as well as consulting fees from Alnylam Pharmaceuticals, Althera, Amarin, Amgen, Arrowhead, AstraZeneca, Esperion, Genentech, Gilead, Matinas BioPharma, Merck, New Amsterdam, Novartis, Pfizer, and Regeneron. Dr. Heffron and Dr. Jia have disclosed no relevant financial relationships.

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

Regular consumption of fish and other foods rich in omega-3 fatty acids (FA) won’t raise an individual’s risk for developing atrial fibrillation (AFib), suggests a meta-analysis of population-based studies.

Lynda Banzi/MDedge News

The finding may alleviate recent concerns about higher-dose omega-3 FA supplement intake in clinical-trial patients at elevated cardiovascular (CV) risk, researchers say.

Indeed, across the 17 cohort studies in the meta-analysis, risk for incident AFib was unaffected by elevated circulating and adipose tissue levels of eicosapentaenoic acid (EPA) from dietary intake. Moreover, the risk appeared to drop significantly with such levels of docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), and EPA plus DHA.

The signals of AFib risk associated with high-dose omega-3 FA in supplements or prescription form in some clinical trials “may not necessarily be generalizable to lower-dose habitual dietary omega-3 intakes,” concludes the study’s report published in the Journal of the American College of Cardiology.

Other recent research suggests that any elevated AFib risk from omega-3 FA intake is dose-related and may be associated with omega-3 FA supplement or medication intake in high doses, such as 4 g/day.

“Coupled with the more consistent benefits of these fatty acids in the prevention of adverse coronary events, our study suggests that current dietary guidelines recommending fish/omega-3 fatty acid consumption should be maintained,” conclude the authors of the report, led by Frank Qian, MD, MPH, Harvard T.H. Chan School of Public Health and Beth Israel Deaconess Medical Center, Boston.

The current study is “important in showing that physiologic levels of omega-3s that would accumulate through diet don’t seem to increase the risk of arrhythmia,” preventive cardiologist Sean Heffron, MD, NYU Langone Health and Grossman School of Medicine, told this news organization.

“It also lends credence to the fact that the increased risk is specific to the high dose supplementation, because that’s the only instance in which we’ve seen increased atrial fibrillation in association with omega-3s,” said Dr. Heffron, who wasn’t involved in the meta-analysis.

An accompanying editorial agrees. “Based on present evidence, moderate dietary intake of fish and seafood is unlikely to achieve sufficiently high levels of omega-3-FAs in blood or tissue that would result in increased AFib risk as observed in clinical trials of fish oil supplements and high-dose prescriptions,” write Christie Ballantyne, MD, and Xiaoming Jia, MD, Baylor College of Medicine, Houston.

Therefore, they conclude, “fish should continue to be an important part of the menu of a heart-healthy diet.”

The meta-analysis comprised 54,799 participants from 21 countries worldwide in 17 prospective cohort studies that yielded data on incident AFib, in which there were 7,720 cases of the arrhythmia over a median follow-up of 13 years. It looked at associations between such cases and levels of omega-3 FA in blood and adipose tissue samples.

In multivariable analysis, EPA levels were not associated with incident AFib, with a hazard ratio of 1.00 (95% confidence interval, 0.95-1.05) per interquintile range, which the report describes as the difference between the 90th and 10th percentiles.

In contrast, levels of DPA, DHA, and EPA plus DHA were all associated with reduced AFib incidence at interquintile-range HRs of 0.89 (95% CI, 0.83-0.95) for DPA, 0.90 (95% CI, 0.85-0.96) for DHA and 0.93 (95% CI, 0.87-0.99) for EPA and DHA combined.

“We found little evidence that the associations significantly varied by age, sex, or global region, or across the various lipid compartments,” the report states. “Moreover, the relationship between omega-3 fatty acids and AFib did not significantly differ among individuals at higher CV risk.”

The authors observe that the prevalence of omega-3 FA supplement use in the cohorts was very low, suggesting that the omega-3 FA biomarker levels largely reflected habitual dietary intake.

Most of the meta-analysis population were free of CV disease or at relatively low CV risk, they write, and “it is conceivable that the effects of omega-3 fatty acids on atrial arrhythmias may differ in those with existing CV disease versus without.”

However, they note, in a prespecified subgroup analysis of participants mirroring the REDUCE-IT cohort of people with established CV disease or at elevated CV risk, no association with incident AFib was observed for EPA and inverse associations emerged for DPA, DHA, and EPA plus DHA.

In their editorial, Dr. Ballantyne and Dr. Jia say the meta-analysis “represents the largest epidemiological study assessing laboratory-measured omega-3 fatty acid concentrations and AFib risk in the general population.”

But significant heterogeneity across the studies and their populations is a major limitation of the analysis, they write, and made for differences in protocols, sample preparation, outcomes ascertainment, follow-up time, and other variables.

“Despite a rigorous approach to harmonize the data across cohorts and adjusting for multiple confounders,” note Dr. Ballantyne and Dr. Jia, “observational studies always have potential for residual confounders.”

The findings support fish consumption as heart-healthy, they write, but “clinicians should be aware of and discuss with patients the risks versus benefits when prescribing high-dose omega-3 FA therapies.”

The Fatty Acid Research Institute retrospectively provided a small honorarium to a subset of the analysts who participated in this study, but it had no role in its design, analysis, manuscript writing, or decision to submit for publication, the report states. Dr. Ballantyne received grant/research support through his institution from Akcea, Amgen, Arrowhead, Esperion, Ionis, Merck, Novartis, and Regeneron, as well as consulting fees from Alnylam Pharmaceuticals, Althera, Amarin, Amgen, Arrowhead, AstraZeneca, Esperion, Genentech, Gilead, Matinas BioPharma, Merck, New Amsterdam, Novartis, Pfizer, and Regeneron. Dr. Heffron and Dr. Jia have disclosed no relevant financial relationships.

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

Regular consumption of fish and other foods rich in omega-3 fatty acids (FA) won’t raise an individual’s risk for developing atrial fibrillation (AFib), suggests a meta-analysis of population-based studies.

Lynda Banzi/MDedge News

The finding may alleviate recent concerns about higher-dose omega-3 FA supplement intake in clinical-trial patients at elevated cardiovascular (CV) risk, researchers say.

Indeed, across the 17 cohort studies in the meta-analysis, risk for incident AFib was unaffected by elevated circulating and adipose tissue levels of eicosapentaenoic acid (EPA) from dietary intake. Moreover, the risk appeared to drop significantly with such levels of docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), and EPA plus DHA.

The signals of AFib risk associated with high-dose omega-3 FA in supplements or prescription form in some clinical trials “may not necessarily be generalizable to lower-dose habitual dietary omega-3 intakes,” concludes the study’s report published in the Journal of the American College of Cardiology.

Other recent research suggests that any elevated AFib risk from omega-3 FA intake is dose-related and may be associated with omega-3 FA supplement or medication intake in high doses, such as 4 g/day.

“Coupled with the more consistent benefits of these fatty acids in the prevention of adverse coronary events, our study suggests that current dietary guidelines recommending fish/omega-3 fatty acid consumption should be maintained,” conclude the authors of the report, led by Frank Qian, MD, MPH, Harvard T.H. Chan School of Public Health and Beth Israel Deaconess Medical Center, Boston.

The current study is “important in showing that physiologic levels of omega-3s that would accumulate through diet don’t seem to increase the risk of arrhythmia,” preventive cardiologist Sean Heffron, MD, NYU Langone Health and Grossman School of Medicine, told this news organization.

“It also lends credence to the fact that the increased risk is specific to the high dose supplementation, because that’s the only instance in which we’ve seen increased atrial fibrillation in association with omega-3s,” said Dr. Heffron, who wasn’t involved in the meta-analysis.

An accompanying editorial agrees. “Based on present evidence, moderate dietary intake of fish and seafood is unlikely to achieve sufficiently high levels of omega-3-FAs in blood or tissue that would result in increased AFib risk as observed in clinical trials of fish oil supplements and high-dose prescriptions,” write Christie Ballantyne, MD, and Xiaoming Jia, MD, Baylor College of Medicine, Houston.

Therefore, they conclude, “fish should continue to be an important part of the menu of a heart-healthy diet.”

The meta-analysis comprised 54,799 participants from 21 countries worldwide in 17 prospective cohort studies that yielded data on incident AFib, in which there were 7,720 cases of the arrhythmia over a median follow-up of 13 years. It looked at associations between such cases and levels of omega-3 FA in blood and adipose tissue samples.

In multivariable analysis, EPA levels were not associated with incident AFib, with a hazard ratio of 1.00 (95% confidence interval, 0.95-1.05) per interquintile range, which the report describes as the difference between the 90th and 10th percentiles.

In contrast, levels of DPA, DHA, and EPA plus DHA were all associated with reduced AFib incidence at interquintile-range HRs of 0.89 (95% CI, 0.83-0.95) for DPA, 0.90 (95% CI, 0.85-0.96) for DHA and 0.93 (95% CI, 0.87-0.99) for EPA and DHA combined.

“We found little evidence that the associations significantly varied by age, sex, or global region, or across the various lipid compartments,” the report states. “Moreover, the relationship between omega-3 fatty acids and AFib did not significantly differ among individuals at higher CV risk.”

The authors observe that the prevalence of omega-3 FA supplement use in the cohorts was very low, suggesting that the omega-3 FA biomarker levels largely reflected habitual dietary intake.

Most of the meta-analysis population were free of CV disease or at relatively low CV risk, they write, and “it is conceivable that the effects of omega-3 fatty acids on atrial arrhythmias may differ in those with existing CV disease versus without.”

However, they note, in a prespecified subgroup analysis of participants mirroring the REDUCE-IT cohort of people with established CV disease or at elevated CV risk, no association with incident AFib was observed for EPA and inverse associations emerged for DPA, DHA, and EPA plus DHA.

In their editorial, Dr. Ballantyne and Dr. Jia say the meta-analysis “represents the largest epidemiological study assessing laboratory-measured omega-3 fatty acid concentrations and AFib risk in the general population.”

But significant heterogeneity across the studies and their populations is a major limitation of the analysis, they write, and made for differences in protocols, sample preparation, outcomes ascertainment, follow-up time, and other variables.

“Despite a rigorous approach to harmonize the data across cohorts and adjusting for multiple confounders,” note Dr. Ballantyne and Dr. Jia, “observational studies always have potential for residual confounders.”

The findings support fish consumption as heart-healthy, they write, but “clinicians should be aware of and discuss with patients the risks versus benefits when prescribing high-dose omega-3 FA therapies.”

The Fatty Acid Research Institute retrospectively provided a small honorarium to a subset of the analysts who participated in this study, but it had no role in its design, analysis, manuscript writing, or decision to submit for publication, the report states. Dr. Ballantyne received grant/research support through his institution from Akcea, Amgen, Arrowhead, Esperion, Ionis, Merck, Novartis, and Regeneron, as well as consulting fees from Alnylam Pharmaceuticals, Althera, Amarin, Amgen, Arrowhead, AstraZeneca, Esperion, Genentech, Gilead, Matinas BioPharma, Merck, New Amsterdam, Novartis, Pfizer, and Regeneron. Dr. Heffron and Dr. Jia have disclosed no relevant financial relationships.

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

Three California nurse practitioners with doctorates (DNP) have sued the state over its law that only physicians can call themselves doctors, saying it violates their first amendment right to use the honorific title without fear of regulatory repercussions.

The case highlights ongoing scope-creep battles as the American Medical Association tries to preserve the physician-led team model and nursing organizations and some lawmakers push for greater autonomy for allied professionals.

In the complaint filed in district court in June, plaintiffs Jacqueline Palmer, DNP, Heather Lewis, DNP, and Rodolfo Jaravata-Hanson, DNP, say they fear the state will sanction them. They note that “Doctor Sarah,” another DNP, was fined nearly $20,000 by the state last November for false advertising and fraud after using the moniker in her online advertising and social media accounts.

The fine was part of a settlement that the DNP, Sarah Erny, reached with the state to resolve allegations that she failed to identify her supervising physician and inform the public that she was not a medical doctor.

Under California’s Medical Practice Act, individuals cannot refer to themselves as “doctor, physician, or any other terms or letters indicating or implying that he or she is a physician and surgeon ... without having ... a certificate as a physician and surgeon.”

Instead, nurse practitioners certified by the California Board of Registered Nursing may use titles like “Certified Nurse Practitioner” and “Advanced Practice Registered Nurse,” corresponding letters such as APRN-CNP, RN, and NP, and phrases like pediatric nurse practitioner to identify specialization.

Individuals who misrepresent themselves are subject to misdemeanor charges and civil penalties.

The nonprofit Pacific Legal Foundation represents the plaintiffs. In court records, its attorneys argue that after “years earning their advanced degrees and qualifications ... they should be able to speak truthfully about them in their workplaces, on their business cards, the Internet, and social media, so long as they clarify that they are nurse practitioners.”

State lawmakers’ attempts to clarify the roles of physicians and nurse practitioners have seen mixed results. Florida legislators recently passed a bill to prevent advanced practice nurses from using the honorific title, reserving it only for MDs and DOs. Gov. Ron DeSantis vetoed it last month.

In May, Georgia lawmakers passed the Health Care Practitioners Truth and Transparency Act. It requires advanced practice nurses and physician assistants with doctoral degrees who refer to themselves as doctors in a clinical setting to state they are not medical doctors or physicians.

Still, some health professionals say that the designation should only be used in academic settings or among peers, and that all doctoral degree holders should ditch the moniker at the bedside to ease patient communications.

Named as defendants in the suit are three state officials: California Attorney General Rob Bonta, state Medical Board President Kristina Lawson, and California Board of Registered Nursing Executive Officer Loretta Melby.

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

Three California nurse practitioners with doctorates (DNP) have sued the state over its law that only physicians can call themselves doctors, saying it violates their first amendment right to use the honorific title without fear of regulatory repercussions.

The case highlights ongoing scope-creep battles as the American Medical Association tries to preserve the physician-led team model and nursing organizations and some lawmakers push for greater autonomy for allied professionals.

In the complaint filed in district court in June, plaintiffs Jacqueline Palmer, DNP, Heather Lewis, DNP, and Rodolfo Jaravata-Hanson, DNP, say they fear the state will sanction them. They note that “Doctor Sarah,” another DNP, was fined nearly $20,000 by the state last November for false advertising and fraud after using the moniker in her online advertising and social media accounts.

The fine was part of a settlement that the DNP, Sarah Erny, reached with the state to resolve allegations that she failed to identify her supervising physician and inform the public that she was not a medical doctor.

Under California’s Medical Practice Act, individuals cannot refer to themselves as “doctor, physician, or any other terms or letters indicating or implying that he or she is a physician and surgeon ... without having ... a certificate as a physician and surgeon.”

Instead, nurse practitioners certified by the California Board of Registered Nursing may use titles like “Certified Nurse Practitioner” and “Advanced Practice Registered Nurse,” corresponding letters such as APRN-CNP, RN, and NP, and phrases like pediatric nurse practitioner to identify specialization.

Individuals who misrepresent themselves are subject to misdemeanor charges and civil penalties.

The nonprofit Pacific Legal Foundation represents the plaintiffs. In court records, its attorneys argue that after “years earning their advanced degrees and qualifications ... they should be able to speak truthfully about them in their workplaces, on their business cards, the Internet, and social media, so long as they clarify that they are nurse practitioners.”

State lawmakers’ attempts to clarify the roles of physicians and nurse practitioners have seen mixed results. Florida legislators recently passed a bill to prevent advanced practice nurses from using the honorific title, reserving it only for MDs and DOs. Gov. Ron DeSantis vetoed it last month.

In May, Georgia lawmakers passed the Health Care Practitioners Truth and Transparency Act. It requires advanced practice nurses and physician assistants with doctoral degrees who refer to themselves as doctors in a clinical setting to state they are not medical doctors or physicians.

Still, some health professionals say that the designation should only be used in academic settings or among peers, and that all doctoral degree holders should ditch the moniker at the bedside to ease patient communications.

Named as defendants in the suit are three state officials: California Attorney General Rob Bonta, state Medical Board President Kristina Lawson, and California Board of Registered Nursing Executive Officer Loretta Melby.

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

Three California nurse practitioners with doctorates (DNP) have sued the state over its law that only physicians can call themselves doctors, saying it violates their first amendment right to use the honorific title without fear of regulatory repercussions.

The case highlights ongoing scope-creep battles as the American Medical Association tries to preserve the physician-led team model and nursing organizations and some lawmakers push for greater autonomy for allied professionals.

In the complaint filed in district court in June, plaintiffs Jacqueline Palmer, DNP, Heather Lewis, DNP, and Rodolfo Jaravata-Hanson, DNP, say they fear the state will sanction them. They note that “Doctor Sarah,” another DNP, was fined nearly $20,000 by the state last November for false advertising and fraud after using the moniker in her online advertising and social media accounts.

The fine was part of a settlement that the DNP, Sarah Erny, reached with the state to resolve allegations that she failed to identify her supervising physician and inform the public that she was not a medical doctor.

Under California’s Medical Practice Act, individuals cannot refer to themselves as “doctor, physician, or any other terms or letters indicating or implying that he or she is a physician and surgeon ... without having ... a certificate as a physician and surgeon.”

Instead, nurse practitioners certified by the California Board of Registered Nursing may use titles like “Certified Nurse Practitioner” and “Advanced Practice Registered Nurse,” corresponding letters such as APRN-CNP, RN, and NP, and phrases like pediatric nurse practitioner to identify specialization.

Individuals who misrepresent themselves are subject to misdemeanor charges and civil penalties.

The nonprofit Pacific Legal Foundation represents the plaintiffs. In court records, its attorneys argue that after “years earning their advanced degrees and qualifications ... they should be able to speak truthfully about them in their workplaces, on their business cards, the Internet, and social media, so long as they clarify that they are nurse practitioners.”

State lawmakers’ attempts to clarify the roles of physicians and nurse practitioners have seen mixed results. Florida legislators recently passed a bill to prevent advanced practice nurses from using the honorific title, reserving it only for MDs and DOs. Gov. Ron DeSantis vetoed it last month.

In May, Georgia lawmakers passed the Health Care Practitioners Truth and Transparency Act. It requires advanced practice nurses and physician assistants with doctoral degrees who refer to themselves as doctors in a clinical setting to state they are not medical doctors or physicians.

Still, some health professionals say that the designation should only be used in academic settings or among peers, and that all doctoral degree holders should ditch the moniker at the bedside to ease patient communications.

Named as defendants in the suit are three state officials: California Attorney General Rob Bonta, state Medical Board President Kristina Lawson, and California Board of Registered Nursing Executive Officer Loretta Melby.

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

Several recent developments in Lyme disease treatment and diagnosis may pave the way forward for combating disease that persists following missed or delayed diagnoses or remains following standard treatment. These include combination therapy to address “persister” bacteria and diagnostic tests that test directly for the pathogen and/or indirectly test for host response, according to experts who presented at a 2-day National Academies of Science, Engineering and Medicine workshop on infection-associated chronic illnesses.

Research has shown that 60% of people who are infected and not treated during the early or early disseminated stages of Lyme disease go on to develop late Lyme arthritis, said John Aucott, MD, director of the Johns Hopkins Lyme Disease Clinical Research Center in Baltimore. And in the real world, there’s an additional category of patients: Those who are misdiagnosed and develop infection-related persistent symptoms – such as fatigue, brain fog/cognitive dysfunction, and musculoskeletal problems – that don’t match the “textbook schematic” involving late Lyme arthritis and late neurologic disease.

Moreover, of patients who are treated with protocols recommended by the Infectious Diseases Society of America (IDSA), about 15% go on to develop persistent symptoms at 6 months – again, symptoms that don’t match textbook manifestations and do match symptoms of other infection-associated chronic illnesses. As a “research construct,” this has been coined posttreatment Lyme disease (PTLD), he said at the workshop, “Toward a Common Research Agenda in Infection-Associated Chronic Illnesses.”

(On a practical level, it is hard to know clinically who has early disseminated disease unless they have multiple erythema migrans rashes or neurologic or cardiac involvement, he said after the meeting.)

All this points to the need for tests that are sensitive and specific for diagnosis at all stages of infection and disease, he said in a talk on diagnostics. Currently available tests – those that fit into the widely used two-tiered enzyme-linked immunosorbent assay, Western Blot serology testing – have significant limitations in sensitivity and specificity, including for acute infection when the body has not generated enough antibodies, yet treatment is most likely to succeed.
 

Move toward combination therapy research

Lyme disease is most commonly treated with doxycycline, and that’s problematic because the antibiotic is a microstatic whose efficacy relies on immune clearance of static bacteria, said Monica E. Embers, PhD, director of vector-borne disease at the Tulane National Primate Research Center and associate professor of immunology at Tulane University, New Orleans.

courtesy Tulane University-Paula Burch-Celentano

“But we know that Borrelia burgdorferi has the capability to evade the host immune response in almost every way possible. Persistence is the norm in an immunocompetent host ... [and] dormant bacteria/persisters are more tolerant of microstatic antibiotics,” she said.

Other considerations for antibiotic efficacy include the fact that B. burgdorferi survives for many months inside ticks without nutrient replenishment or replication, “so dormancy is part of their life cycle,” she said. Moreover, the bacteria can be found deep in connective tissues and joints.

The efficacy of accepted regimens of antibiotic treatment has been “a very contentious issue,” she said, noting that guidelines from the International Lyme and Associated Diseases Society “leave open the possibility for antibiotic retreatment when a chronic infection is judged to be a possible cause [of ongoing symptoms].”

The development of persister B. burgdorferi in the presence of antibiotics has been well studied in vitro, which has limitations, Dr. Embers said. But her group specializes in animal models and has shown persistence of antimicrobial-tolerant B. burgdorferi in tick-inoculated rhesus macaques 8-9 months after treatment with oral doxycycline.

“We [also] saw persistence of mild-moderate inflammation in the brain, peripheral nerves, spinal cord, joints and skeletal muscle, and in the heart,” Dr. Embers said, who coauthored a 2022 review of B. burgdorferi antimicrobial-tolerant persistence in Lyme disease and PTLD.

Her work has also shown that ceftriaxone, which is recommended by IDSA for patients with clinically evident neurological and/or cardiac involvement, does not clear infection in mice. “In general, single drugs have not been capable of clearing the infection, yet combinations show promise,” she said.

Dr. Embers has combed large drug libraries looking for combinations of antibiotics that employ different mechanisms of action in hopes of eliminating persister spirochetes. Certain combinations have shown promise in mice and have been tested in her rhesus macaque model; data analyses are underway.

Other research teams, such as that of Ying Zhang, MD, PhD, at Johns Hopkins, have similarly been screening combinations of antibiotics and other compounds, identifying candidates for further testing.

During a question and answer period, Dr. Embers said her team is also investigating the pathophysiology and long-term effects of tick-borne coinfections, including Bartonella, and is pursuing a hypothesis that infection with Borrelia allows Bartonella to cause more extensive disease and persist longer. “I think Lyme is at the core because of its ability to evade and suppress the immune response so effectively.”
 

Diagnostic possibilities, biomarkers for PTLD

Direct diagnostic tests for microbial nucleic acid and proteins “are promising alternatives for indirect serologic tests,” Dr. Aucott said. For instance, in addition to polymerase chain reaction tests, which “are making advances,” it may be possible to target the B. burgdorferi peptidoglycan for antigen detection.

Researchers have shown that peptidoglycan, a component of the B. burgdorferi cell envelope, is a persistent antigen in the synovial fluid of patients with Lyme arthritis who have been treated with oral and intravenous antibiotics, and that it likely contributes to inflammation.

“Maybe the infection is gone but parts of the bacteria are still there that are driving inflammation,” said Dr. Aucott, also associate professor of medicine at John Hopkins.

Researchers have also been looking at the host response to B. burgdorferi – including cytokines, chemokines, and autoantibiodies – to identify biomarkers for PTLD and to identify patients during posttreatment follow-up who are at increased risk of developing PTLD, with the hope of someday intervening. Persistently high levels of interleukin-23, CCL19, and interferon-alpha have each been associated in different studies with persistent symptoms after treatment, Dr. Aucott said.

In addition, metabolomics research is showing that patients with PTLD have metabolic fingerprints that are different from those who return to good health after treatment, and it may be possible to identify an epigenetic signature for Lyme disease. A project sponsored by the Defense Advanced Research Projects Agency called ECHO (Epigenetic Characterization and Observation) aims to identify epigenetic signatures of exposures to various threats, including B. burgdorferi.

“At the very proximal end of [indirectly testing for host response], there are modifications of the DNA that can occur in response to infectious insults ... and that changed DNA changes RNA expression and protein synthesis,” Dr. Aucott explained. DARPA’s project is “exciting because their goal [at DARPA] is to have a diagnostic test quickly as a result of this epigenetics work.”

Imaging research is also fast offering diagnostic opportunities, Dr. Aucott said. Levels of microglial activation on brain PET imaging have been found to correlate with PTLD, and a study at Johns Hopkins of multimodal neuroimaging with functional MRI and diffusion tensor imaging has shown distinct changes to white matter activation within the frontal lobe of patients with PTLD, compared with controls.

The NASEM workshop did not collect or require disclosures of its participants.

Several recent developments in Lyme disease treatment and diagnosis may pave the way forward for combating disease that persists following missed or delayed diagnoses or remains following standard treatment. These include combination therapy to address “persister” bacteria and diagnostic tests that test directly for the pathogen and/or indirectly test for host response, according to experts who presented at a 2-day National Academies of Science, Engineering and Medicine workshop on infection-associated chronic illnesses.

Research has shown that 60% of people who are infected and not treated during the early or early disseminated stages of Lyme disease go on to develop late Lyme arthritis, said John Aucott, MD, director of the Johns Hopkins Lyme Disease Clinical Research Center in Baltimore. And in the real world, there’s an additional category of patients: Those who are misdiagnosed and develop infection-related persistent symptoms – such as fatigue, brain fog/cognitive dysfunction, and musculoskeletal problems – that don’t match the “textbook schematic” involving late Lyme arthritis and late neurologic disease.

Moreover, of patients who are treated with protocols recommended by the Infectious Diseases Society of America (IDSA), about 15% go on to develop persistent symptoms at 6 months – again, symptoms that don’t match textbook manifestations and do match symptoms of other infection-associated chronic illnesses. As a “research construct,” this has been coined posttreatment Lyme disease (PTLD), he said at the workshop, “Toward a Common Research Agenda in Infection-Associated Chronic Illnesses.”

(On a practical level, it is hard to know clinically who has early disseminated disease unless they have multiple erythema migrans rashes or neurologic or cardiac involvement, he said after the meeting.)

All this points to the need for tests that are sensitive and specific for diagnosis at all stages of infection and disease, he said in a talk on diagnostics. Currently available tests – those that fit into the widely used two-tiered enzyme-linked immunosorbent assay, Western Blot serology testing – have significant limitations in sensitivity and specificity, including for acute infection when the body has not generated enough antibodies, yet treatment is most likely to succeed.
 

Move toward combination therapy research

Lyme disease is most commonly treated with doxycycline, and that’s problematic because the antibiotic is a microstatic whose efficacy relies on immune clearance of static bacteria, said Monica E. Embers, PhD, director of vector-borne disease at the Tulane National Primate Research Center and associate professor of immunology at Tulane University, New Orleans.

courtesy Tulane University-Paula Burch-Celentano

“But we know that Borrelia burgdorferi has the capability to evade the host immune response in almost every way possible. Persistence is the norm in an immunocompetent host ... [and] dormant bacteria/persisters are more tolerant of microstatic antibiotics,” she said.

Other considerations for antibiotic efficacy include the fact that B. burgdorferi survives for many months inside ticks without nutrient replenishment or replication, “so dormancy is part of their life cycle,” she said. Moreover, the bacteria can be found deep in connective tissues and joints.

The efficacy of accepted regimens of antibiotic treatment has been “a very contentious issue,” she said, noting that guidelines from the International Lyme and Associated Diseases Society “leave open the possibility for antibiotic retreatment when a chronic infection is judged to be a possible cause [of ongoing symptoms].”

The development of persister B. burgdorferi in the presence of antibiotics has been well studied in vitro, which has limitations, Dr. Embers said. But her group specializes in animal models and has shown persistence of antimicrobial-tolerant B. burgdorferi in tick-inoculated rhesus macaques 8-9 months after treatment with oral doxycycline.

“We [also] saw persistence of mild-moderate inflammation in the brain, peripheral nerves, spinal cord, joints and skeletal muscle, and in the heart,” Dr. Embers said, who coauthored a 2022 review of B. burgdorferi antimicrobial-tolerant persistence in Lyme disease and PTLD.

Her work has also shown that ceftriaxone, which is recommended by IDSA for patients with clinically evident neurological and/or cardiac involvement, does not clear infection in mice. “In general, single drugs have not been capable of clearing the infection, yet combinations show promise,” she said.

Dr. Embers has combed large drug libraries looking for combinations of antibiotics that employ different mechanisms of action in hopes of eliminating persister spirochetes. Certain combinations have shown promise in mice and have been tested in her rhesus macaque model; data analyses are underway.

Other research teams, such as that of Ying Zhang, MD, PhD, at Johns Hopkins, have similarly been screening combinations of antibiotics and other compounds, identifying candidates for further testing.

During a question and answer period, Dr. Embers said her team is also investigating the pathophysiology and long-term effects of tick-borne coinfections, including Bartonella, and is pursuing a hypothesis that infection with Borrelia allows Bartonella to cause more extensive disease and persist longer. “I think Lyme is at the core because of its ability to evade and suppress the immune response so effectively.”
 

Diagnostic possibilities, biomarkers for PTLD

Direct diagnostic tests for microbial nucleic acid and proteins “are promising alternatives for indirect serologic tests,” Dr. Aucott said. For instance, in addition to polymerase chain reaction tests, which “are making advances,” it may be possible to target the B. burgdorferi peptidoglycan for antigen detection.

Researchers have shown that peptidoglycan, a component of the B. burgdorferi cell envelope, is a persistent antigen in the synovial fluid of patients with Lyme arthritis who have been treated with oral and intravenous antibiotics, and that it likely contributes to inflammation.

“Maybe the infection is gone but parts of the bacteria are still there that are driving inflammation,” said Dr. Aucott, also associate professor of medicine at John Hopkins.

Researchers have also been looking at the host response to B. burgdorferi – including cytokines, chemokines, and autoantibiodies – to identify biomarkers for PTLD and to identify patients during posttreatment follow-up who are at increased risk of developing PTLD, with the hope of someday intervening. Persistently high levels of interleukin-23, CCL19, and interferon-alpha have each been associated in different studies with persistent symptoms after treatment, Dr. Aucott said.

In addition, metabolomics research is showing that patients with PTLD have metabolic fingerprints that are different from those who return to good health after treatment, and it may be possible to identify an epigenetic signature for Lyme disease. A project sponsored by the Defense Advanced Research Projects Agency called ECHO (Epigenetic Characterization and Observation) aims to identify epigenetic signatures of exposures to various threats, including B. burgdorferi.

“At the very proximal end of [indirectly testing for host response], there are modifications of the DNA that can occur in response to infectious insults ... and that changed DNA changes RNA expression and protein synthesis,” Dr. Aucott explained. DARPA’s project is “exciting because their goal [at DARPA] is to have a diagnostic test quickly as a result of this epigenetics work.”

Imaging research is also fast offering diagnostic opportunities, Dr. Aucott said. Levels of microglial activation on brain PET imaging have been found to correlate with PTLD, and a study at Johns Hopkins of multimodal neuroimaging with functional MRI and diffusion tensor imaging has shown distinct changes to white matter activation within the frontal lobe of patients with PTLD, compared with controls.

The NASEM workshop did not collect or require disclosures of its participants.

Several recent developments in Lyme disease treatment and diagnosis may pave the way forward for combating disease that persists following missed or delayed diagnoses or remains following standard treatment. These include combination therapy to address “persister” bacteria and diagnostic tests that test directly for the pathogen and/or indirectly test for host response, according to experts who presented at a 2-day National Academies of Science, Engineering and Medicine workshop on infection-associated chronic illnesses.

Research has shown that 60% of people who are infected and not treated during the early or early disseminated stages of Lyme disease go on to develop late Lyme arthritis, said John Aucott, MD, director of the Johns Hopkins Lyme Disease Clinical Research Center in Baltimore. And in the real world, there’s an additional category of patients: Those who are misdiagnosed and develop infection-related persistent symptoms – such as fatigue, brain fog/cognitive dysfunction, and musculoskeletal problems – that don’t match the “textbook schematic” involving late Lyme arthritis and late neurologic disease.

Moreover, of patients who are treated with protocols recommended by the Infectious Diseases Society of America (IDSA), about 15% go on to develop persistent symptoms at 6 months – again, symptoms that don’t match textbook manifestations and do match symptoms of other infection-associated chronic illnesses. As a “research construct,” this has been coined posttreatment Lyme disease (PTLD), he said at the workshop, “Toward a Common Research Agenda in Infection-Associated Chronic Illnesses.”

(On a practical level, it is hard to know clinically who has early disseminated disease unless they have multiple erythema migrans rashes or neurologic or cardiac involvement, he said after the meeting.)

All this points to the need for tests that are sensitive and specific for diagnosis at all stages of infection and disease, he said in a talk on diagnostics. Currently available tests – those that fit into the widely used two-tiered enzyme-linked immunosorbent assay, Western Blot serology testing – have significant limitations in sensitivity and specificity, including for acute infection when the body has not generated enough antibodies, yet treatment is most likely to succeed.
 

Move toward combination therapy research

Lyme disease is most commonly treated with doxycycline, and that’s problematic because the antibiotic is a microstatic whose efficacy relies on immune clearance of static bacteria, said Monica E. Embers, PhD, director of vector-borne disease at the Tulane National Primate Research Center and associate professor of immunology at Tulane University, New Orleans.

courtesy Tulane University-Paula Burch-Celentano

“But we know that Borrelia burgdorferi has the capability to evade the host immune response in almost every way possible. Persistence is the norm in an immunocompetent host ... [and] dormant bacteria/persisters are more tolerant of microstatic antibiotics,” she said.

Other considerations for antibiotic efficacy include the fact that B. burgdorferi survives for many months inside ticks without nutrient replenishment or replication, “so dormancy is part of their life cycle,” she said. Moreover, the bacteria can be found deep in connective tissues and joints.

The efficacy of accepted regimens of antibiotic treatment has been “a very contentious issue,” she said, noting that guidelines from the International Lyme and Associated Diseases Society “leave open the possibility for antibiotic retreatment when a chronic infection is judged to be a possible cause [of ongoing symptoms].”

The development of persister B. burgdorferi in the presence of antibiotics has been well studied in vitro, which has limitations, Dr. Embers said. But her group specializes in animal models and has shown persistence of antimicrobial-tolerant B. burgdorferi in tick-inoculated rhesus macaques 8-9 months after treatment with oral doxycycline.

“We [also] saw persistence of mild-moderate inflammation in the brain, peripheral nerves, spinal cord, joints and skeletal muscle, and in the heart,” Dr. Embers said, who coauthored a 2022 review of B. burgdorferi antimicrobial-tolerant persistence in Lyme disease and PTLD.

Her work has also shown that ceftriaxone, which is recommended by IDSA for patients with clinically evident neurological and/or cardiac involvement, does not clear infection in mice. “In general, single drugs have not been capable of clearing the infection, yet combinations show promise,” she said.

Dr. Embers has combed large drug libraries looking for combinations of antibiotics that employ different mechanisms of action in hopes of eliminating persister spirochetes. Certain combinations have shown promise in mice and have been tested in her rhesus macaque model; data analyses are underway.

Other research teams, such as that of Ying Zhang, MD, PhD, at Johns Hopkins, have similarly been screening combinations of antibiotics and other compounds, identifying candidates for further testing.

During a question and answer period, Dr. Embers said her team is also investigating the pathophysiology and long-term effects of tick-borne coinfections, including Bartonella, and is pursuing a hypothesis that infection with Borrelia allows Bartonella to cause more extensive disease and persist longer. “I think Lyme is at the core because of its ability to evade and suppress the immune response so effectively.”
 

Diagnostic possibilities, biomarkers for PTLD

Direct diagnostic tests for microbial nucleic acid and proteins “are promising alternatives for indirect serologic tests,” Dr. Aucott said. For instance, in addition to polymerase chain reaction tests, which “are making advances,” it may be possible to target the B. burgdorferi peptidoglycan for antigen detection.

Researchers have shown that peptidoglycan, a component of the B. burgdorferi cell envelope, is a persistent antigen in the synovial fluid of patients with Lyme arthritis who have been treated with oral and intravenous antibiotics, and that it likely contributes to inflammation.

“Maybe the infection is gone but parts of the bacteria are still there that are driving inflammation,” said Dr. Aucott, also associate professor of medicine at John Hopkins.

Researchers have also been looking at the host response to B. burgdorferi – including cytokines, chemokines, and autoantibiodies – to identify biomarkers for PTLD and to identify patients during posttreatment follow-up who are at increased risk of developing PTLD, with the hope of someday intervening. Persistently high levels of interleukin-23, CCL19, and interferon-alpha have each been associated in different studies with persistent symptoms after treatment, Dr. Aucott said.

In addition, metabolomics research is showing that patients with PTLD have metabolic fingerprints that are different from those who return to good health after treatment, and it may be possible to identify an epigenetic signature for Lyme disease. A project sponsored by the Defense Advanced Research Projects Agency called ECHO (Epigenetic Characterization and Observation) aims to identify epigenetic signatures of exposures to various threats, including B. burgdorferi.

“At the very proximal end of [indirectly testing for host response], there are modifications of the DNA that can occur in response to infectious insults ... and that changed DNA changes RNA expression and protein synthesis,” Dr. Aucott explained. DARPA’s project is “exciting because their goal [at DARPA] is to have a diagnostic test quickly as a result of this epigenetics work.”

Imaging research is also fast offering diagnostic opportunities, Dr. Aucott said. Levels of microglial activation on brain PET imaging have been found to correlate with PTLD, and a study at Johns Hopkins of multimodal neuroimaging with functional MRI and diffusion tensor imaging has shown distinct changes to white matter activation within the frontal lobe of patients with PTLD, compared with controls.

The NASEM workshop did not collect or require disclosures of its participants.